Role of ranitidine in negative symptoms of schizophrenia--an open label study.

PubMed

Mehta, Varun S; Ram, Daya

2014-12-01

In this open label study, 75 patients with a diagnosis of schizophrenia were randomized to three groups of 25 each, receiving 150mg/day ranitidine, 300mg/day ranitidine and receiving only olanzapine. They were rated on PANSS at baseline, 4 and 8 weeks. There was a significant reduction in the scores of negative scale in patients receiving 300mg/day ranitidine in comparison to patients not receiving ranitidine at the end of 4 weeks but was not seen again when assessed at the end of 8 weeks. Though effective in reducing the negative symptoms, the effect was not sustained due to the tolerance to the actions of ranitidine. Copyright © 2014 Elsevier B.V. All rights reserved.

Open-Label Uridine for Treatment of Depressed Adolescents with Bipolar Disorder

PubMed Central

Sung, Young-Hoon; Hellem, Tracy L.; Delmastro, Kristen K.; Jeong, Eun-Kee; Kim, Namkug; Shi, Xianfeng; Renshaw, Perry F.

2011-01-01

Abstract This report is an open-label case series of seven depressed adolescents with bipolar disorder treated with uridine for 6 weeks. Treatment response was measured with the Children's Depression Rating Scale-Revised and the Clinical Global Impressions scale. Uridine was associated with decreased depressive symptoms, and was well tolerated by study participants. Further systematic studies of uridine are warranted. PMID:21486171

Atomoxetine and Methylphenidate Treatment in Children with ADHD: The Efficacy, Tolerability and Effects on Executive Functions

ERIC Educational Resources Information Center

Yildiz, Ozlem; Sismanlar, Sahika G.; Memik, Nursu Cakin; Karakaya, Isik; Agaoglu, Belma

2011-01-01

The aim of this study was to compare the safety, efficacy, tolerability, and the effects of atomoxetine and OROS-MPH on executive functions in children with ADHD. This study was an open-label study that only included two medication groups. Children were randomized to open-label atomoxetine or OROS-MPH for 12 weeks. Primary efficacy measures were…

Open-label dose optimization of methylphenidate modified release long acting (MPH-LA): a post hoc analysis of real-life titration from a 40-week randomized trial.

PubMed

Huss, Michael; Ginsberg, Ylva; Arngrim, Torben; Philipsen, Alexandra; Carter, Katherine; Chen, Chien-Wei; Gandhi, Preetam; Kumar, Vinod

2014-09-01

In the management of attention-deficit hyperactivity disorder (ADHD) in adults it is important to recognize that individual patients respond to a wide range of methylphenidate doses. Studies with methylphenidate modified release long acting (MPH-LA) in children have reported the need for treatment optimization for improved outcomes. We report the results from a post hoc analysis of a 5-week dose optimization phase from a large randomized, placebo-controlled, multicenter 40-week study (9-week double-blind dose confirmation phase, 5-week open-label dose optimization phase, and 26-week double-blind maintenance of effect phase). Patients entering the open-label dose optimization phase initiated treatment with MPH-LA 20 mg/day; up/down titrated to their optimal dose (at which there was balance between control of symptoms and side effects) of 40, 60, or 80 mg/day in increments of 20 mg/week by week 12 or 13. Safety was assessed by monitoring the adverse events (AEs) and serious AEs. Efficacy was assessed by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, Attention-Deficit Hyperactivity Disorder Rating Scale (DSM-IV ADHD RS) and Sheehan Disability Scale (SDS) total scores. At the end of the dose confirmation phase, similar numbers of patients were treated optimally with each of the 40, 60, and 80 mg/day doses (152, 177, and 160, respectively) for MPH-LA. Mean improvement from baseline in the dose confirmation phase in total scores of DSM-IV ADHD RS and SDS were 23.5 ± 9.90 and 9.7 ± 7.36, respectively. Dose optimization with MPH-LA (40, 60, or 80 mg/day) improved treatment outcomes and was well-tolerated in adult ADHD patients.

Open-label trial of atomoxetine hydrochloride in adults with ADHD.

PubMed

Johnson, Mats; Cederlund, Mats; Råstam, Maria; Areskoug, Björn; Gillberg, Christopher

2010-03-01

While atomoxetine is an established treatment for attention-deficit/hyperactivity disorder in children, few studies have examined its efficacy for adults. Open-label trial of atomoxetine in 20 individuals with ADHD, aged 19-47 years, for 10 weeks, and a total of one year for responders. Ten patients met primary efficacy criteria at 10 weeks. Only one patient completed the whole study. Six patients discontinued before 10 weeks and thirteen at 10 weeks or later, mainly because of side-effects (aggression, depressed mood, raised liver enzymes, thyroid hormones, diastolic blood pressure), decreasing efficacy or non-compliance. Fifty percent responded to treatment, but only one patient (5%) felt sufficient improvement to continue for one year. Dosage may have been too low, and baseline impairment too high, for atomoxetine to have sufficient effect on ADHD symptoms in our group of adults. The majority had few side-effects, but several terminated treatment because of adverse effects.

Efficacy of Lisdexamfetamine in Adults With Moderate to Severe Binge-Eating Disorder: A Randomized Clinical Trial.

PubMed

Hudson, James I; McElroy, Susan L; Ferreira-Cornwell, M Celeste; Radewonuk, Jana; Gasior, Maria

2017-09-01

The ability of pharmacotherapies to prevent relapse and maintain efficacy with long-term treatment in psychiatric conditions is important. To assess lisdexamfetamine dimesylate maintenance of efficacy in adults with moderate to severe binge-eating disorder. A multinational, phase 3, double-blind, placebo-controlled, randomized withdrawal study including 418 participants was conducted at 49 clinical research study sites from January 27, 2014, to April 8, 2015. Eligible adults met DSM-IV-R binge-eating disorder criteria and had moderate to severe binge eating disorder (≥3 binge-eating days per week for 14 days before open-label baseline; Clinical Global Impressions-Severity [CGI-S] scores ≥4 [moderate severity] at screening and open-label baseline). Following a 12-week, open-label phase (dose optimization, 4 weeks [lisdexamfetamine dimesylate, 50 or 70 mg]; dose maintenance, 8 weeks), lisdexamfetamine responders (≤1 binge eating day per week for 4 consecutive weeks and CGI-S scores ≤2 at week 12) were randomized to placebo or continued lisdexamfetamine during a 26-week, double-blind, randomized withdrawal phase. Lisdexamfetamine administration. The primary outcome variable, time to relapse (≥2 binge-eating days per week for 2 consecutive weeks and ≥2-point CGI-S score increases from randomized withdrawal baseline), was analyzed using a log-rank test (primary analysis); the analysis was stratified for dichotomized 4-week cessation status. Safety assessments included treatment-emergent adverse events. Of the 418 participants enrolled in the open-label phase of the study, 411 (358 [87.1%] women; mean [SD] age, 38.3 [10.4] years) were included in the safety analysis set. Of 275 randomized lisdexamfetamine responders (placebo, n = 138; lisdexamfetamine, n = 137), the observed proportions of participants meeting relapse criteria were 3.7% (5 of 136) for lisdexamfetamine and 32.1% (42 of 131) for placebo. Lisdexamfetamine demonstrated superiority over placebo on the log-rank test (χ21, 40.37; P < .001) for time to relapse; the hazard ratio, based on a Cox proportional hazards model for lisdexamfetamine vs placebo, was 0.09 (95% CI, 0.04-0.23). The treatment-emergent adverse events observed were generally consistent with the known profile of lisdexamfetamine. Risk of binge-eating relapse over 6 months was lower in participants continuing lisdexamfetamine than in those randomized to placebo. The hazard for relapse was lower with lisdexamfetamine than placebo. clinicaltrials.gov Identifier: NCT02009163.

Efficacy of Lisdexamfetamine in Adults With Moderate to Severe Binge-Eating Disorder

PubMed Central

McElroy, Susan L.; Ferreira-Cornwell, M. Celeste; Radewonuk, Jana; Gasior, Maria

2017-01-01

Importance The ability of pharmacotherapies to prevent relapse and maintain efficacy with long-term treatment in psychiatric conditions is important. Objective To assess lisdexamfetamine dimesylate maintenance of efficacy in adults with moderate to severe binge-eating disorder. Design, Setting, and Participants A multinational, phase 3, double-blind, placebo-controlled, randomized withdrawal study including 418 participants was conducted at 49 clinical research study sites from January 27, 2014, to April 8, 2015. Eligible adults met DSM-IV-R binge-eating disorder criteria and had moderate to severe binge eating disorder (≥3 binge-eating days per week for 14 days before open-label baseline; Clinical Global Impressions−Severity [CGI-S] scores ≥4 [moderate severity] at screening and open-label baseline). Following a 12-week, open-label phase (dose optimization, 4 weeks [lisdexamfetamine dimesylate, 50 or 70 mg]; dose maintenance, 8 weeks), lisdexamfetamine responders (≤1 binge eating day per week for 4 consecutive weeks and CGI-S scores ≤2 at week 12) were randomized to placebo or continued lisdexamfetamine during a 26-week, double-blind, randomized withdrawal phase. Interventions Lisdexamfetamine administration. Main Outcomes and Measures The primary outcome variable, time to relapse (≥2 binge-eating days per week for 2 consecutive weeks and ≥2-point CGI-S score increases from randomized withdrawal baseline), was analyzed using a log-rank test (primary analysis); the analysis was stratified for dichotomized 4-week cessation status. Safety assessments included treatment-emergent adverse events. Results Of the 418 participants enrolled in the open-label phase of the study, 411 (358 [87.1%] women; mean [SD] age, 38.3 [10.4] years) were included in the safety analysis set. Of 275 randomized lisdexamfetamine responders (placebo, n = 138; lisdexamfetamine, n = 137), the observed proportions of participants meeting relapse criteria were 3.7% (5 of 136) for lisdexamfetamine and 32.1% (42 of 131) for placebo. Lisdexamfetamine demonstrated superiority over placebo on the log-rank test (χ21, 40.37; P < .001) for time to relapse; the hazard ratio, based on a Cox proportional hazards model for lisdexamfetamine vs placebo, was 0.09 (95% CI, 0.04-0.23). The treatment-emergent adverse events observed were generally consistent with the known profile of lisdexamfetamine. Conclusions and Relevance Risk of binge-eating relapse over 6 months was lower in participants continuing lisdexamfetamine than in those randomized to placebo. The hazard for relapse was lower with lisdexamfetamine than placebo. Trial Registration clinicaltrials.gov Identifier: NCT02009163 PMID:28700805

Participant-Perceived Quality of Life in a Long-Term, Open-Label Trial of Lisdexamfetamine Dimesylate in Adolescents with Attention-Deficit/Hyperactivity Disorder

PubMed Central

Cutler, Andrew J.; Saylor, Keith; Gasior, Maria; Hamdani, Mohamed; Ferreira-Cornwell, M. Celeste; Findling, Robert L.

2014-01-01

Abstract Objectives: The purpose of this study was to assess long-term improvement in quality of life (QOL) in adolescents with attention-deficit/hyperactivity disorder (ADHD) treated with lisdexamfetamine dimesylate (LDX). Methods: Adolescents with ADHD treated for ≥3 weeks in a 4 week, placebo-controlled study entered a 1 year, open-label study. After the 4 week dose optimization (30, 50, and 70 mg/day LDX) period, treatment was maintained for 48 additional weeks. Change from baseline (of prior study) to week 52/early termination (ET) (of open-label study) in ADHD Rating Scale IV (ADHD-RS-IV) assessed effectiveness, and the Youth QOL-Research Version (YQOL-R) assessed participant-perceived QOL. Post-hoc analyses described effectiveness and QOL for participants with self-perceived poor QOL at baseline (≥1 SD below the mean) versus all others, and for study completers versus study noncompleters. Results: These post-hoc analyses included 265 participants. Participants with baseline self-perceived poor QOL (n=32) versus all others (n=232) exhibited robust YQOL-R perceptual score changes (improvement) with LDX, emerging by week 28 and maintained to week 52/ET. Week 52/ET mean change score ranged from +9.8 to +17.6 for participants with baseline self-perceived poor QOL and +0.4 to +5.1 for all others; week 52/ET improvements in ADHD-RS-IV total scores were similar, regardless of baseline YQOL-R total score. At week 52/ET, study completers had greater YQOL-R improvements than did noncompleters; ADHD-RS-IV total score changes were also numerically larger at week 52/ET for completers than for noncompleters. Conclusion: Participant-perceived QOL and ADHD symptoms improved from baseline with LDX in adolescents with ADHD; greatest improvements occurred among participants with baseline self-perceived poor QOL. PMID:24815910

An open-label pilot study to assess the efficacy and safety of virgin coconut oil in reducing visceral adiposity.

PubMed

Liau, Kai Ming; Lee, Yeong Yeh; Chen, Chee Keong; Rasool, Aida Hanum G

2011-01-01

Introduction. This is an open-label pilot study on four weeks of virgin coconut oil (VCO) to investigate its efficacy in weight reduction and its safety of use in 20 obese but healthy Malay volunteers. Methodology. Efficacy was assessed by measuring weight and associated anthropometric parameters and lipid profile one week before and one week after VCO intake. Safety was assessed by comparing organ function tests one week before and one week after intake of VCO. Paired t-test was used to analyse any differences in all the measurable variables. Results. Only waist circumference (WC) was significantly reduced with a mean reduction of 2.86 cm or 0.97% from initial measurement (P = .02). WC reduction was only seen in males (P < .05). There was no change in the lipid profile. There was a small reduction in creatinine and alanine transferase levels. Conclusion. VCO is efficacious for WC reduction especially in males and it is safe for use in humans.

An Open-Label Pilot Study to Assess the Efficacy and Safety of Virgin Coconut Oil in Reducing Visceral Adiposity

PubMed Central

Liau, Kai Ming; Lee, Yeong Yeh; Chen, Chee Keong; Rasool, Aida Hanum G.

2011-01-01

Introduction. This is an open-label pilot study on four weeks of virgin coconut oil (VCO) to investigate its efficacy in weight reduction and its safety of use in 20 obese but healthy Malay volunteers. Methodology. Efficacy was assessed by measuring weight and associated anthropometric parameters and lipid profile one week before and one week after VCO intake. Safety was assessed by comparing organ function tests one week before and one week after intake of VCO. Paired t-test was used to analyse any differences in all the measurable variables. Results. Only waist circumference (WC) was significantly reduced with a mean reduction of 2.86 cm or 0.97% from initial measurement (P = .02). WC reduction was only seen in males (P < .05). There was no change in the lipid profile. There was a small reduction in creatinine and alanine transferase levels. Conclusion. VCO is efficacious for WC reduction especially in males and it is safe for use in humans. PMID:22164340

A Multicenter, Open-Label Trial to Evaluate the Quality of Life in Adults with ADHD Treated with Long-Acting Methylphenidate (OROS MPH): Concerta Quality of Life (CONQoL) Study

ERIC Educational Resources Information Center

Mattos, Paulo; Rodrigues Louza, Mario; Fernandes Palmini, Andre Luis; de Oliveira, Irismar Reis; Lopes Rocha, Fabio

2013-01-01

The available literature provides few studies on the effectiveness of methylphenidate in improving quality of life in individuals with ADHD. Objective: To assess the effectiveness of Methyphenidate OROS formulation (OROS MPH) through QoL in adults with ADHD. Method: A 12-week, multicenter, open-label trial involving 60 patients was used. The…

An Open-Label Study of Risperidone in the Improvement of Quality of Life and Treatment of Symptoms of Violent and Self-Injurious Behaviour in Adults with Intellectual Disability

ERIC Educational Resources Information Center

Read, Stephen G.; Rendall, Maureen

2007-01-01

Background: We examined the benefits of risperidone, including quality of life (QoL), in the treatment of violent and self-injurious behaviour in adults with moderate, severe or profound intellectual disability. Methods: Twenty-four participants received open-label, oral, flexible-dose risperidone of 0.5-6 mg/day for 12 weeks. Efficacy was…

Efficacy and Safety of Methylnaltrexone for Opioid-Induced Constipation in Patients With Chronic Noncancer Pain

PubMed Central

Viscusi, Eugene R.; Barrett, Andrew C.; Paterson, Craig; Forbes, William P.

2016-01-01

Background and Objectives In patients with chronic noncancer pain, subcutaneous methylnaltrexone for opioid-induced constipation (OIC) was examined in a randomized controlled trial (RCT) followed by an open-label extension (OLE). This study examined the reproducibility of RCT findings by analyzing data from placebo-treated patients who crossed over to methylnaltrexone. Methods Adults with less than 3 weekly rescue-free bowel movements (RFBMs), taking 50 mg or more of an oral morphine equivalent per day, were randomized to receive methylnaltrexone 12 mg or placebo for 4 weeks, followed by open-label methylnaltrexone 12 mg as needed for 8 weeks. Results A total of 134 placebo-treated patients (median morphine equivalent dose, 150 mg/d; mean of 1.1 RFBM per week) crossed over to methylnaltrexone in OLE. During the RCT, 9.7% of placebo-treated patients experienced an RFBM within 4 hours of first dose and 9.0% of all placebo injections resulted in an RFBM within 4 hours compared with 45.9% and 34.5%, respectively, with methylnaltrexone treatment in the OLE. When expressed as percentage of patients experiencing 3 or more RFBMs per week and a 1-RFBM increase over baseline, weekly values ranged from 35% to 40% during placebo treatment; at week 5 of OLE methylnaltrexone, this percentage increased to more than 70% and remained relatively stable throughout the OLE. The most common adverse events during methylnaltrexone treatment were abdominal pain (9.7% vs 1.5% for placebo) and nausea (5.2% vs 6.7%). Conclusions Findings during placebo treatment further establish the profile of OIC and support that little or no gastrointestinal tolerance develops across time. Findings under open-label conditions established the reproducibility and durability of methylnaltrexone for OIC. PMID:26650429

Testosterone replacement therapy with long-acting testosterone undecanoate improves sexual function and quality-of-life parameters vs. placebo in a population of men with type 2 diabetes.

PubMed

Hackett, Geoffrey; Cole, Nigel; Bhartia, Mithun; Kennedy, David; Raju, Jessie; Wilkinson, Peter

2013-06-01

Sexual dysfunction, particularly erectile dysfunction (ED), is common in men with type 2 diabetes, occurring in up to 75% of cases. The prevalence of hypogonadism is also high in men with diabetes and low testosterone is associated with both sexual dysfunction and a reduced response to oral therapy for ED. This study aimed to determine the effect of testosterone replacement with long-acting Testosterone Undecanoate (TU) on sexual function, mood and quality of life vs. placebo over a treatment period of 30 weeks followed by 52 weeks of open-label medication. The study was conducted in a primary care population of men with type 2 diabetes attending their primary care physician for routine visits. The male diabetic populations of seven general practices were screened at routine diabetes visits to detect symptomatic men with total testosterone levels of 12 nmol/L or less or with free testosterones of 250 pmol/L or less. Two hundred eleven men were screened. A double-blind placebo-controlled study was conducted in 199 men with type 2 diabetes and hypogonadism treated for 30 weeks with either 1,000 mg of TU or matching placebo followed by 52-week open-label follow on. The primary outcome measure, International Index of Erectile Function (IIEF), was used to evaluate sexual dysfunction, and the Ageing Male Symptom (AMS), Hospital Anxiety and Depression Scale, and Global Efficacy Question were used as secondary outcome measures to assess mood and self-reported quality of life. Testosterone replacement therapy with long-acting TU improved all domains of sexual function at 30 weeks (erectile function [EF], P = 0.005; intercourse satisfaction, P = 0.015; sexual desire, P = 0.001; overall satisfaction, P = 0.05; and orgasm, P = 0.04), with benefit as early as 6 weeks. Improvements in AMS score were significant in men without depression (P = 0.02) and the presence of depression at baseline was associated with marked reduction in response to both sexual function and psychological scores. All responses in sexual function continued to improve significantly up to 18 months with an improvement in EF score of 4.31 from baseline. In a small cohort of 35 men taking phosphodiesterase type 5 inhibitors, there was no change during the double-blind phase but a nine-point improvement in EF domain during 52-week open-label treatment. After 30 weeks, 46% vs. 17% of patients on active therapy vs. placebo felt that the treatment had improved their health, reaching 70% after open-label therapy. Less obese and older patients responded better to testosterone therapy. There were no significant adverse events. TU significantly improved all domains of the IIEF and patient reported quality of life at 30 weeks and more significantly after 52-week open-label extension. Improvement was most marked in less obese patient and those without coexisting depression. In men with type 2 diabetes, trials of therapy may need to be given for much longer than 3-6 months suggested in current guidelines. © 2013 International Society for Sexual Medicine.

Effect of comorbid tics on a clinically meaningful response to 8-week open-label trial of fluoxetine in obsessive compulsive disorder.

PubMed

Husted, David S; Shapira, Nathan A; Murphy, Tanya K; Mann, Giselle D; Ward, Herbert E; Goodman, Wayne K

2007-01-01

Currently, there are limited published data evaluating the effects of tics on serotonin reuptake inhibitor (SRI) monotherapy responses in treating obsessive-compulsive disorder (OCD). One retrospective case-controlled analysis of OCD patients treated with SRI monotherapy showed lesser improvement in OCD symptoms in patients with tics than those without. However, more recently there were preliminary reports of OCD subjects treated with SRI monotherapy which did not demonstrate poorer response in subjects with tics or Tourette's Syndrome (TS). The specific aim of this study was to investigate whether the presence of comorbid chronic tics affected "clinically meaningful improvement" [McDougle, C.J., Goodman, W.K., Leckman, J.F., Barr, L.C., Heninger, G.R., Price, L.H., 1993. The efficacy of fluvoxamine in obsessive-compulsive disorder: effects of comorbid chronic tic disorder. Journal of Clinical Psychopharmacology 13, 354-358] of OCD in an 8-week open-label trial of fluoxetine monotherapy. Seventy-four adult subjects (13 patients with comorbid chronic tics and 61 patients without tics) with a primary DSM-IV OCD diagnosis were treated with up to 40mg fluoxetine for 8 weeks and had at least one post-baseline evaluation. The results indicate that there was a significant response by time in both fluoxetine-with-tic subjects and fluoxetine-without-tic subjects. Additionally, there were 3 (23.0%) OCD subjects with tics who had clinically meaningful improvement versus 16 (26.2%) OCD subjects without tics that demonstrated similar levels of improvement. These findings indicate that OCD patients with or without chronic tic disorders did not have a differential response to an 8-week open-label trial of fluoxetine. Limitations include the relatively low number of tic subjects and the open-label nature of the study. Additional data are needed on how comorbid tics may affect SRI treatment response in OCD.

An Open-Label, Randomized Trial of Methylphenidate and Atomoxetine Treatment in Adults With ADHD.

PubMed

Ni, Hsing-Chang; Lin, Yu-Ju; Gau, Susan Shur-Fen; Huang, Hui-Chun; Yang, Li-Kuang

2017-01-01

To directly compare the efficacy of methylphenidate and atomoxetine in improving symptoms, social functions, and quality of life among adults with ADHD. This was an 8-to-10-week, open-label, head-to-head, randomized clinical trial with two treatment arms: immediate-release methylphenidate (IR-methylphenidate; n = 31) and atomoxetine once daily ( n = 32). The outcome measures included ADHD symptom severity, quality of life, and functional impairments. We found a significant reduction in overall ADHD symptoms and improvement in social functions and quality of life for both groups at Weeks 4 to 5 and Weeks 8 to 10. There was no significant difference in the slope of improvements over time except that atomoxetine was superior to IR-methylphenidate in reducing hyperactive/impulsive symptoms at Weeks 4 to 5. There was no significant group difference in the rates of adverse effects. Both IR-methylphenidate and atomoxetine are well tolerated and efficacious in ethnic Chinese adults with ADHD.

Ziprasidone Augmentation of Escitalopram for Major Depressive Disorder: Efficacy Results From a Randomized, Double-Blind, Placebo-Controlled Study.

PubMed

Papakostas, George I; Fava, Maurizio; Baer, Lee; Swee, Michaela B; Jaeger, Adrienne; Bobo, William V; Shelton, Richard C

2015-12-01

The authors sought to test the efficacy of adjunctive ziprasidone in adults with nonpsychotic unipolar major depression experiencing persistent symptoms after 8 weeks of open-label treatment with escitalopram. This was an 8-week, randomized, double-blind, parallel-group, placebo-controlled trial conducted at three academic medical centers. Participants were 139 outpatients with persistent symptoms of major depression after an 8-week open-label trial of escitalopram (phase 1), randomly assigned in a 1:1 ratio to receive adjunctive ziprasidone (escitalopram plus ziprasidone, N=71) or adjunctive placebo (escitalopram plus placebo, N=68), with 8 weekly follow-up assessments. The primary outcome measure was clinical response, defined as a reduction of at least 50% in score on the 17-item Hamilton Depression Rating Scale (HAM-D). The Hamilton Anxiety Rating scale (HAM-A) and Visual Analog Scale for Pain were defined a priori as key secondary outcome measures. Rates of clinical response (35.2% compared with 20.5%) and mean improvement in HAM-D total scores (-6.4 [SD=6.4] compared with -3.3 [SD=6.2]) were significantly greater for the escitalopram plus ziprasidone group. Several secondary measures of antidepressant efficacy also favored adjunctive ziprasidone. The escitalopram plus ziprasidone group also showed significantly greater improvement on HAM-A score but not on Visual Analog Scale for Pain score. Ten (14%) patients in the escitalopram plus ziprasidone group discontinued treatment because of intolerance, compared with none in the escitalopram plus placebo group. Ziprasidone as an adjunct to escitalopram demonstrated antidepressant efficacy in adult patients with major depressive disorder experiencing persistent symptoms after 8 weeks of open-label treatment with escitalopram.

Civamide cream 0.075% in patients with osteoarthritis of the knee: a 12-week randomized controlled clinical trial with a longterm extension.

PubMed

Schnitzer, Thomas J; Pelletier, Jean-Pierre; Haselwood, Doug M; Ellison, William T; Ervin, John E; Gordon, Richard D; Lisse, Jeffrey R; Archambault, W Tad; Sampson, Allan R; Fezatte, Heidi B; Phillips, Scott B; Bernstein, Joel E

2012-03-01

To evaluate the safety and efficacy of civamide cream 0.075% for the treatment of osteoarthritis (OA) of the knee. We conducted a 12-week, multicenter, randomized, double-blind study with a 52-week open-label extension. Patients with OA of the knee received either civamide cream 0.075% or a lower dose of civamide cream, 0.01%, as the control. The 3 co-primary endpoints in the double-blind study were the time-weighted average (TWA) of change from baseline to Day 84 in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale, the WOMAC physical function subscale, and the Subject Global Evaluation (SGE). In the 52-week open-label extension study, the Osteoarthritis Pain Score and SGE were assessed. A total of 695 patients were randomized to receive civamide cream 0.075% (n = 351) or civamide cream 0.01% (control; n = 344) in the double-blind study. Significance in favor of civamide cream 0.075% was achieved for the TWA for all 3 co-primary efficacy variables: WOMAC pain (p = 0.009), WOMAC physical function (p < 0.001), and SGE (p = 0.008); and at Day 84 for these 3 variables (p = 0.013, p < 0.001, and p = 0.049, respectively). These analyses accounted for significant baseline-by-treatment interactions. In the 52-week open-label extension, efficacy was maintained. Civamide cream 0.075% was well tolerated throughout the studies. These studies demonstrate the efficacy of civamide cream for up to 1 year of continuous use. Civamide cream, with its lack of systemic absorption, does not have the potential for serious systemic toxicity, in contrast to several other OA treatments.

Rifaximin is associated with modest, transient decreases in multiple taxa in the gut microbiota of patients with diarrhoea-predominant irritable bowel syndrome.

PubMed

Fodor, Anthony A; Pimentel, Mark; Chey, William D; Lembo, Anthony; Golden, Pamela L; Israel, Robert J; Carroll, Ian M

2018-04-30

Rifaximin, a non-systemic antibiotic, is efficacious for the treatment of diarrhoea-predominant irritable bowel syndrome (IBS-D). Given the emerging association between the gut microbiota and IBS, this study examined potential effects of rifaximin on the gastrointestinal microbial community in patients with IBS-D. TARGET 3 was a randomised, double-blind, placebo-controlled, phase 3 study. Patients with IBS-D initially received open-label rifaximin 550 mg 3 times daily (TID) for 2 weeks. Patients who responded to the initial treatment and then relapsed were randomised to receive 2 repeat courses of rifaximin 550 mg TID or placebo for 2 weeks, with each course separated by 10 weeks. Stool samples were collected at the beginning and end of open-label treatment, at the beginning and end of the first double-blind treatment, and at the end of the study. As a secondary analysis to the TARGET 3 trial, the composition and diversity of the gut microbiota were assessed, from a random subset of patients, using variable 4 hypervariable region 16S ribosomal RNA gene sequencing. Samples from 103 patients were included. After open-label rifaximin treatment for 2 weeks, 7 taxa (e.g. Peptostreptococcaceae, Verrucomicrobiaceae, Enterobacteriaceae) had significantly lower relative abundance at a 10% false discovery rate threshold. The effects of rifaximin were generally short-term, as there was little evidence of significantly different changes in taxa relative abundance at the end of the study (up to 46 weeks) versus baseline. The results suggest that rifaximin has a modest, largely transient effect across a broad range of stool microbes. Future research may determine whether the taxa affected by rifaximin are causally linked to IBS-D. ClinicalTrials.gov identifier number: NCT01543178.

Combined treatment with memantine/es-citalopram for older depressed patients with cognitive impairment: a pilot study.

PubMed

Pelton, Gregory H; Harper, Oliver L; Roose, Steven P; Marder, Karen; D'Antonio, Kristina; Devanand, D P

2016-06-01

The objective of the study is to assess combined antidepressant and memantine treatment in older patients presenting with depression and cognitive impairment. Thirty-five depressed patients with cognitive impairment participated in this open-label pilot study. We evaluated whether, over a 48-week period, combined antidepressant (primarily es-citalopram) and memantine treatment was effective in the treatment of cognitive impairment and depression. Neuropsychological testing was performed, and antidepressant response monitored at baseline and at the 12, 24, and 48-week time points. Treatment with escitalopram (mean daily dose 18.62 mg, SD 5.15) and memantine (mean daily dose 13.62 mg, SD 6.67) was associated with improvement in Hamilton Depression Rating Scale scores over the 48-week study period. Patients demonstrated significant improvement in the primary outcome of cognitive performance (Selective Reminding Test total immediate recall; SRT-IR) over the 48-week treatment period (p = 0.0147). Significant improvement was also observed in measures of naming and verbal fluency but not in the other cognitive domains. One of the 35 patients (2.9%) converted to Alzheimer's disease over the 48-week treatment period. In the amnestic mild cognitive impairment subsample (n = 22), the conversion rate was 4.5%, a rate lower than in other reports of patients with DEP-CI. In this open-label trial, combined antidepressant and memantine treatment in patients with DEP-CI was associated with improved cognition and a low rate of conversion to dementia compared with published studies in patients with DEP-CI. Although limited by the open-label study design that incorporates practice effects that can improve cognitive test performance, the findings suggest the need for a larger randomized placebo-controlled trial. Copyright © 2015 John Wiley & Sons, Ltd.

Erenumab (AMG 334) in episodic migraine: Interim analysis of an ongoing open-label study.

PubMed

Ashina, Messoud; Dodick, David; Goadsby, Peter J; Reuter, Uwe; Silberstein, Stephen; Zhang, Feng; Gage, Julia R; Cheng, Sunfa; Mikol, Daniel D; Lenz, Robert A

2017-09-19

To assess long-term safety and efficacy of anti-calcitonin gene-related peptide receptor erenumab in patients with episodic migraine (EM). Patients enrolled in a 12-week, double-blind, placebo-controlled clinical trial (NCT01952574) who continued in an open-label extension (OLE) study will receive erenumab 70 mg every 4 weeks for up to 5 years. This preplanned interim analysis, conducted after all participants had completed the 1-year open-label follow-up, evaluated changes in monthly migraine days (MMD), achievement of ≥50%, ≥75%, and 100% reductions, Headache Impact Test (HIT-6) score, Migraine-Specific Quality of Life (MSQ), Migraine Disability Assessment (MIDAS), and safety. Data reported as observed without imputation for missing data. Of 472 patients enrolled in the parent study, 383 continued in the OLE with a median exposure to erenumab of 575 days (range 28-822 days). Mean (SD) MMD were 8.8 (2.6) at parent study baseline, 6.3 (4.2) at week 12 (beginning of OLE), and 3.7 (4.0) at week 64 (mean change from baseline [reduction] of 5.0 days). At week 64, 65%, 42%, and 26% achieved ≥50%, ≥75%, and 100% reduction in MMD, respectively. Mean HIT-6 scores were 60.2 (6.3) at baseline and 51.7 (9.2) at week 64. MSQ and MIDAS improvements from baseline were maintained through week 64. Safety profiles during the OLE were similar to those in the double-blind phase, which overall were similar to placebo. One-year efficacy, supported by functional improvements and favorable safety and tolerability profiles, supports further investigation of erenumab as a preventive treatment in patients with EM. NCT01952574. This study provides Class IV evidence that for patients with episodic migraine, erenumab reduces long-term MMD and improves headache-related disability and migraine-specific quality of life. © 2017 American Academy of Neurology.

Satisfaction with Subcutaneous Golimumab and its Auto-Injector among Rheumatoid Arthritis Patients with Inadequate Response to Adalimumab or Etanercept.

PubMed

Dehoratius, Raphael J; Brent, Lawrence H; Curtis, Jeffrey R; Ellis, Lorie A; Tang, Kezhen L

2018-06-01

Patient perceptions of treatment success, including satisfaction/preference, may complement clinical efficacy assessments. Our objective was to evaluate satisfaction with subcutaneous golimumab and its auto-injector in patients with rheumatoid arthritis (RA) and an inadequate adalimumab/etanercept response. In the multicenter, assessor-blinded GO-SAVE study, 433 patients with active RA (28-joint Disease Activity Score incorporating erythrocyte sedimentation rate [DAS28-ESR] ≥ 3.6 and six or more swollen and six or more tender joints) despite methotrexate and past adalimumab/etanercept treatment received open-label subcutaneous golimumab 50 mg every 4 weeks (q4w) through week 12. Week 16 responders (DAS28-ESR improvement from baseline > 1.2 and score ≤ 3.2) continued therapy through week 52; nonresponders were randomized (1:2) to double-blind subcutaneous golimumab 50 mg q4w or intravenous golimumab 2 mg/kg [weeks 16, 20, every 8 weeks (q8w)]. Patients rated satisfaction with their injection experience on a 5-point scale (1 = very dissatisfied; 5 = very satisfied) at screening, week 8 (all enrolled patients), and week 44 (for patients continuing open-label subcutaneous golimumab 50 mg q4w). Discomfort, pain, stinging, burning, and redness related to injection were assessed (none, mild, moderate, severe). Similar proportions of patients (N = 433) had most recently received adalimumab (50.3%) or etanercept (49.7%) prior to golimumab. Overall satisfaction (somewhat/very) with the golimumab injection experience was reported by 84.4% of patients at week 8 versus 63.4% of patients who were satisfied with prior adalimumab/etanercept. Patients receiving open-label subcutaneous golimumab through week 44 (N = 75) reported much less discomfort (60.9%), redness (60.9%), pain (59.4%), stinging (67.2%), and burning (65.6%) with the golimumab injection than with their previous tumor necrosis factor antagonist medication injection. Most patients with RA receiving golimumab following adalimumab/etanercept inadequate response were satisfied with their overall golimumab experience, including its auto-injector versus their previous injection device. CLINICAL TRIALS.GOV: NCT01004432; EudraCT 2009-010582-23.

An open-label naturalistic pilot study of acamprosate in youth with autistic disorder.

PubMed

Erickson, Craig A; Early, Maureen; Stigler, Kimberly A; Wink, Logan K; Mullett, Jennifer E; McDougle, Christopher J

2011-12-01

To date, placebo-controlled drug trials targeting the core social impairment of autistic disorder (autism) have had uniformly negative results. Given this, the search for new potentially novel agents targeting the core social impairment of autism continues. Acamprosate is U.S. Food and Drug Administration-approved drug to treat alcohol dependence. The drug likely impacts both gamma-aminobutyric acid and glutamate neurotransmission. This study describes our initial open-label experience with acamprosate targeting social impairment in youth with autism. In this naturalistic report, five of six youth (mean age, 9.5 years) were judged treatment responders to acamprosate (mean dose 1,110 mg/day) over 10 to 30 weeks (mean duration, 20 weeks) of treatment. Acamprosate was well tolerated with only mild gastrointestinal adverse effects noted in three (50%) subjects.

How informative are open-label studies for youth with bipolar disorder? A meta-analysis comparing open-label versus randomized, placebo-controlled clinical trials.

PubMed

Biederman, Joseph; Petty, Carter R; Woodworth, K Yvonne; Lomedico, Alexandra; O'Connor, Katherine B; Wozniak, Janet; Faraone, Stephen V

2012-03-01

To examine the informativeness of open-label trials toward predicting results in subsequent randomized, placebo-controlled clinical trials of psychopharmacologic treatments for pediatric bipolar disorder. We searched journal articles through PubMed at the National Library of Medicine using bipolar disorder, mania, pharmacotherapy, treatment and clinical trial as keywords. This search was supplemented with scientific presentations at national and international scientific meetings and submitted manuscripts from our group. Selection criteria included (1) enrollment of children diagnosed with DSM-IV bipolar disorder; (2) prospective assessment of at least 3 weeks; (3) monotherapy of a pharmacologic treatment for bipolar disorder; (4) use of a randomized placebo-controlled design or an open-label design for the same therapeutic compound; and (5) repeated use of the Young Mania Rating Scale (YMRS) as an outcome. The following information and data were extracted from 14 studies: study design, name of medication, class of medication, dose of medication, sample size, age, sex, trial length, and YMRS mean and standard deviation baseline and follow-up scores. For both study designs, the pooled effect size was statistically significant (open-label studies, z = 8.88, P < .001; randomized placebo-controlled studies, z = 13.75, P < .001), indicating a reduction in the YMRS from baseline to endpoint in both study designs. In a meta-analysis regression, study design was not a significant predictor of mean change in the YMRS. We found similarities in the treatment effects between open-label and randomized placebo-controlled studies in youth with bipolar disorder indicating that open-label studies are useful predictors of the potential safety and efficacy of a given compound in the treatment of pediatric bipolar disorder. © Copyright 2012 Physicians Postgraduate Press, Inc.

Effect of vacuum-assisted closure combined with open bone grafting to promote rabbit bone graft vascularization.

PubMed

Hu, Chao; Zhang, Taogen; Ren, Bin; Deng, Zhouming; Cai, Lin; Lei, Jun; Ping, Ansong

2015-04-27

Patients with composite bone non-union and soft tissue defects are difficult to treat. Vacuum-assisted closure (VAC) combined with open bone grafting is one of the most effective treatments at present. The aim of the present study was to preliminarily investigate the effect and mechanism of VAC combined with open bone grafting to promote rabbit bone graft vascularization, and to propose a theoretical basis for clinical work. Twenty-four New Zealand white rabbits were randomly divided into an experimental and a control group. Allogeneic bones were grafted and banded with the proximal femur with a suture. The experimental group had VAC whereas the control group had normal wound closure. The bone vascularization rate was compared based on X-ray imaging, fluorescent bone labeling (labeled tetracycline hydrochloride and calcein), calcium content in the callus, and expression of fibroblast growth factor-2 (FGF-2) in bone allografts by Western blot analysis at the 4th, 8th, and 12th week after surgery. At the 4th, 8th, and 12th week after surgery, the results of the tests demonstrated that the callus was larger, contained more calcium (p<0.05), and expressed FGF-2 at higher levels (p<0.05) in the experimental group than in the control group. Fluorescent bone labeling showed the distance between the two fluorescent ribbons was significantly shorter in the control group than in the experimental group at the 8th and 12th week after surgery. VAC combined with open bone grafting promoted rabbit bone graft vascularization.

A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of pomaglumetad methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia

PubMed Central

2013-01-01

Background We compared the time to discontinuation due to lack of tolerability over 24 weeks in patients suffering from schizophrenia treated with pomaglumetad methionil (LY2140023 monohydrate, the prodrug of metabotropic glutamate 2/3 receptor agonist, LY404039) or standard of care (SOC: olanzapine, risperidone, or aripiprazole). Methods Study HBBR was a multicenter, randomized, open-label study comparing the long-term safety and tolerability of LY2140023 with SOC for schizophrenia. Patients had moderate symptomatology with prominent negative symptoms and evidence of functional impairment. Those who met entry criteria were randomized to open-label treatment with either LY2140023 (target dose: 40 mg twice daily [BID]; n = 130) or SOC (n = 131). Results There was no statistically significant difference between LY2140023 and SOC for time to discontinuation due to lack of tolerability (primary objective; P = .184). The Kaplan-Meier estimates revealed comparable time to event profiles. Only 27% of LY2140023 and 45% of SOC patients completed the 24-week open-label, active treatment phase. Twenty-seven patients (20.8%) in the LY2140023 group and 15 patients (11.5%) in the SOC group discontinued due to lack of efficacy (P = .044). Twenty-three patients (17.7%) in the LY2140023 group and 19 patients (14.5%) in the SOC group discontinued due to adverse events (physician and subject decision combined, P = .505). The incidence of serious adverse events was comparable between groups. LY2140023-treated patients reported significantly more treatment-emergent adverse events of vomiting, agitation, and dyspepsia, while SOC-treated patients reported significantly more akathisia and weight gain. The incidence of treatment-emergent parkinsonism (P = .011) and akathisia (P = .029) was significantly greater in SOC group. Improvement in PANSS total score over the initial 6 to 8 weeks of treatment was similar between groups, but improvement was significantly greater in the SOC group at 24-week endpoint (P = .004). LY2140023 and SOC groups had comparable negative symptom improvement at 24-week endpoint (P = .444). Conclusion These data provide further evidence that the potential antipsychotic LY2140023 monohydrate, with a glutamatergic mechanism of action, may have a unique tolerability profile characterized by a low association with some adverse events such as extrapyramidal symptoms and weight gain that may characterize currently available dopaminergic antipsychotics. Trials registration A Long-term, Phase 2, Multicenter, Randomized, Open-label, Comparative Safety Study of LY2140023 Versus Atypical Antipsychotic Standard of Care in Patients with DSM-IV-TR Schizophrenia ClinicalTrials.gov identifier: NCT00845026. PMID:23694720

Efficacy and safety of luseogliflozin added to insulin therapy in Japanese patients with type 2 diabetes: a multicenter, 52-week, clinical study with a 16-week, double-blind period and a 36-week, open-label period.

PubMed

Seino, Yutaka; Sasaki, Takashi; Fukatsu, Atsushi; Imazeki, Hisae; Ochiai, Hidekazu; Sakai, Soichi

2018-06-01

To evaluate the efficacy and safety of luseogliflozin in Japanese patients with type 2 diabetes (T2D) inadequately controlled with insulin monotherapy. This 52-week multicenter study entailed a 16-week, double-blind period followed by a 36-week, open-label period. Patients were randomized to receive either luseogliflozin 2.5 mg (n = 159) or placebo (n = 74) during the double-blind period. All patients who entered the open-label period received luseogliflozin. Major efficacy endpoints included the changes from baseline in HbA1c, fasting plasma glucose (FPG), postprandial plasma glucose (PPG) and bodyweight. Safety assessments included adverse events, laboratory tests and vital signs. In the double-blind period, luseogliflozin significantly decreased HbA1c (-1.18%), FPG (-42.4 mg/dL), 2 hour PPG (-68.7 mg/dL) and bodyweight (-1.27 kg) compared with placebo (all p < .001); these reductions were maintained over 52 weeks. The changes from baseline at Week 52 were -1.00%, -35.1 mg/dL, -68.8 mg/dL and -1.81 kg, respectively (all p < .001). In the placebo group, favorable glycemic control and bodyweight reduction were also observed after switching to luseogliflozin. Most adverse events were mild in severity. During the double-blind period, the incidences of hypoglycemia were 20.8% and 13.5% in the luseogliflozin and placebo groups, respectively. During the 52 weeks of luseogliflozin treatment, the frequency of hypoglycemia was 33.3%, but no serious hypoglycemia occurred. The safety profile other than hypoglycemia was also acceptable. There were no new safety concerns about luseogliflozin added to insulin. Luseogliflozin added to insulin therapy significantly improved glycemic control with bodyweight reduction and was well tolerated in Japanese patients with T2D. Japan Pharmaceutical Information Center (JapicCTI-142582).

Randomized, Double-Blind, Placebo-Controlled Trial of Asenapine Maintenance Therapy in Adults With an Acute Manic or Mixed Episode Associated With Bipolar I Disorder.

PubMed

Szegedi, Armin; Durgam, Suresh; Mackle, Mary; Yu, Sung Yun; Wu, Xiao; Mathews, Maju; Landbloom, Ronald P

2018-01-01

The authors determined the efficacy and safety of asenapine in preventing recurrence of any mood episode in adults with bipolar I disorder. Adults with an acute manic or mixed episode per DSM-IV-TR criteria were enrolled in this randomized, placebo-controlled trial consisting of an initial 12- to 16-week open-label period and a 26-week double-blind randomized withdrawal period. The target asenapine dosage was 10 mg b.i.d. in the open-label period but could be titrated down to 5 mg b.i.d. After completing the open-label period, subjects meeting stabilization/stable-responder criteria were randomized to asenapine or placebo treatment in the double-blind period. The primary efficacy endpoint was time to recurrence of any mood event during the double-blind period. Kaplan-Meier estimation was performed, and 95% confidence intervals were determined. Safety was assessed throughout. A total of 549 subjects entered the open-label period, of whom 253 enrolled in the double-blind randomized withdrawal period (127 in the placebo group; 126 in the asenapine group). Time to recurrence of any mood episode was statistically significantly longer for asenapine- than placebo-treated subjects. In post hoc analyses, significant differences in favor of asenapine over placebo were seen in time to recurrence of manic and depressive episodes. The most common treatment-emergent adverse events were somnolence (10.0%), akathisia (7.7%), and sedation (7.7%) in the open-label period and mania (11.9% of the placebo group compared with 4.0% of the asenapine group) and bipolar I disorder (6.3% compared with 1.6%) in the double-blind period. Long-term treatment with asenapine was more effective than placebo in preventing recurrence of mood events in adults with bipolar I disorder and was generally well-tolerated.

Aripiprazole for Irritability in Asian Children and Adolescents with Autistic Disorder: A 12-Week, Multinational, Multicenter, Prospective Open-Label Study.

PubMed

Kim, Hyo-Won; Park, Eun-Jin; Kim, Ji-Hoon; Boon-Yasidhi, Vitharon; Tarugsa, Jariya; Reyes, Alexis; Manalo, Stella; Joung, Yoo-Sook

2018-04-24

We investigated the effectiveness and tolerability of aripiprazole in the treatment of irritability in Asian children and adolescents (6-17 years) with autistic disorder in a 12-week, multinational, multicenter, open-label study. Sixty-seven subjects (10.0 ± 3.1 years old, 52 boys) were enrolled and treated with flexibly dosed aripiprazole for 12 weeks (mean dose, 5.1 ± 2.5 mg; range 2-15 mg). Aripiprazole significantly reduced the mean caregiver-rated scores for the Irritability, Lethargy/Social Withdrawal, Stereotypy, Hyperactivity, and Inappropriate Speech subscales of the Aberrant Behavior Checklist from baseline to week 12 (p < 0.001 for all subscales). Clinician-rated Clinical Global Impression Severity of Illness scale score also improved from baseline through week 12 (p < 0.001). The most common adverse event was weight gain and no serious adverse event related to aripiprazole treatment was noted. Our results suggest that aripiprazole is effective and generally tolerable in the treatment of irritability in Asian children and adolescents with autistic disorder. Further studies with larger sample sizes and longer treatment durations are required.

An Open-Label Naturalistic Pilot Study of Acamprosate in Youth with Autistic Disorder

PubMed Central

Early, Maureen; Stigler, Kimberly A.; Wink, Logan K.; Mullett, Jennifer E.; McDougle, Christopher J.

2011-01-01

Abstract To date, placebo-controlled drug trials targeting the core social impairment of autistic disorder (autism) have had uniformly negative results. Given this, the search for new potentially novel agents targeting the core social impairment of autism continues. Acamprosate is U.S. Food and Drug Administration–approved drug to treat alcohol dependence. The drug likely impacts both gamma-aminobutyric acid and glutamate neurotransmission. This study describes our initial open-label experience with acamprosate targeting social impairment in youth with autism. In this naturalistic report, five of six youth (mean age, 9.5 years) were judged treatment responders to acamprosate (mean dose 1,110 mg/day) over 10 to 30 weeks (mean duration, 20 weeks) of treatment. Acamprosate was well tolerated with only mild gastrointestinal adverse effects noted in three (50%) subjects. PMID:22136091

Maintenance N-acetyl cysteine treatment for bipolar disorder: a double-blind randomized placebo controlled trial.

PubMed

Berk, Michael; Dean, Olivia M; Cotton, Sue M; Gama, Clarissa S; Kapczinski, Flavio; Fernandes, Brisa; Kohlmann, Kristy; Jeavons, Susan; Hewitt, Karen; Moss, Kirsteen; Allwang, Christine; Schapkaitz, Ian; Cobb, Heidi; Bush, Ashley I; Dodd, Seetal; Malhi, Gin S

2012-08-14

N-acetyl cysteine (NAC) is a glutathione precursor that has been shown to have antidepressant efficacy in a placebo-controlled trial. The current study aimed to investigate the maintenance effects of NAC following eight weeks of open-label treatment for bipolar disorder. The efficacy of a double blind randomized placebo controlled trial of 2 g/day NAC as adjunct maintenance treatment for bipolar disorder was examined. Participants (n = 149) had a Montgomery Asberg Depression Rating Score of ≥12 at trial entry and, after eight weeks of open-label NAC treatment, were randomized to adjunctive NAC or placebo, in addition to treatment as usual. Participants (primarily outpatients) were recruited through public and private services and through newspaper advertisements. Time to intervention for a mood episode was the primary endpoint of the study, and changes in mood symptoms, functionality and quality of life measures were secondary outcomes. There was a substantial decrease in symptoms during the eight-week open-label NAC treatment phase. During the subsequent double-blind phase, there was minimal further change in outcome measures with scores remaining low. Consequently, from this low plateau, between-group differences did not emerge on recurrence, clinical functioning or quality of life measures. There were no significant between-group differences in recurrence or symptomatic outcomes during the maintenance phase of the trial; however, these findings may be confounded by limitations. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12607000074493).

Repeat Rifaximin for Irritable Bowel Syndrome: No Clinically Significant Changes in Stool Microbial Antibiotic Sensitivity.

PubMed

Pimentel, M; Cash, B D; Lembo, A; Wolf, R A; Israel, R J; Schoenfeld, P

2017-09-01

Rifaximin has demonstrated efficacy and safety for diarrhea-predominant irritable bowel syndrome (IBS-D). To determine the rifaximin repeat treatment effect on fecal bacterial antibiotic susceptibility. Patients with IBS in Trial 3 (TARGET 3) study who responded to open-label rifaximin 550 mg three times daily for 2 weeks, with symptom recurrence within 18 weeks, were randomized to double-blind treatment: two 2-week repeat courses of rifaximin or placebo, separated by 10 weeks. Prospective stool sample collection occurred before and after open-label rifaximin, before and after the first repeat course, and at the end of the study. Susceptibility testing was performed with 11 antibiotics, including rifaximin and rifampin, using broth microdilution or agar dilution methods. Of 103 patients receiving open-label rifaximin, 73 received double-blind rifaximin (n = 37) or placebo (n = 36). A total of 1429 bacterial and yeast isolates were identified, of which Bacteroidaceae (36.7%) and Enterobacteriaceae (33.9%) were the most common. In the double-blind phase, Clostridium difficile was highly susceptible to rifaximin [minimum inhibitory concentration (MIC) range 0.008-1 µg/mL] and rifampin (MIC range 0.004-0.25 µg/mL). Following double-blind rifaximin treatment, Staphylococcus isolates remained susceptible to rifaximin at all visits (MIC 50 range ≤0.06-32 µg/mL). Rifaximin exposure was not associated with long-term cross-resistance of Bacteroidaceae, Enterobacteriaceae, and Enterococcaceae to rifampin or nonrifamycin antibiotics tested. In this study, short-term repeat treatment with rifaximin has no apparent long-term effect on stool microbial susceptibility to rifaximin, rifampin, and nonrifamycin antibiotics. CLINICALTRIALS. NCT01543178.

A phase III, open-label, multicenter study to evaluate the safety and efficacy of long-term triple combination therapy with azilsartan, amlodipine, and hydrochlorothiazide in patients with essential hypertension.

PubMed

Rakugi, Hiromi; Shimizu, Kohei; Nishiyama, Yuya; Sano, Yuhei; Umeda, Yuusuke

2018-06-01

Patients with essential hypertension who are receiving treatment with an angiotensin II receptor blocker and a calcium channel blocker often develop inadequate blood pressure (BP) control and require the addition of a diuretic. This study aimed to evaluate the long-term safety and efficacy of a triple combination therapy with 20 mg azilsartan (AZL), 5 mg amlodipine (AML) and 12.5 mg hydrochlorothiazide (HCTZ). The phase III, open-label, multicenter study (NCT02277691) comprised a 4-week run-in period and 52-week treatment period. Patients with inadequate BP control despite AZL/AML therapy (n = 341) received 4 weeks' treatment with AZL/AML (combination tablet) + HCTZ (tablet) and 4 weeks' treatment with AZL/AML/HCTZ (combination tablet) in a crossover manner, followed by AZL/AML/HCTZ (combination tablet) from Week 8 of the treatment period up to Week 52. The primary and secondary endpoints were long-term safety and BP (office and home), respectively. Most adverse events (AEs) were mild or moderate in intensity, and no deaths or treatment-related serious AEs were reported. The triple therapy provided consistent BP-lowering effects in both office and home measurements. The triple combination therapy with AZL/AML/HCTZ was well tolerated and effective for 52 weeks in Japanese patients with essential hypertension.

A small-scale open-label study of the treatment of canine flea allergy dermatitis with fluralaner.

PubMed

Fisara, Petr; Shipstone, Michael; von Berky, Andrew; von Berky, Janet

2015-12-01

Fluralaner is an isoxazoline systemic insecticide and acaricide that provides persistent flea-killing activity on dogs for 12 weeks. European and US field studies have shown that fluralaner treatment alleviates the signs of flea allergy dermatitis (FAD) in client-owned dogs. To assess the clinical response in FAD affected dogs over the 12-week period following a single oral fluralaner treatment. Twenty client-owned dogs were diagnosed with FAD on the basis of compatible clinical signs and a positive response in flea antigen tests, using intradermal and or serological methods. An open-label small-scale study with all dogs receiving a single oral fluralaner treatment. All enrolled dogs were diagnosed with FAD and then clinically monitored at 4-week intervals for 12 weeks. Twenty dogs completed the study. All dogs were flea-free at all post-treatment assessments except for one dog that had a single flea at the first post-enrollment assessment at 4 weeks. At the 4-week post-treatment assessment active FAD signs had resolved in all dogs; at 8 weeks post-treatment, two dogs showed mild signs. All clinical signs of FAD had resolved at the final assessment of 12 weeks after treatment. A single administration of fluralaner alleviated or resolved signs associated with FAD in all treated dogs over the recommended 12-week treatment period. © 2015 The Authors. Veterinary Dermatology published by John Wiley & Sons Ltd on behalf of Intervet Australia Pty Ltd.

Tipepidine in children with attention deficit/hyperactivity disorder: a 4-week, open-label, preliminary study

PubMed Central

Sasaki, Tsuyoshi; Hashimoto, Kenji; Tachibana, Masumi; Kurata, Tsutomu; Okawada, Keiko; Ishikawa, Maki; Kimura, Hiroshi; Komatsu, Hideki; Ishikawa, Masatomo; Hasegawa, Tadashi; Shiina, Akihiro; Hashimoto, Tasuku; Kanahara, Nobuhisa; Shiraishi, Tetsuya; Iyo, Masaomi

2014-01-01

Background Tipepidine (3-[di-2-thienylmethylene]-1-methylpiperidine) has been used solely as a nonnarcotic antitussive in Japan since 1959. The safety of tipepidine in children and adults has already been established. It is reported that tipepidine inhibits G-protein-coupled inwardly rectifying potassium (GIRK)-channel currents. The inhibition of GIRK channels by tipepidine is expected to modulate the level of monoamines in the brain. We put forward the hypothesis that tipepidine can improve attention deficit/hyperactivity disorder (ADHD) symptoms by modulating monoaminergic neurotransmission through the inhibition of GIRK channels. The purpose of this open-label trial was to confirm whether treatment with tipepidine can improve symptoms in pediatric patients with ADHD. Subjects and methods This was a 4-week, open-label, proof-of-efficacy pilot study for pediatric subjects with ADHD. Ten pediatric ADHD subjects (70% male; mean age, 9.9 years; combined [inattentive and hyperactive/impulsive] subtype, n=7; inattentive subtype, n=3; hyperimpulsive subtype, n=0) received tipepidine hibenzate taken orally at 30 mg/day for 4 weeks. All subjects were assessed using the ADHD Rating Scale IV (ADHD-RS), Japanese version, and the Das–Naglieri Cognitive Assessment System (DN-CAS), Japanese version. Results A comparison of baseline scores and 4-week end-point scores showed that all the ADHD-RS scores (total scores, hyperimpulsive subscores, and inattentive subscores) improved significantly (P<0.001). Furthermore, a comparison of baseline DN-CAS total scores and 4-week end-point scores showed a mild trend of improvement (P=0.093). Tipepidine was well tolerated, with no patients discontinuing medication because of side effects. Conclusion Our pilot study suggests that tipepidine therapy may prove to be an effective alternative treatment for pediatric patients with ADHD. Nonetheless, more detailed randomized, double-blind trials are needed to confirm tipepidine’s efficacy. PMID:24493927

Safety and Tolerability of Methylphenidate in Preschool Children with ADHD

ERIC Educational Resources Information Center

Wigal, Tim; Greenhill, Laurence; Chuang, Shirley; McGough, James; Vitiello, Benedetto; Skrobala, Anne; Swanson, James; Wigal, Sharon; Abikoff, Howard; Kollins, Scott; McCracken, James; Riddle, Mark; Posner, Kelly; Ghuman, Jaswinder; Davies, Mark; Thorp, Ben; Stehli, Annamarie

2006-01-01

Objective: To report on the safety and tolerability of methylphenidate (MPH) 3- to 5-year-old children with attention-deficit/hyperactivity disorder (ADHD) during 1 year of treatment. Method: Exactly 183 children (3-5 years old) entered a treatment study of MPH, consisting of a 1-week open-label lead-in (n = 183); a 5-week placebo-controlled,…

Effects of risperidone on core symptoms of autistic disorder based on childhood autism rating scale: an open label study.

PubMed

Ghaeli, Padideh; Nikvarz, Naemeh; Alaghband-Rad, Javad; Alimadadi, Abbas; Tehrani-Doost, Mehdi

2014-01-01

The aim of the present study was to evaluate the effect of risperidone in patients afflicted by autistic disorder especially with regards to its three core symptoms, including "relating to others", "communication skills", and "stereotyped behaviors" based on Childhood Autism Rating Scale (CARS). An 8-week open-label study of risperidone for treatment of autistic disorder in children 4-17 years old was designed. Risperidone dose titration was as follow: 0.02 mg/kg/day at the first week, 0.04 mg/kg/day at the second week, and 0.06 mg/kg/day at the third week and thereafter. The outcome measures were scores obtained by CARS, Aberrant Behavior Checklist (ABC), and Clinical Global Impression-Improvement (CGI-I) scale. Fifteen patients completed this study. After 8 weeks, CARS total score decreased significantly, (P=0.001). At the end of the study, social interactions and verbal communication skills of the patients were significantly improved (P<0.001, P=0.03, respectively). However, stereotypic behaviors did not show any significant change in this study. Increase in appetite and somnolence were the most reported side effects. This study suggests that risperidone may be an effective treatment for the management of core symptoms of autistic disorder.

Enhanced understanding of the relationship between erection and satisfaction in ED treatment: application of a longitudinal mediation model.

PubMed

Bushmakin, A G; Cappelleri, J C; Symonds, T; Stecher, V J

2014-01-01

To apportion the direct effect and the indirect effect (through erections) that sildenafil (vs placebo) has on individual satisfaction and couple satisfaction over time, longitudinal mediation modeling was applied to outcomes on the Sexual Experience Questionnaire. The model included data from weeks 4 and 10 (double-blind phase) and week 16 (open-label phase) of a controlled study. Data from 167 patients with erectile dysfunction (ED) were available for analysis. Estimation of statistical significance was based on bootstrap simulations, which allowed inferences at and between time points. Percentages (and corresponding 95% confidence intervals) for direct and indirect effects of treatment were calculated using the model. For the individual satisfaction and couple satisfaction domains, direct treatment effects were negligible (not statistically significant) whereas indirect treatment effects via the erection domain represented >90% of the treatment effects (statistically significant). Week 4 vs week 10 percentages of direct and indirect effects were not statistically different, indicating that the mediation effects are longitudinally invariant. As there was no placebo arm in the open-label phase, mediation effects at week 16 were not estimable. In conclusion, erection has a crucial role as a mediator in restoring individual satisfaction and couple satisfaction in men with ED treated with sildenafil.

Maintenance N-acetyl cysteine treatment for bipolar disorder: A double-blind randomized placebo controlled trial

PubMed Central

2012-01-01

Background N-acetyl cysteine (NAC) is a glutathione precursor that has been shown to have antidepressant efficacy in a placebo-controlled trial. The current study aimed to investigate the maintenance effects of NAC following eight weeks of open-label treatment for bipolar disorder. Method The efficacy of a double blind randomized placebo controlled trial of 2 g/day NAC as adjunct maintenance treatment for bipolar disorder was examined. Participants (n = 149) had a Montgomery Asberg Depression Rating Score of ≥12 at trial entry and, after eight weeks of open-label NAC treatment, were randomized to adjunctive NAC or placebo, in addition to treatment as usual. Participants (primarily outpatients) were recruited through public and private services and through newspaper advertisements. Time to intervention for a mood episode was the primary endpoint of the study, and changes in mood symptoms, functionality and quality of life measures were secondary outcomes. Results There was a substantial decrease in symptoms during the eight-week open-label NAC treatment phase. During the subsequent double-blind phase, there was minimal further change in outcome measures with scores remaining low. Consequently, from this low plateau, between-group differences did not emerge on recurrence, clinical functioning or quality of life measures. Conclusions There were no significant between-group differences in recurrence or symptomatic outcomes during the maintenance phase of the trial; however, these findings may be confounded by limitations. Trial Registration The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12607000074493). PMID:22891797

Defining success in clinical trials--profiling pregabalin, the newest AED.

PubMed

Ryvlin, P

2005-11-01

The efficacy and safety of pregabalin as adjunctive therapy for patients with partial epilepsy with or without secondary generalization has been established by four randomized, 12-week, double-blind, placebo-controlled trials (n = 1396) and four long-term open-label studies (n = 1480). Patients in the three fixed-dose trials were >/=12 years of age, had >/=6 partial seizures and no 4-week seizure-free period during the 8-week baseline period. Seventy-three per cent of patients were taking >/=2 concomitant antiepileptic drugs. Responder rates across the effective doses (150-600 mg/day) ranged from 14% to 51% and demonstrated a significant dose-response relationship. The most common adverse events were central nervous system related, generally mild or moderate, transient, and tended to be dose related. The fourth placebo-controlled trial compared a fixed dose of pregabalin 600 mg/day with a flexible-dose regimen (150-600 mg/day). Responder rates were greater for both the fixed dose (45.3%, P < 0.001) and flexible dose (31.3%, P < 0.001) when compared with placebo (11.0%). Compared with the fixed-dose group, the flexible-dose patients had a lower incidence of adverse events and study discontinuations. In long-term open-label trials, the efficacy of pregabalin was maintained with respect to 50% responder rates suggesting no obvious tolerance developing over 2 years. Seizure-free rates were 8.9% and 5.8% for the last 6 months and 1 year of pregabalin treatment, respectively. Long-term open-label pregabalin treatment was well tolerated.

Concurrent Improvement in Both Binge Eating and Depressive Symptoms with Naltrexone/Bupropion Therapy in Overweight or Obese Subjects with Major Depressive Disorder in an Open-Label, Uncontrolled Study.

PubMed

Guerdjikova, Anna I; Walsh, Brandon; Shan, Kevin; Halseth, Amy E; Dunayevich, Eduardo; McElroy, Susan L

2017-10-01

Binge eating disorder (BED) is associated with obesity and major depressive disorder (MDD). Naltrexone extended-release (ER)/bupropion ER (NB) is approved as an adjunct to diet and physical activity for chronic weight management. In a prospectively designed 24-week open-label, single-arm, single-site trial of 25 women with MDD and overweight/obesity, NB reduced weight and depressive symptoms. This post hoc analysis investigated the relationship between change in self-reported binge eating behavior (evaluated with the Binge Eating Scale [BES]) and changes in weight, control of eating, and depressive symptoms. At baseline, 91% of subjects had moderate or severe BES scores, suggesting BED. BES scores were significantly improved from week 4, and by week 24, 83% reported "little or no problem." Improvement in BES scores correlated with improvement in depressive symptoms and control of eating. NB may be effective in reducing binge eating symptoms associated with MDD and overweight/obesity. Evaluation of NB in BED appears warranted. Orexigen Therapeutics, Inc.

Efficacy and safety of triple therapy with dapagliflozin add-on to saxagliptin plus metformin over 52 weeks in patients with type 2 diabetes.

PubMed

Mathieu, C; Herrera Marmolejo, M; González González, J G; Hansen, L; Chen, H; Johnsson, E; Garcia-Sanchez, R; Iqbal, N

2016-11-01

We previously reported that dapagliflozin versus placebo as add-on to saxagliptin plus metformin resulted in greater reductions in glycated haemoglobin (A1C), fasting plasma glucose (FPG) and body weight (BW) after 24 weeks of treatment in patients with type 2 diabetes (T2D). Here we report results after 52 weeks of treatment. Patients stabilized on open-label metformin and saxagliptin 5 mg/day for 8-16 weeks were randomized to placebo or dapagliflozin 10 mg/day plus open-label saxagliptin plus metformin for 52 weeks. Changes from baseline to week 52 were greater with dapagliflozin versus placebo in A1C (-0.74% vs. 0.07%), FPG (-27 vs. 10 mg/dL) and BW (-2.1 vs. -0.4 kg). More patients achieved A1C <7% with dapagliflozin (29.4%) versus placebo (12.6%). Adverse events were similar with dapagliflozin (66%) and placebo (71%), and hypoglycaemia was rare (≤2%). Genital infections occurred more often with dapagliflozin (6%) than with placebo (1%); frequency of urinary tract infections was similar between the two groups (9% vs. 10%). Triple therapy with dapagliflozin add-on to saxagliptin plus metformin is a durable, effective and well-tolerated intervention for the treatment of T2D. © 2016 John Wiley & Sons Ltd.

A multicenter, open-label, 52-week study of 2% rebamipide (OPC-12759) ophthalmic suspension in patients with dry eye.

PubMed

Kinoshita, Shigeru; Awamura, Saki; Nakamichi, Norihiro; Suzuki, Hiroyuki; Oshiden, Kazuhide; Yokoi, Norihiko

2014-03-01

To investigate the efficacy and safety of 2% rebamipide ophthalmic suspension administered 4 times daily for 52 weeks in patients with dry eye. Multicenter (17 sites), open-label, single-arm study. A total of 154 patients with dry eye were enrolled in this study. After a 2-week screening period, patients received 2% rebamipide, instilled as 1 drop in each eye, 4 times daily for 52 weeks. The signs and symptoms measures were assessed at baseline, at weeks 2 and 4, and at every 4 weeks thereafter. The objective signs were fluorescein corneal staining score, lissamine green conjunctival staining score, and tear film break-up time, while subjective symptoms were dry eye-related ocular symptoms (foreign body sensation, dryness, photophobia, eye pain, and blurred vision). The safety variable was the occurrence of adverse events. For all objective signs and subjective symptoms, the scores significantly improved at week 2 compared with baseline (P < .001, paired t test). Interestingly, further improvements of those scores were observed at every visit up to week 52. No deaths were reported, yet serious adverse events that were not thought to be drug related were observed in 6 patients. The incidence of any of the adverse events did not markedly increase throughout the 52-week treatment period. The results of this study show that 2% rebamipide is effective in improving both the objective signs and subjective symptoms of dry eye patients for at least 52 weeks. In addition, 2% rebamipide treatment was generally well tolerated. Copyright © 2014. Published by Elsevier Inc.

Longterm Safety and Efficacy of Subcutaneous Tocilizumab Monotherapy: Results from the 2-year Open-label Extension of the MUSASHI Study.

PubMed

Ogata, Atsushi; Amano, Koichi; Dobashi, Hiroaki; Inoo, Masayuki; Ishii, Tomonori; Kasama, Tsuyoshi; Kawai, Shinichi; Kawakami, Atsushi; Koike, Tatsuya; Miyahara, Hisaaki; Miyamoto, Toshiaki; Munakata, Yasuhiko; Murasawa, Akira; Nishimoto, Norihiro; Ogawa, Noriyoshi; Ojima, Tomohiro; Sano, Hajime; Shi, Kenrin; Shono, Eisuke; Suematsu, Eiichi; Takahashi, Hiroki; Tanaka, Yoshiya; Tsukamoto, Hiroshi; Nomura, Akira

2015-05-01

To evaluate the longterm safety and efficacy of subcutaneous tocilizumab (TCZ-SC) as monotherapy in patients with rheumatoid arthritis (RA). Of 346 patients who received 24 weeks of double-blind treatment with either TCZ-SC monotherapy, 162 mg every 2 weeks (q2w); or intravenous TCZ (TCZ-IV) monotherapy, 8 mg/kg every 4 weeks; 319 patients continued to receive TCZ-SC q2w in the 84-week open-label extension (OLE) of the MUSASHI study (JAPICCTI-101117). Efficacy, safety, and immunogenicity were evaluated for all patients treated with TCZ during 108 weeks. The proportions of patients who achieved American College of Rheumatology 20/50/70 responses, low disease activity [28-joint Disease Activity Score (DAS28) ≤ 3.2], or remission (DAS28 < 2.6) at Week 24 were maintained until Week 108. The incidences of adverse events and serious adverse events were 498.3 and 16.9 per 100 patient-years (PY), respectively. The overall safety of TCZ-SC monotherapy was similar to that of TCZ-IV monotherapy. Rates of injection site reactions (ISR) through 108 weeks remained similar to rates through 24 weeks. ISR were mild and did not cause any patient withdrawals. No serious hypersensitivity events (including anaphylactic reactions) occurred. Anti-TCZ antibodies were present in 2.1% of patients treated with TCZ-SC monotherapy. TCZ-SC monotherapy maintained a favorable safety profile and consistent efficacy throughout the 108-week study. Like TCZ-IV, TCZ-SC could provide an additional treatment option for patients with RA.

Clinical and MRI responses to etanercept in early non-radiographic axial spondyloarthritis: 48-week results from the EMBARK study

PubMed Central

Maksymowych, Walter P; Dougados, Maxime; Sieper, Joachim; Braun, Jürgen; Citera, Gustavo; Van den Bosch, Filip; Logeart, Isabelle; Wajdula, Joseph; Jones, Heather; Marshall, Lisa; Bonin, Randi; Pedersen, Ron; Vlahos, Bonnie; Kotak, Sameer; Bukowski, Jack F

2016-01-01

Objective To evaluate the efficacy and safety of etanercept (ETN) after 48 weeks in patients with early active non-radiographic axial spondyloarthritis (nr-axSpA). Methods Patients meeting Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA, but not modified New York radiographic criteria, received double-blind ETN 50 mg/week or placebo (PBO) for 12 weeks, then open-label ETN (ETN/ETN or PBO/ETN). Clinical, health, productivity, MRI and safety outcomes were assessed and the 48-week data are presented here. Results 208/225 patients (92%) entered the open-label phase at week 12 (ETN, n=102; PBO, n=106). The percentage of patients achieving ASAS40 increased from 33% to 52% between weeks 12 and 48 for ETN/ETN and from 15% to 53% for PBO/ETN (within-group p value <0.001 for both). For ETN/ETN and PBO/ETN, the EuroQol 5 Dimensions utility score improved by 0.14 and 0.08, respectively, between baseline and week 12 and by 0.23 and 0.22 between baseline and week 48. Between weeks 12 and 48, MRI Spondyloarthritis Research Consortium of Canada sacroiliac joint (SIJ) scores decreased by −1.1 for ETN/ETN and by −3.0 for PBO/ETN, p<0.001 for both. Decreases in MRI SIJ inflammation and C-reactive protein correlated with several clinical outcomes at weeks 12 and 48. Conclusions Patients with early active nr-axSpA demonstrated improvement from week 12 in clinical, health, productivity and MRI outcomes that was sustained to 48 weeks. Trial registration number NCT01258738. PMID:26269397

Effect of minoxidil topical foam on frontotemporal and vertex androgenetic alopecia in men: a 104-week open-label clinical trial.

PubMed

Kanti, V; Hillmann, K; Kottner, J; Stroux, A; Canfield, D; Blume-Peytavi, U

2016-07-01

Topical minoxidil formulations have been shown to be effective in treating androgenetic alopecia (AGA) for 12 months. Efficacy and safety in both frontotemporal and vertex regions over longer application periods have not been studied so far. To evaluate the effect of 5% minoxidil topical foam (5% MTF) in the frontotemporal and vertex areas in patients with moderate AGA over 104 weeks. An 80-week, open-label extension phase was performed, following a 24-week randomized, double-blind, placebo-controlled study in men with AGA grade IIIvertex to VI. Group 1 (n = 22) received ongoing 5% MTF for 104 weeks, Group 2 (n = 23) received placebo topical foam (plaTF) until week 24, followed by 5% MTF until week 104 during the extension phase. Frontotemporal and vertex target area non-vellus hair counts (f-TAHC, v-TAHC) and cumulative hair width (f-TAHW, v-TAHW) were assessed at baseline and at weeks 24, 52, 76 and 104. In Group 1, f-TAHW and f-TAHC showed a statistically significant increase from baseline to week 52 and week 76, respectively, returning to values comparable to baseline at week 104. No significant differences were found between baseline and week 104 in v-TAHC in Group 1 as well as f-TAHC, v-TAHC, f-TAHW and v-TAHW values in Group 2. 5% MTF is effective in stabilizing hair density, hair width and scalp coverage in both frontotemporal and vertex areas over an application period of 104 weeks, while showing a good safety and tolerability profile with a low rate of irritant contact dermatitis. © 2015 European Academy of Dermatology and Venereology.

The evaluation of an open source online training system for teaching 12 lead electrocardiographic interpretation.

PubMed

Breen, Cathal; Zhu, Tingting; Bond, Raymond; Finlay, Dewar; Clifford, Gari

2016-01-01

The aim of this study is to present and evaluate the integration of a low resource JavaScript based ECG training interface (CrowdLabel) and a standardised curriculum for self-guided tuition in ECG interpretation. Participants practiced interpreting ECGs weekly using the CrowdLabel interface to assist with the learning of the traditional didactic taught course material during a 6 week training period. To determine competency students were tested during week 7. A total of 245 unique ECG cases were submitted by each student. Accuracy scores during the training period ranged from 0-59.5% (median = 33.3%). Conversely accuracy scores during the test ranged from 30 - 70% (median = 37.5%) (p < 0.05). There was no correlation between students who interpreted high numbers of ECGs during the training period and their marks obtained. CrowdLabel is shown to be a readily accessible dedicated learning platform to support ECG interpretation competency. Copyright © 2016 Elsevier Inc. All rights reserved.

Canakinumab: in patients with cryopyrin-associated periodic syndromes.

PubMed

Curran, Monique P

2012-02-01

Canakinumab is a recombinant, fully human, monoclonal, anti-human interleukin-1β (IL-1β) antibody that binds with high affinity and specificity to human IL-1β, preventing its interaction with IL-1 receptors. Canakinumab (150 mg in patients weighing >40 kg or 2 mg/kg in those weighing 15-40 kg) administered once every 8 weeks as a single dose via subcutaneous injection provided a rapid and sustained response in patients with cryopyrin-associated periodic syndromes (CAPS). During the initial 8-week phase of a three-part, phase III trial, a complete response to a single dose of canakinumab occurred in 97% of the 35 patients with CAPS, with 71% of responses occurring within 8 days. After 8 weeks, 31 responders entered a 24-week, randomized, double-blind, withdrawal phase; there was a significant between-group difference in this phase in that none of the canakinumab recipients relapsed compared with 81% of placebo recipients. All patients from the second phase of the trial entered a third, 16-week phase of open-label treatment with canakinumab once every 8 weeks; clinical and biochemical remission was maintained in 28 of 29 patients who completed the trial. In a 2-year, open-label, phase III trial, subcutaneous canakinumab once every 8 weeks provided sustained disease control in the majority of patients with CAPS. Canakinumab was generally well tolerated in all trials, with the predominant adverse events being mild to moderate infections that were responsive to standard treatment.

An open-label trial examining the efficacy and safety of a pre- and postprocedure topical five-product system (Clinique Medical Optimizing Regimen) specifically formulated to complement laser/light-based facial cosmetic procedures.

PubMed

Narurkar, Vic A; Beer, Kenneth R; Cohen, Joel L

2010-12-01

Specialized skin care regimens may help to minimize adverse events (AEs) following non-ablative facial procedures. A 14-week, open-label, three-center study evaluated the efficacy and safety of a topical five-product system (Clinique Medical Optimizing Regimen; Allergan, Inc., Irvine, CA, USA) for minimizing localized AEs during two 6-week procedure cycles with fractionated laser (FL) or intense pulsed light (IPL). The skin care regimen consisted of a 2-week preprocedure phase, a 1-week postprocedure phase, and a 3-week maintenance phase. Investigators and patients rated the presence and severity of erythema, itching, stinging/burning, edema, pain, pruritus, swelling, crusts/erosion, and photodamage. Two days after the FL/IPL treatment (IPL: n = 27; FL: n = 21), most assessments, including erythema, were near baseline values; at 4 weeks postprocedure, all investigator scores were comparable to baseline. Patients missed work or avoided social situations a mean of only 0.8 days. Mean subject ratings for itching, stinging/burning, pain, swelling, and redness for 2 weeks postprocedure were 'none' to 'mild'. Treatment-related AEs (acne, facial rash) occurred in four patients. All investigators stated they would recommend this topical over-the-counter regimen again in conjunction with non-ablative FL/IPL treatments. This topical five-product skin care system was safe and effective in conjunction with non-ablative FL/IPL procedures.

An Open-Label Pilot Study of Combined Augmentation With Creatine Monohydrate and 5-Hydroxytryptophan for Selective Serotonin Reuptake Inhibitor- or Serotonin-Norepinephrine Reuptake Inhibitor-Resistant Depression in Adult Women.

PubMed

Kious, Brent M; Sabic, Hana; Sung, Young-Hoon; Kondo, Douglas G; Renshaw, Perry

2017-10-01

Many women with major depressive disorder (MDD) respond inadequately to standard treatments. Augmentation of conventional antidepressants with creatine monohydrate and 5-hydroxytryptophan (5-HTP) could correct deficits in serotonin production and brain bioenergetics associated with depression in women, yielding synergistic benefit. We describe an open-label study of 5-HTP and creatine augmentation in women with MDD who had failed selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) monotherapy. Fifteen women who were adequately adherent to an SSRI or SNRI and currently experiencing MDD, with a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or higher, were treated with 5 g of creatine monohydrate daily and 100 mg of 5-HTP twice daily for 8 weeks, with 4 weeks of posttreatment follow-up. The primary outcome was change in mean HAM-D scores. Mean HAM-D scores declined from 18.9 (SD, 2.5) at pretreatment visits to 7.5 (SD, 4.4) (P < 0.00001), a decrease of 60%. Participants did not experience any serious treatment-related adverse events. Combination treatment with creatine and 5-HTP may represent an effective augmentation strategy for women with SSRI- or SNRI-resistant depression. Given the limitations of this small, open-label trial, future study in randomized, placebo-controlled trials is warranted.

Effects of aripiprazole once-monthly on symptoms of schizophrenia in patients switched from oral antipsychotics.

PubMed

Peters-Strickland, Timothy; Zhao, Cathy; Perry, Pamela P; Eramo, Anna; Salzman, Phyllis M; McQuade, Robert D; Johnson, Brian R; Sanchez, Raymond

2016-12-01

To assess the effects of aripiprazole once-monthly 400 mg (AOM 400) on clinical symptoms and global improvement in schizophrenia after switching from an oral antipsychotic. In a multicenter, open-label, mirror-image, naturalistic study in patients with schizophrenia (>1 year, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR] criteria), changes in efficacy measures were assessed during prospective treatment (6 months) with AOM 400 after switching from standard-of-care oral antipsychotics. During prospective treatment, patients were cross-titrated to oral aripiprazole monotherapy (1-4) weeks followed by open-label AOM 400 (24 weeks). Mean change from baseline of the open-label AOM 400 phase in Positive and Negative Syndrome Scale (PANSS) scores (total, positive and negative subscales) and Clinical Global Impression-Severity (CGI-S) scores; mean CGI-Improvement (CGI-I) score; and proportion of responders (≥30% decrease from baseline in PANSS total score or CGI-I score of 1 [very much improved] or 2 [much improved]) were assessed. PANSS and CGI-S scores improved from baseline (P<0.0001) and CGI-I demonstrated improvement at all time points. By the end of the study, 49.0% of patients were PANSS or CGI-I responders. In a community setting, patients with schizophrenia who were stabilized at baseline and switched to AOM 400 from oral antipsychotics showed clear improvements in clinical symptoms.

Efficacy, safety and risk of augmentation of rotigotine for treating restless legs syndrome.

PubMed

Inoue, Yuichi; Hirata, Koichi; Hayashida, Kenichi; Hattori, Nobutaka; Tomida, Takayuki; Garcia-Borreguero, Diego

2013-01-10

The present study aimed to examine the long-term efficacy and safety of rotigotine treatment for restless legs syndrome (RLS), as well as the rate of clinically significant augmentation, in a 1-year open-label study of Japanese subjects. Japanese patients with RLS who had been treated with rotigotine or placebo in a double-blind trial were enrolled in a 1-year, open-label, uncontrolled extension study and treated with rotigotine at a dose of up to 3 mg/24 h after an 8-week titration phase. Outcomes included International Restless Legs Syndrome Study Group rating scale (IRLS scale), Pittsburgh Sleep Quality Index (PSQI), safety, and investigator-/expert panel-assessed augmentation (including Augmentation Severity Rating Scale). Overall, 185 patients entered the open-label study and 133 completed the study. IRLS and PSQI total scores improved throughout the 52-week treatment period (IRLS, from 23.2±5.1 to 7.8±7.6 and PSQI, from 8.0±3.1 to 5.0±2.9). Treatment-emergent adverse events were mild to moderate in severity, and included application site reactions (52.4%) and nausea (28.6%). Clinically significant augmentation occurred in five patients (2.7%). These results indicate a good long-term efficacy of rotigotine for treating RLS, with a relatively low risk of clinically significant augmentation. Copyright © 2012 Elsevier Inc. All rights reserved.

Safety and Efficacy of Baricitinib Through 128 Weeks in an Open-label, Longterm Extension Study in Patients with Rheumatoid Arthritis.

PubMed

Keystone, Edward C; Genovese, Mark C; Schlichting, Douglas E; de la Torre, Inmaculada; Beattie, Scott D; Rooney, Terence P; Taylor, Peter C

2018-01-01

To assess the safety and efficacy of baricitinib in patients with rheumatoid arthritis (RA) up to 128 weeks in a phase IIb study (NCT01185353). After a 24-week blinded period, eligible patients entered an initial 52-week open-label extension (OLE); patients receiving 8 mg once daily (QD) continued with that dose and all others received 4 mg QD. Doses could be escalated to 8 mg QD at 28 or 32 weeks at investigator discretion when ≥ 6 tender and ≥ 6 swollen joints were present. Patients completing the first OLE were eligible to enter a second 52-week OLE and receive 4 mg QD regardless of previous dose. In the 4-mg (n = 108) and 8-mg (n = 93) groups, treatment-emergent adverse events (AE) occurred in 63% and 67%, serious AE in 16% and 13%, infections in 35% and 40%, and serious infections in 5% and 3% of patients, respectively. Exposure-adjusted incidence rates for AE for all baricitinib groups in the second OLE were similar to or lower than rates observed in the first OLE. No opportunistic infections, tuberculosis cases, or lymphomas were observed through 128 weeks; 1 death occurred during the first OLE. Among all patients in both OLE, the proportions who achieved disease improvement at Week 24 were similar or increased at weeks 76 and 128. In a phase IIb study in RA, the safety and tolerability profile of baricitinib, up to 128 weeks, remained consistent with earlier observations, without unexpected late signals. Clinical improvements seen in the 24-week blinded period were maintained during the OLE.

Memantine and constraint-induced aphasia therapy in chronic poststroke aphasia.

PubMed

Berthier, Marcelo L; Green, Cristina; Lara, J Pablo; Higueras, Carolina; Barbancho, Miguel A; Dávila, Guadalupe; Pulvermüller, Friedemann

2009-05-01

We conducted a randomized, double-blind, placebo-controlled, parallel-group study of both memantine and constraint-induced aphasia therapy (CIAT) on chronic poststroke aphasia followed by an open-label extension phase. Patients were randomized to memantine (20 mg/day) or placebo alone during 16 weeks, followed by combined drug treatment with CIAT (weeks 16-18), drug treatment alone (weeks 18-20), and washout (weeks 20-24), and finally, an open-label extension phase of memantine (weeks 24-48). After baseline evaluations, clinical assessments were done at two end points (weeks 16 and 18), and at weeks 20, 24, and 48. Outcome measures were changes in the Western Aphasia Battery-Aphasia Quotient and the Communicative Activity Log. Twenty-eight patients were included, and 27 completed both treatment phases. The memantine group showed significantly better improvement on Western Aphasia Battery-Aphasia Quotient compared with the placebo group while the drug was taken (week 16, p = 0.002; week 18, p = 0.0001; week 20, p = 0.005) and at the washout assessment (p = 0.041). A significant increase in Communicative Activity Log was found in favor of memantine-CIAT relative to placebo-CIAT (week 18, p = 0.040). CIAT treatment led to significant improvement in both groups (p = 0.001), which was even greater under additional memantine treatment (p = 0.038). Beneficial effects of memantine were maintained in the long-term follow-up evaluation, and patients who switched to memantine from placebo experienced a benefit (p = 0.02). Both memantine and CIAT alone improved aphasia severity, but best outcomes were achieved combining memantine with CIAT. Beneficial effects of memantine and CIAT persisted on long-term follow-up.

Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial.

PubMed

Rog, David J; Nurmikko, Turo J; Young, Carolyn A

2007-09-01

Central neuropathic pain (CNP), pain initiated or caused by a primary lesion or dysfunction of the central nervous system, occurs in ~28% of patients with multiple sclerosis (MS). Delta(9)-Tetrahydrocannabinol/cannabidiol (THC/CBD), an endocannabinoid system modulator, has demonstrated efficacy for up to 4 weeks in randomized controlled trials in the treatment of CNP in patients with MS. The purpose of this extension was to establish long-term tolerability and effectiveness profiles for THC/CBD (Sativex (R), GW Pharmaceuticals plc, Salisbury, United Kingdom) oromucosal spray in CNP associated with MS. This uncontrolled, open-label trial was an indefinite-duration extension of a previously reported 5-week randomized study in patients with MS and CNP. In the initial trial, patients were randomized to placebo or THC/CBD. Patients were only required to maintain their existing analgesia in the randomized study. In the open-label trial they could vary their other analgesia as required. All patients (placebo and THC/CBD) who completed the randomized trial commenced the open-label follow-up on THC/CBD (27 mg/mL: 25 mg/mL). Patients titrated their dosage, maintaining their existing analgesia. The primary end point of the trial was the number, frequency, and type of adverse events (AEs) reported by patients. Secondary end points included changes from baseline in 11-point numerical rating scale (NRS-11) neuropathic pain score, hematology and clinical chemistry test results, vital signs, trial drug usage, and intoxication visual analogue scale scores. Sixty-six patients were enrolled in the randomized trial; 64 (97%) completed the randomized trial and 63 (95%) entered the open-label extension (race, white, 100%; sex, male, 14 [22%]; mean [SD] age, 49 [8.4] years [range, 27-71 years[). The mean (SD) duration of open-label treatment was 463 (378) days (median, 638 days; range, 3-917 days), with 34 (54%) patients completing >1 year of treatment with THC/CBD and 28 (44%) patients completing the open-label trial with a mean (SD) duration of treatment of 839 (42) days (median, 845 days; range, 701-917 days). Mean NRS-11 pain scores in the final week of the randomized trial were 3.8 in the treatment group and 5.0 in the placebo group. In the 28 (44%) patients who completed the 2-year follow up, the mean (SD) NRS-11 pain score in the final week of treatment was 2.9 (2.0) (range, 0-8.0). Fifty-eight (92%) patients experienced > or =1 treatment-related AE. These AEs were rated by the investigator as mild in 47 (75%) patients, moderate in 49 (78%), and severe in 32 (51%). The most commonly reported AEs were dizziness (27%), nausea (18 %), and feeling intoxicated (11%). Two treatment-related serious AEs (ventricular bigeminy and circulatory collapse) were judged to be treatment-related. Both serious AEs occurred in the same patient and resolved completely following a period of discontinuation. Eleven (17%) patients experienced oral discomfort, 4 persistently. Regular oral examinations revealed that 7 (11%) patients developed white buccal mucosal patches and 2 (3%) developed red buccal mucosal patches; all cases were deemed mild and resolved. Seventeen (25%) patients withdrew due to AEs. The mean number of sprays and patients experiencing intoxication remained stable throughout the follow-up trial. THC/CBD was effective, with no evidence of tolerance, in these select patients with CNP and MS who completed approximately 2 years of treatment (n = 28). Ninety-two percent of patients experienced an AE, the most common of which were dizziness and nausea. The majority of AEs were deemed to be of mild to moderate severity by the investigators.

Open-Label Milnacipran for Patients With Persistent Knee Pain 1 Year or Longer After Total Knee Arthroplasty: A Pilot Study

PubMed Central

Bolognesi, Michael P.

2013-01-01

Objective: The current study investigates whether milnacipran is effective in reducing pain and improving function in patients with persistent pain ≥ 1 year after total knee arthroplasty. Method: This was a 12-week open-label study of flexibly dosed milnacipran in patients (N = 5) experiencing chronic persistent knee pain ≥ 1 year following total knee arthroplasty in the absence of new injury, infection, or implant failure. Subjects were identified from October 2010 to August 2011 through the Duke University Medical Center orthopedic clinic (Durham, North Carolina), typically during 1-year postoperative follow-up visits, and were referred by their orthopedic surgeon. Results: Milnacipran treatment was associated with reduction in pain according to the primary outcome measure of the visual analog scale (VAS) score for pain (effect size of 1.15) and secondary outcome measures of Knee Society Score (KSS) evaluation subscale score (effect size of 1.37) and Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) bodily pain subscale (effect size of 1.16) at week 12. Secondary outcome measures of functional change were mixed in such that, at week 12, the SF-36 physical functioning subscale showed improvement (effect size of 1.16), but the KSS function subscale score was just below the threshold for meaningful effect size (0.98). Conclusions: Open-label milnacipran demonstrated reduced pain and some evidence of functional improvement in this small sample of patients with chronic persistent pain 1 year or more after total knee arthroplasty such that well-powered studies are warranted. Trial Registration: ClinicalTrials.gov identifier: NCT01780389 PMID:24392250

Efficacy and safety of secukinumab in patients with generalized pustular psoriasis: A 52-week analysis from phase III open-label multicenter Japanese study.

PubMed

Imafuku, Shinichi; Honma, Masaru; Okubo, Yukari; Komine, Mayumi; Ohtsuki, Mamitaro; Morita, Akimichi; Seko, Noriko; Kawashima, Naoko; Ito, Saori; Shima, Tomohiro; Nakagawa, Hidemi

2016-09-01

Generalized pustular psoriasis (GPP) is a severe inflammatory skin disease characterized by the presence of sterile pustules covering almost the entire body and systemic symptoms such as fever. Secukinumab, a fully human-recombinant anti-interleukin-17A monoclonal antibody was indicated for psoriasis vulgaris and psoriatic arthritis in Japan but is not yet investigated for GPP. In this phase III, open-label multicenter single arm study, the efficacy and safety of secukinumab as monotherapy or with co-medication was evaluated in 12 Japanese patients with GPP. All the patients received secukinumab 150 mg s.c. at baseline, week 1, 2, 3 and 4, and then every 4 weeks. Two non-responders were up-titrated to 300 mg. Change in GPP severity from baseline was evaluated by clinical global impression (CGI) categorized as "worsened", "no change", "minimally improved", "much improved" or "very much improved". Treatment success was achieved by 83.3% (n = 10) of patients at week 16 (primary end-point) with CGI evaluated as "very much improved" (n = 9) and "much improved" (n = 1). Moreover, the area of erythema with pustules improved as early as week 1 and resolved by week 16 in most of the patients. The improvements were sustained throughout 52 weeks. Over the 52-week treatment period, secukinumab was well tolerated with no unexpected safety signals. Nasopharyngitis, urticaria, diabetes mellitus and arthralgia were the frequent adverse events reported. The data from this study shows that secukinumab can become one of the potent treatment options for GPP. © 2016 Japanese Dermatological Association.

Long-term efficacy and safety of certolizumab pegol in Japanese rheumatoid arthritis patients with an inadequate response to methotrexate: 52-week results from an open-label extension of the J-RAPID study

PubMed Central

Tanaka, Yoshiya; Yamamoto, Kazuhiko; Takeuchi, Tsutomu; Yamanaka, Hisashi; Ishiguro, Naoki; Eguchi, Katsumi; Watanabe, Akira; Origasa, Hideki; Shoji, Toshiharu; Miyasaka, Nobuyuki; Koike, Takao

2014-01-01

Abstract Objectives. To evaluate the long-term efficacy and safety of certolizumab pegol (CZP) plus methotrexate treatment and to assess the efficacy of two CZP maintenance dosing schedules in Japanese rheumatoid arthritis (RA) patients with an inadequate response to methotrexate. Methods. J-RAPID double-blind patients were entered into an open-label extension (OLE) study. Patients withdrawn due to lack of efficacy at 16 weeks and double-blind completers without a week-24 American College of Rheumatology (ACR) 20 response received CZP 200 mg every other week (Q2W) plus methotrexate. Double-blind completers with week-24 ACR20 responses were randomized to CZP 200 mg Q2W plus methotrexate or CZP 400 mg every 4 weeks plus methotrexate. Results. The ACR20/ACR50/ACR70 response rates of double-blind completers (n = 204) were 89.7%/67.2%/36.3% at OLE entry and 95.6%/84.8%/58.3% at 52 weeks, respectively. Other clinical, functional and radiographic outcomes were sustained with long-term CZP plus methotrexate. Long-term treatment with CZP was well-tolerated with no new unexpected adverse events observed. The efficacy and safety of CZP treatment were similar between the two dosing schedules. Conclusions. Continued CZP administration with methotrexate maintained efficacy over 52 weeks and was well-tolerated for Japanese RA patients. No obvious differences in clinical efficacy and safety were observed between the two dosing schedules, giving flexibility in maintenance administration schedules. PMID:24593170

Safety and efficacy of enzyme replacement therapy with agalsidase beta: an international, open-label study in pediatric patients with Fabry disease.

PubMed

Wraith, J Edmond; Tylki-Szymanska, Anna; Guffon, Nathalie; Lien, Y Howard; Tsimaratos, Michel; Vellodi, Ashok; Germain, Dominique P

2008-04-01

To evaluate the safety and explore the efficacy of enzyme replacement therapy with agalsidase beta (recombinant human alpha-galactosidase A; Fabrazyme [Genzyme Corporation, Cambridge, MA]) in pediatric patients with Fabry disease, a genetic disorder in which deficient endogenous enzyme causes pathogenic tissue accumulation of globotriaosylceramide (GL-3). Fourteen male and 2 female patients, 8 to 16 years old, were treated in this open-label study. A 12-week observation period to collect baseline data preceded the 48-week treatment period when agalsidase beta (1 mg/kg) was infused intravenously every 2 weeks. No primary efficacy end point was specified. Before treatment, results of skin biopsies from 12 male patients showed moderate or severe GL-3 accumulation in superficial dermal capillary endothelial cells; with treatment, these cells were completely cleared of GL-3 in week-24 biopsies from all 12 male patients and in all available week-48 biopsies. With treatment, reports of gastrointestinal symptoms declined steadily. Patient diaries documented significant reductions in school absences due to sickness. Agalsidase beta was generally well tolerated; most treatment-related adverse events were mild or moderate infusion-associated reactions involving rigors, fever, or rhinitis. Agalsidase beta safely and effectively reduced the GL-3 accumulation in dermal endothelium already evident in children with Fabry disease. Early intervention may prevent irreversible end-organ damage from chronic GL-3 deposition.

Improved Lipid Profile Associated with Daily Consumption of Tri-Sura-Phon in Healthy Overweight Volunteers: An Open-Label, Randomized Controlled Trial

PubMed Central

Kuamsub, Sirigoon; Singthong, Pariyaphat; Chanthasri, Wipawee; Chobngam, Nicharee; Sangkaew, Warissara; Hemdecho, Sasithorn; Kaewmanee, Thammarat

2017-01-01

Tri-Sura-Phon (TSP), a traditional Thai polyherbal formula renowned for its rejuvenating properties, is commonly used as a blood tonic. It comprises Cinnamomum bejolghota, Cinnamomum parthenoxylon, and Aquilaria crassna. The aim of this study is to evaluate the beneficial properties of TSP tea consumption on blood glucose regulation and serum lipid profiles of healthy overweight volunteers. This open-label, randomized controlled trial was conducted in 70 healthy overweight adults. Two groups of 35 subjects took a TSP infusion or a placebo (cornstarch) twice daily for 8 weeks. The blood glucose regulation, serum lipid profiles, BMI, and liver function tests of the subjects were determined at the baseline, 4th week, and endpoint (8th week). Significant decreases in the average fasting levels of total cholesterol (p = 0.013), triglyceride (p = 0.001), and low-density lipoprotein (LDL, p = 0.017) were observed in the TSP group at the 8th week compared to those at the baseline. The average HDL level in the TSP group at the beginning of the study was 65.2 mg/dL, and it increased significantly (p = 0.005) to 72.4 mg/dL after 8 weeks of TSP intake. This study showed that the intake of TSP tea as an antioxidant-rich beverage might be safe and improve lipid profiles in overweight adults. PMID:28484502

Long-term safety and effectiveness of brexpiprazole in Japanese patients with schizophrenia: A 52-week, open-label study.

PubMed

Ishigooka, Jun; Iwashita, Shuichi; Tadori, Yoshihiro

2018-06-01

This study assessed the long-term safety, tolerability, and maintenance of the therapeutic effect of brexpiprazole in Japanese patients with schizophrenia. This 52-week, open-label, flexible-dose (1-4 mg/day) study included patients with schizophrenia who continued treatment from a short-term randomized placebo-controlled fixed-dose (1, 2, or 4 mg/day) trial and de novo patients who switched from other antipsychotics. A total of 282 patients (184 de novo and 98 rolled over from short-term trial) entered the 52-week treatment with brexpiprazole, and 150 (53.2%) patients completed the week-52 assessment. Treatment-emergent adverse events (TEAE) were experienced by 235/281 patients (83.6%), and TEAE reported by ≥10% of all patients were nasopharyngitis (23.1%) and worsening of schizophrenia (22.4%). During the study, most of the TEAE were mild or moderate in severity, and there were no deaths, and no clinically meaningful mean changes in laboratory values, vital signs, or electrocardiogram parameters. Mean scores for the Positive and Negative Syndrome Scale total and Clinical Global Impression-Severity remained stable until week 52. Brexpiprazole was generally safe and well tolerated and maintained therapeutic effects in the long-term treatment of Japanese patients with schizophrenia. © 2018 The Authors. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology.

Blonanserin Augmentation of Atypical Antipsychotics in Patients with Schizophrenia-Who Benefits from Blonanserin Augmentation?: An Open-Label, Prospective, Multicenter Study.

PubMed

Woo, Young Sup; Park, Joo Eon; Kim, Do-Hoon; Sohn, Inki; Hwang, Tae-Yeon; Park, Young-Min; Jon, Duk-In; Jeong, Jong-Hyun; Bahk, Won-Myong

2016-07-01

The purpose of this study was to investigate the efficacy and tolerability of atypical antipsychotics (AAPs) with augmentation by blonanserin in schizophrenic patients. aA total of 100 patients with schizophrenia who were partially or completely unresponsive to treatment with an AAP were recruited in this 12-week, open-label, non-comparative, multicenter study. Blonanserin was added to their existing AAP regimen, which was maintained during the study period. Efficacy was primarily evaluated using the Positive and Negative Syndrome Scale (PANSS) at baseline and at weeks 2, 4, 8, and 12. Predictors for PANSS response (≥20% reduction) were investigated. The PANSS total score was significantly decreased at 12 weeks of blonanserin augmentation (-21.0±18.1, F=105.849, p<0.001). Moreover, 51.0% of participants experienced a response at week 12. Premature discontinuation of blonanserin occurred in 17 patients (17.0%); 4 of these patients dropped out due to adverse events. The patients who benefited the most from blonanserin were those with severe symptoms despite a treatment with a higher dose of AAP. Blonanserin augmentation could be an effective strategy for patients with schizophrenia who were partially or completely unresponsive to treatment with an AAP.

Blonanserin Augmentation of Atypical Antipsychotics in Patients with Schizophrenia-Who Benefits from Blonanserin Augmentation?: An Open-Label, Prospective, Multicenter Study

PubMed Central

Woo, Young Sup; Park, Joo Eon; Kim, Do-Hoon; Sohn, Inki; Hwang, Tae-Yeon; Park, Young-Min; Jon, Duk-In; Jeong, Jong-Hyun

2016-01-01

Objective The purpose of this study was to investigate the efficacy and tolerability of atypical antipsychotics (AAPs) with augmentation by blonanserin in schizophrenic patients. Methods aA total of 100 patients with schizophrenia who were partially or completely unresponsive to treatment with an AAP were recruited in this 12-week, open-label, non-comparative, multicenter study. Blonanserin was added to their existing AAP regimen, which was maintained during the study period. Efficacy was primarily evaluated using the Positive and Negative Syndrome Scale (PANSS) at baseline and at weeks 2, 4, 8, and 12. Predictors for PANSS response (≥20% reduction) were investigated. Results The PANSS total score was significantly decreased at 12 weeks of blonanserin augmentation (-21.0±18.1, F=105.849, p<0.001). Moreover, 51.0% of participants experienced a response at week 12. Premature discontinuation of blonanserin occurred in 17 patients (17.0%); 4 of these patients dropped out due to adverse events. The patients who benefited the most from blonanserin were those with severe symptoms despite a treatment with a higher dose of AAP. Conclusion Blonanserin augmentation could be an effective strategy for patients with schizophrenia who were partially or completely unresponsive to treatment with an AAP. PMID:27482249

Safety and tolerability of azilsartan medoxomil in subjects with essential hypertension: a one-year, phase 3, open-label study.

PubMed

Handley, Alison; Lloyd, Eric; Roberts, Andrew; Barger, Bruce

2016-01-01

This 56-week phase 3, open-label, treat-to-target study, involving 2 consecutive, non-randomized cohorts, evaluated the safety and tolerability of azilsartan medoxomil (AZL-M) in essential hypertension (mean baseline blood pressure [BP] 152/100 mmHg). All subjects (n = 669) initiated AZL-M 40 mg QD, force-titrated to 80 mg QD at week 4, if tolerated. From week 8, subjects could receive additional medications, starting with chlorthalidone (CLD) 25 mg QD (Cohort 1) or hydrochlorothiazide (HCTZ) 12.5-25 mg QD (Cohort 2), if required, to reach BP targets. Adverse events (AEs) were reported in 75.9% of subjects overall in the two cohorts (73.8% Cohort 1, 78.5% Cohort 2). The most common AEs were dizziness (14.3%), headache (9.9%) and fatigue (7.2%). Transient serum creatinine elevations were more frequent with add-on CLD. Clinic systolic/diastolic BP (observed cases at week 56) decreased by 25.2/18.4 mmHg (Cohort 1) and 24.2/17.9 mmHg (Cohort 2). These results demonstrate that AZL-M is well tolerated over the long term and provides stable BP improvements when used in a treat-to-target BP approach with thiazide-type diuretics.

Ramelteon for Insomnia Symptoms in a Community Sample of Adults with Generalized Anxiety Disorder: An Open Label Study

PubMed Central

Gross, Paul K.; Nourse, Rosemary; Wasser, Thomas E.

2009-01-01

Objective: Prior research confirms the relationship between insomnia and psychiatric disorders, particularly anxiety and depression. The effectiveness and tolerability of ramelteon was examined in adult generalized anxiety disorder (GAD) patients with insomnia symptoms. Methods: Twenty-seven adults with sleep disturbance meeting DSM-IV diagnostic criteria for GAD and partially responsive on an SSRI or SNRI by randomization visit (as signified by a Hamilton Anxiety scale [HAMA] maximum score of 15 and minimum of 8, Clinical Global Impressions Severity of Illness [CGI-S] scale of ≤ 4 and ≥ 2 [measuring anxiety symptoms], CGI-S of ≥ 4 [measuring insomnia symptoms], ≥ 5 on the Pittsburgh Sleep Quality Index [PSQI], and ≥ 10 on the Epworth Sleepiness Scale [ESS]) were treated openly for 10 weeks on ramelteon 8 mg at bedtime. Analysis was conducted using repeated measures methodology. Patient reported sleep diaries were maintained throughout the study. Results: Significant symptom reduction was observed on all scales (HAMA, ESS, CGI-I, CGI-S), with subjects falling asleep faster and sleeping longer. Headache upon stopping ramelteon, daytime tiredness, agitation, and depression were the most commonly reported side effects and were cited as transient. Conclusion: Data from this 12-week open-label study suggests ramelteon is an effective and generally well tolerated treatment for insomnia symptoms in this community sample of adults with GAD. Citation: Gross PK; Nourse R; Wasser TE. Ramelteon for insomnia symptoms in a community sample of adults with generalized anxiety disorder: an open label study. J Clin Sleep Med 2009;5(1):28–33. PMID:19317378

Effectiveness and tolerability of open label olanzapine in children and adolescents with Tourette syndrome.

PubMed

McCracken, James T; Suddath, Robert; Chang, Susanna; Thakur, Sarika; Piacentini, John

2008-10-01

The primary aim of the study was to evaluate the effectiveness and tolerability of open-label olanzapine on motor and vocal tics in children and adolescents with Tourette syndrome (TS). Secondary aims included assessing the response of TS-associated disruptive behaviors to olanzapine exposure. Twelve children and adolescents (mean age 11.3 +/- 2.4 years, range 7-14 years) with Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) TS were enrolled in a single-site, 6-week, open-label, prospective, flexible-dose design in outpatients receiving monotherapy with olanzapine. Standardized ratings of tic symptoms, disruptive behaviors, and aggression were obtained, along with adverse events and safety data. Over the 6-week trial, olanzapine administration was associated with a significant decrease in total tic severity as measured by the Yale Global Tic Severity Scale (30% reduction by week 6; effect size 0.49). A significant majority of subjects were rated as "much improved" or "very much improved" on the Clinical Global Impressions-Improvement Scale (GCI-I) by both clinicians (67%; 8/12) and parents (64%; 7/11). Attention-deficit/hyperactivity disorder (ADHD) symptoms showed significant improvements from baseline for both inattention (33% decrease) and hyperactive/impulsivity (50% decrease) scores (effect sizes 0.44 and 0.43, respectively). Aggression was also decreased as assessed by fewer numbers of aggressive episodes on the Overt Aggression Scale (OAS). Little change in anxiety symptoms was noted. The most widely reported side effects were drowsiness/sedation and weight gain; adverse events were generally well tolerated. Mean weight gain of 4.1 +/- 2.0 kg was observed over the 6-week trial, a mean percent change of 8.4 +/- 4.4 (p < 0.001). Additional studies of the benefits of olanzapine treatment for tic control as well as the commonly associated co-morbid features of TS are indicated, especially if approaches to predict or minimize weight gain can be determined.

Open-labelled observations of language dysfunction in old ischemic stroke patients with aphasia when given plant and marine-based nutrient supplements for 12 weeks.

PubMed

Lin, Guan-Yu; Chan, Hsiu-Yu; Cheng, Chun-An; Lin, Lan-Ping; Peng, Giia-Sheun; Hsiao, Pei-Min; Lin, Chun-Chieh; Lin, Chun-Chih; Lee, Jiunn-Tay

2016-01-01

This study aimed to explore the effect of functional foods on aphasia related to a previous ischemic stroke. When stroke-related neurological deficits result in physical dependency and poor selfcare that persists longer than 6 months, full recovery is almost impossible and the patient often requires long-term care. The functional foods, EASE123 and BioBalance#6, include numerous plant and marine-based nutrient supplements that could prove beneficial for such patients. This open-labelled study included 10 patients diagnosed with prior ischemic stroke and aphasia lasting longer than 6 months. Each patient was administered 6 tablets of EASE123 at 10:30 AM and at 90 minutes before sleeping, and 3 tablets of BioBalance# 6 at 2:30 PM. After a treatment period of 12 weeks, the patients were followed during a 4-week withdrawal period. Functional improvement was assessed by scores and subscores on the Concise Chinese Aphasia Test (CCAT) at weeks 4, 8, 12, and 16. Average total CCAT scores and matching ability improved significantly at weeks 4, 8, 12, and 16 (p<0.05). Simple response scores improved significantly at weeks 8 and 12 (p<0.05). Auditory comprehension improved significantly at weeks 4 and 12 (p<0.05), and reading comprehension, at week 12 (p<0.05). Repetition ability improved significantly at weeks 8, 12, and 16 (p<0.05), and spontaneous writing, at weeks 4, 12, and 16 (p<0.05). Matching, repetition, and average total CCAT scores improved over the course of the study. Therefore, 6 months after ischemic stroke, EASE123 and BioBalance# 6 administration may improve stroke-related aphasia.

Use of levetiracetam in a population of patients aged 65 years and older: a subset analysis of the KEEPER trial.

PubMed

Ferrendelli, J A; French, J; Leppik, I; Morrell, M J; Herbeuval, A; Han, J; Magnus, L

2003-12-01

Levetiracetam (Keppra) was evaluated in a subset of patients aged >/=65 years (n=78) enrolled in a large (n=1030) open-label, phase IV trial (the KEEPER trial). A 4-week dose adjustment was followed by a 12-week evaluation period. An overall median reduction in partial seizures of 80.1% (n=65) was observed. Overall, 76.9% of patients were >/=50% responders, 56.9% were >/=75% responders, and 40.0% were 100% responders. Levetiracetam was well tolerated, with 42.3% of patients reporting one or more adverse events. A total of 15 patients (19.2%) experienced an adverse event that led to discontinuation. Somnolence (n=13,16.7%) and dizziness (n=7,9.0%) were the most commonly reported adverse events. Despite the limitations of the open-label study design, these data provide information regarding the use of levetiracetam as add-on therapy for the treatment of partial-onset seizures in patients >/=65 years of age, including those requiring concomitant medications.

Cognitex supplementation in elderly adults with memory complaints: an uncontrolled open label trial.

PubMed

Richter, Yael; Herzog, Yael; Eyal, Inbal; Cohen, Tzafra

2011-06-01

The components of the nutritional supplement Cognitex have been individually shown to have beneficial effects on cognitive function. We evaluated the efficacy of the nutritional supplement in improving cognitive function in elderly with memory complaints. Thirty participants received three capsules of the nutritional supplement per day for 12 weeks in an open label study. Efficacy and safety measures, assessed at baseline, 2 weeks, and 12 weeks of treatment, included cognitive evaluation using a computerized cognitive assessment tool, vital signs measurements, and physical examination. Twenty-six participants completed the 12-week study. A significant improvement in memory abilities (recall, recognition, and spatial short term) was observed following 2 weeks of Cognitex treatment (mean change from baseline: 11.15 ± 2.90, 8.68 ± 2.50, and 19.85 ± 6.19, respectively). Attention (sustained and focused), visual learning, and activities of daily living (executive functions and mental flexibility) were improved as well following this short supplementation period (mean change from baseline: 9.46 ± 3.80, 3.76 ± 1.50, 17.31 ± 5.33, 9.45 ± 3.73, and 9.92 ± 4.08, respectively). After 10 additional treatment weeks, activities of daily living demonstrated an additional statistically significant improvement while the beneficial effect observed for the rest of the tested parameters remained unchanged. The results indicate that the nutritional supplement may improve cognitive performance in elderly with memory complaints; however, further blinded and placebo-controlled studies are needed. Clinicaltrials.gov, Identifier: NCT00719953.

Randomized, Controlled Trial of Intravenous Immunoglobulin for Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections.

PubMed

Williams, Kyle A; Swedo, Susan E; Farmer, Cristan A; Grantz, Heidi; Grant, Paul J; D'Souza, Precilla; Hommer, Rebecca; Katsovich, Liliya; King, Robert A; Leckman, James F

2016-10-01

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are hypothesized to occur as a result of cross-reactive antibodies produced in response to group A streptococcal infections. Previous research suggests that immunomodulatory therapies, such as intravenous immunoglobulin (IVIG), may lead to rapid and sustained symptom improvement in patients with PANDAS. A total of 35 children meeting criteria for PANDAS and moderate to severe obsessive-compulsive disorder (OCD) were enrolled in a randomized-entry, double-blind, placebo-controlled, 6-week trial of IVIG (1 g/kg/day on 2 consecutive days), followed by optional open-label treatment for nonresponders, with follow-up at 12 and 24 weeks. Primary outcome measures were the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) and the Clinical Global Impressions-Improvement (CGI-I) rating. "Responders" were defined, a priori, by a ≥ 30% decrease in CY-BOCS total score, and a "much" or "very much" improved rating on CGI-I. During the double-blind phase, the mean decrease in CY-BOCS score was 24% ± 31% in the IVIG group (n = 17) and 12% ± 27% in the placebo group (n = 18), with six responders in the IVIG group (35%) versus four (22%) in the placebo group; these differences were not statistically significant. Twenty-four participants met criteria for nonresponse to double-blind infusion and received open-label IVIG at week 6. Among all participants, the mean CY-BOCS improvement from baseline was 55% ± 33% at week 12 and 62% ± 33% at week 24. IVIG was safe and well tolerated. Between-group differences were smaller than anticipated, and the double-blind comparison failed to demonstrate superiority of IVIG over placebo. The observed open-label improvements indicate that future trials would benefit from larger sample sizes designed in part to aid in the identification of biomarkers predictive of a positive response to immunotherapy. Future investigations focused on the natural history of PANDAS are also warranted. Clinical trial registration information-Intravenous Immunoglobulin for PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections); http://clinicaltrials.gov/; NCT01281969ZIAMH002666. Published by Elsevier Inc.

Regression of nifedipine-induced gingival hyperplasia following switch to a same class calcium channel blocker, isradipine.

PubMed

Westbrook, P; Bednarczyk, E M; Carlson, M; Sheehan, H; Bissada, N F

1997-07-01

Patients with nifedipine-induced gingival hyperplasia (GH) often require continued calcium channel blocker therapy. Switches to diltiazem and verapamil have been described; however, these drugs are of a different chemical class and present therapeutic limitations in some patients. The purpose of this study was to evaluate the effect on nifedipine-induced GH of a switch to a dihydropyridine derivative with a low incidence of GH. Fourteen patients with nifedipine-induced GH were given a medical exam and a periodontal exam. The following parameters were assessed: probing depth (PD), gingival margin (GM), gingival thickness (GT), plaque index (PI), and gingival index (GI). Intraoral photographs, study models, and a gingival biopsy for histological examination were taken. Following baseline measures, patients were randomized to continued treatment with nifedipine or an equivalent dose of isradipine in a single-blind fashion. Biweekly periodontal parameters were taken for 8 weeks. At the end of 8 weeks, some patients elected to receive 4 weeks of open label isradipine therapy, with biweekly examination continuing through the open label phase. The isradipine treatment arm showed a mean decrease in PD of 0.59 mm at week 8 (P < 0.05). No other measured parameter (GM, GT, PI, GI) was significantly changed, compared either to baseline or to the alternate treatment arm. Clinically, 60% of patients treated with isradipine exhibited a decrease in hyperplasia, while 66% of patients treated with nifedipine demonstrated an increase in hyperplasia, a significant difference (P < 0.05). When combined with open label data, patients switching therapy to isradipine exhibited an increase in GM (increase in recession) of 0.74 mm from baseline to week 12 (P < 0.05). No patients treated with isradipine exhibited an increase in gingival overgrowth. All patients exhibited adequate control of hypertension. We conclude that in hypertensive patients with nifedipine-induced GH, switching hypertensive therapy to isradipine may result in a regression of GH. When coupled with aggressive oral hygiene treatment, this drug may provide a reasonable option for patients requiring dihydropyridine treatment.

Sustained remission of symptoms and improved health-related quality of life in patients with cryopyrin-associated periodic syndrome treated with canakinumab: results of a double-blind placebo-controlled randomized withdrawal study.

PubMed

Koné-Paut, Isabelle; Lachmann, Helen J; Kuemmerle-Deschner, Jasmin B; Hachulla, Eric; Leslie, Kieron S; Mouy, Richard; Ferreira, Alberto; Lheritier, Karine; Patel, Neha; Preiss, Ralph; Hawkins, Philip N

2011-01-01

To assess the effect of canakinumab, a fully human anti-interleukin-1β antibody, on symptoms and health-related quality of life (HRQoL) in patients with cryopyrin-associated periodic syndrome (CAPS). In this 48-week, phase 3 study, patients with CAPS received canakinumab 150 mg subcutaneously at 8-week intervals. All patients (n = 35) received canakinumab during weeks 1 through 8; weeks 9 through 24 constituted a double-blind placebo-controlled withdrawal phase, and weeks 24 through 48 constituted an open-label phase in which all patients received canakinumab. Patient and physician assessments of symptoms, levels of inflammatory markers, and HRQoL were performed. Rapid symptom remission was achieved, with 89% of patients having no or minimal disease activity on day 8. Responses were sustained in patients receiving 8-weekly canakinumab. Responses were lost during the placebo-controlled phase in the placebo group and were regained on resuming canakinumab therapy in the open-label phase. Clinical responses were accompanied by decreases in serum levels of C-reactive protein, serum amyloid A protein, and interleukin-6. HRQoL scores at baseline were considerably below those of the general population. Improvements in all 36-item Short-Form Health Survey (SF-36) domain scores were evident by day 8. Scores approached or exceeded those of the general U.S. population by week 8 and remained stable during canakinumab therapy. Improvements in bodily pain and role-physical were particularly marked, increasing by more than 25 points from baseline to week 8. Therapy was generally well tolerated. Canakinumab, 150 mg, 8-weekly, induced rapid and sustained remission of symptoms in patients with CAPS, accompanied by substantial improvements in HRQoL. Clintrials.gov NCT00465985.

Clinical Benefit of Long-Term Adalimumab Treatment in Patients With Crohn's Disease Following Loss of Response or Intolerance to Infliximab: 96-Week Efficacy Data From GAIN/ADHERE Trials.

PubMed

Panaccione, Remo; Sandborn, William J; D'Haens, Geert; Wolf, Douglas C; Berg, Sofie; Maa, Jen-Fue; Petersson, Joel; Robinson, Anne M

2018-04-25

In the 4-week GAIN clinical trial, adalimumab was efficacious in inducing remission in patients with moderate to severe Crohn's disease (CD) who had prior loss of response/intolerance to infliximab. The efficacy and safety of adalimumab in these patients are reported here up to 96 weeks or for 3 years, respectively, in ADHERE open-label extension study. Patients who completed GAIN could enrol in ADHERE and receive open-label adalimumab 40 mg every other week. Efficacy variables included clinical response (Crohn's Disease Activity Index [CDAI] decrease from baseline ≥70/≥100 points [CR-70/CR-100]) and remission (CDAI<150), steroid discontinuation and fistula remission (absence of drainage). Data were reported using hybrid non-responder imputation (hNRI), last observation carried forward and as-observed analysis. Subgroup analyses were performed by randomised group in GAIN and by Week 4 efficacy in GAIN. Safety was also assessed. A total of 310 patients from GAIN enrolled in ADHERE. CR-70, CR-100 and remission rates at Week 96 were 39.0%, 35.5% and 26.5% (hNRI), respectively. Of the patients with CR-70 response or remission at Week 4 of GAIN, 45.5% and 44.4% (hNRI), respectively, maintained effect at Week 96. Steroid discontinuation and steroid-free remission rates increased from Week 12 to 96 in patients using corticosteroids at GAIN baseline. Long-term adalimumab maintenance therapy led to sustained clinical remission and response, and steroid discontinuation in a considerable proportion of patients with CD previously treated with infliximab. No new safety signals were observed in this patient population.

Clinical response and symptomatic remission in short- and long-term trials of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder.

PubMed

Mattingly, Greg W; Weisler, Richard H; Young, Joel; Adeyi, Ben; Dirks, Bryan; Babcock, Thomas; Lasser, Robert; Scheckner, Brian; Goodman, David W

2013-01-29

Despite the overall high degree of response to pharmacotherapy, consensus is lacking on how to judge clinical response or define optimal treatment/remission when treating adults with attention-deficit/hyperactivity disorder (ADHD). This study examined clinical response and symptomatic remission in analyses of 2 studies of lisdexamfetamine dimesylate (LDX) in adults with ADHD. In a 4-week, double-blind, forced-dose trial, adults with ADHD were randomized to LDX 30, 50, and 70 mg/day (mg/d) or placebo. In a second, open-label, follow-up trial, adults entering from the 4-week study were titrated to an "optimal" LDX dose (30 mg/d [n=44], 50 mg/d [n=112], and 70 mg/d [n=171]) over 4 weeks, and maintained for 11 additional months. The ADHD Rating Scale IV (ADHD-RS-IV) with adult prompts and the Clinical Global Impressions-Improvement (CGI-I) scale assessed efficacy. Clinical response was defined, post hoc, as ≥30% reduction from baseline in ADHD-RS-IV and CGI-I rating of 1 or 2; symptomatic remission was defined as ADHD-RS-IV total score ≤18. Log rank analysis examined overall significance among the treatment groups in time to response or remission. Four hundred and fourteen participants in the 4-week study and 345 in the open-label, extension study were included in the efficacy populations. All LDX groups improved by ADHD-RS-IV and CGI-I scores in both studies. In the 4-week study (n=414), 69.3% responded and 45.5% achieved remission with LDX (all doses); 37.1% responded and 16.1% achieved remission with placebo; time (95% CI) to median clinical response (all LDX doses) was 15.0 (15.0, 17.0) days and to remission was 31.0 (28.0, 37.0) days (P<.0001 overall). In the open-label study, with LDX (all doses), 313 (95.7%) and 278 (85.0%) of 327 participants with evaluable maintenance-phase data met criteria for response and remission, respectively. Of participants who completed dose optimization, 75.2% remained responders and 65.7% remained in remission in the 12-month study. Overall, 285 (82.6%) and 227 (65.8%) of 345 participants were responders and remitters, respectively, at their final visits. In the long-term study, with open-label, dose-optimized LDX treatment, most adults with ADHD achieved clinical response and/or symptomatic remission; almost two-thirds maintained symptomatic remission over the remaining 11 months. Clinical Trial Numbers: NCT00334880 and NCT01070394CLINICAL TRIAL REGISTRY: clinicaltrials.gov.

Clinical response and symptomatic remission in short- and long-term trials of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder

PubMed Central

2013-01-01

Background Despite the overall high degree of response to pharmacotherapy, consensus is lacking on how to judge clinical response or define optimal treatment/remission when treating adults with attention-deficit/hyperactivity disorder (ADHD). This study examined clinical response and symptomatic remission in analyses of 2 studies of lisdexamfetamine dimesylate (LDX) in adults with ADHD. Methods In a 4-week, double-blind, forced-dose trial, adults with ADHD were randomized to LDX 30, 50, and 70 mg/day (mg/d) or placebo. In a second, open-label, follow-up trial, adults entering from the 4-week study were titrated to an “optimal” LDX dose (30 mg/d [n=44], 50 mg/d [n=112], and 70 mg/d [n=171]) over 4 weeks, and maintained for 11 additional months. The ADHD Rating Scale IV (ADHD-RS-IV) with adult prompts and the Clinical Global Impressions-Improvement (CGI-I) scale assessed efficacy. Clinical response was defined, post hoc, as ≥30% reduction from baseline in ADHD-RS-IV and CGI-I rating of 1 or 2; symptomatic remission was defined as ADHD-RS-IV total score ≤18. Log rank analysis examined overall significance among the treatment groups in time to response or remission. Results Four hundred and fourteen participants in the 4-week study and 345 in the open-label, extension study were included in the efficacy populations. All LDX groups improved by ADHD-RS-IV and CGI-I scores in both studies. In the 4-week study (n=414), 69.3% responded and 45.5% achieved remission with LDX (all doses); 37.1% responded and 16.1% achieved remission with placebo; time (95% CI) to median clinical response (all LDX doses) was 15.0 (15.0, 17.0) days and to remission was 31.0 (28.0, 37.0) days (P<.0001 overall). In the open-label study, with LDX (all doses), 313 (95.7%) and 278 (85.0%) of 327 participants with evaluable maintenance-phase data met criteria for response and remission, respectively. Of participants who completed dose optimization, 75.2% remained responders and 65.7% remained in remission in the 12-month study. Overall, 285 (82.6%) and 227 (65.8%) of 345 participants were responders and remitters, respectively, at their final visits. Conclusion In the long-term study, with open-label, dose-optimized LDX treatment, most adults with ADHD achieved clinical response and/or symptomatic remission; almost two-thirds maintained symptomatic remission over the remaining 11 months. Trial registration Clinical Trial Numbers: NCT00334880 and NCT01070394 Clinical Trial Registry: clinicaltrials.gov URLs http://www.clinicaltrials.gov/show/NCT00334880 http://www.clinicaltrials.gov/ct2/show/NCT01070394?term=NCT01070394&rank=1 PMID:23356790

Effect of Aromatherapy Massage on Chemotherapy-Induced Peripheral Neuropathic Pain and Fatigue in Patients Receiving Oxaliplatin: An Open Label Quasi-Randomized Controlled Pilot Study.

PubMed

Izgu, Nur; Ozdemir, Leyla; Bugdayci Basal, Fatma

2017-12-02

Patients receiving oxaliplatin may experience peripheral neuropathic pain and fatigue. Aromatherapy massage, a nonpharmacological method, may help to control these symptoms. The aim of this open-label, parallel-group, quasi-randomized controlled pilot study was to investigate the effect of aromatherapy massage on chemotherapy-induced peripheral neuropathic pain and fatigue in patients receiving oxaliplatin. Stratified randomization was used to allocate 46 patients to 2 groups: intervention (n = 22) and control (n = 24). Between week 1 and week 6, participants in the intervention group (IG) received aromatherapy massage 3 times a week. There was no intervention in weeks 7 and 8. The control group (CG) received routine care. Neuropathic pain was identified using the Douleur Neuropathique 4 Questions; severity of painful paresthesia was assessed with the numerical rating scale; fatigue severity was identified with the Piper Fatigue Scale. At week 6, the rate of neuropathic pain was significantly lower in the IG, when compared with the CG. The severity of painful paresthesia based on numerical rating scale in the IG was significantly lower than that in the CG at weeks 2, 4, and 6. At week 8, fatigue severity in the IG was significantly lower when compared with CG (P < .05). Aromatherapy massage may be useful in the management of chemotherapy-induced peripheral neuropathic pain and fatigue. This pilot study suggests that aromatherapy massage may be useful to relieve neuropathic pain and fatigue. However, there is a need for further clinical trials to validate the results of this study.

Effectiveness of Platelet-rich Plasma Injection for Rotator Cuff Tendinopathy: A Prospective Open-label Study.

PubMed

Scarpone, Michael; Rabago, David; Snell, Edward; Demeo, Patrick; Ruppert, Kristine; Pritchard, Perry; Arbogast, Gennie; Wilson, John J; Balzano, John F

2013-03-01

Assess platelet rich plasma (PRP) injection for rotator cuff tendinopathy (RCT). Prospective open label study with 1-year follow-up. Participants recruited from an outpatient sports medicine clinic had clinically and magnetic resonance image (MRI)-demonstrated RCT refractory to physical therapy and corticosteroid injection. They received one ultrasound-guided injection of 3.0 mL of 1% xylocaine followed by 3.5 mL of PRP at the lesion and surrounding tendon. 0-10 visual analog scale (VAS; baseline, 8, 12, and 52 weeks). functional shoulder tests assessing rotator cuff strength and endurance (at baseline and 8 and 12 weeks), MRI severity (1-5 points [at baseline and 4 and 8 weeks]), and patient satisfaction (52 weeks). Eighteen participants with 19 assessed shoulders reported VAS pain score improvement from 7.5 ± 0.3 points to 0.5 ± 0.3 points by week 12 and 0.4 ± 0.2 (P = .0001) points at week 52. Functional outcomes significantly improved; the largest effect was seen in the external rotation test: 33.5 ± 5.7 seconds to 62.6 ± 7.2 seconds at week 12 (P = .0001). MRI appearance improved by 1 to 3 points in 16 of 18 assessed shoulders. Seventeen participants were "completely satisfied" (12) or "satisfied" (5). One participant was "unsatisfied." A single ultrasound-guided, intralesional injection of PRP resulted in safe, significant, sustained improvement of pain, function, and MRI outcomes in participants with refractory RCT. Randomized multidisciplinary effectiveness trials that add ultrasound and validated clinical outcome measures are needed to further assess PRP for RCT.

Cardiovascular Safety of Droxidopa in Patients With Symptomatic Neurogenic Orthostatic Hypotension.

PubMed

White, William B; Hauser, Robert A; Rowse, Gerald J; Ziemann, Adam; Hewitt, L Arthur

2017-04-01

The norepinephrine prodrug droxidopa improves symptoms of neurogenic orthostatic hypotension, a condition that is associated with diseases of neurogenic autonomic failure (e.g., Parkinson disease, multiple system atrophy, pure autonomic failure). These conditions are more prevalent in older patients who also have cardiovascular co-morbidities. Hence, we evaluated the cardiovascular safety of droxidopa in patients with symptomatic neurogenic orthostatic hypotension who participated in randomized controlled studies (short-term studies of 1 to 2 weeks and an intermediate 8- to 10-week study) and long-term open-label studies. Rates of cardiovascular adverse events (AEs) for patients treated with droxidopa were 4.4% in the intermediate study and 10.8% in the long-term open-label studies. Adjusting for exposure time, cardiovascular AE rates were 0.30 events/patient-year in the short-term and intermediate studies and 0.15 events/patient-year in the long-term open-label studies. The incidence of treatment discontinuation due to blood pressure-related events was approximately 2.5%. Among patients with a history of cardiac disorders at baseline, the rates of cardiovascular-related and blood pressure-related AEs were nominally higher with droxidopa compared to placebo. Most of these events were minor atrial arrhythmias; none were major adverse cardiovascular events or deaths. In conclusion, small increases in cardiovascular AEs were observed with droxidopa compared to placebo; this was most evident in patients with preexisting cardiac disorders. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

A double-blind, placebo-controlled study of risperidone in adults with autistic disorder and other pervasive developmental disorders.

PubMed

McDougle, C J; Holmes, J P; Carlson, D C; Pelton, G H; Cohen, D J; Price, L H

1998-07-01

Neurobiological research has implicated the dopamine and serotonin systems in the pathogenesis of autism. Open-label reports suggest that the serotonin2A-dopamine D2 antagonist risperidone may be safe and effective in reducing the interfering symptoms of patients with autism. Thirty-one adults (age [mean+/-SD], 28.1+/-7.3 years) with autistic disorder (n=17) or pervasive developmental disorder not otherwise specified (n=14) participated in a 12-week double-blind, placebo-controlled trial of risperidone. Patients treated with placebo subsequently received a 12-week open-label trial of risperidone. For persons completing the study, 8 (57%) of 14 patients treated with risperidone were categorized as responders (daily dose [mean+/-SD], 2.9+/-1.4 mg) compared with none of 16 in the placebo group (P<.002). Risperidone was superior to placebo in reducing repetitive behavior (P<.001), aggression (P<.001), anxiety or nervousness (P<.02), depression (P<.03), irritability (P<.01), and the overall behavioral symptoms of autism (P<.02). Objective, measurable change in social behavior and language did not occur. Nine (60%) of 15 patients who received treatment with open-label risperidone following the double-blind placebo phase responded. Other than mild, transient sedation, risperidone was well tolerated, with no evidence of extrapyramidal effects, cardiac events, or seizures. Risperidone is more effective than placebo in the short-term treatment of symptoms of autism in adults.

Effects of Topiramate in Adults with Prader-Willi Syndrome

ERIC Educational Resources Information Center

Shapira, Nathan A.; Lessig, Mary C.; Lewis, Mark H.; Goodman, Wayne K.; Driscoll, Daniel J.

2004-01-01

Prader-Willi syndrome is a multisystem neurogenetic obesity disorder with behavioral manifestations, including hyperphagia, compulsive behavior, self-injury, and mild to moderate mental retardation. In an 8-week open-label study, we evaluated adjunctive therapy with the anticonvulsant topiramate in 8 adults with Prader-Willi syndrome. Appetite was…

Hematological Adverse Events in Clozapine-Treated Children and Adolescents

ERIC Educational Resources Information Center

Gerbino-Rosen, Ginny; Roofeh, David; Tompkins, D. Andrew; Feryo, Doug; Nusser, Laurie; Kranzler, Harvey; Napolitano, Barbara; Frederickson, Anne; Henderson, Inika; Rhinewine, Joe; Kumra, Sanjiv

2005-01-01

Objective: To retrospectively examine rates of hematological adverse events (HAEs) in psychiatrically ill, hospitalized children treated with clozapine. Method: Clozapine treatment was administered in an open-label fashion using a flexible titration schedule, and data from weekly complete blood counts was obtained. The rate of neutropenia and…

Health-related quality of life and functional outcomes from a randomized-withdrawal study of long-term lisdexamfetamine dimesylate treatment in children and adolescents with attention-deficit/hyperactivity disorder.

PubMed

Banaschewski, Tobias; Johnson, Mats; Lecendreux, Michel; Zuddas, Alessandro; Adeyi, Ben; Hodgkins, Paul; Squires, Liza A; Coghill, David R

2014-12-01

The stimulant prodrug lisdexamfetamine dimesylate (LDX) is an effective and generally well tolerated treatment for the symptoms of attention-deficit/hyperactivity disorder (ADHD). Positive impacts of LDX on health-related quality of life and functional impairment have previously been demonstrated in a 7-week, randomized, double-blind, placebo-controlled, phase III study in children and adolescents in Europe. Maintenance of these broad benefits, as well as symptomatic control, is a key goal of long-term management of ADHD. Secondary objectives of this multinational study in children and adolescents with ADHD were to assess the long-term maintenance of effectiveness of LDX in improving health-related quality of life and reducing functional impairment, as gauged using the Child Health and Illness Profile-Child Edition: Parent Report Form (CHIP-CE: PRF) and the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P), respectively. Patients aged 6-17 years with diagnosed ADHD and a baseline ADHD Rating Scale IV total score of at least 28 were enrolled from the previous European study and from US sites. Patients who completed an open-label LDX treatment period of at least 26 weeks were randomized (1:1) to continue on their optimized dose of LDX or to switch to placebo for a 6-week, double-blind, withdrawal period. Parents completed CHIP-CE: PRF and WFIRS-P questionnaires at weeks 0, 8 and 26 of the open-label period and at weeks 0 and 6 of the randomized-withdrawal period, or at early termination. The endpoint of each period was defined as the last visit with valid data. Effect sizes were the difference (LDX minus placebo) in least-squares (LS)-mean change from baseline to endpoint divided by root-mean-square error. P values were nominal and not adjusted for multiple comparisons. The open-label and randomized full analysis sets comprised 262 and 153 (LDX n = 76; placebo n = 77) patients, respectively. Mean pretreatment CHIP-CE: PRF T-scores were more than one standard deviation below the normative mean in four of the five domains, and there was significant improvement across all domains from baseline to endpoint of the open-label period. In the randomized-withdrawal period, LS-mean CHIP-CE: PRF T-scores deteriorated in all domains in the placebo group, but not in the LDX group. Compared with placebo, the effect of LDX was significant in the Risk Avoidance (effect size 0.829; p < 0.001), Achievement (0.696; p < 0.001) and Satisfaction (0.636; p < 0.001) domains. Mean pretreatment WFIRS-P scores were lowest in the Family domain and the Learning and School domain. WFIRS-P total score and scores in all domains improved significantly from baseline to endpoint of the open-label period. In the randomized-withdrawal period, LS-mean scores deteriorated in the placebo group but not in the LDX group. Compared with placebo, the effect of LDX was significant in the Family, Learning and School, and Risky Activities domains and in total (effect size 0.908; p < 0.001). Using parent-rated instruments, long-term maintenance of the beneficial effect of LDX in multiple domains of health-related quality of life and functional impairment was demonstrated by comparison of treatment continuation and withdrawal under randomized, double-blind, placebo-controlled conditions.

Clinical evaluation of paroxetine in post-traumatic stress disorder (PTSD): 52-week, non-comparative open-label study for clinical use experience.

PubMed

Kim, Yoshiharu; Asukai, Nozomu; Konishi, Takako; Kato, Hiroshi; Hirotsune, Hideto; Maeda, Masaharu; Inoue, Hirotaka; Narita, Hiroyasu; Iwasaki, Masaru

2008-12-01

The present study was a 52-week, non-comparative, open-label study of flexible dose paroxetine (20-40 mg) in 52 Japanese post-traumatic stress disorder (PTSD) patients in order to obtain clinical experience regarding efficacy and safety in regular clinical practice. Efficacy was measured using the Clinician-Administered PTSD Scale One Week Symptom Status Version (CAPS-SX). The mean change from baseline in CAPS-SX total score was -19.1, -22.8 and -32.3 at weeks 4, 12 and 52, respectively, and that in the Clinical Global Impression (CGI) Severity of Illness score was -1.1 at week 12 and -1.7 at week 52. A total of 46.9% were CGI responders at week 12, while 67.3% were improved on the CGI at week 52. Of 52 subjects who entered into the drug treatment, 25 completed the study. Only one patient withdrew from the study due to lack of efficacy. In patients who were rated as 'moderately ill' or less at baseline, the proportion of CGI responders at end-point was higher at a dose of 20 mg/day than at higher doses, whereas in patients rated as 'markedly ill' or more, it was higher at 30 and 40 mg/day, suggesting that severely ill patients could benefit from higher doses. Paroxetine appeared generally tolerated in short- and long-term use, and the safety profile in this study was consistent with international trials and other Japanese populations (i.e. patients suffering from depression, panic disorder or obsessive-compulsive disorder). Although the study was not conducted in double-blind fashion, the current findings suggest that paroxetine may contribute to clinically meaningful improvement that is maintained during long-term use and is generally well tolerated.

Itolizumab in combination with methotrexate modulates active rheumatoid arthritis: safety and efficacy from a phase 2, randomized, open-label, parallel-group, dose-ranging study.

PubMed

Chopra, Arvind; Chandrashekara, S; Iyer, Rajgopalan; Rajasekhar, Liza; Shetty, Naresh; Veeravalli, Sarathchandra Mouli; Ghosh, Alakendu; Merchant, Mrugank; Oak, Jyotsna; Londhey, Vikram; Barve, Abhijit; Ramakrishnan, M S; Montero, Enrique

2016-04-01

The objective of this study was to assess the safety and efficacy of itolizumab with methotrexate in active rheumatoid arthritis (RA) patients who had inadequate response to methotrexate. In this open-label, phase 2 study, 70 patients fulfilling American College of Rheumatology (ACR) criteria and negative for latent tuberculosis were randomized to four arms: 0.2, 0.4, or 0.8 mg/kg itolizumab weekly combined with oral methotrexate, and methotrexate alone (2:2:2:1). Patients were treated for 12 weeks, followed by 12 weeks of methotrexate alone during follow-up. Twelve weeks of itolizumab therapy was well tolerated. Forty-four patients reported adverse events (AEs); except for six severe AEs, all others were mild or moderate. Infusion-related reactions mainly occurred after the first infusion, and none were reported after the 11th infusion. No serum anti-itolizumab antibodies were detected. In the full analysis set, all itolizumab doses showed evidence of efficacy. At 12 weeks, 50 % of the patients achieved ACR20, and 58.3 % moderate or good 28-joint count Disease Activity Score (DAS-28) response; at week 24, these responses were seen in 22 and 31 patients. Significant improvements were seen in Short Form-36 Health Survey and Health Assessment Questionnaire Disability Index scores. Overall, itolizumab in combination with methotrexate was well tolerated and efficacious in RA for 12 weeks, with efficacy persisting for the entire 24-week evaluation period. (Clinical Trial Registry of India, http://ctri.nic.in/Clinicaltrials/login.php , CTRI/2008/091/000295).

Effect of consuming a purple-fleshed sweet potato beverage on health-related biomarkers and safety parameters in Caucasian subjects with elevated levels of blood pressure and liver function biomarkers: a 4-week, open-label, non-comparative trial

PubMed Central

OKI, Tomoyuki; KANO, Mitsuyoshi; WATANABE, Osamu; GOTO, Kazuhisa; BOELSMA, Esther; ISHIKAWA, Fumiyasu; SUDA, Ikuo

2016-01-01

An open-label study with one treatment arm was conducted to investigate changes in health-related biomarkers (blood pressure and liver enzyme activity) and the safety of 4 weeks of consuming a purple-fleshed sweet potato beverage in Caucasian subjects. Twenty healthy adults, 18–70 years of age, with a body mass index >25 kg/m2, elevated blood pressure and elevated levels of liver function biomarkers consumed two cartons of purple-fleshed sweet potato beverage (125 ml, including 117 mg anthocyanin per carton) daily for 4 weeks. Hematology, serum clinical profile, dipstick urinalysis and blood pressure were determined before consumption, at 2 and 4 weeks of consumption and after a 2-week washout period. A trend was found toward lowering systolic blood pressure during the treatment period (p=0.0590). No significant changes were found in diastolic blood pressure throughout the study period. Systolic blood pressure was significantly lower after 4 weeks of consumption compared with before consumption (p=0.0125) and was significantly higher after the 2-week washout period compared with after consumption (p=0.0496). The serum alanine aminotransferase level significantly increased over time, but aspartate aminotransferase and γ-glutamyltransferase levels stayed within the normal range of reference values. Safety parameters of the blood and urine showed no clinically relevant changes. The consumption of a purple-fleshed sweet potato beverage for 4 weeks resulted in no clinically relevant changes in safety parameters of the blood and urine and showed a trend toward lowering systolic blood pressure. PMID:27508114

Clinical and MRI responses to etanercept in early non-radiographic axial spondyloarthritis: 48-week results from the EMBARK study.

PubMed

Maksymowych, Walter P; Dougados, Maxime; van der Heijde, Désirée; Sieper, Joachim; Braun, Jürgen; Citera, Gustavo; Van den Bosch, Filip; Logeart, Isabelle; Wajdula, Joseph; Jones, Heather; Marshall, Lisa; Bonin, Randi; Pedersen, Ron; Vlahos, Bonnie; Kotak, Sameer; Bukowski, Jack F

2016-07-01

To evaluate the efficacy and safety of etanercept (ETN) after 48 weeks in patients with early active non-radiographic axial spondyloarthritis (nr-axSpA). Patients meeting Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA, but not modified New York radiographic criteria, received double-blind ETN 50 mg/week or placebo (PBO) for 12 weeks, then open-label ETN (ETN/ETN or PBO/ETN). Clinical, health, productivity, MRI and safety outcomes were assessed and the 48-week data are presented here. 208/225 patients (92%) entered the open-label phase at week 12 (ETN, n=102; PBO, n=106). The percentage of patients achieving ASAS40 increased from 33% to 52% between weeks 12 and 48 for ETN/ETN and from 15% to 53% for PBO/ETN (within-group p value <0.001 for both). For ETN/ETN and PBO/ETN, the EuroQol 5 Dimensions utility score improved by 0.14 and 0.08, respectively, between baseline and week 12 and by 0.23 and 0.22 between baseline and week 48. Between weeks 12 and 48, MRI Spondyloarthritis Research Consortium of Canada sacroiliac joint (SIJ) scores decreased by -1.1 for ETN/ETN and by -3.0 for PBO/ETN, p<0.001 for both. Decreases in MRI SIJ inflammation and C-reactive protein correlated with several clinical outcomes at weeks 12 and 48. Patients with early active nr-axSpA demonstrated improvement from week 12 in clinical, health, productivity and MRI outcomes that was sustained to 48 weeks. NCT01258738. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

An open-label pilot trial of alpha-lipoic acid for weight loss in patients with schizophrenia without diabetes.

PubMed

Ratliff, Joseph C; Palmese, Laura B; Reutenauer, Erin L; Tek, Cenk

2015-01-01

A possible mechanism of antipsychotic-induced weight gain is activation of hypothalamic monophosphate-dependent kinase (AMPK) mediated by histamine 1 receptors. Alpha-lipoic acid (ALA), a potent antioxidant, counteracts this effect and may be helpful in reducing weight for patients taking antipsychotics. The objective of this open-label study was to assess the efficacy of ALA (1,200 mg) on twelve non-diabetic schizophrenia patients over ten weeks. Participants lost significant weight during the intervention (-2.2 kg±2.5 kg). ALA was well tolerated and was particularly effective for individuals taking strongly antihistaminic antipsychotics (-2.9 kg±2.6 kg vs. -0.5 kg±1.0 kg). NCT01355952.

An open-label study to evaluate the long-term safety and efficacy of lanadelumab for prevention of attacks in hereditary angioedema: design of the HELP study extension.

PubMed

Riedl, Marc A; Bernstein, Jonathan A; Craig, Timothy; Banerji, Aleena; Magerl, Markus; Cicardi, Marco; Longhurst, Hilary J; Shennak, Mustafa M; Yang, William H; Schranz, Jennifer; Baptista, Jovanna; Busse, Paula J

2017-01-01

Hereditary angioedema (HAE) is characterized by recurrent attacks of subcutaneous or submucosal edema. Attacks are unpredictable, debilitating, and have a significant impact on quality of life. Patients may be prescribed prophylactic therapy to prevent angioedema attacks. Current prophylactic treatments may be difficult to administer (i.e., intravenously), require frequent administrations or are not well tolerated, and breakthrough attacks may still occur frequently. Lanadelumab is a subcutaneously-administered monoclonal antibody inhibitor of plasma kallikrein in clinical development for prophylaxis of hereditary angioedema attacks. A Phase 1b study supported its efficacy in preventing attacks. A Phase 3, randomized, double-blind, placebo-controlled, parallel-arm study has been completed and an open-label extension is currently ongoing. The primary objective of the open-label extension is to evaluate the long-term safety of repeated subcutaneous administrations of lanadelumab in patients with type I/II HAE. Secondary objectives include evaluation of efficacy and time to first angioedema attack to determine outer bounds of the dosing interval. The study will also evaluate immunogenicity, pharmacokinetics/pharmacodynamics, quality of life, characteristics of breakthrough attacks, ease of self-administration, and safety/efficacy in patients who switch to lanadelumab from another prophylactic therapy. The open-label extension will enroll patients who completed the double-blind study ("rollover patients") and those who did not participate in the double-blind study ("non-rollover patients"), which includes patients who may or may not be currently using another prophylactic therapy. Rollover patients will receive a single 300 mg dose of lanadelumab on Day 0 and the second dose after the patient's first confirmed angioedema attack. Thereafter, lanadelumab will be administered every 2 weeks. Non-rollover patients will receive 300 mg lanadelumab every 2 weeks regardless of the first attack. All patients will receive their last dose on Day 350 (maximum of 26 doses), and will then undergo a 4-week follow-up. Prevention of attacks can reduce the burden of illness associated with HAE. Prophylactic therapy requires extended, repeated dosing and the results of this study will provide important data on the long-term safety and efficacy of lanadelumab, a monoclonal antibody inhibitor of plasma kallikrein for subcutaneous administration for the treatment of HAE. Trial registration NCT02741596.

DRY CUPPING IN CHILDREN WITH FUNCTIONAL CONSTIPATION: A RANDOMIZED OPEN LABEL CLINICAL TRIAL.

PubMed

Shahamat, Mahmoud; Daneshfard, Babak; Najib, Khadijeh-Sadat; Dehghani, Seyed Mohsen; Tafazoli, Vahid; Kasalaei, Afshineh

2016-01-01

As a common disease in pediatrics, constipation poses a high burden to the community. In this study, we aimed to investigate the efficacy of dry cupping therapy (an Eastern traditional manipulative therapy) in children with functional constipation. One hundred and twenty children (4-18 years old) diagnosed as functional constipation according to ROME III criteria were assigned to receive a traditional dry cupping protocol on the abdominal wall for 8 minutes every other day or standard laxative therapy (Polyethylene glycol (PEG) 40% solution without electrolyte), 0.4 g/kg once daily) for 4 weeks, in an open label randomized controlled clinical trial using a parallel design with a 1:1 allocation ratio. Patients were evaluated prior to and following 2, 4, 8 and 12 weeks of the intervention commencement in terms of the ROME III criteria for functional constipation. There were no significant differences between the two arms regarding demographic and clinical basic characteristics. After two weeks of the intervention, there was a significant better result in most of the items of ROME III criteria of patients in PEG group. In contrast, after four weeks of the intervention, the result was significantly better in the cupping group. There was no significant difference in the number of patients with constipation after 4 and 8 weeks of the follow-up period. This study showed that dry cupping of the abdominal wall, as a traditional manipulative therapy, can be as effective as standard laxative therapy in children with functional constipation.

Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome-an open label pilot study.

PubMed

Nakao, Atsunori; Toyoda, Yoshiya; Sharma, Prachi; Evans, Malkanthi; Guthrie, Najla

2010-03-01

Metabolic syndrome is characterized by cardiometabolic risk factors that include obesity, insulin resistance, hypertension and dyslipidemia. Oxidative stress is known to play a major role in the pathogenesis of metabolic syndrome. The objective of this study was to examine the effectiveness of hydrogen rich water (1.5-2 L/day) in an open label, 8-week study on 20 subjects with potential metabolic syndrome. Hydrogen rich water was produced, by placing a metallic magnesium stick into drinking water (hydrogen concentration; 0.55-0.65 mM), by the following chemical reaction; Mg + 2H(2)O --> Mg (OH)(2) + H(2). The consumption of hydrogen rich water for 8 weeks resulted in a 39% increase (p<0.05) in antioxidant enzyme superoxide dismutase (SOD) and a 43% decrease (p<0.05) in thiobarbituric acid reactive substances (TBARS) in urine. Further, subjects demonstrated an 8% increase in high density lipoprotein (HDL)-cholesterol and a 13% decrease in total cholesterol/HDL-cholesterol from baseline to week 4. There was no change in fasting glucose levels during the 8 week study. In conclusion, drinking hydrogen rich water represents a potentially novel therapeutic and preventive strategy for metabolic syndrome. The portable magnesium stick was a safe, easy and effective method of delivering hydrogen rich water for daily consumption by participants in the study.

An open-label study to evaluate sildenafil for the treatment of lymphatic malformations.

PubMed

Danial, Christina; Tichy, Andrea L; Tariq, Umar; Swetman, Glenda L; Khuu, Phuong; Leung, Thomas H; Benjamin, Latanya; Teng, Joyce; Vasanawala, Shreyas S; Lane, Alfred T

2014-06-01

Lymphatic malformations can be challenging to treat. Mainstay interventions including surgery and sclerotherapy are invasive and can result in local recurrence and complications. We sought to assess the effect of 20 weeks of oral sildenafil on reducing lymphatic malformation volume and symptoms in children. Seven children (4 boys, 3 girls; ages 13-85 months) with lymphatic malformations were given oral sildenafil for 20 weeks in this open-label study. The volume of the lymphatic malformation was calculated blindly using magnetic resonance imaging performed before and after 20 weeks of sildenafil. Lymphatic malformations were assessed clinically on weeks 4, 12, 20, and 32. Both the physician and parents evaluated the lymphatic malformation in comparison with baseline. Four subjects had a lymphatic malformation volume decrease (1.0%-31.7%). In 2 subjects, despite a lymphatic malformation volume increase (1.1%-3.7%), clinical improvement was noted while on sildenafil. One subject had a 29.6% increase in lymphatic malformation volume and no therapeutic response. Lymphatic malformations of all 6 subjects who experienced a therapeutic response on sildenafil softened and became easily compressible. Adverse events were minimal. A randomized controlled trial will be necessary to verify the effects of sildenafil on lymphatic malformations. Sildenafil can reduce lymphatic malformation volume and symptoms in some children. Copyright © 2014 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Clobazam : in patients with Lennox-Gastaut syndrome.

PubMed

Yang, Lily P H; Scott, Lesley J

2012-11-01

Clobazam, as with other benzodiazepines, has a long history of use in the treatment of epilepsy. More recently, it was approved in the USA as adjunctive therapy for the treatment of seizures associated with Lennox-Gastaut syndrome in patients aged ≥2 years. In the pivotal, placebo-controlled CONTAIN trial in paediatric and adult patients with Lennox-Gastaut syndrome (n = 217 evaluable), adjunctive therapy with clobazam 5-40 mg/day for 12 weeks significantly reduced mean weekly drop seizure rates from baseline compared with adjunctive placebo (primary endpoint), with a significant dosage-dependent improvement in these rates. Results from a dosage-ranging, double-blind, multi-centre, phase II trial add further support for the efficacy of clobazam in paediatric and adult patients with Lennox-Gastaut syndrome (n = 61 evaluable). Improvements in mean weekly drop seizure rates with adjunctive clobazam treatment in these short-term trials was maintained in an ongoing, open-label extension study, with a 91.6 % reduction in mean weekly drop seizure rates from baseline (at randomization in the initial trials) to 24 months in the overall population. Treatment with adjunctive clobazam was generally well tolerated in these clinical trials and after at least 2 years of treatment in an open-label extension study. Most adverse events were mild or moderate and similar to those typically observed with other benzodiazepines.

Safety and tolerability of azilsartan medoxomil in subjects with essential hypertension: a one-year, phase 3, open-label study

PubMed Central

Handley, Alison; Lloyd, Eric; Roberts, Andrew; Barger, Bruce

2016-01-01

Abstract This 56-week phase 3, open-label, treat-to-target study, involving 2 consecutive, non-randomized cohorts, evaluated the safety and tolerability of azilsartan medoxomil (AZL-M) in essential hypertension (mean baseline blood pressure [BP] 152/100 mmHg). All subjects (n = 669) initiated AZL-M 40 mg QD, force-titrated to 80 mg QD at week 4, if tolerated. From week 8, subjects could receive additional medications, starting with chlorthalidone (CLD) 25 mg QD (Cohort 1) or hydrochlorothiazide (HCTZ) 12.5–25 mg QD (Cohort 2), if required, to reach BP targets. Adverse events (AEs) were reported in 75.9% of subjects overall in the two cohorts (73.8% Cohort 1, 78.5% Cohort 2). The most common AEs were dizziness (14.3%), headache (9.9%) and fatigue (7.2%). Transient serum creatinine elevations were more frequent with add-on CLD. Clinic systolic/diastolic BP (observed cases at week 56) decreased by 25.2/18.4 mmHg (Cohort 1) and 24.2/17.9 mmHg (Cohort 2). These results demonstrate that AZL-M is well tolerated over the long term and provides stable BP improvements when used in a treat-to-target BP approach with thiazide-type diuretics. PMID:26817604

Intravenous immunoglobulin for maintenance treatment of chronic inflammatory demyelinating polyneuropathy: a multicentre, open-label, 52-week phase III trial

PubMed Central

Mori, Masahiro; Misawa, Sonoko; Suzuki, Miki; Nishiyama, Kazutoshi; Mutoh, Tatsuro; Doi, Shizuki; Kokubun, Norito; Kamijo, Mikiko; Yoshikawa, Hiroo; Abe, Koji; Nishida, Yoshihiko; Okada, Kazumasa; Sekiguchi, Kenji; Sakamoto, Ko; Kusunoki, Susumu; Sobue, Gen; Kaji, Ryuji

2017-01-01

Objective Short-term efficacy of induction therapy with intravenous immunoglobulin (Ig) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) is well established. However, data of previous studies on maintenance therapy were limited up to 24-week treatment period. We aimed to investigate the efficacy and safety of longer-term intravenous Ig therapy for 52 weeks. Methods This study was an open-label phase 3 clinical trial conducted in 49 Japanese tertiary centres. 49 patients with CIDP who fulfilled diagnostic criteria were included. After an induction intravenous Ig therapy (0.4 g/kg/day for five consecutive days), maintenance dose intravenous Ig (1.0 g/kg) was given every 3 weeks for up to 52 weeks. The primary outcome measures were the responder rate at week 28 and relapse rate at week 52. The response and relapse were defined with the adjusted Inflammatory Neuropathy Cause and Treatment scale. Results At week 28, the responder rate was 77.6% (38/49 patients; 95% CI 63% to 88%), and the 38 responders continued the maintenance therapy. At week 52, 4 of the 38 (10.5%) had a relapse (95% CI 3% to 25%). During 52 weeks, 34 (69.4%) of the 49 enrolled patients had a maintained improvement. Adverse events were reported in 94% of the patients; two patients (66-year-old and 76-year-old men with hypertension or diabetes) developed cerebral infarction (lacunar infarct with good recovery), and the other adverse effects were mild and resolved by the end of the study period. Conclusions Maintenance treatment with 1.0 g/kg intravenous Ig every 3 weeks is an efficacious therapy for patients with CIDP, and approximately 70% of them had a sustained remission for 52 weeks. Thrombotic complications should be carefully monitored, particularly in elderly patients with vascular risk factors. Trial registration number ClinicalTrials.gov (NCT01824251). PMID:28768822

Efficacy and safety of abatacept for patients with Sjögren's syndrome associated with rheumatoid arthritis: Rheumatoid Arthritis with Orencia Trial toward Sjögren's syndrome Endocrinopathy (ROSE) trial—an open-label, one-year, prospective study—Interim analysis of 32 patients for 24 weeks

PubMed Central

Tsuboi, Hiroto; Matsumoto, Isao; Hagiwara, Shinya; Hirota, Tomoya; Takahashi, Hiroyuki; Ebe, Hiroshi; Yokosawa, Masahiro; Hagiya, Chihiro; Asashima, Hiromitsu; Takai, Chinatsu; Miki, Haruka; Umeda, Naoto; Kondo, Yuya; Ogishima, Hiroshi; Suzuki, Takeshi; Hirata, Shintaro; Saito, Kazuyoshi; Tanaka, Yoshiya; Horai, Yoshiro; Nakamura, Hideki; Kawakami, Atsushi

2015-01-01

Objective To assess the efficacy and safety of abatacept for secondary Sjögren's syndrome (SS) associated with rheumatoid arthritis (RA). Methods The primary endpoint of this 1-year, open-labeled, prospective, observational multicenter study of RA-associated secondary SS was the rate of SDAI remission at 52 weeks after initiation of abatacept therapy. The secondary endpoints included that of Saxson's test and Schirmer's test. Adverse events during the study period were also analyzed. Results Thirty-two patients (all females) were enrolled in this study. Interim analysis at 24 weeks included assessment of efficacy (n = 31) and safety (n = 32). The mean SDAI decreased from 19.8 ± 11.0 (± SD) at baseline to 9.9 ± 9.9 at 24 weeks (P < 0.05). Patients with clinical remission, as assessed by SDAI, increased from 0 patient (0 week) to 8 patients (25.8%) at 24 weeks. Saliva volume (assessed by Saxson's test) increased slightly from 2232 ± 1908 (0 week) to 2424 ± 2004 (24 weeks) mg/2 min (n = 29). In 11 patients with Greenspan grading 1/2 of labial salivary glands biopsy, saliva volume increased from 2945 ± 2090 (0 week) to 3419 ± 2121 (24 weeks) mg/2 min (P < 0.05). Schirmer's test for tear volume showed increase from 3.6 ± 4.6 (0 week) to 5.5 ± 7.1 (24 weeks) mm/5 min (n = 25; P < 0.05). Five adverse events occurred in five of 32 patients (15.6%), and three of these events were infections. Conclusion Abatacept seems to be effective for both RA and RA-related secondary SS. PMID:25211401

Effect of heart failure reversal treatment as add-on therapy in patients with chronic heart failure: A randomized, open-label study.

PubMed

Sane, Rohit; Aklujkar, Abhijeet; Patil, Atul; Mandole, Rahul

The present study was designed to evaluate effect of heart failure reversal therapy (HFRT) using herbal procedure (panchakarma) and allied therapies, as add-on to standard CHF treatment (SCT) in chronic heart failure (CHF) patients. This open-label, randomized study conducted in CHF patients (aged: 25-65 years, ejection fraction: 30-65%), had 3-phases: 1-week screening, 6-week treatment (randomized [1:1] to HFRT+SCT or SCT-alone) and follow-up (12-week). Twice weekly HFRT (60-75min) consisting of snehana (external oleation), swedana (passive heat therapy), hrudaydhara (concoction dripping treatment) and basti (enema) was administered. Primary endpoints included evaluation of change in metabolic equivalents of task (MET) and peak oxygen uptake (VO 2peak ) from baseline, at end of 6-week treatment and follow-up at week-18 (non-parametric rank ANCOVA analysis). Safety and quality of life (QoL) was assessed. Seventy CHF patients (n=35, each treatment-arm; mean [SD] age: 53.0 [8.6], 80% men) were enrolled in the study. All patients completed treatment phase. Add-on HFRT caused a significant increase in METs (least square mean difference [LSMD], 6-week: 1.536, p=0.0002; 18-week: -1.254, p=0.0089) and VO 2peak (LSMD, 6-week: -5.52, p=0.0002; 18-week: -4.517, p=0.0089) as compared with SCT-alone. Results were suggestive of improved functional capacity in patients with HFRT (QoL; Mean [SD] HFRT+SCT vs. SCT-alone; 6-week: -0.44 [0.34] vs. -0.06 [0.25], p<0.0001 and 18-week: -0.53 [0.35] vs. -0.29 [0.26], p=0.0013). Seven treatment-emergent adverse events (mild severity) were reported in HFRT-arm. Findings of this study highlight therapeutic efficacy of add-on HFRT vs. SCT-alone in CHF patients. The non-invasive HFRT showed no safety concerns. Copyright © 2016. Published by Elsevier B.V.

The Long-Term Safety of S-Flurbiprofen Plaster for Osteoarthritis Patients: An Open-Label, 52-Week Study.

PubMed

Yataba, Ikuko; Otsuka, Noboru; Matsushita, Isao; Matsumoto, Hideo; Hoshino, Yuichi

2016-08-01

The newly developed S-flurbiprofen plaster (SFPP) is a tape-type patch that shows innovative percutaneous absorption. This study was designed to evaluate the safety of a long-term 52-week SFPP application to osteoarthritis (OA) patients. This was a multi-center, open-label, uncontrolled prospective study that included 201 OA patients. SFPP at 40 mg/day was applied to the site of pain in 101 patients and at 80 mg/day (2 patches) in 100 patients at a total of 301 sites for 52 weeks. The affected sites assessed included the knee (192), lumbar spine (66), cervical spine (26), and others (17). Drug safety was evaluated by medical examination, laboratory tests, and examination of vital signs. Efficacy was evaluated by the patient's and clinician's global assessments and clinical symptoms. Most patients (80.1 %) completed the 52-week SFPP application. The majority of drug-related adverse events (AEs) included mild dermatitis at the application sites and occurred in 46.8 % of the sites. No photosensitive dermatitis was observed. Systemic AEs occurred in 9.0 % of the patients; a serious AE (gastric ulcer hemorrhage) occurred in one patient. No clinically significant changes in the laboratory tests and vital signs were observed. The efficacy evaluation showed an improvement from 2 weeks after the SFPP application, which continued during the 52 weeks' treatment. No apparent safety concerns were observed, even during the long-term SFPP application. Therefore, SFPP could be an additional pharmacotherapy in OA treatment.

Phase I Study of Concomitant Pemetrexed and Cisplatin Plus External Beam Radiation Therapy in Patients with Locally Advanced or Metastatic Esophageal or Gastroesophageal Junction Carcinomas.

PubMed

Elquza, Emad; Babiker, Hani M; Howell, Krisha J; Kovoor, Andrew I; Brown, Thomas David; Patel, Hitendra; Malangone, Steven A; Borad, Mitesh J; Dragovich, Tomislav

2016-01-01

To establish the maximum tolerated dose (MTD) and safety profile of bi-weekly Pemetrexed (PEM) when combined with weekly cisplatin (CDDP) and standard dose external beam radiation (EBRT) in patients with locally advanced or metastatic esophageal and gastroesophageal junction (GEJ) carcinomas. We conducted an open label, single institution, phase I dose escalation study designed to evaluate up to 15-35 patients with advanced or metastatic esophageal and GEJ carcinomas. 10 patients were treated with bi-weekly PEM, weekly CDDP, and EBRT. The MTD of bi-weekly PEM was determined to be 500 mg/m(2).

Two-Year Safety and Efficacy Experience in Patients with Methotrexate-Resistant Active Rheumatoid Arthritis Treated with Etanercept and Conventional Disease-Modifying Anti-rheumatic Drugs in the Latin American Region.

PubMed

Machado, Daniel A; Guzman, Renato; Xavier, Ricardo M; Simon, Jesus A; Mele, Linda; Shen, Qi; Pedersen, Ronald; Kotak, Sameer; Vlahos, Bonnie

2016-01-01

Although long-term data are available from biologic studies in North American/European populations with rheumatoid arthritis (RA), long-term findings in Latin American RA populations are limited. To examine long-term safety/efficacy of etanercept, methotrexate, and/or other disease-modifying anti-rheumatic drugs (DMARDs) in Latin American patients with moderate-to-severe active RA. In the first phase of this open-label study, patients were randomized to etanercept 50 mg weekly plus methotrexate or conventional DMARD (hydroxychloroquine or sulfasalazine) plus methotrexate for 24 weeks. At the start of the second phase (week 24), investigators selected a treatment regimen that included any combination/dosage of etanercept, methotrexate, hydroxychloroquine, or sulfasalazine based on previous treatment response, preference, and local product labeling, and was continued for the 104-week extension. In the extension, in the group previously randomized to etanercept-plus-methotrexate therapy, etanercept was continued in 259/260 patients; methotrexate continued in 260/260; and hydroxychloroquine and sulfasalazine added in 8/260 and 3/260, respectively. In the group previously randomized to conventional DMARD-plus-methotrexate therapy, conventional DMARD was discontinued in 86/126 and etanercept added in 105/126. Among etanercept-exposed patients (total exposure, 798.1 patient-year [PY]), rates of adverse events, serious adverse events, and serious infections per PY were 1.7, 0.07, and 0.02 events per PY. In both groups, after treatment modification was permitted, clinical response rates and improvements in clinical/patient-reported outcomes from baseline were sustained to week 128. After investigators were permitted to modify treatment, etanercept was part of the treatment regimen in 95% of patients. Continuation or addition of etanercept in the 2-year extension resulted in a consistently good risk:benefit profile. Open-Label Study Comparing Etanercept to Conventional Disease Modifying Antirheumatic Drug (DMARD) Therapy; ClinicalTrials.gov, number NCT00848354; https://clinicaltrials.gov/ct2/show/NCT00848354.

Psilocybin with psychological support for treatment-resistant depression: six-month follow-up.

PubMed

Carhart-Harris, R L; Bolstridge, M; Day, C M J; Rucker, J; Watts, R; Erritzoe, D E; Kaelen, M; Giribaldi, B; Bloomfield, M; Pilling, S; Rickard, J A; Forbes, B; Feilding, A; Taylor, D; Curran, H V; Nutt, D J

2018-02-01

Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy. Here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression. Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure. Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen's d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen's d = 1.5 and 1.4, respectively, both p < 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience. Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.

Add-on levetiracetam in children and adolescents with refractory epilepsy: results of an open-label multi-centre study.

PubMed

Callenbach, Petra M C; Arts, Willem Frans M; ten Houten, Robert; Augustijn, Paul; Gunning, W Boudewijn; Peeters, Els A J; Weber, Alma M; Stroink, Hans; Geerts, Yvette; Geerts, Ada T; Brouwer, Oebele F

2008-07-01

To study the efficacy and tolerability of add-on levetiracetam in children and adolescents with refractory epilepsy. In this prospective multi-centre, open-label, add-on study, 33 children aged 4-16 years (median 8.5 years) with epilepsy refractory to at least two antiepileptic drugs were treated with levetiracetam in addition to their present treatment regimen with a follow-up of 26 weeks. The starting dose of 10 mg/kg/day was increased with 2-week steps of 10 mg/kg/day, if necessary, up to a maximum dose of 60 mg/kg/day. Retention rate was 69.7% after 26 weeks on a median levetiracetam dosage of 22 mg/kg/day. Four children dropped-out because levetiracetam was ineffective, four because seizure frequency increased and/or seizures became more severe, and two because they developed aggressive behaviour. Compared to their baseline seizure frequency, 13 children (39.4%) had a >50% seizure reduction 12 weeks after initiation of levetiracetam, and 17 children (51.5%) at 26 weeks. At 26 weeks, nine children (27.3%) had been seizure-free for at least the last 4 weeks, terminal remission ranged from 0 to 187 days (mean 46 days). Levetiracetam was effective in both partial and primary generalized seizures, but had most effect in partial seizures. Most reported side effects were hyperactivity (48.5%), somnolence (36.4%), irritability (33.3%) and aggressive behaviour (27.3%). Severity of most side effects was mild. Five children had a serious adverse event, which all concerned hospital admissions that were not related to levetiracetam use. Levetiracetam proved to be an effective and well-tolerated add-on treatment in this group of children with refractory epilepsy.

Safety and tolerability of varenicline tartrate (Champix(®)/Chantix(®)) for smoking cessation in HIV-infected subjects: a pilot open-label study.

PubMed

Cui, Qu; Robinson, Linda; Elston, Dawn; Smaill, Fiona; Cohen, Jeffrey; Quan, Corinna; McFarland, Nancy; Thabane, Lehana; McIvor, Andrew; Zeidler, Johannes; Smieja, Marek

2012-01-01

The prevalence of smoking in HIV-infected subjects is high. As a smoking cessation aid, varenicline (Champix(®), Pfizer, Saint-Laurent, QC, Canada or Chantix(®), Pfizer, Mission, KS) has not been previously evaluated in HIV-infected smokers. In this multicenter pilot open label study, varenicline 1.0 mg was used twice daily for 12 weeks with dose titration in the first week. Adverse events (AEs) during the treatment period were recorded. Changes from baseline in laboratory tests, vital signs, daily cigarette consumption, nicotine dependence, and withdrawal were measured through week 24. Self-reported abstinence was validated by serum cotinine at week 12. We enrolled 36 subjects with a mean of 29 pack-years of smoking and a minimum of 4 cigarettes per day. All but 1 were male, 33 (92%) were white. The most frequently reported AEs were nausea (33%), abnormal dreams (31%), affect lability (19%), and insomnia (19%). Six (17%) subjects discontinued varenicline due to AEs. No grade 3/4 laboratory abnormalities or serious AEs occurred during the study. There was no significant change in HIV viral load. CD4 counts increased by 69 cells/mm3 (p = 0.001) at week 24. Serum cotinine-verified 4-week continuous abstinence rate through weeks 9-12 was 42% (95% confidence interval [CI]: 26-58%). AEs and abstinence rates were comparable to those in published randomized controlled trials conducted in generally healthy HIV-negative smokers. Varenicline was safe and appears effective among HIV-infected smokers in this exploratory study, although AEs were common. The most common AE was nausea, with no adverse effect on HIV treatment outcome. Close monitoring of liver enzymes and blood pressure is recommended for HIV-positive smokers taking varenicline.

Long-term safety and efficacy of canakinumab in cryopyrin-associated periodic syndrome: results from an open-label, phase III pivotal study in Japanese patients.

PubMed

Yokota, Shumpei; Imagawa, Tomoyuki; Nishikomori, Ryuta; Takada, Hidetoshi; Abrams, Ken; Lheritier, Karine; Heike, Toshio; Hara, Toshiro

2017-01-01

To assess the long-term safety and efficacy of canakinumab in Japanese patients with cryopyrin-associated periodic syndrome (CAPS). In this open-label phase 3 study, Japanese patients aged ≥2 years with CAPS received canakinumab 2-8 mg/kg subcutaneously every 8 weeks. The duration of the core treatment phase was 24 weeks followed by 22 months extension phase. The primary objective was the proportion of patients free of clinical and serologic relapse at week 24. The study enrolled 19 Japanese patients (median age, 14 years; range, 2-48 years) with CAPS [MWS, 7 (36.8%); NOMID, 12 (63.2%)] for a median of 109 weeks. Fifteen patients (79%) achieved a complete response by day 15, 18 (94.7%) by week 24 and all by week 48. At the end of the study, 18 (95%) were free from relapse and 11 (57.9%) were assessed as having no disease activity by the PGA. Thirteen (68%) patients (MWS, 4; NOMID, 9) had their canakinumab dose increased during the trial. All patients experienced at least one adverse event (AE), the most common being infections (100%) and 5 (26.3%) reported serious AEs. No deaths were reported and the only patient who discontinued the study early withdrew consent. Regular canakinumab treatment every 8 weeks at dose levels from 2-8 mg/kg, based on the clinical need, represents a successful strategy to induce rapid and complete response while maintain long-term disease control in Japanese patients with CAPS. The safety profile of canakinumab was consistent with that observed from previous studies.

Executive function in adults with attention-deficit/hyperactivity disorder during treatment with atomoxetine in a randomized, placebo-controlled, withdrawal study.

PubMed

Adler, Lenard; Tanaka, Yoko; Williams, David; Trzepacz, Paula T; Goto, Taro; Allen, Albert J; Escobar, Rodrigo; Upadhyaya, Himanshu P

2014-08-01

We assessed the executive function in adults with attention-deficit/hyperactivity disorder (ADHD) during atomoxetine treatment in a randomized withdrawal trial. Responders (Conners' ADHD Rating Scale-Investigator Rated: Screening Version [adult prompts] ≥30% reduction from baseline and Clinical Global Impression Scale-ADHD Severity score ≤3) to open-label atomoxetine (40-100 mg/d, 12 weeks) entered a 37-week double-blind maintenance period. Patients who maintained response (double-blind atomoxetine for 12 weeks) were randomized 1:1 to atomoxetine (80-100 mg/d, n = 266) or placebo (n = 258) for 25 weeks (total duration, 1 year). Patients and investigators were blinded to response criteria and randomization timing. Change in executive function was assessed with the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Self-Report and Informant T scores from the randomization to the last-observation-carried-forward postrandomization week 25 (after week 17). Of the enrolled patients (n = 2017; mean age, 33.2 years; male, 58.7%), 524 responders were randomized. During open-label atomoxetine, subscales and individual items on both BRIEF-A questionnaires showed significant improvement (P < 0.001). After randomization, the following T scores improved significantly (P ≤ 0.05) with patients in the atomoxetine group versus those in the placebo group: global executive composite, behavioral regulation, and metacognition indices; plan/organize, working memory, inhibit, task monitor and shift (both BRIEF-A questionnaires), emotional control and organization of materials (BRIEF-A Informant), and initiate (BRIEF-A Self-Report). Atomoxetine significantly improved the executive function compared with placebo, which was maintained for 25 weeks or more; the executive function of patients in the placebo group worsened but did not return to baseline levels after randomization.

An open-label, multicenter, flexible dose study to evaluate the efficacy and safety of Viagra (sildenafil citrate) in Korean men with erectile dysfunction and arterial hypertension who are taking antihypertensive agents.

PubMed

Park, Hyun Jun; Park, Nam Cheol; Shim, Hong Bang; Park, Jong Kwan; Lee, Sung Won; Park, Kwangsung; Kim, Sae Woong; Moon, Ki Hak; Lee, Dong Hyeon; Yoon, Sang Jin

2008-10-01

Erectile dysfunction (ED) is common among men taking antihypertensive agents to control blood pressure. We evaluated the efficacy and safety of sildenafil citrate in men with ED taking antihypertensive agents. A total of 198 male subjects, aged 20 years and older were enrolled. This study was conducted for 10 weeks as an open-label, multicenter and flexible dose trial with a 2-week screening period and an 8-week treatment phase. Subjects were asked to complete Event Log Worksheets, as well as the International Index of Erectile Function (IIEF) and the Global Efficacy Assessment Questions (GEAQ) questionnaires during the study period. The average age among the 167 subjects who completed the study was 55.8 (31.7 to 77.1). The scores for questions 3 and 4 of IIEF improved from 2.3 and 1.8 at baseline to 3.7 and 3.4 at week 4 and 3.8 and 3.4 at week 8, respectively. There were 86.3% of the patients reported improved erectile function at week 8; 88.3% of the patients reported improved ability to achieve sexual intercourse at week 8. There were no significant differences observed in the responses to questions 3 and 4 of IIEF and GEAQ by the number of antihypertensive agents taken. The adverse events were facial flushing (20.1%), headache (11.7%), palpitation (5.0%), rhinitis (2.8%), URI (2.8%), dizziness (2.2%), dyspnea (2.2%), and nausea (1.7%). Sildenafil citrate is an effective treatment for ED; it is safe and well tolerated by patients with ED taking multiple antihypertensive agents for arterial hypertension.

Tolerability and safety of Souvenaid in patients with mild Alzheimer's disease: results of multi-center, 24-week, open-label extension study.

PubMed

Olde Rikkert, Marcel G M; Verhey, Frans R; Blesa, Rafael; von Arnim, Christine A F; Bongers, Anke; Harrison, John; Sijben, John; Scarpini, Elio; Vandewoude, Maurits F J; Vellas, Bruno; Witkamp, Renger; Kamphuis, Patrick J G H; Scheltens, Philip

2015-01-01

The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to improve synapse formation and function in patients with Alzheimer's disease (AD). Two double-blind randomized controlled trials (RCT) with Souvenaid of 12 and 24 week duration (Souvenir I and Souvenir II) showed that memory performance was improved in drug-naïve mild AD patients, whereas no effects on cognition were observed in a 24-week RCT (S-Connect) in mild to moderate AD patients using AD medication. Souvenaid was well-tolerated in all RCTs. In this 24-week open-label extension (OLE) study to the 24-week Souvenir II RCT, long-term safety and intake adherence of the medical food Souvenaid was evaluated. Patients with mild AD (n = 201) received Souvenaid once-daily during the OLE. Main outcome parameters were safety and product intake adherence. The memory domain z-score from a revised neuropsychological test battery was continued as exploratory parameter. Compared to the RCT, a similar (low) incidence and type of adverse events was observed, being mainly (68.3%) of mild intensity. Pooled data (RCT and OLE) showed that 48-week use of Souvenaid was well tolerated with high intake adherence (96.1%). Furthermore, a significant increase in the exploratory memory outcome was observed in both the active-active and control-active groups during Souvenaid intervention. Souvenaid use for up to 48-weeks was well tolerated with a favorable safety profile and high intake adherence. The findings in this OLE study warrant further investigation toward the long-term safety and efficacy of Souvenaid in a well-controlled, double-blind RCT.

Safety and Tolerability of Varenicline Tartrate (Champix®/Chantix®) for Smoking Cessation in HIV-Infected Subjects: A Pilot Open-Label Study

PubMed Central

Robinson, Linda; Elston, Dawn; Smaill, Fiona; Cohen, Jeffrey; Quan, Corinna; McFarland, Nancy; Thabane, Lehana; McIvor, Andrew; Zeidler, Johannes; Smieja, Marek

2012-01-01

Abstract The prevalence of smoking in HIV-infected subjects is high. As a smoking cessation aid, varenicline (Champix®, Pfizer, Saint-Laurent, QC, Canada or Chantix®, Pfizer, Mission, KS) has not been previously evaluated in HIV-infected smokers. In this multicenter pilot open label study, varenicline 1.0 mg was used twice daily for 12 weeks with dose titration in the first week. Adverse events (AEs) during the treatment period were recorded. Changes from baseline in laboratory tests, vital signs, daily cigarette consumption, nicotine dependence, and withdrawal were measured through week 24. Self-reported abstinence was validated by serum cotinine at week 12. We enrolled 36 subjects with a mean of 29 pack-years of smoking and a minimum of 4 cigarettes per day. All but 1 were male, 33 (92%) were white. The most frequently reported AEs were nausea (33%), abnormal dreams (31%), affect lability (19%), and insomnia (19%). Six (17%) subjects discontinued varenicline due to AEs. No grade 3/4 laboratory abnormalities or serious AEs occurred during the study. There was no significant change in HIV viral load. CD4 counts increased by 69 cells/mm3 (p=0.001) at week 24. Serum cotinine-verified 4-week continuous abstinence rate through weeks 9–12 was 42% (95% confidence interval [CI]: 26–58%). AEs and abstinence rates were comparable to those in published randomized controlled trials conducted in generally healthy HIV-negative smokers. Varenicline was safe and appears effective among HIV-infected smokers in this exploratory study, although AEs were common. The most common AE was nausea, with no adverse effect on HIV treatment outcome. Close monitoring of liver enzymes and blood pressure is recommended for HIV-positive smokers taking varenicline. PMID:22007690

Adjunctive memantine in clozapine-treated refractory schizophrenia: an open-label 1-year extension study.

PubMed

Veerman, S R T; Schulte, P F J; Deijen, J B; de Haan, L

2017-01-01

In a recent placebo-controlled, double-blind crossover trial (n = 52), significant beneficial effects on memory (d = 0.30) and negative symptoms (d = 0.29) were found after 12 weeks of memantine augmentation in patients with clozapine-refractory schizophrenia. In this open-label 1-year extension study we report the long-term effects and tolerability of memantine add-on therapy to clozapine. Completers of the first trial who experienced beneficial effects during 12 weeks of memantine treatment received memantine for 1 year. Primary endpoints were memory and executive function using the Cambridge Neuropsychological Test Automated Battery, the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impression Severity Scale (CGI-S). Of 31 randomized controlled trial completers who experienced beneficial effects from memantine, 24 received memantine for 1 year. The small improvement in memory found in the memantine condition in the placebo-controlled trial remained stable in the extension study. Executive function did not improve. After 26 weeks of memantine add-on therapy to clozapine, PANSS negative symptoms (r = 0.53), PANSS positive symptoms (r = 0.50) and PANSS total symptoms (r = 0.54) significantly improved. Even further significant improvement in all these measures was observed between 26 weeks and 52 weeks of memantine, with effect sizes varying from 0.39 to 0.51. CGI-S showed a non-significant moderate improvement at 26 weeks (r = 0.36) and 52 weeks (r = 0.34). Memantine was well tolerated without serious adverse effects. In the 1-year extension phase the favourable effect of adjunctive memantine on memory was sustained and we observed further improvement of negative, positive and overall symptoms in patients with clozapine-treated refractory schizophrenia.

Intravenous immunoglobulin for maintenance treatment of multifocal motor neuropathy: A multi-center, open-label, 52-week phase 3 trial.

PubMed

Kuwabara, Satoshi; Misawa, Sonoko; Mori, Masahiro; Iwai, Yuta; Ochi, Kazuhide; Suzuki, Hidekazu; Nodera, Hiroyuki; Tamaoka, Akira; Iijima, Masahiro; Toda, Tatsushi; Yoshikawa, Hiroo; Kanda, Takashi; Sakamoto, Ko; Kusunoki, Susumu; Sobue, Gen; Kaji, Ryuji

2018-06-01

Intravenous immunoglobulin (IVIg) therapy is currently the only established treatment in patients with multifocal motor neuropathy (MMN), and many patients have an IVIg-dependent fluctuation. We aimed to investigate the efficacy and safety of every 3 week IVIg (1.0 g/kg) for 52 weeks. This study was an open-label phase 3 clinical trial, enrolling 13 MMN patients. After an induction IVIg therapy (0.4 g/kg/d for 5 consecutive days), maintenance dose (1.0 g/kg) was given every 3 weeks for 52 weeks. The major outcome measures were the Medical Research Council (MRC) sum score and hand-grip strength at week 52. This trial is registered with ClinicalTrials.gov, number NCT01827072. At week 52, 11 of the 13 patients completed the study, and all 11 had a sustained improvement. The mean (SD) MRC sum score was 85.6 (8.7) at the baseline, and 90.6 (12.8) at week 52. The mean grip strength was 39.2 (30.0) kPa at the baseline and 45.2 (32.8) kPa at week 52. Two patients dropped out because of adverse event (dysphagia) and decision of an investigator, respectively. Three patients developed coronary spasm, dysphagia, or inguinal herniation, reported as the serious adverse events, but considered not related with the study drug. The other adverse effects were mild and resolved by the end of the study period. Our results show that maintenance treatment with 1.0 g/kg IVIg every 3 week is safe and efficacious for MMN patients up to 52 weeks. Further studies are required to investigate optimal dose and duration of maintenance IVIg for MMN. © 2018 The Authors. Journal of the Peripheral Nervous System published by Wiley Periodicals, Inc. on behalf of Peripheral Nerve Society.

A randomised, open-label, parallel group phase 2 study of antisense oligonucleotide therapy in acromegaly.

PubMed

Trainer, Peter J; Newell-Price, John; Ayuk, John; Aylwin, Simon; Rees, D Aled; Drake, Wm; Chanson, Philippe; Brue, Thierry; Webb, Susan M; Montañana, Carmen Fajardo; Aller, Javier; McCormack, Ann I; Torpy, David J; Tachas, George; Atley, Lynne; Ryder, David; Bidlingmaier, Martin

2018-05-22

ATL1103 is a second-generation antisense oligomer targeting the human GH receptor. This phase 2 randomised, open-label, parallel-group study assessed the potential of ATL1103 as a treatment for acromegaly. 26 patients with active acromegaly (IGF-I >130% upper limit of normal) were randomised to subcutaneous ATL1103 200 mg either once- or twice-weekly for 13 weeks, and monitored for a further 8-week washout period. The primary efficacy measures were change in IGF-I at week 14, compared to baseline and between cohorts. For secondary endpoints (IGFBP3, ALS, GH, GHBP), comparison was between baseline and week 14. Safety was assessed by reported adverse events. Baseline median IGF-I was 447 and 649 ng/mL in the once- and twice-weekly groups, respectivey. Compared to baseline, at week 14 twice-weekly ATL1103 resulted in a median fall in IGF-I of 27.8% (p=0.0002). Between cohort comparison at week 14 demonstrated the median fall in IGF-I to be 25.8% (p=0.0012) greater with twice-weekly dosing. In the twice-weekly cohort, IGF-I was still declining at week 14, and at week 21 remained lower than at baseline by a median of 18.7% (p=0.0005). Compared to baseline, by week 14 IGFBP3 and ALS had declined by a median of 8.9% (p=0.027) and 16.7% (p=0.017) with twice-weekly ATL1103; GH had increased by a median of 46% at week 14 (p=0.001). IGFBP3, ALS and GH did not change with weekly ATL1103. GHBP fell by a median of 23.6% and 48.8% in the once- and twice-weekly cohorts (p=0.027 and p=0.005), respectively. ATL1103 was well tolerated, although 84.6% of patients experienced mild to moderate injection-site reactions (ISR). This study provides proof-of-concept that ATL1103 is able to significantly lower IGF-I in patients with acromegaly.

Extended Treatment with Bupropion SR for Cigarette Smoking Cessation

ERIC Educational Resources Information Center

Killen, Joel D.; Fortmann, Stephen P.; Murphy, Greer M.; Hayward, Chris; Arredondo, Christina; Cromp, DeAnn; Celio, Maria; Abe, Laurie; Wang, Yun; Schatzberg, Alan F.

2006-01-01

The authors present results of a randomized clinical trial of the efficacy of extended treatment with bupropion SR in producing longer term cigarette smoking cessation. Adult smokers (N = 362) received open-label treatment (11 weeks) that combined relapse prevention training, bupropion SR, and nicotine patch followed by extended treatment (14…

Effectiveness, Safety, and Pharmacokinetics of Quetiapine in Aggressive Children with Conduct Disorder

ERIC Educational Resources Information Center

Findling, Robert L.; Reed, Michael D.; O'Riordan, Mary Ann; Demeter, Christine A.; Stansbrey, Robert J.; McNamara, Nora K.

2006-01-01

Objective: To provide an initial description of the effectiveness and pharmacokinetics (PK) of quetiapine in aggressive children with conduct disorder (CD). Method: This 8-week, open-label outpatient trial, enrolled patients ages 6 to 12 years with CD. Outcome measures included the Rating of Aggression Against People and/or Property Scale…

A multicenter, open-label trial to evaluate the quality of life in adults with ADHD treated with long-acting methylphenidate (OROS MPH): Concerta Quality of Life (CONQoL) study.

PubMed

Mattos, Paulo; Louzã, Mário Rodrigues; Palmini, André Luís Fernandes; de Oliveira, Irismar Reis; Rocha, Fábio Lopes

2013-07-01

The available literature provides few studies on the effectiveness of methylphenidate in improving quality of life in individuals with ADHD. To assess the effectiveness of methylphenidate OROS formulation (OROS MPH) through QoL in adults with ADHD. A 12-week, multicenter, open-label trial involving 60 patients was used. The measures used were Adult Self-Rating Scale, Adult ADHD Quality of Life Scale (AAQoL), State and Trait Anxiety Inventory (STAI), Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression (CGI), and safety measures. A significance statistic level of 5% was adopted. Analyses included 60 patients (66.7% male; M age = 31.1 years) for safety and 58 patients for effectiveness. All AAQoL subscales improved from baseline to Week 12 (p < .0001), as well as the Total AAQoL (p < .0001). A significant reduction on Clinical Global Impression-Improvement (CGI-I), HAM-D, STAI, and ASRS scores was observed (p < .0001). No serious adverse event was reported. Treatment of adult ADHD patients with OROS MPH improves QoL.

Concordance between actual and pharmacogenetic predicted desvenlafaxine dose needed to achieve remission in major depressive disorder: a 10-week open-label study

PubMed Central

Müller, Daniel J.; Ng, Chee H.; Byron, Keith; Berk, Michael; Singh, Ajeet B.

2017-01-01

Background Pharmacogenetic-based dosing support tools have been developed to personalize antidepressant-prescribing practice. However, the clinical validity of these tools has not been adequately tested, particularly for specific antidepressants. Objective To examine the concordance between the actual dose and a polygene pharmacogenetic predicted dose of desvenlafaxine needed to achieve symptom remission. Materials and methods A 10-week, open-label, prospective trial of desvenlafaxine among Caucasian adults with major depressive disorder (n=119) was conducted. Dose was clinically adjusted and at the completion of the trial, the clinical dose needed to achieve remission was compared with the predicted dose needed to achieve remission. Results Among remitters (n=95), there was a strong concordance (Kendall’s τ-b=0.84, P=0.0001; Cohen’s κ=0.82, P=0.0001) between the actual and the predicted dose need to achieve symptom remission, showing high sensitivity (≥85%), specificity (≥86%), and accuracy (≥89%) of the tool. Conclusion Findings provide initial evidence for the clinical validity of a polygene pharmacogenetic-based tool for desvenlafaxine dosing. PMID:27779571

Examining the effectiveness of an intensive, 2-week treatment program for military personnel and veterans with PTSD: Results of a pilot, open-label, prospective cohort trial.

PubMed

Bryan, Craig J; Leifker, Feea R; Rozek, David C; Bryan, AnnaBelle O; Reynolds, Mira L; Oakey, D Nicolas; Roberge, Erika

2018-06-19

This study aimed to examine the effectiveness of cognitive processing therapy (CPT) for posttraumatic stress disorder (PTSD) when administered on a daily basis during a 2-week period of time. In an open-label, prospective cohort pilot trial, 20 U.S. military personnel and veterans diagnosed with PTSD or subthreshold PTSD participated in 12 daily sessions of CPT. Primary outcomes included Clinician Administered PTSD Scale for DSM-5 and PTSD Checklist for DSM-5 scores. Secondary outcomes included Patient Health Questionnaire-8 and Beck Scale for Suicide Ideation (BSSI) scores. Interviews and self-report scales were completed at pretreatment, posttreatment, and 6 months after the treatment. Relative to baseline, PTSD symptom severity and rates of PTSD diagnosis were significantly reduced at posttreatment and 6-month follow-up. Depression symptom severity did not significantly improve, but suicide ideation significantly decreased at 6-month follow-up. Daily administration of CPT is associated with significant reductions in PTSD and suicide ideation. © 2018 Wiley Periodicals, Inc.

Concordance between actual and pharmacogenetic predicted desvenlafaxine dose needed to achieve remission in major depressive disorder: a 10-week open-label study.

PubMed

Bousman, Chad A; Müller, Daniel J; Ng, Chee H; Byron, Keith; Berk, Michael; Singh, Ajeet B

2017-01-01

Pharmacogenetic-based dosing support tools have been developed to personalize antidepressant-prescribing practice. However, the clinical validity of these tools has not been adequately tested, particularly for specific antidepressants. To examine the concordance between the actual dose and a polygene pharmacogenetic predicted dose of desvenlafaxine needed to achieve symptom remission. A 10-week, open-label, prospective trial of desvenlafaxine among Caucasian adults with major depressive disorder (n=119) was conducted. Dose was clinically adjusted and at the completion of the trial, the clinical dose needed to achieve remission was compared with the predicted dose needed to achieve remission. Among remitters (n=95), there was a strong concordance (Kendall's τ-b=0.84, P=0.0001; Cohen's κ=0.82, P=0.0001) between the actual and the predicted dose need to achieve symptom remission, showing high sensitivity (≥85%), specificity (≥86%), and accuracy (≥89%) of the tool. Findings provide initial evidence for the clinical validity of a polygene pharmacogenetic-based tool for desvenlafaxine dosing.

Acetyl-L-Carnitine Augmentation of Clozapine in Partial-Responder Schizophrenia: A 12-Week, Open-Label Uncontrolled Preliminary Study.

PubMed

Bruno, Antonio; Pandolfo, Gianluca; Crucitti, Manuela; Lorusso, Simona; Zoccali, Rocco Antonio; Muscatello, Maria Rosaria Anna

This was the first 12-week, open-label, uncontrolled trial aimed at exploring the efficacy of acetyl-L-carnitine (ALC) add-on pharmacotherapy on clinical symptoms and cognitive functioning in 15 schizophrenia patients with suboptimal clinical response despite receiving clozapine (CLZ) monotherapy at the highest tolerated dosage. After clinical (Positive and Negative Symptoms Scale [PANSS]) and neuropsychological (Wisconsin Card Sorting Test, Stroop Color-Word Test, Verbal Fluency Test) assessments, patients received 1 g/d of ALC for 12 weeks. A final sample of 9 subjects completed the study. Acetyl-L-carnitine augmentation of CLZ significantly reduced only PANSS domains "positive" (P = 0.049); at end point, only 2 subjects (22.2% of the completers) reached a minimal improvement (25% reduction in PANSS total score). No significant differences emerged in cognitive performances at the end of the study; effect sizes were small in each explored cognitive dimension. The findings provide preliminary evidence that ALC added to ongoing CLZ treatment appeared to be ineffective to improve symptoms in schizophrenia patients who have failed to respond sufficiently to CLZ. Further trials with adequately powered methodology are needed to identify which augmentation strategies are more effective in schizophrenia patients showing a suboptimal response to CLZ.

Open-label pilot study of memantine in the treatment of compulsive buying.

PubMed

Grant, Jon E; Odlaug, Brian L; Mooney, Marc; O'Brien, Robert; Kim, Suck Won

2012-05-01

Although compulsive buying (CB) is relatively common, pharmacotherapy research for CB is limited. Memantine, an N-methyl-D-aspartate receptor antagonist, appears to reduce glutamate excitability and improve impulsive behaviors, suggesting it may help individuals with CB. Nine patients (8 females) with CB were enrolled in a 10-week open-label treatment study of memantine (dose ranging from 10 to 30 mg/d). Participants were enrolled from December 2008 until May 2010. The primary outcome measure was change from baseline to study endpoint on the Yale-Brown Obsessive Compulsive Scale-Shopping Version (Y-BOCS-SV). Of the 9 participants, 8 (88.9%) completed the 10-week study. Y-BOCS-SV scores decreased from a mean of 22.0 ± 1.3 at baseline to 11.0 ± 5.3 at endpoint (P < .001). Hours spent shopping per week and money spent shopping both decreased significantly (P < .001). The mean effective dose of memantine was 23.4 ± 8.1 mg/d. Memantine treatment was associated with diminished impulsive buying and improvements on cognitive tasks of impulsivity. In addition, the medication was well-tolerated. These findings suggest that pharmacologic manipulation of the glutamate system may target the impulsive behavior underlying CB. Placebo-controlled, double-blind studies are warranted in order to confirm these preliminary findings in a controlled design.

Long-term efficacy and safety of lamotrigine monotherapy in Japanese and South Korean pediatric patients with newly diagnosed typical absence seizures: An open-label extension study.

PubMed

Yasumoto, Sawa; Ohtsuka, Yoko; Sato, Katsuaki; Kurata, Atsuyo; Numachi, Yotaro; Shimizu, Masahiro

2018-05-31

To investigate the efficacy and safety of long-term lamotrigine (LTG) monotherapy in Japanese and South Korean pediatric patients with newly diagnosed typical absence seizures. Six Japanese patients and one South Korean patient were enrolled in the extension phase of the study after completing the 12-week maintenance phase of an open-label clinical study of LTG monotherapy. During the extension phase, patients underwent efficacy and safety evaluation every 12 weeks. Of the seven patients, six patients completed the extension phase. The seizure-free rate confirmed by hyperventilation (HV)-electroencephalography ranged from 71.4% to 100.0% at each visit up to Week 168 of the extension phase. Similar effects were confirmed by HV-clinical signs and seizure diaries. Although no unexpected adverse events were observed, one Japanese patient was withdrawn from the extension phase due to mild drug-related rash developed 842 days after the start of LTG. Although the number of patients is limited, long-term LTG monotherapy appeared to be effective and generally well tolerated in Japanese and South Korean pediatric patients with typical absence seizures. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Effect of thalidomide on clinical remission in children and adolescents with refractory Crohn disease: a randomized clinical trial.

PubMed

Lazzerini, Marzia; Martelossi, Stefano; Magazzù, Giuseppe; Pellegrino, Salvatore; Lucanto, Maria Cristina; Barabino, Arrigo; Calvi, Angela; Arrigo, Serena; Lionetti, Paolo; Lorusso, Monica; Mangiantini, Francesca; Fontana, Massimo; Zuin, Giovanna; Palla, Gabriella; Maggiore, Giuseppe; Bramuzzo, Matteo; Pellegrin, Maria Chiara; Maschio, Massimo; Villanacci, Vincenzo; Manenti, Stefania; Decorti, Giuliana; De Iudicibus, Sara; Paparazzo, Rossella; Montico, Marcella; Ventura, Alessandro

2013-11-27

Pediatric-onset Crohn disease is more aggressive than adult-onset disease, has high rates of resistance to existing drugs, and can lead to permanent impairments. Few trials have evaluated new drugs for refractory Crohn disease in children. To determine whether thalidomide is effective in inducing remission in refractory pediatric Crohn disease. Multicenter, double-blind, placebo-controlled, randomized clinical trial of 56 children with active Crohn disease despite immunosuppressive treatment, conducted August 2008-September 2012 in 6 pediatric tertiary care centers in Italy. Thalidomide, 1.5 to 2.5 mg/kg per day, or placebo once daily for 8 weeks. In an open-label extension, nonresponders to placebo received thalidomide for an additional 8 weeks. All responders continued to receive thalidomide for an additional minimum 52 weeks. Primary outcomes were clinical remission at week 8, measured by Pediatric Crohn Disease Activity Index (PCDAI) score and reduction in PCDAI by ≥25% or ≥75% at weeks 4 and 8. Primary outcomes during the open-label follow-up were clinical remission and 75% response. Twenty-eight children were randomized to thalidomide and 26 to placebo. Clinical remission was achieved by significantly more children treated with thalidomide (13/28 [46.4%] vs 3/26 [11.5%]; risk ratio [RR], 4.0 [95% CI, 1.2-12.5]; P = .01; number needed to treat [NNT], 2.86). Responses were not different at 4 weeks, but greater improvement was observed at 8 weeks in the thalidomide group (75% response, 13/28 [46.4%] vs 3/26 [11.5%]; RR, 4.0 [95% CI, 1.2-12.5]; NNT = 2.86; P = .01; and 25% response, 18/28 [64.2%] vs 8/26 [30.8%]; RR, 2.1 [95% CI, 1.1-3.9]; NNT = 2.99; P = .01). Of the nonresponders to placebo who began receiving thalidomide, 11 of 21 (52.4%) subsequently reached remission at week 8 (RR, 4.5 [95% CI, 1.4-14.1]; NNT = 2.45; P = .01). Overall, 31 of 49 children treated with thalidomide (63.3%) achieved clinical remission, and 32 of 49 (65.3%) achieved 75% response. Mean duration of clinical remission in the thalidomide group was 181.1 weeks (95% CI, 144.53-217.76) vs 6.3 weeks (95% CI, 3.51-9.15) in the placebo group (P < .001). Cumulative incidence of severe adverse events was 2.1 per 1000 patient-weeks, with peripheral neuropathy the most frequent severe adverse event. In children and adolescents with refractory Crohn disease, thalidomide compared with placebo resulted in improved clinical remission at 8 weeks of treatment and longer-term maintenance of remission in an open-label follow-up. These findings require replication to definitively determine clinical utility of this treatment. clinicaltrials.gov Identifier: NCT00720538.

Coformulated bictegravir, Emtricitabine (F), tenofovir alafenamide (TAF) after initial treatment with bictegravir or dolutegravir plus F/TAF.

PubMed

Sax, Paul E; Dejesus, Edwin; Crofoot, Gordon; Ward, Douglas; Benson, Paul; Dretler, Robin; Mills, Anthony; Brinson, Cynthia; Wei, Xuelian; Collins, Sean E; Cheng, Andrew

2018-05-22

: A phase 2, randomized, active-controlled study of initial antiretroviral therapy with bictegravir or dolutegravir in combination with emtricitabine and tenofovir alafenamide showed excellent efficacy. After 60 weeks of blinded treatment, participants switched to a single tablet regimen of bictegravir, emtricitabine and tenofovir alafenamide. Switching maintained viral suppression in all participants who chose to remain on the study through at least 12 weeks in the open-label phase, was safe and well tolerated.

Adjunctive low-dose docosahexaenoic acid (DHA) for major depression: An open-label pilot trial.

PubMed

Smith, Deidre J; Sarris, Jerome; Dowling, Nathan; O'Connor, Manjula; Ng, Chee H

2018-04-01

Whilst the majority of evidence supports the adjunctive use of eicosapentaenoic acid (EPA) in improving mood, to date no study exists using low-dose docosahexaenoic acid (DHA) alone as an adjunctive treatment in patients with mild to moderate major depressive disorder (MDD). A naturalistic 8-week open-label pilot trial of low-dose DHA, (260 mg or 520 mg/day) in 28 patients with MDD who were non-responsive to medication or psychotherapy, with a Hamilton Depression Rating Scale (HAM-D) score of greater than 17, was conducted. Primary outcomes of depression, clinical severity, and daytime sleepiness were measured. After 8 weeks, 54% of patients had a ≥50% reduction on the HAM-D, and 45% were in remission (HAM-D ≤ 7). The eta-squared statistic (0.59) indicated a large effect size for the reduction of depression (equivalent to Cohen's d of 2.4). However confidence in this effect size is tempered due to the lack of a placebo. The mean score for the Clinical Global Impression Severity Scale was significantly improved by 1.28 points (P < 0.05). Despite a significant reduction in the HAM-D score for middle insomnia (P = 0.02), the reduction in excessive daytime somnolence on the total Epworth Sleepiness Scale (ESS) did not reach significance. No significant adverse reactions to DHA were found. Within the major limits of this open-label pilot study, the results suggest that DHA may provide additional adjunctive benefits in patients with mild- to -moderate depression.

The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial.

PubMed

Berk, Michael; Dean, Olivia; Cotton, Sue M; Gama, Clarissa S; Kapczinski, Flavio; Fernandes, Brisa S; Kohlmann, Kristy; Jeavons, Susan; Hewitt, Karen; Allwang, Christine; Cobb, Heidi; Bush, Ashley I; Schapkaitz, Ian; Dodd, Seetal; Malhi, Gin S

2011-12-01

Evidence is accumulating to support the presence of redox dysregulation in a number of psychiatric disorders, including bipolar disorder. This dysregulation may be amenable to therapeutic intervention. Glutathione is the predominant non-enzymatic intracellular free radical scavenger in the brain, and the most generic of all endogenous antioxidants in terms of action. N-acetylcysteine (NAC) is a glutathione precursor that effectively replenishes brain glutathione. Given the failure of almost all modern trials of antidepressants in bipolar disorder to demonstrate efficacy, and the limited efficacy of mood stabilisers in the depressive phase of the disorder, this is a major unmet need. This study reports data on the treatment of 149 individuals with moderate depression during the 2 month open label phase of a randomised placebo controlled clinical trial of the efficacy of 1g BID of NAC that examined the use of NAC as a maintenance treatment for bipolar disorder. In this trial, the estimated mean baseline Bipolar Depression Rating Scale (BDRS) score was 19.7 (SE=0.8), and the mean BDRS score at the end of the 8 week open label treatment phase was 11.1 (SE=0.8). This reduction was statistically significant (p<0.001). Improvements in functioning and quality of life were similarly evident. These open label data demonstrate a robust decrement in depression scores with NAC treatment. Large placebo controlled trials of acute bipolar depression are warranted. Copyright © 2011 Elsevier B.V. All rights reserved.

Escitalopram treatment of pathological gambling with co-occurring anxiety: an open-label pilot study with double-blind discontinuation.

PubMed

Grant, Jon E; Potenza, Marc N

2006-07-01

Although co-occurring disorders are common in pathological gambling (PG), investigations of the response to pharmacotherapy in individuals with PG and co-occurring psychiatric symptomatology are limited. Thirteen subjects with DSM-IV PG and co-occurring anxiety were treated in a 12-week open-label trial of escitalopram. Subjects were assessed with the Yale-Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS; primary outcome measure), the Hamilton Anxiety Rating Scale (HAM-A), the Clinical Global Impressions scale (CGI), and measures of psychosocial functioning and quality of life. Those subjects who 'responded' (defined as a 30% or greater reduction in PG-YBOCS total score at endpoint) were offered inclusion in an 8-week double-blind discontinuation phase. PG-YBOCS scores decreased from a mean of 22.2+/-4.5 at baseline to 11.9+/-10.7 at endpoint (P=0.002) and 61.5% were responders. Scores on the HAM-A decreased by 82.8% over the 12-week period (mean of 15.9+/-3.2 at baseline to a mean of 2.8+/-3.6 at endpoint) (P<0.001). On the CGI, 38.5% of subjects (n=5) were 'very much improved' and 23.1% (n=3) were 'much improved' by study endpoint. The Sheehan Disability Scale, Perceive Stress Scale and Quality of Life Inventory all showed improvement (P< or = 0.001, P=0.002 and P=0.029, respectively). The mean end-of-study dose of escitalopram was 25.4+/-6.6 mg/day. Of three subjects assigned to escitalopram during the discontinuation phase, none reported statistically significant worsening of gambling symptoms. However, one subject assigned to placebo reported that gambling symptoms returned within 4 weeks. Open-label escitalopram treatment was associated with improvements in gambling and anxiety symptoms and measures of psychosocial functioning and quality of life. Larger, longer, placebo-controlled, double-blind studies are needed to evaluate further the safety and tolerability of escitalopram in the treatment of PG and co-occurring anxiety.

Adjunctive lacosamide for focal epilepsy: an open-label trial evaluating the impact of flexible titration and dosing on safety and seizure outcomes.

PubMed

Baulac, Michel; Coulbaut, Safia; Doty, Pamela; McShea, Cindy; De Backer, Marc; Bartolomei, Fabrice; Vlaicu, Mihaela

2017-06-01

To evaluate the safety and effectiveness of lacosamide in a real-life setting with the use of a flexible dose titration schedule and individualised maintenance doses up to the maximum approved dose of 400 mg/day. Adults with a diagnosis of focal seizures, with or without secondary generalization, were enrolled in this open-label Phase IV trial (NCT01235403). Lacosamide was initiated at 100 mg/day (50 mg bid) and uptitrated over a 12-week period to 200, 300 or 400 mg/day, based on safety and seizure control. Although dose increases were to be in increments of 100 mg/day, intermediate doses were permitted at each escalation step for one week for patients known to be particularly sensitive to starting new AEDs. After receiving a stable, effective dose for three weeks, patients entered the 12-week maintenance period. Primary outcomes were incidence of treatment-emergent adverse events (TEAEs) and withdrawal due to TEAEs. Seizure outcomes, all secondary, were median focal seizure frequency, ≥50% reduction in focal seizure frequency, and seizure freedom. One hundred patients with a mean age of 44 years were enrolled and 74 completed the trial. The incidence of TEAEs was 64.0% (n=100), with the most frequently reported (≥5% of patients) being dizziness, headache, and asthenia. Fourteen patients withdrew due to TEAEs, most frequently due to dizziness (six patients; 6.0%), vomiting (two patients; 2%), and tremor (two patients; 2%). Among patients with baseline and maintenance phase seizure data (n=75), median reduction in focal seizure frequency from baseline was 69.7% and the ≥50% responder rate was 69.3%. Among 74 patients who completed the maintenance phase, 21 (28.4%) were seizure-free. Flexible lacosamide dosing in this open-label trial was associated with a favourable tolerability and safety profile; the nature of the TEAEs was consistent with that observed in previous pivotal trials. Treatment with lacosamide was also associated with effective seizure control.

The Effect of Reduced or Withdrawn Etanercept-methotrexate Therapy on Patient-reported Outcomes in Patients with Early Rheumatoid Arthritis.

PubMed

Wiland, Piotr; Dudler, Jean; Veale, Douglas; Tahir, Hasan; Pedersen, Ron; Bukowski, Jack; Vlahos, Bonnie; Williams, Theresa; Gaylord, Stefanie; Kotak, Sameer

2016-07-01

An analysis of a clinical trial to assess the effects of treatment reduction and withdrawal on patient-reported outcomes (PRO) in patients with early, moderate to severe rheumatoid arthritis (RA) who achieved 28-joint Disease Activity Score (DAS28) low disease activity (LDA) or remission with etanercept (ETN) plus methotrexate (MTX) therapy. During treatment induction, patients received open-label ETN 50 mg weekly plus MTX for 52 weeks. In the reduced-treatment phase, patients with DAS28-erythrocyte sedimentation rate (ESR) ≤ 3.2 at Week 39 and DAS28-ESR < 2.6 at Week 52 in the open-label phase were randomized to double-blind treatment with ETN 25 mg plus MTX, MTX, or placebo (PBO) for 39 weeks (weeks 0-39). In the third phase, patients who achieved DAS28 remission (DAS28-ESR < 2.6) or LDA (2.6 ≤ DAS28-ESR ≤ 3.2) at Week 39 in the double-blind phase had all treatment withdrawn and were observed for an additional 26 weeks (weeks 39-65). Of the 306 patients enrolled, 193 were randomized in the double-blind phase and 131 participated in the treatment-withdrawal phase. After reduction or withdrawal of ETN 50 mg/MTX, patients reduced to ETN 25 mg/MTX experienced slight, nonsignificant declines in the majority of PRO measures, whereas switching to PBO or MTX alone caused significant declines. Presenteeism and activity impairment scores were significantly better in the ETN reduced-dose group versus MTX monotherapy and PBO at Week 39 (p ≤ 0.05). In patients with early RA who achieved remission while receiving full-dose ETN/MTX, continuing combination therapy at a lower dose did not cause a significant worsening of PRO response, but switching to MTX alone or PBO did. ClinicalTrials.gov identifier: NCT00913458.

Safety, tolerability and efficacy of lixisenatide as monotherapy in Japanese patients with type 2 diabetes mellitus: An open-label, multicenter study.

PubMed

Seino, Yutaka; Terauchi, Yasuo; Wang, Xiangling; Watanabe, Daisuke; Niemoeller, Elisabeth

2018-01-01

To assess the overall safety of lixisenatide monotherapy in Japanese patients with type 2 diabetes mellitus. Patients with type 2 diabetes mellitus, previously treated with ≤1 oral antidiabetic drug, were enrolled in an uncontrolled, open-label, single-arm study over 24 and 52 weeks. Any oral antidiabetic drug treatment was stopped at the start of the 6-week run-in period. From baseline, patients received once-daily lixisenatide monotherapy (10 μg for 1 week, 15 μg for 1 week, 20 μg thereafter) for 52 weeks (first 140 patients enrolled) or 24 weeks (subsequently enrolled patients). The primary end-point was safety over 24 and 52 weeks. Secondary efficacy end-points included absolute change in glycated hemoglobin, fasting plasma glucose and bodyweight from baseline. Of 428 patients screened, 361 and 140 were treated for 24 and 52 weeks, respectively; 88.4 and 90.0% completed treatment. During the 24- and 52-week treatment periods, 268/361 (74.2%) and 117/140 (83.6%) patients, respectively, had treatment-emergent adverse events; the most frequently reported was nausea (33.2 and 31.4%, respectively). The risk of severe hypoglycemia was low; only one case was reported. Lixisenatide treatment resulted in a decrease in mean glycated hemoglobin A1c (-0.98 and -0.86%), fasting plasma glucose (-1.05 and -0.85 mmol/L), and bodyweight (-1.33 and -1.48 kg) for the 24- and 52-week treatment periods, respectively. Once-daily lixisenatide monotherapy was associated with a safety profile in line with the glucagon-like peptide-1 receptor agonist class, and improved glycemic control in Japanese patients with type 2 diabetes mellitus. © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Efficacy and safety of ixekizumab treatment for Japanese patients with moderate to severe plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis: Results from a 52-week, open-label, phase 3 study (UNCOVER-J).

PubMed

Saeki, Hidehisa; Nakagawa, Hidemi; Nakajo, Ko; Ishii, Taeko; Morisaki, Yoji; Aoki, Takehiro; Cameron, Gregory S; Osuntokun, Olawale O

2017-04-01

Psoriasis, a chronic, immune-mediated skin disease characterized by red, scaly plaques, affects approximately 0.3% of the population in Japan. The aim of this open-label study was to evaluate the long-term efficacy and safety of ixekizumab, a humanized, anti-interleukin-17A monoclonal antibody, in Japanese patients with plaque psoriasis (n = 78, including 11 psoriatic arthritis), erythrodermic psoriasis (n = 8) and generalized pustular psoriasis (n = 5). Ixekizumab was administrated s.c. at baseline (week 0, 160 mg), from weeks 2 to 12 (80 mg every 2 weeks), and from weeks 16 to 52 (80 mg every 4 weeks). At week 52, 92.3% of patients with plaque psoriasis achieved Psoriasis Area and Severity Index (PASI) 75, 80.8% achieved PASI 90, 48.7% achieved PASI 100, and 52.6% had remission of plaques (by static Physician Global Assessment, sPGA [0]). Difficult to treat areas of psoriasis (nail or scalp) also responded to ixekizumab. All patients with psoriatic arthritis who were assessed (5/5) achieved an American College of Rheumatology 20 response. Most patients with erythrodermic psoriasis or generalized pustular psoriasis responded to ixekizumab and the clinical outcome was maintained over 52 weeks (75% and 60% of patients achieved sPGA [0, 1] at week 52, respectively). Mostly mild or moderate treatment-emergent adverse events were reported by 79 of 91 patients; the most common were nasopharyngitis, eczema, seborrheic dermatitis, urticaria and injection site reactions. In conclusion, 52-week ixekizumab treatment was efficacious and well tolerated in Japanese patients with plaque psoriasis. Efficacy was also observed in patients with erythrodermic psoriasis, generalized pustular psoriasis and psoriatic arthritis. © 2016 Eli Lilly Japan K.K. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.

Ferric maltol therapy for iron deficiency anaemia in patients with inflammatory bowel disease: long-term extension data from a Phase 3 study.

PubMed

Schmidt, C; Ahmad, T; Tulassay, Z; Baumgart, D C; Bokemeyer, B; Howaldt, S; Stallmach, A; Büning, C

2016-08-01

Ferric maltol was effective and well-tolerated in iron deficiency anaemia patients with inflammatory bowel disease during a 12-week placebo-controlled trial. To perform a Phase 3 extension study evaluating long-term efficacy and safety with ferric maltol in inflammatory bowel disease patients in whom oral ferrous therapies had failed to correct iron deficiency anaemia. After 12 weeks of randomised, double-blind treatment, patients with iron deficiency anaemia and mild-to-moderate ulcerative colitis or Crohn's disease received open-label ferric maltol 30 mg b.d. for 52 weeks. 111 patients completed randomised treatment and 97 entered the open-label ferric maltol extension. In patients randomised to ferric maltol ('continued'; n = 50), mean ± s.d. haemoglobin increased by 3.07 ± 1.46 g/dL between baseline and Week 64. In patients randomised to placebo ('switch'; n = 47), haemoglobin increased by 2.19 ± 1.61 g/dL. Normal haemoglobin was achieved in high proportions of both continued and switch patients (89% and 83% at Week 64, respectively). Serum ferritin increased from 8.9 μg/L (baseline) to 26.0 μg/L (Week 12) in ferric maltol-treated patients, and to 57.4 μg/L amongst all patients at Week 64. In total, 80% of patients reported ≥1 adverse event by Week 64. Adverse events considered related to ferric maltol were recorded in 27/111 (24%) patients: 8/18 discontinuations due to adverse events were treatment-related. One patient was withdrawn due to increased ulcerative colitis activity. Normal haemoglobin was observed in ≥80% of patients from weeks 20-64 of long-term ferric maltol treatment, with concomitant increases in iron storage parameters. Ferric maltol was well-tolerated throughout this 64-week study. © 2016 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Short-term open-label chamomile (Matricaria chamomilla L.) therapy of moderate to severe generalized anxiety disorder.

PubMed

Keefe, John R; Mao, Jun J; Soeller, Irene; Li, Qing S; Amsterdam, Jay D

2016-12-15

Conventional drug treatments for Generalized Anxiety Disorder (GAD) are often accompanied by substantial side effects, dependence, and/or withdrawal syndrome. A prior controlled study of oral chamomile (Matricaria chamomilla L.) extract showed significant efficacy versus placebo, and suggested that chamomile may have anxiolytic activity for individuals with GAD. We hypothesized that treatment with chamomile extract would result in a significant reduction in GAD severity ratings, and would be associated with a favorable adverse event and tolerability profile. We report on the open-label phase of a two-phase randomized controlled trial of chamomile versus placebo for relapse-prevention of recurrent GAD. Subjects with moderate to severe GAD received open-label treatment with pharmaceutical-grade chamomile extract 1500mg/day for up to 8 weeks. Primary outcomes were the frequency of clinical response and change in GAD-7 symptom scores by week 8. Secondary outcomes included the change over time on the Hamilton Rating Scale for Anxiety, the Beck Anxiety Inventory, and the Psychological General Well Being Index. Frequency of treatment-emergent adverse events and premature treatment discontinuation were also examined. Of 179 subjects, 58.1% (95% CI: 50.9% to 65.5%) met criteria for response, while 15.6% prematurely discontinued treatment. Significant improvement over time was also observed on the GAD-7 rating (β=-8.4 [95% CI=-9.1 to -7.7]). A similar proportion of subjects demonstrated statistically significant and clinically meaningful reductions in secondary outcome ratings of anxiety and well-being. Adverse events occurred in 11.7% of subjects, although no serious adverse events occurred. Chamomile extract produced a clinically meaningful reduction in GAD symptoms over 8 weeks, with a response rate comparable to those observed during conventional anxiolytic drug therapy and a favorable adverse event profile. Future comparative effectiveness trials between chamomile and conventional drugs may help determine the optimal risk/benefit of these therapies for patients suffering from GAD. Copyright © 2016 Elsevier GmbH. All rights reserved.

The effect of ziprasidone on metabolic syndrome risk factors in subjects with schizophrenia: a 1 year, open-label, prospective study.

PubMed

Chue, Pierre; Mandel, Francine S; Therrien, François

2014-06-01

Metabolic syndrome (MetS) is prevalent in subjects with schizophrenia-related psychotic disorders and contributes to increased rates of premature death due to cardiovascular disease. This study examined the impact of switching from another antipsychotic to ziprasidone on the distribution of the number of risk factors for MetS in subjects with schizophrenia or related psychotic disorders. In this 1 year, open-label, prospective study, all subjects received ziprasidone 40-160 mg/day. Standard exclusion criteria included treatment resistance, physical health disorders, and substance abuse. The primary end point was the percentage of subjects achieving a reduction from baseline of at least one risk factor for MetS at end point (week 52 or premature discontinuation) in the per-protocol population (treated for at least 16 weeks). Secondary end points included the mean change from baseline in number of MetS risk factors, the prevalence of MetS, individual MetS risk factors (waist circumference, blood pressure, fasting triglycerides, high-density lipoprotein cholesterol, and glucose), and 10 year coronary heart disease (Framingham score) risk. www.clinicaltrials.gov: NCT00748566. Of 114 evaluable subjects, 58.77% demonstrated one less MetS risk factor at week 52 (last observation carried forward) compared with baseline. Secondary end points also improved, with reductions in other metabolic parameters (fasting low-density lipoprotein cholesterol, total cholesterol and serum insulin, weight, body mass index and glycosylated hemoglobin [HbA1c]). The 10 year coronary heart disease risk decreased continually over time. The open-label and uncontrolled design is a limitation of the study. Ziprasidone treatment reduced both the rate of MetS and its individual risk factors in subjects with schizophrenia and related psychotic disorders. The results have implications for the selection of first-line treatments in schizophrenia and related psychotic disorders, and provide treatment options for subjects who have developed MetS as a result of other antipsychotics.

Agomelatine: AGO 178, AGO178, S 20098.

PubMed

2008-01-01

Novartis and Servier are developing agomelatine for the treatment of depression. Agomelatine is a specific melatonin (MT1 and MT2) receptor agonist that also has antagonistic activities at serotonin-(2C) (5-HT(2C)) receptors. Novartis believes agomelatine is comparable to current standard therapies for depression with improved tolerability, including a low propensity to cause sexual dysfunction and weight gain. Clinical development is being conducted in the US for the treatment of depression; approval for this indication was declined in the EU, apparently due to insufficient data. Servier has also conducted a trial of the agent in patients with generalized anxiety disorder in France, South Africa and Finland, and a phase II trial in sleep disorders in France. In March 2006, Servier and Novartis signed a licensing agreement for agomelatine. Novartis obtained the exclusive rights for the development and marketing of agomelatine in the US and several other countries. Servier retained the rights to the product in the rest of the world. The clinical development plan for agomelatine includes phase III trials being conducted under the parAGOn clinical trial programme. One US-based trial that began in March 2007 (NCT00463242) is recruiting 490 patients with depression who will receive placebo or agomelatine 25 or 50 mg for 8 weeks and will then receive open-label agomelatine for 52 weeks. Novartis is also conducting an 8-week phase III trial (NCT00411099) comparing the safety and efficacy of agomelatine 25 and 50 mg in patients with major depressive disorder. A follow-up, 52-week open-label extension study (CAGO178A2301E) will also be conducted. Another phase III study underway is NCT00411242, which has the same design and is also followed by a 52-week open-label extension study (CAGO178A2302E). These studies are all expected to be completed by January 2009. In July 2006, the Committee for Medicinal Products for Human Use recommended the refusal of marketing authorisation for agomelatine for the treatment of depression. Servier had applied for a re-examination of the finding but withdrew the request in November 2006. Servier's MAA was not supported due to insufficient data and no recent development has been reported in this indication in the EU. Agomelatine prevented relapse in patients with depression compared with placebo and was well tolerated in an international phase III trial.

Effectiveness of barnidipine 10 or 20 mg plus losartan 50-mg combination versus losartan 100-mg monotherapy in patients with essential hypertension not controlled by losartan 50-mg monotherapy: A 12-week, multicenter, randomized, open-label, parallel-group study.

PubMed

Parati, Gianfranco; Giglio, Alessia; Lonati, Laura; Destro, Maurizio; Ricci, Alessandra Rossi; Cagnoni, Francesca; Pini, Claudio; Venco, Achille; Maresca, Andrea Maria; Monza, Michela; Grandi, Anna Maria; Omboni, Stefano

2010-07-01

Increasing the dose or adding a second antihypertensive agent are 2 possible therapeutic choices when blood pressure (BP) is poorly controlled with monotherapy. This study investigated the effectiveness and tolerability of barnidipine 10 or 20 mg added to losartan 50 mg versus losartan 100 mg alone in patients with mild to moderate essential hypertension whose BP was uncontrolled by losartan 50-mg monotherapy. This was a 12-week, multicenter, randomized, open-label, parallel-group study. Eligible patients (aged 30-74 years) had uncontrolled hypertension, defined as office sitting diastolic BP (DBP) > or =90 mm Hg and/or systolic BP (SBP) > or =140 mm Hg, and mean daytime DBP > or =85 mm Hg and/or SBP > or =135 mm Hg. All were being treated with losartan 50 mg at enrollment. After a 1-week run-in period while taking losartan 50 mg, patients were randomly assigned to 6 weeks of treatment with open-label barnidipine 10 mg plus losartan 50 mg or losartan 100-mg monotherapy. At the end of this period, patients with uncontrolled BP had barnidipine doubled to 20 mg and continued for an additional 6 weeks, whereas patients not achieving control on treatment with losartan 100 mg were discontinued. Office BP was measured at each visit, whereas 24-hour ambulatory BP monitoring (ABPM) was performed at randomization and at the final visit (ie, after 12 weeks of treatment, or at 6 weeks for patients not controlled on losartan 100 mg). The intent-to-treat population included all randomized patients who received at least one dose of study treatment and had valid ABPM recordings at baseline and the final visit. The primary end point was the change in daytime DBP between baseline and 12 weeks of treatment, compared between the combination treatment and monotherapy. Adverse events (AEs) were evaluated during each study visit. A total of 93 patients were enrolled (age range, 30-75 years; 60% [56/93] men). After the 1-week run-in period, 68 patients were randomly assigned to 6 weeks of treatment with open-label barnidipine 10 mg plus losartan 50 mg (n = 34) or losartan 100-mg monotherapy (n = 34). A total of 53 patients were evaluable (barnidipine plus losartan, n = 28; losartan, n = 25). After 6 weeks of treatment, 18 patients in the combination treatment group (64.3%) had their dose of barnidipine doubled from 10 to 20 mg because BP was not normalized by treatment, whereas 8 patients in the losartan group (32.0%) were discontinued for the same reason. The between-treatment difference (losartan alone - combination treatment) for changes from baseline in daytime DBP was -1.7 mm Hg (95% CI, -5.8 to 2.4 mm Hg; P = NS). A similar result was observed for daytime SBP (-3.2 mm Hg; 95% CI, -8.1 to 1.7 mm Hg; P = NS). Likewise, no significant differences were found for nighttime values (mean [95% CI] DBP, 0.5 mm Hg [-3.7 to 4.7 mm Hg]; SBP, 1.5 mm Hg [-4.1 to 7.1 mm Hg]) or 24-hour values (DBP, -0.9 mm Hg [-4.8 to 2.9 mm Hg]; SBP, -1.6 mm Hg [-5.9 to 2.7 mm Hg]). Combination treatment was associated with a significantly higher rate of SBP responder patients (ie, <140 mm Hg or a reduction of > or =20 mm Hg) compared with monotherapy (82.1% [23/28] vs 56.0% [14/25]; P = 0.044). Drug-related AEs were reported in 4 patients taking combination treatment (total of 7 AEs, including 2 cases of peripheral edema and 1 each of tachycardia, atrial flutter, tinnitus, confusion, and polyuria) and in 2 patients taking losartan alone (total of 2 AEs, both tachycardia). This open-label, parallel-group study found that there was no significant difference in the BP-lowering effect of barnidipine 10 or 20 mg in combination with losartan 50 mg compared with losartan 100-mg monotherapy in these patients with essential hypertension previously uncontrolled by losartan 50-mg monotherapy. However, the percentage of responders for SBP was significantly higher with the combination. Both treatments were generally well tolerated. European Union Drug Regulating Authorities Clinical Trials (EudraCT) no. 2006-001469-41. 2010 Excerpta Medica Inc. All rights reserved.

Sustainable Efficacy of Switching From Intravenous to Subcutaneous Tocilizumab Monotherapy in Patients With Rheumatoid Arthritis.

PubMed

Ogata, Atsushi; Atsumi, Tatsuya; Fukuda, Takaaki; Hirabayashi, Yasuhiko; Inaba, Masaaki; Ishiguro, Naoki; Kai, Motokazu; Kawabata, Daisuke; Kida, Daihei; Kohsaka, Hitoshi; Matsumura, Ryutaro; Minota, Seiji; Mukai, Masaya; Sumida, Takayuki; Takasugi, Kiyoshi; Tamaki, Shigenori; Takeuchi, Tsutomu; Ueda, Atsuhisa; Yamamoto, Kazuhiko; Yamanaka, Hisashi; Yoshifuji, Hajime; Nomura, Akira

2015-10-01

To evaluate the efficacy and safety of switching from intravenous (IV) tocilizumab (TCZ) to subcutaneous (SC) TCZ monotherapy in rheumatoid arthritis patients. Patients who had completed 24 weeks of TCZ-SC (162 mg/2 weeks) or TCZ-IV (8 mg/kg/4 weeks) monotherapy in the double-blind period of the MUSASHI study were enrolled in an 84-week open-label extension period. All received TCZ-SC (162 mg/2 weeks) monotherapy. Effects of the IV to SC switch were evaluated at week 36 (12 weeks after switching). Overall, 319 patients received ≥1 dose of TCZ-SC during the open-label extension period; 160 switched from TCZ-IV to TCZ-SC (TCZ IV/SC) and 159 continued TCZ-SC (TCZ SC/SC). Disease Activity Score in 28 joints using the erythrocyte sedimentation rate clinical remission rates were 62.5% (100 of 160) for TCZ IV/SC and 50.0% (79 of 158) for TCZ SC/SC at week 24, and were maintained at 62.5% (100 of 160) and 57.0% (90 of 158), respectively, at week 36. In the TCZ IV/SC group, 9% of patients (9 of 100) who had achieved remission at week 24 could not maintain remission at week 36. In TCZ IV/SC patients weighing ≥70 kg, the percentage with a sufficient serum TCZ concentration (≥1 μg/ml) decreased from 90.9% (10 of 11) at week 24 to 45.5% (5 of 11) at week 36. Overall safety profiles were similar in TCZ IV/SC and TCZ SC/SC except for mild injection site reactions in TCZ IV/SC. Efficacy is adequately maintained in most patients switching from TCZ-IV (8 mg/kg/4 weeks) to TCZ-SC (162 mg/2 weeks) monotherapy. Patients receiving TCZ-IV can switch to TCZ-SC without serious safety concerns. Clinical efficacy may be reduced after switching in some patients with high body weight. © 2015 The Authors. Arthritis Care & Research is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

Intermittent theta-burst transcranial magnetic stimulation for autism spectrum disorder: an open-label pilot study.

PubMed

Abujadi, Caio; Croarkin, Paul E; Bellini, Bianca B; Brentani, Helena; Marcolin, Marco A

2017-12-11

Theta-burst stimulation (TBS) modulates synaptic plasticity more efficiently than standard repetitive transcranial magnetic stimulation delivery and may be a promising modality for neuropsychiatric disorders such as autism spectrum disorder (ASD). At present there are few effective interventions for prefrontal cortex dysfunction in ASD. We report on an open-label, pilot study of intermittent TBS (iTBS) to target executive function deficits and restricted, repetitive behaviors in male children and adolescents with ASD. Ten right-handed, male participants, aged 9-17 years with ASD were enrolled in an open-label trial of iTBS treatment. Fifteen sessions of neuronavigated iTBS at 100% motor threshold targeting the right dorsolateral prefrontal cortex were delivered over 3 weeks. Parent report scores on the Repetitive Behavior Scale Revised and the Yale-Brown Obsessive Compulsive Scale demonstrated improvements with iTBS treatment. Participants demonstrated improvements in perseverative errors on the Wisconsin Card Sorting Test and total time for the Stroop test. The iTBS treatments were well tolerated with no serious adverse effects. These preliminary results suggest that further controlled interventional studies of iTBS for ASD are warranted.

Effect of the Probiotic Saccharomyces boulardii on Cholesterol and Lipoprotein Particles in Hypercholesterolemic Adults: A Single-Arm, Open-Label Pilot Study.

PubMed

Ryan, Jennifer Joan; Hanes, Douglas Allen; Schafer, Morgan Beth; Mikolai, Jeremy; Zwickey, Heather

2015-05-01

Elevated blood cholesterol levels are a major risk factor for coronary artery disease, the leading cause of death worldwide. Probiotics have been investigated as potential cholesterol-lowering therapies, but no previous studies have assessed the effect of the probiotic yeast Saccharomyces boulardii on cholesterol levels in human volunteers. The objective of this study was to examine the effect of S. boulardii on serum cholesterol and lipoprotein particles in hypercholesterolemic adults. This study was a single-arm, open-label pilot study. Twelve hypercholesterolemic participants were recruited into the study; one dropped out. Participants took 5.6×10(10) colony forming unit (CFU) encapsulated S. boulardii (Saccharomyces cerevisiae var. boulardii CNCM I-1079) twice daily for an 8-week period. Fasting concentrations of cholesterol (total cholesterol, low-density lipoprotein-cholesterol [LDL-C], high-density lipoprotein-cholesterol [HDL-C], and triglycerides), lipoprotein particles (very-low-density lipoprotein-particle [VLDL-P], remnant lipoprotein particle [RLP-P], total LDL-P, LDL III-P, LDL IV-P, total HDL-P, and HDL 2b-P), and additional cardiovascular biomarkers (apo B-100, lipoprotein [a], high-sensitivity C-reactive protein, homocysteine, fibrinogen, and insulin) were measured at baseline, after 4 weeks, and after 8 weeks. Remnant lipoprotein particles decreased by 15.5% (p=0.03) over the 8-week period. The remaining outcome measures were not significantly altered. In this pilot study, 8 weeks of daily supplementation with S. boulardii lowered remnant lipoprotein, a predictive biomarker and potential therapeutic target in the treatment and prevention of coronary artery disease.

DRY CUPPING IN CHILDREN WITH FUNCTIONAL CONSTIPATION: A RANDOMIZED OPEN LABEL CLINICAL TRIAL

PubMed Central

Shahamat, Mahmoud; Daneshfard, Babak; Najib, Khadijeh-Sadat; Dehghani, Seyed Mohsen; Tafazoli, Vahid; Kasalaei, Afshineh

2016-01-01

Background: As a common disease in pediatrics, constipation poses a high burden to the community. In this study, we aimed to investigate the efficacy of dry cupping therapy (an Eastern traditional manipulative therapy) in children with functional constipation. Materials and Methods: One hundred and twenty children (4-18 years old) diagnosed as functional constipation according to ROME III criteria were assigned to receive a traditional dry cupping protocol on the abdominal wall for 8 minutes every other day or standard laxative therapy (Polyethylene glycol (PEG) 40% solution without electrolyte), 0.4 g/kg once daily) for 4 weeks, in an open label randomized controlled clinical trial using a parallel design with a 1:1 allocation ratio. Patients were evaluated prior to and following 2, 4, 8 and 12 weeks of the intervention commencement in terms of the ROME III criteria for functional constipation. Results: There were no significant differences between the two arms regarding demographic and clinical basic characteristics. After two weeks of the intervention, there was a significant better result in most of the items of ROME III criteria of patients in PEG group. In contrast, after four weeks of the intervention, the result was significantly better in the cupping group. There was no significant difference in the number of patients with constipation after 4 and 8 weeks of the follow-up period. Conclusion: This study showed that dry cupping of the abdominal wall, as a traditional manipulative therapy, can be as effective as standard laxative therapy in children with functional constipation. PMID:28852716

Budesonide Foam Has a Favorable Safety Profile for Inducing Remission in Mild-to-Moderate Ulcerative Proctitis or Proctosigmoiditis.

PubMed

Rubin, David T; Sandborn, William J; Bosworth, Brian; Zakko, Salam; Gordon, Glenn L; Sale, Mark E; Rolleri, Robert L; Golden, Pamela L; Barrett, Andrew C; Bortey, Enoch; Forbes, William P

2015-11-01

Budesonide foam, a rectally administered, second-generation corticosteroid with extensive hepatic first-pass metabolism, is efficacious for the treatment of mild-to-moderate ulcerative proctitis and ulcerative proctosigmoiditis. The aim of this study was to comprehensively assess the safety and pharmacokinetic profile of budesonide foam. Data from five phase III studies were pooled to further evaluate safety, including an open-label study (once-daily treatment for 8 weeks), an active-comparator study (once-daily treatment for 4 weeks), and two placebo-controlled studies and an open-label extension study (twice-daily treatment for 2 weeks, then once daily for 4 weeks). Data from the placebo-controlled studies and two phase I studies (i.e., patients with mild-to-moderate ulcerative colitis and healthy volunteers) were pooled to evaluate the pharmacokinetics of budesonide foam. A similar percentage of patients reported adverse events in the budesonide foam and placebo groups, with the majority of adverse events being mild or moderate in intensity (93.3 vs 96.0%, respectively). Adverse events occurred in 41.4 and 36.3% of patients receiving budesonide foam and placebo, respectively. Mean morning cortisol concentrations remained within the normal range for up to 8 weeks of treatment; there were no clinically relevant effects of budesonide foam on the hypothalamic-pituitary-adrenal axis. Population pharmacokinetic analysis demonstrated low systemic exposure after budesonide foam administration. This integrated analysis demonstrated that budesonide foam for the induction of remission of distal ulcerative colitis is safe overall, with no clinically relevant effects on the hypothalamic-pituitary-adrenal axis.

Maintenance of remission with combination etanercept-DMARD therapy versus DMARDs alone in active rheumatoid arthritis: results of an international treat-to-target study conducted in regions with limited biologic access.

PubMed

Pavelka, Karel; Akkoç, Nurullah; Al-Maini, Mustafa; Zerbini, Cristiano A F; Karateev, Dmitry E; Nasonov, Evgeny L; Rahman, Mahboob U; Pedersen, Ronald; Dinh, Andrew; Shen, Qi; Vasilescu, Radu; Kotak, Sameer; Mahgoub, Ehab; Vlahos, Bonnie

2017-09-01

In this transglobal, randomized, double-blind, placebo-controlled, treat-to-target study, the maintenance of efficacy was compared between biologic-and biologic-free-disease-modifying antirheumatic drug (DMARD) combination regimens after low disease activity (LDA) was achieved with biologic DMARD induction therapy. Patients with moderate-to-severe rheumatoid arthritis despite methotrexate therapy received open-label etanercept 50 mg subcutaneously once weekly plus methotrexate with or without other conventional synthetic (cs) DMARDs for 24 weeks. Patients achieving LDA [disease activity score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) <3.2] at week 24 were randomized to receive etanercept-methotrexate combination therapy or placebo-methotrexate combination therapy, with or without other csDMARDs, for 28 weeks. In the open-label period, 72% of patients achieved DAS28-ESR LDA at week 24. Patients enrolled in the double-blind period had long-standing rheumatoid arthritis and high disease activity at baseline (mean duration, 8.1 years; DAS28-ESR, 6.4). In the etanercept and placebo combination groups, 44% versus 17% achieved DAS28-ESR LDA and 34 versus 13% achieved DAS28-ESR remission at week 52 (p < 0.001). Adverse events were reported in 37 and 43%, serious adverse events in 0 and 4%, and serious infections in 0 and 2% in these groups, respectively, in the double-blind period. After induction of response with etanercept combination therapy following a treat-to-target approach in patients with long-standing rheumatoid arthritis and high disease activity at baseline, the etanercept combination regimen was significantly more effective in maintaining LDA and remission than a biologic-free regimen. ClinicalTrials.gov identifier. NCT01578850.

Efficacy, safety, and pharmacokinetics of sustained-release lanreotide (lanreotide Autogel) in Japanese patients with acromegaly or pituitary gigantism.

PubMed

Shimatsu, Akira; Teramoto, Akira; Hizuka, Naomi; Kitai, Kazuo; Ramis, Joaquim; Chihara, Kazuo

2013-01-01

The somatostatin analog lanreotide Autogel has proven to be efficacious for treating acromegaly in international studies and in clinical practices around the world. However, its efficacy in Japanese patients has not been extensively evaluated. We examined the dose-response relationship and long-term efficacy and safety in Japanese patients with acromegaly or pituitary gigantism. In an open-label, parallel-group, dose-response study, 32 patients (29 with acromegaly, 3 with pituitary gigantism) received 5 injections of 60, 90, or 120 mg of lanreotide Autogel over 24 weeks. Four weeks after the first injection, 41% of patients achieved serum GH level of <2.5 ng/mL and insulin-like growth factor-I (IGF-I) level was normalized in 31%. Values at Week 24 were 53% for GH and 44% for IGF-I. Dose-dependent decreases in serum GH and IGF-I levels were observed with dose-related changes in pharmacokinetic parameters. In an open-label, long-term study, 32 patients (30 with acromegaly, 2 with pituitary gigantism) received lanreotide Autogel once every 4 weeks for a total of 13 injections. Dosing was initiated with 90 mg and adjusted according to clinical responses at Weeks 16 and/or 32. At Week 52, 47% of patients had serum GH levels of <2.5 ng/mL and 53% had normalized IGF-I level. In both studies, acromegaly symptoms improved and treatment was generally well tolerated although gastrointestinal symptoms and injection site induration were reported. In conclusion, lanreotide Autogel provided early and sustained control of elevated GH and IGF-I levels, improved acromegaly symptoms, and was well tolerated in Japanese patients with acromegaly or pituitary gigantism.

Effects of Lobeglitazone, a Novel Thiazolidinedione, on Bone Mineral Density in Patients with Type 2 Diabetes Mellitus over 52 Weeks

PubMed Central

Lim, Soo; Kim, Kyoung Min; Kim, Sin Gon; Kim, Doo Man; Woo, Jeong-Taek; Chung, Choon Hee; Ko, Kyung Soo; Park, Jeong Hyun; Park, Yongsoo; Kim, Sang Jin; Jang, Hak Chul

2017-01-01

Background The aim of this multicenter, randomized, double-blind study was to examine the effect of lobeglitazone, a novel thiazolidinedione, on the changes in bone mineral density (BMD) in patients with type 2 diabetes mellitus. Methods A 24-week, double-blinded phase was followed by a 28-week, open-label phase, in which the placebo group also started to receive lobeglitazone. A total of 170 patients aged 34 to 76 years were randomly assigned in a 2:1 ratio to receive lobeglitazone 0.5 mg or a matching placebo orally, once daily. BMD was assessed using dual-energy X-ray absorptiometry at week 24 and at the end of the study (week 52). Results During the double-blinded phase, the femur neck BMD showed decreasing patterns in both groups, without statistical significance (−0.85%±0.36% and −0.78%±0.46% in the lobeglitazone and placebo groups, respectively). The treatment difference between the groups was 0.07%, which was also not statistically significant. Further, minimal, nonsignificant decreases were observed in both groups in the total hip BMD compared to values at baseline, and these differences also did not significantly differ between the groups. During the open-label phase, the BMD was further decreased, but not significantly, by −0.32% at the femur neck and by −0.60% at the total hip in the lobeglitazone group, and these changes did not significantly differ compared with the original placebo group switched to lobeglitazone. Conclusion Our results indicate that treatment with lobeglitazone 0.5 mg over 52 weeks showed no detrimental effect on the BMD compared to the placebo. PMID:29086536

Open-Label Treatment of Moderate or Marked Melasma with a 4% Hydroquinone Skin Care System Plus 0.05% Tretinoin Cream

PubMed Central

Rendon, Marta; Dibernardo, Barry; Bruce, Suzanne; Lucas-Anthony, Chere; Watson, Joanne

2013-01-01

Objective: To evaluate treating epidermal melasma using a 4% hydroquinone skin care system plus tretinoin 0.05% cream. Design: Multicenter open-label study with all patients receiving above-mentioned treatment for up to 24 weeks. Setting: Private dermatology and plastic surgery clinics and clinical research facilities. Participants: Thirty-seven adult females with moderate or marked epidermal melasma, melasma pigmentation of mild-to-marked intensity and Fitzpatrick skin type III to VI. Measurements: Melasma severity melasma pigmentation intensity melasma improvement, patient satisfaction, quality-of-life measures, erythema, dryness, peeling, burning/stinging. Results: No patient discontinued due to lack of efficacy or treatment-related adverse events. Treatment was associated with a significant reduction from baseline in melasma severity and melasma pigmentation intensity from Week 4 onward (P≤0.001), and 100 percent of patients showed improvement from Week 8 onward. At Week 24, 100 percent of patients were “satisfied” or “very satisfied” with the overall effectiveness of their treatment. Patients’ quality of life also improved (e.g., the proportion of patients feeling embarrassed or self-conscious about their skin “a lot” or “very much” declined from 78 percent at baseline to four percent at Week 24). Mean and median scores for erythema, dryness, peeling, and burning/stinging did not exceed trace levels. Conclusion: Treating moderate-to-severe melasma using the 4% hydroquinone skin care system plus 0.05% tretinoin can significantly reduce the severity of melasma and the intensity of melasma pigmentation within four weeks. Treatment was generally well tolerated and associated with an improved quality of life and high levels of patient satisfaction. PMID:24307923

A phase II, open-label study of the efficacy and safety of imiquimod in the treatment of superficial and mixed infantile hemangioma.

PubMed

McCuaig, Catherine C; Dubois, Josée; Powell, Julie; Belleville, Claude; David, Michèle; Rousseau, Elisabeth; Gendron, Roxanne; Jafarian, Fatemeh; Auger, Isabelle

2009-01-01

To explore the efficacy and safety of imiquimod 5% cream as a treatment for infantile hemangioma. Phase II, open-label, noncomparative study of imiquimod applied during 16 weeks, with posttherapy follow-up 16 weeks later (8 months total). Outpatient pediatric tertiary care referral center in Quebec, Canada. Healthy infants up to 8.8 months of age with previously untreated, nonulcerated, proliferative superficial or mixed infantile hemangioma, excluding periorbital, or perineal localization, > or =100 cm2 in size. Topical imiquimod applied three to seven times per week for 16 weeks to infantile hemangioma. Lesion area, volume, depth (Doppler ultrasound), and color (erythema), serum drug, and interferon-alpha levels. Sixteen infants (11 girls, 5 boys) with a mean age at entry of 4.1 months and mean lesion area of 32.89 cm2, and volume of 39.98 cm3 were enrolled. Two participants discontinued treatment early, one for an adverse event (crying upon application), the other because of the lack of compliance. Local skin reactions were consistent with those reported in adults. Two cases had a decrease and three had an increase in lesion parameters; otherwise no meaningful changes in lesion area, volume, or depth were observed. At the 4-month posttreatment visit, 11 of 14 subjects had improvement in erythema (marginal homogeneity test = 2.668, p = 0.008). Measured serum drug and interferon-alpha levels were low or undetectable. Treatment of infants with infantile hemangioma with imiquimod up to seven times per week for 16 weeks was generally well tolerated with low systemic exposure. Improvement was observed in hemangioma coloration, but not lesion size, suggesting effects were limited to the superficial component.

Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension.

PubMed

Santos, Raul D; Duell, P Barton; East, Cara; Guyton, John R; Moriarty, Patrick M; Chin, Wai; Mittleman, Robert S

2015-03-01

To evaluate the efficacy and safety of extended dosing with mipomersen in patients with familial hypercholesterolaemia (HC) taking maximally tolerated lipid-lowering therapy. A planned interim analysis of an ongoing, open-label extension trial in patients (n = 141) with familial HC receiving a subcutaneous injection of 200 mg mipomersen weekly plus maximally tolerated lipid-lowering therapy for up to 104 weeks. The mean changes in low-density lipoprotein cholesterol (LDL-C) from baseline to weeks 26 (n = 130), 52 (n = 111), 76 (n = 66), and 104 (n = 53) were -28, -27, -27, and -28%; and in apolipoprotein B -29, -28, -30, and -31%, respectively. Reductions in total cholesterol, non-high-density lipoprotein-cholesterol, and lipoprotein(a) were comparable with decreases in LDL-C and apolipoprotein B levels. Mean high-density lipoprotein cholesterol increased from baseline by 7 and 6% at weeks 26 and 52, respectively. The long-term safety profile of mipomersen was similar to that reported in the associated randomized placebo-controlled Phase 3 trials. Adverse events included injection site reactions and flu-like symptoms. There was an incremental increase in the median liver fat during the initial 6-12 months that appeared to diminish with continued mipomersen exposure beyond 1 year and returned towards baseline 24 weeks after last drug dose suggestive of adaptation. The median alanine aminotransferase level showed a similar trend over time. Long-term treatment with mipomersen for up to 104 weeks provided sustained reductions in all atherosclerotic lipoproteins measured and a safety profile consistent with prior controlled trials in these high-risk patient populations. CLINICALTRIALS.GOV: NCT00694109. © The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.

Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension

PubMed Central

Santos, Raul D.; Duell, P. Barton; East, Cara; Guyton, John R.; Moriarty, Patrick M.; Chin, Wai; Mittleman, Robert S.

2015-01-01

Aims To evaluate the efficacy and safety of extended dosing with mipomersen in patients with familial hypercholesterolaemia (HC) taking maximally tolerated lipid-lowering therapy. Methods and results A planned interim analysis of an ongoing, open-label extension trial in patients (n = 141) with familial HC receiving a subcutaneous injection of 200 mg mipomersen weekly plus maximally tolerated lipid-lowering therapy for up to 104 weeks. The mean changes in low-density lipoprotein cholesterol (LDL-C) from baseline to weeks 26 (n = 130), 52 (n = 111), 76 (n = 66), and 104 (n = 53) were −28, −27, −27, and −28%; and in apolipoprotein B −29, −28, −30, and −31%, respectively. Reductions in total cholesterol, non-high-density lipoprotein-cholesterol, and lipoprotein(a) were comparable with decreases in LDL-C and apolipoprotein B levels. Mean high-density lipoprotein cholesterol increased from baseline by 7 and 6% at weeks 26 and 52, respectively. The long-term safety profile of mipomersen was similar to that reported in the associated randomized placebo-controlled Phase 3 trials. Adverse events included injection site reactions and flu-like symptoms. There was an incremental increase in the median liver fat during the initial 6–12 months that appeared to diminish with continued mipomersen exposure beyond 1 year and returned towards baseline 24 weeks after last drug dose suggestive of adaptation. The median alanine aminotransferase level showed a similar trend over time. Conclusion Long-term treatment with mipomersen for up to 104 weeks provided sustained reductions in all atherosclerotic lipoproteins measured and a safety profile consistent with prior controlled trials in these high-risk patient populations. Clinicaltrials.gov NCT00694109. PMID:24366918

An Open Label Clinical Trial to Evaluate the Efficacy and Tolerance of a Retinol and Vitamin C Facial Regimen in Women With Mild-to-Moderate Hyperpigmentation and Photodamaged Facial Skin.

PubMed

Herndon, James H; Jiang, Lily I; Kononov, Tatiana; Fox, Theresa

2016-04-01

A 12-week open-label, single-center clinical usage trial was conducted to determine the effectiveness of a dual product regimen consisting of a 0.5% retinol treatment and an anti-aging moisturizer with 30% vitamin C in women with mild to moderate hyperpigmented and photodamaged facial skin. Clinical grading of several efficacy parameters, tolerability evaluations, subject self-assessment questionnaires, and digital photography were completed at baseline and at weeks 4, 8, and 12. A total of 44 women completed the study. Effective ingredients incorporated into the 0.5% retinol treatment included encapsulated retinol for a retinol concentration of 0.5%, bakuchiol, and Ophiopogon japonicus root extract. The anti-aging moisturizer with 30% vitamin C contained 30% vitamin C in the form of tetrahexyldecyl ascorbate (THD ascorbate), alpha-tocopheryl acetate (vitamin E) and ubiquinone (coenzyme Q10). The facial regimen produced a statistically significant decrease (improvement) in clinical grading scores for all parameters assessed at weeks 8 and 12 when compared with baseline scores. In addition, the majority of these parameters were improved at week 4. The test regimen was well-perceived by the subjects for various inquiries regarding facial skin condition, product efficacy, and product attributes. Several tolerability parameters were assessed with no statistically significant increase except for dryness. A statistically significant increase in clinical grading scores for dryness on the face occurred at weeks 4 and 8 when compared to baseline scores. The increase in dryness is expected when introducing a retinol product to a facial regimen and the dryness did not persist to the week 12 time point.

A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes.

PubMed

Platzbecker, U; Symeonidis, A; Oliva, E N; Goede, J S; Delforge, M; Mayer, J; Slama, B; Badre, S; Gasal, E; Mehta, B; Franklin, J

2017-09-01

The use of darbepoetin alfa to treat anemia in patients with lower-risk myelodysplastic syndromes (MDS) was evaluated in a phase 3 trial. Eligible patients had low/intermediate-1 risk MDS, hemoglobin ⩽10 g/dl, low transfusion burden and serum erythropoietin (EPO) ⩽500 mU/ml. Patients were randomized 2:1 to receive 24 weeks of subcutaneous darbepoetin alfa 500 μg or placebo every 3 weeks (Q3W), followed by 48 weeks of open-label darbepoetin alfa. A total of 147 patients were randomized, with median hemoglobin of 9.3 (Q1:8.8, Q3:9.7) g/dl and median baseline serum EPO of 69 (Q1:36, Q3:158) mU/ml. Transfusion incidence from weeks 5-24 was significantly lower with darbepoetin alfa versus placebo (36.1% (35/97) versus 59.2% (29/49), P=0.008) and erythroid response rates increased significantly with darbepoetin alfa (14.7% (11/75 evaluable) versus 0% (0/35 evaluable), P=0.016). In the 48-week open-label period, dose frequency increased from Q3W to Q2W in 81% (102/126) of patients; this was associated with a higher hematologic improvement-erythroid response rate (34.7% (34/98)). Safety results were consistent with a previous darbepoetin alfa phase 2 MDS trial. In conclusion, 24 weeks of darbepoetin alfa Q3W significantly reduced transfusions and increased rates of erythroid response with no new safety signals in lower-risk MDS (registered as EudraCT#2009-016522-14 and NCT#01362140).

Guselkumab, a human interleukin-23 monoclonal antibody in Japanese patients with generalized pustular psoriasis and erythrodermic psoriasis: Efficacy and safety analyses of a 52-week, phase 3, multicenter, open-label study.

PubMed

Sano, Shigetoshi; Kubo, Hiroshi; Morishima, Hitomi; Goto, Ryosuke; Zheng, Richuan; Nakagawa, Hidemi

2018-05-01

Generalized pustular psoriasis (GPP) and erythrodermic psoriasis (EP) are the rare and severe subtypes of psoriasis, which are often difficult to treat. The aim of this phase 3, open-label study was to evaluate efficacy and safety of guselkumab, a human interleukin-23 monoclonal antibody, in Japanese patients with GPP and EP. Guselkumab 50 mg was administrated to GPP (n = 10) and EP (n = 11) patients at weeks 0, 4 and thereafter every 8 weeks (q8w). Beginning at week 20, patients were escalated to 100 mg q8w if they met the dose escalation criteria. The primary end-point was the proportion of patients achieving treatment success (Clinical Global Impression score of "very much improved", "much improved" or "minimally improved") at week 16. Safety evaluations included assessment of treatment-emergent adverse events (TEAE) through week 52. At week 16, the proportions of GPP and EP patients achieving treatment success were 77.8% (7/9) and 90.9% (10/11), respectively. Furthermore, guselkumab treatment consistently showed improvement in responses of secondary end-points such as Psoriasis Area and Severity Index, Investigator's Global Assessment, Japanese Dermatological Association severity index and improvement in body surface area involvement. Improvements in quality of life, as assessed by the Dermatology Life Quality Index, were also observed through week 52. The most commonly reported TEAE was nasopharyngitis (28.6%, 6/21). Safety findings were consistent with those observed previously in other studies. In conclusion, guselkumab treatment demonstrated efficacy and showed no safety concerns in Japanese patients with GPP and EP through week 52. © 2018 Janssen Pharmaceutical K.K. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.

Long-term safety and effectiveness of once-daily, single-entity, extended-release hydrocodone over 76 weeks of an open-label study in patients with chronic noncancer and nonneuropathic pain.

PubMed

Taber, Louise; Lynch, Shau Yu; He, Ellie; Ripa, Steven R

2016-01-01

To evaluate long-term use of Hysingla(®) ER (HYD), a single-entity, extended-release, once-daily hydrocodone bitartrate tablet with abuse-deterrent properties in patients with moderate-to-severe chronic noncancer and nonneuropathic pain. This open-label study consisted of a dose-titration period (up to 45 days), a 52-week maintenance period and a 24-week extension period. Opioid-naïve or opioid-experienced patients with controlled or uncontrolled chronic pain conditions were treated with HYD 20-120 mg daily. Supplemental nonopioid and short-acting opioid analgesics were permitted. This paper presents the results of 106 patients who continued HYD treatment for up to 76 weeks. Primary safety measures included the incidence of adverse events, as well as audiologic, clinical laboratory and electrocardiogram measurements. Effectiveness was measured by the change between baseline and the overall 76-week treatment period in "average pain over the last 24 h" (0 = no pain, 10 = pain as bad as you can imagine), Brief Pain Inventory-Short Form survey, Medical Outcomes Study 36-Item Short Form Health Survey, Medical Outcomes Study Sleep Scale-Revised and concomitant nonstudy opioid analgesic use. Among 410 patients who completed the maintenance period, 106 continued into the extension. Of these, 83 (78%) completed the entire 76-week treatment period. Treatment-emergent adverse events were typical of those observed with μ-opioid agonists. No study drug abuse or diversion was reported. Clinically important analgesia and functional improvement were achieved during the dose-titration period and were maintained in most patients throughout 76 weeks without the need for continued HYD dose increases or changes in concomitant nonstudy opioid analgesics. The mean pain score was 6.1 at baseline, 3.8 at the end of the dose titration period and 3.8 through 76 weeks. HYD was generally well tolerated. No unexpected safety concerns emerged. Pain control was sustained throughout 76 weeks of treatment.

Comparison of acarbose and voglibose in diabetes patients who are inadequately controlled with basal insulin treatment: randomized, parallel, open-label, active-controlled study.

PubMed

Lee, Mi Young; Choi, Dong Seop; Lee, Moon Kyu; Lee, Hyoung Woo; Park, Tae Sun; Kim, Doo Man; Chung, Choon Hee; Kim, Duk Kyu; Kim, In Joo; Jang, Hak Chul; Park, Yong Soo; Kwon, Hyuk Sang; Lee, Seung Hun; Shin, Hee Kang

2014-01-01

We studied the efficacy and safety of acarbose in comparison with voglibose in type 2 diabetes patients whose blood glucose levels were inadequately controlled with basal insulin alone or in combination with metformin (or a sulfonylurea). This study was a 24-week prospective, open-label, randomized, active-controlled multi-center study. Participants were randomized to receive either acarbose (n=59, 300 mg/day) or voglibose (n=62, 0.9 mg/day). The mean HbA1c at week 24 was significantly decreased approximately 0.7% from baseline in both acarbose (from 8.43% ± 0.71% to 7.71% ± 0.93%) and voglibose groups (from 8.38% ± 0.73% to 7.68% ± 0.94%). The mean fasting plasma glucose level and self-monitoring of blood glucose data from 1 hr before and after each meal were significantly decreased at week 24 in comparison to baseline in both groups. The levels 1 hr after dinner at week 24 were significantly decreased in the acarbose group (from 233.54 ± 69.38 to 176.80 ± 46.63 mg/dL) compared with the voglibose group (from 224.18 ± 70.07 to 193.01 ± 55.39 mg/dL). In conclusion, both acarbose and voglibose are efficacious and safe in patients with type 2 diabetes who are inadequately controlled with basal insulin. (ClinicalTrials.gov number, NCT00970528).

Comparison of Acarbose and Voglibose in Diabetes Patients Who Are Inadequately Controlled with Basal Insulin Treatment: Randomized, Parallel, Open-Label, Active-Controlled Study

PubMed Central

Lee, Mi Young; Lee, Moon Kyu; Lee, Hyoung Woo; Park, Tae Sun; Kim, Doo Man; Chung, Choon Hee; Kim, Duk Kyu; Kim, In Joo; Jang, Hak Chul; Park, Yong Soo; Kwon, Hyuk Sang; Lee, Seung Hun; Shin, Hee Kang

2014-01-01

We studied the efficacy and safety of acarbose in comparison with voglibose in type 2 diabetes patients whose blood glucose levels were inadequately controlled with basal insulin alone or in combination with metformin (or a sulfonylurea). This study was a 24-week prospective, open-label, randomized, active-controlled multi-center study. Participants were randomized to receive either acarbose (n=59, 300 mg/day) or voglibose (n=62, 0.9 mg/day). The mean HbA1c at week 24 was significantly decreased approximately 0.7% from baseline in both acarbose (from 8.43% ± 0.71% to 7.71% ± 0.93%) and voglibose groups (from 8.38% ± 0.73% to 7.68% ± 0.94%). The mean fasting plasma glucose level and self-monitoring of blood glucose data from 1 hr before and after each meal were significantly decreased at week 24 in comparison to baseline in both groups. The levels 1 hr after dinner at week 24 were significantly decreased in the acarbose group (from 233.54 ± 69.38 to 176.80 ± 46.63 mg/dL) compared with the voglibose group (from 224.18 ± 70.07 to 193.01 ± 55.39 mg/dL). In conclusion, both acarbose and voglibose are efficacious and safe in patients with type 2 diabetes who are inadequately controlled with basal insulin. (ClinicalTrials.gov number, NCT00970528) PMID:24431911

Augmentation of light therapy in difficult-to-treat depressed patients: an open-label trial in both unipolar and bipolar patients

PubMed Central

Camardese, Giovanni; Leone, Beniamino; Serrani, Riccardo; Walstra, Coco; Di Nicola, Marco; Della Marca, Giacomo; Bria, Pietro; Janiri, Luigi

2015-01-01

Objectives We investigated the clinical benefits of bright light therapy (BLT) as an adjunct treatment to ongoing psychopharmacotherapy, both in unipolar and bipolar difficult-to-treat depressed (DTD) outpatients. Methods In an open-label study, 31 depressed outpatients (16 unipolar and 15 bipolar) were included to undergo 3 weeks of BLT. Twenty-five completed the treatment and 5-week follow-up. Main outcome measures Clinical outcomes were evaluated by the Hamilton Depression Rating Scale (HDRS). The Snaith–Hamilton Pleasure Scale and the Depression Retardation Rating Scale were used to assess changes in anhedonia and psychomotor retardation, respectively. Results The adjunctive BLT seemed to influence the course of the depressive episode, and a statistically significant reduction in HDRS scores was reported since the first week of therapy. The treatment was well-tolerated, and no patients presented clinical signs of (hypo)manic switch during the overall treatment period. At the end of the study (after 5 weeks from BLT discontinuation), nine patients (36%, eight unipolar and one bipolar) still showed a treatment response. BLT augmentation also led to a significant improvement of psychomotor retardation. Conclusion BLT combined with the ongoing pharmacological treatment offers a simple approach, and it might be effective in rapidly ameliorating depressive core symptoms of vulnerable DTD outpatients. These preliminary results need to be confirmed in placebo-controlled, randomized, double-blind clinical trial on larger samples. PMID:26396517

Treatment of vitiligo with the topical Janus kinase inhibitor ruxolitinib.

PubMed

Rothstein, Brooke; Joshipura, Deep; Saraiya, Ami; Abdat, Rana; Ashkar, Huda; Turkowski, Yana; Sheth, Vaneeta; Huang, Victor; Au, Shiu Chung; Kachuk, Courtney; Dumont, Nicole; Gottlieb, Alice B; Rosmarin, David

2017-06-01

Existing therapies for vitiligo are limited in efficacy and can be associated with undesirable side effects. Topical Janus kinase inhibitors may offer a new therapeutic option for vitiligo. We sought to assess the role of topical ruxolitinib 1.5% cream, a Janus kinase inhibitor, in vitiligo treatment. This 20-week, open-label, proof-of-concept trial of twice-daily topical ruxolitinib 1.5% cream was conducted in 12 patients with a minimum of 1% affected body surface area of vitiligo. The primary outcome was percent improvement in Vitiligo Area Scoring Index from baseline to week 20. Of 12 patients screened, 11 were enrolled and 9 completed the study (54.5% men; mean age, 52 years). Four patients with significant facial involvement at baseline had a 76% improvement in facial Vitiligo Area Scoring Index scores at week 20 (95% confidence interval, 53-99%; P = .001). A 23% improvement in overall Vitiligo Area Scoring Index scores was observed in all enrolled patients at week 20 (95% confidence interval, 4-43%; P = .02). Three of 8 patients responded on body surfaces and 1 of 8 patients responded on acral surfaces. Adverse events were minor, including erythema, hyperpigmentation, and transient acne. Limitations of the study include the small sample size and open-label study design. Topical ruxolitinib 1.5% cream provided significant repigmentation in facial vitiligo and may offer a valuable new treatment for vitiligo. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

The Effect of a Novel form of Extended-Release Gabapentin on Pain and Sleep in Fibromyalgia Subjects: An Open-Label Pilot Study.

PubMed

North, James M; Hong, Kyung-Soo J; Rauck, Richard L

2016-07-01

We assessed the efficacy and safety of extended-release gabapentin in a 15-week, open-label, single-arm, single-center study in patients with fibromyalgia (FM). Subjects with documented diagnosis of FM were allowed to participate in the study. We opened enrollment to those who have tried and failed gabapentinoids such as gabapentin or pregabalin due to side effects. Subjects with autoimmune conditions, and or taking opioids for management of their FM pain, were excluded from the study. Subjects were given an extended-release gabapentin starter pack and treated for total of 12 weeks. The primary study endpoint of pain relief was measured using Numeric Pain Rating System (NPRS) scores, and secondary study endpoints were measured with Fibromyalgia Impact Questionnaire (FIQ), Patient's Global Impression of Change (PGIC), and Medical Outcome Sleep questionnaires (MOS). A total of 34 subjects were enrolled and 29 subjects completed the starter pack (85%). Patients reported significant pain relief on NPRS by end of 4 weeks (P < 0.0001) on NPRS. Subjects also reported similar magnitude of improvements in FM and its impact on daily life by end of 4 weeks on FIQ (P < 0.0001). Survey of MOS showed our subjects reporting improved sleep quantity (on average, 1.2 hours over baseline) with gradual and statistically significant improvement in quality. Improvements in primary and secondary measurements were reflected in PGIC, with significant improvement in patient's impression of FM by week 8. Small sample size, geographical bias, relatively short duration of treatment, and single-arm study without control group. Extended-release gabapentin relieved FM pain symptoms and improved quality-of-life for the FM subjects studied. Subjects reported improvements in both quantity and quality of sleep. © 2015 World Institute of Pain.

Relapse Prevention in Pediatric Patients with ADHD Treated with Atomoxetine: A Randomized, Double-Blind, Placebo-Controlled Study

ERIC Educational Resources Information Center

Michelson, David; Buitelaar, Jan K.; Danckaerts, Marina; Gillberg, Christopher; Spencer, Thomas J.; Zuddas, Alessandro; Faries, Douglas E.; Zhang, Shuyu; Biederman, Joseph

2004-01-01

Objective: Attention-deficit/hyperactivity disorder (ADHD) is typically treated over extended periods; however, few placebo-controlled, long-term studies of efficacy have been reported. Method: In a global multicenter study, children and adolescents who responded to an initial 12-week, open-label period of treatment with atomoxetine, a…

A Multicenter, Open-label Study of CMX001 Treatment of Serious Diseases or Conditions Caused by dsDNA Viruses

ClinicalTrials.gov

2013-08-28

Male or Female Patients With a Serious or Immediately Life-threatening; Disease or Condition Caused by CMV, ADV, HSV, VAVC, VARV or; Monkeypox Viruses(s) Who Have a Life Expectancy of ≥ 2 Weeks and for; Whom no Comparable or Satisfactory Alternative Therapy is Available

Effectiveness of a Therapeutic Summer Camp for Children with ADHD: Phase I Clinical Intervention Trial

ERIC Educational Resources Information Center

Hantson, Julie; Wang, Pan Pan; Grizenko-Vida, Michael; Ter-Stepanian, Marina; Harvey, William; Joober, Ridha; Grizenko, Natalie

2012-01-01

Objective: The objective of this study was to evaluate the effectiveness of a 2-week therapeutic summer day camp for children with ADHD, which included a social skills training program and parent psychoeducation and training program. This was an open-label, nonrandomized Phase I Clinical Intervention Trial. Method: Parents completed the Weiss…

Clinically Relevant Changes in Emotional Expression in Children with ADHD Treated with Lisdexamfetamine Dimesylate

ERIC Educational Resources Information Center

Katic, Alain; Ginsberg, Lawrence; Jain, Rakesh; Adeyi, Ben; Dirks, Bryan; Babcock, Thomas; Scheckner, Brian; Richards, Cynthia; Lasser, Robert; Turgay, Atilla; Findling, Robert L.

2012-01-01

Objective: To describe clinically relevant effects of lisdexamfetamine dimesylate (LDX) on emotional expression (EE) in children with ADHD. Method: Children with ADHD participated in a 7-week, open-label, LDX dose-optimization study. Expression and Emotion Scale for Children (EESC) change scores were analyzed post hoc using two methods to…

An Open-Label Trial of 12-Week Simeprevir plus Peginterferon/Ribavirin (PR) in Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype 1 (GT1)

PubMed Central

Asselah, Tarik; Moreno, Christophe; Sarrazin, Christoph; Gschwantler, Michael; Foster, Graham R.; Craxí, Antonio; Buggisch, Peter; Ryan, Robert; Lenz, Oliver; Scott, Jane; Van Dooren, Gino; Lonjon-Domanec, Isabelle; Schlag, Michael; Buti, Maria

2016-01-01

Background Shortening duration of peginterferon-based HCV treatment reduces associated burden for patients. Primary objectives of this study were to assess the efficacy against the minimally acceptable response rate 12 weeks post-treatment (SVR12) and safety of simeprevir plus PR in treatment-naïve HCV GT1 patients treated for 12 weeks. Additional objectives included the investigation of potential associations of rapid viral response and baseline factors with SVR12. Methods In this Phase III, open-label study in treatment-naïve HCV GT1 patients with F0–F2 fibrosis, patients with HCV-RNA <25 IU/mL (detectable/undetectable) at Week 2, and undetectable HCV-RNA at Weeks 4 and 8, stopped all treatment at Week 12. All other patients continued PR for a further 12 weeks. Baseline factors significantly associated with SVR12 were identified through logistic regression. Results Of 163 patients who participated in the study, 123 (75%) qualified for 12-week treatment; of these, 81 (66%) achieved SVR12. Baseline factors positively associated with SVR12 rates in patients receiving the 12-week regimen were: IL28B CC genotype: (94% SVR12); HCV RNA ≤800,000 IU/mL (82%); F0–F1 fibrosis (74%). Among all 163 patients, 94% experienced ≥1 adverse event (AE), 4% a serious AE, and 2.5% discontinued due to an AE. Reduced impairment in patient-reported outcomes was observed in the 12-week vs >12-week regimen. Conclusions Overall SVR12 rate (66%) was below the target of 80%, indicating that shortening of treatment with simeprevir plus PR to 12 weeks based on very early response is not effective. However, baseline factors associated with higher SVR12 rates were identified. Therefore, while Week 2 response alone is insufficient to predict efficacy, GT1 patients with favourable baseline factors may benefit from a shortened simeprevir plus PR regimen. Trial Registration ClinicalTrials.gov NCT01846832 PMID:27428331

Switching from adalimumab to tofacitinib in the treatment of patients with rheumatoid arthritis.

PubMed

Genovese, Mark C; van Vollenhoven, Ronald F; Wilkinson, Bethanie; Wang, Lisy; Zwillich, Samuel H; Gruben, David; Biswas, Pinaki; Riese, Richard; Takiya, Liza; Jones, Thomas V

2016-06-23

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The aim of this study was to explore the safety and efficacy of open-label tofacitinib following blinded treatment with adalimumab or tofacitinib for moderate to severe RA. Analyses included patients treated with adalimumab 40 mg once every 2 weeks or tofacitinib 10 mg twice daily (BID) with background methotrexate (MTX) in a 12-month randomized study (NCT00853385), who subsequently received tofacitinib 10 mg BID (with/without background MTX) in an open-label extension (NCT00413699). Patients with treatment-related serious adverse events (AEs) and serious or recurrent infections in the index study were excluded from the extension study. Exposure-adjusted incidence rates of safety-related events were assessed in 3-month and 12-month periods in the year before and in the year after switching. Efficacy was assessed 3 months before, at the time of, and 3 months after switching. There were 233 (107 adalimumab to tofacitinib 10 mg BID, 126 blinded to open-label tofacitinib 10 mg BID) patients included in these analyses. Patients in both treatment sequences had similar incidence rates (per 100 patient-years) of discontinuation due to AEs, serious AEs, and serious infections in the year before and in the year after switching. Incidence rates of AEs were increased in the first 3 months after switching compared with the last 3 months before switching in both treatment groups. Switching from either blinded adalimumab or tofacitinib to open-label tofacitinib resulted in numerically higher incidence of responders for signs and symptoms of disease and improved physical function. Treatment can be directly switched from adalimumab to tofacitinib. A similar safety and efficacy profile was seen when patients received open-label tofacitinib after receiving either blinded adalimumab or tofacitinib. ClinicalTrials.gov Identifiers: NCT00853385 , registered 27 February 2009; NCT00413699 , registered 18 December 2006.

Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis.

PubMed

Ruperto, Nicolino; Lovell, Daniel J; Quartier, Pierre; Paz, Eliana; Rubio-Pérez, Nadina; Silva, Clovis A; Abud-Mendoza, Carlos; Burgos-Vargas, Ruben; Gerloni, Valeria; Melo-Gomes, Jose A; Saad-Magalhães, Claudia; Chavez-Corrales, J; Huemer, Christian; Kivitz, Alan; Blanco, Francisco J; Foeldvari, Ivan; Hofer, Michael; Horneff, Gerd; Huppertz, Hans-Iko; Job-Deslandre, Chantal; Loy, Anna; Minden, Kirsten; Punaro, Marilynn; Nunez, Alejandro Flores; Sigal, Leonard H; Block, Alan J; Nys, Marleen; Martini, Alberto; Giannini, Edward H

2010-06-01

We previously documented that abatacept was effective and safe in patients with juvenile idiopathic arthritis (JIA) who had not previously achieved a satisfactory clinical response with disease-modifying antirheumatic drugs or tumor necrosis factor blockade. Here, we report results from the long-term extension (LTE) phase of that study. This report describes the long-term, open-label extension phase of a double-blind, randomized, controlled withdrawal trial in 190 patients with JIA ages 6-17 years. Children were treated with 10 mg/kg abatacept administered intravenously every 4 weeks, with or without methotrexate. Efficacy results were based on data derived from the 153 patients who entered the open-label LTE phase and reflect >or=21 months (589 days) of treatment. Safety results include all available open-label data as of May 7, 2008. Of the 190 enrolled patients, 153 entered the LTE. By day 589, 90%, 88%, 75%, 57%, and 39% of patients treated with abatacept during the double-blind and LTE phases achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria for improvement, respectively. Similar response rates were observed by day 589 among patients previously treated with placebo. Among patients who had not achieved an ACR Pedi 30 response at the end of the open-label lead-in phase and who proceeded directly into the LTE, 73%, 64%, 46%, 18%, and 5% achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses, respectively, by day 589 of the LTE. No cases of tuberculosis and no malignancies were reported during the LTE. Pneumonia developed in 3 patients, and multiple sclerosis developed in 1 patient. Abatacept provided clinically significant and durable efficacy in patients with JIA, including those who did not initially achieve an ACR Pedi 30 response during the initial 4-month open-label lead-in phase.

An open treatment trial of venlafaxine for elderly patients with dysthymic disorder.

PubMed

Devanand, D P; Juszczak, Nicole; Nobler, Mitchell S; Turret, Nancy; Fitzsimons, Linda; Sackeim, Harold A; Roose, Steven P

2004-12-01

Treatment response and side effects of venlafaxine were evaluated in an open-label trial of elderly outpatients with dysthymic disorder (DD). Patients received flexible dose (up to 300 mg/d) venlafaxine (Effexor XR) for 12 weeks. Of 23 study patients, 18 completed the trial. Fourteen (60.9%) were responders in intent-to-treat analyses with the last observation carried forward, and 77.8% were responders in completer analyses. Nearly half the sample (47.8%) met criteria for remission. In the intent-to-treat sample, increased severity of depression at baseline was associated with superior response, and the presence of cardiovascular disease was associated with poorer response. Venlafaxine open-label treatment was associated with fairly high response rates and generally good tolerability in elderly patients with DD. These results indicate that in elderly patients with DD, placebo-controlled trials of a dual reuptake inhibitor such as venlafaxine would be needed to assess its efficacy or to compare its efficacy to that of other antidepressants.

Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension.

PubMed

Aman, Michael G; Findling, Robert L; Hardan, Antonio Y; Hendren, Robert L; Melmed, Raun D; Kehinde-Nelson, Ola; Hsu, Hai-An; Trugman, Joel M; Palmer, Robert H; Graham, Stephen M; Gage, Allyson T; Perhach, James L; Katz, Ephraim

2017-06-01

Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension. A total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day. There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks. This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.

Open-label randomized multicenter selection study of once daily antiretroviral treatment regimen comparing ritonavir-boosted atazanavir to efavirenz with fixed-dose abacavir and lamivudine.

PubMed

Honda, Miwako; Ishisaka, Michiyo; Ishizuka, Naoki; Kimura, Satoshi; Oka, Shinichi

2011-01-01

The side-effects of anti-retroviral drugs are different between Japanese and Caucasian patients. Severe central nerve system (CNS) side-effects to efavirenz and low rate of hypersensitivity against abacavir characterize the Japanese. The objective of this study was to select a once daily regimen for further non-inferior study comparing the virological efficacy and safety of the first line once daily antiretroviral treatment regimens in the current HIV/AIDS guideline. The study design was a randomized, open label, multicenter, selection study. One arm was treated with efavirenz and the other with ritonavir-boosted atazanavir. A fixed-dose lamivudine plus abacavir were used in both arms. The primary endpoint was virologic success (viral load less than 50 copies/mL) rate at 48 weeks. Patients were followed-up to 96 weeks with safety as the secondary endpoint. Clinicaltrials.Gov (NCT00280969) and the University hospital Medical Information Network (UMIN000000243). A total of 71 participants were enrolled. Virologic success rates in both arms were similar at week 48 [efavirenz arm 28/36 (77.8%); atazanavir arm 27/35 (77.1%)], but were decreased at week 96 to 55.6% in the efavirenz arm and 68.8% in the atazanavir arm (p=0.33). At the 96-week follow-up, 52.8% of the EFV arm and 34.3% of the ATV/r arm reached total cholesterol more than 220 mg/dL and required treatment. None of the patients developed cardiovascular complications in this study by week 96. There was no significant difference in the efficacy of efavirenz and ritonavir-boosted atazanavir combined with lamivudine plus abacavir at 48 weeks. The evaluation of safety was extended to 96 weeks, which also showed no significant difference in both arms.

Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension

PubMed Central

Findling, Robert L.; Hardan, Antonio Y.; Hendren, Robert L.; Melmed, Raun D.; Kehinde-Nelson, Ola; Hsu, Hai-An; Trugman, Joel M.; Palmer, Robert H.; Graham, Stephen M.; Gage, Allyson T.; Perhach, James L.; Katz, Ephraim

2017-01-01

Abstract Objective: Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension. Methods: A total of 121 children 6–12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day. Results: There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks. Conclusions: This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications. PMID:26978327

Single-center, open-label study of a proprietary topical 0.5% salicylic acid-based treatment regimen containing sandalwood oil in adolescents and adults with mild to moderate acne.

PubMed

Moy, Ronald L; Levenson, Corey; So, Jeffrey J; Rock, James A

2012-12-01

A proprietary topical blend of salicylic acid and highly purified sandalwood oil from Australia was used in this open-label study in adolescents and adults with mild to moderate facial acne. The investigational regimen consisted of a foaming cleanser, an acne serum, a spot treatment, and a mask. Patients applied the treatment regimen as directed for 8 weeks. The primary efficacy measure was the percentage of patients assessed as improved, much improved, or very much improved according to the Global Aesthetic Improvement Scale (GAIS) ratings at week 8. Severity was rated using the Evaluator's Global Severity Scores (EGSS) at baseline and weeks 2, 4, and 8. Tolerability was assessed at baseline and weeks 2, 4, and 8 by asking patients to rate the severity of itching, scaling, erythema, burning, dryness, and stinging. Patients were also asked to complete an acne questionnaire. 89.4% (42/47) met the primary end point determined by the GAIS of improved (66%), much improved (19%), or very much improved (4%). Notable reductions in lesion counts were observed in patients with more severe or inflamed lesions. Tolerability was queried at all visits. No itching, scaling, or erythema was reported after initial application. Symptoms of intolerability peaked at week 2; however, most events were mild to moderate and were typically reported with use of the mask component. Intolerance decreased by week 4 and by week 8. The treatment regimen was well tolerated by patients. Results from this study support the use of a proprietary investigational regimen in patients with mild to moderate acne and warrant further investigation to determine whether longer-term therapy (ie, beyond 8 weeks) results in enhanced efficacy with minimal side effects, leading to continued patient compliance and skin improvement.

Centchroman as First-line Treatment for Mastalgia: Results of an Open-label, Single-arm Trial.

PubMed

Rathi, Jalaj; Chawla, Inderjit; Singh, Karnail; Chawla, Arjun

2016-07-01

Mastalgia is a distressing symptom and may be severe enough to interfere with usual daily activities. Breast pain is either cyclical or noncyclical. Currently; multiple options are available for the treatment of mastalgia including hormonal and nonhormonal agents. This study was conducted to evaluate the role of centchroman as a nonhormonal first-line treatment for moderate to severe mastalgia. To accomplish this; a prospective open-label, single-arm study was done using the Pretest-Posttest Design. A total of 100 women suffering from mastalgia were grouped according to the characteristic pattern of breast pain (cyclic and noncyclic) and received centchroman 30 mg/day for 12 weeks followed by observation for 12 weeks. The efficacy analysis of centchroman was done by comparing median Visual Analog Scale score, median pain duration and side effects over time among the two groups. Centchroman significantly alleviates mastalgia with minimal side effects. The median pain score was significantly reduced over successive visits (1, 4, 12, and 24 weeks). The median pain duration decreased remarkably over time in comparison to the baseline (p = 0.001). Overall the response rate was 88% at the end of 12 weeks and 85% at the end of 24 weeks. The drug was found more effective with a quicker response in cyclic pattern of matalgia. Complete response was observed in 66% of cyclic mastalgia and 40% of noncyclic mastalgia patients at 1 week of therapy. The response was improved over time in both groups and at completion of treatment (12 weeks) 92% patients in cyclic group and 80% patients in noncyclic group were pain free. The effect of the drug persisted till the completion (24 weeks) of the study (p = 0.001). These results imply that centchroman is very effective in treating breast pain and can be prescribed as drug of first choice for mastalgia. © 2016 Wiley Periodicals, Inc.

Dextromethorphan/quinidine pharmacotherapy in patients with treatment resistant depression: A proof of concept clinical trial.

PubMed

Murrough, James W; Wade, Elizabeth; Sayed, Sehrish; Ahle, Gabriella; Kiraly, Drew D; Welch, Alison; Collins, Katherine A; Soleimani, Laili; Iosifescu, Dan V; Charney, Dennis S

2017-08-15

At least one-third of patients with major depressive disorder (MDD) have treatment-resistant depression (TRD), defined as lack of response to two or more adequate antidepressant trials. For these patients, novel antidepressant treatments are urgently needed. The current study is a phase IIa open label clinical trial examining the efficacy and tolerability of a combination of dextromethorphan (DM) and the CYP2D6 enzyme inhibitor quinidine (Q) in patients with TRD. Dextromethorphan acts as an antagonist at the glutamate N-methyl-d-aspartate (NMDA) receptor, in addition to other pharmacodynamics properties that include activity at sigma-1 receptors. Twenty patients with unipolar TRD who completed informed consent and met all eligibility criteria we enrolled in an open-label study of DM/Q up to 45/10mg by mouth administered every 12h over the course of a 10-week period, and constitute the intention to treat (ITT) sample. Six patients discontinued prior to study completion. There was no treatment-emergent suicidal ideation, psychotomimetic or dissociative symptoms. Montgomery-Asberg Depression Rating Scale (MADRS) score was reduced from baseline to the 10-week primary outcome (mean change: -13.0±11.5, t 19 =5.0, p<0.001), as was QIDS-SR score (mean change: -5.9±6.6, t 19 =4.0, p<0.001). The response and remission rates in the ITT sample were 45% and 35%, respectively. Open-label, proof-of-concept design. Herein we report acceptable tolerability and preliminary efficacy of DM/Q up to 45/10mg administered every 12h in patients with TRD. Future larger placebo controlled randomized trials in this population are warranted. Copyright © 2017 Elsevier B.V. All rights reserved.

Open-label placebo treatment in chronic low back pain: a randomized controlled trial

PubMed Central

Carvalho, Cláudia; Caetano, Joaquim Machado; Cunha, Lidia; Rebouta, Paula; Kaptchuk, Ted J.; Kirsch, Irving

2016-01-01

Abstract This randomized controlled trial was performed to investigate whether placebo effects in chronic low back pain could be harnessed ethically by adding open-label placebo (OLP) treatment to treatment as usual (TAU) for 3 weeks. Pain severity was assessed on three 0- to 10-point Numeric Rating Scales, scoring maximum pain, minimum pain, and usual pain, and a composite, primary outcome, total pain score. Our other primary outcome was back-related dysfunction, assessed on the Roland–Morris Disability Questionnaire. In an exploratory follow-up, participants on TAU received placebo pills for 3 additional weeks. We randomized 97 adults reporting persistent low back pain for more than 3 months' duration and diagnosed by a board-certified pain specialist. Eighty-three adults completed the trial. Compared to TAU, OLP elicited greater pain reduction on each of the three 0- to 10-point Numeric Rating Scales and on the 0- to 10-point composite pain scale (P < 0.001), with moderate to large effect sizes. Pain reduction on the composite Numeric Rating Scales was 1.5 (95% confidence interval: 1.0-2.0) in the OLP group and 0.2 (−0.3 to 0.8) in the TAU group. Open-label placebo treatment also reduced disability compared to TAU (P < 0.001), with a large effect size. Improvement in disability scores was 2.9 (1.7-4.0) in the OLP group and 0.0 (−1.1 to 1.2) in the TAU group. After being switched to OLP, the TAU group showed significant reductions in both pain (1.5, 0.8-2.3) and disability (3.4, 2.2-4.5). Our findings suggest that OLP pills presented in a positive context may be helpful in chronic low back pain. PMID:27755279

Open-label placebo treatment in chronic low back pain: a randomized controlled trial.

PubMed

Carvalho, Cláudia; Caetano, Joaquim Machado; Cunha, Lidia; Rebouta, Paula; Kaptchuk, Ted J; Kirsch, Irving

2016-12-01

This randomized controlled trial was performed to investigate whether placebo effects in chronic low back pain could be harnessed ethically by adding open-label placebo (OLP) treatment to treatment as usual (TAU) for 3 weeks. Pain severity was assessed on three 0- to 10-point Numeric Rating Scales, scoring maximum pain, minimum pain, and usual pain, and a composite, primary outcome, total pain score. Our other primary outcome was back-related dysfunction, assessed on the Roland-Morris Disability Questionnaire. In an exploratory follow-up, participants on TAU received placebo pills for 3 additional weeks. We randomized 97 adults reporting persistent low back pain for more than 3 months' duration and diagnosed by a board-certified pain specialist. Eighty-three adults completed the trial. Compared to TAU, OLP elicited greater pain reduction on each of the three 0- to 10-point Numeric Rating Scales and on the 0- to 10-point composite pain scale (P < 0.001), with moderate to large effect sizes. Pain reduction on the composite Numeric Rating Scales was 1.5 (95% confidence interval: 1.0-2.0) in the OLP group and 0.2 (-0.3 to 0.8) in the TAU group. Open-label placebo treatment also reduced disability compared to TAU (P < 0.001), with a large effect size. Improvement in disability scores was 2.9 (1.7-4.0) in the OLP group and 0.0 (-1.1 to 1.2) in the TAU group. After being switched to OLP, the TAU group showed significant reductions in both pain (1.5, 0.8-2.3) and disability (3.4, 2.2-4.5). Our findings suggest that OLP pills presented in a positive context may be helpful in chronic low back pain.

Improvements in Irritability with Open-Label Methylphenidate Treatment in Youth with Comorbid Attention Deficit/Hyperactivity Disorder and Disruptive Mood Dysregulation Disorder.

PubMed

Winters, Drew E; Fukui, Sadaaki; Leibenluft, Ellen; Hulvershorn, Leslie A

2018-06-01

The purpose of this open-label study was to examine the effects of long-acting methylphenidate (MPH) treatment on irritability and related emotional symptoms associated with disruptive mood dysregulation disorder (DMDD) in youth with comorbid attention-deficit/hyperactivity disorder (ADHD). The sample included 22 medication-free male and female subjects (ages 9-15) who met criteria for both DMDD and ADHD. Participants underwent a 4-week trial of long-acting MPH treatment (Concerta ® ), with weekly dosing increases until a therapeutic dose was reached. Repeated measures t-tests were used to compare pre- and posttreatment ratings of primary and secondary measures. The primary outcome was self-report irritability. Secondary outcomes included parent and child ratings of emotional frequency, emotional lability, and negative affect (NA). Multiple regression was used to examine the impact baseline hyperactivity, age, gender, race, socioeconomic status, or comorbid diagnosis had on treatment outcomes. Significant improvements (medium to large effect sizes) in child-rated irritability as well as parent and child ratings of emotional lability, NA, and anger were found. As anticipated, ADHD symptoms also improved. While a majority of the sample saw improvement in child-rated irritability (71%), symptoms worsened a small proportion (19%), and an even smaller portion experienced no change (10%). No demographics, psychiatric comorbidities, or severity of ADHD symptoms influenced treatment outcomes. Study findings suggest that MPH treatment significantly improved mood and emotional symptoms associated with DMDD comorbid with ADHD. These findings, coupled with good tolerability in this open-label pilot study supports further research into the use of MPH as a first-line treatment for DMDD. Future work examining MPH treatment of youth with DMDD with and without comorbid ADHD is needed.

A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain.

PubMed

Hoggart, B; Ratcliffe, S; Ehler, E; Simpson, K H; Hovorka, J; Lejčko, J; Taylor, L; Lauder, H; Serpell, M

2015-01-01

Peripheral neuropathic pain (PNP) poses a significant clinical challenge. The long-term efficacy of delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray was investigated in this 38-week open-label extension study. In total, 380 patients with PNP associated with diabetes or allodynia entered this study from two parent randomised, controlled trials. Patients received THC/CBD spray for a further 38 weeks in addition to their current analgesic therapy. Neuropathic pain severity was the primary efficacy measure using a pain 0-10 numerical rating scale (NRS). Additional efficacy, safety and tolerability outcomes were also investigated. In total, 234 patients completed the study (62 %). The pain NRS showed a decrease in score over time in patients from a mean of 6.9 points (baseline in the parent studies) to a mean of 4.2 points (end of open-label follow-up). The proportion of patients who reported at least a clinically relevant 30 % improvement in pain continued to increase with time (up to 9 months); at least half of all patients reported a 30 % improvement at all time points. Improvements were observed for all secondary efficacy outcomes, including sleep quality 0-10 NRS scores, neuropathic pain scale scores, subject global impression of change and EQ-5D questionnaire scores. THC/CBD spray was well tolerated for the study duration and patients did not seek to increase their dose with time, with no new safety concerns arising from long-term use. In this previously difficult to manage patient population, THC/CBD spray was beneficial for the majority of patients with PNP associated with diabetes or allodynia.

Intravenous immunoglobulin for maintenance treatment of chronic inflammatory demyelinating polyneuropathy: a multicentre, open-label, 52-week phase III trial.

PubMed

Kuwabara, Satoshi; Mori, Masahiro; Misawa, Sonoko; Suzuki, Miki; Nishiyama, Kazutoshi; Mutoh, Tatsuro; Doi, Shizuki; Kokubun, Norito; Kamijo, Mikiko; Yoshikawa, Hiroo; Abe, Koji; Nishida, Yoshihiko; Okada, Kazumasa; Sekiguchi, Kenji; Sakamoto, Ko; Kusunoki, Susumu; Sobue, Gen; Kaji, Ryuji

2017-10-01

Short-term efficacy of induction therapy with intravenous immunoglobulin (Ig) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) is well established. However, data of previous studies on maintenance therapy were limited up to 24-week treatment period. We aimed to investigate the efficacy and safety of longer-term intravenous Ig therapy for 52 weeks. This study was an open-label phase 3 clinical trial conducted in 49 Japanese tertiary centres. 49 patients with CIDP who fulfilled diagnostic criteria were included. After an induction intravenous Ig therapy (0.4 g/kg/day for five consecutive days), maintenance dose intravenous Ig (1.0 g/kg) was given every 3 weeks for up to 52 weeks. The primary outcome measures were the responder rate at week 28 and relapse rate at week 52. The response and relapse were defined with the adjusted Inflammatory Neuropathy Cause and Treatment scale. At week 28, the responder rate was 77.6% (38/49 patients; 95% CI 63% to 88%), and the 38 responders continued the maintenance therapy. At week 52, 4 of the 38 (10.5%) had a relapse (95% CI 3% to 25%). During 52 weeks, 34 (69.4%) of the 49 enrolled patients had a maintained improvement. Adverse events were reported in 94% of the patients; two patients (66-year-old and 76-year-old men with hypertension or diabetes) developed cerebral infarction (lacunar infarct with good recovery), and the other adverse effects were mild and resolved by the end of the study period. Maintenance treatment with 1.0 g/kg intravenous Ig every 3 weeks is an efficacious therapy for patients with CIDP, and approximately 70% of them had a sustained remission for 52 weeks. Thrombotic complications should be carefully monitored, particularly in elderly patients with vascular risk factors. ClinicalTrials.gov (NCT01824251). © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Safety and efficacy of canagliflozin in Japanese patients with type 2 diabetes mellitus: post hoc subgroup analyses according to body mass index in a 52-week open-label study.

PubMed

Inagaki, Nobuya; Goda, Maki; Yokota, Shoko; Maruyama, Nobuko; Iijima, Hiroaki

2015-01-01

The safety and efficacy of sodium glucose co-transporter 2 inhibitors in non-obese compared with obese patients with type 2 diabetes mellitus is unknown. We conducted post hoc analyses of the results of a 52-week open-label study of Japanese type 2 diabetes mellitus patients treated with 100 or 200 mg canagliflozin. Patients were divided into four subgroups according to their baseline body mass index (BMI): group I, BMI < 22 kg/m(2); group II, BMI ≥ 22 to < 25 kg/m(2); group III, BMI ≥ 25 to < 30 kg/m(2) and group IV, BMI ≥ 30 kg/m(2). The overall safety was similar among the four BMI subgroups, although there were slight differences in terms of the incidences of hypoglycemia, asymptomatic hypoglycemia, female genital infections and proportions of patients with total ketone body levels exceeding 1000 μmol/l at any time for both canagliflozin doses. Hemoglobin A1c, fasting plasma glucose and body weight decreased significantly from baseline to week 52 at both canagliflozin doses. The changes in hemoglobin A1c, and fasting plasma glucose were not significantly different among the four BMI subgroups for either dose. Canagliflozin was tolerated in patients irrespective of their BMI at the start of treatment, although some caution may be needed.

Adherence to subcutaneous interferon beta-1a treatment using an electronic injection device: a prospective open-label Scandinavian noninterventional study (the ScanSmart study)

PubMed Central

Pedersen, Elena Didenko; Stenager, Egon; Vadgaard, JL; Jensen, MB; Schmid, R; Meland, N; Magnussen, G; Frederiksen, Jette L

2018-01-01

Background Disease modifying drugs help control the course of relapsing remitting multiple sclerosis (RRMS); however, good adherence is needed for long-term outcomes. Objective To evaluate patient adherence to treatment with subcutaneous interferon beta-1a using RebiSmart® and assess injection-site reactions and treatment satisfaction. Methods This prospective, single-arm, open-label, noninterventional multicenter Phase IV trial included disease modifying drug-experienced mobile patients with RRMS. Adherence was measured over 12 weeks. Items 13–23, 35, 37, and 38 of the Multiple Sclerosis Treatment Concerns Questionnaire (injection-site reactions and treatment satisfaction) were recorded at 12 weeks. Results Sixty patients were recruited (mean age 43.7 [±SD 7.9] years; 83% female; mean years since multiple sclerosis diagnosis 6.7 [SD 4.5]). Adherence data were obtained in 54 patients only due to technical problems with six devices. Over 12 weeks, 89% (n=48) of patients had ≥90% adherence to treatment. Most patients experienced mild influenza-like symptoms and injection-site reactions, and global side effects were minimal. Most patients (78%) rated the convenience as the most important aspect of the device, and most experienced no or mild pain. Conclusion RRMS patients treated with subcutaneous interferon beta-1a, administered with RebiSmart, demonstrated generally good adherence, and the treatment was generally well tolerated. PMID:29720872

Adherence to subcutaneous interferon beta-1a treatment using an electronic injection device: a prospective open-label Scandinavian noninterventional study (the ScanSmart study).

PubMed

Pedersen, Elena Didenko; Stenager, Egon; Vadgaard, J L; Jensen, M B; Schmid, R; Meland, N; Magnussen, G; Frederiksen, Jette L

2018-01-01

Disease modifying drugs help control the course of relapsing remitting multiple sclerosis (RRMS); however, good adherence is needed for long-term outcomes. To evaluate patient adherence to treatment with subcutaneous interferon beta-1a using RebiSmart ® and assess injection-site reactions and treatment satisfaction. This prospective, single-arm, open-label, noninterventional multicenter Phase IV trial included disease modifying drug-experienced mobile patients with RRMS. Adherence was measured over 12 weeks. Items 13-23, 35, 37, and 38 of the Multiple Sclerosis Treatment Concerns Questionnaire (injection-site reactions and treatment satisfaction) were recorded at 12 weeks. Sixty patients were recruited (mean age 43.7 [±SD 7.9] years; 83% female; mean years since multiple sclerosis diagnosis 6.7 [SD 4.5]). Adherence data were obtained in 54 patients only due to technical problems with six devices. Over 12 weeks, 89% (n=48) of patients had ≥90% adherence to treatment. Most patients experienced mild influenza-like symptoms and injection-site reactions, and global side effects were minimal. Most patients (78%) rated the convenience as the most important aspect of the device, and most experienced no or mild pain. RRMS patients treated with subcutaneous interferon beta-1a, administered with RebiSmart, demonstrated generally good adherence, and the treatment was generally well tolerated.

Efficacy of Atomoxetine in Children with Severe Autistic Disorders and Symptoms of ADHD: An Open-Label Study

ERIC Educational Resources Information Center

Charnsil, Chawanun

2011-01-01

Objective: This study aims to examine the efficacy of atomoxetine in treating symptoms of attention deficit hyperactivity disorder (ADHD) in children with severe autistic disorder. Method: Children with severe autistic disorder who had symptoms of ADHD were given atomoxetine for 10 weeks. The efficacy of atomoxetine was evaluated by using the…

Open-label study of duloxetine for the treatment of obsessive-compulsive disorder.

PubMed

Dougherty, Darin D; Corse, Andrew K; Chou, Tina; Duffy, Amanda; Arulpragasam, Amanda R; Deckersbach, Thilo; Jenike, Michael A; Keuthen, Nancy J

2015-01-01

This study sought to investigate the efficacy of duloxetine for the treatment of obsessive-compulsive disorder (DSM-IV). Twenty individuals were enrolled in a 17-week, open-label trial of duloxetine at Massachusetts General Hospital. Data were collected between March 2007 and September 2012. Study measures assessing obsessive-compulsive disorder symptoms, quality of life, depression, and anxiety were administered at baseline and weeks 1, 5, 9, 13, and 17. The primary outcome measures were the Yale-Brown Obsessive Compulsive Scale and Clinical Global Improvement scale. For the 12 study completers, pre- and posttreatment analyses revealed significant improvements (P<.05) on clinician- and self-rated measures of obsessive-compulsive disorder symptoms and quality of life. Among the 12 completers, more than one-half (n=7) satisfied full medication response criteria. Intention-to-treat analyses (n=20) showed similar improvements (P<.05) on primary and secondary study outcome measures. The results of this study suggest that duloxetine may provide a significant reduction in symptoms for patients with obsessive-compulsive disorder. ClinicalTrials.gov NCT00464698; http://clinicaltrials.gov/ct2/show/NCT00464698?term=NCT00464698&rank=1. © The Author 2015. Published by Oxford University Press on behalf of CINP.

The Efficacy of Neurofeedback in Patients with Major Depressive Disorder: An Open Labeled Prospective Study.

PubMed

Cheon, Eun-Jin; Koo, Bon-Hoon; Choi, Joong-Hyun

2016-03-01

The purpose of this study was to evaluate the effect of neurofeedback on depressive symptoms and electrophysiological disturbances in patients with major depressive disorder. We recruited participants suffering from depression to evaluate efficacy of left prefrontal beta with alpha/theta training. An 8-week, prospective, open-label study was undertaken. Twenty participants were recruited. The treatment protocol was twice or three times a week training of beta at F3 with alpha/theta at Pz for 8 weeks. When every visit, patients were received beta training for 30 min, and then alpha/theta training for 30 min. Baseline, 4 and 8 week scores of; the Hamilton rating scale for Depression (HAM-D), the Hamilton rating scale for Anxiety (HAM-A), the Beck Depression Inventory (BDI)-II, the Beck Anxiety Inventory (BAI), Clinical global impression-severity (CGI-S), and pre- and post-treatment resting state EEGs were compared. Interhemispheric alpha power asymmetry (A score) was computed for homologous sites F3-F4. Pre- and post-training clinical assessments revealed significant improvements in HAM-D, HAM-A, BDI, and CGI-S scores. Cumulative response rates by HAM-D were 35.0 and 75.0 % at 4 and 8 weeks, respectively, corresponding cumulative remission rates by HAM-D were 15.0 and 55.0 %, respectively. No significant differences were found between pre- and post-treatment A score. Neurofeedback treatment could improve depressive symptoms significantly. In addition, anxiety symptoms and clinical illness severity decreased significantly after neurofeedback treatment. Despite its several limitations, such as, small sample size and lack of a control group, this study suggested neurofeedback has significant effects in patients with major depressive disorder.

Efficacy of the Ubiquitous Spaced Retrieval-based Memory Advancement and Rehabilitation Training (USMART) program among patients with mild cognitive impairment: a randomized controlled crossover trial.

PubMed

Han, Ji Won; Son, Kyung Lak; Byun, Hye Jin; Ko, Ji Won; Kim, Kayoung; Hong, Jong Woo; Kim, Tae Hyun; Kim, Ki Woong

2017-06-06

Spaced retrieval training (SRT) is a nonpharmacological intervention for mild cognitive impairment (MCI) and dementia that trains the learning and retention of target information by recalling it over increasingly long intervals. We recently developed the Ubiquitous Spaced Retrieval-based Memory Advancement and Rehabilitation Training (USMART) program as a convenient, self-administered tablet-based SRT program. We also demonstrated the utility of USMART for improving memory in individuals with MCI through an open-label uncontrolled trial. This study had an open-label, single-blind, randomized, controlled, two-period crossover design. Fifty patients with MCI were randomized into USMART-usual care and usual care-USMART treatment sequences. USMART was completed or usual care was provided biweekly over a 4-week treatment period with a 2-week washout period between treatment periods. Primary outcome measures included the Word List Memory Test, Word List Recall Test (WLRT), and Word List Recognition Test. Outcomes were measured at baseline, week 5, and week 11 by raters who were blinded to intervention type. An intention-to-treat analysis and linear mixed modeling were used. Of 50 randomized participants, 41 completed the study (18% dropout rate). The USMART group had larger improvements in WLRT score (effect size = 0.49, p = 0.031) than the usual care group. There were no significant differences in other primary or secondary measures between the USMART and usual care groups. Moreover, no USMART-related adverse events were reported. The 4-week USMART modestly improved information retrieval in older people with MCI, and was well accepted with minimal technical support. ClinicalTrials.gov NCT01688128 . Registered 12 September 2012.

Long-term safety and effectiveness of lubiprostone, a chloride channel (ClC-2) activator, in patients with chronic idiopathic constipation.

PubMed

Lembo, Anthony J; Johanson, John F; Parkman, Henry P; Rao, Satish S; Miner, Philip B; Ueno, Ryuji

2011-09-01

Lubiprostone helps relieve constipation in short-term 4-week studies. There are limited data on long-term pharmacological treatment with lubiprostone for chronic idiopathic constipation. To examine the long-term safety and effectiveness of lubiprostone in patients with chronic idiopathic constipation. In this prospective, multicenter, open-labeled trial, 248 patients aged ≥18 years with chronic idiopathic constipation were directed to take lubiprostone 24 mcg BID as needed for 48 weeks. Patients were allowed to decrease the dose in response to the perceived severity of constipation and need for relief. Hematology and chemistry profiles and assessment of constipation symptoms and its severity were performed at all visits. Adverse events (AEs) were recorded. Of the 248 patients who entered the trial, 127 (51%) completed the trial. A dose reduction was observed in 17% of the patients, resulting in an average study medication exposure across the study of approximately 1.7 capsules (or approximately 40.8 mcg) per day. The most common treatment-related AEs were nausea (19.8%), diarrhea (9.7%), abdominal distension (6.9%), headache (6.9%), and abdominal pain (5.2%). No deaths were reported and of the 16 reported serious AEs, one was considered possibly treatment related. Average changes in serum electrolytes were not clinically relevant at any time point during the study. On average, lubiprostone significantly (p < 0.0001) reduced patient-reported constipation severity, abdominal bloating, and abdominal discomfort across 48 weeks when compared to baseline. During this 48-week open-label study, lubiprostone was well tolerated. Bowel symptoms consistently improved over 48 weeks in adult patients with chronic idiopathic constipation.

Two-Year Safety and Efficacy Experience in Patients with Methotrexate-Resistant Active Rheumatoid Arthritis Treated with Etanercept and Conventional Disease-Modifying Anti-rheumatic Drugs in the Latin American Region

PubMed Central

Machado, Daniel A.; Guzman, Renato; Xavier, Ricardo M.; Simon, Jesus A.; Mele, Linda; Shen, Qi; Pedersen, Ronald; Kotak, Sameer; Vlahos, Bonnie

2016-01-01

Background: Although long-term data are available from biologic studies in North American/European populations with rheumatoid arthritis (RA), long-term findings in Latin American RA populations are limited. Objective: To examine long-term safety/efficacy of etanercept, methotrexate, and/or other disease-modifying anti-rheumatic drugs (DMARDs) in Latin American patients with moderate-to-severe active RA. Methods: In the first phase of this open-label study, patients were randomized to etanercept 50 mg weekly plus methotrexate or conventional DMARD (hydroxychloroquine or sulfasalazine) plus methotrexate for 24 weeks. At the start of the second phase (week 24), investigators selected a treatment regimen that included any combination/dosage of etanercept, methotrexate, hydroxychloroquine, or sulfasalazine based on previous treatment response, preference, and local product labeling, and was continued for the 104-week extension. Results: In the extension, in the group previously randomized to etanercept-plus-methotrexate therapy, etanercept was continued in 259/260 patients; methotrexate continued in 260/260; and hydroxychloroquine and sulfasalazine added in 8/260 and 3/260, respectively. In the group previously randomized to conventional DMARD-plus-methotrexate therapy, conventional DMARD was discontinued in 86/126 and etanercept added in 105/126. Among etanercept-exposed patients (total exposure, 798.1 patient-year [PY]), rates of adverse events, serious adverse events, and serious infections per PY were 1.7, 0.07, and 0.02 events per PY. In both groups, after treatment modification was permitted, clinical response rates and improvements in clinical/patient-reported outcomes from baseline were sustained to week 128. Conclusion: After investigators were permitted to modify treatment, etanercept was part of the treatment regimen in 95% of patients. Continuation or addition of etanercept in the 2-year extension resulted in a consistently good risk:benefit profile. Trial Registration: Open-Label Study Comparing Etanercept to Conventional Disease Modifying Antirheumatic Drug (DMARD) Therapy; ClinicalTrials.gov, number NCT00848354; https://clinicaltrials.gov/ct2/show/NCT00848354 PMID:27006728

Safety and efficacy from a 6-week double-blind study and a 52-week open-label extension of aripiprazole in adolescents with schizophrenia in Japan.

PubMed

Matsumoto, Hideo; Ishigooka, Jun; Ono, Hiroaki; Tadori, Yoshihiro

2018-05-18

The purpose of this study was to evaluate the safety and efficacy of aripiprazole in adolescents with schizophrenia in Japan. In a 6-week, randomized, double-blind, dose-comparison study, adolescents (aged 13-17 years) with schizophrenia were randomized to receive aripiprazole 2, 6-12, or 24-30 mg/day. Patients who completed the 6-week study participated in a 52-week, flexible-dose, open-label extension (OLE) study of aripiprazole (initial dose: 2 mg/day, maintenance dose: 6-24 mg/day, maximum dose: 30 mg/day). In the 6-week study, the percentage of patients completing treatment was 77.1% (27/35) for 2 mg/day, 80.0% (24/30) for 6-12 mg/day, and 85.4% (35/41) for 24-30 mg/day. The least squares mean change in the Positive and Negative Syndrome Scale (PANSS) total score from baseline to endpoint (primary efficacy endpoint, last observation carried forward) was -19.6 for 2 mg/day, -16.5 for 6-12 mg/day, and -21.6 for 24-30 mg/day. The most common (≥20% patients in any group) treatment-emergent adverse events (TEAEs) were nausea, akathisia, insomnia, and somnolence. Most TEAEs were mild or moderate in severity. There were no deaths. In the OLE, 60.3% (41/68) of patients completed treatment, and the PANSS total score decreased by -7.9 from OLE baseline to week 52. The most common (≥20% patients) TEAEs were nasopharyngitis and somnolence. Most TEAEs were mild or moderate in severity. There were no deaths. These study results suggested that aripiprazole would be safe and well tolerated in both short- and long-term treatment for adolescents with schizophrenia in Japan. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Efficacy and safety of lacosamide as first add-on or later adjunctive treatment for uncontrolled partial-onset seizures: A multicentre open-label trial.

PubMed

Zadeh, Wendy Waldman; Escartin, Antonio; Byrnes, William; Tennigkeit, Frank; Borghs, Simon; Li, Ting; Dedeken, Peter; De Backer, Marc

2015-09-01

To evaluate the efficacy and safety of lacosamide administered as either first add-on or later add-on antiepileptic drug (AED) therapy for patients with uncontrolled partial-onset seizures (POS). In this open-label, multicentre trial, patients with POS initiated oral lacosamide (titrated to 400 mg/day) either as add-on to first AED monotherapy, or as later add-on to 1-3 concomitant AEDs after ≥ 2 previous AEDs. The primary efficacy variable was the proportion of patients achieving seizure freedom for the first 12 weeks of the 24-week Maintenance Phase. 456 patients received ≥ 1 dose of lacosamide (96 as first add-on, 360 as later add-on). In the first add-on cohort, 27/72 (37.5%) patients completed 12 weeks treatment and remained seizure-free; 18/68 (26.5%) remained seizure-free after 24 weeks. 64/91 (70.3%) patients achieved ≥ 50% reduction in seizure frequency during maintenance treatment. This was accompanied by a mean 7.1 ± 16.00 point improvement from Baseline in the Quality of Life Inventory in Epilepsy (QOLIE-31-P) total score for 24-week completers, with improvement reported in all subscales. Most common treatment-emergent adverse events (TEAEs) were dizziness (31.3%) and headache (13.5%). In the later add-on cohort, 39/261 (14.9%) and 29/249 (11.6%) patients remained seizure-free after completing 12 and 24 weeks' treatment, respectively. 178/353 (50.4%) patients achieved ≥ 50% reduction in seizure frequency during maintenance treatment. Mean change in QOLIE-31-P total score was 4.8 ± 14.74 points among 24-week completers. Common TEAEs were dizziness (33.6%), somnolence (15.0%) and headache (11.4%). Lacosamide initiated as first add-on treatment was efficacious and well tolerated in patients with uncontrolled POS. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

[Use of itopride in the symptoms of functional dyspepsia in Russia: results of a phase IV prospective open-label multicenter clinical trial].

PubMed

Kas'ianenko, V I; Denisov, N L; Vasil'ev, Iu V

2014-01-01

To evaluate the efficacy and safety of itopride used to treat the symptoms of functional dyspepsia (FD) of the upper gastrointestinal tract. A prospective, open-label, multicenter trial using as a control the placebo response obtained in the previous investigations enrolled 96 adult patients. The diagnosis of FD corresponded to its Rome II criteria. Patients received itopride (Ganaton) oral tablets (50 mg) 3 times daily for 8 weeks. When included into the trial, the patients were orally given itopride (ganaton) tablets (50 mg) thrice daily before meals for 8 weeks. The patients' status was evaluated during (at weeks 4 and 8) and after (at week 12) treatment. Treatment response was assessed using the Global Patient Assessment (GPA) and the Leeds Dyspepsia Questionnaire (LDQ). To evaluate the safety of itopride use, the investigators studied the frequency of adverse events and carried out laboratory tests (renal and liver function tests) and electrocardiography (ECG). The GPA showed that 53.76, 85.71, and 82.22% of the patients achieved a therapeutic effect of itopride at weeks 4, 8, and 12, respectively. The proportion of the patients who achieved the therapeutic effect (86%) at week 8 was higher than the historical placebo controls in the previous studies--45% (86% vs 45%; X2 = 68.868, df = 3; p < 0.001). The mean LDQ score at week 8 was significantly lower than that at baseline (2.09 and 9.36 scores; p < 0.001); 6 nonserious adverse events occurred in 3 (3.12%) of the 96 patients. During the follow-up period, there was a mild adverse event that was related to the test drug (atrial extrasystole as evidenced by ECG) and resolved a few days later. Itopride is an effective and well-tolerated drug in the treatment of functional dyspepsia in the Russian patients.

Lopinavir/ritonavir, atazanavir/ritonavir, and efavirenz in antiretroviral-naïve HIV-1-infected individuals over 144 weeks: an open-label randomized controlled trial.

PubMed

Andersson, Lars-Magnus; Vesterbacka, Jan; Blaxhult, Anders; Flamholc, Leo; Nilsson, Staffan; Ormaasen, Vidar; Sönnerborg, Anders; Gisslén, Magnus

2013-07-01

The objective of this study was to compare the efficacy of ritonavir boosted atazanavir versus ritonavir boosted lopinavir or efavirenz, all in combination with 2 nucleoside analogue reverse transcriptase inhibitors (NRTIs), over 144 weeks in antiretroviral-naïve HIV-1-infected individuals. A prospective open-label randomized controlled trial was conducted at 29 sites in Sweden and Norway between April 2004 and December 2009. Patients were randomized to receive either efavirenz 600 mg once daily (EFV), or atazanavir 300 mg and ritonavir 100 mg once daily (AZV/r), or lopinavir 400 mg and ritonavir 100 mg twice daily (LPV/r). The primary endpoints were the proportion of patients with HIV-1 RNA < 50 copies/ml at 48 and 144 weeks. Of 245 patients enrolled, 243 were randomized and 239 received the allocated intervention: 77 EFV, 81 AZV/r, and 81 LPV/r. Median (interquartile range) CD4 cell counts at baseline were 150 (80-200), 170 (80-220), and 150 (90-216) per microlitre, respectively. At week 48 the proportion (95% confidence interval (CI)) of patients achieving HIV-1 RNA < 50 copies/ml was 86 (78-94)% in the EFV arm, 78 (69-87)% in the AZV/r arm and, 69 (59-78)% in the LPV/r arm in the intention-to-treat analysis. There was a significant difference between the EFV and LPV/r arm (p = 0.014). At week 144, the proportion (95% CI) of patients achieving HIV-1 RNA < 50 copies/ml was 61 (50-72)%, 58 (47-69)%, 51 (41-63)%, respectively (p = 0.8). Patients with CD4 cell counts of ≤ 200/μl or HIV-1 RNA > 100,000 copies/ml at baseline had similar response rates in all arms. EFV was superior to LPV/r at week 48, but there were no significant differences between the 3 arms in the long-term (144 weeks) follow-up.

Levocetirizine in persistent allergic rhinitis: continuous or on-demand use? A pilot study.

PubMed

Canonica, Giorgio Walter; Fumagalli, Federica; Guerra, Laura; Baiardini, Ilaria; Compalati, Enrico; Rogkakou, Anthi; Massacane, Pierangela; Gamalero, Cinzia; Riccio, Anna Maria; Scordamaglia, Antonio; Passalacqua, Giovanni

2008-10-01

Allergic rhinitis is a high-prevalence disease that affects quality of life (QOL), sleep quality and productivity of patients. According to the ARIA initiative, it is classified as intermittent and persistent, the latter being the most troublesome. The aim of this randomized, open-label, 6-month, pilot study was to determine whether levocetirizine 5 mg administered continuously once daily in the morning was better than levocetirizine 5 mg on-demand in symptomatic subjects with persistent allergic rhinitis. Total and individual symptom scores were recorded in a diary card throughout the study. QOL, quality of sleep, nasal cytology, rate of drug intake, and safety were also assessed at pre-defined time-points. In all, adult patients (31 in each group) were enrolled, of whom 22 dropped out. Both treatment regimens considerably decreased the total and individual symptoms scores from baseline and achieved similar levels up to week 14. Continuous treatment was generally better than on-demand from week 15 onwards, reaching statistical significance from weeks 17 to 21 (from week 19 to 21 for nasal pruritus). Both regimens substantially improved QOL and sleep quality. Both treatments were well tolerated, although the on-demand group reported more adverse events. The present open label study in 62 patients indicates that levocetirizine 5 mg reliably controls persistent rhinitis over a period of 6 months, and shows a trend to be more effective in controlling the symptoms of rhinitis, improving QOL and decreasing nasal inflammation, when administered as long-term continuous therapy rather than as on-demand therapy.

Phosphatidylserine containing omega-3 Fatty acids may improve memory abilities in nondemented elderly individuals with memory complaints: results from an open-label extension study.

PubMed

Vakhapova, Veronika; Cohen, Tzafra; Richter, Yael; Herzog, Yael; Kam, Yossi; Korczyn, Amos D

2014-01-01

The present study is an open-label extension (OLE) aimed at evaluating the effect of 100 mg/day of phosphatidylserine enriched with docosahexaenoic acid (PS-DHA) on cognitive performance in nondemented elderly individuals with memory complaints. From the participants who completed the core study, 122 continued with a 15-week OLE. Efficacy was assessed using a computerized tool and the Clinical Global Impression of Change (CGI-C) rating scale. A significant improvement in sustained attention and memory recognition was observed in the PS-DHA naïve group, while the PS-DHA continuers maintained their cognitive status. Additionally, a significant improvement in CGI-C was observed in the naïve group. The results demonstrate that consumption of 100 mg/day of PS-DHA might be associated with improving or maintaining cognitive status in elderly subjects with memory complaints.

Long-Term Effectiveness and Safety of Dexmethylphenidate Extended-Release Capsules in Adult ADHD

ERIC Educational Resources Information Center

Adler, Lenard A.; Spencer, Thomas; McGough, James J.; Jiang, Hai; Muniz, Rafael

2009-01-01

Objective: This study evaluates dexmethylphenidate extended release (d-MPH-ER) in adults with ADHD. Method: Following a 5-week, randomized, controlled, fixed-dose study of d-MPH-ER 20 to 40 mg/d, 170 adults entered a 6-month open-label extension (OLE) to assess long-term safety, with flexible dosing of 20 to 40 mg/d. Exploratory effectiveness…

Safety and Durability of Effect with Long-Term, Open-Label Droxidopa Treatment in Patients with Symptomatic Neurogenic Orthostatic Hypotension (NOH303).

PubMed

Isaacson, Stuart; Shill, Holly A; Vernino, Steven; Ziemann, Adam; Rowse, Gerald J

2016-10-19

Neurogenic orthostatic hypotension (nOH) is associated with insufficient norepinephrine release in response to postural change. The objective of this study was to evaluate the long-term safety and durability of efficacy of the norepinephrine precursor droxidopa in patients with symptomatic nOH. This multinational study consisted of 3 sequential phases: a 3-month open-label droxidopa treatment phase followed by a 2-week double-blind, placebo-controlled withdrawal phase, and a 9-month open-label extension phase in which all patients received droxidopa. Patients were adults diagnosed with symptomatic nOH associated with Parkinson's disease, multiple system atrophy, pure autonomic failure, dopamine β-hydroxylase deficiency, or nondiabetic autonomic neuropathy. Efficacy was evaluated using patient- and investigator-reported questionnaire responses and the orthostatic standing test. Safety was assessed through adverse event (AE) reports and vital signs. A total of 102 patients received treatment with droxidopa. Initial improvements from baseline in patient-reported nOH symptom severity and impact on daily activities, evaluated using the Orthostatic Hypotension Questionnaire, exceeded 50% and were maintained throughout the 12-month study. Decreased nOH severity was also reflected in clinician and patient ratings on the Clinical Global Impression questionnaire. Standing systolic and diastolic blood pressures were increased from baseline throughout the study with droxidopa treatment. The most frequently reported AEs were falls, urinary tract infection, and headache. There was a low incidence (≤2%) of cardiac AEs (eg, first-degree atrioventricular block, supraventricular extrasystoles). Long-term, open-label treatment with droxidopa for up to 12 months was generally well tolerated and provided durable improvements in nOH signs and symptoms.

Open-label, 9-month extension study investigating the uro-selective alpha-blocker silodosin in men with LUTS associated with BPH.

PubMed

Osman, Nadir I; Chapple, Christopher R; Tammela, Teuvo L; Eisenhardt, Andreas; Oelke, Matthias

2015-05-01

To evaluate the long-term safety (primary objective) and efficacy/impact on quality of life (QoL, secondary objectives) of silodosin 8 mg once daily in men with LUTS/BPH. Men who completed the 12-week double-blind study with silodosin 8 mg, tamsulosin 0.4 mg, or placebo were offered to continue with the 9-month open-label study during which all patients received silodosin 8 mg once daily. Safety was assessed by analysing vital signs, electrocardiograms, laboratory tests, and adverse events. Efficacy was evaluated with the International Prostate Symptom Score (IPSS), IPSS voiding and storage sub-scores, IPSS-QoL, and maximum urinary flow rate (Q max). A total of 500 patients (mean age 66 years) entered the 9-month open-label study. Treatment-emergent adverse events (TEAE) were experienced by 33.4% patients. Ejaculation dysfunction was the most common TEAE (9.0%) but led to study discontinuations in only 1.6% of patients. Dizziness without orthostatic hypotension occurred in 0.8%. A marked reduction in total IPSS (-2.7 ± 3.8) was documented at the first visit of this extension phase in patients having de novo silodosin compared with lesser improvement in patients previously treated with silodosin (-0.82 ± 4.2) or tamsulosin (-0.83 ± 3.8). Improvements were maintained throughout the open-label phase. QoL also improved, with the greatest improvement in de novo silodosin patients. No relevant changes in Q max occurred. Long-term treatment with silodosin was safe and efficacious. Abnormal ejaculation was the most common TEAE, but led to treatment discontinuation in only 1.6% of patients. Orthostatic hypotension was not seen, and only a few patients experienced dizziness.

Magnetic Resonance Imaging-Guided, Open-Label, High-Frequency Repetitive Transcranial Magnetic Stimulation for Adolescents with Major Depressive Disorder.

PubMed

Wall, Christopher A; Croarkin, Paul E; Maroney-Smith, Mandie J; Haugen, Laura M; Baruth, Joshua M; Frye, Mark A; Sampson, Shirlene M; Port, John D

2016-09-01

Preliminary studies suggest that repetitive transcranial magnetic stimulation (rTMS) may be an effective and tolerable intervention for adolescents with treatment-resistant depression. There is limited rationale to inform coil placement for rTMS dosing in this population. We sought to examine and compare three localization techniques for coil placement in the context of an open-label trial of high-frequency rTMS for adolescents with treatment-resistant depression. Ten adolescents with treatment-resistant depression were enrolled in an open-label trial of high-frequency rTMS. Participants were offered 30 rTMS sessions (10 Hz, 120% motor threshold, left 3000 pulses applied to the dorsolateral prefrontal cortex) over 6-8 weeks. Coil placement for treatment was MRI guided. The scalp location for treatment was compared with the locations identified with standard 5 cm rule and Beam F3 methods. Seven adolescents completed 30 rTMS sessions. No safety or tolerability concerns were identified. Depression severity as assessed with the Children's Depression Rating Scale Revised improved from baseline to treatment 10, treatment 20, and treatment 30. Gains in depressive symptom improvement were maintained at 6 month follow-up visits. An MRI-guided approach for coil localization was feasible and efficient. Our results suggest that the 5 cm rule, Beam F3, and the MRI-guided localization approaches provided variable scalp targets for rTMS treatment. Open-label, high-frequency rTMS was feasible, tolerable, and effective for adolescents with treatment-resistant depression. Larger, blinded, sham-controlled trials are needed for definitive safety and efficacy data. Further efforts to understand optimal delivery, dosing, and biomarker development for rTMS treatments of adolescent depression are warranted.

Effects of Long-Term Etanercept Treatment on Clinical Outcomes and Objective Signs of Inflammation in Early Nonradiographic Axial Spondyloarthritis: 104-Week Results From a Randomized, Placebo-Controlled Study.

PubMed

Dougados, Maxime; van der Heijde, Désirée; Sieper, Joachim; Braun, Jürgen; Citera, Gustavo; Lenaerts, Jan; van den Bosch, Filip; Wei, James Cheng-Chung; Pedersen, Ron; Bonin, Randi; Jones, Heather; Marshall, Lisa; Logeart, Isabelle; Vlahos, Bonnie; Bukowski, Jack F; Maksymowych, Walter P

2017-10-01

To evaluate the long-term clinical and imaging efficacy of etanercept in patients with early, active nonradiographic axial spondyloarthritis (SpA). Adult patients who satisfied the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial SpA (but not the modified New York radiographic criteria), with symptom duration >3 months to <5 years, and who were unresponsive to ≥2 nonsteroidal antirheumatic drugs (NSAIDs) received double-blind etanercept 50 mg/week or placebo for 12 weeks, followed by open-label etanercept 50 mg/week to week 104. Clinical, magnetic resonance imaging (MRI; Spondyloarthritis Research Consortium of Canada [SPARCC] scores), and safety outcomes at 104 weeks were analyzed. Of 215 randomized patients (etanercept: n = 106; placebo: n = 109), 205 entered the study (etanercept/etanercept: n = 100; placebo/etanercept: n = 105) and 169 completed the open-label period (etanercept/etanercept: n = 83; placebo/etanercept: n = 86). At week 104, 61 of 81 (75%), 49 of 81 (61%), 48 of 80 (60%), and 57 of 81 (70%) patients who received etanercept throughout the trial achieved ASAS20, ASAS40, Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease, and Bath Ankylosing Spondylitis Disease Activity Index criteria for 50% improvement (BASDAI 50) scores, respectively (observed). From baseline to week 104, continued improvements in clinical outcomes (ASDAS-C-reactive protein: -1.5 and -1.7; BASDAI: -3.3 and -3.8 [last observation carried forward]), and SPARCC MRI scores (sacroiliac joint: -6.0 and -3.4; spinal: -2.1 and -0.8 [observed]) were seen in patients receiving etanercept/etanercept and placebo/etanercept. During the study, 8% in the etanercept/etanercept group and 7% in the placebo/etanercept group had serious adverse events; no new safety signals were seen. Patients with early, active nonradiographic axial SpA and an inadequate response to at least 2 NSAIDs demonstrated improvement in clinical and imaging outcomes that were sustained through 104 weeks of etanercept treatment. © 2017, American College of Rheumatology.

Naltrexone/Bupropion Combination Therapy in Overweight or Obese Patients With Major Depressive Disorder: Results of a Pilot Study

PubMed Central

Guerdjikova, Anna I.; Kim, Dennis D.; Burns, Colleen; Harris-Collazo, Raúl; Landbloom, Ronald; Dunayevich, Eduardo

2013-01-01

Objective: To evaluate the effect of 32-mg/d naltrexone sustained release and 360-mg/d bupropion sustained release (NB32) in overweight and obese patients with major depressive disorder (MDD). Method: Twenty-five female patients with a DSM-IV diagnosis of MDD, an Inventory of Depressive Symptomatology—Self-Report score > 26, and a body mass index ≥ 27 and ≤ 43 kg/m2 received up to 24 weeks of open-label treatment with NB32 with dietary and behavioral counseling (data collection: March 2008–July 2009). The primary endpoint was change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at 12 weeks; secondary endpoints included MADRS total score at week 24, change in weight, and Clinical Global Impressions–Improvement scale responder status (CGI-I score ≤ 2) at weeks 12 and 24 (modified intent-to-treat [mITT]: patients with ≥ 1 postbaseline MADRS total score on study drug; N = 23). Results: MADRS scores showed significant reductions at weeks 12 and 24 (mITT–last observation carried forward [LOCF]: –13.1 ± 7.1 and –15.3 ± 8.1, respectively, P < .001 vs baseline for all). Mean ± SD weight loss was –4.0% ± 4.6% (mITT-LOCF) and –6.1% ± 4.7% (observed cases) at week 12 and –5.3% ± 6.5% (mITT-LOCF) and –9.2% ± 6.2% (observed cases) at week 24 (P < .001 vs baseline for all). By week 24, 95% of patients (mITT-LOCF) were responders (CGI-I score ≤ 2) and 70% were in remission (CGI-I score = 1). The safety/tolerability profile of NB32 was consistent with its individual components; the most common adverse events were nausea, constipation, headache, and insomnia, with no serious adverse events attributed to NB32. Conclusion: Twenty-four weeks of open-label NB32 therapy with dietary and behavioral counseling was associated with improvement in depressive symptoms and reduced body weight in overweight/obese women with MDD. Trial Registration: ClinicalTrials.gov Identifier: NCT00624858 PMID:24171147

Dapagliflozin once daily plus exenatide once weekly in obese adults without diabetes: Sustained reductions in body weight, glycaemia and blood pressure over 1 year.

PubMed

Lundkvist, Per; Pereira, Maria J; Katsogiannos, Petros; Sjöström, C David; Johnsson, Eva; Eriksson, Jan W

2017-09-01

Dapagliflozin and exenatide reduce body weight by differing mechanisms. Dual therapy with these agents reduces body weight, adipose tissue volume, glycaemia and systolic blood pressure (SBP) over 24 weeks. Here, we examined these effects over 1 year in obese adults without diabetes. Obese adults without diabetes (N = 50; aged 18-70 years; body mass index, 30-45 kg/m 2 ) were initially randomized to double-blind oral dapagliflozin 10 mg once daily plus subcutaneous long-acting exenatide 2 mg once weekly or to placebo. They entered an open-label extension from 24 to 52 weeks during which all participants received active treatment. Of the original 25 dapagliflozin + exenatide-treated and 25 placebo-treated participants, respectively, 21 (84%) and 17 (68%) entered the open-label period and 16 (64%) and 17 (68%) completed 52 weeks of treatment. At baseline, mean body weight was 104.6 kg, and 73.5% of participants had prediabetes (impaired fasting glucose or impaired glucose tolerance). Reductions with dapagliflozin + exenatide at 24 weeks were sustained at 52 weeks, respectively, for body weight (-4.5 and -5.7 kg), total adipose tissue volume (-3.8 and -5.3 L), proportion with prediabetes (34.8% and 35.3%), and SBP (-9.8 and -12.0 mm Hg). Effects on body weight, SBP and glycaemia at 52 weeks with placebo → dapagliflozin + exenatide were similar to those observed with continuation of dapagliflozin + exenatide. Nausea and injection-site reactions were more frequent with dapagliflozin + exenatide than with placebo and diminished over time. Safety and tolerability were similar to that in previous diabetes trials with these agents. No clear difference in adverse event-related withdrawals between placebo and active treatment periods was observed. Dapagliflozin + exenatide dual therapy produced sustained reductions in body weight, prediabetes and SBP over 52 weeks and was well tolerated in obese adults without diabetes. © 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Ustekinumab for patients with primary biliary cholangitis who have an inadequate response to ursodeoxycholic acid: A proof-of-concept study.

PubMed

Hirschfield, Gideon M; Gershwin, M Eric; Strauss, Richard; Mayo, Marlyn J; Levy, Cynthia; Zou, Bin; Johanns, Jewel; Nnane, Ivo P; Dasgupta, Bidisha; Li, Katherine; Selmi, Carlo; Marschall, Hanns-Ulrich; Jones, David; Lindor, Keith

2016-07-01

The interleukin (IL)-12 signaling cascade has been associated with primary biliary cholangitis (PBC). This multicenter, open-label, proof-of-concept study evaluated the anti-IL12/23 monoclonal antibody, ustekinumab (90 mg subcutaneous at weeks 0 and 4, then every 8 weeks through week 20), in adults with PBC and an inadequate response to ursodeoxycholic acid therapy (i.e., alkaline phosphatase [ALP] >1.67× upper limit of normal [ULN] after ≥6 months). ALP response was defined as a >40% decrease from baseline and ALP remission as ALP normalization (if baseline ALP 1.67×-2.8× ULN) or <1.67× ULN (if baseline ALP >2.8× ULN). Changes in Enhanced Liver Fibrosis (ELF) scores and serum bile acids were also assessed. At baseline, patients had median disease duration of 3.2 years, median ELF score of 9.8, and highly elevated total bile acid concentration (median, 43.3 μmol/L); 13 of 20 (65%) patients had baseline ALP >3× ULN. Although steady-state serum ustekinumab concentrations were reached by week 12, no patient achieved ALP response or remission. Median percent ALP reduction from baseline to week 28 was 12.1%. ELF score decreased slightly from baseline to week 28 (median reduction: 0.173), and total serum bile acid concentrations decreased from baseline to week 28 (median reduction: 8.8 μmol/L). No serious infections or discontinuations resulting from adverse events were reported through week 28. One patient had a serious upper gastrointestinal hemorrhage considered unrelated to test agent by the investigator. Open-label ustekinumab therapy, though associated with a modest decrease in ALP after 28 weeks of therapy, did not otherwise appreciably change ALP and overt proof-of-concept was not established as per prespecified primary endpoint of proposed efficacy. No new ustekinumab safety signals were observed. (Hepatology 2016;64:189-199). © 2015 by the American Association for the Study of Liver Diseases.

Efficacy of Femarelle for the treatment of climacteric syndrome in postmenopausal women: An open label trial.

PubMed

Chen, Fang-Ping; Chang, Chee Jen; Chao, An-Shine; Huang, Hong-Yuan; Huang, Jian-Pei; Wu, Meng-Hsing; Tsai, Ching-Chou; Kung, Fu-Tsai; Chang, Ching-Wen; Tsai, Yung-Chieh

2016-06-01

To assess the effects of 2 months of treatment with Femarelle for climacteric syndrome in Taiwanese postmenopausal women. A multi-center, open-label trial of 260 postmenopausal women, age ≥ 45 years with vasomotor symptoms. Women were enrolled after obtaining a detailed medical history and a thorough physical examination. They then received Femarelle (640 mg/d) twice daily for 8 weeks. The primary outcome was the changes in the frequency and severity of hot flushes from baseline to 4 weeks (1 month) and 8 weeks (2 months). Changes of general climacteric syndrome were assessed using a modified climacteric scale designed by Greene. The frequency and severity of hot flushes were significantly improved with Femarelle use (p < 0.001). After 8 weeks of treatment, the percentage of women with various climacteric syndromes was reduced (from 100% to 20.9% for hot flushes, from 97.7% to 87.9% for psychological symptoms, from 93.8% to 78.8% for somatic symptoms, and from 87.8% to 74.9% for sexual symptoms). General climacteric syndrome scores also significantly decreased, from 20.8 ± 0.7 at the time of enrollment to 12.9 ± 0.7 after 8 weeks of Femarelle treatment (p < 0.0001). Participants experienced improvement of various climacteric symptoms and signs after 8 weeks of treatment (75.1% for hot flushes, 68.7% for psychological symptoms, 70.6% for somatic symptoms, and 69.0% for sexual problems respectively). After 4 weeks and 8 weeks of treatment with Femarelle, patients showed statistically significant improvement in climacteric symptoms (p < 0.0001). Three women (1.2%) withdrew from the study after 4 weeks of treatment due to adverse effects. Femarelle significantly improved climacteric symptoms in Taiwanese postmenopausal women. However, further evaluation is needed regarding the safety of long-term consumption. Copyright © 2016. Published by Elsevier B.V.

The Tolerability Profile of Clindamycin 1%/Benzoyl Peroxide 5% Gel vs. Adapalene 0.1%/Benzoyl Peroxide 2.5% Gel for Facial Acne

PubMed Central

Cirigliano, Marcela; Gwazdauskas, Jennifer A; Gonzalez, Pablo

2012-01-01

Objective: To compare the first two weeks of tolerability of clindamycin/benzoyl peroxide gel versus adapalene/benzoyl peroxide gel followed by six weeks of open-label clindamycin/benzoyl peroxide gel therapy in subjects with mild-to-moderate acne who participated in two eight-week, identically designed, clinical studies. Methods: Using a split-face method, patients received both clindamycin/benzoyl peroxide gel and adapalene/benzoyl peroxide gel once daily for two weeks (allocation to the right or left side of the face was randomized) in an investigator-blinded fashion. Patients then went on to receive a further six weeks of open-label, full-face clindamycin/benzoyl peroxide gel. The primary outcome was to compare signs and symptoms of tolerability during the first two weeks of treatment using an investigator-assessed 4-point rating scale. Secondary endpoints included assessment of acne severity (Investigator Static Global Assessment and lesion counts), quality of life, product acceptability/preference, and patient assessments of tolerability and safety. Results: Of the 76 subjects enrolled in the two studies, 72 completed them. Overall both products were well tolerated, but mean scores for erythema, dryness, and peeling were significantly higher with adapalene/benzoyl peroxide gel than with clindamycin/benzoyl peroxide gel at both Weeks 1 and 2 (p<0.03). Patients also rated clindamycin/benzoyl peroxide gel significantly more tolerable than adapalene/benzoyl peroxide gel for redness, dryness, burning, itching, and scaling at Weeks 1 and 2 (p 0.0073). Mean Investigator Static Global Assessment score improved with both products during the first two weeks of treatment and continued to show significant improvement versus baseline when treatment with clindamycin/benzoyl peroxide gel was continued for a further six weeks (p<0.001 at Week 8). Lesion counts improved throughout the study with significant reductions from baseline occurring at Weeks 5 and 8 (p<0.0001 for both time points for total lesion counts). Clindamycin/benzoyl peroxide gel and adapalene/benzoyl peroxide gel were well tolerated, with most adverse events of mild-to-moderate severity. Conclusion: Clindamycin/benzoyl peroxide gel had better tolerability with regard to erythema, dryness, and peeling than adapalene/benzoyl peroxide gel during the first two weeks of treatment. PMID:22808305

An open-label pilot study of granulocyte colony-stimulating factor for the treatment of severe endoscopic postoperative recurrence in Crohn's disease.

PubMed

Dejaco, Clemens; Lichtenberger, Conny; Miehsler, Wolfgang; Oberhuber, Georg; Herbst, Friedrich; Vogelsang, Harald; Gangl, Alfred; Reinisch, Walter

2003-01-01

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) promoted healing of Crohn's disease (CD)-like intestinal lesions in chronic granulomatous disease and glycogen storage disease Ib, both characterized by defective neutrophil functions. We performed a prospective, open-label pilot study with rhG-CSF for the treatment of CD. Five patients with clinically inactive CD, but with severe endoscopic ileitis within 1 year after intestinal resection and ileocolonic anastomosis, received 300 microg of rhG-CSF (Filgrastim; Neupogen) subcutaneously, three times weekly for a total of 12 weeks. Safety was evaluated by assessment of clinical and laboratory data and disease activity. The primary parameter of efficacy was complete mucosal healing, as defined by the Rutgeerts score. Anti-inflammatory mediators were repeatedly measured during treatment. All patients completed the protocol in clinical remission. In 1 subject transient headache resolved after halving the rhG-CSF dosage. Complete mucosal healing was observed in 2 patients: in 1 patient after 12 weeks of therapy and in 1 patient 9 months after treatment cessation. In a single patient, closure of an anovaginal and of a perianal fistula was noted. Neutrophil counts and interleukin-1 receptor antagonist and soluble tumor necrosis factor receptor p55 and p75 levels were found to be increased during drug administration. rhG-CSF seems to be safe, well tolerated, and might provide efficacy in CD. Copyright 2003 S. Karger AG, Basel

Safety and Efficacy of Bupropion Extended Release in Treating a Community Sample of Hispanic and African American Adults With Major Depressive Disorder: An Open-Label Study

PubMed Central

Gross, Paul K.; Nourse, Rosemary; Wasser, Thomas E.; Bukenya, Deo

2007-01-01

Objectives: Many publications and federal agencies call for more trials and research on the effectiveness of medications and treatment needs in diverse patient populations with psychiatric disorders. This study investigates the effectiveness of bupropion extended release (XL) on a community sample of men and women of either Hispanic or African American heritage with major depressive disorder (MDD). Method: Twenty-six patients of Hispanic or African American descent with MDD as diagnosed by means of the Structured Clinical Interview for DSM-IV Axis I Disorders were required to have a score of 20 or greater on the Hamilton Rating Scale for Depression (17-item) (HAM-D-17) at baseline and prior to randomization. Patients were also required to have a score of 4 or greater on the Clinical Global Impressions-Severity of Illness scale (CGI-S) at baseline and prior to initiation of treatment. Patients were treated openly for an optimum of 9 weeks. Bupropion XL was initiated at 150 mg daily and then increased to 300 mg daily after 1 week and 450 mg daily 4 weeks later if judged clinically necessary by the investigator. Tools utilized for repeated-measures methodology indicating efficacy were the HAM-D-17, CGI-S, Clinical Global Impressions-Improvement scale (CGI-I), Change in Sexual Functioning Questionnaire (CSFQ), and the 18-item Motivation and Energy Inventory. The study was conducted from February 9, 2005, to March 23, 2006. Results: Efficacy was demonstrated on the HAM-D-17, CGI-S, CGI-I, and CSFQ (p < .05). Mean times ranged from 50% symptom reduction in about 2 weeks to 90% symptom reduction in less than 2 months. Dry mouth, transient stomach discomfort, and headache were the most commonly reported side effects. Conclusions: Data from this 10-week open-label study suggest bupropion XL is an effective and well tolerated treatment for depressive symptoms in the moderately to markedly ill Hispanic and African American community. PMID:17607332

Safety and efficacy of canakinumab in Japanese patients with phenotypes of cryopyrin-associated periodic syndrome as established in the first open-label, phase-3 pivotal study (24-week results).

PubMed

Imagawa, Tomoyuki; Nishikomori, Ryuta; Takada, Hidetoshi; Takeshita, Saoko; Patel, Neha; Kim, Dennis; Lheritier, Karine; Heike, Toshio; Hara, Toshiro; Yokota, Shumpei

2013-01-01

Cryopyrin-associated periodic syndrome (CAPS), a rare hereditary auto-inflammatory disease, is associated with mutations in the NLRP3 gene resulting in elevated interleukin-1β (IL-1 β) release. CAPS generally occurs in early childhood with most patients presenting with periodic fever, skin rash, osteoarthropathy, aseptic meningitis, sensorineural hearing loss and optic neuritis. Canakinumab, a fully human anti-IL-1β monoclonal antibody which binds selectively to IL-1β, has demonstrated good efficacy with CAPS. This is the first study to evaluate the safety and efficacy of canakinumab in Japanese patients with CAPS. In this open-label study, 19 Japanese CAPS patients aged ≥2 years received canakinumab either 150 mg s.c. or 2 mg/kg for patients with a body weight ≤ 40 kg every 8 weeks for 24 weeks. The primary objective was to assess the proportion of patients who were free of relapse at week 24. A complete response was achieved in 18 (94.7%) patients with some requiring a dose and/or a frequency adjustment to attain full clinical response. The majority of patients (14/18; 77.8%) were in remission, i.e. free of relapse at week 24. Auto-inflammatory disease activity as assessed by physician's global assessment declined from baseline to end of the study (score of absent in 10.5% at baseline versus 31.6% at end of the study). Two patients had serious adverse events (SAEs), which resolved with standard treatment. One patient reported a mild injection-site reaction. No malignancies or deaths were reported during the study. Canakinumab 150 mg s.c. every 8 weeks was well-tolerated, highly efficacious and offered a convenient dosing regimen for treating Japanese patients with CAPS.

Lacosamide for uncontrolled primary generalized tonic-clonic seizures: An open-label pilot study with 59-week extension.

PubMed

Wechsler, Robert T; Yates, Stephen L; Messenheimer, John; Leroy, Robert; Beller, Cynthia; Doty, Pamela

2017-02-01

Assess the safety of adjunctive lacosamide for the treatment of uncontrolled primary generalized tonic-clonic seizures in patients (16-65 years) with primary generalized (genetic) epilepsy (PGE). An open-label pilot safety study (SP0961; NCT01118949), comprising 12 weeks' historical baseline, 4 weeks' prospective baseline, 3 weeks' titration (target: 400mg/day adjunctive lacosamide) and 6 weeks' maintenance. Patients who continued to the extension study (SP0962; NCT01118962) then received ≤59 weeks of flexible treatment (100-800mg/day lacosamide with flexible dosing of concomitant antiepileptic drugs). The primary outcomes for SP0961 were the mean change (±standard deviation) in absence seizure or myoclonic seizure days per 28days from prospective baseline to maintenance; for SP0962, the incidence of treatment-emergent adverse events (TEAEs) and withdrawals because of TEAEs. Of the 49 patients who enrolled, 40 (82%) completed the pilot study and 9 discontinued (5 because of adverse events). Of the 39 patients who continued to the extension study, 10 discontinued (2 owing to TEAEs) and 29 (74%) completed the study. During the pilot study, patients reported a reduction in mean (±standard deviation) absence and myoclonic seizure days per 28days (-0.37±4.80, -2.19±5.80). Reductions were also observed during the extension study (-2.38±5.54, -2.78±6.43). Five patients in SP0961 and 2 patients in SP0962 experienced TEAEs of new or increased frequency of absence seizures or myoclonic seizures. The most common TEAEs during SP0961 were dizziness (39%) and nausea (27%), and during SP0962 were dizziness (26%) and upper respiratory tract infection (26%). The safety profile of adjunctive lacosamide was similar to that previously published. Adjunctive lacosamide did not systematically worsen absence or myoclonic seizures, and appears to be well tolerated in patients with PGE. Copyright © 2016. Published by Elsevier B.V.

Double-blind, Randomized, 8-week Placebo-controlled followed by a 16-week open label extension study, with the LPA1 receptor antagonist SAR100842 for Patients With Diffuse Cutaneous Systemic Sclerosis.

PubMed

Allanore, Yannick; Distler, Oliver; Jagerschmidt, Alexandre; Illiano, Stephane; Ledein, Laetitia; Boitier, Eric; Agueusop, Inoncent; Denton, Christopher P; Khanna, Dinesh

2018-05-06

Preclinical studies suggest a role for lysophosphatidic acid (LPA) in the pathogenesis of systemic sclerosis (SSc). SAR100842, a potent selective oral antagonist of LPA1 receptor, was assessed for safety, biomarkers and clinical efficacy in patients with diffuse cutaneous SSc (dcSSc). An 8-week double-blind, randomized, placebo-controlled study followed by a 16-week open label extension with SAR100842 was performed in patients with early dcSSc and a baseline Rodnan skin score (mRSS) of at least 15. The primary endpoint was safety during the double-blind phase of the trial. Exploratory endpoints included the identification of a LPA-induced gene signature in patients 'skin. 17 of 32 subjects were randomized to placebo and 15 to SAR100842; 30 patients participated in the extension study. The most frequent adverse events reported for SAR100842 during the blinded phase were headache, diarrhea, nausea and fall and the safety profile was acceptable during the extension part. At Week 8, mean reduction in mRSS was numerically greater in the SAR100842 compared to placebo (mean change [SD]: -3.57 [4.18] versus -2.76 [4.85]; difference [95% CI]: -1.2 [-4.37 to 2.02], p=0.46). A greater reduction of LPA related genes was observed in skin of SAR100842 group at Week 8, indicating LPA 1 target engagement. SAR100842, a selective orally available LPA 1 receptor antagonist, was well tolerated in patients with dcSSc. MRSS improved during the study although not reaching significance, and additional gene signature analysis suggested target engagement. These results need to be confirmed in a larger controlled trial. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Maintenance of efficacy and safety with subcutaneous golimumab among patients with active rheumatoid arthritis who previously received intravenous golimumab.

PubMed

Taylor, Peter C; Ritchlin, Christopher; Mendelsohn, Alan; Baker, Daniel; Kim, Lilianne; Xu, Zhenhua; Mack, Michael; Kremer, Joel

2011-12-01

To evaluate the efficacy/safety of subcutaneous (SC) golimumab in patients with rheumatoid arthritis (RA) who previously received intravenous (IV) golimumab with or without methotrexate (MTX). Adult patients with RA (n = 643) with persistent disease despite MTX (≥ 15 mg/wk for ≥ 3 months) were randomized to IV placebo + MTX (n = 129) or IV golimumab 2-4 mg/kg (± MTX) every 12 weeks (n = 514). Patients who completed the study through Week 48 could participate in the longterm extension (LTE), comprising open-label golimumab 50 mg SC every 4 weeks (± MTX) for 24 weeks (LTE-0 to LTE-24) followed by 16 weeks of safety followup (LTE-24 to LTE-40; MTX could be adjusted). At Week 48, 28% (nominal p < 0.001 vs placebo), 11%, and 8% of patients who received IV golimumab + MTX, golimumab alone, and placebo + MTX, respectively, achieved ≥ 50% improvement in the American College of Rheumatology response criteria (ACR50). Among the 505 patients who entered the LTE and were still participating, the proportion of patients treated with golimumab 50 mg SC (± MTX) achieving an ACR50 response increased to 44% at both LTE-14 and LTE-24. ACR20, ACR70, and 28-joint Disease Activity Score using C-reactive protein exhibited similar response patterns as ACR50. Infections were the most commonly reported adverse events through the end of IV golimumab dosing (37% placebo + MTX, 45% golimumab, 51% golimumab + MTX) and with SC golimumab from LTE-0 through LTE-40 (35% golimumab, 36% golimumab + MTX). Concomitant MTX use yielded lower incidences of antibodies to SC golimumab and injection-related reactions. Clinical improvements observed in golimumab-treated patients were sustained or improved in patients switched from IV (2-4 mg/kg ± MTX) to open-label SC (50 mg ± MTX) golimumab. Both IV and SC golimumab demonstrated acceptable safety profiles (Clinicaltrials.gov NCT00361335).

Long-term safety and efficacy of a novel once-weekly oral trelagliptin as monotherapy or in combination with an existing oral antidiabetic drug in patients with type 2 diabetes mellitus: A 52-week open-label, phase 3 study.

PubMed

Inagaki, Nobuya; Sano, Hiroki; Seki, Yoshifumi; Kuroda, Shingo; Kaku, Kohei

2016-09-01

Trelagliptin is a novel once-weekly oral dipeptidyl peptidase-4 inhibitor for type 2 diabetes mellitus that was first approved in Japan. We evaluated long-term safety and efficacy of trelagliptin in Japanese patients with type 2 diabetes mellitus. This was a phase 3, multicenter, open-label study to evaluate long-term safety and efficacy of trelagliptin. Patients with type 2 diabetes mellitus inadequately controlled despite diet/exercise or treatment with one of the existing oral antidiabetic drugs along with diet/exercise received trelagliptin 100 mg orally once weekly for 52 weeks as monotherapy or combination therapies. The primary end-points were the safety variables, and the secondary end-points were glycosylated hemoglobin and fasting plasma glucose. A total of 680 patients received the following antidiabetic therapies: trelagliptin monotherapy (n = 248), combination with a sulfonylurea (n = 158), a glinide (n = 67), an α-glucosidase inhibitor (n = 65), a biguanide (n = 70), or a thiazolidinedione (n = 72). During the study, 79.8% of the patients experienced at least one adverse event for monotherapy, 87.3% for combination with a sulfonylurea, 77.6% for a glinide, 81.5% for an α-glucosidase inhibitor, 64.3% for a biguanide, and 84.7% for a thiazolidinedione, respectively. Most of the adverse events were mild or moderate. The change in glycosylated hemoglobin from baseline at the end of the treatment period was -0.74 to -0.25% for each therapy. Once-weekly oral trelagliptin provides well-tolerated long-term safety and efficacy in both monotherapy and combination therapies in Japanese patients with type 2 diabetes mellitus. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Early intervention of long-acting nifedipine GITS reduces brachial-ankle pulse wave velocity and improves arterial stiffness in Chinese patients with mild hypertension: a 24-week, single-arm, open-label, prospective study.

PubMed

Zhang, Jidong; Wang, Yan; Hu, Haijuan; Yang, Xiaohong; Tian, Zejun; Liu, Demin; Gu, Guoqiang; Zheng, Hongmei; Xie, Ruiqin; Cui, Wei

2016-01-01

Nifedipine gastrointestinal therapeutic system (GITS) is used to treat angina and hypertension. The authors aimed to study the early intervention impact on arterial stiffness and pulse wave velocity (PWV) independent of its blood-pressure-(BP) lowering effect in mild hypertensive patients. This single-center, single-arm, open-label, prospective, Phase IV study recruited patients with mild hypertension and increased PWV from December 2013 to December 2014 (N=138; age, 18-75 years; systolic blood pressure, 140-160 mmHg; diastolic BP, 90-100 mmHg; increased brachial-ankle pulse wave velocity [baPWV, ≥12 m/s]). Nifedipine GITS (30 mg/d) was administered for 24 weeks to achieve target BP of <140/90 mmHg. The dose was uptitrated at 60 mg/d in case of unsatisfactory BP reduction after 4 weeks. Primary study end point was the change in baPWV after nifedipine GITS treatment. Hemodynamic parameters (office BP, 24-hour ambulatory BP monitoring, and heart rate and adverse events) were evaluated at baseline and followed-up at 2, 4, 8, 12, 18, and 24 weeks. Majority of patients (n=117; 84.8%) completed the study. baPWV decreased significantly at 4 weeks compared with baseline (1,598.87±239.82 vs 1,500.89±241.15 cm/s, P <0.001), was stable at 12 weeks (1,482.24±215.14 cm/s, P <0.001), and remained steady through 24 weeks (1,472.58±205.01 cm/s, P <0.001). Office BP reduced from baseline to week 4 (154/95 vs 136/85 mmHg) and remained steady until 24 weeks. Nifedipine GITS significantly decreased 24-hour ambulatory BP monitoring ( P <0.001) after 24 weeks from baseline. Mean arterial pressure and pulse pressure were lowered significantly after 4, 12, and 24 weeks of treatment ( P <0.001). These changes in baPWV were significantly correlated with changes in systolic blood pressure, diastolic BP, and mean arterial pressure ( P <0.05), but not with changes in pulse pressure ( P >0.05). There were no other drug-related serious adverse events. Nifedipine GITS was considerably effective in reducing baPWV and BP, indicating improvement in arterial stiffness as early as 4 weeks.

Wearing blue light-blocking glasses in the evening advances circadian rhythms in the patients with delayed sleep phase disorder: An open-label trial.

PubMed

Esaki, Yuichi; Kitajima, Tsuyoshi; Ito, Yasuhiro; Koike, Shigefumi; Nakao, Yasumi; Tsuchiya, Akiko; Hirose, Marina; Iwata, Nakao

2016-01-01

It has been recently discovered that blue wavelengths form the portion of the visible electromagnetic spectrum that most potently regulates circadian rhythm. We investigated the effect of blue light-blocking glasses in subjects with delayed sleep phase disorder (DSPD). This open-label trial was conducted over 4 consecutive weeks. The DSPD patients were instructed to wear blue light-blocking amber glasses from 21:00 p.m. to bedtime, every evening for 2 weeks. To ascertain the outcome of this intervention, we measured dim light melatonin onset (DLMO) and actigraphic sleep data at baseline and after the treatment. Nine consecutive DSPD patients participated in this study. Most subjects could complete the treatment with the exception of one patient who hoped for changing to drug therapy before the treatment was completed. The patients who used amber lens showed an advance of 78 min in DLMO value, although the change was not statistically significant (p = 0.145). Nevertheless, the sleep onset time measured by actigraph was advanced by 132 min after the treatment (p = 0.034). These data suggest that wearing amber lenses may be an effective and safe intervention for the patients with DSPD. These findings also warrant replication in a larger patient cohort with controlled observations.

A Complex Multiherbal Regimen Based on Ayurveda Medicine for the Management of Hepatic Cirrhosis Complicated by Ascites: Nonrandomized, Uncontrolled, Single Group, Open-Label Observational Clinical Study.

PubMed

Patel, Manish V; Patel, Kalapi B; Gupta, Shivenarain; Michalsen, Andreas; Stapelfeldt, Elmar; Kessler, Christian S

2015-01-01

Hepatic cirrhosis is one of the leading causes of death worldwide, especially if complicated by ascites. This chronic condition can be related to the classical disease entity jalodara in Traditional Indian Medicine (Ayurveda). The present paper aims to evaluate the general potential of Ayurvedic therapy for overall clinical outcomes in hepatic cirrhosis complicated by ascites (HCcA). In form of a nonrandomized, uncontrolled, single group, open-label observational clinical study, 56 patients fulfilling standardized diagnostic criteria for HCcA were observed during their treatment at the P. D. Patel Ayurveda Hospital, Nadiad, India. Based on Ayurvedic tradition, a standardized treatment protocol was developed and implemented, consisting of oral administration of single and compound herbal preparations combined with purificatory measures as well as dietary and lifestyle regimens. The outcomes were assessed by measuring liver functions through specific clinical features and laboratory parameters and by evaluating the Child-Pugh prognostic grade score. After 6 weeks of treatment and a follow-up period of 18 weeks, the outcomes showed statistically significant and clinically relevant improvements. Further larger and randomized trials on effectiveness, safety, and quality of the Ayurvedic approach in the treatment of HCcA are warranted to support these preliminary findings.

Ocular safety of sildenafil citrate when administered chronically for pulmonary arterial hypertension: results from phase III, randomised, double masked, placebo controlled trial and open label extension

PubMed Central

Tressler, Charles; Hwang, Lie-Ju; Burgess, Gary; Laties, Alan M

2012-01-01

Objective To assess the ocular effects and safety profile of chronic sildenafil oral dosing in patients with pulmonary arterial hypertension. Design 12 week, double masked, randomised, placebo controlled, phase III trial with open label extension. Setting 53 institutions worldwide. Participants 277 adults with idiopathic pulmonary arterial hypertension or pulmonary arterial hypertension associated with connective tissue disease or after congenital heart disease repair (mean pulmonary artery pressure ≥25 mm Hg; pulmonary capillary wedge pressure ≤15 mm Hg at rest). Interventions During the double masked study, oral sildenafil 20 mg, 40 mg, or 80 mg or placebo (1:1:1:1) three times daily for 12 weeks was added to baseline drug treatment. In the extension study, the placebo, 20 mg and 40 mg groups received 40 mg three times daily titrated to 80 mg three times daily at week 6. After unmasking, the dose was titrated according to clinical need. Main outcome measure Ocular safety (ocular examinations, visual function tests, participants’ reports of adverse events, and visual disturbance questionnaire completed by investigators) by treatment group at 12 weeks, 24 weeks, 18 months, and yearly. Results Findings of the objective assessments—that is, intraocular pressure and visual function tests (visual acuity, colour vision, and visual field)—were similar across groups (20 mg, n=69; 40 mg, n=67; 80 mg, n=71; placebo, n=70). No clinically significant changes occurred between baseline and 12 weeks, except for an efficacy signal in contrast sensitivity for the sildenafil 40 mg three times daily group. In right eyes, changes in intraocular pressure from baseline to week 12 ranged from a mean of −0.5 (95% confidence interval −1.3 to 0.2) mm Hg with placebo, −0.2 (−0.9 to 0.5) mm Hg with sildenafil 40 mg, and −0.1 (−0.7 to 0.5) mm Hg with 80 mg to 0.3 (−0.4 to 0.9) mm Hg with sildenafil 20 mg (the approved dose for pulmonary arterial hypertension). Mean changes from baseline to week 12 in contrast sensitivity in right eyes were −0.02 (SD 0.12) in the sildenafil 20 mg three times daily group compared with −0.05 (0.18) in the placebo group (P=0.044). Percentages of participants with deterioration in visual acuity (Snellen) from baseline to week 12 ranged from 10% (n=7) in the placebo group to 3% (n=2) in the sildenafil 20 mg three times daily group; the same percentages had visual field changes from normal to abnormal during the period in these two groups. The investigators did not deem any findings on colour vision assessment to be clinically significant. Findings of the objective assessments in the 40 mg and 80 mg three times daily sildenafil treatment groups and in left eyes were not substantially different, nor were any measures different throughout the open label extension compared with week 12. However, objective data were limited after month 18, as most participants had missing data or visual parameters were no longer collected by investigators. Incidence of ocular adverse events reported on the case report forms and assessed by the investigator was low with all doses, but a modest, dose related incidence of chromatopsia, cyanopsia, photophobia, and visual disturbance was reported with 80 mg three times daily consistent with the indicated dosing for erectile dysfunction. Retinal haemorrhages, captured on funduscopy, occurred in 2% (4/207) of sildenafil treated participants and none in the placebo group during the double masked study and in 4% (10/259) during the open label extension. Conclusions Sildenafil dosing up to 80 mg three times daily is safe and well tolerated from an ocular perspective in patients with pulmonary arterial hypertension. Daily chronic dosing in this patient population was not associated with visual change and had no detrimental effect on best corrected visual acuity, contrast sensitivity, colour vision, or visual field, or on slit lamp examinations, funduscopy, or intraocular pressure during the duration of this study. Trial registration Clinical trials NCT00644605 and NCT00159887. PMID:22354598

Remission and recovery associated with lurasidone in the treatment of major depressive disorder with subthreshold hypomanic symptoms (mixed features): post-hoc analysis of a randomized, placebo-controlled study with longer-term extension.

PubMed

Goldberg, Joseph F; Ng-Mak, Daisy; Siu, Cynthia; Chuang, Chien-Chia; Rajagopalan, Krithika; Loebel, Antony

2017-04-01

This post-hoc analysis assessed rates of symptomatic and functional remission, as well as recovery (combination of symptomatic and functional remission), in patients treated with lurasidone for major depressive disorder (MDD) associated with subthreshold hypomanic symptoms (mixed features). Patients with MDD plus two or three manic symptoms (defined as per the DSM-5 mixed-features specifier) were randomly assigned to flexible-dose lurasidone 20-60 mg/day (n=109) or placebo (n=100) for 6 weeks, followed by a 3-month open-label, flexible-dose extension study for U.S. sites only (n=48). Cross-sectional recovery was defined as the presence of both symptomatic remission (Montgomery-Åsberg Depression Rating Scale score ≤ 12) and functional remission (all Sheehan Disability Scale [SDS] domain scores ≤3) at week 6, and at both months 1 and 3 of the extension study ("sustained recovery"). A significantly higher proportion of lurasidone-treated patients (31.3%) achieved recovery (assessed cross-sectionally) compared to placebo (12.2%, p=0.002) at week 6. The number of manic symptoms at baseline moderated the effect size for attaining cross-sectional recovery for lurasidone treatment (vs. placebo) (p=0.028). Sustained recovery rates were higher in patients initially treated with lurasidone (20.8%) versus placebo (12.5%). In this post-hoc analysis of a placebo-controlled study with open-label extension that involved patients with MDD and mixed features, lurasidone was found to significantly improve the rate of recovery at 6 weeks (vs. placebo) that was sustained at month 3 of the extension study. The presence of two (as opposed to three) manic symptoms moderated recovery at the acute study endpoint.

Vaccination response to tetanus toxoid and 23-valent pneumococcal vaccines following administration of a single dose of abatacept: a randomized, open-label, parallel group study in healthy subjects

PubMed Central

Tay, Lee; Leon, Francisco; Vratsanos, George; Raymond, Ralph; Corbo, Michael

2007-01-01

The effect of abatacept, a selective T-cell co-stimulation modulator, on vaccination has not been previously investigated. In this open-label, single-dose, randomized, parallel-group, controlled study, the effect of a single 750 mg infusion of abatacept on the antibody response to the intramuscular tetanus toxoid vaccine (primarily a memory response to a T-cell-dependent peptide antigen) and the intramuscular 23-valent pneumococcal vaccine (a less T-cell-dependent response to a polysaccharide antigen) was measured in 80 normal healthy volunteers. Subjects were uniformly randomized to receive one of four treatments: Group A (control group), subjects received vaccines on day 1 only; Group B, subjects received vaccines 2 weeks before abatacept; Group C, subjects received vaccines 2 weeks after abatacept; and Group D, subjects received vaccines 8 weeks after abatacept. Anti-tetanus and anti-pneumococcal (Danish serotypes 2, 6B, 8, 9V, 14, 19F and 23F) antibody titers were measured 14 and 28 days after vaccination. While there were no statistically significant differences between the dosing groups, geometric mean titers following tetanus or pneumococcal vaccination were generally lower in subjects who were vaccinated 2 weeks after receiving abatacept, compared with control subjects. A positive response (defined as a twofold increase in antibody titer from baseline) to tetanus vaccination at 28 days was seen, however, in ≥ 60% of subjects across all treatment groups versus 75% of control subjects. Similarly, over 70% of abatacept-treated subjects versus all control subjects (100%) responded to at least three pneumococcal serotypes, and approximately 25–30% of abatacept-treated subjects versus 45% of control subjects responded to at least six serotypes. PMID:17425783

High-dose transdermal nicotine in Parkinson's disease patients: a randomized, open-label, blinded-endpoint evaluation phase 2 study.

PubMed

Villafane, G; Thiriez, C; Audureau, E; Straczek, C; Kerschen, P; Cormier-Dequaire, F; Van Der Gucht, A; Gurruchaga, J-M; Quéré-Carne, M; Evangelista, E; Paul, M; Defer, G; Damier, P; Remy, P; Itti, E; Fénelon, G

2018-01-01

Studies of the effects of nicotine on motor symptoms in Parkinson's disease (PD) brought out discordant results. The aim of the present study was to evaluate the efficacy and safety of high doses of transdermal nicotine on motor symptoms in PD. Forty PD patients were randomly assigned to a treated and untreated arm in an open-label study. Treated patients received increasing doses of nicotine to reach 90 mg/day by 11 weeks. This dosage was maintained for 28 weeks (W39) and then reduced over 6 weeks. Final evaluation was performed 6 weeks after washout. The main outcome measure was the OFF-DOPA Unified Parkinson's Disease Rating Scale (UPDRS) motor score measured on video recordings by raters blinded to the medication status of the patients. There was no significant difference in OFF-DOPA UPDRS motor scores between the nicotine-treated and non-treated groups, neither at W39 (19.4 ± 9.3 vs. 21.5 ± 14.2) nor considering W39 differences from baseline (-1.5 ± 12.1 vs. +0.9 ± 12.1). The 39-item Parkinson's disease questionnaire scores decreased in nicotine-treated patients and increased in non-treated patients, but the difference was not significant. Overall tolerability was acceptable, and 12/20 treated patients reached the maximal dosage. High doses of transdermal nicotine were tolerated, but our study failed to demonstrate significant improvement in UPDRS motor scores. Improvement in unblinded secondary outcomes (UPDRS-II, UPDRS-IV, doses of l-DOPA equivalents) suggest a possible benefit for patients treated with nicotine, which should be confirmed in larger double blind, placebo-controlled studies. © 2017 EAN.

Agomelatine versus Sertraline: An Observational, Open-labeled and 12 Weeks Follow-up Study on Efficacy and Tolerability

PubMed Central

Akpınar, Esma; Cerit, Cem; Talas, Anıl; Tural, Ümit

2016-01-01

Objective In this open-labeled, 12 weeks follow-up study, we aimed to compare the efficacy and tolerability of agomelatine with sertraline Methods The outpatients of adult psychiatry clinic who have a new onset of depression and diagnosed as ‘major depressive episode’ by clinician according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition and prescribed agomelatine (25 mg/day) or sertraline (50 mg/day) were included in the study. Results The decline of mean Montgomery-Asberg Depression Rating Scale (MADRS) scores of agomelatine group was significantly higher than the sertraline group at the end of 2nd week; however, the difference was not significant at the end of 3 months. Mean Clinical Global Impression-Improvement scale (CGI-I) scores of agomelatine group was lower than sertraline group at first week. Mean CGI-Severity scale and CGI-I scores were favour to sertraline group at the end of the study. Remission rates were 46.7% for sertraline group and 33.3% for agomelatine group while response rates were 76.7% for both groups. Any patient from agomelatine group dropped-out due to adverse effects. The amount of side effects was also less with agomelatine. Conclusion Agomelatine has a rapid onset efficacy on depressive symptoms and this can be beneficial for some critical cases. Considering MADRS scores, agomelatine seems to have similar efficacy with sertraline but we also point the need for long term studies since CGI scores were favour to sertraline group at the end of the study. Agomelatine has a favourable tolerability profile both in terms of discontinuation and the amount of side effects compared to sertraline. PMID:27776387

S220. BLONANSERIN AUGMENTATION IN PATIENTS WITH SCHIZOPHRENIA – WHO IS BENEFITED FROM BLONANSERIN AUGMENTATION? AN OPEN-LABEL, PROSPECTIVE, MULTI-CENTER STUDY

PubMed Central

Bahk, Won-Myong; Kwon, Young Joon; Yoon, Bo-Hyun; Lee, Sang-Yeol; Lee, Kwanghun; Jon, Duk-In; Kim, Moon Doo; Lim, Eunsung

2018-01-01

Abstract Background Evidences for antipsychotic augmentation for schizophrenic patients with sub-optimal efficacy have been lacking although it has been widespread therapeutic strategy in clinical practice. The purpose of this study was to investigate the efficacy and tolerability of blonanserin augmentation with an atypical antipsychotics (AAPs) in schizophrenic patients. Methods A total of 100 patients with schizophrenia partially or completely unresponsive to treatment with an AAP recruited in this 12-week, open-label, non-comparative, multicenter study. Blonanserin was added to existing AAPs which were maintained during the study period. Efficacy was primarily evaluated using Positive and Negative Syndrome Scale (PANSS) at baseline, week 2, 4, 8, and 12. Predictors for PANSS response (≥20% reduction) was investigated. Results The PANSS total score was significantly decreased at 12 weeks after blonanserin augmentation (-21.0 ± 18.1, F=105.849, p<0.001). Response rate on PANSS at week 12 was 51.0%. Premature discontinuation was occurred in 17 patients (17.0%) and 4 patients among them discontinued the study due to adverse events. Nine patients experienced significant weight gain during the study. Response to blonanserin augmentation was associated with severe (PANSS>85) baseline symptom (OR=10.298, p=0.007) and higher dose (>600mg/day of chlorpromazine equivalent dose) of existing AAPs (OR=4.594, p=0.014). Discussion Blonanserin augmentation improved psychiatric symptoms of schizophrenic patients in cases of partial or non-responsive to an AAP treatment with favorable tolerability. Patients with severe symptom despite treatment with higher dose of AAP were benefited from this augmentation. These results suggested that blonanserin augmentation could be an effective strategy for specific patients with schizophrenia.

N-Acetylcysteine for Nonsuicidal Self-Injurious Behavior in Adolescents: An Open-Label Pilot Study.

PubMed

Cullen, Kathryn R; Klimes-Dougan, Bonnie; Westlund Schreiner, Melinda; Carstedt, Patricia; Marka, Nicholas; Nelson, Katharine; Miller, Michael J; Reigstad, Kristina; Westervelt, Ana; Gunlicks-Stoessel, Meredith; Eberly, Lynn E

2018-03-01

Nonsuicidal self-injury (NSSI) is common in adolescents and young adults, and few evidence-based treatments are available for this significant problem. N-acetylcysteine (NAC) is a widely available nutritional supplement that has been studied in some psychiatric disorders relevant to NSSI including mood and addictive disorders. This pilot study tested the use of NAC as a potential treatment for NSSI in youth. Thirty-five female adolescents and young adults with NSSI aged 13-21 years were enrolled in this study that had an open-label, single-arm study design. All participants were given oral NAC as follows: 600 mg twice daily (weeks 1-2), 1200 mg twice daily (weeks 3-4), and 1800 mg twice daily (weeks 5-8). Patients were seen every 2 weeks throughout the trial, at which time youth reported the frequency of NSSI episodes. Levels of depression, impulsivity, and global psychopathology were measured at baseline and at the end of the trial using the Beck Depression Inventory-II (BDI-II), Barratt Impulsivity Scale, and Symptoms Checklist-90 (SCL-90). About two-thirds of the enrolled female youth completed the trial (24/35). NAC was generally well tolerated in this sample. NAC treatment was associated with a significant decrease in NSSI frequency at visit 6 and visit 8 compared to baseline. We also found that depression scores and global psychopathology scores (but not impulsivity scores) decreased after NAC treatment. Decrease in NSSI was not correlated with decrease in BDI-II or SCL-90 scores, suggesting these might be independent effects. We provide preliminary evidence that NAC may have promise as a potential treatment option for adolescents with NSSI. The current results require follow-up with a randomized, placebo-controlled trial to confirm efficacy.

A D1 receptor antagonist, ecopipam, for treatment of tics in Tourette syndrome.

PubMed

Gilbert, Donald L; Budman, Cathy L; Singer, Harvey S; Kurlan, Roger; Chipkin, Richard E

2014-01-01

Dysregulation of dopaminergic signaling has been hypothesized to underlie the motor and phonic tics in Tourette syndrome (TS). The objective of this trial was to evaluate the safety and tic-reducing activity of the selective dopamine D1 receptor antagonist ecopipam in adults with TS. This was a multicenter, nonrandomized, open-label study of 50-mg ecopipam daily (weeks 1-2) and then 100 mg daily (weeks 3-8), taken orally before bedtime. The primary efficacy end point was the change in the Yale Global Tic Severity Scale (YGTSS) total tic score. Comorbid psychiatric symptoms and premonitory urges were rated; weight, serum metabolic studies, and adverse effects were monitored. Eighteen adults (15 men; 15 white, 2 African American, 1 Asian), with a mean age of 36.2 years (range, 18-63 years), were enrolled, and 15 completed the study. Mean (SD) YGTSS Total Tic score was 30.6 (8.8) at baseline and 25.3 (9.2) at 8 weeks (2-tailed paired t17 = 4.4; P = 0.0004). Mean (SD) YGTSS impairment score was 29.7 (10.9) at baseline and 22.8 (13.7) at final visit (t17 = 2.2; P = 0.04). There was no significant change in premonitory urges or psychiatric symptoms. Mean change in weight was -0.7 kg (P = 0.07). The most commonly reported adverse events were sedation (39%), fatigue (33%), insomnia (33%), somnolence (28%), anxiety (22%), headache (22%), and muscle twitching (22%). In this open-label study in adults with TS, tics were reduced after 8 weeks of treatment with ecopipam. To confirm safety and efficacy, randomized, double blind, placebo-controlled trials are warranted.

A randomized, multicenter, open-label study of poly-L-lactic acid for HIV-1 facial lipoatrophy.

PubMed

Carey, Dianne L; Baker, David; Rogers, Gary D; Petoumenos, Kathy; Chuah, John; Easey, Nicole; Machon, Kirsty; Cooper, David A; Emery, Sean; Carr, Andrew

2007-12-15

Facial lipoatrophy can stigmatize and can reduce quality of life, self esteem, and antiretroviral adherence. Poly-L-lactic acid (PLA) injections seem safe and effective, but no randomized study has included objective endpoints. HIV-positive adults with moderate/severe facial lipoatrophy were randomized to 4 open-label PLA treatments administered every 2 weeks from week 0 (immediate group, n = 51) or after week 24 (deferred group, n = 50). The primary endpoint was mean change in facial soft tissue volume (FSTV), as assessed by spiral computed tomography. Analyses were by intention to treat. At week 24, mean changes in FSTV were 0 cm3 in the intermediate group and -10 cm3 in the deferred group (between-group difference of 10 [95% confidence interval (CI): -7 to 28] cm3; P = 0.24). The immediate group had a greater mean change in soft tissue depth at the maxilla (2.2 mm [95% CI: 1.6 to 2.9]; P < 0.0001) and base of the nasal septum (1.0 mm [95% CI: 0.3 to 1.6]; P = 0.003) levels. PLA did not have an impact on peripheral fat mass, viral load, or antiretroviral adherence. Patient and physician subjectively assessed facial lipoatrophy severity (P < 0.0001), 2 of 8 Short Form-36 Health Survey and 2 of 5 Multidimensional Body-Self Relations Questionnaire-Appearance Scales, scores improved significantly. The median duration of treatment-related adverse events was 2 (interquartile range: 1 to 3) days. PLA did not increase FSTV, although tissue thickness in injection planes increased modestly, an improvement observed by patients. PLA was safe and well tolerated. Facial lipoatrophy severity and some quality-of-life domains improved.

A lower starting dose of eltrombopag is efficacious in Japanese patients with previously treated chronic immune thrombocytopenia.

PubMed

Tomiyama, Y; Miyakawa, Y; Okamoto, S; Katsutani, S; Kimura, A; Okoshi, Y; Ninomiya, H; Kosugi, H; Nomura, S; Ozaki, K; Ikeda, Y; Hattori, T; Katsura, K; Kanakura, Y

2012-05-01

Eltrombopag is an oral, non-peptide thrombopoietin receptor agonist that has shown efficacy and safety in chronic immune thrombocytopenia (ITP). However, ethnic differences in eltrombopag exposure have been reported: area under the curve exposure to eltrombopag was 87% greater among ITP patients of East Asian descent than among ITP patients of non-East Asian ITP descent. To evaluate the efficacy and safety of eltrombopag by using, in Japanese ITP patients, lower starting (12.5 mg) and maximum (50 mg) doses of eltrombopag than the standard starting (50 mg) and maximum (75 mg) doses approved in the USA and Europe. We examined 23 Japanese patients with previously treated chronic ITP with a platelet count of < 30,000 μL(-1) in a multicenter study comprising a randomized, double-blind, placebo-controlled phase for 6-week evaluation (15 eltrombopag, and eight placebo) and an open-label phase for 6-month evaluation (23 eltrombopag). The response rate (platelet count of ≥ 50,000 μL(-1) ) at week 6 of the 6-week double-blind phase was 60% in eltrombopag-treated patients and 0% in placebo-treated patients. Ten of 23 patients (43.5%) responded for ≥ 75% of predefined assessment visits during the 6-month open-label phase. Notably, 22% (5/23) of patients responded to 12.5 mg of eltrombopag, which was administered within the first 3 weeks of eltrombopag treatment. Bleeding decreased with eltrombopag treatment as compared with baseline. Eltrombopag was generally well tolerated; one patient experienced a transient ischemic attack on day 9. Eltrombopag (12.5-50 mg) is effective for the management of Japanese patients with chronic ITP (NCT00540423). © 2012 International Society on Thrombosis and Haemostasis.

Unanticipated increases in hepatic steatosis among human immunodeficiency virus patients receiving mineralocorticoid receptor antagonist eplerenone for non-alcoholic fatty liver disease.

PubMed

Chaudhury, Chloe S; Purdy, Julia B; Liu, Chia-Ying; Morse, Caryn G; Stanley, Takara L; Kleiner, David; Hadigan, Colleen

2018-05-01

Non-alcoholic fatty liver disease is common in human immunodeficiency virus, but there are no approved therapies. The aim of this open-label proof-of-concept study was to determine the effect of the mineralocorticoid receptor antagonist eplerenone on hepatic fat in human immunodeficiency virus-infected patients with hepatic fat ≥5% by magnetic resonance spectroscopy. Five subjects received eplerenone (25 mg daily × 1 week followed by 50 mg daily × 23 weeks). Laboratory tests were done at each visit, and the primary endpoint, change in hepatic fat content, was determined by MRI spectroscopy at baseline and week 24. The study was stopped early after observing unexpected significant increases in hepatic fat at week 24 (mean increase 13.0 ± 7.3%, P = .02). The increases in steatosis were accompanied by a tendency for transaminase values to decrease (alanine aminotransferase mean change -14 ± 16 IU/L, P = .14). There were no consistent changes in other metabolic parameters or blood pressure. Repeat assessment of hepatic steatosis 1-2 months after stopping study medication revealed improvements in steatosis towards baseline values. The unexpected observation of increased hepatic steatosis with the administration of eplerenone led to early termination of the investigation. While limited because of the small number of participants and the open-label design, this study provides data to suggest that mineralocorticoid receptor antagonism with eplerenone may not be an effective approach to treat hepatic steatosis in human immunodeficiency virus or the general population. Additional research is needed to determine the pathophysiological mechanism behind these unanticipated observations. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Simeprevir in combination with sofosbuvir in treatment-naïve and -experienced patients with hepatitis C virus genotype 4 infection: a Phase III, open-label, single-arm study (PLUTO).

PubMed

Buti, M; Calleja, J L; Lens, S; Diago, M; Ortega, E; Crespo, J; Planas, R; Romero-Gómez, M; Rodríguez, F G; Pascasio, J M; Fevery, B; Kurland, D; Corbett, C; Kalmeijer, R; Jessner, W

2017-02-01

Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and subsequent hepatocellular carcinoma. HCV genotype 4 is found widely in the Middle East, Egypt and Africa, and has also spread into Europe. There are limited data available regarding the use of direct-acting antiviral agents in HCV genotype 4-infected patients with cirrhosis. To evaluate in the phase III, open-label, single-arm PLUTO study the efficacy and safety of 12 weeks of simeprevir (HCV NS3/4A protease inhibitor) plus sofosbuvir (HCV nucleotide-analogue NS5B polymerase inhibitor) in treatment-naïve and (peg)interferon ± ribavirin-experienced HCV genotype 4-infected patients, with or without compensated cirrhosis. Adult patients with chronic HCV genotype 4 infection received simeprevir 150 mg once-daily and sofosbuvir 400 mg once-daily for 12 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Safety was also assessed. Forty patients received treatment; the majority were male (73%) and treatment-experienced (68%). Overall, 7/40 (18%) patients had compensated cirrhosis. All patients achieved SVR12 [100% (Clopper-Pearson 95% confidence interval: 91-100%)]. Adverse events, all Grade 1 or 2, were reported in 20/40 (50%) patients. No serious adverse events were reported and no patients discontinued study treatment. Grade 3 treatment-emergent laboratory abnormalities were noted in 2/40 (5%) patients. Treatment with simeprevir plus sofosbuvir for 12 weeks resulted in SVR12 rates of 100% in treatment-naïve and -experienced patients with HCV genotype 4 infection with or without compensated cirrhosis, and was well tolerated. [NCT02250807]. © 2016 John Wiley & Sons Ltd.

Long-Term Safety and Efficacy of Lubiprostone in Opioid-induced Constipation in Patients with Chronic Noncancer Pain.

PubMed

Spierings, Egilius L H; Rauck, Richard; Brewer, Randall; Marcuard, Stefano; Vallejo, Ricardo

2015-08-29

Chronic opioid analgesic use often causes opioid-induced constipation (OIC). This open-label extension study evaluated the safety and efficacy of lubiprostone, a chloride channel (ClC-2) activator, for treatment of OIC in patients with chronic noncancer pain. Adults with OIC were enrolled from two 12-week, placebo-controlled, double-blind studies and received lubiprostone 24 μg twice daily for up to 9 months. OIC was defined as < 3 spontaneous bowel movements (SBMs)/week during the 2-week baseline period, of which ≥ 25% were characterized by hard to very hard stool consistency, subjectively incomplete evacuation, and/or moderate or worse straining. Inclusion criteria required consistent treatment with full opioid agonists ≥ 30 days prior to screening and throughout the study. All 439 patients who received lubiprostone were analyzed for safety and efficacy. Overall, 24.6% of patients reported treatment-related adverse events (AEs), most commonly nausea (5.0%), diarrhea (4.6%), headache (1.6%), and vomiting (1.4%). No treatment-related serious AEs were reported. Nausea and diarrhea each led to study discontinuation in 5 patients (1.1%); 2 cases each of nausea and diarrhea were rated as severe. Rescue medication usage decreased from month 1 (33.0%) to month 9 (18.6%). Mean weekly SBM frequency (1.4) was significantly increased from baseline at all months (P < 0.001, range 4.9 to 5.3). Straining, abdominal bloating, abdominal discomfort, stool consistency, constipation severity, and bowel habit regularity were significantly improved from baseline at all months (P < 0.001). Lubiprostone treatment was well tolerated and improved symptoms and signs of OIC in this 9-month, open-label study of patients with chronic noncancer pain. © 2015 World Institute of Pain.

Tocilizumab in patients with active rheumatoid arthritis and inadequate responses to DMARDs and/or TNF inhibitors: a large, open-label study close to clinical practice

PubMed Central

Bykerk, Vivian P; Östör, Andrew J K; Alvaro-Gracia, José; Pavelka, Karel; Ivorra, José Andrés Román; Graninger, Winfried; Bensen, William; Nurmohamed, Michael T; Krause, Andreas; Bernasconi, Corrado; Stancati, Andrea; Sibilia, Jean

2012-01-01

Objective To evaluate the safety and efficacy of tocilizumab in clinical practice in patients with rheumatoid arthritis (RA) with inadequate responses (IR) to disease-modifying antirheumatic drugs (DMARDs) or both DMARDs and tumour necrosis factor α inhibitors (TNFis). Methods Patients—categorised as TNFi-naive, TNFi-previous (washout) or TNFi-recent (no washout) —received open-label tocilizumab (8 mg/kg) every 4 weeks ± DMARDs for 24 weeks. Adverse events (AEs) and treatment discontinuations were monitored. Efficacy end points included American College of Rheumatology (ACR) responses, 28-joint disease activity score (DAS28) and European League Against Rheumatism responses. Results Overall, 1681 (976 TNF-naive, 298 TNFi-previous and 407 TNFi-recent) patients were treated; 5.1% discontinued treatment because of AEs. The AE rate was numerically higher in TNFi-recent (652.6/100 patient-years (PY)) and TNFi-previous (653.6/100PY) than in TNFi-naive (551.1/100PY) patients. Serious AE rates were 18.0/100PY, 28.0/100PY and 18.6/100PY; serious infection rates were 6.0/100PY, 6.8/100PY and 4.2/100PY, respectively. At week 4, 36.5% of patients achieved ACR20 response and 14.9% DAS28 remission (<2.6); at week 24, 66.9%, 46.6%, 26.4% and 56.8% achieved ACR20/ACR50/ACR70 responses and DAS28 remission, respectively. Overall, 61.6% (TNFi-naive), 48.5% (TNFi-previous) and 50.4% (TNFi-recent) patients achieved DAS28 remission. Conclusions In patients with RA who were DMARD-IR/TNFi-IR, tocilizumab ± DMARDs provided rapid and sustained efficacy without unexpected safety concerns. PMID:22615456

Long-term safety and efficacy of tofogliflozin as add-on to insulin in patients with type 2 diabetes: Results from a 52-week, multicentre, randomized, double-blind, open-label extension, Phase 4 study in Japan (J-STEP/INS).

PubMed

Terauchi, Yasuo; Tamura, Masahiro; Senda, Masayuki; Gunji, Ryoji; Kaku, Kohei

2018-05-01

To evaluate the long-term safety and efficacy of tofogliflozin as an add-on treatment to insulin over 52 weeks. This 52-week, multicentre, Phase 4 study consisted of a 16-week, randomized, double-blind, placebo-controlled phase and a 36-week open label extension phase (NCT02201004). Japanese patients with type 2 diabetes mellitus, aged 20 to 75 years, with suboptimal glycaemic control (7.5%-10.5%) receiving insulin monotherapy (basal-bolus, bolus, premix [low and high] and basal) or receiving combination therapy with basal insulin and dipeptidyl peptidase-4 inhibitor were eligible for participation. Patients who received tofogliflozin throughout the study (52 weeks) were referred to as the 'tofo-tofo group' and patients who received placebo and tofogliflozin (36 weeks) were referred to as the 'pla-tofo group'. A total of 210 patients received treatment per randomization. Hypoglycaemia was the most common treatment-emergent adverse event (AE) (42.9% in the tofo-tofo group and 29.4% in the pla-tofo group). Patients reported genital infection, urinary tract infection, excessive urination and AEs related to volume depletion (2.1%, 2.1%, 7.1% and 10.0% of patients in the tofo-tofo group, and 0%, 1.5%, 2.9% and 7.4% of patients in the pla-tofo group, respectively). Mean HbA1c and body weight at baseline (mean changes ± standard error from baseline to Week 52) in the tofo-tofo and pla-tofo groups were 8.53% (-0.76% ± 0.077) and 8.40% (-0.73% ± 0.102); 68.84 kg (-1.52 kg ± 0.207) and 72.24 kg (-2.13 kg ± 0.313), respectively. This study demonstrates the safety and efficacy of tofogliflozin as add-on to insulin therapy in type 2 diabetes mellitus patients, offering a new therapeutic solution to diabetes management. © 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Phase 1, open-label, dose escalation, safety, and pharmacokinetics study of ME-344 as a single agent in patients with refractory solid tumors.

PubMed

Bendell, Johanna C; Patel, Manish R; Infante, Jeffrey R; Kurkjian, Carla D; Jones, Suzanne F; Pant, Shubham; Burris, Howard A; Moreno, Ofir; Esquibel, Vanessa; Levin, Wendy; Moore, Kathleen N

2015-04-01

The current phase 1, open-label, dose escalation study was conducted to establish the safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity of the novel mitochondrial inhibitor ME-344 in patients with refractory solid tumors. Patients with refractory solid tumors were treated in a 3 + 3 dose escalation design. ME-344 was administered via intravenous infusion on days 1, 8, and 15 of the first 28-day cycle and weekly thereafter. Pharmacokinetics was assessed on days 1 and 15 of the first cycle. A total of 30 patients (median age, 65 years; 67% of whom were female) received ME-344. There were 5 dose-limiting toxicities reported. Four patients developed grade 3 neuropathy (2 patients each at doses of 15 mg/kg and 20 mg/kg) and 1 patient treated at a dose of 10 mg/kg developed a grade 3 acute myocardial infarction (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]). The maximum tolerated dose (MTD) was defined as 10 mg/kg weekly. The most common adverse events were nausea, dizziness, and fatigue. At the MTD of 10 mg/kg, the maximal plasma concentration (Cmax) was 25.8 µg/mL and the area under the concentration curve from time zero to infinity was 25.9 hour*µg/mL. One patient with small cell lung cancer achieved a partial response for ≥ 52 weeks. Four patients had prolonged stable disease (1 patient each with urothelial carcinoma [47 weeks], carcinoid tumor [≥ 40 weeks], cervical leiomyosarcoma [39 weeks], and cervical cancer [≥ 31 weeks]). The once-weekly administration of ME-344 was generally well tolerated in the current study, a first-in-human study; dose-limiting neuropathy was noted, but not at the MTD. Exposures at the 10-mg/kg dose level suggest a sufficient therapeutic index. The preliminary clinical activity as a monotherapy supports the further clinical development of ME-344 in combination with chemotherapy. © 2014 American Cancer Society.

Efficacy and Tolerability of Nilvadipine in Combination with an Angiotensin II Receptor Antagonist in Patients with Essential Hypertension: A Multicenter, Open-Label, Uncontrolled Study

PubMed Central

Noda, Keita; Ideishi, Munehito; Tashiro, Eiichiro; Nakashima, Yoshiyuki; Imamura, Mitsuhide; Seki, Masahiko; Fujino, Masanori; Sou, Toshimitsu; Kohara, Masaki; Kanaya, Hisashi; Saku, Nishiki; Kamei, Ritsu; Yamasaki, Misao; Sakai, Hiroshi; Gondo, Naoki; Saku, Keijiro

2003-01-01

Background: Combination therapy with different classes of antihypertensive drugs often is needed to achieve controlled blood pressure (BP). The combination of an angiotensin II receptor antagonist (AIIA) and a calcium antagonist is a preferred option for reducing uncontrolled BP. Objective: The aim of this study was to assess the clinical efficacy and tolerability of nilvadipine, a dihydropyridine calcium antagonist, in combination with an AIIA. Methods: Patients with essential hypertension whose BP was not controlled by an AIIA alone were eligible for this multicenter, open-label, uncontrolled study. One of 3 AIIAs (candesartan cilexetil, losartan potassium, or valsartan) was given for at least 10 weeks before the addition of nilvadipine (daily dose, 4 or 8 mg orally). This combination therapy was given for 8 weeks. BP and heart rate were measured between 2 and 4 weeks before and 0, 4, and 8 weeks after the start of combination therapy. Adverse events were monitored at each visit. Results: Thirty-one patients (18 women [58.1%], 13 men [41.9%]; mean [SD] age, 58.5 [10.5] years) were enrolled. At weeks 4 and 8 of combination therapy, mean systolic BP (SBP) and diastolic BP (DBP) were significantly decreased (P<0.01) (at week 8, by 22.0 mm Hg and 12.5 mm Hg, respectively). The mean BP-lowering effect did not differ significantly between the 3 AIIAs tested. Pulse pressure also decreased significantly at week 8, by 9.6 mm Hg (P<0.01). The responder rate (ie, the percentage of patients with DBP <90 mm Hg or a decrease in DBP ≥10 mm Hg) was 72.0% at week 8. Three patients experienced a total of 4 adverse events: mild or severe flushing, mild headache, and mild palpitation. All of these symptoms resolved after nilvadipine treatment was discontinued. Conclusions: Nilvadipine in combination with an AIIA showed good antihypertensive efficacy and was well tolerated in the hypertensive patients in this study. This combination also significantly decreased pulse pressure, suggesting that this combination therapy also may have a beneficial effect in elderly patients with isolated systolic hypertension. PMID:25053855

Open-label study of etanercept treatment in patients with moderate-to-severe plaque psoriasis who lost a satisfactory response to adalimumab.

PubMed

Bagel, J; Tyring, S; Rice, K C; Collier, D H; Kricorian, G; Chung, J; Iles, J; Stolshek, B S; Kaliyaperumal, A; Papp, K A

2017-08-01

Some patients with plaque psoriasis experience secondary failure of tumour necrosis factor inhibitor therapy. To evaluate efficacy, safety and patient-reported outcomes (PROs) with etanercept in patients with secondary adalimumab failure. This phase IV open-label single-arm estimation study (NCT01543204) enrolled patients on adalimumab who had achieved static Physician's Global Assessment (sPGA) score 0/1 (clear/almost clear). Patients subsequently lost response, defined as sPGA ≥ 3 or loss of 50% improvement in Psoriasis Area and Severity Index (PASI 50). At baseline, patients had involved body surface area ≥ 10%, sPGA ≥ 3 and PASI ≥ 10. Antiadalimumab antibodies (ADAs) were measured at screening. Patients received etanercept 50 mg twice weekly for 12 weeks, followed by 50 mg weekly. The primary end point was sPGA 0/1 at week 12 (intention-to-treat analysis; no hypothesis tested). Additional outcomes included rates of sPGA 0/1, PASI responses, safety, PROs of itch, pain and flaking, Dermatology Life Quality Index, treatment satisfaction and Work Productivity and Activity Impairment questionnaire. Sixty-four patients enrolled; 67% had ADAs. sPGA 0/1 rates at week 12 were 39·7% [95% confidence interval (CI) 27·6-52·8; primary end point] and 45% (95% CI 29·3-61·5) for patients positive for ADAs and 35% (95% CI 15·4-59·2) for patients negative for ADAs. PASI 75 response rates at week 12 were 47·5% (95% CI 31·5-63·9) for patients who were positive for ADAs and 50% (95% CI 27·2-72·8) for patients negative for ADAs. No new safety signals were observed. PROs of itch, pain and flaking consistently improved at week 12 and were maintained through week 24. Patients with psoriasis who experienced secondary failure of adalimumab achieved satisfactory response to etanercept regardless of ADA status. © 2016 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

An open-label clinical trial to investigate the efficacy and safety of corifollitropin alfa combined with hCG in adult men with hypogonadotropic hypogonadism.

PubMed

Nieschlag, Eberhard; Bouloux, Pierre-Marc G; Stegmann, Barbara J; Shankar, R Ravi; Guan, Yanfen; Tzontcheva, Anjela; McCrary Sisk, Christine; Behre, Hermann M

2017-03-07

Hypogonadotropic hypogonadism (HH) in men results in insufficient testicular function and deficiencies in testosterone and spermatogenesis. Combinations of human chorionic gonadotropin (hCG) and recombinant follicle-stimulating hormone (recFSH) have been successful in the treatment of HH. Corifollitropin alfa is a long-acting FSH-analog with demonstrated action in women seeking infertility care. The aim of this study was to investigate the efficacy and safety of corifollitropin alfa combined with hCG to increase testicular volume and induce spermatogenesis in men with HH. This was a Phase III, multi-center, open-label, single-arm trial of corifollitropin alfa in azoospermic men aged 18 to 50 years with HH. After 16 weeks of pretreatment of 23 subjects with hCG alone, 18 subjects with normalized testosterone (T) levels who remained azoospermic entered the 52-week combined treatment phase with hCG twice-weekly and 150 μg corifollitropin alfa every other week. The increase in testicular volume (primary efficacy endpoint) and induction of spermatogenesis resulting in a sperm count ≥1 × 10 6 /mL (key secondary efficacy endpoint) during 52 weeks of combined treatment were assessed. Safety was evaluated by the presence of anti-corifollitropin alfa antibodies and the occurrence of adverse events (AEs). Mean (±SD) testicular volume increased from 8.6 (±6.09) mL to 17.8 (±8.93) mL (geometric mean fold increase, 2.30 [95% CI: 2.03, 2.62]); 14 (77.8%) subjects reached a sperm count ≥1 × 10 6 /mL. No subject developed confirmed anti-corifollitropin alfa antibodies during the trial. Treatment was generally well tolerated. Corifollitropin alfa 150 μg administrated every other week combined with twice-weekly hCG for 52 weeks increased testicular volume significantly, and induced spermatogenesis in >75% of men with HH who had remained azoospermic after hCG treatment alone. ClinicalTrials.gov: NCT01709331 .

An open-label six-month extension study to investigate the safety and efficacy of an extract of Artemisia annua for managing pain, stiffness and functional limitation associated with osteoarthritis of the hip and knee.

PubMed

Hunt, Sheena; Stebbings, Simon; McNamara, Debra

2016-10-28

This six-month single-centre open-label extension study, conducted at the University of Otago, Dunedin, follows from a previously published 12-week pilot double-blind randomised placebo-controlled study of dietary supplement, Arthrem® (ART) in patients with osteoarthritis (OA) of the hip or knee. The pilot double-blind study showed that treatment with ART 150 mg twice-daily was associated with clinically relevant pain reduction. The extension study aims were to assess longer-term safety and efficacy during six months' treatment following the pilot trial. Patients who completed the pilot double-blind study had the option to continue on open-label treatment with ART for a further six months. Safety was assessed by adverse event monitoring and laboratory tests at three and six months. Efficacy was assessed at three and six months using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®). Thirty-four patients entered the optional extension and 28 completed six months' treatment. ART was well tolerated when taken for up to nine months. Improvements in WOMAC® efficacy parameters reported in the double-blind phase of the study were maintained over six months. ART appears to be a safe and effective alternative for managing the symptoms of OA over an extended period.

Latanoprostene Bunod 0.024% in Subjects With Open-angle Glaucoma or Ocular Hypertension: Pooled Phase 3 Study Findings.

PubMed

Weinreb, Robert N; Liebmann, Jeffrey M; Martin, Keith R; Kaufman, Paul L; Vittitow, Jason L

2018-01-01

To compare the diurnal intraocular pressure (IOP)-lowering effect of latanoprostene bunod (LBN) 0.024% with timolol maleate 0.5% in subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT). Pooled analysis of two phase 3, randomized, multicenter, double-masked, parallel-group, noninferiority trials (APOLLO and LUNAR), each with open-label safety extension phases. Adults with OAG or OHT were randomized 2:1 to double-masked treatment with LBN once daily (qd) or timolol twice daily (bid) for 3 months followed by open-label LBN treatment for 3 (LUNAR) or 9 (APOLLO) months. IOP was measured at 8 AM, 12 PM, and 4 PM at week 2, week 6, and months 3, 6, 9, and 12. Of the 840 subjects randomized, 774 (LBN, n=523; timolol crossover to LBN, n=251) completed the efficacy phase, and 738 completed the safety extension phase. Mean IOP was significantly lower with LBN versus timolol at all 9 evaluation timepoints during the efficacy phase (P<0.001). A significantly greater proportion of LBN-treated subjects attained a mean IOP ≤18 mm Hg and IOP reduction ≥25% from baseline versus timolol-treated subjects (P<0.001). The IOP reduction with LBN was sustained through the safety phase; subjects crossed over from timolol to LBN experienced additional significant IOP lowering (P≤0.009). Both treatments were well tolerated, and there were no safety concerns with long-term LBN treatment. In this pooled analysis of subjects with OAG and OHT, LBN 0.024% qd provided greater IOP-lowering compared with timolol 0.5% bid and maintained lowered IOP through 12 months. LBN demonstrated a safety profile comparable to that of prostaglandin analogs.

A Randomized, Multicenter, Phase III Trial to Evaluate the Efficacy and Safety of Polmacoxib Compared with Celecoxib and Placebo for Patients with Osteoarthritis.

PubMed

Lee, Myungchul; Yoo, Juhyung; Kim, Jin Goo; Kyung, Hee-Soo; Bin, Seong-Il; Kang, Seung-Baik; Choi, Choong Hyeok; Moon, Young-Wan; Kim, Young-Mo; Han, Seong Beom; In, Yong; Choi, Chong Hyuk; Kim, Jongoh; Lee, Beom Koo; Cho, Sangsook

2017-12-01

The aim of this study was to evaluate the safety and analgesic efficacy of polmacoxib 2 mg versus placebo in a superiority comparison or versus celecoxib 200 mg in a noninferiority comparison in patients with osteoarthritis (OA). This study was a 6-week, phase III, randomized, double-blind, and parallel-group trial followed by an 18-week, single arm, open-label extension. Of the 441 patients with knee or hip OA screened, 362 were randomized; 324 completed 6 weeks of treatment and 220 completed the extension. Patients were randomized to receive oral polmacoxib 2 mg (n = 146), celecoxib 200 mg (n = 145), or placebo (n = 71) once daily for 6 weeks. During the extension, all participants received open-label polmacoxib 2 mg. The primary endpoint was the change in Western Ontario and McMaster Universities (WOMAC)-pain subscale score from baseline to week 6. Secondary endpoints included WOMAC-OA Index, OA subscales (pain, stiffness, and physical function) and Physician's and Subject's Global Assessments at weeks 3 and 6. Other outcome measures included adverse events (AEs), laboratory tests, vital signs, electrocardiograms, and physical examinations. After 6 weeks, the polmacoxib-placebo treatment difference was -2.5 (95% confidence interval [CI], -4.4 to -0.6; p = 0.011) and the polmacoxib-celecoxib treatment difference was 0.6 (CI, -0.9 to 2.2; p = 0.425). According to Physician's Global Assessments, more subjects were "much improved" at week 3 with polmacoxib than with celecoxib or placebo. Gastrointestinal and general disorder AEs occurred with a greater frequency with polmacoxib or celecoxib than with placebo. Polmacoxib 2 mg was relatively well tolerated and demonstrated efficacy superior to placebo and noninferior to celecoxib after 6 weeks of treatment in patients with OA. The results obtained during the 18-week trial extension with polmacoxib 2 mg were consistent with those observed during the 6-week treatment period, indicating that polmacoxib can be considered safe for long-term use based on this relatively small scale of study in a Korean population. More importantly, the results of this study showed that polmacoxib has the potential to be used as a pain relief drug with reduced gastrointestinal side effects compared to traditional nonsteroidal anti-inflammatory drugs for OA.

Armodafinil for fatigue associated with menopause: an open-label trial.

PubMed

Meyer, Fremonta; Freeman, Marlene P; Petrillo, Laura; Barsky, Maria; Galvan, Thania; Kim, Semmie; Cohen, Lee; Joffe, Hadine

2016-02-01

This study aims to obtain preliminary data on the efficacy of armodafinil for improving menopause-related fatigue and quality of life. Women (aged 40-65 y) experiencing menopause-related fatigue received open-label armodafinil therapy (up to 150 mg/d) for 4 weeks. Changes from baseline in Brief Fatigue Inventory score and Menopause-Specific Quality of Life (MENQOL) physical domain score were examined using the Wilcoxon signed rank test. Exploratory analyses examined the effects of armodafinil on hot flashes, overall quality of life, insomnia, depression, anxiety, and perceived cognitive performance. After open-label treatment, participants were randomized to double-blind continuation of armodafinil versus placebo for 2 weeks to examine whether treatment discontinuation would precipitate symptom recurrence. Of 29 eligible participants, 20 women (69.0%) completed the trial. During treatment with armodafinil (mean dose, 120 mg/d), median Brief Fatigue Inventory scores decreased by 57.7% from 5.2 (interquartile range [IQR], 4.6-6.2) to 2.2 (IQR, 1.1-4.4; P = 0.0002), and median MENQOL physical domain scores decreased by 51.3% from 3.9 (IQR, 2.3-4.8) to 1.9 (IQR, 1.3-2.7; P = 0.0001). Median hot flashes for 24 hours decreased by 48.3% from 2.9 (IQR, 1.1-4.6) to 1.5 (IQR, 0.4-2.4; P = 0.0005). Improvements in MENQOL total score (49%; P = 0.0001), cognitive function (59.2%; P = 0.0002), depressive symptoms (64.7%; P = 0.0006), insomnia (72.7%; P = 0.0012), and excessive sleepiness (57.1%; P = 0.0006) were noted. Randomized continuation (n = 10) or discontinuation (n = 10) did not indicate group differences. Armodafinil was well-tolerated; three women (12%) were withdrawn for adverse events. These preliminary results suggest a therapeutic effect of armodafinil on fatigue affecting quality of life during menopause, and a potential benefit for other menopause-related symptoms.

Open-label add-on treatment trial of minocycline in fragile X syndrome.

PubMed

Paribello, Carlo; Tao, Leeping; Folino, Anthony; Berry-Kravis, Elizabeth; Tranfaglia, Michael; Ethell, Iryna M; Ethell, Douglas W

2010-10-11

Fragile X syndrome (FXS) is a disorder characterized by a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socio-emotional problems. It is hypothesized that the absence of the fragile X mental retardation protein (FMRP) leads to higher levels of matrix metallo-proteinase-9 activity (MMP-9) in the brain. Minocycline inhibits MMP-9 activity, and alleviates behavioural and synapse abnormalities in fmr1 knockout mice, an established model for FXS. This open-label add-on pilot trial was conducted to evaluate safety and efficacy of minocycline in treating behavioural abnormalities that occur in humans with FXS. Twenty individuals with FXS, ages 13-32, were randomly assigned to receive 100 mg or 200 mg of minocycline daily. Behavioural evaluations were made prior to treatment (baseline) and again 8 weeks after daily minocycline treatment. The primary outcome measure was the Aberrant Behaviour Checklist-Community Edition (ABC-C) Irritability Subscale, and the secondary outcome measures were the other ABC-C subscales, clinical global improvement scale (CGI), and the visual analog scale for behaviour (VAS). Side effects were assessed using an adverse events checklist, a complete blood count (CBC), hepatic and renal function tests, and antinuclear antibody screen (ANA), done at baseline and at 8 weeks. The ABC-C Irritability Subscale scores showed significant improvement (p < 0.001), as did the VAS (p = 0.003) and the CGI (p < 0.001). The only significant treatment-related side effects were minor diarrhea (n = 3) and seroconversion to a positive ANA (n = 2). Results from this study demonstrate that minocycline provides significant functional benefits to FXS patients and that it is well-tolerated. These findings are consistent with the fmr1 knockout mouse model results, suggesting that minocycline modifies underlying neural defects that account for behavioural abnormalities. A placebo-controlled trial of minocycline in FXS is warranted. ClinicalTrials.gov Open-Label Trial NCT00858689.

Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial.

PubMed

Bernard, Louis; Dinh, Aurélien; Ghout, Idir; Simo, David; Zeller, Valerie; Issartel, Bertrand; Le Moing, Vincent; Belmatoug, Nadia; Lesprit, Philippe; Bru, Jean-Pierre; Therby, Audrey; Bouhour, Damien; Dénes, Eric; Debard, Alexa; Chirouze, Catherine; Fèvre, Karine; Dupon, Michel; Aegerter, Philippe; Mulleman, Denis

2015-03-07

Duration of treatment for patients with vertebral osteomyelitis is mainly based on expert recommendation rather than evidence. We aimed to establish whether 6 weeks of antibiotic treatment is non-inferior to 12 weeks in patients with pyogenic vertebral osteomyelitis. In this open-label, non-inferiority, randomised controlled trial, we enrolled patients aged 18 years or older with microbiologically confirmed pyogenic vertebral osteomyelitis and typical radiological features from 71 medical care centres across France. Patients were randomly assigned to either 6 weeks or 12 weeks of antibiotic treatment (physician's choice in accordance with French guidelines) by a computer-generated randomisation list of permuted blocks, stratified by centre. The primary endpoint was the proportion of patients who were classified as cured at 1 year by a masked independent validation committee, analysed by intention to treat. Non-inferiority would be declared if the proportion of cured patients assigned to 6 weeks of treatment was not less than the proportion of cured patients assigned to 12 weeks of treatment, within statistical variability, by an absolute margin of 10%. This trial is registered with EudraCT, number 2006-000951-18, and Clinical Trials.gov, number NCT00764114. Between Nov 15, 2006, and March 15, 2011, 359 patients were randomly assigned, of whom six in the 6-week group and two in the 12-week group were excluded after randomisation. 176 patients assigned to the 6-week treatment regimen and 175 to the 12-week treatment regimen were analysed by intention to treat. 160 (90·9%) of 176 patients in the 6-week group and 159 (90·9%) of 175 of those in the 12-week group met the criteria for clinical cure. The difference between the groups (0·05%, 95% CI -6·2 to 6·3) showed the non-inferiority of the 6-week regimen when compared with the 12-week regimen. 50 patients in the 6-week group and 51 in the 12-week group had adverse events, the most common being death (14 [8%] in the 6-week group vs 12 [7%] in the 12-week group), antibiotic intolerance (12 [7%] vs 9 [5%]), cardiorespiratory failure (7 [4%] vs 12 [7%]), and neurological complications (7 [4%] vs 3 [2%]). 6 weeks of antibiotic treatment is not inferior to 12 weeks of antibiotic treatment with respect to the proportion of patients with pyogenic vertebral osteomyelitis cured at 1 year, which suggests that the standard antibiotic treatment duration for patients with this disease could be reduced to 6 weeks. French Ministry of Health. Copyright © 2015 Elsevier Ltd. All rights reserved.

Safety and tolerability of vortioxetine (15 and 20 mg) in patients with major depressive disorder: results of an open-label, flexible-dose, 52-week extension study.

PubMed

Jacobsen, Paula L; Harper, Linda; Chrones, Lambros; Chan, Serena; Mahableshwarkar, Atul R

2015-09-01

Vortioxetine is approved for the treatment of adults with major depressive disorder. This open-label extension (OLE) study evaluated the safety and tolerability of vortioxetine in the long-term treatment of major depressive disorder patients, as well as evaluated its effectiveness using measures of depression, anxiety, and overall functioning. This was a 52-week, flexible-dose, OLE study in patients who completed one of three randomized, double-blind, placebo-controlled, 8-week vortioxetine trials. All patients were switched to 10 mg/day vortioxetine for week 1, then adjusted between 15 and 20 mg for the remainder of the study, but not downtitrated below 15 mg. Safety and tolerability were assessed on the basis of treatment-emergent adverse events (TEAEs), vital signs, laboratory values, physical examination, and the Columbia-Suicide Severity Rating Scale. Efficacy measures included the Montgomery-Åsberg Depression Rating Scale, the Hamilton Anxiety Scale, the Clinical Global Impression Scale-Severity of Illness, and the Sheehan Disability Scale. Of the 1075 patients enrolled, 1073 received at least one dose of vortioxetine and 538 (50.0%) completed the study. A total of 537 patients withdrew early, with 115 (10.7% of the original study population) withdrawing because of TEAEs. Long-term treatment with vortioxetine was well tolerated; the most common TEAEs (≥10%) were nausea and headache. Laboratory values, vital signs, and physical examinations revealed no trends of clinical concern. The mean Montgomery-Åsberg Depression Rating Scale total score was 19.9 at the start of the extension study and 9.0 after 52 weeks of treatment (observed cases). Similar improvements were observed with the Hamilton Anxiety Scale (Δ-4.2), the Clinical Global Impression Scale-Severity of Illness (Δ-1.2), and the Sheehan Disability Scale (Δ-4.7) total scores after 52 weeks of treatment (observed case). In this 52-week, flexible-dose OLE study, 15 and 20 mg vortioxetine were safe and well tolerated. After entry into this study, patients continued to show improvement in depression and anxiety symptoms, as well as overall functioning, throughout the treatment period.

Tanacetum parthenium and Salix alba (Mig-RL) combination in migraine prophylaxis: a prospective, open-label study.

PubMed

Shrivastava, R; Pechadre, J C; John, G W

2006-01-01

Tanacetum parthenium (feverfew) has been used traditionally to treat migraine, and although its mechanism of action is not fully understood, serotonin 5-HT receptor blocking effects have been suggested. T. parthenium and Salix alba (white willow) either alone or in combination (Mig-RL) were recently shown to inhibit binding to 5-HT(2A/2C) receptors; T. parthenium failed to recognise 5-HT(1D) receptors, whereas S. alba or the combination did. It was hypothesised that S. alba in combination with T. parthenium may provide superior migraine prophylactic activity compared with T. parthenium alone. A prospective, open-label study was performed in 12 patients diagnosed with migraine without aura. Twelve weeks' treatment with T. parthenium 300 mg plus S. alba 300 mg (Mig-RL) twice daily was administered to determine the effects of therapy on migraine attack frequency (primary efficacy criterion), intensity and duration (secondary efficacy criteria), and quality of life, together with tolerability for patients. Attack frequency was reduced by 57.2% at 6 weeks (p < 0.029) and by 61.7% at 12 weeks (p < 0.025) in nine of ten patients, with 70% patients having a reduction of at least 50%. Attack intensity was reduced by 38.7% at 6 weeks (p < 0.005) and by 62.6% at 12 weeks (p < 0.004) in ten of ten patients, with 70% of patients having a reduction of at least 50%. Attack duration decreased by 67.2% at 6 weeks (p < 0.001) and by 76.2% at 12 weeks (p < 0.001) in ten of ten patients. Two patients were excluded for reasons unrelated to treatment. Self-assessed general health, physical performance, memory and anxiety also improved by the end of the study. Mig-RL treatment was well tolerated and no adverse events occurred. The remarkable efficacy of Mig-RL in not only reducing the frequency of migraine attacks but also their pain intensity and duration in this trial warrants further investigation of this therapy in a double-blind, randomised, placebo-controlled investigation involving a larger patient population.

Safety and efficacy of pregabalin in adolescents with fibromyalgia: a randomized, double-blind, placebo-controlled trial and a 6-month open-label extension study.

PubMed

Arnold, Lesley M; Schikler, Kenneth N; Bateman, Lucinda; Khan, Tahira; Pauer, Lynne; Bhadra-Brown, Pritha; Clair, Andrew; Chew, Marci L; Scavone, Joseph

2016-07-30

Fibromyalgia (FM) is a common pain condition characterized by widespread musculoskeletal pain and tenderness. Pregabalin is an approved treatment for adults in the United States, but there are no approved treatments for adolescents with FM. This was a 15-week, randomized, double-blind, placebo-controlled study and 6-month open-label safety trial of flexible-dose pregabalin (75-450 mg/day) for the treatment of adolescents (12-17 years) with FM. Primary outcome was change in mean pain score at endpoint (scored from 0-10, with 24-h recall). Secondary outcomes included global assessments and measures of pain, sleep, and FM impact. A total of 107 subjects were randomized to treatment (54 pregabalin, 53 placebo) and 80 completed the study (44 pregabalin, 36 placebo). Improvement in mean pain score at endpoint with pregabalin versus placebo was not statistically significant, treatment difference (95 % CI), -0.66 (-1.51, 0.18), P = 0.121. There were significant improvements with pregabalin versus placebo in secondary outcomes of change in pain score by week (P < 0.05 for 10 of 15 weeks); change in pain score at week 15 (1-week recall), treatment difference (95 % CI), -0.87 (-1.68, -0.05), P = 0.037; and patient global impression of change, 53.1 % versus 29.5 % very much or much improved (P = 0.013). Trends toward improvement with pregabalin in other secondary outcomes measuring pain, sleep, and FM impact were not significant. Safety was consistent with the known profile of pregabalin in adults with FM. Pregabalin did not significantly improve the mean pain score in adolescents with FM. There were significant improvements in secondary outcomes measuring pain and impression of change. NCT01020474 ; NCT01020526 .

Use of insulin sensitizers for the treatment of major depressive disorder: a pilot study of pioglitazone for major depression accompanied by abdominal obesity.

PubMed

Kemp, David E; Ismail-Beigi, Faramarz; Ganocy, Stephen J; Conroy, Carla; Gao, Keming; Obral, Sarah; Fein, Elizabeth; Findling, Robert L; Calabrese, Joseph R

2012-02-01

This study was conducted to examine the safety and efficacy of pioglitazone, a thiazolidinedione insulin sensitizer, in adult outpatients with major depressive disorder. In a 12-week, open-label, flexible-dose study, 23 patients with major depressive disorder received pioglitazone monotherapy or adjunctive therapy initiated at 15 mg daily. Subjects were required to meet criteria for abdominal obesity (waist circumference>35 in. in women and >40 in. in men) or metabolic syndrome. The primary efficacy measure was the change from baseline to Week 12 on the Inventory of Depressive Symptomatology (IDS) total score. Partial responders (≥25% decrease in IDS total score) were eligible to participate in an optional extension phase for an additional three months. Pioglitazone decreased depression symptom severity from a total IDS score of 40.3±1.8 to 19.2±1.8 at Week 12 (p<.001). Among partial responders (≥25% decrease in IDS total score), an improvement in depressive symptoms was maintained during an additional 3-month extension phase (total duration=24 weeks) according to IDS total scores (p<.001). Patients experienced a reduction in insulin resistance from baseline to Week 12 according to the log homeostasis model assessment (-0.8±0.75; p<.001) and a significant reduction in inflammation as measured by log highly- sensitive C-reactive protein (-0.87±0.72; p<.001). During the current episode, the majority of participants (74%, n=17), had already failed at least one antidepressant trial. The most common side effects were headache and dizziness; no patient discontinued due to side effects. These data are limited by a small sample size and an open-label study design with no placebo control. Although preliminary, pioglitazone appears to reduce depression severity and improve several markers of cardiometabolic risk, including insulin resistance and inflammation. Larger, placebo-controlled studies are indicated. Copyright © 2011 Elsevier B.V. All rights reserved.

A Prospective, Nonrandomized, Open-Label Study of the Efficacy and Safety of OnabotulinumtoxinA in Adolescents with Primary Axillary Hyperhidrosis.

PubMed

Glaser, Dee Anna; Pariser, David M; Hebert, Adelaide A; Landells, Ian; Somogyi, Chris; Weng, Emily; Brin, Mitchell F; Beddingfield, Frederick

2015-01-01

To evaluate the efficacy and safety of onabotulinumtoxinA in adolescents with primary axillary hyperhidrosis. This 52-week, multicenter, nonrandomized, open-label study was conducted in 141 adolescents ages 12 to 17 years with severe primary axillary hyperhidrosis. Patients could receive up to six treatments with onabotulinumtoxinA (50 U per axilla), with re-treatment occurring no sooner than 8 weeks after the prior treatment cycle and no later than 44 weeks after the initial treatment cycle. The primary efficacy measure was treatment response, based on self-assessed hyperhidrosis severity following the first two treatments using the 4-point Hyperhidrosis Disease Severity Scale (HDSS). Other efficacy measures included spontaneous resting sweat production and health outcomes. Fifty-six (38.9%) participants underwent one treatment, 59 (41.0%) underwent two, 20 (13.9%) underwent three, 6 (4.2%) underwent four, and 3 (2.1%) underwent five. OnabotulinumtoxinA significantly improved HDSS scores and decreased sweat production compared with treatment cycle baselines. Seventy-nine patients (54.9%) responded to treatment based on HDSS criteria. From 56.6% to 72.3% of patients experienced a two-grade or more improvement at 4 and 8 weeks after each of the first two treatments. The majority (79.4%-93.2%) had a 75% or greater reduction in sweat production at week 4 (treatments 1-3). The median duration of effect for responders ranged from 134 to 152 days. Using quality of life measures, health outcomes improved markedly. Eight patients (5.6%) had mild or moderate treatment-related adverse events. No unexpected safety signals were observed in this study. Neutralizing antibodies to onabotulinumtoxinA did not develop. OnabotulinumtoxinA injections provided beneficial effects in adolescents with primary axillary hyperhidrosis. © 2015 The Authors. Pediatric Dermatology Published by Wiley Periodicals, Inc.

Rifaximin in non-alcoholic steatohepatitis: An open-label pilot study.

PubMed

Cobbold, Jeremy F L; Atkinson, Stephen; Marchesi, Julian R; Smith, Ann; Wai, Sann N; Stove, Julie; Shojaee-Moradie, Fariba; Jackson, Nicola; Umpleby, A Margot; Fitzpatrick, Julie; Thomas, E Louise; Bell, Jimmy D; Holmes, Elaine; Taylor-Robinson, Simon D; Goldin, Robert D; Yee, Michael S; Anstee, Quentin M; Thursz, Mark R

2018-01-01

Gut microbial dysbiosis is implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH). We investigated downstream effects of gut microbiota modulation on markers of hepatic inflammation, steatosis, and hepatic and peripheral insulin sensitivity in patients with NASH using rifaximin therapy. Patients with biopsy-proven NASH and elevated aminotransferase values were included in this open-label pilot study, all receiving 6 weeks rifaximin 400 mg twice daily, followed by a 6-week observation period. The primary endpoint was change in alanine aminotransferase (ALT) after 6 weeks of rifaximin. Secondary endpoints were change in hepatic lipid content and insulin sensitivity measured with a hyperinsulinemic-euglycemic clamp. Fifteen patients (13 men and 2 women) with a median (range) age of 46 (32-63) years were included. Seven had diabetes on oral hypoglycemic medications and 8 had no diabetes. After 6 weeks of therapy, no differences were seen in ALT (55 [33-191] vs. 63 [41-218] IU/L, P = 0.41), peripheral glucose uptake (28.9 [19.4-48.3] to 25.5 [17.7-47.9] μmol/kg/min, P = 0.30), hepatic insulin sensitivity (35.2 [15.3-51.7]% vs. 30.0 [10.8-50.5]%, P = 0.47), or hepatic lipid content (21.6 [2.2-46.2]% vs. 24.8 [1.7-59.3]%, P = 0.59) before and after rifaximin treatment. After 12 weeks from baseline, serum ALT increased to 83 (30-217) IU/L, P = 0.02. There was a significant increase in the homeostasis model assessment-estimated insulin resistance index (P = 0.05). The urinary metabolic profile indicated a significant reduction in urinary hippurate with treatment, which reverted to baseline after cessation of rifaximin, although there was no consistent difference in relative abundance of fecal microbiota with treatment. These data do not indicate a beneficial effect of rifaximin in patients with NASH. © 2017 The Japan Society of Hepatology.

Head-to-Head Comparison of Aripiprazole and Risperidone in the Treatment of ADHD Symptoms in Children with Autistic Spectrum Disorder and ADHD: A Pilot, Open-Label, Randomized Controlled Study.

PubMed

Lamberti, Marco; Siracusano, Rosamaria; Italiano, Domenico; Alosi, Norma; Cucinotta, Francesca; Di Rosa, Gabriella; Germanò, Eva; Spina, Edoardo; Gagliano, Antonella

2016-08-01

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are frequently overlapping neurodevelopmental disorders. Individuals in whom the disorders are comorbid show more severe impairment because of deficits in the processing of social situations, adaptive functioning, and executive control than individuals with either disorder alone. This open-label pilot study aimed to evaluate and compare the efficacy and tolerability of risperidone and aripiprazole for treating ADHD symptoms in patients with both ASD and ADHD over the course of 24 weeks of treatment. Patients (n = 44) were randomly assigned to start treatment with risperidone (22 patients) or aripiprazole (22 patients). Children were evaluated before starting treatment (T0), and after 12 weeks (T1) and 24 weeks (T2) of treatment. At each visit, specific psychiatric clinical scales were administered to assess the efficacy of the two drugs. The mean age was 8.4 ± 2.9 years in the aripiprazole group and 7.8 ± 2.3 years in the risperidone group. A total of 37 children (29 boys and 8 girls) completed the study (18 in the aripiprazole group and 19 in the risperidone group). Aripiprazole and risperidone appeared to have similar benefits in terms of efficacy and tolerability, although there were slight differences between the two drugs. Both groups showed a significant improvement in ADHD symptoms after 24 weeks of treatment (ADHD Rating Scale, Conners Parent Rating Scale-Hyperactivity, and Clinical Global Improvement-Severity Scale). No significant difference between the two drugs on any parameters at 24 weeks were found. Prolactin levels were decreased in the aripiprazole group. Both drugs were well tolerated, with no serious adverse events detected. Our study confirms the efficacy of both aripiprazole and risperidone in ameliorating ADHD symptoms of children also presenting with ASD.

Brief report: effect of ambrisentan treatment on exercise-induced pulmonary hypertension in systemic sclerosis: a prospective single-center, open-label pilot study.

PubMed

Saggar, Rajeev; Khanna, D; Shapiro, S; Furst, D E; Maranian, P; Clements, P; Abtin, F; Dua, Shiv; Belperio, J; Saggar, Rajan

2012-12-01

Exercise-induced pulmonary hypertension (ePH) may represent an early, clinically relevant phase in the spectrum of pulmonary vascular disease. The purpose of this pilot study was to describe the changes in hemodynamics and exercise capacity in patients with systemic sclerosis (SSc) spectrum-associated ePH treated with open-label daily ambrisentan. Patients were treated with ambrisentan, 5 mg or 10 mg once daily, for 24 weeks. At baseline and 24 weeks, patients with SSc spectrum disorders exercised in a supine position, on a lower extremity cycle ergometer. All patients had normal hemodynamics at rest. We defined baseline ePH as a mean pulmonary artery pressure of >30 mm Hg with maximum exercise and a transpulmonary gradient (TPG) of >15 mm Hg. The primary end point was change in pulmonary vascular resistance (PVR) with exercise. Secondary end points included an improvement from baseline in 6-minute walking distance, health-related quality of life assessments, and cardiopulmonary hemodynamics. Of the 12 enrolled patients, 11 completed the study. At 24 weeks there were improvements in mean exercise PVR (85.8 dynes × second/cm(5) ; P = 0.003) and mean distance covered during 6-minute walk (44.5 meters; P = 0.0007). Improvements were also observed in mean exercise cardiac output (1.4 liters/minute; P = 0.006), mean pulmonary artery pressure (-4.1 mm Hg; P = 0.02), and total pulmonary resistance (-93.0 dynes × seconds/cm(5) ; P = 0.0008). Three patients developed resting pulmonary arterial hypertension during the 24 weeks. Exercise hemodynamics and exercise capacity in patients with SSc spectrum-associated ePH improved over 24 weeks with exposure to ambrisentan. Placebo-controlled studies are needed to confirm whether this is a drug-related effect and to determine optimal therapeutic regimens for patients with ePH. Copyright © 2012 by the American College of Rheumatology.

Open-label, randomized, multicenter, phase III study to evaluate the safety and efficacy of benzoyl peroxide gel in long-term use in patients with acne vulgaris: A secondary publication.

PubMed

Kawashima, Makoto; Nagare, Toshitaka; Katsuramaki, Tsuneo

2017-06-01

An open-label, randomized, multicenter study was conducted to evaluate the safety and efficacy of long-term use of 2.5% and 5% benzoyl peroxide (BPO) gels administrated once daily for 52 weeks to Japanese patients with acne vulgaris. The efficacy of the study drugs was evaluated by counting inflammatory lesions and non-inflammatory lesions. Safety was evaluated based on adverse events, local skin tolerability scores and laboratory test values. In total, 458 subjects were included in the efficacy and safety analyses. The total lesion count, the efficacy end-point, was similarly changed both in the 2.5% and 5% BPO groups over the course of the study. The median rates of reduction from baseline to week 12 were approximately 65%. Thereafter, the counts were maintained at a reduced level without increasing until week 52. The median rates at week 52 were approximately 80%. Similar trends were observed for inflammatory and non-inflammatory lesion counts. Bacteriological evaluation indicated similar distribution of the minimum inhibitory concentration of each of the antibacterial drugs against Propionibacterium acnes between the values at baseline and at week 52, suggesting that long-term use did not result in changes in the drug sensitivity. The incidence of adverse events was 84.0% in the 2.5% BPO group and 87.2% in the 5% BPO group. Many of the adverse events occurred within the first month and were mild or moderate in severity and transient. The results suggest that both 2.5% and 5% BPO gels are effective and safe for long-term treatment of patients with acne vulgaris. © 2017 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.

A randomized, open-label trial of iron isomaltoside 1000 (Monofer®) compared with iron sucrose (Venofer®) as maintenance therapy in haemodialysis patients.

PubMed

Bhandari, Sunil; Kalra, Philip A; Kothari, Jatin; Ambühl, Patrice M; Christensen, Jeppe H; Essaian, Ashot M; Thomsen, Lars L; Macdougall, Iain C; Coyne, Daniel W

2015-09-01

Iron deficiency anaemia is common in patients with chronic kidney disease, and intravenous iron is the preferred treatment for those on haemodialysis. The aim of this trial was to compare the efficacy and safety of iron isomaltoside 1000 (Monofer®) with iron sucrose (Venofer®) in haemodialysis patients. This was an open-label, randomized, multicentre, non-inferiority trial conducted in 351 haemodialysis subjects randomized 2:1 to either iron isomaltoside 1000 (Group A) or iron sucrose (Group B). Subjects in Group A were equally divided into A1 (500 mg single bolus injection) and A2 (500 mg split dose). Group B were also treated with 500 mg split dose. The primary end point was the proportion of subjects with haemoglobin (Hb) in the target range 9.5-12.5 g/dL at 6 weeks. Secondary outcome measures included haematology parameters and safety parameters. A total of 351 subjects were enrolled. Both treatments showed similar efficacy with >82% of subjects with Hb in the target range (non-inferiority, P = 0.01). Similar results were found when comparing subgroups A1 and A2 with Group B. No statistical significant change in Hb concentration was found between any of the groups. There was a significant increase in ferritin from baseline to Weeks 1, 2 and 4 in Group A compared with Group B (Weeks 1 and 2: P < 0.001; Week 4: P = 0.002). There was a significant higher increase in reticulocyte count in Group A compared with Group B at Week 1 (P < 0.001). The frequency, type and severity of adverse events were similar. Iron isomaltoside 1000 and iron sucrose have comparative efficacy in maintaining Hb concentrations in haemodialysis subjects and both preparations were well tolerated with a similar short-term safety profile. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA.

Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study

PubMed Central

2014-01-01

Introduction Type I interferons (IFNs) are implicated in the pathogenesis of systemic sclerosis (SSc). MEDI-546 is an investigational human monoclonal antibody directed against the type I IFN receptor. This Phase 1 study evaluated the safety/tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of single and multiple intravenous doses of MEDI-546 in adults with SSc. Methods Subjects (≥18 years) with SSc were enrolled in an open-label, dose-escalation study to receive single (0.1, 0.3, 1.0, 3.0, 10.0, or 20.0 mg/kg), or 4 weekly intravenous doses (0.3, 1.0, or 5.0 mg/kg/week) of MEDI-546. Subjects were followed for 12 weeks. Safety assessments included adverse events (AEs), laboratory results, and viral monitoring. Blood samples were collected from all subjects for determination of PK, presence of anti-drug antibodies (ADAs), and expression of type I IFN-inducible genes. Results Of 34 subjects (mean age 47.4 years), 32 completed treatment and 33 completed the study. Overall, 148 treatment-emergent AEs (TEAEs) were reported (68.9% mild, 27.7% moderate). TEAEs included one grade 1 infusion reaction (5.0 mg/kg/week multiple dose). Of 4 treatment-emergent serious AEs (skin ulcer, osteomyelitis, vertigo, and chronic myelogenous leukemia (CML)), only CML (1.0 mg/kg/week multiple dose) was considered possibly treatment-related. MEDI-546 exhibited non-linear PK at lower doses. ADAs were detected in 5 subjects; no apparent impact on PK was observed. Peak inhibition of the type I IFN signature in whole blood was achieved within 1 day and in skin after 7 days. Conclusion The safety/tolerability, PK, and PD profiles observed in this study support further clinical development of MEDI-546. Trial Registration ClinicalTrials.gov NCT00930683 PMID:24559157

AN OPEN-LABEL EXTENSION STUDY OF PARATHYROID HORMONE RHPTH(1-84) IN ADULTS WITH HYPOPARATHYROIDISM.

PubMed

Lakatos, Peter; Bajnok, Laszlo; Lagast, Hjalmar; Valkusz, Zsuzsanna

2016-05-01

Hypoparathyroidism is characterized by inadequate parathyroid hormone (PTH), resulting in hypocalcemia, hyperphosphatemia, and bone abnormalities. Adults with hypoparathyroidism treated with recombinant human PTH, rhPTH(1-84), in the 24-week, phase III REPLACE study maintained serum calcium despite reductions in oral calcium and active vitamin D. This study assessed the long-term efficacy and safety of rhPTH(1-84) for hypoparathyroidism. This was a 24-week, open-label, flexible-dose extension study of REPLACE (REPEAT) conducted in 3 outpatient centers in Hungary. Patients who previously completed or enrolled in REPLACE received 50 μg/day rhPTH(1-84), escalated to 75 and then to 100 μg/day, if needed, to reduce active vitamin D and oral calcium. The primary endpoint was ≥50% reduction in oral calcium (or ≤500 mg/day) and active vitamin D (or calcitriol ≤0.25 μg/day or alfacalcidol ≤0.50 μg/day) with normocalcemia. Twenty-four patients (n = 16 previously treated with rhPTH[1-84]; n = 8 rhPTH[1-84]-naïve) were enrolled and completed the study. At Week 24, 75% of patients (95% confidence interval [CI], 53.3-90.2%) achieved the study endpoint; 58% eliminated oral calcium and active vitamin D. Urinary calcium, serum phosphate, and calcium × phosphate (Ca × P) product decreased by Week 24. Mean serum bone turnover markers increased with rhPTH(1-84). Treatment-emergent adverse events (TEAEs) were reported by 92% of patients. No serious adverse events (AEs) occurred. This study used a simplified treatment algorithm intended to better mimic typical clinical practice and demonstrated the extended efficacy and safety of rhPTH(1-84) in patients with hypoparathyroidism and confirmed the REPLACE findings. Sustained rhPTH(1-84) efficacy up to 48 weeks was observed despite treatment interruption between studies.

Efficacy and safety of dapagliflozin over 1 year as add-on to insulin therapy in Japanese patients with type 2 diabetes: the DAISY (Dapagliflozin Added to patients under InSulin therapY) trial.

PubMed

Araki, Eiichi; Onishi, Yukiko; Asano, Michiko; Kim, Hyosung; Yajima, Toshitaka

2017-04-01

To evaluate the efficacy and safety of dapagliflozin as add-on to insulin in Japanese patients with type 2 diabetes. Insulin-treated Japanese patients were randomized to 5 mg dapagliflozin or placebo during a 16-week double-blind treatment period. Both groups then received dapagliflozin 5 or 10 mg (the dose was increased at or after week 24 if glycated haemoglobin [HbA1c] at the previous visit was >7.5%) during a 36-week open-label extension period. The exploratory efficacy endpoint was to assess the maintenance efficacy of 5/10 mg dapagliflozin + insulin over 52 weeks of treatment. Safety was assessed in terms of adverse events, laboratory variables and vital signs. The changes in HbA1c from baseline to weeks 16 and 52 were -0.62% and -0.74%, respectively, in the dapagliflozin group, vs -0.08% and -0.83%, respectively, in the placebo-dapagliflozin group. Body weight decreased at both time points in the dapagliflozin group and after switching to open-label dapagliflozin in the placebo-dapagliflozin group. The total insulin dose decreased slightly after starting dapagliflozin. Adverse events occurred in 82.9% and 71.7% of patients in the dapagliflozin and placebo-dapagliflozin groups, respectively. Hypoglycaemia occurred in 35.0% and 41.7% of patients in the dapagliflozin and placebo-dapagliflozin groups, respectively, but the incidence was not increased by use of dapagliflozin in either trial period. Genital/urinary tract infections, renal impairment/failure, volume depletion, fracture and hepatic disorders occurred in ≤5% of patients. This trial showed that administration of dapagliflozin as an add-on to insulin therapy was effective, was well tolerated and had insulin-sparing effects in Japanese patients with type 2 diabetes. © 2016 John Wiley & Sons Ltd.

Impact of solifenacin on resource utilization, work productivity and health utility in overactive bladder patients switching from tolterodine ER.

PubMed

Zinner, Norman; Noe, Les; Rasouliyan, Lawrence; Marshall, Thomas; Seifeldin, Raafat

2008-06-01

Assess changes in resource utilization, work and activity impairment, and health utility among OAB patients continuing to have urgency symptoms with tolterodine ER 4 mg and willing to try solifenacin 5/10 mg. This was an open-label, non-comparative, flexible-dosing, multicenter, 12-week study assessing the efficacy and safety of solifenacin 5/10 mg/day. Patients receiving tolterodine ER 4 mg/day for >/=4 weeks but continuing to experience residual urgency symptoms (>/=3 urgency episodes/24 h) were enrolled into the study. After a 14-day washout, patients began treatment with solifenacin 5 mg/day with dosing adjustments allowed at Weeks 4 and 8. Outcomes were assessed using the Work Productivity and Activity Impairment Questionnaire - Specific Health Problem (WPAI-SHP), Health Utilities Index (HUI), and a resource utilization questionnaire administered at Pre-Washout and Week 12. Patients (n=440) reported significantly fewer physician office visits (p<0.0001), UTIs (p<0.0001), and pads/diapers (p=0.0009) during the study period while receiving solifenacin 5/10 mg/day, compared with the Pre-Washout period when receiving tolterodine ER 4 mg/day. After 12 weeks of treatment with solifenacin 5/10 mg/day, patients reported a reduction in work time missed (p=0.0017), less impairment while working (p<0.0001), less overall work impairment (p<0.0001) and a reduction in activity impairment (p<0.0001) compared to Pre-Washout. There was no significant difference in health utility scores. Treatment-emergent adverse events were mostly anticholinergic in nature, and were mild to moderate in severity. Overall, solifenacin 5/10 mg/day improved work productivity, activity participation, and reduced medical care use in OAB patients who continued to have urgency symptoms with tolterodine ER 4 mg/day and wished to switch to solifenacin 5/10 mg. This was an open-label, non-comparative study; therefore, further research is needed to confirm these results.

Neuroendocrine and Inflammatory Responses to Losartan and Continuous Positive Airway Pressure in Patients with Hypertension and Obstructive Sleep Apnea. A Randomized Controlled Trial.

PubMed

Thunström, Erik; Manhem, Karin; Yucel-Lindberg, Tülay; Rosengren, Annika; Lindberg, Caroline; Peker, Yüksel

2016-11-01

Blood pressure reduction in response to antihypertensive agents is less for patients with obstructive sleep apnea (OSA). Increased sympathetic and inflammatory activity, as well as alterations in the renin-angiotensin-aldosterone system, may play a role in this context. To address the cardiovascular mechanisms involved in response to an angiotensin II receptor antagonist, losartan, and continuous positive airway pressure (CPAP) as add-on treatment for hypertension and OSA. Newly diagnosed hypertensive patients with or without OSA (allocated in a 2:1 ratio for OSA vs. no OSA) were treated with losartan 50 mg daily during a 6-week two-center, open-label, prospective, case-control, parallel-design study. In the second 6-week, sex-stratified, open-label, randomized, parallel-design study, all subjects with OSA continued to receive losartan and were randomly assigned to either CPAP as add-on therapy or to no CPAP (1:1 ratio for CPAP vs. no CPAP). Study subjects without OSA were followed in parallel while they continued to take losartan. Blood samples were collected at baseline, after 6 weeks, and after 12 weeks for analysis of renin, aldosterone, noradrenaline, adrenaline, and inflammatory markers. Fifty-four patients with OSA and 35 without OSA were included in the first 6-week study. Losartan significantly increased renin levels and reduced aldosterone levels in the group without OSA. There was no significant decrease in aldosterone levels among patients with OSA. Add-on CPAP treatment tended to lower aldosterone levels, but reductions were more pronounced in measures of sympathetic activity. No significant changes in inflammatory markers were observed following treatment with losartan and CPAP. Hypertensive patients with OSA responded to losartan treatment with smaller reductions in aldosterone compared with hypertensive patients without OSA. Sympathetic system activity seemed to respond primarily to add-on CPAP treatment in patients with newly discovered hypertension and OSA. Clinical trial registered with www.clinicaltrials.gov (NCT00701428).

Effect of mouth cleaning with hinokitiol-containing gel on oral malodor: a randomized, open-label pilot study.

PubMed

Iha, Kosaku; Suzuki, Nao; Yoneda, Masahiro; Takeshita, Toru; Hirofuji, Takao

2013-10-01

The aim of the study was to evaluate the effect of mouth cleaning with hinokitiol-containing gel on oral malodor. An open-label, randomized, controlled trial was conducted to assess oral malodor and clinical parameters related to oral malodor before and after mouth cleaning with hinokitiol-containing gel (n = 9) or with gel not including hinokitiol (n = 9). Mouth cleaning included the teeth, gingiva, and tongue and was carried out 3 times per day for 4 weeks. Organoleptic test (OLT) scores (P = .021), levels of hydrogen sulfide (P = .008) and methyl mercaptan (P = .020), frequency of bleeding on probing, average probing pocket depth, and plaque index significantly improved in the group using hinokitiol. In contrast, only the OLT score (P = .031) significantly improved in the control group after the treatment regimen. Mouth cleaning with hinokitiol-containing gel may be effective for reduction of oral malodor. Copyright © 2013 Elsevier Inc. All rights reserved.

Chymodiactin in patients with herniated lumbar intervertebral disc(s). An open-label, multicenter study.

PubMed

McDermott, D J; Agre, K; Brim, M; Demma, F J; Nelson, J; Wilson, R R; Thisted, R A

1985-04-01

To extent the safety information for Chymodiactin (chymopapain for injection), 37 neurologic and orthopedic surgeons conducted an open-label, multicenter, phase 3 clinical study. A total of 1,498 patients with one or two herniated lumbar intervertebral discs were enrolled. Therapeutic results were generally favorable, with the percentages of patients achieving either excellent or good (or successful) results ranging from 79.6% to 88.9%, depending on criteria employed in the tabulation. There were 13 cases of anaphylaxis, and 2 of these patients died of complications of anaphylaxis. Two additional patients experienced serious neurologic problems. The first of these two patients developed transverse myelitis and paraplegia approximately 3 weeks following chemonucleolysis. Transdural discograms at three levels had been done approximately 2 days prior to chemonucleolysis, in violation of the protocol. The second patient developed acute cauda equina syndrome, and, despite emergency laminectomy, had permanent neurologic sequelae. Back spasm and stiffness/soreness were the most frequently encountered adverse experiences.

Omega-3 fatty acid monotherapy for pediatric bipolar disorder: a prospective open-label trial.

PubMed

Wozniak, Janet; Biederman, Joseph; Mick, Eric; Waxmonsky, James; Hantsoo, Liisa; Best, Catherine; Cluette-Brown, Joanne E; Laposata, Michael

2007-01-01

To test the effectiveness and safety of omega-3 fatty acids (Omegabrite(R) brand) in the treatment of pediatric bipolar disorder (BPD). Subjects (N=20) were outpatients of both sexes, 6 to 17 years of age, with a DSM-IV diagnosis of BPD and Young Mania Rating Scale (YMRS) score of >15 treated over an 8-week period in open-label trial with omega-3 fatty acids 1290 mg-4300 mg combined EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid). Subjects experienced a statistically significant but modest 8.9+/-2.9 point reduction in the YMRS scores (baseline YMRS=28.9+/-10.1; endpoint YMRS=19.1+/-2.6, p<0.001). Adverse events were few and mild. Red blood cell membrane levels of EPA and DHA increased in treated subjects. As only 35% of these subjects had a response by the usual accepted criteria of >50% decrease on the YMRS, omega-3 fatty acids treatment was associated with a very modest improvement in manic symptoms in children with BPD.

Open-label 24-week extension study of edaravone (MCI-186) in amyotrophic lateral sclerosis.

PubMed

2017-10-01

We aimed to explore the longer-term efficacy and safety of edaravone in an active-treatment extension period following the double-blind period of the second phase III study. Patients who met all the following criteria (scores ≥2 points on all 12 items of the revised amyotrophic lateral sclerosis functional rating scale [ALSFRS-R], forced vital capacity ≥80%, definite or probable ALS, and disease duration ≤2 years) were randomised to 60 mg intravenous edaravone or placebo for six cycles in the double-blind period, and then offered the opportunity to proceed to this 24-week open-label extension period. One hundred and twenty-three of 137 patients continued to the extension period: 65 edaravone-edaravone (E-E group) and 58 placebo-edaravone (P-E group). Change (mean ± standard deviation; SD) in the ALSFRS-R score from baseline in the double-blind period was -4.1 ± 3.4 and -6.9 ± 5.1 in the E-E group and P-E group, respectively, while it was -8.0 ± 5.6 in the E-E group and -10.9 ± 6.9 in the P-E group over the whole 48-week period. The ALSFRS-R score changed almost linearly throughout Cycles 1-12 in the E-E group. The most commonly reported adverse events were constipation, dysphagia, and contusion. There was no sudden deterioration in the ALSFRS-R score of the E-E group. No safety concerns related to edaravone were detected.

Comparative efficacy trial of cupping and serkangabin versus conventional therapy of migraine headaches: A randomized, open-label, comparative efficacy trial.

PubMed

Firoozabadi, Mohammad Dehghani; Navabzadeh, Maryam; Roudsari, Mohammad Khodashenas; Zahmatkash, Mohsen

2014-12-01

Migraine headaches are the most common acute and recurrent headaches. Current treatment of a migraine headache consists of multiple medications for control and prevention of recurrent attacks. Global emergence of alternative medicine led us to examine the efficacy of cupping therapy plus serkangabin syrup in the treatment of migraine headaches. This study was a randomized, controlled, open-label, comparative efficacy trial. We randomly assigned patients with migraine into cupping therapy plus serkangabin group (30 patients) and conventional treatment group (30 patients). An investigator assessed the severity of headache, frequency of attacks in a week and duration of attacks per hour in 5 visits (at the end of 2 weeks, 1, 3 and 6 months). Generalized estimating equations approach was used to analyze repeated measures data to compare outcomes in both groups. Average age for cupping therapy group and conventional treatment group were 31.7 (±7.6) and 32.6 (±12.7) years, respectively (P = 0.45). After treatment for 2 weeks; and 1, 3 and 6 months, severity of headache (P = 0.80), frequency of migraine attacks (P = 0.63) and duration of attacks per hours (P = 0.48) were similar in conventional and cupping groups but these symptoms were decreased in each group during the study (P < 0.001). There was no significant difference between cupping plus serkangabin therapy and conventional treatment in the treatment and prophylaxis of migraine. The alternative therapy may be used in cases of drug intolerance, no medication response, and in primary care.

Comparative efficacy trial of cupping and serkangabin versus conventional therapy of migraine headaches: A randomized, open-label, comparative efficacy trial

PubMed Central

Firoozabadi, Mohammad Dehghani; Navabzadeh, Maryam; Roudsari, Mohammad Khodashenas; Zahmatkash, Mohsen

2014-01-01

Background: Migraine headaches are the most common acute and recurrent headaches. Current treatment of a migraine headache consists of multiple medications for control and prevention of recurrent attacks. Global emergence of alternative medicine led us to examine the efficacy of cupping therapy plus serkangabin syrup in the treatment of migraine headaches. Materials and Methods: This study was a randomized, controlled, open-label, comparative efficacy trial. We randomly assigned patients with migraine into cupping therapy plus serkangabin group (30 patients) and conventional treatment group (30 patients). An investigator assessed the severity of headache, frequency of attacks in a week and duration of attacks per hour in 5 visits (at the end of 2 weeks, 1, 3 and 6 months). Generalized estimating equations approach was used to analyze repeated measures data to compare outcomes in both groups. Results: Average age for cupping therapy group and conventional treatment group were 31.7 (±7.6) and 32.6 (±12.7) years, respectively (P = 0.45). After treatment for 2 weeks; and 1, 3 and 6 months, severity of headache (P = 0.80), frequency of migraine attacks (P = 0.63) and duration of attacks per hours (P = 0.48) were similar in conventional and cupping groups but these symptoms were decreased in each group during the study (P < 0.001). Conclusion: There was no significant difference between cupping plus serkangabin therapy and conventional treatment in the treatment and prophylaxis of migraine. The alternative therapy may be used in cases of drug intolerance, no medication response, and in primary care. PMID:25709653

Efalizumab in the Treatment of Scalp, Palmoplantar and Nail Psoriasis: Results of a 24-Week Latin American Study

PubMed Central

Takahashi, María Denise; Chouela, Edgardo Néstor; Dorantes, Gladys Leon; Roselino, Ana Maria; Santamaria, Jesùs; Allevato, Miguel Angel; Cestari, Tania; de Aillaud, Maria Eugenia Manzanera; Stengel, Fernando Miguel; Licu, Daiana

2010-01-01

Introduction Plaque-type psoriasis affecting the nails, scalp, hands or feet can often be difficult to treat; for example, topical treatments and phototherapy may not penetrate the nail plate or scalp. The objective of this large, international, multicentre study was to investigate the efficacy of efalizumab in a Latin American population of adult patients with moderate-to-severe chronic plaque psoriasis who were candidates for systemic therapy or phototherapy. Methods Eligible patients were enrolled in a 24-week, open-label, single-arm, Phase IIIb/IV study of continuous treatment with subcutaneous efalizumab, 1.0 mg/kg/wk. Involvement of the nails, scalp, or hands or feet was assessed using the Nail Psoriasis Severity Index (NAPSI), the Psoriasis Scalp Severity Index (PSSI), or the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI), respectively. Missing data were handled using a last observation carried forward or nonresponder imputation approach. Results Of the 189 patients who received treatment, 112 patients had nail involvement, 172 had scalp involvement, and 19 had palmoplantar disease at baseline. At Week 24, ≥50% improvement on the NAPSI, PSSI and PPPASI was observed in 31%, 71% and 68% of patients, respectively, whereas ≥75% improvement on these scores was observed in 17%, 52% and 63%, respectively. Descriptive statistics showed lower NAPSI-75 and higher PSSI-75 and -50 response rates among patients with higher baseline scores. Conclusions This open-label, uncontrolled study provides supportive evidence of the potential of efalizumab as a treatment for nail, scalp and palmoplantar psoriasis. PMID:20428227

Analysis of Nausea in Clinical Studies of Lubiprostone for the Treatment of Constipation Disorders.

PubMed

Cryer, Byron; Drossman, Douglas A; Chey, William D; Webster, Lynn; Habibi, Sepideh; Wang, Martin

2017-12-01

Lubiprostone is a ClC-2 chloride channel activator approved for the treatment of chronic idiopathic constipation (CIC) and opioid-induced constipation (OIC) in adults and irritable bowel syndrome with constipation (IBS-C) in women. Lubiprostone is generally well tolerated, with nausea being the most common adverse event. To characterize nausea with lubiprostone using pooled results from clinical studies in patients with CIC, OIC, or IBS-C. Data from three 3- and 4-week placebo-controlled studies and three long-term open-label studies were pooled for the CIC analysis. The OIC and IBS-C analyses each used pooled data from three 12-week placebo-controlled studies and one 36-week open-label extension study. The populations included the following numbers of patients: CIC, 316 (placebo) and 1113 (lubiprostone 24 mcg twice daily [BID]); OIC, 652 (placebo) and 889 (lubiprostone 24 mcg BID); and IBS-C, 435 (placebo) and 1011 (lubiprostone 8 mcg BID). The incidence of nausea in lubiprostone-treated patients ranged from 11.4 to 31.1%, with the highest incidence in patients with CIC. Among patients with any nausea, most reported only mild or moderate severity (96.5-99.1% across indications) and only one event (83.6-88.7%); most events occurred within the first 5 days of treatment. Nausea was the most common adverse event following the treatment with lubiprostone. Event rates varied by indication and dose, and the majority of nausea adverse events were mild to moderate in severity. Nausea events predominantly occurred early in the treatment period in all of the pooled study populations.

Analysis of lung function and survival in RECAP: An open-label extension study of pirfenidone in patients with idiopathic pulmonary fibrosis.

PubMed

Costabel, Ulrich; Albera, Carlo; Bradford, Williamson Z; Hormel, Phil; King, Talmadge E; Noble, Paul W; Sahn, Steven A; Valeyre, Dominique; du Bois, Roland M

2014-10-20

RECAP is an open-label extension study evaluating pirfenidone in patients with idiopathic pulmonary fibrosis (IPF) who completed the Phase 3 CAPACITY program. We examined the effect of pirfenidone on lung function and survival in patients who were previously randomised to the placebo group in one of the two CAPACITY studies and received pirfenidone for the first time in RECAP. Eligible patients received oral pirfenidone 2403 mg/day. Forced vital capacity (FVC) was measured at baseline and at weeks 12, 36, and 60. To facilitate comparison with CAPACITY outcomes, analyses were based on patients newly treated with pirfenidone in RECAP who had baseline FVC and carbon monoxide diffusing capacity (DLCO) values that met CAPACITY entry criteria. A total of 178 patients were included in the analysis. Among these, 16.3% experienced an FVC decline ≥10% at week 60, compared with 16.8% and 24.8%, respectively, in the CAPACITY pirfenidone (n=345) and placebo (n=347) groups. The mean change from baseline to week 60 in %FVC was -5.9%, compared with -7.0% and -9.4% in the CAPACITY pirfenidone and placebo groups. Overall survival was similar to that of pirfenidone treated patients in CAPACITY. Treatment was safe and generally well tolerated; the type and frequency of adverse events were consistent with previous clinical experience. FVC and survival outcomes in IPF patients newly treated with pirfenidone in RECAP were similar to those in the CAPACITY pirfenidone group. These data provide further evidence to support the use of pirfenidone in patients with IPF.

Post-Acute Effectiveness of Lithium in Pediatric Bipolar I Disorder

PubMed Central

Kafantaris, Vivian; Pavuluri, Mani; McNamara, Nora K; Frazier, Jean A; Sikich, Linmarie; Kowatch, Robert; Rowles, Brieana M; Clemons, Traci E; Taylor-Zapata, Perdita

2013-01-01

Abstract Objective This study examined the long-term effectiveness of lithium for the treatment of pediatric bipolar disorder within the context of combination mood stabilizer therapy for refractory mania and pharmacological treatment of comorbid psychiatric conditions. Methods Outpatients, ages 7–17 years, meeting American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnostic criteria for bipolar disorder I (BP-I) (manic or mixed) who demonstrated at least a partial response to 8 weeks of open-label treatment with lithium (Phase I) were eligible to receive open-label lithium for an additional 16 weeks (Phase II). Up to two adjunctive medications could be prescribed to patients experiencing residual symptoms of mania or comorbid psychiatric conditions, following a standardized algorithm. Results Forty-one patients received continued open-label long-term treatment with lithium for a mean of 14.9 (3.0) weeks during Phase II. The mean weight-adjusted total daily dose at end of Phase II was 27.8 (6.7) mg/kg/day, with an average lithium concentration of 1.0 (0.3) mEq/L. Twenty-five of the 41 patients (60.9%) were prescribed adjunctive psychotropic medications for residual symptoms. The most frequent indications for adjunctive medications were refractory mania (n=13; 31.7%) and attention-deficit/hyperactivity disorder (ADHD) (n=15; 36.6%). At the end of this phase 28 (68.3%) patients met a priori criteria for response (≥50% reduction from Phase I baseline in Young Mania Rating Scale [YMRS] summary score and a Clinical Global Impressions-Improvement [CGI-I] score of 1 or 2), with 22 (53.7%) considered to be in remission (YMRS summary score≤12 and CGI-Severity score of 1 or 2). These data suggest that patients who initially responded to lithium maintained mood stabilization during continuation treatment, but partial responders did not experience further improvement during Phase II, despite the opportunity to receive adjunctive medications. The most commonly reported (≥20%) adverse events associated with lithium treatment were vomiting, headache, abdominal pain, and tremor. Conclusions Lithium may be a safe and effective longer-term treatment for patients with pediatric bipolar disorder who respond to acute treatment with lithium. Partial responders to acute lithium did not appear to experience substantial symptom improvement during the continuation phase, despite the possibility that adjunctive medications could be prescribed. PMID:23510444

Self-esteem in adolescent patients with attention-deficit/hyperactivity disorder during open-label atomoxetine treatment: psychometric evaluation of the Rosenberg Self-Esteem Scale and clinical findings.

PubMed

Dittmann, Ralf W; Wehmeier, Peter M; Schacht, Alexander; Lehmann, Martin; Lehmkuhl, Gerd

2009-12-01

To report on (1) psychometric properties of the Rosenberg Self-Esteem Scale (SES) studied in adolescents with ADHD, (2) correlations of SES with ADHD scale scores, and (3) change in patient-reported self-esteem with atomoxetine treatment. ADHD patients (12-17 years), treated in an open-label study for 24 weeks. Secondary analyses on ADHD symptoms (assessed with ADHD-RS, CGI, GIPD scales) and self-esteem (SES) were performed. One hundred and fifty-nine patients were treated. A dichotomous structure of the SES could be confirmed. Reliability and internal consistency were moderate to excellent. Highest coefficients were found for the correlation between SES and GIPD scores. Self-esteem significantly increased over time, accompanied by an improvement of ADHD symptoms and related perceived difficulties. The Rosenberg SES was shown to be internally consistent, reliable, and sensitive to treatment-related changes of self-esteem. According to these findings, self-esteem may be an important individual patient outcome beyond the core symptoms of ADHD. © The Author(s) 2009. This article is published with open access at Springerlink.com

Acarbose compared with metformin as initial therapy in patients with newly diagnosed type 2 diabetes: an open-label, non-inferiority randomised trial.

PubMed

Yang, Wenying; Liu, Jie; Shan, Zhongyan; Tian, Haoming; Zhou, Zhiguang; Ji, Qiuhe; Weng, Jianping; Jia, Weiping; Lu, Juming; Liu, Jing; Xu, Yuan; Yang, Zhaojun; Chen, Wei

2014-01-01

Metformin is the only first-line oral hypoglycaemic drug for type 2 diabetes recommended by international guidelines with proven efficacy, safety, and cost-effectiveness. However, little information exists about its use in Asian populations. We aimed to ascertain the effectiveness of the α-glucosidase inhibitor acarbose, extensively adopted in China, compared with metformin as the alternative initial therapy for newly diagnosed type 2 diabetes. In this 48-week, randomised, open-label, non-inferiority trial, patients who were newly diagnosed with type 2 diabetes, with a mean HbA1c of 7·5%, were enrolled from 11 sites in China. After a 4-week lifestyle modification run-in, patients were assigned to 24 weeks of monotherapy with metformin or acarbose as the initial treatment, followed by a 24-week therapy phase during which add-on therapy was used if prespecified glucose targets were not achieved. Primary endpoints were to establish whether acarbose was non-inferior to metformin in HbA1c reduction at week 24 and week 48 timepoints. The non-inferiority margin was 0·3%, with an expected null difference in the change from baseline to week 48 in HbA1c. Analysis was done on a modified intention-to-treat population. This study was registered with Chinese Clinical Trial Registry, number ChiCTR-TRC-08000231. Of the 788 patients randomly assigned to treatment groups, 784 patients started the intended study drug. HbA1c reduction at week 24 was -1·17% in the acarbose group and -1·19% in the metformin group. At week 48, the HbA1c reduction was -1·11% (acarbose) and -1·12% (metformin) with difference 0·01% (95% CI -0·12 to 0·14, p=0·8999). Six (2%) patients in the acarbose group and seven (2%) patients in the metformin group had serious adverse events, and two (1%) and four (1%) had hypoglycaemic episodes. This study provides evidence that acarbose is similar to metformin in efficacy, and is therefore a viable choice for initial therapy in Chinese patients newly diagnosed with type 2 diabetes. Bayer Healthcare (China) and Double Crane Phama. Copyright © 2014 Elsevier Ltd. All rights reserved.

Clinical Efficacy and Safety of Oral Qing-Dai in Patients with Ulcerative Colitis: A Single-Center Open-Label Prospective Study.

PubMed

Sugimoto, Shinya; Naganuma, Makoto; Kiyohara, Hiroki; Arai, Mari; Ono, Keiko; Mori, Kiyoto; Saigusa, Keiichiro; Nanki, Kosaku; Takeshita, Kozue; Takeshita, Tatsuya; Mutaguchi, Makoto; Mizuno, Shinta; Bessho, Rieko; Nakazato, Yoshihiro; Hisamatsu, Tadakazu; Inoue, Nagamu; Ogata, Haruhiko; Iwao, Yasushi; Kanai, Takanori

2016-01-01

Chinese herbal medicine Qing-Dai (also known as indigo naturalis) has been used to treat various inflammatory conditions. However, not much has been studied about the use of oral Qing-Dai in the treatment for ulcerative colitis (UC) patients. Studies exploring alternative treatments for UC are of considerable interest. In this study, we aimed at prospectively evaluating the safety and efficacy of Qing-Dai for UC patients. The open-label, prospective pilot study was conducted at Keio University Hospital. A total of 20 patients with moderate UC activity were enrolled. Oral Qing-Dai in capsule form was taken twice a day (daily dose, 2 g) for 8 weeks. At week 8, the rates of clinical response, clinical remission, and mucosal healing were 72, 33, and 61%, respectively. The clinical and endoscopic scores, CRP levels, and fecal occult blood results were also significantly improved. We observed 2 patients with mild liver dysfunction; 1 patient discontinued due to infectious colitis and 1 patient discontinued due to mild nausea. This is the first prospective study indicating that oral Qing-Dai is effective for inducing remission in patients with moderate UC activity and can be tolerated. Thus, Qing-Dai may be considered an alternative treatment for patients, although further investigation is warranted. © 2016 S. Karger AG, Basel.

Psychiatric adverse events during treatment with brodalumab: Analysis of psoriasis clinical trials.

PubMed

Lebwohl, Mark G; Papp, Kim A; Marangell, Lauren B; Koo, John; Blauvelt, Andrew; Gooderham, Melinda; Wu, Jashin J; Rastogi, Shipra; Harris, Susan; Pillai, Radhakrishnan; Israel, Robert J

2018-01-01

Individuals with psoriasis are at increased risk for psychiatric comorbidities, including suicidal ideation and behavior (SIB). To distinguish between the underlying risk and potential for treatment-induced psychiatric adverse events in patients with psoriasis being treated with brodalumab, a fully human anti-interleukin 17 receptor A monoclonal antibody. Data were evaluated from a placebo-controlled, phase 2 clinical trial; the open-label, long-term extension of the phase 2 clinical trial; and three phase 3, randomized, double-blind, controlled clinical trials (AMAGINE-1, AMAGINE-2, and AMAGINE-3) and their open-label, long-term extensions of patients with moderate-to-severe psoriasis. The analysis included 4464 patients with 9161.8 patient-years of brodalumab exposure. The follow-up time-adjusted incidence rates of SIB events were comparable between the brodalumab and ustekinumab groups throughout the 52-week controlled phases (0.20 vs 0.60 per 100 patient-years). In the brodalumab group, 4 completed suicides were reported, 1 of which was later adjudicated as indeterminate; all patients had underlying psychiatric disorders or stressors. There was no comparator arm past week 52. Controlled study periods were not powered to detect differences in rare events such as suicide. Comparison with controls and the timing of events do not indicate a causal relationship between SIB and brodalumab treatment. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Donepezil for cancer fatigue: a double-blind, randomized, placebo-controlled trial.

PubMed

Bruera, Eduardo; El Osta, Badi; Valero, Vicente; Driver, Larry C; Pei, Be-Lian; Shen, Loren; Poulter, Valerie A; Palmer, J Lynn

2007-08-10

To evaluate the effectiveness of donepezil compared with placebo in cancer patients with fatigue as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F). Patients with fatigue score >or= 4 on a scale of 0 to 10 (0 = no fatigue, 10 = worst possible fatigue) for more than 1 week were included. Patients were randomly assigned to receive donepezil 5 mg or placebo orally every morning for 7 days. A research nurse contacted the patients by telephone daily to assess toxicity and fatigue level. All patients were offered open-label donepezil during the second week. FACIT-F and/or the Edmonton Symptom Assessment System (ESAS) were assessed at baseline, and days 8, 11, and 15. The FACIT-F fatigue subscale score on day 8 was considered the primary end point. Of 142 patients randomly assigned to treatment, 47 patients in the donepezil group and 56 in the placebo group were assessable for final analysis. Fatigue intensity improved significantly on day 8 in both donepezil and placebo groups. However, there was no significant difference in fatigue improvement by FACIT-F (P = .57) or ESAS (P = .18) between groups. In the open-label phase, fatigue intensity continued to be low as compared with baseline. No significant toxicities were observed. Donepezil was not significantly superior to placebo in the treatment of cancer-related fatigue.

Open-label evaluation of a novel skin brightening system containing 0.01% decapeptide-12 in combination with 20% buffered glycolic acid for the treatment of mild to moderate facial melasma.

PubMed

Ramírez, Sandra P; Carvajal, Alfonso C; Salazar, Juan C; Arroyave, Gladys; Flórez, Ana M; Echeverry, Hector F

2013-06-01

Melasma is a cutaneous disorder that primarily affects females of Hispanic and Asian descent. Previous studies have shown that use of a brightening system comprised of 0.01% decapeptide-12 cream, an antioxidant cleanser, a 20% buffered glycolic acid lotion, and a broad spectrum SPF 30 sunscreen yields good clearance of mild-to-moderate melasma in Caucasian and Asian volunteers. The present open-label, prospective, and multicenter study sought to determine the tolerability and efficacy of the above-mentioned brightening system on mild-to-moderate melasma in 33 Hispanic females over 16 weeks. Clinical measures included self-assessment of tolerability, clinical grading, determination of Melasma Area and Severity Index (MASI) scores, and standardized clinical photography. Results showed that the system was well tolerated with no adverse events reported. Mean decreases of 36%, 46%, 54%, and 60% in MASI scores were observed at weeks 4, 8, 12, and 16, respectively, which were further corroborated by standardized photography showing visible reduction in the appearance of melasma. Results suggest that the brightening system consisting of 0.01% decapeptide-12 cream, an antioxidant cleanser, 20% buffered glycolic acid lotion, and broad spectrum SPF 30 sunscreen is safe and efficacious for the treatment of mild-to-moderate melasma in Hispanic females.

Onabotulinumtoxin A Treatment of Drooling in Children with Cerebral Palsy: A Prospective, Longitudinal Open-Label Study

PubMed Central

Møller, Eigild; Pedersen, Søren Anker; Vinicoff, Pablo Gustavo; Bardow, Allan; Lykkeaa, Joan; Svendsen, Pia; Bakke, Merete

2015-01-01

The aim of this prospective open-label study was to treat disabling drooling in children with cerebral palsy (CP) with onabotulinumtoxin A (A/Ona, Botox®) into submandibular and parotid glands and find the lowest effective dosage and least invasive method. A/Ona was injected in 14 children, Mean age 9 years, SD 3 years, under ultrasonic guidance in six successive Series, with at least six months between injections. Doses and gland involvement increased from Series A to F (units (U) per submandibular/parotid gland: A, 10/0; B, 15/0; C, 20/0; D, 20/20; E, 30/20; and F, 30/30). The effect was assessed 2, 4, 8, 12, and 20 weeks after A/Ona (drooling problems (VAS), impact (0–7), treatment effect (0–5), unstimulated whole saliva (UWS) flow and composition)) and analyzed by two-way ANOVA. The effect was unchanged–moderate in A to moderate–marked in F. Changes in all parameters were significant in E and F, but with swallowing problems ≤5 weeks in 3 of 28 treatments. F had largest VAS and UWS reduction (64% and 49%). We recommend: Start with dose D A/Ona (both submandibular and parotid glands and a total of 80 U) and increase to E and eventually F (total 120 U) without sufficient response. PMID:26134257

Switching patients with erectile dysfunction from sildenafil citrate to tadalafil: results of a European multicenter, open-label study of patient preference.

PubMed

Ströberg, Peter; Murphy, Aileen; Costigan, Tim

2003-11-01

Three inhibitors of phosphodiesterase 5 (PDE5) are now available for the treatment of erectile dysfunction (ED): sildenafil citrate, vardenafil, and tadalafil. Pharmacologic differences between these compounds may result in patient preferences for one over another and may influence treatment decisions made by the physician and patient. Therefore, clinical research is needed to investigate whether individual properties of the PDE5 inhibitors play a role in shaping patient preference. The goal of this study was to determine what proportion of ED patients currently taking sildenafil would, after a period of treatment with tadalafil, elect to resume treatment with sildenafil at the customary dose and what proportion would elect a switch to tadalafil 20 mg for a longer period. The tolerability of both treatments was also investigated. This was a short-term, multicenter, open-label, 1-way crossover trial conducted in Sweden and Italy. Eligible patients included men aged >or=18 years with a minimum 3-month history of ED who had been taking sildenafil at stable fixed doses of 25, 50, or 100 mg as needed for at least 6 weeks and up to 24 weeks. The study consisted of 6 phases: a 1-week screening phase, a 3-week sildenafil assessment phase, a 1-week washout phase, a 6-week tadalafil initiation phase, a 3-week tadalafil assessment phase, and a 6-month extension phase, during which patients received their treatment of choice free of charge. The primary outcome measure was the proportion of patients electing to take sildenafil or tadalafil during the extension phase. Of 155 men enrolled, 147 (97.8%) completed the assessment phases of the trial. Of these 147 men, 133 (90.5%) elected to receive tadalafil in the 6-month extension phase and 14 (9.5%) elected to receive sildenafil (P < 0.001). The proportions preferring tadalafil to sildenafil were similar irrespective of age group (>or=50 years, 92%; <50 years, 90%), severity of ED (mild, 95%; moderate, 88%; severe, 96%), etiology of ED (psychogenic, 94%; organic, 91%; mixed, 87%), and sildenafil dose at study entry (50 mg, 90%; 100 mg, 89%). Both medications were well tolerated. The most common treatment-emergent adverse events occurring in >or=2% of patients during the tadalafil assessment phase included headache (4.8%), nasal congestion (4.1%), dyspepsia (3.4%), flushing (2.7%), back pain (2.0%), diarrhea (2.0%), and nausea (2.0%); the most common treatment-emergent adverse events during the sildenafil assessment phase were flusing (7.1%), nasal congestion (6.5%), headache (4.5%), and nasopharyngitis (3.2%). In this short-term, open-label study, patients who were currently taking sildenafil for ED and then received tadalafil preferred to continue oral therapy with tadalafil over sildenafil by a ratio of approximately 9:1. Although the study sought to mimic the experience of actual patients receiving treatment for ED, the results are subject to potential limitations due to the design of the study, which included differences in dosing instructions and dosages for sildenafil and tadalafil. Both sildenafil and tadalafil were well tolerated.

Early intervention of long-acting nifedipine GITS reduces brachial–ankle pulse wave velocity and improves arterial stiffness in Chinese patients with mild hypertension: a 24-week, single-arm, open-label, prospective study

PubMed Central

Zhang, Jidong; Wang, Yan; Hu, Haijuan; Yang, Xiaohong; Tian, Zejun; Liu, Demin; Gu, Guoqiang; Zheng, Hongmei; Xie, Ruiqin; Cui, Wei

2016-01-01

Background Nifedipine gastrointestinal therapeutic system (GITS) is used to treat angina and hypertension. The authors aimed to study the early intervention impact on arterial stiffness and pulse wave velocity (PWV) independent of its blood-pressure-(BP) lowering effect in mild hypertensive patients. Methods This single-center, single-arm, open-label, prospective, Phase IV study recruited patients with mild hypertension and increased PWV from December 2013 to December 2014 (N=138; age, 18–75 years; systolic blood pressure, 140–160 mmHg; diastolic BP, 90–100 mmHg; increased brachial–ankle pulse wave velocity [baPWV, ≥12 m/s]). Nifedipine GITS (30 mg/d) was administered for 24 weeks to achieve target BP of <140/90 mmHg. The dose was uptitrated at 60 mg/d in case of unsatisfactory BP reduction after 4 weeks. Primary study end point was the change in baPWV after nifedipine GITS treatment. Hemodynamic parameters (office BP, 24-hour ambulatory BP monitoring, and heart rate and adverse events) were evaluated at baseline and followed-up at 2, 4, 8, 12, 18, and 24 weeks. Results Majority of patients (n=117; 84.8%) completed the study. baPWV decreased significantly at 4 weeks compared with baseline (1,598.87±239.82 vs 1,500.89±241.15 cm/s, P<0.001), was stable at 12 weeks (1,482.24±215.14 cm/s, P<0.001), and remained steady through 24 weeks (1,472.58±205.01 cm/s, P<0.001). Office BP reduced from baseline to week 4 (154/95 vs 136/85 mmHg) and remained steady until 24 weeks. Nifedipine GITS significantly decreased 24-hour ambulatory BP monitoring (P<0.001) after 24 weeks from baseline. Mean arterial pressure and pulse pressure were lowered significantly after 4, 12, and 24 weeks of treatment (P<0.001). These changes in baPWV were significantly correlated with changes in systolic blood pressure, diastolic BP, and mean arterial pressure (P<0.05), but not with changes in pulse pressure (P>0.05). There were no other drug-related serious adverse events. Conclusion Nifedipine GITS was considerably effective in reducing baPWV and BP, indicating improvement in arterial stiffness as early as 4 weeks. PMID:27799740

Pharmacokinetics of a novel human intravenous immunoglobulin 10% in patients with primary immunodeficiency diseases: Analysis of a phase III, multicentre, prospective, open-label study.

PubMed

Melamed, Isaac R; Borte, Michael; Trawnicek, Laurenz; Kobayashi, Ai-Lan; Kobayashi, Roger H; Knutsen, Alan; Gupta, Sudhir; Smits, William; Pituch-Noworolska, Anna; Strach, Magdalena; Pulka, Grazyna; Ochs, Hans D; Moy, James N

2018-06-15

Intravenous immunoglobulin (IVIG) therapy is commonly used to treat patients with primary antibody deficiency. This prospective, open-label, non-randomised, multicentre, phase III trial investigated the pharmacokinetics of a new 10% liquid IVIG product (panzyga®; Octapharma) in 51 patients aged 2-75 years with common variable immunodeficiency (n = 43) or X-linked agammaglobulinaemia (n = 8). Patients were treated with IVIG 10% every 3 (n = 21) or 4 weeks (n = 30) at a dose of 200-800 mg/kg for 12 months. Total immunoglobulin G (IgG) and subclass concentrations approximately doubled from pre- to 15 min post-infusion. The maximum concentration of total IgG (mean ± SD) was 21.82 ± 5.83 g/L in patients treated 3-weekly and 17.42 ± 3.34 g/L in patients treated 4-weekly. Median trough IgG concentrations were nearly constant over the course of the study, remaining between 11.0 and 12.2 g/L for patients on the 3-week schedule and between 8.10 and 8.65 g/L for patients on the 4-week schedule. The median terminal half-life of total IgG was 36.1 (range 18.5-65.9) days, with generally similar values for the IgG subclasses (26.7-38.0 days). Median half-lives for specific antibodies ranged between 21.3 and 51.2 days for anti-cytomegalovirus, anti-Haemophilus influenzae, anti-measles, anti-tetanus toxoid, anti-varicella zoster virus antibodies, and anti-Streptococcus pneumoniae subtype antibodies. Overall, IVIG 10% demonstrated pharmacokinetic properties similar to those of other commercial IVIG 10% preparations and 3- or 4-weekly administration achieved sufficient concentrations of IgG, IgG subclasses, and specific antibodies, exceeding the recommended level needed to effectively prevent serious bacterial infections. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study.

PubMed

Kang, Dae-Wook; Adams, James B; Gregory, Ann C; Borody, Thomas; Chittick, Lauren; Fasano, Alessio; Khoruts, Alexander; Geis, Elizabeth; Maldonado, Juan; McDonough-Means, Sharon; Pollard, Elena L; Roux, Simon; Sadowsky, Michael J; Lipson, Karen Schwarzberg; Sullivan, Matthew B; Caporaso, J Gregory; Krajmalnik-Brown, Rosa

2017-01-23

Autism spectrum disorders (ASD) are complex neurobiological disorders that impair social interactions and communication and lead to restricted, repetitive, and stereotyped patterns of behavior, interests, and activities. The causes of these disorders remain poorly understood, but gut microbiota, the 10 13 bacteria in the human intestines, have been implicated because children with ASD often suffer gastrointestinal (GI) problems that correlate with ASD severity. Several previous studies have reported abnormal gut bacteria in children with ASD. The gut microbiome-ASD connection has been tested in a mouse model of ASD, where the microbiome was mechanistically linked to abnormal metabolites and behavior. Similarly, a study of children with ASD found that oral non-absorbable antibiotic treatment improved GI and ASD symptoms, albeit temporarily. Here, a small open-label clinical trial evaluated the impact of Microbiota Transfer Therapy (MTT) on gut microbiota composition and GI and ASD symptoms of 18 ASD-diagnosed children. MTT involved a 2-week antibiotic treatment, a bowel cleanse, and then an extended fecal microbiota transplant (FMT) using a high initial dose followed by daily and lower maintenance doses for 7-8 weeks. The Gastrointestinal Symptom Rating Scale revealed an approximately 80% reduction of GI symptoms at the end of treatment, including significant improvements in symptoms of constipation, diarrhea, indigestion, and abdominal pain. Improvements persisted 8 weeks after treatment. Similarly, clinical assessments showed that behavioral ASD symptoms improved significantly and remained improved 8 weeks after treatment ended. Bacterial and phagedeep sequencing analyses revealed successful partial engraftment of donor microbiota and beneficial changes in the gut environment. Specifically, overall bacterial diversity and the abundance of Bifidobacterium, Prevotella, and Desulfovibrio among other taxa increased following MTT, and these changes persisted after treatment stopped (followed for 8 weeks). This exploratory, extended-duration treatment protocol thus appears to be a promising approach to alter the gut microbiome and virome and improve GI and behavioral symptoms of ASD. Improvements in GI symptoms, ASD symptoms, and the microbiome all persisted for at least 8 weeks after treatment ended, suggesting a long-term impact. This trial was registered on the ClinicalTrials.gov, with the registration number  NCT02504554.

Combination Varenicline and Lorcaserin for Tobacco Dependence Treatment and Weight Gain Prevention in Overweight and Obese Smokers: A Pilot Study.

PubMed

Hurt, Ryan T; Croghan, Ivana T; Schroeder, Darrell R; Hays, J Taylor; Choi, Doo-Sup; Ebbert, Jon O

2017-08-01

Post-cessation weight gain (PCWG) is a major barrier to maintaining abstinence, especially in weight-concerned smokers. Varenicline is the most effective medication for smoking cessation but has minimal impact on PCWG. Lorcaserin is an FDA-approved medication for weight management in overweight or obese patients which also provides a noticeable benefit in treating drug dependence. We hypothesized that combining varenicline with lorcaserin may help prevent PCWG. We conducted an open-label, single arm, Phase II clinical pilot study to obtain preliminary data on the safety and effectiveness of combination varenicline and lorcaserin in preventing PCWG in overweight and obese smokers. Twenty overweight or obese (body mass index 27-40 kg/m2) cigarette smokers were enrolled. The primary outcomes were weight and waist circumference (WC) changes at 12 and 26 weeks in smokers meeting criteria for prolonged smoking abstinence. All participants received open-label varenicline (1 mg twice a day) and lorcaserin (10 mg twice a day) for 12 weeks with follow-up at 26 weeks. Ten subjects met criteria for prolonged smoking abstinence at 12 weeks (50%) and 6 at 26 weeks (30%). Among those achieving prolonged smoking abstinence at 12 weeks, WC was +0.2 ± 6.0 cm (90% CI; -2.9, +3.4) and weight gain was +1.1 ± 3.9 kg (90% CI; -0.9, +3.1). Weight gain and WC increases following prolonged smoking abstinence may be reduced among overweight and obese smokers using combination varenicline and lorcaserin. This combinatory treatment warrants further research in the obese and weight-concerned smoking population. This is the first published prospective pilot study to evaluate lorcaserin for use in reducing PCWG in overweight and obese smokers. When combined with varenicline, lorcaserin minimized PCWG and increases in WC. In addition to the benefit on PCWG reduction, lorcaserin may be a potential new pharmacological treatment for smoking cessation and warrants further larger studies. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Efficacy and safety of the adjustable gastric band - pooled interim analysis of the APEX and HERO studies at 48 weeks.

PubMed

Ponce, Jaime; Taheri, Shahrad; Lusco, Vincent; Cornell, Christopher; Ng-Mak, Daisy S; Shi, Rui; Okerson, Ted

2014-05-01

This 48 week combined analysis reports safety and clinical effectiveness of the LAP-BAND AP * laparoscopic adjustable gastric band (LAGB) in severely obese patients enrolled in the 5 year, prospective, observational, open-label APEX (NCT00501085) and HERO (NCT00953173) studies. The studies enrolled 1620 patients (APEX: N = 514; HERO: N = 1106), 1140 patients in the US (including all APEX patients), and 480 patients in the European Union (EU), Canada or Australia. APEX and HERO are non-randomized, non-comparator, open-label studies with differences in study management practices and follow-up. Notably, laboratory data were not collected during the APEX study. After 48 weeks, mean (SD) percentage weight loss (%WL) was for APEX: 18.7% (7.9); HERO-US: 17.9% (8.5); HERO-EU: 16.5% (10.3); HERO-Canada: 13.4% (8.9); and HERO-Australia: 12.3% (6.9). After 48 weeks, there were no significant differences in %WL for APEX vs. HERO-US. After 48 weeks in the combined analysis (APEX + HERO): (1) patients without vs. with type 2 diabetes at baseline had greater %WL (18% [8.7] vs. 16% [8.5], p = 0.002); (2) female patients had greater %WL vs. male patients (17.9% [8.5] vs. 15.9% [9.3], p = 0.003); (3) younger patients had greater %WL vs. older patients (<50 years: 17.8% [8.7] vs. ≥50 years: 16.7% [8.6], p = 0.035); (4) baseline BMI did not affect %WL (≤35 to ≤45 kg/m(2): 17.7% [8.4] vs. >45 kg/m(2): 17.1% [9.1], p = 0.272). Device-related serious adverse events and adverse events were reported in 1.9% and 17.7% of patients, respectively. Revision and explantation surgeries were carried out on 3.4% and 2.3% of patients, respectively during the 48 weeks of follow-up. This analysis demonstrates the effective weight loss and safety profile of the current LAGB system, with US patients achieving better weight loss than patients from outside the US.

The effect of polycarbophil gel (Replens) on bacterial vaginosis: a pilot study.

PubMed

Wu, Justine P; Fielding, Stephen L; Fiscella, Kevin

2007-01-01

To determine if use of intravaginal polycarbophil gel (Replens) for 1 month will: (1) lower vaginal pH; (2) improve signs of bacterial vaginosis (BV). Seventeen women with BV self-administered polycarbophil gel every third day for 4 weeks in an open-label, prospective pilot study. Primary outcome measures included vaginal pH, presence of amines and Nugent scores. At week 4, there was improvement in Nugent scores, vaginal odor and clue cell count (p<0.05). Eleven women converted from amine positive to negative (73+/-20%). There was no significant change in vaginal pH. Polycarbophil gel is associated with improved signs of BV, although not vaginal pH.

Prophylaxis vs. on-demand treatment with BAY 81-8973, a full-length plasma protein-free recombinant factor VIII product: results from a randomized trial (LEOPOLD II).

PubMed

Kavakli, K; Yang, R; Rusen, L; Beckmann, H; Tseneklidou-Stoeter, D; Maas Enriquez, M

2015-03-01

BAY 81-8973 is a new full-length human recombinant factor VIII product manufactured with technologies to improve consistency in glycosylation and expression to optimize clinical performance. To demonstrate superiority of prophylaxis vs. on demand therapy with BAY 81-8973 in patients with severe hemophilia A. In this multinational,randomized, open-label crossover study (LEOPOLD II;ClinicalTrials.gov identifier: NCT01233258), males aged 12–65 years with severe hemophilia A were randomized to twice-weekly prophylaxis (20-30 IU kg(-1)), 3-times-weekly prophylaxis (30-40 IU kg(-1)), or on-demand treatment with BAY 81-8973. Potency labeling for BAY 81-8973 was based on the chromogenic substrate assay or adjusted to the one-stage assay. Primary efficacy endpoint was annualized number of all bleeds (ABR). Adverse events (AEs)and immunogenicity were also assessed. Eighty patients (on demand, n = 21; twice-weekly prophylaxis, n = 28; 3-times-weekly prophylaxis, n = 31) were treated and analyzed. Mean ± SD ABR was significantly lower with prophylaxis (twice-weekly, 5.7 ± 7.2; 3-times-weekly, 4.3 ± 6.5; combined, 4.9 ± 6.8) vs. on-demand treatment (57.7 ± 24.6; P < 0.0001, ANOVA). Median ABR was reduced by 97% with prophylaxis (twice-weekly, 4.0;3-times-weekly, 2.0; combined, 2.0) vs. on-demand treatment (60.0). Median ABR was higher with twice-weekly vs. 3-times-weekly prophylaxis during the first 6-month treatment period (4.1 vs. 2.0) but was comparable in the second 6-month period (1.1 vs. 2.0). Few patients reported treatment-related AEs (4%); no treatment-related serious AEs or inhibitors were reported. Twice weekly or 3-times-weekly prophylaxis with BAY 81-8973 reduced median ABR by 97% compared with on-demand therapy, confirming the superiority of prophylaxis. Treatment with BAY 81-8973 was well tolerated.

Safety and efficacy of elobixibat for chronic constipation: results from a randomised, double-blind, placebo-controlled, phase 3 trial and an open-label, single-arm, phase 3 trial.

PubMed

Nakajima, Atsushi; Seki, Mitsunori; Taniguchi, Shinya; Ohta, Akira; Gillberg, Per-Göran; Mattsson, Jan P; Camilleri, Michael

2018-05-24

A subset of patients with constipation has reduced colonic bile acid concentrations, which are associated with slow colonic transit. In a previous study, elobixibat, a locally acting ileal bile acid transporter inhibitor, accelerated colonic transit in Japanese patients with functional constipation. In this study, we aimed to determine the efficacy of elobixibat for short-term treatment of chronic constipation, and safety, patient satisfaction, and quality of life with long-term treatment. We did two phase 3 studies of patients aged 20-80 years in Japan with at least 6 months of chronic constipation, who satisfied Rome III criteria for functional constipation, including fewer than three spontaneous bowel movements per week. The first trial, including patients enrolled at 16 clinics, was a 2-week, randomised, double-blind, placebo-controlled study in which (after a 2-week run-in period) patients were randomly assigned (1:1) to either elobixibat 10 mg/day for 2 weeks or placebo. Randomisation was done with permuted block method (block size six) without stratification. Masking to treatment allocation was achieved with identical appearances of elobixibat and placebo, which were supplied in sealed, opaque containers. Group assignment was concealed from patients, investigators, and analysts. The second trial, including patients enrolled at 34 clinics or hospitals, was an open-label, 1-year study in which all patients received elobixibat; participants could titrate the dose to 5 mg/day or 15 mg/day, or maintain the 10 mg/day dose. In both studies, participants took the study drug as an oral tablet once per day before breakfast. The primary outcome of the 2-week randomised trial was the change from baseline (ie, last week of the 2-week run-in) in the frequency of spontaneous bowel movements during week 1 of treatment. The primary outcome of the 52-week open-label trial was safety (type, severity, and incidence of adverse drug reactions) at all times from treatment initiation. All efficacy analyses were based on the modified intention-to-treat (ITT) population without imputation for any missing data. Safety analyses included all patients who received at least one dose of study drug. These trials are registered with the Japan Pharmaceutical Information Center (numbers JapicCTI-153061 and JapicCTI-153062) and have been completed. Between Nov 4, 2015, and June 11, 2016, we assigned 133 patients to treatment in the 2-week randomised trial: 70 to elobixibat (69 included in the modified ITT and safety populations) and 63 to placebo. The frequency of spontaneous bowel movements per week during week 1 of treatment was greater with elobixibat (least-squares mean 6·4, 95% CI 5·3-7·6) than with placebo (1·7, 1·2-2·2), p<0·0001). Between Oct 31, 2015, and March 15, 2017, we allocated 341 patients to 52 weeks of elobixibat (340 included in the modified ITT and safety populations). 163 (48%) patients in the 52-week trial had an adverse drug reaction, the most common of which were mild gastrointestinal disorders (in 135 [40%] patients). Inguinal hernia was reported in one patient with elobixibat in the 52-week study as a moderate adverse drug reaction. The most common adverse drug reactions in both trials were mild abdominal pain (13 [19%] patients with elobixibat and one [2%] with placebo in the 2-week randomised trial, and 82 [24%] patients in the 52-week trial) and diarrhoea (nine [13%] patients with elobixibat and none with placebo in the 2-week randomised trial and 50 [15%] in the 52-week trial). Elobixibat resolved constipation in the short-term, and was well tolerated with both short-term and long-term treatment. The evidence supports the use of this novel approach to increase intracolonic concentrations of endogenous bile acid for the treatment of chronic constipation. EA Pharma and Mochida Pharmaceutical. Copyright © 2018 Elsevier Ltd. All rights reserved.

A Pilot Study of Safety and Efficacy of Cranial Electrotherapy Stimulation in Treatment of Bipolar II Depression

PubMed Central

McClure, Deimante; Greenman, Samantha C.; Koppolu, Siva Sundeep; Varvara, Maria; Yaseen, Zimri S.; Galynker, Igor I.

2015-01-01

Abstract This double-blind, sham-controlled study sought to investigate the effectiveness of cranial electrotherapy stimulation (CES) for the treatment of bipolar II depression (BD II). After randomization, the active group participants (n = 7) received 2 mA CES treatment for 20 minutes five days a week for 2 weeks, whereas the sham group (n = 9) had the CES device turned on and off. Symptom non-remitters from both groups received an additional 2 weeks of open-label active treatment. Active CES treatment but not sham treatment was associated with a significant decrease in the Beck Depression Inventory (BDI) scores from baseline to the second week (p = 0.003) maintaining significance until week 4 (p = 0.002). There was no difference between the groups in side effects frequency. The results of this small study indicate that CES may be a safe and effective treatment for BD II suggesting that further studies on safety and efficacy of CES may be warranted. PMID:26414234

A Pilot Study of Safety and Efficacy of Cranial Electrotherapy Stimulation in Treatment of Bipolar II Depression.

PubMed

McClure, Deimante; Greenman, Samantha C; Koppolu, Siva Sundeep; Varvara, Maria; Yaseen, Zimri S; Galynker, Igor I

2015-11-01

This double-blind, sham-controlled study sought to investigate the effectiveness of cranial electrotherapy stimulation (CES) for the treatment of bipolar II depression (BD II). After randomization, the active group participants (n = 7) received 2 mA CES treatment for 20 minutes five days a week for 2 weeks, whereas the sham group (n = 9) had the CES device turned on and off. Symptom non-remitters from both groups received an additional 2 weeks of open-label active treatment. Active CES treatment but not sham treatment was associated with a significant decrease in the Beck Depression Inventory (BDI) scores from baseline to the second week (p = 0.003) maintaining significance until week 4 (p = 0.002). There was no difference between the groups in side effects frequency. The results of this small study indicate that CES may be a safe and effective treatment for BD II suggesting that further studies on safety and efficacy of CES may be warranted.

One week treatment with the IL-1 receptor antagonist anakinra leads to a sustained improvement in insulin sensitivity in insulin resistant patients with type 1 diabetes mellitus.

PubMed

van Asseldonk, Edwin J P; van Poppel, Pleun C M; Ballak, Dov B; Stienstra, Rinke; Netea, Mihai G; Tack, Cees J

2015-10-01

Inflammation associated with obesity is involved in the development of insulin resistance. We hypothesized that anti-inflammatory treatment with the Interleukin-1 receptor antagonist anakinra would improve insulin sensitivity. In an open label proof-of-concept study, we included overweight patients diagnosed with type 1 diabetes with an HbA1c level over 7.5%. Selecting insulin resistant patients with longstanding type 1 diabetes allowed us to study the effects of anakinra on insulin sensitivity. Patients were treated with 100mg anakinra daily for one week. Insulin sensitivity, insulin need and blood glucose profiles were measured before, after one week and after four weeks of follow-up. Fourteen patients completed the study. One week of anakinra treatment led to an improvement of insulin sensitivity, an effect that was sustained for four weeks. Similarly, glucose profiles, HbA1c levels and insulin needs improved. In conclusion, one week of treatment with anakinra improves insulin sensitivity in patients with type 1 diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

Duloxetine in the long-term management of diabetic peripheral neuropathic pain: An open-label, 52-week extension of a randomized controlled clinical trial.

PubMed

Wernicke, Joachim F; Raskin, Joel; Rosen, Amy; Pritchett, Yili L; D'Souza, Deborah N; Iyengar, Smriti; Knopp, Kelly; Le, Trong K

2006-09-01

Duloxetine hydrochloride, a selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor, is relatively balanced in its affinity for both 5-HT and NE reuptake inhibition and is the first US Food and Drug Administration-approved prescription drug for the management of diabetic peripheral neuropathic pain (DPNP). The aim of this study was to determine whether management of DPNP with duloxetine interferes with the treatment of diabetes. It also examined the tolerability of long-term exposure to duloxetine with regard to the progression of diabetic complications, and assessed the impact of DPNP management with duloxetine versus routine care. This was a 52-week, multicenter, re-randomized, open-label extension of a parallel, double-blind, randomized, placebo-controlled, acute (12-week) study. Patients who completed the duloxetine or placebo acute treatment period were randomly reassigned in a 2:1 ratio to treatment with duloxetine 60 mg BID or routine care for an additional 52 weeks. The study included male and female outpatients aged ≥18 years with a diagnosis of DPNP caused by type 1 or type 2 diabetes. Over the course of the 52-week study, visits were scheduled on the following weeks (of the extension phase of the study): 1 (via phone only), 2, 4, 8, 12, 20, 28, 40, and 52. Tolerability was assessed by review and analyses of discontinuation rates, adverse events (AEs), laboratory data, vital signs, electrocardiographic results, concomitant medications, and diabetic complications. Treatment-emergent AEs (TEAEs) were defined as AEs that appeared during therapy (were not present at baseline) or were exacerbated during treatment. Data on AEs and concomitant medications were collected at every visit. Data on blood pressure, heart rate, and significant hypoglycemic events were collected at every visit starting from week 2. Fasting clinical chemistry and electrolyte group laboratory assessments were done at every visit, starting from week 4. Electrocardiographic data was collected at weeks 4 and 52, and glycosylated hemoglobin and lipid profile data were collected at weeks 20 and 52. Hematology and urinalysis laboratory assessments and diabetic complication assessments were done at week 52. All safety data was assessed in cases of early discontinuation. Treatment differences on quality of life (QOL) were compared using the Short Form-36 Health Status Survey (SF-36) and the EQ-5D instrument of the European Health-Related Quality of Life Measures. This was assessed at the last visit or at early discontinuation. The open-label extension-phase study included 337 patients (duloxetine, n = 222; routine care, n = 115). For the duloxetine group, mean age was 60.2 years, 61.3% were male, and 78.4% were white. For the routine-care group, mean age was 58.9 years, 60.0% were male, and 74.8% were white. Mean weight was 95.3 kg for both groups. None of the TEAEs occurred significantly more often in the duloxetine-treated group than in the routine-care-treated group. No TEAEs were reported by >10% of patients in the duloxetine group. The TEAEs reported by >10% of patients in the routine-care group included dizziness (11.3%), somnolence (13.0%), headache (10.4%), and vomiting (10.4%). No significant differences were found between treatment groups in the occurrence of serious AEs or in the number of patients discontinuing because of AEs. Duloxetine was significantly better than routine care on the bodily pain subscale of the SF-36 (mean change: 1.5 vs -4.1; P= 0.021) and on the EQ-5D (mean change: -0.00 vs -0.09; P = 0.001). Over 52 weeks of follow-up, treatment of these diabetic patients with duloxetine for peripheral neuropathic pain was associated with outcomes similar to, or significantly better than, that of routine care on most measures of tolerability, diabetic complications, and QOL.

Duloxetine in the long-term management of diabetic peripheral neuropathic pain: An open-label, 52-week extension of a randomized controlled clinical trial

PubMed Central

Wernicke, Joachim F.; Raskin, Joel; Rosen, Amy; Pritchett, Yili L.; D'Souza, Deborah N.; Iyengar, Smriti; Knopp, Kelly; Le, Trong K.

2006-01-01

Background: Duloxetine hydrochloride, a selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor, is relatively balanced in its affinity for both 5-HT and NE reuptake inhibition and is the first US Food and Drug Administration-approved prescription drug for the management of diabetic peripheral neuropathic pain (DPNP). Objectives: The aim of this study was to determine whether management of DPNP with duloxetine interferes with the treatment of diabetes. It also examined the tolerability of long-term exposure to duloxetine with regard to the progression of diabetic complications, and assessed the impact of DPNP management with duloxetine versus routine care. Methods: This was a 52-week, multicenter, re-randomized, open-label extension of a parallel, double-blind, randomized, placebo-controlled, acute (12-week) study. Patients who completed the duloxetine or placebo acute treatment period were randomly reassigned in a 2:1 ratio to treatment with duloxetine 60 mg BID or routine care for an additional 52 weeks. The study included male and female outpatients aged ≥18 years with a diagnosis of DPNP caused by type 1 or type 2 diabetes. Over the course of the 52-week study, visits were scheduled on the following weeks (of the extension phase of the study): 1 (via phone only), 2, 4, 8, 12, 20, 28, 40, and 52. Tolerability was assessed by review and analyses of discontinuation rates, adverse events (AEs), laboratory data, vital signs, electrocardiographic results, concomitant medications, and diabetic complications. Treatment-emergent AEs (TEAEs) were defined as AEs that appeared during therapy (were not present at baseline) or were exacerbated during treatment. Data on AEs and concomitant medications were collected at every visit. Data on blood pressure, heart rate, and significant hypoglycemic events were collected at every visit starting from week 2. Fasting clinical chemistry and electrolyte group laboratory assessments were done at every visit, starting from week 4. Electrocardiographic data was collected at weeks 4 and 52, and glycosylated hemoglobin and lipid profile data were collected at weeks 20 and 52. Hematology and urinalysis laboratory assessments and diabetic complication assessments were done at week 52. All safety data was assessed in cases of early discontinuation. Treatment differences on quality of life (QOL) were compared using the Short Form-36 Health Status Survey (SF-36) and the EQ-5D instrument of the European Health-Related Quality of Life Measures. This was assessed at the last visit or at early discontinuation. Results: The open-label extension-phase study included 337 patients (duloxetine, n = 222; routine care, n = 115). For the duloxetine group, mean age was 60.2 years, 61.3% were male, and 78.4% were white. For the routine-care group, mean age was 58.9 years, 60.0% were male, and 74.8% were white. Mean weight was 95.3 kg for both groups. None of the TEAEs occurred significantly more often in the duloxetine-treated group than in the routine-care-treated group. No TEAEs were reported by >10% of patients in the duloxetine group. The TEAEs reported by >10% of patients in the routine-care group included dizziness (11.3%), somnolence (13.0%), headache (10.4%), and vomiting (10.4%). No significant differences were found between treatment groups in the occurrence of serious AEs or in the number of patients discontinuing because of AEs. Duloxetine was significantly better than routine care on the bodily pain subscale of the SF-36 (mean change: 1.5 vs −4.1; P= 0.021) and on the EQ-5D (mean change: −0.00 vs −0.09; P = 0.001). Conclusions: Over 52 weeks of follow-up, treatment of these diabetic patients with duloxetine for peripheral neuropathic pain was associated with outcomes similar to, or significantly better than, that of routine care on most measures of tolerability, diabetic complications, and QOL. PMID:24678103

Disease control and safety of belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus.

PubMed

Ginzler, Ellen M; Wallace, Daniel J; Merrill, Joan T; Furie, Richard A; Stohl, William; Chatham, W Winn; Weinstein, Arthur; McKay, James D; McCune, W Joseph; Zhong, Z John; Freimuth, William W; Petri, Michelle A

2014-02-01

To evaluate the efficacy/safety of belimumab plus standard therapy in patients (n = 449) with active systemic lupus erythematosus (SLE) treated up to 7 years (n = 177 currently ongoing). Patients (n = 345) who completed a double-blind, placebo-controlled, 52-week study of belimumab 1, 4, or 10 mg/kg and 24-week extension of belimumab (placebo switched to 10 mg/kg; belimumab same dose or switched to 10 mg/kg) could receive belimumab 10 mg/kg in an open-label continuation study (n = 296). Disease activity was analyzed in patients with active SLE at baseline of the initial study. Biomarker and SLE medication changes were evaluated, and adverse events (AE) were monitored throughout the study. Total belimumab exposure over 7 years (double-blind and open-label periods): 1746 patient-years. SLE Responder Index (SRI) response rates at Week 52 in autoantibody-positive patients: placebo, 29%; belimumab, 46% (p < 0.05). In the continuation study, 57% of auto-antibody-positive patients had an SRI response by Year 2 and 65% by Year 7; severe flares occurred in 19% with placebo and 17% with belimumab during the first year, with the annual rate declining to 2%-9% during years 2-7. Anti-dsDNA autoantibodies in patients positive for them at baseline had a progressive decline of 40%-60% from baseline over 2-7 years with belimumab. Corticosteroid use decreased over time with ≥ 50-55% reduction in median dose during years 5-7. Serious and overall annual AE rates, including infections, were generally stable or decreased during 7-year treatment. Disease control and safety profile were maintained in patients with active SLE taking belimumab plus standard therapy for up to 7 years. [ClinicalTrials.gov numbers: NCT00071487 and NCT00583362].

Poor predictive value of breath hydrogen response for probiotic effects in IBS.

PubMed

Yao, Chu K; Barrett, Jacqueline S; Philpott, Hamish; Chung, Alvin R T; van Langenberg, Daniel; Garg, Mayur; Gibson, Peter R

2015-12-01

Previous observations suggested that an early rise in breath hydrogen after lactulose (ERBHAL) may identify patients with irritable bowel syndrome (IBS) likely to respond to probiotics. Therefore, we aimed to (i) investigate whether treatment with a probiotic changes breath hydrogen response in patients with ERBHAL and (ii) whether these changes identify patients who may benefit symptomatically from probiotics. In a randomized, double-blind, placebo-controlled trial, patients with IBS (Rome III) were randomized to either 65 mL/day fermented milk product containing probiotic (FMPP) or placebo for 6 weeks, followed by 6 weeks' open-label treatment and 6 weeks' withdrawal. Breath hydrogen responses to lactulose (15 g) and liquid-gastric emptying time were evaluated before and at the end of each treatment period. Symptoms were measured using a 100-mm visual analog scale. Loss of ERBHAL occurred in 36% of 23 patients receiving FMPP and 41% of 22 receiving placebo (P = 1.00). Amongst 40 patients who completed open-label FMPP treatment, ERBHAL was lost in a further 38%, continued in 25%, and regained in 10%. Similar variability occurred in the withdrawal phase. Variability was unrelated to changes in gastric emptying. No differences in symptom response were seen between treatment groups nor in relation to the loss or retention of ERBHAL. Breath hydrogen patterns after lactulose are poorly reproducible. No FMPP-specific effects on fermentation patterns or symptoms were observed. The presence of ERBHAL is not useful to predict symptomatic response to probiotic therapy in patients with IBS. © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: Long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study.

PubMed

Papp, Kim A; Krueger, James G; Feldman, Steven R; Langley, Richard G; Thaci, Diamant; Torii, Hideshi; Tyring, Stephen; Wolk, Robert; Gardner, Annie; Mebus, Charles; Tan, Huaming; Luo, Yingchun; Gupta, Pankaj; Mallbris, Lotus; Tatulych, Svitlana

2016-05-01

Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. We sought to report longer-term tofacitinib efficacy and safety in patients with moderate to severe psoriasis. Data from 2 identical phase-III studies, Oral-treatment Psoriasis Trial Pivotal 1 and 2, were pooled with data from these patients in an ongoing open-label long-term extension study. Patients (n = 1861) were randomized 2:2:1 to tofacitinib 5 mg, 10 mg, or placebo twice daily (BID). At week 16, placebo patients were rerandomized to tofacitinib. Pivotal study participants could enroll into the long-term extension where they received tofacitinib at 10 mg BID for 3 months, after which dosing could be 5 or 10 mg BID. At week 28, the proportions of patients randomized to tofacitinib 5 and 10 mg BID achieving 75% or greater reduction in Psoriasis Area and Severity Index score from baseline were 55.6% and 68.8%, and achieving Physician Global Assessment of clear or almost clear were 54.7% and 65.9%. Efficacy was maintained in most patients through 24 months. Serious adverse events and discontinuations because of adverse events were reported in less than 11% of patients over 33 months of tofacitinib exposure. There was no dose comparison beyond week 52. Oral tofacitinib demonstrated sustained efficacy in patients with psoriasis through 2 years, with 10 mg BID providing greater efficacy than 5 mg BID. No unexpected safety findings were observed. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

A phase 2, open-label, multicenter study of the long-term safety of siltuximab (an anti-interleukin-6 monoclonal antibody) in patients with multicentric Castleman disease.

PubMed

van Rhee, Frits; Casper, Corey; Voorhees, Peter M; Fayad, Luis E; van de Velde, Helgi; Vermeulen, Jessica; Qin, Xiang; Qi, Ming; Tromp, Brenda; Kurzrock, Razelle

2015-10-06

Multicentric Castleman disease (MCD) is a rare, systemic lymphoproliferative disorder driven by interleukin (IL)-6 overproduction. Siltuximab, an anti-IL-6 monoclonal antibody, has demonstrated durable tumor and symptomatic responses in a multinational, randomized, placebo-controlled study of MCD. This preplanned safety analysis was conducted to evaluate the long-term safety of siltuximab treatment among 19 patients with MCD who had stable disease or better and were enrolled in a phase-1 study and subsequent ongoing, open-label, phase-2 extension study. Dosing was 11 mg/kg administered intravenously every 3 weeks, per protocol, or every 6 weeks at the investigator's discretion. Safety monitoring focused on potential risks associated with the anti-IL-6 mechanism of action. Investigator-assessed disease control status was also documented. Median treatment duration for the 19 patients was 5.1 (range 3.4, 7.2) years, with 14 (74%) patients treated for >4 years. Grade-≥ 3 adverse events (AEs) reported in >1 patient included hypertension (n = 3) and nausea, cellulitis, and fatigue (n = 2 each). Grade-≥ 3 AEs at least possibly attributed to siltuximab were leukopenia, lymphopenia, and a serious AE of polycythemia (n = 1 each). Hypertriglyceridemia and hypercholesterolemia (total cholesterol) were reported in 8 and 9 patients, respectively. No disease relapses were observed, and 8 of 19 patients were able to switch to an every-6-week dosing schedule. All MCD patients in this extension study have received siltuximab for a prolonged duration (up to 7 years) without evidence of cumulative toxicity or treatment discontinuations and with few serious infections. All patients are alive, demonstrate sustained disease control, and continue to receive siltuximab.

Efficacy and safety of extended- versus immediate-release pramipexole in Japanese patients with advanced and L-dopa-undertreated Parkinson disease: a double-blind, randomized trial.

PubMed

Mizuno, Yoshikuni; Yamamoto, Mitsutoshi; Kuno, Sadako; Hasegawa, Kazuko; Hattori, Nobutaka; Kagimura, Tatsuro; Sarashina, Akiko; Rascol, Olivier; Schapira, Anthony H V; Barone, Paolo; Hauser, Robert A; Poewe, Werner

2012-01-01

To compare the efficacy, safety, tolerability, and trough plasma levels of pramipexole extended-release (ER) and pramipexole immediate-release (IR), and to assess the effects of overnight switching from an IR to an ER formulation, in L-dopa-treated patients with Parkinson disease (PD). After a 1- to 4-week screening/enrollment, 112 patients who had exhibited L-dopa-related problems or were receiving suboptimal L-dopa dosage were randomized in double-blind, double-dummy, 1:1 fashion to pramipexole ER once daily or pramipexole IR 2 to 3 times daily for 12 weeks, both titrated to a maximum daily dose of 4.5 mg. Successful completers of double-blind treatment were switched to open-label pramipexole ER, beginning with a 4-week dose-adjustment phase. Among the double-blind treatment patients (n = 56 in each group), Unified Parkinson's Disease Rating Scale Parts II+III total scores decreased significantly from baseline and to a similar degree with pramipexole ER and IR formulations. In each group, 47 double-blind patients (83.9%) reported adverse events (AEs), requiring withdrawal of 3 ER patients (5.4%) and 2 IR patients (3.6%). Trough plasma levels at steady state (at the same doses and dose-normalized concentrations) were also similar with both formulations. Among open-label treatment patients (n = 53 from IR to ER), 83% were successfully switched (no worsening of PD symptoms) to pramipexole ER. In L-dopa-treated patients, pramipexole ER and pramipexole IR demonstrated similar efficacy, safety, tolerability, and trough plasma levels. Patients can be safely switched overnight from pramipexole IR to pramipexole ER with no impact on efficacy.

Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks' gestation (HYPITAT): a multicentre, open-label randomised controlled trial.

PubMed

Koopmans, Corine M; Bijlenga, Denise; Groen, Henk; Vijgen, Sylvia M C; Aarnoudse, Jan G; Bekedam, Dick J; van den Berg, Paul P; de Boer, Karin; Burggraaff, Jan M; Bloemenkamp, Kitty W M; Drogtrop, Addy P; Franx, Arie; de Groot, Christianne J M; Huisjes, Anjoke J M; Kwee, Anneke; van Loon, Aren J; Lub, Annemiek; Papatsonis, Dimitri N M; van der Post, Joris A M; Roumen, Frans J M E; Scheepers, Hubertina C J; Willekes, Christine; Mol, Ben W J; van Pampus, Maria G

2009-09-19

Robust evidence to direct management of pregnant women with mild hypertensive disease at term is scarce. We investigated whether induction of labour in women with a singleton pregnancy complicated by gestational hypertension or mild pre-eclampsia reduces severe maternal morbidity. We undertook a multicentre, parallel, open-label randomised controlled trial in six academic and 32 non-academic hospitals in the Netherlands between October, 2005, and March, 2008. We enrolled patients with a singleton pregnancy at 36-41 weeks' gestation, and who had gestational hypertension or mild pre-eclampsia. Participants were randomly allocated in a 1:1 ratio by block randomisation with a web-based application system to receive either induction of labour or expectant monitoring. Masking of intervention allocation was not possible. The primary outcome was a composite measure of poor maternal outcome--maternal mortality, maternal morbidity (eclampsia, HELLP syndrome, pulmonary oedema, thromboembolic disease, and placental abruption), progression to severe hypertension or proteinuria, and major post-partum haemorrhage (>1000 mL blood loss). Analysis was by intention to treat and treatment effect is presented as relative risk. This study is registered, number ISRCTN08132825. 756 patients were allocated to receive induction of labour (n=377 patients) or expectant monitoring (n=379). 397 patients refused randomisation but authorised use of their medical records. Of women who were randomised, 117 (31%) allocated to induction of labour developed poor maternal outcome compared with 166 (44%) allocated to expectant monitoring (relative risk 0.71, 95% CI 0.59-0.86, p<0.0001). No cases of maternal or neonatal death or eclampsia were recorded. Induction of labour is associated with improved maternal outcome and should be advised for women with mild hypertensive disease beyond 37 weeks' gestation. ZonMw.

An open-label extension long-term study of the safety and efficacy of aripiprazole for irritability in children and adolescents with autistic disorder in Japan.

PubMed

Ichikawa, Hironobu; Hiratani, Michio; Yasuhara, Akihiro; Tsujii, Noa; Oshimo, Takashi; Ono, Hiroaki; Tadori, Yoshihiro

2018-02-01

The purpose of this study was to evaluate the long-term safety and efficacy of aripiprazole in treating irritability in pediatric patients (6-17 years) with autistic disorder (AD) in Japan. In this open-label extension study, patients who had completed a previous randomized, double-blind, placebo-controlled 8-week study were enrolled and were flexibly dosed with aripiprazole (1-15 mg/day) until the new indication of irritability in pediatric autism spectrum disorder was approved in Japan. Seventy (81%) out of 86 enrolled patients completed week-48 assessments. The mean duration of treatment was 694.9 days. The mean daily dose of aripiprazole over the treatment period was 7.2 mg and the mean of the final dose was 8.5 mg. The most common treatment-emergent adverse events (TEAE; ≥20%) included nasopharyngitis, somnolence, influenza, and increased weight. The majority of these TEAE were mild or moderate in severity, and there were no deaths, and no clinically relevant findings in laboratory values except prolactin decrease, vital signs, height, or ECG parameters. At week 48 (observed case), the mean change from baseline in the Irritability subscale score for the Aberrant Behavior Checklist Japanese Version was -6.3 in prior placebo patients and -2.6 in prior aripiprazole patients. Aripiprazole was generally safe, well tolerated, and effective in the long-term treatment of irritability associated with AD in Japanese pediatric patients. © 2017 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.

Ledipasvir-Sofosbuvir Plus Ribavirin in Treatment-Naive Patients With Hepatitis C Virus Genotype 3 Infection: An Open-Label Study.

PubMed

Feld, Jordan J; Ramji, Alnoor; Shafran, Stephen D; Willems, Bernard; Marotta, Paul; Huchet, Emmanuelle; Vachon, Marie-Louise; Svarovskaia, Evguenia S; Huang, K C; Hyland, Robert H; Yun, Chohee; Massetto, Benedetta; Brainard, Diana M; McHutchison, John G; Tam, Edward; Bailey, Robert; Cooper, Curtis; Yoshida, Eric M; Greenbloom, Susan; Elkhashab, Magdy; Borgia, Sergio; Swain, Mark G

2017-07-01

Patients chronically infected with genotype 3 hepatitis C virus (HCV) have faster disease progression and are less responsive to current direct-acting antiviral regimens than patients infected with other genotypes. We conducted an open-label trial to evaluate the safety, tolerability, and efficacy of ledipasvir and sofosbuvir plus ribavirin in patients with genotype 3 HCV infection. We enrolled treatment-naive patients with and without compensated cirrhosis at 15 sites in Canada. All patients were treated with ledipasvir-sofosbuvir (90 mg and 400 mg) plus weight-based ribavirin for 12 weeks. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). Secondary endpoints included evaluation of baseline and treatment-emergent drug resistance. Of the 111 patients enrolled, 105 (95%) had subtype 3a HCV and 39 (35%) had compensated cirrhosis. SVR12 was achieved by 99 of 111 patients (89%; 95% confidence interval, 82%-94%). Of the 39 patients with cirrhosis, 31 (79%) achieved SVR12, compared with 68 of 72 (94%) patients without cirrhosis. No treatment-emergent resistance mutations occurred in those who failed treatment. One patient discontinued treatment due to liver cancer and died 22 days after treatment discontinuation. The most common adverse events were fatigue (51%), headache (36%), and nausea (23%). In this multicenter trial involving treatment-naive patients with genotype 3 HCV, 12 weeks of ledipasvir-sofosbuvir provided a high level of SVR in those without cirrhosis. NCT02413593. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Reduced folate and serum vitamin metabolites in patients with rectal carcinoma: an open-label feasibility study of pemetrexed with folic acid and vitamin B12 supplementation

PubMed Central

Odin, Elisabeth A.; Carlsson, Göran U.; Kurlberg, Göran K.; Björkqvist, Hillevi G.; Tångefjord, Maria T.; Gustavsson, Bengt G.

2016-01-01

The objectives of this single-center, open-label, phase II study were to evaluate (a) the feasibility and safety of neoadjuvant administration of pemetrexed with oral folic acid and vitamin B12 (FA/B12) in newly diagnosed patients with resectable rectal cancer and (b) intracellular and systemic vitamin metabolism. Patients were treated with three cycles of pemetrexed (500 mg/m2, every 3 weeks) and FA/B12 before surgery. The reduced folates tetrahydrofolate, 5-methyltetrahydrofolate, and 5,10-methylenetetrahydrofolate were evaluated from biopsies in tumor tissue and in adjacent mucosa. Serum levels of homocysteine, cystathionine, and methylmalonic acid were also measured. All 37 patients received three cycles of pemetrexed; 89.2% completed their planned dosage within a 9-week feasibility time frame. Neither dose reductions nor study drug-related serious adverse events were reported. Reduced folate levels were significantly higher in tumor tissue compared with adjacent mucosa at baseline. After FA/B12 administration, tissue levels of reduced folates increased significantly and remained high during treatment in both tumor and mucosa until surgery. Serum levels of cystathionine increased significantly compared with baseline after FA/B12 administration, but then decreased, fluctuating cyclically during pemetrexed therapy. Homocysteine and methylmalonic acid levels decreased significantly after FA/B12 administration, and remained below baseline levels during the study. These results indicate that administration of three neoadjuvant cycles of single-agent pemetrexed, every 3 weeks, with FA/B12 in patients with resectable rectal cancer is feasible and tolerable. Tissue and serum vitamin metabolism results demonstrate the influence of pemetrexed and FA/B12 on vitamin metabolism and warrant further study. PMID:26825869

Responsive cortical stimulation for the treatment of medically intractable partial epilepsy.

PubMed

Morrell, Martha J

2011-09-27

This multicenter, double-blind, randomized controlled trial assessed the safety and effectiveness of responsive cortical stimulation as an adjunctive therapy for partial onset seizures in adults with medically refractory epilepsy. A total of 191 adults with medically intractable partial epilepsy were implanted with a responsive neurostimulator connected to depth or subdural leads placed at 1 or 2 predetermined seizure foci. The neurostimulator was programmed to detect abnormal electrocorticographic activity. One month after implantation, subjects were randomized 1:1 to receive stimulation in response to detections (treatment) or to receive no stimulation (sham). Efficacy and safety were assessed over a 12-week blinded period and a subsequent 84-week open-label period during which all subjects received responsive stimulation. Seizures were significantly reduced in the treatment (-37.9%, n = 97) compared to the sham group (-17.3%, n = 94; p = 0.012) during the blinded period and there was no difference between the treatment and sham groups in adverse events. During the open-label period, the seizure reduction was sustained in the treatment group and seizures were significantly reduced in the sham group when stimulation began. There were significant improvements in overall quality of life (p < 0.02) and no deterioration in mood or neuropsychological function. Responsive cortical stimulation reduces the frequency of disabling partial seizures, is associated with improvements in quality of life, and is well-tolerated with no mood or cognitive effects. Responsive stimulation may provide another adjunctive treatment option for adults with medically intractable partial seizures. This study provides Class I evidence that responsive cortical stimulation is effective in significantly reducing seizure frequency for 12 weeks in adults who have failed 2 or more antiepileptic medication trials, 3 or more seizures per month, and 1 or 2 seizure foci.

Rheumatoid Arthritis Treatment After Methotrexate: The Durability of Triple Therapy Versus Etanercept.

PubMed

Peper, Shana M; Lew, Robert; Mikuls, Ted; Brophy, Mary; Rybin, Denis; Wu, Hongseng; O'Dell, James

2017-10-01

Although it is common for rheumatologists to initiate biologic agents after failure of methotrexate monotherapy in rheumatoid arthritis (RA), ample data support the initial use of combinations of conventional therapies in this clinical scenario. Our study explores the durability of triple therapy (methotrexate, sulfasalazine, and hydroxychloroquine) versus methotrexate-etanercept in RA. RA patients with suboptimal response to methotrexate (n = 353) were randomized to either triple therapy or methotrexate-etanercept therapy in a 48-week, double-blinded, noninferiority trial. Patients without clinical improvement at 24 weeks were switched to the alternative treatment. Of the total, 289 participated in followup. We report treatment durability, Disease Activity Score in 28 joints (DAS28), and other measures during an open-label extension for an additional period up to 72 weeks. Mean ± SD duration of open-label followup was 11 ± 6 months. The likelihood of continuing conventional therapy at 1 year was 78% for triple therapy versus 63% for methotrexate-etanercept, with most treatment changes occurring at the start of followup. More patients changed from methotrexate-etanercept to triple therapy than from triple therapy to methotrexate-etanercept (P = 0.005). DAS28 scores and other disease activity measures were not different for the 2 treatments and were stable during followup. In RA patients with suboptimal methotrexate response randomized to receive triple therapy or methotrexate-etanercept, the former was found to be significantly more durable. Given cost differences and similar outcomes, the variable durability demonstrated provides additional evidence supporting conventional combinations over biologic agent combinations as the first choice after methotrexate inadequate response. © 2017, American College of Rheumatology.

Aripiprazole plus topiramate in opioid-dependent patients with schizoaffective disorder: an 8-week, open-label, uncontrolled, preliminary study.

PubMed

Bruno, Antonio; Romeo, Vincenzo M; Pandolfo, Gianluca; Scimeca, Giuseppe; Zoccali, Rocco A; Muscatello, Maria Rosaria A

2014-01-01

The aims of this study were to evaluate a combination of aripiprazole and topiramate in the treatment of opioid-dependent patients with schizoaffective disorder undergoing methadone maintenance therapy (MMT) and, further, to taper off patients from methadone treatment. Twenty patients who met DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) criteria for opioid dependence and schizoaffective disorder receiving MMT (80 mg/day) were given aripiprazole (10 mg/day) plus topiramate (up to 200 mg/day) for 8 weeks. A methadone dose reduction of 3 mg/day until suspension at week 4 was established. Aripiprazole plus topiramate was effective in reducing clinical symptoms, and a rapid tapering off of MMT was achieved. Combining aripiprazole and topiramate may be effective in patients with a dual diagnosis of opioid dependency and schizoaffective disorder.

Efficacy and safety of once-weekly oral trelagliptin switched from once-daily dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes mellitus: An open-label, phase 3 exploratory study.

PubMed

Inagaki, Nobuya; Sano, Hiroki; Seki, Yoshifumi; Kuroda, Shingo; Kaku, Kohei

2018-03-01

Trelagliptin, a novel once-weekly oral dipeptidyl peptidase-4 (DPP-4) inhibitor, has shown favorable efficacy and safety in type 2 diabetes mellitus patients. Trelagliptin was launched in Japan, and is expected to be initially used for switchover from a daily DPP-4 inhibitor in the clinical setting. Thus, the present study was carried out to explore the efficacy and safety of trelagliptin after a daily DPP-4 inhibitor was switched to it. This was an open-label, phase 3 exploratory study to evaluate the efficacy and safety of trelagliptin in Japanese type 2 diabetes mellitus patients who had stable glycemic control on once-daily sitagliptin therapy. Eligible patients received trelagliptin 100 mg orally before breakfast once a week for 12 weeks. The primary end-point was blood glucose by the meal tolerance test, and additional end-points were glycemic control (efficacy) and safety. Altogether, 14 patients received the study drug. The blood glucose did not markedly change from baseline at major assessment points in the meal tolerance test, and a decrease in blood glucose was observed at several other assessment points. Adverse events were reported in 42.9% (6/14) of patients, but all adverse events were mild or moderate in severity, and most were not related to the study drug. No cases of death, serious adverse events or hypoglycemia were reported. It is considered possible to switch a once-daily DPP-4 inhibitor to trelagliptin in type 2 diabetes mellitus patients with stable glycemic control in combination with diet and exercise therapy without any major influences on glycemic control or safety. © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Efficacy and safety of saxagliptin compared with acarbose in Chinese patients with type 2 diabetes mellitus uncontrolled on metformin monotherapy: Results of a Phase IV open-label randomized controlled study (the SMART study).

PubMed

Du, Jin; Liang, Li; Fang, Hui; Xu, Fengmei; Li, Wei; Shen, Liya; Wang, Xueying; Xu, Chun; Bian, Fang; Mu, Yiming

2017-11-01

To investigate the efficacy, safety and tolerability of saxagliptin compared with acarbose in Chinese patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy. SMART was a 24-week, multicentre, randomized, parallel-group, open-label Phase IV study conducted at 35 sites in China (September 24, 2014 to September 29, 2015). The primary outcome was absolute change from baseline in HbA1c at Week 24. Secondary outcomes assessed at Week 24 included the proportion of patients achieving HbA1c < 7.0%, the proportion of patients with gastrointestinal adverse events (GI AEs), and the proportion of patients achieving HbA1c < 7.0% without GI AEs. Safety and tolerability were also assessed in all patients who received ≥1 dose of study medication. Four-hundred and eighty-eight patients were randomized (1:1) to saxagliptin or acarbose via a central randomization system (interactive voice/web response system); 241 and 244 patients received saxagliptin and acarbose, respectively, and 238 and 243 of these had ≥1 pre- and ≥1 post-baseline efficacy values recorded. Saxagliptin was non-inferior to acarbose for glycaemic control [Week 24 HbA1c change: -0.82% and -0.78%, respectively; difference (95% confidence interval): -0.04 (-0.22, 0.13)%], with similar proportions of patients in both treatment groups achieving HbA1c < 7.0%. However, fewer GI AEs were reported with saxagliptin compared with acarbose, and a greater number of patients who received saxagliptin achieved HbA1c < 7.0% without GI AEs compared with those receiving acarbose. Both therapies had similar efficacy profiles. However, saxagliptin was associated with fewer GI AEs, suggesting it might be preferential for clinical practice. NCT02243176, clinicaltrials.gov. © 2017 John Wiley & Sons Ltd.

Direct-Acting Antiviral Prophylaxis in Kidney Transplantation From Hepatitis C Virus-Infected Donors to Noninfected Recipients: An Open-Label Nonrandomized Trial.

PubMed

Durand, Christine M; Bowring, Mary G; Brown, Diane M; Chattergoon, Michael A; Massaccesi, Guido; Bair, Nichole; Wesson, Russell; Reyad, Ashraf; Naqvi, Fizza F; Ostrander, Darin; Sugarman, Jeremy; Segev, Dorry L; Sulkowski, Mark; Desai, Niraj M

2018-04-17

Given the high mortality rate for patients with end-stage kidney disease receiving dialysis and the efficacy and safety of hepatitis C virus (HCV) treatments, discarded kidneys from HCV-infected donors may be a neglected public health resource. To determine the tolerability and feasibility of using direct-acting antivirals (DAAs) as prophylaxis before and after kidney transplantation from HCV-infected donors to non-HCV-infected recipients (that is, HCV D+/R- transplantation). Open-label nonrandomized trial. (ClinicalTrials.gov: NCT02781649). Single center. 10 HCV D+/R- kidney transplant candidates older than 50 years with no available living donors. Transplantation of kidneys from deceased donors aged 13 to 50 years with positive HCV RNA and HCV antibody test results. All recipients received a dose of grazoprevir (GZR), 100 mg, and elbasvir (EBR), 50 mg, immediately before transplantation. Recipients of kidneys from donors with genotype 1 infection continued receiving GZR-EBR for 12 weeks after transplantation; those receiving organs from donors with genotype 2 or 3 infection had sofosbuvir, 400 mg, added to GZR-EBR for 12 weeks of triple therapy. The primary safety outcome was the incidence of adverse events related to GZR-EBR treatment. The primary efficacy outcome was the proportion of recipients with an HCV RNA level below the lower limit of quantification 12 weeks after prophylaxis. Among 10 HCV D+/R- transplant recipients, no treatment-related adverse events occurred, and HCV RNA was not detected in any recipient 12 weeks after treatment. Nonrandomized study design and a small number of patients. Pre- and posttransplantation HCV treatment was safe and prevented chronic HCV infection in HCV D+/R- kidney transplant recipients. If confirmed in larger studies, this strategy should markedly expand organ options and reduce mortality for kidney transplant candidates without HCV infection. Merck Sharp & Dohme.

Efficacy and Safety of Paliperidone Palmitate 3-Month Formulation for Patients with Schizophrenia: A Randomized, Multicenter, Double-Blind, Noninferiority Study

PubMed Central

Xu, Haiyan; Gopal, Srihari; Nuamah, Isaac; Ravenstijn, Paulien; Janik, Adam; Schotte, Alain; Hough, David; Fleischhacker, Wolfgang W.

2016-01-01

Background: This double-blind, parallel-group, multicenter, phase-3 study was designed to test the noninferiority of paliperidone palmitate 3-month formulation (PP3M) to the currently marketed 1-month formulation (PP1M) in patients (age 18–70 years) with schizophrenia, previously stabilized on PP1M. Methods: After screening (≤3 weeks) and a 17-week, flexible-dosed, open-label phase (PP1M: day 1 [150mg eq. deltoid], day 8 [100mg eq. deltoid.], weeks 5, 9, and 13 [50, 75, 100, or 150mg eq., deltoid/gluteal]), clinically stable patients were randomized (1:1) to PP3M (fixed-dose, 175, 263, 350, or 525mg eq. deltoid/gluteal) or PP1M (fixed-dose, 50, 75, 100, or 150mg eq. deltoid/gluteal) for a 48-week double-blind phase. Results: Overall, 1016/1429 open-label patients entered the double-blind phase (PP3M: n=504; PP1M: n=512) and 842 completed it (including patients with relapse). PP3M was noninferior to PP1M: relapse rates were similar in both groups (PP3M: n=37, 8%; PP1M: n=45, 9%; difference in relapse-free rate: 1.2% [95% CI:-2.7%; 5.1%]) based on Kaplan-Meier estimates (primary efficacy). Secondary endpoint results (changes from double-blind baseline in positive and negative symptom score total and subscale scores, Clinical Global Impression-Severity, and Personal and Social Performance scores) were consistent with primary endpoint results. No clinically relevant differences were observed in pharmacokinetic exposures between PP3M and PP1M. Both groups had similar tolerability profiles; increased weight was the most common treatment-emergent adverse event (double-blind phase; 21% each). No new safety signals were detected. Conclusion: Taken together, PP3M with its 3-month dosing interval is a unique option for relapse prevention in schizophrenia. PMID:26902950

Comparison of the Efficacy and Safety of Aripiprazole Versus Bupropion Augmentation in Patients With Major Depressive Disorder Unresponsive to Selective Serotonin Reuptake Inhibitors: A Randomized, Prospective, Open-Label Study.

PubMed

Cheon, Eun-Jin; Lee, Kwang-Hun; Park, Young-Woo; Lee, Jong-Hun; Koo, Bon-Hoon; Lee, Seung-Jae; Sung, Hyung-Mo

2017-04-01

The purpose of this study was to compare the efficacy and safety of aripiprazole versus bupropion augmentation in patients with major depressive disorder (MDD) unresponsive to selective serotonin reuptake inhibitors (SSRIs). This is the first randomized, prospective, open-label, direct comparison study between aripiprazole and bupropion augmentation. Participants had at least moderately severe depressive symptoms after 4 weeks or more of SSRI treatment. A total of 103 patients were randomized to either aripiprazole (n = 56) or bupropion (n = 47) augmentation for 6 weeks. Concomitant use of psychotropic agents was prohibited. Montgomery Asberg Depression Rating Scale, 17-item Hamilton Depression Rating scale, Iowa Fatigue Scale, Drug-Induced Extrapyramidal Symptoms Scale, Psychotropic-Related Sexual Dysfunction Questionnaire scores were obtained at baseline and after 1, 2, 4, and 6 weeks of treatment. Overall, both treatments significantly improved depressive symptoms without causing serious adverse events. There were no significant differences in the Montgomery Asberg Depression Rating Scale, 17-item Hamilton Depression Rating scale, and Iowa Fatigue Scale scores, and response rates. However, significant differences in remission rates between the 2 groups were evident at week 6 (55.4% vs 34.0%, respectively; P = 0.031), favoring aripiprazole over bupropion. There were no significant differences in adverse sexual events, extrapyramidal symptoms, or akathisia between the 2 groups. The present study suggests that aripiprazole augmentation is at least comparable to bupropion augmentation in combination with SSRI in terms of efficacy and tolerability in patients with MDD. Both aripiprazole and bupropion could help reduce sexual dysfunction and fatigue in patients with MDD. Aripiprazole and bupropion may offer effective and safe augmentation strategies in patients with MDD who are unresponsive to SSRIs. Double-blinded trials are warranted to confirm the present findings.

An open-label, multicenter, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in Chinese men naïve to phosphodiesterase 5 inhibitor therapy

PubMed Central

Bai, Wen-Jun; Li, Hong-Jun; Dai, Yu-Tian; He, Xue-You; Huang, Yi-Ran; Liu, Ji-Hong; Sorsaburu, Sebastian; Ji, Chen; Jin, Jian-Jun; Wang, Xiao-Feng

2015-01-01

The study was to compare treatment preference, efficacy, and tolerability of sildenafil citrate (sildenafil) and tadalafil for treating erectile dysfunction (ED) in Chinese men naïve to phosphodiesterase 5 (PDE5) inhibitor therapies. This multicenter, randomized, open-label, crossover study evaluated whether Chinese men with ED preferred 20-mg tadalafil or 100-mg sildenafil. After a 4 weeks baseline assessment, 383 eligible patients were randomized to sequential 20-mg tadalafil per 100-mg sildenafil or vice versa for 8 weeks respectively and then chose which treatment they preferred to take during the 8 weeks extension. Primary efficacy was measured by Question 1 of the PDE5 Inhibitor Treatment Preference Questionnaire (PITPQ). Secondary efficacy was analyzed by PITPQ Question 2, the International Index of Erectile Function (IIEF) erectile function (EF) domain, sexual encounter profile (SEP) Questions 2 and 3, and the Drug Attributes Questionnaire. Three hundred and fifty men (91%) completed the randomized treatment phase. Two hundred and forty-two per 350 (69.1%) patients preferred 20-mg tadalafil, and 108/350 (30.9%) preferred 100-mg sildenafil (P < 0.001) as their treatment in the 8 weeks extension. Ninety-two per 242 (38%) patients strongly preferred tadalafil and 37/108 (34.3%) strongly the preferred sildenafil. The SEP2 (penetration), SEP3 (successful intercourse), and IIEF-EF domain scores were improved in both tadalafil and sildenafil treatment groups. For patients who preferred tadalafil, getting an erection long after taking the medication was the most reported reason for tadalafil preference. The only treatment-emergent adverse event reported by > 2% of men was headache. After tadalafil and sildenafil treatments, more Chinese men with ED naïve to PDE5 inhibitor preferred tadalafil. Both sildenafil and tadalafil treatments were effective and safe. PMID:25370206

Patiromer Lowers Serum Potassium When Taken without Food: Comparison to Dosing with Food from an Open-Label, Randomized, Parallel Group Hyperkalemia Study.

PubMed

Pergola, Pablo E; Spiegel, David M; Warren, Suzette; Yuan, Jinwei; Weir, Matthew R

2017-01-01

Patiromer is a sodium-free, nonabsorbed, potassium binder approved for treatment of hyperkalemia. This open-label study compares the efficacy and safety of patiromer administered without food versus with food. Adults with hyperkalemia (potassium ≥5.0 mEq/L) were randomized (1:1) to receive patiromer once daily without food or with food for 4 weeks. The dosage was adjusted (maximum: 25.2 g/day) using a prespecified titration schedule to achieve and maintain potassium within a target range (3.8-5.0 mEq/L). The primary efficacy endpoint was the proportion of patients with serum potassium in the target range at either week 3 or week 4. Safety was assessed by adverse events (AEs) and laboratory testing. Efficacy was evaluated in 112 patients; 65.2% were ≥65 years of age, 75.9% had chronic kidney disease, and 82.1% had diabetes. Baseline mean serum potassium was similar in the without-food (5.44 mEq/L) and with-food (5.34 mEq/L) groups. The primary endpoint was achieved by 87.3% (95% CI 75.5-94.7) and 82.5% (95% CI 70.1-91.3) of patients in the with-food and without-food groups, respectively; least squares mean changes in serum potassium from baseline to week 4 were -0.65 and -0.62 mEq/L, respectively (p < 0.0001). The most common AEs were diarrhea and constipation. Serum K+ remained ≥3.5 mEq/L in all patients; 5 patients developed serum magnesium <1.4 mg/dL, including 4 whose baseline magnesium was below the lower limit of normal. Patiromer is equally effective and well tolerated when taken without food or with food, thereby offering the potential for dosing flexibility. © 2017 The Author(s) Published by S. Karger AG, Basel.

Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome.

PubMed

Kulke, Matthew H; Hörsch, Dieter; Caplin, Martyn E; Anthony, Lowell B; Bergsland, Emily; Öberg, Kjell; Welin, Staffan; Warner, Richard R P; Lombard-Bohas, Catherine; Kunz, Pamela L; Grande, Enrique; Valle, Juan W; Fleming, Douglas; Lapuerta, Pablo; Banks, Phillip; Jackson, Shanna; Zambrowicz, Brian; Sands, Arthur T; Pavel, Marianne

2017-01-01

Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1:1:1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were -0.81 for telotristat ethyl 250 mg ( P < .001) and ‒0.69 for telotristat ethyl 500 mg ( P < .001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were -0.9, -1.7, and -2.1, respectively. Responses, predefined as a BM frequency reduction ≥ 30% from baseline for ≥ 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 ( P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.

Maraviroc Intensification Improves Endothelial Function in Abacavir-Treated Patients, an Open-Label Randomized Cross-Over Pilot Study.

PubMed

Krikke, Maaike; Tesselaar, Kiki; Arends, Joop E; Drylewicz, Julia; Otto, Sigrid A; van Lelyveld, Steven F L; Visseren, Frank J L; Hoepelman, Andy I M

2016-09-01

The increased risk of abacavir in cardiovascular disease (CVD) in HIV-infected patients is still being debated. Maraviroc, a CCR5 blocker, has been shown to decrease immune activation and monocyte infiltration in atherosclerotic plaques in murine experiments. Therefore, we examined the effect of maraviroc intensification on flow-mediated dilatation (FMD) in abacavir-treated HIV-infected patients and its effect on immunological and inflammatory parameters. A open-label prospective crossover study with a duration of 16 weeks: 8 weeks of intervention (maraviroc intensification) and 8 weeks of control (unchanged cART regimen). FMD, HIV-specific variables, expression of HIV co-receptors, markers of inflammation and coagulation and cellular markers of immune activation were measured at weeks 0, 8 and 16. The changes (Δ) in these variables were compared between intervention and control periods using non-parametric tests. To evaluate the relation with the change in FMD, linear regression modeling was used. Twenty-one male patients with suppressed plasma HIV-RNA, on cART, had a known HIV infection for 9.2 years (IQR 6.9-13.5) with abacavir use for 6.5 years (2.8-9.3). A significantly increased FMD of 0.73% (IQR -0.25 to 1.70) was seen after maraviroc intensification compared to a decrease of -0.42% (IQR -1.89 to 0.25; p = 0.049) in the control period. There was a negative relation between ΔFMD with ΔD-dimer (β -22.70, 95% CI -39.27; -6.13, p = 0.011) and ΔCD95+ CD4+ T cells (β -0.16, 95% CI -0.28; -0.04, p = 0.013), adjusted for age and duration of HIV. Maraviroc intensification modestly improves endothelial function in HIV-infected patients on an abacavir-containing regimen. NCT01389063.

An open-label, multicenter, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in Chinese men naïve to phosphodiesterase 5 inhibitor therapy.

PubMed

Bai, Wen-Jun; Li, Hong-Jun; Dai, Yu-Tian; He, Xue-You; Huang, Yi-Ran; Liu, Ji-Hong; Sorsaburu, Sebastian; Ji, Chen; Jin, Jian-Jun; Wang, Xiao-Feng

2015-01-01

The study was to compare treatment preference, efficacy, and tolerability of sildenafil citrate (sildenafil) and tadalafil for treating erectile dysfunction (ED) in Chinese men naοve to phosphodiesterase 5 (PDE5) inhibitor therapies. This multicenter, randomized, open-label, crossover study evaluated whether Chinese men with ED preferred 20-mg tadalafil or 100-mg sildenafil. After a 4 weeks baseline assessment, 383 eligible patients were randomized to sequential 20-mg tadalafil per 100-mg sildenafil or vice versa for 8 weeks respectively and then chose which treatment they preferred to take during the 8 weeks extension. Primary efficacy was measured by Question 1 of the PDE5 Inhibitor Treatment Preference Questionnaire (PITPQ). Secondary efficacy was analyzed by PITPQ Question 2, the International Index of Erectile Function (IIEF) erectile function (EF) domain, sexual encounter profile (SEP) Questions 2 and 3, and the Drug Attributes Questionnaire. Three hundred and fifty men (91%) completed the randomized treatment phase. Two hundred and forty-two per 350 (69.1%) patients preferred 20-mg tadalafil, and 108/350 (30.9%) preferred 100-mg sildenafil (P < 0.001) as their treatment in the 8 weeks extension. Ninety-two per 242 (38%) patients strongly preferred tadalafil and 37/108 (34.3%) strongly the preferred sildenafil. The SEP2 (penetration), SEP3 (successful intercourse), and IIEF-EF domain scores were improved in both tadalafil and sildenafil treatment groups. For patients who preferred tadalafil, getting an erection long after taking the medication was the most reported reason for tadalafil preference. The only treatment-emergent adverse event reported by > 2% of men was headache. After tadalafil and sildenafil treatments, more Chinese men with ED naοve to PDE5 inhibitor preferred tadalafil. Both sildenafil and tadalafil treatments were effective and safe.

A pilot, open-label, 8-week study evaluating the efficacy, safety and tolerability of adjunctive minocycline for the treatment of bipolar I/II depression.

PubMed

Soczynska, Joanna K; Kennedy, Sidney H; Alsuwaidan, Mohammad; Mansur, Rodrigo B; Li, Madeline; McAndrews, Mary Pat; Brietzke, Elisa; Woldeyohannes, Hanna O; Taylor, Valerie H; McIntyre, Roger S

2017-05-01

The objectives of the study were to determine if adjunctive minocycline mitigates depressive symptom severity and improves cognitive function in individuals with bipolar I/II disorder (BD). The study also aimed to determine if changes in depressive and/or cognitive symptoms over the course of treatment were associated with changes in circulating inflammatory cytokine levels. A total of 29 (intention-to-treat: n=27) adults meeting DSM-IV-TR criteria for a major depressive episode as part of bipolar I or II disorder (i.e. Hamilton Depression Rating Scale 17-item [HAMD-17] ≥20) were enrolled in an 8-week, open-label study with adjunctive minocycline (100 mg bid). The primary outcome measure was the Montgomery-Åsberg Depression Rating Scale (MADRS). The HAMD-17, Clinical Global Impression-Severity (CGI-S), cognitive test composite scores and plasma cytokines were secondary outcome measures. Plasma cytokines were measured with the 30 V-Plex Immunoassay from Meso Scale Discovery. Adjunctive minocycline was associated with a reduction in depressive symptom severity from baseline to week 8 on the MADRS (P<.001, d=0.835), HAMD-17 (P<.001, d=0.949) and CGI-S (P<.001, d=1.09). Improvement in psychomotor speed, but not verbal memory or executive function, was observed only amongst individuals exhibiting a reduction in depression severity (P=.007, d=0.826). Levels of interleukin (IL)-12/23p40 (P=.002) were increased, while levels of IL-12p70 (P=.001) and C-C motif chemokine ligand 26 (CCL26) (P<.001) were reduced from baseline to week 8. A reduction in CCL26 levels was associated with a less favourable treatment response (P<.001). Results from the pilot study suggest that adjunctive minocycline may exert antidepressant effects in individuals with bipolar depression, possibly by targeting inflammatory cytokines. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Evaluation of Quality of Life, Functioning, Disability, and Work/School Productivity Following Treatment with an Extended-Release Hydrocodone Tablet Formulated with Abuse-Deterrence Technology: A 12-month Open-label Study in Patients with Chronic Pain.

PubMed

Hale, Martin E; Zimmerman, Thomas R; Ma, Yuju; Malamut, Richard

2017-02-01

This phase 3 study evaluated quality of life, functioning, and productivity after treatment with extended-release (ER) hydrocodone formulated with CIMA ® Abuse-Deterrence Technology platform. Patients with chronic pain were rolled over from a 12-week placebo-controlled hydrocodone ER study or were newly enrolled. Hydrocodone ER doses were titrated (15 to 90 mg every 12 hours) to an analgesic dose, and patients received up to 52 weeks of open-label treatment. Assessments included Clinician Assessment of Patient Function (CAPF), Patient Assessment of Function (PAF), Brief Pain Inventory-Short Form (BPI-SF), 36-item Short-Form Health Survey (SF-36), Sheehan Disability Scale (SDS), and World Health Organization Health and Work Performance Questionnaire-Short Form (HPQ-SF). Of 330 enrolled patients, 291 composed the full analysis population. By week 4, ≥ 50% of patients showed improvement from baseline in all 5 CAPF domains (general activities, walking, work/daily living, relationships, and enjoyment of life) and 6 of 7 PAF domains (work attendance, work performance, walking, exercise, socializing, and enjoying life). Mean decreases from baseline of 2 to 3 points were noted for BPI-SF pain interference questions from week 4 through endpoint. Mean improvements from baseline to endpoint in SF-36 subscales ranged from 3.3 to 22.3, and SDS scores improved from moderate (4.8 to 5.1) to mild (2.5 to 2.8) disruptions in work/school, social life, and family life. At endpoint, mean HPQ-SF absolute absenteeism scores decreased from 13.6 to 10.0 hours lost/month and absolute presenteeism scores improved from 67.0 to 77.1. Patients receiving hydrocodone ER showed early numeric improvements in functioning that continued throughout this 12-month study. © 2016 World Institute of Pain.

Safety, immunogenicity, and clinical outcomes in patients with Morquio A syndrome participating in 2 sequential open-label studies of elosulfase alfa enzyme replacement therapy (MOR-002/MOR-100), representing 5 years of treatment.

PubMed

Hendriksz, Christian; Santra, Saikat; Jones, Simon A; Geberhiwot, Tarekegn; Jesaitis, Lynne; Long, Brian; Qi, Yulan; Hawley, Sara M; Decker, Celeste

2018-04-01

Elosulfase alfa is an enzyme replacement therapy for Morquio A syndrome (mucopolysaccharidosis IVA), a multisystemic progressive lysosomal storage disorder. This report includes the primary treatment outcomes and immunogenicity profile of elosulfase alfa in patients with Morquio A syndrome from 2 sequential studies, MOR-002 (ClinicalTrials.govNCT00884949) and MOR-100 (NCT01242111), representing >5 years of clinical study data. MOR-002 was an open-label, single-arm phase 1/2 study that evaluated the pharmacokinetics, safety, immunogenicity, and preliminary efficacy of 3 sequential doses of elosulfase alfa (0.1, 1.0, and 2.0 mg/kg/week) in patients with Morquio A syndrome (n = 20) over 36 weeks, followed by an optional 36- to 48-week treatment period using elosulfase alfa 1.0 mg/kg once weekly (qw). During the 0.1 mg/kg dosing phase, 1 patient discontinued due to a type I hypersensitivity adverse event (AE), and that patient's sibling voluntarily discontinued in the absence of AEs. An additional patient discontinued due to recurrent infusion reactions during the 1.0 mg/kg continuation phase. The remaining 17 patients completed MOR-002 and enrolled in MOR-100, an open-label, long-term extension study that further evaluated safety and clinical outcomes with elosulfase alfa administered at 2.0 mg/kg qw. During the course of MOR-100, patients were given the option of receiving elosulfase alfa infusions at home with nursing assistance. Over the course of both studies, all patients experienced ≥1 AE and most patients experienced a drug-related AE, generally of mild or moderate severity. Hypersensitivity reactions reported as related to study drug occurred in 25% of patients. Thirteen patients who chose to receive infusions at home had the same tolerability and safety profile, as well as comparable compliance rates, as patients who chose to receive on-site infusions. All patients developed antibodies to elosulfase alfa. Positivity for neutralizing antibodies was associated with increased drug half-life and decreased drug clearance. Despite formation of antidrug-binding (total antidrug antibodies, TAb) and in vitro neutralizing antibodies (NAb) in all patients, these types of immunogenicity to elosulfase alfa were not correlated with safety or clinical outcomes. In contrast with the reported natural history of Morquio A, no trends toward decreasing endurance, respiratory function, or ability to perform activities of daily living were observed in this cohort over the 5-year period. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Open-label extension studies: do they provide meaningful information on the safety of new drugs?

PubMed

Day, Richard O; Williams, Kenneth M

2007-01-01

The number of open-label extension studies being performed has increased enormously in recent years. Often it is difficult to differentiate between these extension studies and the double-blind, controlled studies that preceded them. If undertaken primarily to gather more patient-years of exposure to the new drug in order to understand and gain confidence in its safety profile, open-label extension studies can play a useful and legitimate role in drug development and therapeutics. However, this can only occur if the open-label extension study is designed, executed, analysed and reported competently. Most of the value accrued in open-label extension studies is gained from a refinement in the perception of the expected incidence of adverse effects that have most likely already been identified as part of the preclinical and clinical trial programme. We still have to rely heavily on post-marketing safety surveillance systems to alert us to type B (unpredictable) adverse reactions because open-label extension studies are unlikely to provide useful information about these types of often serious and relatively rare adverse reactions. Random allocation into test and control groups is needed to produce precise incidence data on pharmacologically expected, or type A, adverse effects. Some increased confidence about incidence rates might result from the open-label extension study; however, as these studies are essentially uncontrolled and biased, the data are not of great value. Other benefits have been proposed to be gained from open-label extension studies. These include ongoing access to an effective but otherwise unobtainable medicine by the volunteers who participated in the phase III pivotal trials. However, there are unappreciated ethical issues about the appropriateness of enrolling patients whose response to previous treatment is uncertain, largely because treatment allocation in the preceding randomised, double-blind, controlled trial has not been revealed at the time of entry into the open-label extension study. Negative aspects of open-label extension studies revolve around their use as a marketing tool, as they build a market for the drug and generate pressure for subsidised access to the drug from consumers and their physicians. Consumers, institutions where these studies are conducted and research ethics committees need to be convinced of the motives, as well as the quality, of the open-label extension study and its execution before supporting such studies. Open-label extension studies do have a legitimate but limited place in the clinical development of new medicines. The negative perceptions about these studies have arisen because of perversion of acceptable rationales for this type of study and a failure to recognise (or disclose) the limitations resulting from the inherent weaknesses in their design. Increased human exposure to a new medicine under reasonably controlled circumstances to increase confidence in the safety of the medicine is an acceptable rationale for an open-label extension study, and a useful activity to increase the knowledge of the safety profile of a new medicine. However, this goal is increasingly being achieved by means other than open-label extension studies.

Efficacy and safety of once-daily, extended-release hydrocodone in individuals previously receiving hydrocodone/acetaminophen combination therapy for chronic pain.

PubMed

Bartoli, Adrian; Michna, Edward; He, Ellie; Wen, Warren

2015-01-01

Hydrocodone/acetaminophen combination analgesics are frequently prescribed for chronic pain management; however, acetaminophen presents potential hepatotoxicity to patients and thus dose limitations. These opioid medications are also widely abused. Once-daily, single-entity hydrocodone (Hysingla™ ER tablets [HYD]) is a novel formulation with abuse-deterrent properties for the management of chronic pain and represents a suitable option for those patients receiving analgesics containing the same opioid analgesic, hydrocodone. This post-hoc analysis evaluated the efficacy and safety of HYD in patients whose primary pre-study analgesic was hydrocodone/acetaminophen analgesics (23-31% of the study populations). Data were analyzed from two Phase III trials, a 12-week randomized, placebo-controlled trial (RCT) and an open-label, 52-week trial. In both trials, a dose-titration period with HYD was followed by respective periods of fixed-dose double-blind (randomized controlled trial [RCT]) or open-label, flexible-dose maintenance treatment. Pain intensity was assessed using a numerical rating scale (0-10, 0 = no pain). For the RCT, primary and sensitivity analyses of pain scores used different approaches to handle missing data. Safety data for both studies were summarized. In the RCT, the mean baseline pain score was 7.3. Pain relief was greater with HYD than placebo during double-blind treatment. In the open-label, flexible-dose trial, the majority of patients were maintained on their titrated dose. Mean baseline pain score was 6.3, about 57% of patients completed the 1-year maintenance period, and mean pain scores were between 3.6 and 4.1 during the maintenance period. Use of supplemental pain medication decreased or was maintained during the maintenance treatment with HYD. Adverse events in both trials were typical of those associated with opioid analgesics. In patients whose primary pretrial analgesic was hydrocodone/acetaminophen combination tablets, single-entity HYD was effective in reducing pain intensity and in maintaining analgesia over time without need for continued dose increase. HYD's safety and tolerability profiles were similar to other opioid analgesics.

Quality of Life in Childhood Epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol.

PubMed

Rosenberg, Evan C; Louik, Jay; Conway, Erin; Devinsky, Orrin; Friedman, Daniel

2017-08-01

Recent clinical trials indicate that cannabidiol (CBD) may reduce seizure frequency in pediatric patients with certain forms of treatment-resistant epilepsy. Many of these patients experience significant impairments in quality of life (QOL) in physical, mental, and social dimensions of health. In this study, we measured the caregiver-reported Quality of Life in Childhood Epilepsy (QOLCE) in a subset of patients enrolled in a prospective, open-label clinical study of CBD. Results from caregivers of 48 patients indicated an 8.2 ± 9.9-point improvement in overall patient QOLCE (p < 0.001) following 12 weeks of CBD. Subscores with improvement included energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behavior, and global QOL. These differences were not correlated to changes in seizure frequency or adverse events. The results suggest that CBD may have beneficial effects on patient QOL, distinct from its seizure-reducing effects; however, further studies in placebo-controlled, double-blind trials are necessary to confirm this finding. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Effectiveness and Safety of Donepezil in Hispanic Patients with Alzheimer’s Disease: A 12-Week Open-Label Study

PubMed Central

Lopez, Oscar L.; Mackell, Joan A.; Sun, Yijun; Kassalow, Laurent M.; Xu, Yikang; McRae, Thomas; Li, Honglan

2009-01-01

Background Hispanics represent 10% of the U.S. population and are the fastest growing group. Studies show a higher prevalence and incidence of Alzheimer’s disease (AD) in Hispanics than in the non-Hispanic white population, with an earlier age of onset. Among the currently estimated 200,000 Hispanics with AD, a significant number remain undiagnosed and untreated, and Hispanic participation in AD clinical trials has been historically low. This study evaluated the efficacy and safety of donepezil hydrochloride (donepezil) in Hispanics with mild-to-moderate AD. Methods In this multicenter, open-label, 12-week study conducted in the United States, subjects were Hispanic men or women aged ≥50 years with a diagnosis of mild-to-moderate AD (DSMV-IV and NINCDS/ADRDA criteria), with Mini-Mental State Examination (MMSE) scores of 10–26 (inclusive) at screening. Subjects were treated with donepezil 5 mg/day for 6 weeks followed by 10 mg/day for 6 weeks. Clinical evaluation was performed at baseline, week 6 and week 12. Cognitive improvement was measured using the MMSE, Fuld Object Memory Evaluation (FOME) and Symbol Digit Modality Test (SDMT). Behavioral symptoms and associated caregiver distress were assessed with the Neuropsychiatric Inventory (NPI). Results One-hundred-six patients with mild-to-moderate AD (mean age 68.6 years) were enrolled (intent to treat, n=97); most chose to have assessments conducted in Spanish. With 12 weeks of treatment, subjects showed statistically significant improvement from baseline on MMSE (P<0.0001), FOME retrieval (P=0.0042), FOME repeated retrieval (P=0.0020) and SDMT correct scores (P<0.0001). The NPI subdomain “apathy/indifference” showed statistically significant improvement (P=0.0010). The NPI Caregiver Distress scale (NPI-D) total score was statistically significantly improved (P=0.0500), suggesting a positive impact on relieving caregivers’ burden associated with patient behavior. Most patients tolerated the treatment well, with only 2 discontinuing because of adverse events. The most common (>5%) adverse events were insomnia (9.5%), dizziness (7.6%), diarrhea (5.7%) and nausea (5.7%). Conclusion The cognitive improvement and safety results from this study were consistent with those reported for donepezil in the general population. Increased awareness of AD in the Hispanic population will help more Hispanics with AD to benefit from early diagnosis and effective treatment. PMID:19024233

Safety and tolerability of vortioxetine (15 and 20 mg) in patients with major depressive disorder: results of an open-label, flexible-dose, 52-week extension study

PubMed Central

Jacobsen, Paula L.; Harper, Linda; Chrones, Lambros; Chan, Serena

2015-01-01

Vortioxetine is approved for the treatment of adults with major depressive disorder. This open-label extension (OLE) study evaluated the safety and tolerability of vortioxetine in the long-term treatment of major depressive disorder patients, as well as evaluated its effectiveness using measures of depression, anxiety, and overall functioning. This was a 52-week, flexible-dose, OLE study in patients who completed one of three randomized, double-blind, placebo-controlled, 8-week vortioxetine trials. All patients were switched to 10 mg/day vortioxetine for week 1, then adjusted between 15 and 20 mg for the remainder of the study, but not downtitrated below 15 mg. Safety and tolerability were assessed on the basis of treatment-emergent adverse events (TEAEs), vital signs, laboratory values, physical examination, and the Columbia-Suicide Severity Rating Scale. Efficacy measures included the Montgomery–Åsberg Depression Rating Scale, the Hamilton Anxiety Scale, the Clinical Global Impression Scale-Severity of Illness, and the Sheehan Disability Scale. Of the 1075 patients enrolled, 1073 received at least one dose of vortioxetine and 538 (50.0%) completed the study. A total of 537 patients withdrew early, with 115 (10.7% of the original study population) withdrawing because of TEAEs. Long-term treatment with vortioxetine was well tolerated; the most common TEAEs (≥10%) were nausea and headache. Laboratory values, vital signs, and physical examinations revealed no trends of clinical concern. The mean Montgomery–Åsberg Depression Rating Scale total score was 19.9 at the start of the extension study and 9.0 after 52 weeks of treatment (observed cases). Similar improvements were observed with the Hamilton Anxiety Scale (Δ−4.2), the Clinical Global Impression Scale-Severity of Illness (Δ−1.2), and the Sheehan Disability Scale (Δ−4.7) total scores after 52 weeks of treatment (observed case). In this 52-week, flexible-dose OLE study, 15 and 20 mg vortioxetine were safe and well tolerated. After entry into this study, patients continued to show improvement in depression and anxiety symptoms, as well as overall functioning, throughout the treatment period. PMID:26020712

Effects of varenicline therapy in combination with advanced behavioral support on smoking cessation and quality of life in inpatients with acute exacerbation of COPD, bronchial asthma, or community-acquired pneumonia: A prospective, open-label, preference-based, 52-week, follow-up trial.

PubMed

Politis, Alexios; Ioannidis, Vasileios; Gourgoulianis, Konstantinos I; Daniil, Zoe; Hatzoglou, Chrissi

2018-05-01

Quitting smoking is the most important element in the therapeutic management of chronic respiratory diseases. Combining pharmacotherapy with behavioral support increases smoking cessation success rates. In addition, hospitalized smokers have increased motivation to quit. We investigated the efficacy on smoking cessation, of varenicline in combination with behavioral support, in smokers hospitalized due to (a) acute exacerbation of chronic obstructive pulmonary disease (COPD), or (b) bronchial asthma attack, or (c) community-acquired pneumonia (CAP). The method used is prospective, open-label, preference-based, parallel group, 52-week trial. Patients chose the smoking cessation intervention they preferred: a standard regimen of varenicline combined with post-discharge advanced behavioral support (group A) or one private consultation session during hospitalization (group B). Follow-up phone calls were scheduled in weeks 1, 2, and 4 and months 3, 6, and 9. The final hospital visit was performed in week 52. Primary outcome was success rate defined as the percentage (%) of smoking abstinence at week 52 and secondary outcomes were (a) changes in quality of life (QoL) indicated by the scores on the Short Form 36 (SF36) questionnaire and (b) predictors of smoking abstinence investigated with multiple binary logistic regression. One hundred one patients were enrolled, 44 (43.6%) in group A and 57 (56.4%) in group B. Respective abstinence rates were 54.5% and 15.8% at week 12 and 52.3% and 14.0% at week 52. Scores on SF36 were statistically significantly increased in both groups. Predictors of smoking abstinence were varenicline (odds ratio (OR) 7.29; 95% confidence interval (CI) 2.15, 24.77; p = 0.001), age (OR 1.07; 95%CI 1.00, 1.15; p = 0.042), Fagerstrom score (OR 0.37; 95%CI 0.20, 0.68; p = 0.001), SF36 domains "vitality" (OR 1.12; 95%CI 1.04, 1.21; p = 0.003), and "social functioning" (OR 0.95; 95%CI 0.90, 1.00; p = 0.041). Varenicline in combination with behavioral support resulted in high abstinence rates inpatients hospitalized for exacerbation of COPD, asthma attack, or CAP, and improved QoL.

Optimization of Methylphenidate Extended-Release Chewable Tablet Dose in Children with ADHD: Open-Label Dose Optimization in a Laboratory Classroom Study.

PubMed

Wigal, Sharon B; Childress, Ann; Berry, Sally A; Belden, Heidi W; Chappell, Phillip; Wajsbrot, Dalia B; Nagraj, Praneeta; Abbas, Richat; Palumbo, Donna

2018-06-01

To examine methylphenidate extended-release chewable tablets (MPH ERCT) dose patterns, attention-deficit/hyperactivity disorder (ADHD) symptom scores, and safety during the 6-week, open-label (OL) dose-optimization period of a phase 3, laboratory classroom study. Boys and girls (6-12 years) diagnosed with ADHD were enrolled. MPH ERCT was initiated at 20 mg/day; participants were titrated in 10-20 mg/day increments weekly based on efficacy and tolerability (maximum dose, 60 mg/day). Dose-optimization period efficacy assessments included the ADHD Rating Scale (ADHD-RS-IV), analyzed by week in a post hoc analysis using a mixed-effects model for repeated measures with final optimized dose (20, 30/40, or 50/60 mg), visit, final optimized dose and visit interaction, and baseline score as terms. Adverse events (AEs) and concomitant medications were collected throughout the study. Mean MPH ERCT daily dose increased weekly from 29.4 mg/day after the first dose adjustment at week 1 (n = 90) to 42.8 mg/day after the final adjustment at week 5 (n = 86). Final optimized MPH ERCT dose ranged from 20 to 60 mg/day. Mean final optimized MPH ERCT dose ranged from 40.0 mg/day in 6-8 year-old participants to 44.8 mg/day for 11-12 year-old participants. There was a progressive decrease in mean (standard deviation) ADHD-RS-IV total score from 40.1 (8.72) at baseline to 12.4 (7.88) at OL week 5, with similar improvement patterns for hyperactivity/impulsivity and inattentiveness subscale scores. Participants optimized to MPH ERCT 50/60 mg/day had a significantly higher mean (standard error) ADHD-RS-IV score at baseline compared with participants optimized to MPH ERCT 20 mg/day (42.4 [1.34] vs. 35.1 [2.55]; p = 0.013). Treatment-emergent AEs were reported by 65/90 (72.2%) participants in the dose-optimization period. Dose-optimization period results describing relationships between change in ADHD symptom scores and final optimized MPH ERCT dose will be valuable for clinicians optimizing MPH ERCT dose.

An observational study of bimatoprost 0.01% in treatment-naïve patients with primary open angle glaucoma or ocular hypertension: the CLEAR trial

PubMed Central

Nixon, Donald R; Simonyi, Susan; Bhogal, Meetu; Sigouin, Christopher S; Crichton, Andrew C; Discepola, Marino; Hutnik, Cindy ML; Yan, David B

2012-01-01

Background This study was designed to evaluate the occurrence and severity of ocular hyperemia in subjects with elevated intraocular pressure (IOP) due to primary open angle glaucoma (POAG) or ocular hypertension (OHT) following treatment with bimatoprost 0.01% in a real-world clinical setting. Methods This was an open-label, observational study conducted at 67 centers in Canada. Subjects with elevated IOP due to POAG or OHT instilled bimatoprost 0.01% topically as monotherapy once daily. Ocular hyperemia was graded by the investigator at baseline and weeks 6 and 12 using a photographic five-point grading scale. Change in IOP from baseline was also evaluated at these time points. This analysis includes only the subgroup of 522 subjects who were naïve to IOP-lowering medication prior to the study. Results After 12 weeks of treatment with bimatoprost 0.01%, hyperemia was graded as none-to-mild (grades 0, +0.5, or +1) for 93.3% of subjects and as moderate-to-severe (grades +2 or +3) for 6.7%. At weeks 6 and 12, most subjects (93.2% and 93.5%) had no change in hyperemia grade from baseline. IOP was reduced by 7.4 mmHg (29.8%) at week 6 and 7.7 mmHg (30.9%) at week 12 from baseline. Conclusion This real-world, observational study found that bimatoprost 0.01% instilled once daily reduced IOP by a mean of 30% from baseline without moderate or severe ocular hyperemia in 93% of treatment-naïve subjects with POAG or OHT. PMID:23269858

Efficacy and Tolerability of Travoprost 0.004%/Timolol 0.5% Fixed-Dose Combination for the Treatment of Primary Open-Angle Glaucoma or Ocular Hypertension Inadequately Controlled with Beta-Blocker Monotherapy.

PubMed

Lerner, Simon Fabian; Park, Ki Ho; Hubatsch, Douglas A; Erichev, Valeriy; Paczka, Jose A; Roberts, Timothy V

2017-01-01

Objective . To evaluate the efficacy and tolerability of travoprost 0.004%/timolol 0.5% fixed-dose combination (TTFC) in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT) inadequately controlled on beta-blocker monotherapy. Methods . In this phase IV, open-label study, 156 patients on beta-blocker monotherapy with mean intraocular pressure (IOP) between 18 and 32 mmHg were randomized (no washout period) to receive TTFC for 8 weeks (TTFC group) or to continue beta-blocker monotherapy for 4 weeks followed by TTFC for the remaining 4 weeks (beta-blocker group). Results . The mean IOP (±standard deviation) at baseline in the TTFC and beta-blocker groups was 22.5 ± 2.5 mmHg and 22.2 ± 2.3 mmHg, respectively, and at weeks 4 and 8, was 16.7 ± 3.1 mmHg and 16.1 ± 3.1 mmHg, respectively, in TTFC group and 21.1 ± 3.1 mmHg and 16.1 ± 2.8 mmHg, respectively, in the beta-blocker group. There was a significant least squares mean difference between TTFC and beta-blocker in 8 a.m. IOP at week 4 (-4.6 mmHg; one-sided 95% confidence interval [-inf, -3.9]; p < 0.0001 [primary endpoint]); the upper bound of the 95% confidence interval was within the prespecified limit (<0). Both treatments were well tolerated. Conclusion . Superior IOP control was achieved with TTFC in patients with OAG or OHT previously uncontrolled with beta-blockers. No new safety findings were identified. This trial is registered with ClinicalTrials.gov NCT02003391.

Safety assessment of 4-week oral intake of proanthocyanidin-rich grape seed extract in healthy subjects.

PubMed

Sano, Atsushi

2017-10-01

A clinical study was conducted to assess the safety and tolerability of oral doses of proanthocyanidin-rich grape seed extract (GSE) in healthy Japanese adult volunteers. In an open-label, 4-week toxicity test, 29 subjects daily received 1000, 1500, or 2500 mg GSE orally. Serum Fe levels of two subjects in the 2500 mg GSE group decreased to 61 and 60 μg/100 mL from 205 and 182 μg/100 mL at baseline respectively, at second week of GSE consumption; these values are low but within the normal range for the Japanese population. Two weeks after completing the 4-week course of GSE ingestion, the serum Fe levels of both subjects returned to near baseline levels (210 and 189 μg/100 mL). No subject discontinued the study. Oral intake of GSE up to 2500 mg for 4 weeks was found to be generally safe and well tolerated in humans. Research with a larger number of subjects is required to confirm these findings. Copyright © 2016. Published by Elsevier Ltd.

Randomized open-label trial of baclofen for relapse prevention in alcohol dependence.

PubMed

Gupta, Manushree; Verma, Pankaj; Rastogi, Rajesh; Arora, Sheetal; Elwadhi, Deeksha

2017-05-01

Alcohol dependence is a progressive chronic disorder characterized by narrowing of the drinking repertoire, salience of drinking, tolerance and withdrawal phenomenon, compulsion to drink, and frequent relapses. Baclofen has been shown to promote abstinence, to reduce craving, and to reduce anxiety in alcohol-dependent individuals, and it promises to be a useful agent, although clinical data are limited at present. The current study aimed to test the utility of baclofen, a GABA agonist, in improving the relapse rates in alcohol-dependent subjects. A total of 122 alcohol-dependent subjects were randomized into two groups. Groups were administered baclofen (30 mg/day) or benfothiamine (a nutritional supplement) using an open label design. Both groups received brief motivational intervention. Subjects were assessed at 0, 2, 4, 8, and 12 weeks for the primary outcome measures: time to first relapse, heavy drinking days, cumulative abstinence duration, and craving (measured by the Obsessive Compulsive Drinking Scale (OCDS)). Seventy-two participants received baclofen, and 50 received benfothiamine. Participants receiving baclofen remained abstinent for significantly more days than the benfothiamine group (p < 0.05). The percentage of heavy drinking days was significantly lower in the baclofen group (p = 0.001). Craving and anxiety scores (Hamilton Anxiety Rating Scale) were also significantly decreased in the baclofen group relative to the control group (p = 0.001). Time to first relapse was similar in both groups. In this open-label trial, alcohol-dependent participants receiving baclofen showed significant improvements in drinking outcomes compared with participants receiving benfothiamine. This study provides further evidence that baclofen is useful for the treatment of alcohol dependence.

Comparison of the latanoprost 0.005%/timolol 0.5% + brinzolamide 1% versus dorzolamide 1%/timolol 0.5% + latanoprost 0.005%: a 12-week, randomized open-label trial

PubMed Central

Nakakura, Shunsuke; Tabuchi, Hitoshi; Baba, Yukio; Maruiwa, Futoshi; Ando, Nobuko; Kanamoto, Takashi; Kiuchi, Yoshiaki

2012-01-01

Objective To compare the safety and effectiveness of fixed-combination regimes (latanoprost– timolol and brinzolamide 1% compared to dorzolamide 1%/timolol and latanoprost) in open-angle glaucoma patients after switching from a combination of three topical antiglaucoma eye drops. Methods We conducted an open, randomized 12-week multicenter prospective study. We randomly allocated 39 patients who had been treated with three antiglaucoma eye drops (prostaglandin F2α analogues plus beta-blockers and carbonic anhydrase inhibitors) into two groups. Group A (n = 20) were treated with latanoprost–timolol and brinzolamide 1% therapy and Group B (n = 16) were treated with dorzolamide 1%/timolol and latanoprost. Thirty-six patients completed all 12 weeks of this study. The major clinical parameters measured were intraocular pressure (IOP), conjunctive hyperemia, superficial punctate keratopathy and hyperpigmentation of eyelid at baseline, 4, and 12 weeks. Additionally noted were adverse events and patient preferences, measured using a questionnaire at study initiation and at 12 weeks. Results At baseline, IOPs were (Group A: 14.1 ± 2.9 mmHg, B: 14.5 ± 2.9 mmHg; P = 0.658), (Group A: 13.8 ± 2.6 mmHg, B: 14.3 ± 2.8 mmHg; P = 0.715) at 4 weeks, and (Group A: 14.1 ± 2.7 mmHg, B: 14.2 ± 2.7 mmHg; P = 0.538) at 12 weeks. Among the groups, there was no significant difference at any time point after baseline (P = 0.923, 0.951, respectively). All adverse events were not remarkably different after therapy. In regards to patient preference before and after switching therapy, 10 patients (50%) in Group A and 10 patients (63%) in Group B preferred using fixed-combination eye drop therapy. Conclusions Effectiveness and safety were maintained in both groups after switching therapy. Overall, patients generally preferred using a fixed-combination therapy. PMID:22419858

An Open-Label Exploratory Study with Memantine: Correlation between Proton Magnetic Resonance Spectroscopy and Cognition in Patients with Mild to Moderate Alzheimer's Disease

PubMed Central

Gordon, Marc L.; Kingsley, Peter B.; Goldberg, Terry E.; Koppel, Jeremy; Christen, Erica; Keehlisen, Lynda; Kohn, Nina; Davies, Peter

2012-01-01

Aim To characterize progression of Alzheimer's disease (AD) using proton magnetic resonance spectroscopy (1H MRS). Methods Eleven subjects with mild to moderate AD underwent neurocognitive testing and single-voxel 1H MRS from the precuneus and posterior cingulate region at baseline, after 24 weeks of monotherapy with a cholinesterase inhibitor, and after another 24 weeks of combination therapy with open-label memantine and a cholinesterase inhibitor. Baseline metabolites [N-acetylaspartate (NAA), myo-inositol (mI), choline (Cho), and creatine (Cr)] and their ratios in AD subjects were compared with those of an age-matched control group of 28 cognitively normal subjects. Results AD subjects had significantly higher mI/Cr and lower NAA, NAA/Cr, NAA/Cho, and NAA/mI. Baseline Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scores significantly correlated with NAA/Cr, mI/Cr, and NAA/mI. There was an increase in mI and a decrease in NAA/mI, but no significant change in other metabolites or ratios, or neurocognitive measures, when memantine was added to a cholinesterase inhibitor. Conclusion Metabolite ratios significantly differed between AD and control subjects. Baseline metabolite ratios correlated with function (ADCS-ADL). There was an increase in mI and a decrease in NAA/mI, but no changes in other metabolites, ratios, or cognitive measures, when memantine was added to a cholinesterase inhibitor. PMID:22962555

Topical Ketamine 10% for Neuropathic Pain in Spinal Cord Injury Patients: An Open-Label Trial.

PubMed

Rabi, Joseph; Minori, Joshua; Abad, Hasan; Lee, Ray; Gittler, Michelle

2016-01-01

Topical ketamine, an N-methyl-D-aspartate antagonist, has been shown to be effective in certain neuropathic pain syndromes. The objective of this study was to determine the efficacy of topical ketamine in spinal cord injury patients with neuropathic pain. An open label trial enrolled five subjects at an outpatient rehabilitation hospital with traumatic spinal cord injuries who had neuropathic pain at or below the level of injury. Subjects applied topical ketamine 10% three times a day for a two-week duration. Subjects recorded their numerical pain score-ranging from 0 to 10, with 0 representing "no pain, 5 representing "moderate pain," and 10 being described as "worst possible pain"-in a journal at the time of application of topical ketamine and one hour after application. Using a numerical pain scale allows for something as subjective as pain to be given an objective quantification. Subjects also recorded any occurrence of adverse events and level of satisfaction. All five subjects had a decrease in their numerical pain scale by the end of two weeks, ranging from 14% to 63%. The duration ranged from one hour in one subject to the next application in other subjects. There were no adverse effects. Overall, four out of the five subjects stated they were satisfied. Topical ketamine 10% is an effective neuropathic pain medicine in patients with spinal cord injuries; however, further studies need to be done with a placebo and larger sample size. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Impact of a soy drink on climacteric symptoms: an open-label, crossover, randomized clinical trial

PubMed Central

Tranche, Salvador; Brotons, Carlos; Pascual de la Pisa, Beatriz; Macías, Ramón; Hevia, Eduardo; Marzo-Castillejo, Mercè

2016-01-01

Abstract Objectives: The objective of this study is to evaluate the effects of a soy drink with a high concentration of isoflavones (ViveSoy®) on climacteric symptoms. Methods: An open-label, controlled, crossover clinical trial was conducted in 147 peri- and postmenopausal women. Eligible women were recruited from 13 Spanish health centers and randomly assigned to one of the two sequence groups (control or ViveSoy®, 500 mL per day, 15 g of protein and 50 mg of isoflavones). Each intervention phase lasted for 12 weeks with a 6-week washout period. Changes on the Menopause Rating Scale and quality of life questionnaires, as well as lipid profile, cardiovascular risk and carbohydrate and bone metabolism were assessed. Statistical analysis was performed using a mixed-effects model. Results: A sample of 147 female volunteers was recruited of which 90 were evaluable. In both sequence groups, adherence to the intervention was high. Regular consumption of ViveSoy® reduced climacteric symptoms by 20.4% (p = 0.001) and symptoms in the urogenital domain by 21.3% (p < 0.05). It also improved health-related quality life by 18.1%, as per the MRS questionnaire (p <0.05). Conclusion: Regular consumption of ViveSoy® improves both the somatic and urogenital domain symptoms of menopause, as well as health-related quality of life in peri- and postmenopausal women. PMID:26806546

Peyronie's disease and low intensity shock wave therapy: Clinical outcomes and patient satisfaction rate in an open-label single arm prospective study in Australian men

PubMed Central

2015-01-01

Purpose To evaluate the efficacy, safety and patient satisfaction outcomes following low intensity extracorporeal shock wave therapy (LiESWT) in men with Peyronie's disease (PD) using a standardised protocol. Materials and Methods In this open-label single arm prospective study, patients with PD were enrolled following informed consent. Patient demographics, change in penile curvature and plaque hardness, International Index of Erectile Function (IIEF)-5 score, and overall satisfaction score (on a 5-point scale) were recorded. Treatment template consists of 3000 shock waves to the Peyronie's plaque over 20 minutes, twice weekly for 6 weeks. Results The majority of patients have PD history longer than 6 months (mean, 12.8 months; range, 6-28 months). Two thirds of patients have received and failed oral medical therapy. There were improvements in penile curvature (more than 15 degrees in 33% of men), plaque hardness (60% of men) and penile pain (4 out of 6 men) following LiESWT. There was a moderate improvement in IIEF-5 score (>5 points reported in 20% of men). No complication was reported and the majority of patients were satisfied (rated 4 out of 5; 70% of men) and would recommend this therapy to others. Conclusions In a carefully selected group of men with PD, LiESWT appears to be safe, has moderate efficacy and is associated with high patient satisfaction rate in the short term. PMID:26568796

A multicenter, open-label extension study of velaglucerase alfa in Japanese patients with Gaucher disease: Results after a cumulative treatment period of 24months.

PubMed

Ida, Hiroyuki; Tanaka, Akemi; Matsubayashi, Tomoko; Murayama, Kei; Hongo, Teruaki; Lee, Hak-Myung; Mellgard, Björn

2016-07-01

Enzyme replacement therapy (ERT) with exogenous glucocerebrosidase is indicated to treat symptomatic Gaucher disease (GD), a rare, inherited metabolic disorder. ERT with velaglucerase alfa, which is produced in a human cell line using gene activation technology, was studied in a 12-month phase III trial in Japanese patients with type 1 or 3 GD who were switched from imiglucerase ERT (n=6); the current, open-label, 12-month extension study was designed to assess longer-term safety and efficacy. Two adult and three pediatric patients (aged <18years) were enrolled into the extension study. Every-other-week intravenous infusions were administered for 63-78weeks at average doses between 51.5 and 60.7units/kg. Three non-serious adverse events were considered related to velaglucerase alfa treatment, but no patient discontinued from the study. Six serious but non-drug-related adverse events were reported. No patient tested positive for anti-velaglucerase alfa antibodies. Hemoglobin concentrations, platelet counts, and liver and spleen volumes (normalized to body weight) in these patients were generally stable over a cumulative 24-month period from the baseline of the parent trial. The data suggest that velaglucerase alfa was well tolerated and maintained clinical stability in Japanese GD patients over 2years after switching from imiglucerase. ClinicalTrials.gov identifier NCT01842841. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Effect of mirtazapine versus selective serotonin reuptake inhibitors on benzodiazepine use in patients with major depressive disorder: a pragmatic, multicenter, open-label, randomized, active-controlled, 24-week trial.

PubMed

Hashimoto, Tasuku; Shiina, Akihiro; Hasegawa, Tadashi; Kimura, Hiroshi; Oda, Yasunori; Niitsu, Tomihisa; Ishikawa, Masatomo; Tachibana, Masumi; Muneoka, Katsumasa; Matsuki, Satoshi; Nakazato, Michiko; Iyo, Masaomi

2016-01-01

This study aimed to evaluate whether selecting mirtazapine as the first choice for current depressive episode instead of selective serotonin reuptake inhibitors (SSRIs) reduces benzodiazepine use in patients with major depressive disorder (MDD). We concurrently examined the relationship between clinical responses and serum mature brain-derived neurotrophic factor (BDNF) and its precursor, proBDNF. We conducted an open-label randomized trial in routine psychiatric practice settings. Seventy-seven MDD outpatients were randomly assigned to the mirtazapine or predetermined SSRIs groups, and investigators arbitrarily selected sertraline or paroxetine. The primary outcome was the proportion of benzodiazepine users at weeks 6, 12, and 24 between the groups. We defined patients showing a ≥50 % reduction in Hamilton depression rating scale (HDRS) scores from baseline as responders. Blood samples were collected at baseline, weeks 6, 12, and 24. Sixty-five patients prescribed benzodiazepines from prescription day 1 were analyzed for the primary outcome. The percentage of benzodiazepine users was significantly lower in the mirtazapine than in the SSRIs group at weeks 6, 12, and 24 (21.4 vs. 81.8 %; 11.1 vs. 85.7 %, both P  < 0.001; and 12.5 vs. 81.8 %, P  = 0.0011, respectively). No between-group difference was observed in HDRS score changes. Serum proBDNF levels were significantly decreased ( χ 2  = 8.5, df  = 3, P  = 0.036) and serum mature BDNF levels were temporarily significantly decreased ( F  = 3.5, df  = 2.4, P  = 0.027) in the responders of both groups at week 24. This study demonstrated mirtazapine as the first-choice antidepressant for current depressive episodes may reduce benzodiazepine use in patients with MDD. Trial registration UMIN000004144. Registered 2nd September 2010. The date of enrolment of the first participant to the trial was 24th August 2010. This study was retrospectively registered 9 days after the first participant was enrolled.

The effect of physician and patient education when combined with vardenafil treatment in Canadian males with erectile dysfunction: an open-label, factorial-designed, cluster-randomized clinical trial.

PubMed

Brock, Gerald; Carrier, Serge; Alarie, Pierre; Pommerville, Peter; Casey, Richard; Harris, Stewart; Ward, Richard

2008-03-01

Studies evaluating the effect of education on treatment success with phosphodiesterase type 5 (PDE5) inhibitor therapy in men with erectile dysfunction (ED) are limited. Additional education of the primary care physician (PCP) and the patient are thought to optimize the treatment of ED. To assess the impact of education of the PCP or of the patient in the treatment of ED with vardenafil relative to usual care. In this 12-week, open-label, multicenter, factorial-designed, cluster-randomized Canadian study, 1,029 patients with ED were enrolled into four different education groups: usual care, patient education, PCP education, and both PCP and patient education. All groups started on vardenafil 10 mg, with the option to titrate at weeks 4 and 8. The primary efficacy measure was the difference at week 4 last observation carried forward (LOCF) in the overall improvement in erectile function (EF) as measured by the Global Assessment Question (GAQ), while on background vardenafil, between those receiving education vs. those who did not. Other secondary assessments included responses to diary questions regarding penetration (sexual encounter profile, SEP2) and erection maintenance (SEP3), and to questionnaires regarding treatment satisfaction (Erectile Dysfunction Inventory of Treatment Satisfaction [EDITS]). A total of 956 patients were included in the intent-to-treat population. Mean baseline International Index of Erectile Function-EF domain score was 13. GAQ response rates at week 4 LOCF were high (>80%) for all groups, regardless of the education given. Mean per patient SEP2 and SEP3 rates at week 12 LOCF were 86-89% and 79-83%, respectively. In an exploratory analysis, a positive relationship between GAQ responses and EDITS scores was observed (P < or = 0.0007). Vardenafil was generally well tolerated. In men with moderate ED, vardenafil led to high success rates and satisfaction regardless of the education given. The benefits of education for PCP and patients in Canada were possibly masked by a ceiling effect in this study population.

Repeat Treatment With Rifaximin Is Safe and Effective in Patients With Diarrhea-Predominant Irritable Bowel Syndrome.

PubMed

Lembo, Anthony; Pimentel, Mark; Rao, Satish S; Schoenfeld, Philip; Cash, Brooks; Weinstock, Leonard B; Paterson, Craig; Bortey, Enoch; Forbes, William P

2016-12-01

Few treatments have demonstrated efficacy and safety for diarrhea-predominant irritable bowel syndrome (IBS-D). A phase 3, randomized, double-blind, placebo-controlled trial was performed to evaluate the safety and efficacy of repeat treatment with the nonsystemic antibiotic rifaximin. The trial included adults with IBS-D, mean abdominal pain and bloating scores of 3 or more, and loose stool, located at 270 centers in the United States and Europe from February 2012 through June 2014. Those responding to a 2-week course of open-label rifaximin 550 mg 3 times daily, who then relapsed during an observation phase (up to 18 weeks), were randomly assigned to groups given repeat treatments of rifaximin 550 mg or placebo 3 times daily for 2 weeks. The primary end point was percentage of responders after first repeat treatment, defined as a decrease in abdominal pain of ≥30% from baseline and a decrease in frequency of loose stools of ≥50% from baseline, for 2 or more weeks during a 4-week post-treatment period. Of 1074 patients (44.1%) who responded to open-label rifaximin, 382 (35.6%) did not relapse and 692 (64.4%) did; of these, 636 were randomly assigned to receive repeat treatment with rifaximin (n = 328) or placebo (n = 308). The percentage of responders was significantly greater with rifaximin than placebo (38.1% vs 31.5%; P = .03). The percentage of responders for abdominal pain (50.6% vs 42.2%; P = .018) was significantly greater with rifaximin than placebo, but not stool consistency (51.8% vs 50.0%; P = .42). Significant improvements were also noted for prevention of recurrence, durable response, and bowel movement urgency. Adverse event rates were low and similar between groups. In a phase 3 study of patients with relapsing symptoms of IBS-D, repeat rifaximin treatment was efficacious and well tolerated. ClinicalTrials.gov ID: NCT01543178. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Treatment-Free Remission After Second-Line Nilotinib Treatment in Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Single-Group, Phase 2, Open-Label Study.

PubMed

Mahon, François-Xavier; Boquimpani, Carla; Kim, Dong-Wook; Benyamini, Noam; Clementino, Nelma Cristina D; Shuvaev, Vasily; Ailawadhi, Sikander; Lipton, Jeffrey Howard; Turkina, Anna G; De Paz, Raquel; Moiraghi, Beatriz; Nicolini, Franck E; Dengler, Jolanta; Sacha, Tomasz; Takahashi, Naoto; Fellague-Chebra, Rafik; Acharya, Sandip; Wong, Stephane; Jin, Yu; Hughes, Timothy P

2018-04-03

Treatment-free remission (TFR)-that is, stopping tyrosine kinase inhibitor (TKI) therapy without loss of response-is an emerging treatment goal in chronic myeloid leukemia (CML). To evaluate TFR after discontinuation of second-line nilotinib therapy. Single-group, phase 2, open-label study. (ClinicalTrials.gov: NCT01698905). 63 centers in 18 countries. Adults with CML in chronic phase who received TKI therapy for at least 3 years (>4 weeks with imatinib, then ≥2 years with nilotinib) and achieved MR4.5 (BCR-ABL1 ≤0.0032% on the International Scale [BCR-ABL1IS]) while receiving nilotinib entered a 1-year consolidation phase. Those with sustained MR4.5 during consolidation were eligible to enter TFR. Patients received nilotinib during consolidation; those who entered TFR stopped treatment. Patients with loss of major molecular response (MMR) (BCR-ABL1IS ≤0.1%) or confirmed loss of MR4 (BCR-ABL1IS ≤0.01%) during TFR reinitiated nilotinib treatment. Proportion of patients without loss of MMR, confirmed loss of MR4, or treatment reinitiation within 48 weeks of stopping treatment (primary end point). 163 patients who had switched from imatinib to nilotinib (for reasons including resistance, intolerance, and physician preference) enrolled in the study and entered the consolidation phase. Of these patients, 126 met the criteria for entering the TFR phase, and 73 (58% [95% CI, 49% to 67%]) and 67 (53% [CI, 44% to 62%]) maintained TFR at 48 weeks (primary end point) and 96 weeks, respectively. Of the 56 patients who reinitiated nilotinib therapy, 55 regained MMR or better and 52 regained MR4.5. None had CML progression to accelerated phase or blast crisis. Musculoskeletal pain was more frequent during the first 48 weeks after nilotinib discontinuation. The study included a heterogeneous patient population and was not designed to compare outcomes between patients continuing and those stopping treatment. TFR seems achievable in patients with sustained MR4.5 after switching to nilotinib. Novartis Pharmaceuticals Corporation.

Long-term safety and efficacy of bilastine following up to 12 weeks or 52 weeks of treatment in Japanese patients with allergic rhinitis: Results of an open-label trial.

PubMed

Okubo, Kimihiro; Gotoh, Minoru; Togawa, Michinori; Saito, Akihiro; Ohashi, Yoshihiro

2017-06-01

Bilastine is a novel second-generation antihistamine. This open-label, single-arm, phase III study evaluated the safety and efficacy of long-term treatment with bilastine in Japanese patients with seasonal (SAR) or perennial allergic rhinitis (PAR). Patients with SAR or PAR who met the registration criteria and did not violate the exclusion criteria received bilastine (20mg, once daily) for 12 weeks (treatment period). Patients with PAR who met the transition criteria could elect to continue the bilastine treatment for an additional 40 weeks (continuous treatment period: a total of 52 weeks). Safety and tolerability were the primary outcomes, and the main secondary endpoint was to evaluate changes in efficacy variables from baseline measurements. Fifty-eight patients with SAR and 64 patients with PAR received bilastine (20mg/day) for 12 weeks. Fifty-five patients with PAR transitioned to the continuous treatment period. Adverse events (AEs) were reported by 17.2% of patients with SAR and by 31.3% of patients with PAR, and adverse drug reactions (ADRs) were reported by 6.3% of patients with PAR but by no patients with SAR during the 12-week treatment period. All of the ADRs were mild in severity. During the 52-week treatment period, AEs and ADRs were reported by 73.4% and 6.3% of patients with PAR, respectively. All of the ADRs occurred during the 12-week treatment period, and none during the continuous treatment period. The AEs were categorized using the System Organ Class of nervous system disorders; 4.7% of patients reported headache, but none reported somnolence. One serious AE was reported, but it was considered to be unrelated to the bilastine treatment. There were no deaths, and no patients withdrew from the study because of AEs. In patients with SAR, bilastine significantly decreased the total nasal symptom score (TNSS), total ocular symptom score (TOSS), and total symptom score (TSS) relative to baseline. Prolonged treatment with bilastine resulted in the maintenance of a significant reduction in TNSS, TOSS, and TSS from the baseline in patients with PAR. Improvement of quality of life was also observed in patients with SAR and PAR. Bilastine was safe, well tolerated, and effective for patients with SAR and PAR. The observed improvement was maintained for the duration of the study, with no loss of drug efficacy (registration number JapicCTI-142622). Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cortical and subcortical connections of V1 and V2 in early postnatal macaque monkeys.

PubMed

Baldwin, Mary K L; Kaskan, Peter M; Zhang, Bin; Chino, Yuzo M; Kaas, Jon H

2012-02-15

Connections of primary (V1) and secondary (V2) visual areas were revealed in macaque monkeys ranging in age from 2 to 16 weeks by injecting small amounts of cholera toxin subunit B (CTB). Cortex was flattened and cut parallel to the surface to reveal injection sites, patterns of labeled cells, and patterns of cytochrome oxidase (CO) staining. Projections from the lateral geniculate nucleus and pulvinar to V1 were present at 4 weeks of age, as were pulvinar projections to thin and thick CO stripes in V2. Injections into V1 in 4- and 8-week-old monkeys labeled neurons in V2, V3, middle temporal area (MT), and dorsolateral area (DL)/V4. Within V1 and V2, labeled neurons were densely distributed around the injection sites, but formed patches at distances away from injection sites. Injections into V2 labeled neurons in V1, V3, DL/V4, and MT of monkeys 2-, 4-, and 8-weeks of age. Injections in thin stripes of V2 preferentially labeled neurons in other V2 thin stripes and neurons in the CO blob regions of V1. A likely thick stripe injection in V2 at 4 weeks of age labeled neurons around blobs. Most labeled neurons in V1 were in superficial cortical layers after V2 injections, and in deep layers of other areas. Although these features of adult V1 and V2 connectivity were in place as early as 2 postnatal weeks, labeled cells in V1 and V2 became more restricted to preferred CO compartments after 2 weeks of age. Copyright © 2011 Wiley-Liss, Inc.

Smoking cessation, smoking reduction, and delayed quitting among smokers given nicotine patches and a self-help pamphlet.

PubMed

Jolicoeur, Denise G; Richter, Kimber P; Ahluwalia, Jasjit S; Mosier, Michael C; Resnicow, Ken

2003-06-01

Over-the-counter nicotine replacement raises questions regarding its "real world" efficacy. This was an open-label, prospective study of 223 smokers who received 42 free nicotine patches and a self-help booklet via shopping mall distribution. The overall quit rate 6 months following distribution of the nicotine patches was 22% (50/223), almost the same quit rate found 6 weeks following patch distribution (21%, 47/223). Twelve percent (27/223) were abstinent at both 6 weeks and 6 months. Among the 83 participants who did not quit, cigarettes smoked per day dropped from 28 to 18. A substantial subgroup of quitters (14%) who, although still smoking at 6 weeks, were smoke free at 6 months, and it appears they had purposefully delayed a serious quit attempt. These results support the usefulness of nicotine patches in helping smokers quit, even with only minimal intervention such as a self-help manual.

Transcranial direct current stimulation for the treatment of primary progressive aphasia: An open-label pilot study.

PubMed

Gervits, Felix; Ash, Sharon; Coslett, H Branch; Rascovsky, Katya; Grossman, Murray; Hamilton, Roy

2016-11-01

Primary progressive aphasia (PPA) is a neurodegenerative condition characterized by gradual deterioration of language function. We investigated whether two weeks of daily transcranial direct current stimulation (tDCS) treatment would improve language abilities in six people with a non-fluent form of PPA. tDCS was applied in an unblinded trial at an intensity of 1.5mA for 20min/day over 10days. At the time of stimulation, patients were engaged in narrating one of several children's wordless picture stories. A battery of neuropsychological assessments was administered four times: at baseline, immediately following the 2-week stimulation period, and then 6-weeks and 12-weeks following the end of stimulation. We observed improvement in linguistic performance in the domains of speech production and grammatical comprehension. Our encouraging results indicate that larger, sham-controlled studies of tDCS as a potential intervention for PPA are warranted. Copyright © 2016 Elsevier Inc. All rights reserved.

Rational dosages of nutrients have a prolonged effect on learning disabilities.

PubMed

Carlton, R M; Ente, G; Blum, L; Heyman, N; Davis, W; Ambrosino, S

2000-05-01

Reports that administration of nutrients has increased the academic performance of learning-disabled children exist in the literature. To document the effects of nutrients on learning-disabled children in a controlled study. A randomized, double-blind, placebo-controlled crossover trial, which followed 1 year of open-label nutrients. Children who improved in the open-label trial were eligible to enter the controlled phase of the study. Subjects were enrolled from the general community through advertisements. Twenty children met the criteria for being learning disabled. Each child was tried out on some (but not necessarily all) of the B vitamins and minerals used in this study. These were administered semi-blinded for the first year; double-blinded in crossover rotations during the second year; and open-label in the ensuing years. At various time points, school-certified psychologists administered psychoeducational tests. School report cards were evaluated at baseline and for all subsequent periods. Twenty learning-disabled children entered the study, but 1 dropped out because of nausea. The remaining 19 children showed significant academic and behavioral improvements within a few weeks or months of open-label treatment with nutrient supplements. Some children gained 3 to 5 years in reading comprehension within the first year of treatment; and all children in special education classes became mainstreamed, and their grades rose significantly. Twelve of the children completed the 1-year double-blind phase, after which approximately half of the children chose to remain on the nutrients for at least 2 additional years. For those who discontinued, it took at least 1 year to begin to see the first indications of decline in academic performance, and another year for their grades to drop significantly. In contrast, for children who remained on nutrients, the gains continued the upward trend; at the end of year 4, the difference in scores between the 2 groups had reached statistical significance (P < .01). The overall results of this study tentatively support the concept that learning disabilities may in some cases be a nutrient-responsive disorder.

Immunogenicity of type 2 monovalent oral and inactivated poliovirus vaccines for type 2 poliovirus outbreak response: an open-label, randomised controlled trial.

PubMed

Zaman, Khalequ; Estívariz, Concepción F; Morales, Michelle; Yunus, Mohammad; Snider, Cynthia J; Gary, Howard E; Weldon, William C; Oberste, M Steven; Wassilak, Steven G; Pallansch, Mark A; Anand, Abhijeet

2018-06-01

Monovalent type 2 oral poliovirus vaccine (mOPV2) and inactivated poliovirus vaccine (IPV) are used to respond to type 2 poliovirus outbreaks. We aimed to assess the effect of two mOPV2 doses on the type 2 immune response by varying the time interval between mOPV2 doses and IPV co-administration with mOPV2. We did a randomised, controlled, parallel, open-label, non-inferiority, inequality trial at two study clinics in Dhaka, Bangladesh. Healthy infants aged 6 weeks (42-48 days) at enrolment were randomly assigned (1:1:1:1) to receive two mOPV2 doses (each dose consisting of two drops [0·1 mL in total] of about 10 5 50% cell culture infectious dose of type 2 Sabin strain) at intervals of 1 week, 2 weeks, 4 weeks (standard or control group), or 4 weeks with IPV (0·5 mL of type 1 [Mahoney, 40 D-antigen units], type 2 [MEF-1, 8 D-antigen units], and type 3 [Saukett, 32 D-antigen units]) administered intramuscularly with the first mOPV2 dose. We used block randomisation, randomly selecting blocks of sizes four, eight, 12, or 16 stratified by study sites. We concealed randomisation assignment from staff managing participants in opaque, sequentially numbered, sealed envelopes. Parents and clinic staff were unmasked to assignment after the randomisation envelope was opened. Laboratory staff analysing sera were masked to assignment, but investigators analysing data and assessing outcomes were not. The primary outcome was type 2 immune response measured 4 weeks after mOPV2 administration. The primary modified intention-to-treat analysis included participants with testable serum samples before and after vaccination. A non-inferiority margin of 10% and p=0·05 (one-tailed) was used. This trial is registered at ClinicalTrials.gov, number NCT02643368, and is closed to accrual. Between Dec 7, 2015, and Jan 5, 2016, we randomly assigned 760 infants to receive two mOPV2 doses at intervals of 1 week (n=191), 2 weeks (n=191), 4 weeks (n=188), or 4 weeks plus IPV (n=190). Immune responses after two mOPV2 doses were observed in 161 (93%) of 173 infants with testable serum samples in the 1 week group, 169 (96%) of 177 in the 2 week group, and 176 (97%) of 181 in the 4 week group. 1 week and 2 week intervals between two mOPV2 doses were non-inferior to 4 week intervals because the lower bound of the absolute differences in the percentage of immune responses were greater than -10% (-4·2% [90% CI -7·9 to -0·4] in the 1 week group and -1·8% [-5·0 to 1·5] in the 2 week group vs the 4 week group). The immune response elicited by two mOPV2 doses 4 weeks apart was not different when IPV was added to the first dose (176 [97%] of 182 infants with IPV vs 176 [97%] of 181 without IPV; p=1·0). During the trial, two serious adverse events (pneumonia; one [1%] of 186 patients in the 1 week group and one [1%] of 182 in the 4 week group) and no deaths were reported; the adverse events were not attributed to the vaccines. Administration of mOPV2 at short intervals does not interfere with its immunogenicity. The addition of IPV to the first mOPV2 dose did not improve poliovirus type 2 immune response. US Centers for Disease Control and Prevention. Copyright © 2018 Elsevier Ltd. All rights reserved.

Effectiveness and safety of valsartan in children aged 6 to 16 years with hypertension.

PubMed

Wells, Thomas; Blumer, Jeffrey; Meyers, Kevin E C; Neto, Jose P R; Meneses, Rejane; Litwin, Mieczysław; Vande Walle, Johan; Solar-Yohay, Susan; Shi, Victor; Han, Guangyang

2011-05-01

The effectiveness and safety of valsartan have not been assessed in hypertensive children. Therefore, hypertensive patients aged 6 to 16 years (n=261) were randomized to receive weight-stratified low- (10/20 mg), medium- (40/80 mg), or high-dose (80/160 mg) valsartan for 2 weeks. After 2 weeks, patients were randomized to a 2-week placebo-controlled withdrawal phase. Dose-dependent reductions in sitting systolic blood pressure (SSBP) and sitting diastolic blood pressure (SDBP) were observed after 2 weeks (low dose, -7.9/-4.6 mm Hg; medium dose, -9.6/-5.8 mm Hg; high dose, -11.5/-7.4 mm Hg [P<.0001 for all groups]). During the withdrawal phase, SSBP and SDBP were both lower in the pooled valsartan group than in the pooled placebo group (SSBP, -2.7 mm Hg [P=.0368]; SDBP, -3.0 mm Hg [P=.0047]). Similar efficacy was observed in all subgroups. Valsartan was well tolerated and headache was the most commonly observed adverse event during both the double-blind and 52-week open-label phases. © 2011 Wiley Periodicals, Inc.

Ipragliflozin Add-on Therapy to a GLP-1 Receptor Agonist in Japanese Patients with Type 2 Diabetes (AGATE): A 52-Week Open-Label Study.

PubMed

Ishihara, Hisamitsu; Yamaguchi, Susumu; Nakao, Ikko; Sakatani, Taishi

2018-06-20

Few data are available regarding ipragliflozin treatment in combination with glucagon-like peptide-1 (GLP-1) receptor agonists. The aim of this study was to evaluate the efficacy and safety of ipragliflozin in combination with GLP-1 receptor agonists in Japanese patients with inadequately controlled type 2 diabetes mellitus (T2DM). This multicenter study (consisting of three periods: a 4-week washout period, a 6-week observation period, and a 52-week open-label treatment period) included patients aged ≥ 20 years who received a stable dose/regimen of a GLP-1 receptor agonist either solely or in combination therapy with a sulfonylurea for ≥ 6 weeks, with glycosylated hemoglobin (HbA1c) of ≥ 7.5% and a fasting plasma glucose (FPG) of ≥ 126 mg/dL. Ipragliflozin treatment was given at a fixed dose of 50 mg/day for 20 weeks, followed by 50 or 100 mg/day for 32 weeks. Changes from baseline in glycemic control and other parameters were examined; safety was also assessed. The mean changes in HbA1c and body weight from baseline to end of treatment were - 0.92% and - 2.69 kg, respectively, in all ipragliflozin-treated patients (n = 103). Overall, sustained reductions from baseline were observed for HbA1c, FPG, self-monitored blood glucose, and body weight during the 52-week treatment. The dose increase of ipragliflozin to 100 mg/day resulted in better glycemic control and weight reduction for patients in whom the 50-mg dose was insufficient. Overall, 46.6% (48/103) of patients experienced drug-related adverse events. The most common drug-related treatment-emergent adverse events were pollakiuria (9.7%), hypoglycemia (8.7%), constipation (6.8%), and thirst (5.8%). Combined therapy with ipragliflozin and GLP-1 receptor agonists/sulfonylureas was significantly efficacious in reducing glycemic parameters in patients with T2DM with inadequate glycemic control, and no major safety concerns were identified. The results from this study suggest that ipragliflozin can be recommended as a well-tolerated and effective add-on therapy to a GLP-1 receptor agonist for the treatment of T2DM. ClinicalTrials.gov (identifier: NCT02291874). Astellas Pharma Inc., Tokyo, Japan.

Two different solicitation methods for obtaining information on adverse events associated with methylphenidate in adolescents: a 12-week multicenter, open-label study.

PubMed

Lee, Moon-Soo; Lee, Soyoung I; Hong, Sungdo D; Kim, Ji-Hoon; Choi, Jeewook; Joung, Yoo-Sook

2013-02-01

We explored two different methods of determining adverse events (AEs) among methylphenidate (MPH)-treated adolescents with attention-deficit/hyperactivity disorder (ADHD). We performed a 12-week open label study of osmotic-release oral system (OROS) MPH in adolescents with ADHD who were recruited from four child and adolescent psychiatric outpatient clinics. The AEs were evaluated via a two-step procedure at weeks 1, 3, 6, and 12. The first step was to ask a general question to subjects and their parents regarding AEs. The second step included an AE evaluation process by the investigators, which was performed using a drug-specific checklist. One-way repeated measures ANOVA were used to compare the number of AEs reported by patients and their parents compared with the number reported by clinicians. This statistical technique was also used to compare the number of AEs reported by various sources (i.e., patients, parents, and clinicians) at weeks 1, 3, 6, and 12. Of the 55 participants (43 males, 12 females) between the ages of 12 and 18 enrolled in this study, 47 participants completed the trial. When the number of AEs reported by patients, parents and clinicians were compared, there were no statistically significant differences. When the numbers of AEs obtained from the three different information sources at each study visit were compared, we noted differences. At week 6, the number of AEs evaluated by clinical investigators was higher than those reported by patients and their parents (p=0.003). Although the results did not reach statistical significance, the number of AEs reported by clinical investigators appeared to be greater than those obtained from patients or parents at weeks 3 and 12. The number of AEs reported by patients and their parents were similar at every visit. There were some differences in the pattern of AEs reported between patients and their parents. Clinicians should supplement the subjective report on AEs from patients or their parents with a more drug-specific checklist to obtain drug side effects more effectively. As there are some differences in the pattern of AEs reported by patients and their parents, it is generally recommended that clinicians obtain information from both parties when possible.

Dosing Strategies for Lithium Monotherapy in Children and Adolescents with Bipolar I Disorder

PubMed Central

Kafantaris, Vivian; Pavuluri, Mani; McNamara, Nora K.; McClellan, Jon; Frazier, Jean A.; Sikich, Linmarie; Kowatch, Robert; Lingler, Jacqui; Faber, Jon; Rowles, Brieana M.; Clemons, Traci E.; Taylor-Zapata, Perdita

2011-01-01

Abstract Objective The primary goal of this exploratory study was to obtain data that could lead to evidence-based dosing strategies for lithium in children and adolescents suffering from bipolar I disorder. Methods Outpatients aged 7–17 years meeting Diagnostic and Statistical Manual of Mental Disorders, 4th edition, diagnostic criteria for bipolar I disorder (manic or mixed) were eligible for 8 weeks of open label treatment with lithium in one of three dosing arms. In Arm I, participants began treatment at a dose of 300 mg of lithium twice daily. The starting dose of lithium in Arms II and III was 300 mg thrice daily. Patients in Arms I and II could have their dose increased by 300 mg/day, depending on clinical response, at weekly visits. Patients in Arm III also had mid-week telephone interviews after which they could also have their dose of lithium increased by 300 mg per day. Youths weighing <30 kg were automatically assigned to Arm I, whereas youths weighing ≥30 kg were randomly assigned to Arm I, II, or III. Randomization was balanced by age (7–11 years, 12–17 years) and sex in approximately equal numbers. A priori response criteria were defined as a Clinical Global Impressions-Improvement scale score of ≤2 and a 50% decrease from baseline on the Young Mania Rating Scale. Results Of the 61 youths [32 males (52.5%)] who received open-label lithium, 60 youths completed at least 1 week of treatment and returned for a postbaseline assessment. Most patients had a ≥50% improvement in Young Mania Rating Scale score, and more than half of the patients (58%) achieved response. Overall, lithium was well tolerated. All three treatment arms had similar effectiveness, side effect profiles, and tolerability of lithium. Conclusions On the basis of these results, a dosing strategy in which pediatric patients begin lithium at a dose of 300 mg thrice daily (with an additional 300 mg increase during the first week), followed by 300 mg weekly increases until a priori stopping criteria are met, will be used in an upcoming randomized, placebo-controlled trial. PMID:21663422

Prophylaxis vs. on-demand treatment with BAY 81-8973, a full-length plasma protein-free recombinant factor VIII product: results from a randomized trial (LEOPOLD II)

PubMed Central

Kavakli, K; Yang, R; Rusen, L; Beckmann, H; Tseneklidou-Stoeter, D; Maas Enriquez, M

2015-01-01

Background BAY 81-8973 is a new full-length human recombinant factor VIII product manufactured with technologies to improve consistency in glycosylation and expression to optimize clinical performance. Objectives To demonstrate superiority of prophylaxis vs. on-demand therapy with BAY 81-8973 in patients with severe hemophilia A. Patients/Methods In this multinational, randomized, open-label crossover study (LEOPOLD II; ClinicalTrials.gov identifier: NCT01233258), males aged 12–65 years with severe hemophilia A were randomized to twice-weekly prophylaxis (20–30 IU kg−1), 3-times-weekly prophylaxis (30–40 IU kg−1), or on-demand treatment with BAY 81-8973. Potency labeling for BAY 81-8973 was based on the chromogenic substrate assay or adjusted to the one-stage assay. Primary efficacy endpoint was annualized number of all bleeds (ABR). Adverse events (AEs) and immunogenicity were also assessed. Results Eighty patients (on demand, n = 21; twice-weekly prophylaxis, n = 28; 3-times-weekly prophylaxis, n = 31) were treated and analyzed. Mean ± SD ABR was significantly lower with prophylaxis (twice-weekly, 5.7 ± 7.2; 3-times-weekly, 4.3 ± 6.5; combined, 4.9 ± 6.8) vs. on-demand treatment (57.7 ± 24.6; P < 0.0001, anova). Median ABR was reduced by 97% with prophylaxis (twice-weekly, 4.0; 3-times-weekly, 2.0; combined, 2.0) vs. on-demand treatment (60.0). Median ABR was higher with twice-weekly vs. 3-times-weekly prophylaxis during the first 6-month treatment period (4.1 vs. 2.0) but was comparable in the second 6-month period (1.1 vs. 2.0). Few patients reported treatment-related AEs (4%); no treatment-related serious AEs or inhibitors were reported. Conclusions Twice-weekly or 3-times-weekly prophylaxis with BAY 81-8973 reduced median ABR by 97% compared with on-demand therapy, confirming the superiority of prophylaxis. Treatment with BAY 81-8973 was well tolerated. PMID:25546368

Memantine in frontotemporal lobar degeneration: A multicenter, randomised, double-blind, placebo-controlled trial

PubMed Central

Boxer, Adam L.; Knopman, David S.; Kaufer, Daniel I.; Grossman, Murray; Onyike, Chiadi; Graf-Radford, Neill; Mendez, Mario; Kerwin, Diana; Lerner, Alan; Wu, Chuang-Kuo; Koestler, Mary; Shapira, Jill; Sullivan, Kathryn; Klepac, Kristen; Lipowski, Kristine; Ullah, Jerin; Fields, Scott; Kramer, Joel H.; Merrilees, Jennifer; Neuhaus, John; Mesulam, M. Marsel; Miller, Bruce L.

2013-01-01

Background Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26 week open label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory (NPI). Methods We performed a randomized, parallel group, double blind, placebo controlled trial of 20 mg memantine taken orally daily for 26 weeks in FTD. Participants met Neary criteria for behavioral variant (bvFTD) or semantic dementia (SD) and had characteristic brain atrophy. Use of cholinesterase inhibitors was prohibited. The objective of the study was to determine whether memantine is an effective treatment for FTD. Individuals were randomized to memantine or matched placebo tablets in blocks of two and four. Primary endpoints were the change in total NPI score and Clinical Global Impression of Change (CGIC) scores after 26 weeks. Secondary outcomes included a neuropsychological battery, and other cognitive, global and activity of daily living measures. Clinicaltrials.gov identifier: NCT00545974 Findings 100 subjects were screened, 81 were randomized, 5 (6%) discontinued and 76 completed all visits. Enrollment numbers were lower than planned due to many subjects’ preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. 39 memantine and 42 placebo subjects entered the primary intent to treat analysis. There was no effect of memantine treatment on either the NPI (mean difference [MD] 2.2, 95%CI: −3.9, 8.3, p = 0.47) or CGIC (MD 0, 95%CI: −0.4, 0.4, p = 0.90) after 26 weeks of treatment. Memantine was generally well tolerated, however there were more frequent cognitive adverse events in the memantine group. Interpretation There was no benefit of memantine treatment in bvFTD or SD. These data do not support memantine use in FTD. Funding Forest Research Institute PMID:23290598

Deconstructing tolerance with clobazam: Post hoc analyses from an open-label extension study.

PubMed

Gidal, Barry E; Wechsler, Robert T; Sankar, Raman; Montouris, Georgia D; White, H Steve; Cloyd, James C; Kane, Mary Clare; Peng, Guangbin; Tworek, David M; Shen, Vivienne; Isojarvi, Jouko

2016-10-25

To evaluate potential development of tolerance to adjunctive clobazam in patients with Lennox-Gastaut syndrome. Eligible patients enrolled in open-label extension study OV-1004, which continued until clobazam was commercially available in the United States or for a maximum of 2 years outside the United States. Enrolled patients started at 0.5 mg·kg -1 ·d -1 clobazam, not to exceed 40 mg/d. After 48 hours, dosages could be adjusted up to 2.0 mg·kg -1 ·d -1 (maximum 80 mg/d) on the basis of efficacy and tolerability. Post hoc analyses evaluated mean dosages and drop-seizure rates for the first 2 years of the open-label extension based on responder categories and baseline seizure quartiles in OV-1012. Individual patient listings were reviewed for dosage increases ≥40% and increasing seizure rates. Data from 200 patients were included. For patients free of drop seizures, there was no notable change in dosage over 24 months. For responder groups still exhibiting drop seizures, dosages were increased. Weekly drop-seizure rates for 100% and ≥75% responders demonstrated a consistent response over time. Few patients had a dosage increase ≥40% associated with an increase in seizure rates. Two-year findings suggest that the majority of patients do not develop tolerance to the antiseizure actions of clobazam. Observed dosage increases may reflect best efforts to achieve seizure freedom. It is possible that the clinical development of tolerance to clobazam has been overstated. NCT00518713 and NCT01160770. This study provides Class III evidence that the majority of patients do not develop tolerance to clobazam over 2 years of treatment. © 2016 American Academy of Neurology.

Impact of 6-month earlier versus postponed initiation of rotigotine on long-term outcome: post hoc analysis of patients with early Parkinson's disease with mild symptom severity.

PubMed

Timmermann, Lars; Asgharnejad, Mahnaz; Boroojerdi, Babak; Dohin, Elisabeth; Woltering, Franz; Elmer, Lawrence W

2015-01-01

Investigate impact of 6-month earlier versus postponed initiation of rotigotine in patients with early Parkinson's disease (PD) with mild symptom severity. Long-term benefit of rotigotine in early-PD has been demonstrated: SP702 (NCT00594165) and SP716 (NCT00599196) were long-term, open-label extensions of double-blind, placebo-controlled studies of 6-month maintenance; rotigotine was well tolerated for up to 6 years, and demonstrated efficacy (Unified Parkinson's Disease Rating Scale [UPDRS] II + III below baseline) for ∼ 2 years (SP702) and ∼ 4 years (SP716). Post hoc analysis of patients at Hoehn and Yahr 1-2; groups defined by treatment received in 6-month double-blind studies: 'Rotigotine-Rotigotine' received rotigotine (n = 221), 'Placebo-Rotigotine' received placebo (n = 125). At the start of open-label rotigotine maintenance, UPDRS II + III mean ± SD change from double-blind baseline was: -8.5 ± 10.6 'Rotigotine-Rotigotine', -7.7 ± 9.0 'Placebo-Rotigotine.' After this initial improvement scores gradually increased: It took ∼ 45 months for mean scores to cross baseline in 'Rotigotine-Rotigotine', and ∼ 21 months in 'Placebo-Rotigotine.' At the time mean UPDRS II + III had crossed baseline in 'Placebo-Rotigotine' (open-label week 84; ∼ 21 months), treatment difference (LS-mean) to 'Rotigotine-Rotigotine' change from baseline was -3.89 (95% CI -6.94, -0.84); p = 0.013. In this post hoc analysis, 6-month earlier initiation of rotigotine resulted in slower return to baseline mean UPDRS II + III; initiation of rotigotine in patients with minimal/no functional disability or impairment may lead to an extended benefit.

Multicenter, Randomized, Controlled Study Comparing Tafluprost/Timolol Fixed Combination with Latanoprost/Timolol Fixed Combination in Primary Open-Angle Glaucoma and Ocular Hypertension.

PubMed

Suzuki, Katsuyoshi; Otsuka, Naomi; Hizaki, Hiroko; Hashimoto, Masayo; Kuwayama, Yasuaki

2018-06-05

This was the first exploratory randomized controlled study to compare the efficacy and safety of a preserved tafluprost/timolol fixed combination (TAF/TIM) with a preserved latanoprost/timolol fixed combination (LAT/TIM). This prospective, randomized, open-label study was conducted in Japanese patients with primary open-angle glaucoma, including normal-tension glaucoma or ocular hypertension. Following a 4-week LAT/TIM run-in period, eligible patients entered a 12-week treatment period, during which they received either LAT/TIM or TAF/TIM. The efficacy endpoint was the change in intraocular pressure (IOP) from baseline to week 12 and the safety endpoints included the changes from baseline to week 12 in superficial punctate keratopathy (SPK) score, tear breakup time (TBUT), and hyperemia score, as well as adverse events (AEs). At week 6, ocular symptoms were evaluated using a questionnaire. In total, 131 patients provided informed consent. Of these, 115 completed the run-in period and were assigned to receive TAF/TIM (n = 60) or LAT/TIM (n = 55). At week 12, there were no significant differences between the TAF/TIM and LAT/TIM groups in the change from baseline in trough IOP and IOP at 4-6 h after instillation. There were no significant differences between the two groups in the change from baseline to week 12 in SPK score, TBUT, and hyperemia score. However, only in the TAF/TIM group, the total SPK score and the inferior cornea SPK score were significantly lower at week 12 compared with baseline. Eye irritation and eye pain were significantly decreased in the TAF/TIM group compared with the LAT/TIM group. Two treatment-related AEs were reported in the TAF/TIM group (3.3%) and none in the LAT/TIM group, while no serious AEs were reported in either group. TAF/TIM is as effective as LAT/TIM in terms of IOP-reducing effect, with fewer ocular symptoms. TAF/TIM was associated with a significant improvement in SPK scores. UMIN Clinical Trials Registry Identifier, UMIN000023862. Santen Pharmaceutical Co., Ltd., Osaka, Japan.

An open, self-controlled study on the efficacy of topical indoxacarb for eliminating fleas and clinical signs of flea-allergy dermatitis in client-owned dogs in Queensland, Australia.

PubMed

Fisara, Petr; Sargent, Roger M; Shipstone, Michael; von Berky, Andrew; von Berky, Janet

2014-06-01

Canine flea-allergy dermatitis (FAD), a hypersensitivity response to antigenic material in the saliva of feeding fleas, occurs worldwide and remains a common presentation in companion animal veterinary practice despite widespread availability of effective systemic and topical flea-control products. To evaluate the clinical response in dogs with FAD treated topically with indoxacarb, a novel oxadiazine insecticide. Twenty-five client-owned dogs in Queensland, Australia diagnosed with pre-existing FAD on the basis of clinical signs, flea-antigen intradermal and serological tests. An open-label, noncontrolled study, in which all dogs were treated with topical indoxacarb at 4 week intervals, three times over 12 weeks. Twenty-four dogs completed the study. Complete resolution of clinical signs of FAD was observed in 21 cases (87.5%), with nearly complete resolution or marked improvement in the remaining three cases. Mean clinical scores (Canine Atopic Dermatitis Extent and Severity Index-03) were reduced by 93.3% at week 12. Mean owner-assessed pruritus scores were reduced by 88% by week 12. Mean flea counts reduced by 98.7 and 100% in weeks 8 and 12, respectively. Topical indoxacarb treatment applied every 4 weeks for 12 weeks, without concomitant antipruritic or ectoparasiticide therapy, completely alleviated flea infestations in all dogs and associated clinical signs of FAD in a high proportion of this population of dogs in a challenging flea-infestation environment. © 2014 The Authors. Veterinary Dermatology published by John Wiley & Sons Ltd on behalf of the ESVD and the ACVD.

Melatonin for Sleep in Children with Autism: A Controlled Trial Examining Dose, Tolerability, and Outcomes

PubMed Central

Malow, Beth A.; Adkins, Karen W.; McGrew, Susan G.; Wang, Lily; Goldman, Suzanne E.; Fawkes, Diane; Burnette, Courtney

2011-01-01

Supplemental melatonin has shown promise in treating sleep onset insomnia in children with autism spectrum disorders (ASD). Twenty-four children, free of psychotropic medications, completed an open-label dose-escalation study to assess dose-response, tolerability, safety, feasibility of collecting actigraphy data, and ability of outcome measures to detect change during a 14-week intervention. Supplemental melatonin improved sleep latency, as measured by actigraphy, in most children at 1 or 3 mg dosages. It was effective in week 1 of treatment, maintained effects over several months, was well tolerated and safe, and showed improvement in sleep, behavior, and parenting stress. Our findings contribute to the growing literature on supplemental melatonin for insomnia in ASD and inform planning for a large randomized trial in this population. PMID:22160300

Melatonin for sleep in children with autism: a controlled trial examining dose, tolerability, and outcomes.

PubMed

Malow, Beth; Adkins, Karen W; McGrew, Susan G; Wang, Lily; Goldman, Suzanne E; Fawkes, Diane; Burnette, Courtney

2012-08-01

Supplemental melatonin has shown promise in treating sleep onset insomnia in children with autism spectrum disorders (ASD). Twenty-four children, free of psychotropic medications, completed an open-label dose-escalation study to assess dose-response, tolerability, safety, feasibility of collecting actigraphy data, and ability of outcome measures to detect change during a 14-week intervention. Supplemental melatonin improved sleep latency, as measured by actigraphy, in most children at 1 or 3 mg dosages. It was effective in week 1 of treatment, maintained effects over several months, was well tolerated and safe, and showed improvement in sleep, behavior, and parenting stress. Our findings contribute to the growing literature on supplemental melatonin for insomnia in ASD and inform planning for a large randomized trial in this population.

Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study

DOE PAGES

Lau, George; Benhamou, Yves; Chen, Guofeng; ...

2016-07-25

In order to shorten the course of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, we examined the antiviral efficacy and safety of 3 weeks of response-guided therapy with an NS3 protease inhibitor and dual NS5A inhibitor–NS5B nucleotide analogue. In this open-label, phase 2a, single centre study, Chinese patients with chronic HCV genotype 1b infection without cirrhosis were randomly allocated by a computer program to one of three treatment groups (sofosbuvir, ledipasvir, and asunaprevir; sofosbuvir, daclatasvir, and simeprevir; or sofosbuvir, daclatasvir, and asunaprevir) until six patients in each group (1:1:1) achieved an ultrarapid virological response (plasma HCV RNAmore » <500 IU/mL by day 2, measured by COBAS TaqMan HCV test, version 2.0). Patients with an ultrarapid virological response received 3 weeks of therapy. Patients who did not achieve an ultrarapid response were switched to sofosbuvir and ledipasvir for either 8 weeks or 12 weeks. Furthermore, the primary endpoint was the proportion of patients with a sustained virological response at 12 weeks (SVR12) after treatment completion, analysed in the intention-to-treat population. All patients who achieved an ultrarapid virological response were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02470858. Between April 5, 2015, and April 15, 2015, 26 eligible patients were recruited. 12 patients were assigned to sofosbuvir, ledipasvir, and asunaprevir; six to sofosbuvir, daclatasvir, and simeprevir; and eight to sofosbuvir, daclatasvir, and asunaprevir. Six patients in each group achieved an ultrarapid virological response (18 [69%]). All patients with an ultrarapid virological response who were given 3 weeks of triple therapy achieved SVR12. The most common adverse events were fatigue (one [17%] of six patients receiving sofosbuvir, ledipasvir, and asunaprevir; one [17%] of six patients receiving sofosbuvir, daclatasvir, and simeprevir; and two [33%] of six patients receiving sofosbuvir, daclatasvir, and asunaprevir) and headache (one [17%] patient in each group). There were no patients who experienced any serious adverse events. In this proof-of-concept study, all patients with chronic HCV without cirrhosis who achieved an ultrarapid virological response on triple direct-acting antiviral regimens by day 2 and received 3 weeks of treatment were cured, with excellent tolerability. By shortening the duration of therapy from the currently recommended 12 weeks to 3 weeks, we could drastically reduce the cost of therapy and the rate of adverse events. Further large-scale studies should be done to confirm our findings.« less

Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lau, George; Benhamou, Yves; Chen, Guofeng

In order to shorten the course of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, we examined the antiviral efficacy and safety of 3 weeks of response-guided therapy with an NS3 protease inhibitor and dual NS5A inhibitor–NS5B nucleotide analogue. In this open-label, phase 2a, single centre study, Chinese patients with chronic HCV genotype 1b infection without cirrhosis were randomly allocated by a computer program to one of three treatment groups (sofosbuvir, ledipasvir, and asunaprevir; sofosbuvir, daclatasvir, and simeprevir; or sofosbuvir, daclatasvir, and asunaprevir) until six patients in each group (1:1:1) achieved an ultrarapid virological response (plasma HCV RNAmore » <500 IU/mL by day 2, measured by COBAS TaqMan HCV test, version 2.0). Patients with an ultrarapid virological response received 3 weeks of therapy. Patients who did not achieve an ultrarapid response were switched to sofosbuvir and ledipasvir for either 8 weeks or 12 weeks. Furthermore, the primary endpoint was the proportion of patients with a sustained virological response at 12 weeks (SVR12) after treatment completion, analysed in the intention-to-treat population. All patients who achieved an ultrarapid virological response were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02470858. Between April 5, 2015, and April 15, 2015, 26 eligible patients were recruited. 12 patients were assigned to sofosbuvir, ledipasvir, and asunaprevir; six to sofosbuvir, daclatasvir, and simeprevir; and eight to sofosbuvir, daclatasvir, and asunaprevir. Six patients in each group achieved an ultrarapid virological response (18 [69%]). All patients with an ultrarapid virological response who were given 3 weeks of triple therapy achieved SVR12. The most common adverse events were fatigue (one [17%] of six patients receiving sofosbuvir, ledipasvir, and asunaprevir; one [17%] of six patients receiving sofosbuvir, daclatasvir, and simeprevir; and two [33%] of six patients receiving sofosbuvir, daclatasvir, and asunaprevir) and headache (one [17%] patient in each group). There were no patients who experienced any serious adverse events. In this proof-of-concept study, all patients with chronic HCV without cirrhosis who achieved an ultrarapid virological response on triple direct-acting antiviral regimens by day 2 and received 3 weeks of treatment were cured, with excellent tolerability. By shortening the duration of therapy from the currently recommended 12 weeks to 3 weeks, we could drastically reduce the cost of therapy and the rate of adverse events. Further large-scale studies should be done to confirm our findings.« less

Efficacy and Safety of Azithromycin-Chloroquine versus Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment of Plasmodium falciparum Malaria Infection in Pregnant Women in Africa: An Open-Label, Randomized Trial

PubMed Central

Kimani, Joshua; Phiri, Kamija; Kamiza, Steve; Duparc, Stephan; Ayoub, Ayman; Rojo, Ricardo; Robbins, Jeffery; Orrico, Russell; Vandenbroucke, Pol

2016-01-01

Background The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) in African regions with moderate to high malaria transmission. However, growing resistance to SP threatens the effectiveness of IPTp-SP, and alternative drugs are needed. This study tested the efficacy, tolerability, and safety of a fixed-dose combination azithromycin-chloroquine (AZCQ; 250 mg AZ/155 mg CQ base) for IPTp relative to IPTp-SP. Methods and Findings A randomized, Phase 3, open-label, multi-center study was conducted in sub-Saharan Africa (Benin, Kenya, Malawi, Tanzania, and Uganda) between October 2010 and November 2013. Pregnant women received 3 IPTp courses with AZCQ (each course: 1,000/620 mg AZCQ QD for 3 days) or SP (each course 1,500/75 mg SP QD for 1 day) at 4- to 8-week intervals during the second and third trimester. Long-lasting insecticide-treated bednets were also provided at enrollment. Study participants were followed up until day 28 post delivery (time window: day 28–42). The primary endpoint was the proportion of participants with sub-optimal pregnancy outcomes (a composite endpoint comprising live-borne neonates with low birth weight [LBW, <2,500 g], premature birth [<37 weeks], still birth [>28 weeks], abortion [≤28 weeks], lost to follow-up prior to observation of pregnancy outcome, or missing birth weight). The study was terminated early after recruitment of 2,891 of the planned 5,044 participants, due to futility observed in a pre-specified 35% interim analysis. In the final intent-to-treat dataset, 378/1,445 (26.2%) participants in the AZCQ and 342/1,445 (23.7%) in the SP group had sub-optimal pregnancy outcomes, with an estimated risk ratio (RR) of 1.11 (95% CI: 0.97, 1.25; p = 0.12). There was no significant difference in the incidence of LBW between treatment groups (57/1138 [5.0%] in the AZCQ group, 68/1188 [5.7%] in the SP group, RR 0.87 [95% CI: 0.62, 1.23]; p = 0.44). IPTp-AZCQ was less well-tolerated in mothers than IPTp-SP. Occurrences of congenital anomalies, deaths, and serious adverse events were comparable in neonates for both groups. Limitations included the open-label design and early study termination. Conclusions IPTp-AZCQ was not superior to IPTp-SP in this study and alternatives for IPTp-SP remain to be identified. The proportions of sub-optimal pregnancy outcomes and LBW were lower than expected, which may be linked to insecticide-treated bednet use throughout the study. Reduced incidences of symptomatic malaria infection and peripheral parasitemia in the AZCQ group relative to SP suggest that AZCQ warrants further investigation as an alternative treatment of uncomplicated malaria. Trial Registration ClinicalTrials.gov (NCT01103063). PMID:27326859

Double-blind optimization of subcallosal cingulate deep brain stimulation for treatment-resistant depression: a pilot study.

PubMed

Ramasubbu, Rajamannar; Anderson, Susan; Haffenden, Angela; Chavda, Swati; Kiss, Zelma H T

2013-09-01

Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) is reported to be a safe and effective new treatment for treatment-resistant depression (TRD). However, the optimal electrical stimulation parameters are unknown and generally selected by trial and error. This pilot study investigated the relationship between stimulus parameters and clinical effects in SCC-DBS treatment for TRD. Four patients with TRD underwent SCC-DBS surgery. In a double-blind stimulus optimization phase, frequency and pulse widths were randomly altered weekly, and corresponding changes in mood and depression were evaluated using a visual analogue scale (VAS) and the 17-item Hamilton Rating Scale for Depression (HAM-D-17). In the open-label postoptimization phase, depressive symptoms were evaluated biweekly for 6 months to determine long-term clinical outcomes. Longer pulse widths (270-450 μs) were associated with reductions in HAM-D-17 scores in 3 patients and maximal happy mood VAS responses in all 4 patients. Only 1 patient showed acute clinical or mood effects from changing the stimulation frequency. After 6 months of open-label therapy, 2 patients responded and 1 patient partially responded. Limitations include small sample size, weekly changes in stimulus parameters, and fixed-order and carry-forward effects. Longer pulse width stimulation may have a role in stimulus optimization for SCC-DBS in TRD. Longer pulse durations produce larger apparent current spread, suggesting that we do not yet know the optimal target or stimulus parameters for this therapy. Investigations using different stimulus parameters are required before embarking on large-scale randomized sham-controlled trials.

An open-label, dose-titration tolerability study of atomoxetine hydrochloride in Japanese adults with attention-deficit/hyperactivity disorder.

PubMed

Takahashi, Michihiro; Takita, Yasushi; Goto, Taro; Ichikawa, Hironobu; Saito, Kazuhiko; Matsumoto, Hideo; Tanaka, Yasuo

2011-02-01

The main purpose of this first atomoxetine study in Japanese adults with attention-deficit/hyperactivity disorder (ADHD) was to investigate the tolerability of an 8-week treatment regimen. This was an open-label, dose escalation study conducted in 45 Japanese patients aged at least 18 years with DSM-IV-defined ADHD. Patients received atomoxetine orally for 8 weeks. Atomoxetine administration was started at 40 mg/day (7 days), and subsequently increased to a maximum dose of 120 mg/day. Tolerability was assessed by discontinuation rate due to adverse events. Adverse events, laboratory tests, vital signs and electrocardiograms were collected. In addition, ADHD symptoms were assessed by using the Japanese version of the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) scores. Thirty-nine patients completed the study period. Atomoxetine was well tolerated with a 6.7% (3/45) discontinuation rate due to nausea, malaise and anorexia. The most commonly reported adverse events were nausea, nasopharyngitis and headache; there were no unexpected safety concerns. No deaths or serious adverse events were reported. Mean CAARS-Inv:SV-J total ADHD symptom scores decreased in a time-dependent manner; the mean change from baseline to endpoint was -15.0 (P<0.001). This study showed that atomoxetine was well tolerated in these patients and suggested that atomoxetine at a maximum dose of 120 mg/day would be safe in Japanese ADHD patients. © 2011 The Authors. Psychiatry and Clinical Neurosciences © 2011 Japanese Society of Psychiatry and Neurology.

A 24-Week, Open-Label Extension Study to Investigate the Long-term Safety, Tolerability, and Efficacy of 13.3 mg/24 h Rivastigmine Patch in Patients With Severe Alzheimer Disease.

PubMed

Farlow, Martin R; Grossberg, George T; Sadowsky, Carl H; Meng, Xiangyi; Velting, Drew M

2015-01-01

The long-term safety, tolerability, and efficacy of high-dose 13.3 mg/24 h rivastigmine patch in severe Alzheimer disease was evaluated in a 24-week, open-label extension to the double-blind ACTION study. Safety and tolerability, and efficacy on the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV), Severe Impairment Battery (SIB), and ADCS-Clinical Global Impression of Change (ADCS-CGIC) were assessed. Overall, 197 patients continued on 13.3 mg/24 h patch; 199 uptitrated from 4.6 mg/24 h to 13.3 mg/24 h patch. The incidence of adverse events (AEs), serious AEs and discontinuations due to AEs was similar in patients who continued on, and patients who uptitrated to, 13.3 mg/24 h patch (AEs: 57.9% and 59.8%; serious AEs: 16.2% and 16.1%; discontinuations: 11.2% and 12.1%, respectively). Larger mean changes from double-blind baseline were observed in patients uptitrated on the ADCS-ADL-SIV (-4.6; SD=8.7) and SIB (-7.0; SD=16.6), than those who continued on 13.3 mg/24 h patch (-3.9; SD=8.0 and -4.7; SD=16.8, respectively). ADCS-CGIC scores were comparable. There were no clinically relevant between-group differences in safety and tolerability. Greater decline was observed in patients with delayed uptitration to high-dose 13.3 mg/24 h patch than patients who continued on high-dose patch.

Early botulinum toxin treatment for spastic pes equinovarus--a randomized double-blind placebo-controlled study.

PubMed

Fietzek, U M; Kossmehl, P; Schelosky, L; Ebersbach, G; Wissel, J

2014-08-01

Spastic pes equinovarus is a frequent pathological posture of the lower extremity. Botulinum toxin (BoNT/A) has been successfully applied to treat lower limb spasticity. However, the best time to initiate treatment remains unclear. A beneficial effect of an early treatment has been suggested in previous studies. A single-centre double-blind randomized placebo-controlled trial was performed to investigate the efficacy of BoNT/A to reduce muscle hypertonicity at the ankle. Fifty-two patients with unilateral or bilateral spastic pes equinovarus with a modified Ashworth score (mAS) of at least 1+ after stroke, traumatic brain injury or hypoxic encephalopathy were allocated to receive either BoNT/A or placebo treatment. A second, open injection was optional at week 12. Patients received unilateral or bilateral injections with 230 or 460 U onabotulinumtoxinA, respectively. The course of the mAS was explored during the open study phase. Patients who had received BoNT/A treatment had lower mAS compared with placebo at week 12 (P < 0.01). During the open label phase, patients from the placebo group showed further deterioration of muscle tone despite starting from a similar baseline and receiving BoNT treatment. Spastic feet that had received BoNT/A in the first cycle had comparatively lower mAS scores over all follow-up data and at week 24 (P < 0.01). The study demonstrates a reduction of muscular hypertonicity in spastic pes equines with BoNT/A treatment given during the first 3 months after the lesion. Exploratory analyses of the course of muscular hypertonicity during the open phase favour earlier to later treatment. © 2014 The Author(s) European Journal of Neurology © 2014 EAN.

Clinical efficacy of edaravone for the treatment of amyotrophic lateral sclerosis.

PubMed

Sawada, Hideyuki

2017-05-01

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, neurodegenerative disease. Although the pathogenesis remains unresolved, oxidative stress is known to play a pivotal role. Edaravone works in the central nervous system as a potent scavenger of oxygen radicals. In ALS mouse models, edaravone suppresses motor functional decline and nitration of tyrosine residues in the cerebrospinal fluid. Areas covered: Three clinical trials, one phase II open-label trial, and two phase III placebo-control randomized trials were reviewed. In all trials, the primary outcome measure was the changes in scores on the revised ALS functional rating scale (ALSFRS-R) to evaluate motor function of patients. Expert opinion: The phase II open label trial suggested that edaravone is safe and effective in ALS, markedly reducing 3-nitrotyrosine levels in the cerebrospinal fluid. One of the two randomized controlled trials showed beneficial effects in ALSFRS-R, although the differences were not significant. The last trial demonstrated that edaravone provided significant efficacy in ALSFRS-R scores over 24 weeks where concomitant use of riluzole was permitted. Eligibility was restricted to patients with a relatively short disease duration and preserved vital capacity. Therefore, combination therapy with edaravone and riluzole should be considered earlier.

Safety and Efficacy of Rivastigmine in Adolescents with Down Syndrome: Long-Term Follow-Up

PubMed Central

Spiridigliozzi, Gail A.; Crissman, Blythe G.; McKillop, Jane Anne; Yamamoto, Haru; Kishnani, Priya S.

2010-01-01

Abstract Following the completion of a 20-week, open-label study of the safety and efficacy of liquid rivastigmine for adolescents with Down syndrome, 5 of the 10 adolescents in the clinical trial continued long-term rivastigmine therapy and 5 did not. After an average period of 38 months, all 10 subjects returned for a follow-up assessment to determine the safety and efficacy of long-term rivastigmine use. Rivastigmine was well tolerated and overall health appeared to be unaffected by long-term rivastigmine use. Performance change on cognitive and language measures administered at the termination of the open-label clinical trial was compared between the two groups. No between-group difference in median performance change across the long-term period was found, suggesting that the long-term use of rivastigmine does not improve cognitive and language performance. However, two subjects demonstrated remarkable improvement in adaptive function over the long-term period. Both subjects had received long-term rivastigmine therapy. The discussion addresses the challenge of assessing cognitive change in clinical trials using adolescents with Down syndrome as subjects and the use of group versus individual data to evaluate the relevance of medication effects. PMID:21186971

The impact of a disease management program (COACH) on the attainment of better cardiovascular risk control in dyslipidaemic patients at primary care centres (The DISSEMINATE Study): a randomised controlled trial

PubMed Central

2012-01-01

Background To evaluate the efficacy of Counselling and Advisory Care for Health (COACH) programme in managing dyslipidaemia among primary care practices in Malaysia. This open-label, parallel, randomised controlled trial compared the COACH programme delivered by primary care physicians alone (PCP arm) and primary care physicians assisted by nurse educators (PCP-NE arm). Methods This was a multi-centre, open label, randomised trial of a disease management programme (COACH) among dyslipidaemic patients in 21 Malaysia primary care practices. The participating centres enrolled 297 treatment naïve subjects who had the primary diagnosis of dyslipidaemia; 149 were randomised to the COACH programme delivered by primary care physicians assisted by nurse educators (PCP-NE) and 148 to care provided by primary care physicians (PCP) alone. The primary efficacy endpoint was the mean percentage change from baseline LDL-C at week 24 between the 2 study arms. Secondary endpoints included mean percentage change from baseline of lipid profile (TC, LDL-C, HDL-C, TG, TC: HDL ratio), Framingham Cardiovascular Health Risk Score and absolute risk change from baseline in blood pressure parameters at week 24. The study also assessed the sustainability of programme efficacy at week 36. Results Both study arms demonstrated improvement in LDL-C from baseline. The least squares (LS) mean change from baseline LDL-C were −30.09% and −27.54% for PCP-NE and PCP respectively. The difference in mean change between groups was 2.55% (p=0.288), with a greater change seen in the PCP-NE arm. Similar observations were made between the study groups in relation to total cholesterol change at week 24. Significant difference in percentage change from baseline of HDL-C were observed between the PCP-NE and PCP groups, 3.01%, 95% CI 0.12-5.90, p=0.041, at week 24. There was no significant difference in lipid outcomes between 2 study groups at week 36 (12 weeks after the programme had ended). Conclusion Patients who received coaching and advice from primary care physicians (with or without the assistance by nurse educators) showed improvement in LDL-cholesterol. Disease management services delivered by PCP-NE demonstrated a trend towards add-on improvements in cholesterol control compared to care delivered by physicians alone; however, the improvements were not maintained when the services were withdrawn. Trial registration National Medical Research Registration (NMRR) Number: NMRR-08-287-1442 Trial Registration Number (ClinicalTrials.gov Identifier): NCT00708370 PMID:23046818

The impact of a disease management program (COACH) on the attainment of better cardiovascular risk control in dyslipidaemic patients at primary care centres (The DISSEMINATE Study): a randomised controlled trial.

PubMed

Selvaraj, Francis Jude; Mohamed, Mafauzy; Omar, Khairani; Nanthan, Sudha; Kusiar, Zainab; Subramaniam, Selvaraj Y; Ali, Norsiah; Karanakaran, Kamalakaran; Ahmad, Fauziah; Low, Wilson H H

2012-10-10

To evaluate the efficacy of Counselling and Advisory Care for Health (COACH) programme in managing dyslipidaemia among primary care practices in Malaysia. This open-label, parallel, randomised controlled trial compared the COACH programme delivered by primary care physicians alone (PCP arm) and primary care physicians assisted by nurse educators (PCP-NE arm). This was a multi-centre, open label, randomised trial of a disease management programme (COACH) among dyslipidaemic patients in 21 Malaysia primary care practices. The participating centres enrolled 297 treatment naïve subjects who had the primary diagnosis of dyslipidaemia; 149 were randomised to the COACH programme delivered by primary care physicians assisted by nurse educators (PCP-NE) and 148 to care provided by primary care physicians (PCP) alone. The primary efficacy endpoint was the mean percentage change from baseline LDL-C at week 24 between the 2 study arms. Secondary endpoints included mean percentage change from baseline of lipid profile (TC, LDL-C, HDL-C, TG, TC: HDL ratio), Framingham Cardiovascular Health Risk Score and absolute risk change from baseline in blood pressure parameters at week 24. The study also assessed the sustainability of programme efficacy at week 36. Both study arms demonstrated improvement in LDL-C from baseline. The least squares (LS) mean change from baseline LDL-C were -30.09% and -27.54% for PCP-NE and PCP respectively. The difference in mean change between groups was 2.55% (p=0.288), with a greater change seen in the PCP-NE arm. Similar observations were made between the study groups in relation to total cholesterol change at week 24. Significant difference in percentage change from baseline of HDL-C were observed between the PCP-NE and PCP groups, 3.01%, 95% CI 0.12-5.90, p=0.041, at week 24. There was no significant difference in lipid outcomes between 2 study groups at week 36 (12 weeks after the programme had ended). Patients who received coaching and advice from primary care physicians (with or without the assistance by nurse educators) showed improvement in LDL-cholesterol. Disease management services delivered by PCP-NE demonstrated a trend towards add-on improvements in cholesterol control compared to care delivered by physicians alone; however, the improvements were not maintained when the services were withdrawn. National Medical Research Registration (NMRR) Number: NMRR-08-287-1442Trial Registration Number (ClinicalTrials.gov Identifier): NCT00708370.

Effect of Oral Beta-Hydroxy-Beta-Methylbutyrate (HMB) Supplementation on Physical Performance in Healthy Old Women Over 65 Years: An Open Label Randomized Controlled Trial.

PubMed

Berton, Linda; Bano, Giulia; Carraro, Sara; Veronese, Nicola; Pizzato, Simona; Bolzetta, Francesco; De Rui, Marina; Valmorbida, Elena; De Ronch, Irene; Perissinotto, Egle; Coin, Alessandra; Manzato, Enzo; Sergi, Giuseppe

2015-01-01

Although older people are particularly liable to sarcopenia, limited research is available on beta-hydroxy-beta-methylbutyrate (HMB) supplementation in this population, particularly in healthy subjects. In this parallel-group, randomized, controlled, open-label trial, we aimed to evaluate whether an oral supplement containing 1.5 g of calcium HMB for 8 weeks could improve physical performance and muscle strength parameters in a group of community-dwelling healthy older women. Eighty healthy women attending a twice-weekly mild fitness program were divided into two equal groups of 40, and 32 of the treated women and 33 control completed the study. We considered a change in the Short Physical Performance Battery (SPPB) score as the primary outcome and changes in the peak torque (PT) isometric and isokinetic strength of the lower limbs, 6-minute walking test (6MWT), handgrip strength and endurance as secondary outcomes. Body composition was assessed with dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computerized tomography (pQCT). The mean difference between the two groups on pre-post change were finally calculated (delta) for each outcome. After 8 weeks, there were no significant differences between the groups’ SPPB, handgrip strength or DXA parameters. The group treated with HMB scored significantly better than the control group for PT isokinetic flexion (delta = 1.56±1.56 Nm; p = 0.03) and extension (delta = 3.32±2.61 Nm; p = 0.03), PT isometric strength (delta = 9.74±3.90 Nm; p = 0.02), 6MWT (delta = 7.67±8.29 m; p = 0.04), handgrip endurance (delta = 21.41±16.28 s; p = 0.02), and muscle density assessed with pQCT. No serious adverse effects were reported in either group. In conclusion, a nutritional supplement containing 1.5 g of calcium HMB for 8 weeks in healthy elderly women had no significant effects on SPPB, but did significantly improve several muscle strength and physical performance parameters. ClinicalTrials.gov NCT02118181.

Efficacy and tolerability of rivastigmine patch therapy in patients with mild-to-moderate Alzheimer's dementia associated with minimal and moderate ischemic white matter hyperintensities: A multicenter prospective open-label clinical trial.

PubMed

Park, Kyung Won; Kim, Eun-Joo; Han, Hyun Jeong; Shim, Yong S; Kwon, Jae C; Ku, Bon D; Park, Kee Hyung; Yi, Hyon-Ah; Kim, Kwang K; Yang, Dong Won; Lee, Ho-Won; Kang, Heeyoung; Kwon, Oh Dae; Kim, SangYun; Lee, Jae-Hyeok; Chung, Eun Joo; Park, Sang-Won; Park, Mee Young; Yoon, Bora; Kim, Byeong C; Seo, Sang Won; Choi, Seong Hye

2017-01-01

Studies investigating the impact of white matter hyperintensities (WMHs) on the response of acetylcholinesterase inhibitors in patients with Alzheimer's disease (AD) have presented inconsistent results. We aimed to compare the effects of the rivastigmine patch between patients with AD with minimal WMHs and those with moderate WMHs. Three hundred patients with mild to moderate AD were enrolled in this multicenter prospective open-label study and divided into two groups. Group 1 comprised patients with AD with minimal WMHs and group 2 comprised those with moderate WMHs. The patients were treated with a rivastigmine patch for 24 weeks. Efficacy measures were obtained at baseline and after 24 weeks. The primary endpoint was the change in the AD Assessment Scale-Cognitive subscale (ADAS-Cog) from the baseline to the end of the study. Of the 300 patients, there were 206 patients in group 1 and 94 patients in group 2. The intention-to-treat group comprised 198 patients (group 1, n = 136; group 2, n = 46) during the 24-week study period. Demographic factors did not differ between group 1 and group 2. There were no significant differences in change in ADAS-cog between group 1 (-0.62±5.70) and group 2 (-0.23±5.98) after the 24-week rivastigmine patch therapy (p = 0.378). The patients in group 1 had a 0.63-point improvement from baseline on the Frontal Assessment Battery, while group 2 had a 0.16-point decline compared to baseline at the end of the study (p = 0.037). The rates of adverse events (AEs) (42.6 vs. 40.3%) and discontinuation due to AEs (10.3% vs. 4.3%) did not differ between the groups. Although the efficacy and tolerability of rivastigmine patch therapy were not associated with WMH severity in patients with AD, some improvement in frontal function was observed in those with minimal WMHs. ClinicalTrials.gov NCT01380288.

An open label pilot study of citalopram for depression and boredom in ambulatory cancer patients.

PubMed

Theobald, Dale E; Kirsh, Kenneth L; Holtsclaw, Elizabeth; Donaghy, Kathleen; Passik, Steven D

2003-03-01

Significant levels of depressive symptoms are an impediment to adjustment and affect greater than one-third of people with cancer. The clinical diagnosis of major depression is estimated to occur in 25%. Depression is dramatically underrecognized by oncologists and oncology nurses, and as a result, often undertreated. Clinical experience suggests that antidepressants of virtually all types are well tolerated and potentially efficacious. There is, however, a lack of an evidence base for the use of antidepressants in cancer patients. We undertook an open-label pilot study using citalopram in 30 cancer patients who reported a high level of depressive symptoms on the Zung Self-Rating Depression Scale (ZSDS). In addition to the ZSDS, eligible patients completed a series of visual analog scales for pain, depression, and sleep disturbance; the Functional Assessment of Cancer Therapy-General Module; and the Purposelessness, Understimulation, and Boredom Scale developed by the research team. Patients began a 2-month course of therapy with citalopram 20 mg, increasing to 40 mg at the end of the fourth week if the patient was in the same range of depressive symptoms as measured by the ZSDS. Twenty-one of 30 patients completed the protocol. The average age of the sample was 57.32 years (SD = 12.6) and was comprised of 11 women (52.4%) and 10 men (47.6%). Depressive symptoms decreased and quality of life improved during the 8-week treatment period. Of special interest was the rate of improvement in boredom, and using the total boredom score of the PUB, significant improvement compared to baseline was seen in weeks 6 (F = 5.266, p < .05) and 8 (F = 9.248, p < .01). Overall, the positive findings suggest the need for a randomized, double-blind, placebo-controlled trial of citalopram in cancer patients. Regarding the interplay of boredom and depression, the relationship between improvements in depressive symptoms and boredom is complex. This is illustrated by the way in which the different elements respond to antidepressant treatment. Depression began to improve almost immediately upon initiation of treatment whereas improvement in boredom does not become evident until week 6.

The addition of vildagliptin to metformin prevents the elevation of interleukin 1ß in patients with type 2 diabetes and coronary artery disease: a prospective, randomized, open-label study.

PubMed

Younis, Arwa; Eskenazi, Dana; Goldkorn, Ronen; Leor, Jonathan; Naftali-Shani, Nili; Fisman, Enrique Z; Tenenbaum, Alexander; Goldenberg, Ilan; Klempfner, Robert

2017-05-22

Patients with type 2 diabetes present with an accelerated atherosclerotic process. Animal evidence indicates that dipeptidyl peptidase-4 inhibitors (gliptins) have anti-inflammatory and anti-atherosclerotic effects, yet clinical data are scarcely available. A prospective, randomized, open-label study was performed in 60 patients with coronary artery disease (CAD) and type 2 diabetes, who participated in a cardiac rehabilitation program. After a washout period of 3 weeks, patients were randomized in a 2:1 ratio to receive combined vildagliptin/metformin therapy (intervention group: n = 40) vs. metformin alone (control group: n = 20) for a total of 12 weeks. Blinded assessment of interleukin-1ß (IL-1ß, the primary endpoint), hemoglobin A1c (HbA1c), and high sensitivity C reactive protein (hsCRP), were performed at baseline and after 12 weeks. Mean age of study patients was 67 ± 9 years, 75% were males, and baseline HbA1c and inflammatory markers levels were similar between the two groups. At 12 weeks of follow up, levels of IL-1ß, hsCRP, and HbA1c were significantly lower in the intervention group as compared with the control group. There was a continuous elevation of IL-1ß among the control group, which was not observed in the intervention group (49 vs. 4%, respectively; p < 0.001). The hsCRP was lowered by 60% in the vildagliptin/metformin group vs. 23% in the metformin group (p < 0.01). Moreover, a significant relative reduction of the HbA1c was seen in the intervention group (7% reduction, p < 0.03). The addition of vildagliptin to metformin treatment in patients with type 2 diabetes and CAD led to a significant suppression of the IL-1ß elevation during follow up. A significant relative reduction of hsCRP and HbA1c in the intervention group was also observed. Trial registration NCT01604213.

Triptorelin 6-month formulation in the management of patients with locally advanced and metastatic prostate cancer: an open-label, non-comparative, multicentre, phase III study.

PubMed

Lundström, Eija A; Rencken, Rupert K; van Wyk, Johann H; Coetzee, Lance J E; Bahlmann, Johann C M; Reif, Simon; Strasheim, Erdam A; Bigalke, Martin C; Pontin, Alan R; Goedhals, Louis; Steyn, Douw G; Heyns, Chris F; Aldera, Luigi A; Mackenzie, Thomas M; Purcea, Daniela; Grosgurin, Pierre Y; Porchet, Hervé C

2009-01-01

Triptorelin 6-month formulation was developed to offer greater convenience to both patients and physicians by reducing the injection frequency. The efficacy, pharmacokinetics and safety of a new 6-month formulation of triptorelin were investigated over 12 months (48 weeks). The primary objective was to evaluate the formulation in achieving castrate serum testosterone levels (< or = 1.735 nmol/L or < or = 50 ng/dL) on day 29 and in maintaining castration at months 2-12. Absence of luteinizing hormone (LH) stimulation and change in prostate-specific antigen (PSA) level were also assessed. An open-label, non-comparative, phase III study in 120 patients with advanced prostate cancer was conducted from July 2006 to August 2007 in private and public institutions in South Africa. Each patient received two consecutive intramuscular injections of triptorelin embonate (pamoate) 22.5 mg at an interval of 24 weeks. In all patients, testosterone (primary outcome measurement) was measured at baseline and then every 4 weeks; LH was measured before and 2 hours after the two injections. PSA was measured on day 1 and at weeks 12, 24, 36 and 48. Adverse events were recorded at each visit. In the intent-to-treat population, 97.5% (95% CI 92.9, 99.5) of patients achieved castrate serum testosterone levels by day 29, and 93.0% (95% CI 86.8, 97.0) maintained castration at months 2-12. After the second injection, 98.3% of patients showed absence of LH stimulation. The most frequent drug-related adverse events were hot flushes (71.7% of patients). No patient withdrew from the study as a result of an adverse event. The triptorelin 6-month formulation was well tolerated and was able to achieve and maintain castration for the treatment of locally advanced and metastatic prostate cancer. By reducing the frequency of required injections, this new formulation offers a more convenient treatment regimen. (Clinical Trial Registration,NCT00751790 at www.clinicaltrials.gov).

Efficacy and tolerability of rivastigmine patch therapy in patients with mild-to-moderate Alzheimer’s dementia associated with minimal and moderate ischemic white matter hyperintensities: A multicenter prospective open-label clinical trial

PubMed Central

Kim, Eun-Joo; Han, Hyun Jeong; Shim, Yong S.; Kwon, Jae C.; Ku, Bon D.; Park, Kee Hyung; Yi, Hyon-Ah; Kim, Kwang K.; Yang, Dong Won; Lee, Ho-Won; Kang, Heeyoung; Kwon, Oh Dae; Kim, SangYun; Lee, Jae-Hyeok; Chung, Eun Joo; Park, Sang-Won; Park, Mee Young; Yoon, Bora; Kim, Byeong C.; Seo, Sang Won; Choi, Seong Hye

2017-01-01

Background and objective Studies investigating the impact of white matter hyperintensities (WMHs) on the response of acetylcholinesterase inhibitors in patients with Alzheimer’s disease (AD) have presented inconsistent results. We aimed to compare the effects of the rivastigmine patch between patients with AD with minimal WMHs and those with moderate WMHs. Methods Three hundred patients with mild to moderate AD were enrolled in this multicenter prospective open-label study and divided into two groups. Group 1 comprised patients with AD with minimal WMHs and group 2 comprised those with moderate WMHs. The patients were treated with a rivastigmine patch for 24 weeks. Efficacy measures were obtained at baseline and after 24 weeks. The primary endpoint was the change in the AD Assessment Scale-Cognitive subscale (ADAS-Cog) from the baseline to the end of the study. Results Of the 300 patients, there were 206 patients in group 1 and 94 patients in group 2. The intention-to-treat group comprised 198 patients (group 1, n = 136; group 2, n = 46) during the 24-week study period. Demographic factors did not differ between group 1 and group 2. There were no significant differences in change in ADAS-cog between group 1 (-0.62±5.70) and group 2 (-0.23±5.98) after the 24-week rivastigmine patch therapy (p = 0.378). The patients in group 1 had a 0.63-point improvement from baseline on the Frontal Assessment Battery, while group 2 had a 0.16-point decline compared to baseline at the end of the study (p = 0.037). The rates of adverse events (AEs) (42.6 vs. 40.3%) and discontinuation due to AEs (10.3% vs. 4.3%) did not differ between the groups. Conclusions Although the efficacy and tolerability of rivastigmine patch therapy were not associated with WMH severity in patients with AD, some improvement in frontal function was observed in those with minimal WMHs. Trial registration ClinicalTrials.gov NCT01380288 PMID:28786987

Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1): an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment.

PubMed

Ranganath, Lakshminarayan R; Milan, Anna M; Hughes, Andrew T; Dutton, John J; Fitzgerald, Richard; Briggs, Michael C; Bygott, Helen; Psarelli, Eftychia E; Cox, Trevor F; Gallagher, James A; Jarvis, Jonathan C; van Kan, Christa; Hall, Anthony K; Laan, Dinny; Olsson, Birgitta; Szamosi, Johan; Rudebeck, Mattias; Kullenberg, Torbjörn; Cronlund, Arvid; Svensson, Lennart; Junestrand, Carin; Ayoob, Hana; Timmis, Oliver G; Sireau, Nicolas; Le Quan Sang, Kim-Hanh; Genovese, Federica; Braconi, Daniela; Santucci, Annalisa; Nemethova, Martina; Zatkova, Andrea; McCaffrey, Judith; Christensen, Peter; Ross, Gordon; Imrich, Richard; Rovensky, Jozef

2016-02-01

Alkaptonuria (AKU) is a serious genetic disease characterised by premature spondyloarthropathy. Homogentisate-lowering therapy is being investigated for AKU. Nitisinone decreases homogentisic acid (HGA) in AKU but the dose-response relationship has not been previously studied. Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1) was an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study. The primary objective was to investigate the effect of different doses of nitisinone once daily on 24-h urinary HGA excretion (u-HGA24) in patients with AKU after 4 weeks of treatment. Forty patients were randomised into five groups of eight patients each, with groups receiving no treatment or 1 mg, 2 mg, 4 mg and 8 mg of nitisinone. A clear dose-response relationship was observed between nitisinone and the urinary excretion of HGA. At 4 weeks, the adjusted geometric mean u-HGA24 was 31.53 mmol, 3.26 mmol, 1.44 mmol, 0.57 mmol and 0.15 mmol for the no treatment or 1 mg, 2 mg, 4 mg and 8 mg doses, respectively. For the most efficacious dose, 8 mg daily, this corresponds to a mean reduction of u-HGA24 of 98.8% compared with baseline. An increase in tyrosine levels was seen at all doses but the dose-response relationship was less clear than the effect on HGA. Despite tyrosinaemia, there were no safety concerns and no serious adverse events were reported over the 4 weeks of nitisinone therapy. In this study in patients with AKU, nitisinone therapy decreased urinary HGA excretion to low levels in a dose-dependent manner and was well tolerated within the studied dose range. EudraCT number: 2012-005340-24. Registered at ClinicalTrials.gov: NCTO1828463. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

The use of probiotic L. fermentum ME-3 containing Reg'Activ Cholesterol supplement for 4 weeks has a positive influence on blood lipoprotein profiles and inflammatory cytokines: an open-label preliminary study.

PubMed

Kullisaar, Tiiu; Zilmer, Kersti; Salum, Tiit; Rehema, Aune; Zilmer, Mihkel

2016-10-28

Cardiovascular diseases continue to be a challenge and burden to heath. The incidence of type 2 diabetes is increasing. Modifying the (common) risk factors of them is the key of longterm success. The aim of the study was to establish if the special composition of innovative food supplement Reg'Activ Cholesterol (RAC) has a positive influence to the human body cardiovascular-inflammatory and diabetic parameters. Forty-five clinically asymptomatic participants consumed an RAC containing an antioxidative and antiatherogenic probiotic Lactobacillus fermentum ME-3 (LFME-3) for 4 weeks. The parameters measured were total cholesterol, HDL cholesterol, LDL cholesterol, triglyceride, oxLDL, hsCRP, IL-6 and glycosylated haemoglobin (HbA1c%). The cardiovascular and diabetes risk profile of the participants improved significantly after 4 weeks of the intervention. The reduction of total cholesterol (from 6.5 ± 1.0 to 5.7 ± 0.9 mmol/l, p = 9.90806E-11) was on the account of LDL cholesterol as the HDL cholesterol level rose from 1.60 ± 0.31to 1.67 ± 0.34mml/l, p = 0.01. HbA1c% was reduced from 5.85 ± 0.28 to 5.66 ± 0.25 p = 4.64E-05 and oxLDL decreased from 84 ± 20 to 71 ± 15 U/l, p = 4.66292E-08. The consumption of RAC in clinically asymptomatic volunteers with borderline-high values of risk factors for cardiovascular disease (BMI, HbA1c%, LDL cholesterol) for 4 weeks had a positive effect on blood lipoprotein, oxidative stress and inflammatory profile. There are no human trials published before with RAC. The trial described here isa n open label pilot study within the framework of a larger special clinical trial ( ISRCTN55339917 ) [Accessed 20 Feb 2016].

Switching from oral extended-release methylphenidate to the methylphenidate transdermal system: continued ADHD symptom control and tolerability after abrupt conversion

PubMed Central

Arnold, L. E.; Hodgkins, P.; McKay, M.; Beckett-Thurman, L.; Greenbaum, M.; Bukstein, O.; Patel, A.; Bozzolo, D. R.

2013-01-01

Objective To evaluate symptom control and tolerability after abrupt conversion from oral extended-release methylphenidate (ER-MPH) to methylphenidate transdermal system (MTS) via a dose-transition schedule in children with attention-deficit/hyperactivity disorder (ADHD). Methods In a 4-week, prospective, multisite, open-label study, 171 children (164 intent-to-treat) with diagnosed ADHD aged 6–12 years abruptly switched from a stable dose of oral ER-MPH to MTS in nominal dosages of 10, 15, 20, and 30 mg using a predefined dose-transition schedule. After the first week on the scheduled dose, the dose was titrated to optimal effect. The primary effectiveness outcome was the change from baseline (while taking ER-MPH) to week 4 in ADHD-Rating Scale-IV (ADHD-RS-IV) total scores. Adverse events (AEs) were assessed throughout the study. Results Most subjects (58%) remained on the initial MTS dose defined by the dose-transition schedule; 38% increased and 4% decreased their MTS dose for optimization. MTS dose optimization resulted in significantly better ADHD-RS-IV total (mean ± SD) scores at week 4 than at baseline (9.9±7.47 vs 14.1±7.48; p<0.0001). The most commonly reported AEs included headache, decreased appetite, insomnia, and upper abdominal pain. Four subjects (2.3%) discontinued because of application site reactions and 3 discontinued because of other AEs. Conclusions Abrupt conversion from a stable dose of oral ER-MPH to MTS was accomplished using a predefined dose-transition schedule without loss of symptom control; however, careful titration to optimal dose is recommended. Most AEs were mild to moderate and, with the exception of application site reactions, were similar to AEs typically observed with oral MPH. Limitations of this study included its open-label sequential design without placebo, which could result in spurious attribution of improvement to the study treatment and precluded superiority determinations of MTS over baseline ER-MPH treatment. The apparent superiority of MTS was likely due to more careful titration and clinical monitoring rather than the product itself. NCT NCT00151983 PMID:19916704

Aquatic therapy versus conventional land-based therapy for Parkinson's disease: an open-label pilot study.

PubMed

Vivas, Jamile; Arias, Pablo; Cudeiro, Javier

2011-08-01

To assess and compare 2 different protocols of physiotherapy (land or water therapy) for people with Parkinson's disease (PD) focused on postural stability and self-movement, and to provide methodological information regarding progression within the program for a future larger trial. Randomized, controlled, open-label pilot trial. Outpatients, Parkinson's disease Center of Ferrol-Galicia (Spain). Individuals (N=11) with idiopathic PD in stages 2 or 3 according to the Hoehn and Yahr Scale completed the investigation (intervention period plus follow-up). After baseline evaluations, participants were randomly assigned to a land-based therapy (active control group) or a water-based therapy (experimental group). Participants underwent individual sessions for 4 weeks, twice a week, for 45 minutes per session. Both interventions were matched in terms of exercise features, which were structured in stages with clear objectives and progression criteria to pass to the next phase. Participants underwent a first baseline assessment, a posttest immediately after 4 weeks of intervention, and a follow-up assessment after 17 days. Evaluations were performed OFF-dose after withholding medication for 12 hours. Functional assessments included the Functional Reach Test (FRT), the Berg Balance Scale (BBS), the UPDRS, the 5-m walk test, and the Timed Up and Go test. A main effect of both therapies was seen for the FRT. Only the aquatic therapy group improved in the BBS and the UPDRS. In this pilot study, physiotherapy protocols produced improvement in postural stability in PD that was significantly larger after aquatic therapy. The intervention protocols are shown to be feasible and seem to be of value in amelioration of postural stability-related impairments in PD. Some of the methodological aspects detailed here can be used to design larger controlled trials. Copyright © 2011 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

The 5-HT1A receptor agonist buspirone improves esophageal motor function and symptoms in systemic sclerosis: a 4-week, open-label trial.

PubMed

Karamanolis, George P; Panopoulos, Stylianos; Denaxas, Konstantinos; Karlaftis, Anastasios; Zorbala, Alexandra; Kamberoglou, Dimitrios; Ladas, Spiros D; Sfikakis, Petros P

2016-09-01

Acute administration of the oral 5-HT1A receptor agonist buspirone, which is commonly used as an anxiolytic drug, may improve compromised lower esophageal sphincter function. In an open-label trial we assessed the effects of buspirone on esophageal motor function and symptoms in patients with esophageal involvement associated with systemic sclerosis (SSc). Thirty consecutive patients with SSc and symptomatic esophageal involvement, despite treatment with proton pump inhibitors, underwent high resolution manometry and chest computed tomography for assessment of motor function and esophageal dilatation, respectively. Regurgitation, heartburn, dysphagia, and chest pain severity was subjectively scored by visual analog scales. Manometric parameters (primary endpoint) and symptom severity (secondary endpoint) were re-examined after 4-week daily administration of 20 mg buspirone. Other medications remained unchanged. Eight patients did not complete the trial because of buspirone-associated dizziness (n = 2), or nausea (n = 2), or reluctancy to undergo final manometry. In the remaining 22 patients lower esophageal sphincter (LES) resting pressure increased from 7.7 ± 3.9 to 12.2 ± 4.6 mmHg (p = 0.00002) after buspirone administration; other manometric parameters did not change. Statistical analysis revealed negative correlation between individual increases in resting LES pressure and supra-aortic esophageal diameter (r = -0.589, p = 0.017), suggesting a more beneficial effect in patients with less severely affected esophageal function. Heartburn and regurgitation scores decreased at 4 weeks compared to baseline (p = 0.001, and p = 0.022, respectively). Our findings warrant more conclusive evaluation with a double-blind controlled study; however, buspirone could potentially be given under observation for objective improvement in all patients with SSc who report reflux symptoms despite undergoing standard treatment. ClinicalTrials.gov Identifier: NCT02363478 Registered: 21-02-2014.

The safety and tolerability of vortioxetine: Analysis of data from randomized placebo-controlled trials and open-label extension studies

PubMed Central

Baldwin, David S; Chrones, Lambros; Florea, Ioana; Nielsen, Rebecca; Nomikos, George G; Palo, William; Reines, Elin

2016-01-01

The safety and tolerability of vortioxetine in adults with major depressive disorder was assessed. Tolerability was based on the nature, incidence and severity of treatment-emergent adverse events (TEAEs) during acute (6/8) week treatment in 11 randomized, double-blind placebo-controlled short-term studies in major depressive disorder: six with an active reference. Symptoms following discontinuation were assessed through the Discontinuation-Emergent Signs and Symptoms checklist in three studies. Long-term (⩽52 weeks) tolerability was evaluated in five open-label extension studies. Patients (n =5701) were acutely treated with either placebo (n=1817), vortioxetine (5–20mg/day; n=3018), venlafaxine XR (225mg/day; n=113) or duloxetine (60mg/day; n=753). The withdrawal rate due to TEAEs during treatment with vortioxetine (5–20mg/day) was 4.5–7.8%, compared with placebo (3.6%), venlafaxine XR (14.2%) or duloxetine (8.8%). Common TEAEs (incidence ⩾5% and >2 × placebo) with vortioxetine (5–20mg/day) were nausea (20.9–31.2%) and vomiting (2.9–6.5%). For vortioxetine (5–20mg/day), the incidence of TEAEs associated with insomnia was 2.0–5.1% versus 4.0% for placebo, and with sexual dysfunction 1.6–1.8% versus 1.0% for placebo. Discontinuation symptoms as assessed by the mean Discontinuation-Emergent Signs and Symptoms total score after abrupt discontinuation were comparable to placebo in the first and second week. Vortioxetine had no effect relative to placebo on clinical laboratory parameters, body weight, heart rate or blood pressure. Vortioxetine showed no clinically relevant effect on ECG parameters, including the QTcF interval. In long-term treatment, no new types of TEAEs were seen; the mean weight gain was 0.7–0.8kg. Thus, vortioxetine (5–20mg/day) appears safe and generally well tolerated in the treatment of major depressive disorder. PMID:26864543

The safety and tolerability of vortioxetine: Analysis of data from randomized placebo-controlled trials and open-label extension studies.

PubMed

Baldwin, David S; Chrones, Lambros; Florea, Ioana; Nielsen, Rebecca; Nomikos, George G; Palo, William; Reines, Elin

2016-03-01

The safety and tolerability of vortioxetine in adults with major depressive disorder was assessed. Tolerability was based on the nature, incidence and severity of treatment-emergent adverse events (TEAEs) during acute (6/8) week treatment in 11 randomized, double-blind placebo-controlled short-term studies in major depressive disorder: six with an active reference. Symptoms following discontinuation were assessed through the Discontinuation-Emergent Signs and Symptoms checklist in three studies. Long-term (⩽52 weeks) tolerability was evaluated in five open-label extension studies. Patients (n =5701) were acutely treated with either placebo (n=1817), vortioxetine (5-20mg/day; n=3018), venlafaxine XR (225mg/day; n=113) or duloxetine (60mg/day; n=753). The withdrawal rate due to TEAEs during treatment with vortioxetine (5-20mg/day) was 4.5-7.8%, compared with placebo (3.6%), venlafaxine XR (14.2%) or duloxetine (8.8%). Common TEAEs (incidence ⩾5% and >2 × placebo) with vortioxetine (5-20mg/day) were nausea (20.9-31.2%) and vomiting (2.9-6.5%). For vortioxetine (5-20mg/day), the incidence of TEAEs associated with insomnia was 2.0-5.1% versus 4.0% for placebo, and with sexual dysfunction 1.6-1.8% versus 1.0% for placebo. Discontinuation symptoms as assessed by the mean Discontinuation-Emergent Signs and Symptoms total score after abrupt discontinuation were comparable to placebo in the first and second week. Vortioxetine had no effect relative to placebo on clinical laboratory parameters, body weight, heart rate or blood pressure. Vortioxetine showed no clinically relevant effect on ECG parameters, including the QTcF interval. In long-term treatment, no new types of TEAEs were seen; the mean weight gain was 0.7-0.8kg. Thus, vortioxetine (5-20mg/day) appears safe and generally well tolerated in the treatment of major depressive disorder. © The Author(s) 2016.

Ziprasidone Augmentation of Escitalopram for Major Depressive Disorder: Cardiac, Endocrine, Metabolic, and Motoric Effects in a Randomized, Double-Blind, Placebo-Controlled Study.

PubMed

Mischoulon, David; Shelton, Richard C; Baer, Lee; Bobo, William V; Curren, Laura; Fava, Maurizio; Papakostas, George I

2017-04-01

To examine motoric, cardiovascular, endocrine, and metabolic effects of adjunctive ziprasidone in adults with major depressive disorder (MDD) and prior nonresponse to 8 weeks of open-label escitalopram. A multicenter, parallel, randomized, double-blind, placebo-controlled trial was conducted at 3 US academic medical centers from July 2008 to October 2013. Recruited were 139 outpatients with persistent DSM-IV MDD following an 8-week open-label trial of escitalopram. Subjects were then randomized to adjunctive ziprasidone (escitalopram + ziprasidone, n = 71) or placebo (escitalopram + placebo, n = 68) for 8 additional weeks. Cardiac and metabolic measures were obtained at each treatment visit. Barnes Akathisia Scale and Abnormal Involuntary Movement Scale (AIMS) scores were also obtained. Changes in outcome measures for each treatment group were compared by independent-samples t test. A trend toward significance (P = .06) in corrected QT interval (QTc) increase was observed for ziprasidone (mean [SD] = 8.8 [20.2] milliseconds) versus placebo (-0.02 [25.5] milliseconds). Ziprasidone-treated patients had a significantly greater increase in global akathisia scores (P = .01) and significant weight increase (mean [SD] = 3.5 [11.8] kg, or 7.7 [26.1] lb) compared to placebo (1.0 [6.4] kg, or 2.2 [14.1] lb) (P = .03). No significant changes in AIMS scores were observed for either treatment group. Adjunctive ziprasidone, added to escitalopram, led to a greater weight gain and greater but modest akathisia compared to placebo. The effect of ziprasidone on QTc showed a trend toward significance, and therefore caution should be used in the administration of ziprasidone. While ziprasidone augmentation in patients with MDD appears safe, precautions should be taken in practice, specifically regular monitoring of electrocardiogram, weight, extrapyramidal symptoms, and involuntary movements. ClinicalTrials.gov identifier: NCT00633399​​. © Copyright 2016 Physicians Postgraduate Press, Inc.

A phase I open-label dose-escalation study of the anti-HER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer.

PubMed

Reynolds, Kerry Lynn; Bedard, Philippe L; Lee, Se-Hoon; Lin, Chia-Chi; Tabernero, Josep; Alsina, Maria; Cohen, Ezra; Baselga, José; Blumenschein, George; Graham, Donna M; Garrido-Laguna, Ignacio; Juric, Dejan; Sharma, Sunil; Salgia, Ravi; Seroutou, Abdelkader; Tian, Xianbin; Fernandez, Rose; Morozov, Alex; Sheng, Qing; Ramkumar, Thiruvamoor; Zubel, Angela; Bang, Yung-Jue

2017-09-12

Human epidermal growth factor receptor 3 (HER3) is important in maintaining epidermal growth factor receptor-driven cancers and mediating resistance to targeted therapy. A phase I study of anti-HER3 monoclonal antibody LJM716 was conducted with the primary objective to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), and dosing schedule. Secondary objectives were to characterize safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. This open-label, dose-finding study comprised dose escalation, followed by expansion in patients with squamous cell carcinoma of the head and neck or esophagus, and HER2-overexpressing metastatic breast cancer or gastric cancer. During dose escalation, patients received LJM716 intravenous once weekly (QW) or every two weeks (Q2W), in 28-day cycles. An adaptive Bayesian logistic regression model was used to guide dose escalation and establish the RDE. Exploratory pharmacodynamic tumor studies evaluated modulation of HER3 signaling. Patients received LJM716 3-40 mg/kg QW and 20 mg/kg Q2W (54 patients; 36 patients at 40 mg/kg QW). No dose-limiting toxicities (DLTs) were reported during dose-escalation. One patient experienced two DLTs (diarrhea, hypokalemia [both grade 3]) in the expansion phase. The RDE was 40 mg/kg QW, providing drug levels above the preclinical minimum effective concentration. One patient with gastric cancer had an unconfirmed partial response; 17/54 patients had stable disease, two lasting >30 weeks. Down-modulation of phospho-HER3 was observed in paired tumor samples. LJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing. Clinicaltrials.gov registry number NCT01598077 (registered on 4 May, 2012).

A randomized double-blind, placebo-controlled efficacy and safety study of ALO-02 (extended-release oxycodone surrounding sequestered naltrexone) for moderate-to-severe chronic low back pain treatment.

PubMed

Rauck, Richard L; Hale, Martin E; Bass, Almasa; Bramson, Candace; Pixton, Glenn; Wilson, Jacquelyn G; Setnik, Beatrice; Meisner, Paul; Sommerville, Kenneth W; Malhotra, Bimal K; Wolfram, Gernot

2015-09-01

The objective of this multicenter, double-blind, placebo-controlled, randomized withdrawal study was to evaluate the efficacy and safety of ALO-02, an abuse-deterrent formulation containing pellets of extended-release oxycodone hydrochloride (HCl) surrounding sequestered naltrexone HCl, compared with placebo in the treatment of moderate-to-severe chronic low back pain. An open-label titration period in which all patients received ALO-02 was followed by a double-blind treatment period where patients meeting treatment response criteria were randomized to either a fixed dose of ALO-02 or placebo. Daily average low back pain was assessed using an 11-point numeric rating scale (NRS)-Pain. Of the 663 patients screened, 410 received ALO-02 during the open-label conversion and titration period and 281 patients were randomized to the double-blind treatment period (n = 134, placebo; n = 147, ALO-02). Change in the mean NRS-Pain score from randomization baseline to the final 2 weeks of the treatment period was significantly different favoring ALO-02 compared with placebo (P = 0.0114). Forty-four percent of patients treated with placebo and 57.5% of patients treated with ALO-02 reported ≥30% improvement in weekly average NRS-Pain scores from screening to the final 2 weeks of the treatment period (P = 0.0248). In the double-blind treatment period, 56.8% of patients in the ALO-02 group and 56.0% of patients in the placebo group experienced a treatment-emergent adverse event (TEAE). The most common treatment-related TEAEs for ALO-02 during the treatment period were nausea, vomiting, and constipation, consistent with opioid therapy. ALO-02 has been demonstrated to provide significant reduction of pain in patients with chronic low back pain and has a safety profile similar to other opioids.

Proton pump inhibitors and vascular function: A prospective cross-over pilot study.

PubMed

Ghebremariam, Yohannes T; Cooke, John P; Khan, Fouzia; Thakker, Rahul N; Chang, Peter; Shah, Nigam H; Nead, Kevin T; Leeper, Nicholas J

2015-08-01

Proton pump inhibitors (PPIs) are commonly used drugs for the treatment of gastric reflux. Recent retrospective cohorts and large database studies have raised concern that the use of PPIs is associated with increased cardiovascular (CV) risk. However, there is no prospective clinical study evaluating whether the use of PPIs directly causes CV harm. We conducted a controlled, open-label, cross-over pilot study among 21 adults aged 18 and older who are healthy (n=11) or have established clinical cardiovascular disease (n=10). Study subjects were assigned to receive a PPI (Prevacid; 30 mg) or a placebo pill once daily for 4 weeks. After a 2-week washout period, participants were crossed over to receive the alternate treatment for the ensuing 4 weeks. Subjects underwent evaluation of vascular function (by the EndoPAT technique) and had plasma levels of asymmetric dimethylarginine (ADMA, an endogenous inhibitor of endothelial function previously implicated in PPI-mediated risk) measured prior to and after each treatment interval. We observed a marginal inverse correlation between the EndoPAT score and plasma levels of ADMA (r = -0.364). Subjects experienced a greater worsening in plasma ADMA levels while on PPI than on placebo, and this trend was more pronounced amongst those subjects with a history of vascular disease. However, these trends did not reach statistical significance, and PPI use was also not associated with an impairment in flow-mediated vasodilation during the course of this study. In conclusion, in this open-label, cross-over pilot study conducted among healthy subjects and coronary disease patients, PPI use did not significantly influence vascular endothelial function. Larger, long-term and blinded trials are needed to mechanistically explain the correlation between PPI use and adverse clinical outcomes, which has recently been reported in retrospective cohort studies. © The Author(s) 2015.

Dolutegravir versus placebo in subjects harbouring HIV-1 with integrase inhibitor resistance associated substitutions: 48-week results from VIKING-4, a randomized study.

PubMed

Akil, Bisher; Blick, Gary; Hagins, Debbie P; Ramgopal, Moti N; Richmond, Gary J; Samuel, Rafik M; Givens, Naomi; Vavro, Cindy; Song, Ivy H; Wynne, Brian; Ait-Khaled, Mounir

2015-01-01

The Phase III VIKING-3 study demonstrated that dolutegravir (DTG) 50 mg twice daily was efficacious in antiretroviral therapy (ART)-experienced subjects harbouring raltegravir- and/or elvitegravir-resistant HIV-1. VIKING-4 (ING116529) included a placebo-controlled 7-day monotherapy phase to demonstrate that short-term antiviral activity was attributable to DTG. VIKING-4 is a Phase III randomized, double-blind study in therapy-experienced adults with integrase inhibitor (INI)-resistant virus randomized to DTG 50 mg twice daily or placebo while continuing their failing regimen (without raltegravir or elvitegravir) for 7 days (clinicaltrials.gov identifier NCT01568892). At day 8, all subjects switched to open-label DTG 50 mg twice daily and optimized background therapy including ≥1 fully active drug. The primary end point was change from baseline in plasma HIV-1 RNA at day 8. The study population (n=30) was highly ART-experienced with advanced HIV disease. Patients had extensive baseline resistance to all approved antiretroviral classes. Adjusted mean change in HIV-1 RNA at day 8 was 
-1.06 log10 copies/ml for the DTG arm and 0.10 log10 copies/ml for the placebo arm (treatment difference -1.16 log10 copies/ml [-1.52, -0.80]; P<0.001). Overall, 47% and 57% of subjects had plasma HIV-1 RNA <50 and <400 copies/ml at week 24, and 40% and 53% at week 48, respectively. No discontinuations due to drug-related adverse events occurred in the study. The observed day 8 antiviral activity in this highly treatment-experienced population with INI-resistant HIV-1 was attributable to DTG. Longer-term efficacy (after considering baseline ART resistance) and safety during the open-label phase were in-line with the results of the larger VIKING-3 study.

An Open-Label Study of the Long-Term Safety of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis (RECAP).

PubMed

Costabel, Ulrich; Albera, Carlo; Lancaster, Lisa H; Lin, Chin-Yu; Hormel, Philip; Hulter, Henry N; Noble, Paul W

2017-01-01

RECAP (NCT00662038) was an open-label extension study in patients with idiopathic pulmonary fibrosis (IPF) who completed either the Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) 016 phase 3 trial or the Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY) 004/006 phase 3 trials. To obtain long-term safety data for pirfenidone in patients with IPF in RECAP. Of the 1,334 patients who participated in the phase 3 trials, 1,058 entered RECAP. The final analysis from enrollment (September 2008) to June 2015 is presented. Mean (SD) and median (range) pirfenidone exposures in RECAP were 122 (98) weeks and 88 (>0 to 349) weeks, respectively, with a mean daily dose of 2,091.1 mg. Cumulative total exposure was 2,482 patient exposure years (PEY). The treatment-emergent adverse event (TEAE) rate was 701.9 per 100 PEY. The serious TEAE rate was 53.5 per 100 PEY, with the most common serious TEAE being IPF (11.1 per 100 PEY). Of the 231 deaths (9.3 per 100 PEY), the most common cause was IPF (5.4 per 100 PEY). The treatment discontinuation rate due to a TEAE was 17.9 per 100 PEY; discontinuations were due to IPF (7.2 per 100 PEY), pneumonia, respiratory failure, acute respiratory failure, rash (0.5 per 100 PEY each), and nausea (0.4 per 100 PEY). For patients from CAPACITY 004/006 who entered RECAP, the mean change in percent predicted forced vital capacity from RECAP baseline at 180 weeks was -9.6%. Median on-treatment survival from the first pirfenidone dose in RECAP was 77.2 months. RECAP provides long-term follow-up and safety data for pirfenidone that were consistent with the known profile, with no new safety signals observed. © 2017 The Author(s) Published by S. Karger AG, Basel.

Efficacy, safety and tolerability of ongoing statin plus ezetimibe versus doubling the ongoing statin dose in hypercholesterolemic Taiwanese patients: an open-label, randomized clinical trial

PubMed Central

2012-01-01

Background Reducing low-density lipoprotein cholesterol (LDL-C) is associated with reduced risk for major coronary events. Despite statin efficacy, a considerable proportion of statin-treated hypercholesterolemic patients fail to reach therapeutic LDL-C targets as defined by guidelines. This study compared the efficacy of ezetimibe added to ongoing statins with doubling the dose of ongoing statin in a population of Taiwanese patients with hypercholesterolemia. Methods This was a randomized, open-label, parallel-group comparison study of ezetimibe 10 mg added to ongoing statin compared with doubling the dose of ongoing statin. Adult Taiwanese hypercholesterolemic patients not at optimal LDL-C levels with previous statin treatment were randomized (N = 83) to ongoing statin + ezetimibe (simvastatin, atorvastatin or pravastatin + ezetimibe at doses of 20/10, 10/10 or 20/10 mg) or doubling the dose of ongoing statin (simvastatin 40 mg, atorvastatin 20 mg or pravastatin 40 mg) for 8 weeks. Percent change in total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides, and specified safety parameters were assessed at 4 and 8 weeks. Results At 8 weeks, patients treated with statin + ezetimibe experienced significantly greater reductions compared with doubling the statin dose in LDL-C (26.2% vs 17.9%, p = 0.0026) and total cholesterol (20.8% vs 12.2%, p = 0.0003). Percentage of patients achieving treatment goal was greater for statin + ezetimibe (58.6%) vs doubling statin (41.2%), but the difference was not statistically significant (p = 0.1675). The safety and tolerability profiles were similar between treatments. Conclusion Ezetimibe added to ongoing statin therapy resulted in significantly greater lipid-lowering compared with doubling the dose of statin in Taiwanese patients with hypercholesterolemia. Studies to assess clinical outcome benefit are ongoing. Trial registration Registered at ClinicalTrials.gov: NCT00652327 PMID:22621316

A Randomized, Open-Label Trial to Evaluate Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Plus Darunavir in Treatment-Experienced HIV-1-Infected Adults

PubMed Central

Tebas, Pablo; Gallant, Joel; Wilkin, Timothy; Cheng, Andrew; Yan, Mingjin; Zhong, Lijie; Callebaut, Christian; Custodio, Joseph M.; Fordyce, Marshall W.; Das, Moupali; McCallister, Scott

2017-01-01

Background: HIV-infected, treatment-experienced adults with a history of prior resistance and regimen failure can be virologically suppressed but may require multitablet regimens associated with lower adherence and potential resistance development. Methods: We enrolled HIV-infected, virologically suppressed adults with 2-class to 3-class drug resistance and at least 2 prior regimen failures into this phase 3, open-label, randomized study. The primary endpoint was the percentage of participants with HIV-1 RNA <50 copies per milliliter at week 24 [Food and Drug Administration (FDA) snapshot algorithm]. Results: For 135 participants [elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) plus darunavir (DRV), n = 89; baseline regimen, n = 46], most of whom were taking a median of 5 tablets/d, simplification to E/C/F/TAF plus DRV was noninferior to continuation of baseline regimens at week 24 (plasma HIV-1 RNA <50 copies per milliliter: 96.6% vs. 91.3%, difference 5.3%, 95.001% CI: −3.4% to 17.4%). E/C/F/TAF plus DRV met prespecified criteria for noninferiority and superiority at week 48 for the same outcome. E/C/F/TAF plus DRV was well tolerated and had an improved renal safety profile compared with baseline regimens, with statistically significant differences between groups in quantitative total proteinuria and markers of proximal tubular proteinuria. Compared with baseline regimens, participants who switched to E/C/F/TAF plus DRV reported higher mean treatment satisfaction scale total scores and fewer days with missed doses. Conclusions: This study demonstrated that regimen simplification from a 5-tablet regimen to the 2-tablet, once-daily combination of E/C/F/TAF plus DRV has durable maintenance of virologic suppression and improvements in specific markers of renal safety. Such a strategy may lead to greater adherence and improved quality of life. PMID:27753684

Immunogenicity of simultaneous versus sequential administration of a 23-valent pneumococcal polysaccharide vaccine and a quadrivalent influenza vaccine in older individuals: A randomized, open-label, non-inferiority trial.

PubMed

Nakashima, Kei; Aoshima, Masahiro; Ohfuji, Satoko; Yamawaki, Satoshi; Nemoto, Masahiro; Hasegawa, Shinya; Noma, Satoshi; Misawa, Masafumi; Hosokawa, Naoto; Yaegashi, Makito; Otsuka, Yoshihito

2018-03-21

It is unclear whether simultaneous administration of a 23-valent pneumococcal polysaccharide vaccine (PPSV23) and a quadrivalent influenza vaccine (QIV) produces immunogenicity in older individuals. This study tested the hypothesis that the pneumococcal antibody response elicited by simultaneous administration of PPSV23 and QIV in older individuals is not inferior to that elicited by sequential administration of PPSV23 and QIV. We performed a single-center, randomized, open-label, non-inferiority trial comprising 162 adults aged ≥65 years randomly assigned to either the simultaneous (simultaneous injections of PPSV23 and QIV) or sequential (control; PPSV23 injected 2 weeks after QIV vaccination) groups. Pneumococcal immunoglobulin G (IgG) titers of serotypes 23F, 3, 4, 6B, 14, and 19A were assessed. The primary endpoint was the serotype 23F response rate (a ≥2-fold increase in IgG concentrations 4-6 weeks after PPSV23 vaccination). With the non-inferiority margin set at 20% fewer patients, the response rate of serotype 23F in the simultaneous group (77.8%) was not inferior to that of the sequential group (77.6%; difference, 0.1%; 90% confidence interval, -10.8% to 11.1%). None of the pneumococcal IgG serotype titers were significantly different between the groups 4-6 weeks after vaccination. Simultaneous administration did not show a significant decrease in seroprotection odds ratios for H1N1, H3N2, or B/Phuket influenza strains other than B/Texas. Additionally, simultaneous administration did not increase adverse reactions. Hence, simultaneous administration of PPSV23 and QIV shows an acceptable immunogenicity that is comparable to sequential administration without an increase in adverse reactions. (This study was registered with ClinicalTrials.gov [NCT02592486]).

Evaluation of open-label topiramate as primary or adjunctive therapy in infantile spasms.

PubMed

Zou, Li-Ping; Lin, Qing; Qin, Jiong; Cai, Fang-Cheng; Liu, Zhi-Sheng; Mix, Eilhard

2008-01-01

A multicenter open-label clinical trial was conducted to evaluate the clinical usefulness of topiramate (TPM) as primary or adjunctive therapy for infantile spasms in the postmarketing period in China. Thirty-four centers participated in the trial. Patients included in the study had 1 or more seizures per day before treatment. One hundred twenty (22.1%) very young patients with an age younger than 6 month and 64.2% of patients were younger than 1 year at start of treatment. All patients received a starting dose of 0.5 to 1 mg kg d TPM twice daily. The dosage was increased by 0.5 to 1 mg kg d every 5 to 7 days up to 3 to 5 mg kg d. The resulting range of the total TPM dosage was 25 to 200 mg d (3.57-20 mg kg d), with a median value of 73.9 mg d. Seizure outcomes were measured by intention-to-treat analysis. Patients were seen by a neurologist, and their data were evaluated at the day of inclusion and after 4, 8, 12, 16, and 20 weeks (from visit 1 to visit 5) of treatment. Five hundred forty-four patients entered the study. After 20 weeks of TPM treatment, 239 patients (43.9%) were seizure-free. A higher proportion of patients in the monotherapy group than in the add-on therapy group showed a seizure rate reduction. An increase in seizure frequency was observed in 8 patients (1.5%) during the 20-week treatment period. Nineteen patients were withdrawn before completing the study, and in 46 cases, some data of the structured data files and questionnaires were missing. No efficacy of TPM treatment was recorded in these cases. Adverse effects occurred in 211 patients (38.8%). Most frequent side effects were anorexia and somnolence. Topiramate proved to be an effective and safe monotherapy and add-on therapy in patients with infantile spasms younger than 1 year.

Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST).

PubMed

McKone, Edward F; Borowitz, Drucy; Drevinek, Pavel; Griese, Matthias; Konstan, Michael W; Wainwright, Claire; Ratjen, Felix; Sermet-Gaudelus, Isabelle; Plant, Barry; Munck, Anne; Jiang, Ying; Gilmartin, Geoffrey; Davies, Jane C

2014-11-01

Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, is approved for the treatment of patients with cystic fibrosis aged 6 years or older with Gly551Asp-CFTR. We assessed the safety and efficacy of ivacaftor during 96 weeks of PERSIST in patients with cystic fibrosis who completed a previous 48-week, placebo-controlled trial of the drug (STRIVE or ENVISION). In this phase 3, open-label extension study, patients received ivacaftor 150 mg every 12 h in addition to their prescribed cystic fibrosis therapies. Patients who received placebo in their previous study initiated ivacaftor in this extension study. Patients were eligible if they had a Gly551Asp-CFTR mutation on at least one allele. The primary objective was to assess the long-term safety profile of ivacaftor as assessed by adverse events, clinical laboratory assessments, electrocardiograms, vital signs, and physical examination; secondary measures included change in forced expiratory volume in one second (FEV1), weight, and pulmonary exacerbations. This study is registered with ClinicalTrials.gov, number NCT01117012 and EudraCT, number 2009-012997-11. Between July 8, 2010, and April 8, 2013, 144 adolescents/adults (≥12 years) from STRIVE and 48 children (6-11 years) from ENVISION were enrolled. Across both trials, 38 (20%) patients had a serious adverse event during the first 48 weeks and 44 (23%) during the subsequent 48 weeks. Two adults (1%) and one child (<1%) discontinued because of adverse events. The most common adverse events were pulmonary exacerbation, cough, and upper respiratory tract infection. Patients previously treated with ivacaftor had sustained improvements in FEV1, weight, and rate of pulmonary exacerbations for up to 144 weeks of treatment. Among adolescents/adults and children who previously received ivacaftor, absolute change in FEV1 at week 96 (144 weeks ivacaftor) was 9·4 and 10·3 % points and absolute increase in weight was 4·1 kg and 14·8 kg, respectively. For adolescents/adults only, the pulmonary exacerbation rate remained suppressed compared with that of patients who received placebo in the placebo-controlled study. At 144 weeks of treatment, ivacaftor was well tolerated, with no new safety concerns. Ivacaftor also provided durable effects for 144 weeks in patients who had received active treatment in the placebo-controlled study. Those patients who previously received placebo had improvements comparable to those of patients treated with ivacaftor in the placebo-controlled study. Vertex Pharmaceuticals Inc. Copyright © 2014 Elsevier Ltd. All rights reserved.

Comparison of imiquimod, topical fluorouracil, and electrocautery for the treatment of anal intraepithelial neoplasia in HIV-positive men who have sex with men: an open-label, randomised controlled trial.

PubMed

Richel, Olivier; de Vries, Henry J C; van Noesel, Carel J M; Dijkgraaf, Marcel G W; Prins, Jan M

2013-04-01

Anal cancer is an increasing issue in HIV-positive men who have sex with men (MSM). Screening for its precursor, anal intraepithelial neoplasia (AIN), is subject of discussion. Current treatment options are suboptimum and have not been compared in a prospective trial. We compared efficacy and side-effects of imiquimod, topical fluorouracil, and electrocautery for the treatment of AIN. In this open-label randomised trial, we included HIV-positive MSM older than 18 years visiting the HIV outpatient clinic of the Academic Medical Center, Amsterdam, Netherlands. Patients with histologically confirmed AIN were randomly assigned to receive either 16 weeks of imiquimod (three times a week), 16 weeks of topical fluorouracil (twice a week), or monthly electrocautery for 4 months. Randomisation was done with random block sizes of three and six, stratified for AIN grade (AIN grades 1, 2, or 3) and AIN location (peri-anal or intra-anal). Participants were assessed by high-resolution anoscopy 4 weeks after treatment. Responding patients returned for follow-up 24 weeks, 48 weeks, and 72 weeks after treatment. The primary endpoint was histological resolution of AIN measured 4 weeks after treatment and AIN recurrence at week 24, week 48, and week 72 after treatment. The primary analysis was done in a modified intention-to-treat population, including all patients who had received their assigned treatment at least once. The trial is registered at the Netherlands Trial Register, number NTR1236. Between Aug 12, 2008, and Dec 1, 2010, we screened 388 HIV-positive MSM for AIN by high resolution anoscopy. Of the 246 (63%) patients who had AIN, 156 (63%) were randomly assigned to either receive imiquimod (54 patients), topical fluorouracil (48 patients), or electrocautery (46 patients) following withdrawing of consent by eight patients. Modified intention-to-treat analysis showed a complete response in 13 (24%, 95% CI 15-37) patients in the imiquimod group, eight (17%, 8-30) of patients in the fluorouracil group, and 18 (39%, 26-54) of patients in the electrocautery group (p=0·027). At week 24, 11 (22%) of 50 responders had recurrence; at week 48, 22 (46%) of 48 had recurred; and at week 72, 30 (67%) of 45 had recurred. Recurrence was observed at 72 weeks in 10 (71%) of 14 patients treated with imiquimod, seven (58%) of 12 patients treated with fluorouracil, and 13 (68%) of 19 patients treated with electrocautery. Grade 3-4 side-effects were noted in 23 (43%) of 53 patients in the imiquimod group, 13 (27%) of 48 patients in the fluorouracil group, and eight (18%) patients in the electrocautery group (p=0·019). The most common side-effects were pain, bleeding, and itching. Seven serious adverse events occurred, all not related to the study. Electrocautery is better than imiquimod and fluorouracil in the treatment of AIN, but recurrence rates are substantial. Anna Maurits de Cock foundation provided funding for the video colposcope. Copyright © 2013 Elsevier Ltd. All rights reserved.

Efficacy and safety of tadalafil in men with erectile dysfunction with a high prevalence of comorbid conditions: results from MOMENTUS: multiple observations in men with erectile dysfunction in National Tadalafil Study in the US.

PubMed

Goldstein, Irwin; Kim, Edward; Steers, William D; Pryor, Jon L; Wilde, Dixon W; Natanegara, Fanni; Wong, David G; Ahuja, Sanjeev

2007-01-01

Limited efficacy and safety data exist from open-label clinical trials of phosphodiesterase 5 inhibitors in men with erectile dysfunction (ED) and multiple comorbid (MCM) conditions, historically a difficult group to treat. A multicenter study (Multiple Observations in Men with Erectile Dysfunction in National Tadalafil Study in the US) assessed efficacy and safety of tadalafil in men with ED and MCM conditions. The primary end point was change from baseline in the erectile function (EF) domain of the International Index of Erectile Function. Secondary end points included the Sexual Encounter Profile, Global Assessment Questions, and Sexual Self-Confidence and Spontaneity Domains of the Psychological and Interpersonal Relationship Scales. This was an open-label, multicenter study in men with ED. Tadalafil 20 mg was administered as needed prior to sexual activity, up to once/day, for 12 weeks following a 4-week ED-treatment-free period. The MCM group was 155 of 1,911 men enrolled in this study. Men in the MCM group met eligibility criteria but could not be included in other predefined groups: (i) Caucasian; (ii) Black American; (iii) Hispanic (groups 1-3, < or =65 years, no diabetes or depression); (iv) depression, < or =65 years, no diabetes; (v) diabetes, < or =65 years, no depression; (vi) >65 years, no diabetes or depression; and (vii) ED subsequent to traumatic spinal cord injury. Mean baseline EF domain score in MCM (mean age 65 +/- 9 years) was 12.2 +/- 6.5; 52% of subjects had severe ED; 72% diabetes mellitus; 67% cardiovascular disease (including hypertension); 49% hyperlipidemia; 38% depression; 84% had two or more comorbidities. At end point, there was a significant (P < 0.001) mean change of 7.6 from baseline in mean EF domain score. Among men with severe ED, 22% achieved an EF domain score > or =26. Most common adverse events were headache 5.2%; flushing 3.9% and nasal congestion 3.2%; 3% discontinued use because of an adverse event. In this open-label clinical trial of older men with ED and MCMs, tadalafil 20 mg significantly increased all efficacy end points and was well-tolerated.

Antiviral therapy in hepatitis B virus-infected children with immune-tolerant characteristics: A pilot open-label randomized study.

PubMed

Zhu, Shishu; Zhang, Hongfei; Dong, Yi; Wang, Limin; Xu, Zhiqiang; Liu, Weiwei; Gan, Yu; Tang, Hongmei; Chen, Dawei; Wang, Fuchuan; Zhao, Pan

2018-06-01

Chronic infection with hepatitis B virus (HBV) in children is a serious health problem worldwide. How to treat children with immune-tolerant chronic hepatitis B infection, commonly characterized by hepatitis B e antigen (HBeAg) positivity, high viral load, normal or mildly elevated alanine aminotransferase and no or minimal inflammation in liver histology, remains unresolved. This trial aims to study the benefits of antiviral therapy in children with these characteristics. This is a pilot open-label randomized controlled study. From May 2014 to April 2015, 69 treatment-naive chronically HBV-infected children, aged 1 to 16 years, who had immune-tolerant characteristics were recruited to this trial and randomly assigned, in a 2:1 ratio, to treatment group and control group. Patients in the treatment group received either interferon-α (IFN) monotherapy or consecutively received IFN monotherapy, combination therapy of IFN and lamivudine (LAM), and LAM therapy alone. All patients were observed until week 96. At baseline, epidemiological, biochemical, serological, virological and histological indices were consistent across the treatment and control groups. Of the 46 patients in the treatment group, 73.91% had undetectable serum HBV DNA, 32.61% achieved HBeAg seroconversion and 21.74% lost hepatitis B surface antigen (HBsAg) at the endpoint. No LAM resistance emerged at week 96. In the control group, only one (4.35%) patient underwent spontaneous HBeAg seroconversion and had undetectable serum HBV DNA during observation, and moreover, none developed HBsAg clearance. For all patients, no serious adverse events were observed. Antiviral treatment with a sequential combination of IFN and LAM resulted in a significant improvement in the rates of undetectable serum HBV DNA, HBeAg seroconversion and HBsAg loss in children with chronic HBV infection and immune-tolerant characteristics. There is a lack of data regarding treatment of immune-tolerant chronic hepatitis B (CHB). It remains unresolved how children with immune-tolerant CHB should be treated. This paper reports the outcomes from a pilot open-label randomized controlled trial on antiviral therapy in children with immune-tolerant characteristics. It shows that a sequential combination of interferon-α and lamivudine was beneficial. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Adherence to Preexposure Prophylaxis: Current, Emerging, and Anticipated Bases of Evidence

PubMed Central

Amico, K. Rivet; Stirratt, Michael J.

2014-01-01

Despite considerable discussion and debate about adherence to preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV), scant data are available that characterize patterns of adherence to open-label PrEP. The current evidence base is instead dominated by research on adherence to placebo-controlled investigational drug by way of drug detection in active-arm participants of large randomized controlled trials (RCTs). Important differences between the context of blinded RCTs and open-label use suggest caution when generalizing from study product adherence to real-world PrEP use. Evidence specific to open-label PrEP adherence is presently sparse but will expand rapidly over the next few years as roll-out, demonstration projects, and more rigorous research collect and present findings. The current evidence bases established cannot yet predict uptake, adherence, or persistence with open-label effective PrEP. Emerging evidence suggests that some cohorts could execute better adherence in open-label use vs placebo-controlled research. Uptake of PrEP is presently slow in the United States; whether this changes as grassroots and community efforts increase awareness of PrEP as an effective HIV prevention option remains to be determined. As recommended by multiple guidelines for PrEP use, all current demonstration projects offer PrEP education and/or counseling. PrEP support approaches generally fall into community-based, technology, monitoring, and integrated sexual health promotion approaches. Developing and implementing research that moves beyond simple correlates of either study product use or open-label PrEP adherence toward more comprehensive models of sociobehavioral and socioecological adherence determinants would greatly accelerate progress. Intervention research is needed to identify effective models of support for open-label PrEP adherence. PMID:24926036

An automated growth enclosure for metabolic labeling of Arabidopsis thaliana with 13C-carbon dioxide - an in vivo labeling system for proteomics and metabolomics research

PubMed Central

2011-01-01

Background Labeling whole Arabidopsis (Arabidopsis thaliana) plants to high enrichment with 13C for proteomics and metabolomics applications would facilitate experimental approaches not possible by conventional methods. Such a system would use the plant's native capacity for carbon fixation to ubiquitously incorporate 13C from 13CO2 gas. Because of the high cost of 13CO2 it is critical that the design conserve the labeled gas. Results A fully enclosed automated plant growth enclosure has been designed and assembled where the system simultaneously monitors humidity, temperature, pressure and 13CO2 concentration with continuous adjustment of humidity, pressure and 13CO2 levels controlled by a computer running LabView software. The enclosure is mounted on a movable cart for mobility among growth environments. Arabidopsis was grown in the enclosure for up to 8 weeks and obtained on average >95 atom% enrichment for small metabolites, such as amino acids and >91 atom% for large metabolites, including proteins and peptides. Conclusion The capability of this labeling system for isotope dilution experiments was demonstrated by evaluation of amino acid turnover using GC-MS as well as protein turnover using LC-MS/MS. Because this 'open source' Arabidopsis 13C-labeling growth environment was built using readily available materials and software, it can be adapted easily to accommodate many different experimental designs. PMID:21310072

Oral choline supplementation in children with intestinal failure.

PubMed

Guerrerio, Anthony L; Mattis, Lynn; Conner, Kim G; Hampsey, Jenifer; Stasinopoulos, D Mikis; DeJong, Robert; Boctor, Emad M; Sheth, Shelia; Hamper, Ulrike M; Scheimann, Ann O

2011-07-01

Choline deficiency leads to steatohepatitis, elevated transaminases, susceptibility to septic shock, and an increased risk of central catheter thrombosis. Children with intestinal failure (IF) are at risk for choline deficiency. In an unblinded, open-label study, we studied 7 children with IF on parenteral nutrition, measured their plasma free choline level, and, if low, supplemented enterally with adequate intake (AI) doses of choline. Four to 6 weeks later we remeasured their plasma free choline. Unlike adults, infants did not respond to oral choline supplementation at AI doses. Additionally, we have calculated plasma free choline percentiles versus age for normal children.

Laronidase.

PubMed

2002-01-01

BioMarin Pharmaceutical is developing laronidase, recombinant alpha-L-iduronidase enzyme replacement therapy for the treatment of mucopolysaccharidosis I (MPS-I) [the most severe form of this is called Hurler syndrome]. The company has received US and European orphan drug designation for the enzyme and has fast-track review status with the FDA. In 1998, BioMarin Pharmaceutical and Genzyme General formed a joint venture for development and marketing of laronidase. A Phase I trial in 10 patients with a range of disease severity of MPS-I required for US and European filing was completed at the Harbor-UCLA Medical Center in California. This open label trial involved weekly infusions with laronidase. The two-year follow-up data revealed sustained and, in certain parameters, improved clinical results recorded at the end of 1 year of therapy. BioMarin and Genzyme General have completed a pivotal, Phase III trial in the centres in the USA, Canada and Europe, including patients with Hurler-Scheie and Scheie syndromes. In a multicentre, double-blind, placebo-controlled study, all 45 patients with MPS-I have received at least their initial weekly infusion of laronidase. Patients are being evaluated over a 6-month period. BioMarin Pharmaceutical and Genzyme General have filed on 15 April 2002 the first portion of a 'rolling' BLA with the US FDA for use of laronidase in the treatment of MPS-I. The companies are planning to complete the BLA filing in Q3 2002. The application will include 6-month data from the ongoing open-label Phase III extension study and also the 6-month data from the placebo-controlled part of the Phase III study. In the open-label extension study, patients from both the treatment and placebo arms of the Phase III trial received weekly infusions of laronidase for at least 6 months. The response from the US FDA is anticipated during the H1 of 2003. Both companies plan to initiate two new clinical trials in patients with MPS-I. One study will enrol patients with MPS-I under 5 years old. Another study will investigate laronidase in patients with advanced clinical symptoms of MPS-I. Additionally, patients from the ongoing Phase III study will continue to receive treatment with laronidase. On 1 March 2002, BioMarin and Genzyme filed a marketing approval application with European regulatory authorities for AldurazymeOE for the treatment of MPS-I. Mucopolysaccharidosis I is a rare autosomal recessive lysosomal storage disorder caused by alpha-L-iduronidase deficiency. Its manifestations in children can include growth and developmental delay, enlargement of spleen and liver, skeletal deformity, cardiac and pulmonary impairment, vision or hearing loss and mental dysfunction. At present, bone marrow transplantation is the only available treatment.

Antihypertensive effect of barnidipine 10 mg or amlodipine 5 to 10 mg once daily in treatment-naive patients with essential hypertension: A 24-week, randomized, open-label, pilot study

PubMed Central

Rossetti, Giuseppe; Pizzocri, Samuele; Brasca, Francesco; Pozzi, Marta; Beltrami, Laura M.; Bolla, Giovanni B.; Famiani, Roberta; Caimi, Barbara; Omboni, Stefano; Magrini, Fabio; Carugo, Stefano

2008-01-01

Background: Dihydropyridine calcium antagonists are largely employed for the treatment of hypertension, coronary heart disease, and heart failure. Objective: The aim of our study was to compare the antihypertensive effect of the dihydropyridine calcium antagonists barnidipine and amlodipine. Methods: This was a 24-week, randomized, open-label, pilot study. Consecutive treatment-naive patients with grade I or II essential hypertension (office sitting systolic blood pressure [BP] of 140–179 mm Hg and diastolic BP of 90–109 mm Hg) were enrolled. The primary end points were the effect of treatment with either barnidipine 10 mg or amlodipine 5 mg once daily on office and ambulatory BP, left ventricular mass index (LVMI), and markers of cardiac damage, serum procollagen type I C-terminal propeptide, and plasma amino-terminal pro-B-type natriuretic peptide concentrations. Patients were assessed at enrollment, and 12 and 24 weeks. During each visit, the prevalence of adverse events (AEs) was also monitored using spontaneous reporting, patient interview, and physical examination, the relationship to study drug being determined by the investigators. Compliance with treatment was assessed at each study visit by counting returned tablets. Results: Thirty eligible patients (20 men, 10 women; mean [SD] age, 47 [12] years) were included in the study; all patients completed the 24 weeks of study treatment. Twelve weeks after randomization, 6 patients in the amlodipine group had their dose doubled to 10 mg due to inadequate BP control. Mean BP reductions at study end were not significantly different between the barnidipine and amlodipine groups (office BP, −10.3/−9.4 vs −16.6/−9.1 mm Hg; ambulatory BP, 9.4/6.4 vs 8.1/5.1 mm Hg). Reductions in LVMI and markers of cardiac damage were not significantly different between the 2 groups. Significantly more patients in the amlodipine group reported drug-related AEs compared with those in the barnidipine group (9 [60%] vs 2 [13%]; P < 0.05). Conclusion: In this small sample of treatment-naive hypertensive patients, the antihypertensive effect of barnidipine 10 mg once daily was not significantly different from that of amlodipine 5 to 10 mg once daily. PMID:24692798

Intensive combination treatment regimens, including prednisolone, are effective in treating patients with early rheumatoid arthritis regardless of additional etanercept: 1-year results of the COBRA-light open-label, randomised, non-inferiority trial.

PubMed

ter Wee, Marieke M; den Uyl, Debby; Boers, Maarten; Kerstens, Pit; Nurmohamed, Mike; van Schaardenburg, Dirkjan; Voskuyl, Alexandre E; Lems, Willem F

2015-06-01

Recently, we documented the likely non-inferiority of Combinatietherapie Bij Reumatoïde Artritis (COBRA)-light therapy (methotrexate increased to 25 mg/week with initial prednisolone 30 mg/day) compared with the original COBRA therapy (methotrexate 7.5 mg/week, sulfasalazine 2 g/day, with initial prednisolone 60 mg/day) after 26 weeks in patients with early active rheumatoid arthritis (RA). To assess the non-inferiority of COBRA-light versus COBRA after 1 year in terms of disease activity (DAS44), functional outcome (Health Assessment Questionnaire (HAQ)) and radiographic progression (Sharp/van der Heijde score (SHS)), and to assess the effect of adding etanercept. An open-label, randomised controlled, non-inferiority trial of 162 patients with active early RA, following a treat-to-target protocol incorporating the addition of etanercept if DAS44 ≥1.6 at weeks 26 or 39. Both groups showed major improvements in DAS44 after 52 weeks: mean (SD) -2.41 (1.2) in the COBRA and -2.02 (1.0) in the COBRA-light group (p=ns). In both groups, functional ability improved and radiological progression of joints was minimal. At least one adverse event was reported in 96% of the patients in both groups. In total, 25 serious adverse events occurred: 9 vs 16 in COBRA and COBRA-light, respectively. Treatment actually instituted was often less intensive than required by the protocol: of the total population, 108 patients (67%) required etanercept (more in the COBRA-light group), but only 67 of these (62%) actually received it. Intensive COBRA or COBRA-light therapy has major, comparably favourable effects on disease activity, functional ability and radiological outcome after 1 year in patients with early RA. Protocolised addition of etanercept was often not implemented by treating rheumatologists, and patients receiving it appeared to have limited added benefit, probably because of low disease activity levels at its initiation. ISRCTN55552928. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Comparison of Doxycycline, Minocycline, Doxycycline plus Albendazole and Albendazole Alone in Their Efficacy against Onchocerciasis in a Randomized, Open-Label, Pilot Trial

PubMed Central

Batsa, Linda; Ayisi-Boateng, Nana Kwame; Osei-Mensah, Jubin; Mubarik, Yusif; Konadu, Peter; Ricchiuto, Arcangelo; Fimmers, Rolf; Arriens, Sandra; Dubben, Bettina; Ford, Louise; Taylor, Mark; Hoerauf, Achim

2017-01-01

The search for new macrofilaricidal drugs against onchocerciasis that can be administered in shorter regimens than required for doxycycline (DOX, 200mg/d given for 4–6 weeks), identified minocycline (MIN) with superior efficacy to DOX. Further reduction in the treatment regimen may be achieved with co-administration with standard anti-filarial drugs. Therefore a randomized, open-label, pilot trial was carried out in an area in Ghana endemic for onchocerciasis, comprising 5 different regimens: the standard regimen DOX 200mg/d for 4 weeks (DOX 4w, N = 33), the experimental regimens MIN 200mg/d for 3 weeks (MIN 3w; N = 30), DOX 200mg/d for 3 weeks plus albendazole (ALB) 800mg/d for 3 days (DOX 3w + ALB 3d, N = 32), DOX 200mg/d for 3 weeks (DOX 3w, N = 31) and ALB 800mg for 3 days (ALB 3d, N = 30). Out of 158 randomized participants, 116 (74.4%) were present for the follow-up at 6 months of whom 99 participants (63.5%) followed the treatment per protocol and underwent surgery. Histological analysis of the adult worms in the extirpated nodules revealed absence of Wolbachia in 98.8% (DOX 4w), 81.4% (DOX 3w + ALB 3d), 72.7% (MIN 3w), 64.1% (DOX 3w) and 35.2% (ALB 3d) of the female worms. All 4 treatment regimens showed superiority to ALB 3d (p < 0.001, p < 0.001, p = 0.002, p = 0.008, respectively), which was confirmed by real-time PCR. Additionally, DOX 4w showed superiority to all other treatment arms. Furthermore DOX 4w and DOX 3w + ALB 3d showed a higher amount of female worms with degenerated embryogenesis compared to ALB 3d (p = 0.028, p = 0.042, respectively). These results confirm earlier studies that DOX 4w is sufficient for Wolbachia depletion and the desired parasitological effects. The data further suggest that there is an additive effect of ALB (3 days) on top of that of DOX alone, and that MIN shows a trend for stronger potency than DOX. These latter two results are preliminary and need confirmation in a fully randomized controlled phase 2 trial. Trial Registration: ClinicalTrials.gov #06010453 PMID:28056021

Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a prior history - an open-label randomised trial (the EPPI trial): study protocol.

PubMed

Groom, K M; McCowan, L M; Stone, P R; Chamley, L C; McLintock, C

2016-11-22

Preeclampsia and intrauterine fetal growth restriction (IUGR) are two of the most common causes of maternal and perinatal morbidity and mortality. Current methods of predicting those at most risk of these conditions remain relatively poor, and in clinical practice past obstetric history remains the most commonly used tool. Aspirin and, in women at risk of preeclampsia only, calcium have been demonstrated to have a modest effect on risk reduction. Several observational studies and randomised trials suggest that low molecular weight heparin (LMWH) therapy may confer some benefit. This is a multicentre open label randomised controlled trial to determine the effect of the LMWH, enoxaparin, on the prevention of recurrence of preeclampsia and/or IUGR in women at high risk due to their past obstetric history in addition to standard high risk care for all participants. A singleton pregnancy >6 +0 and <16 +0 weeks gestation with most recent prior pregnancy with duration >12 weeks having; (1) preeclampsia delivered <36 +0 weeks, (2) Small for gestational age (SGA) infant <10 th customised birthweight centile delivered <36 +0 weeks or, (3) SGA infant ≤3 rd customised birthweight centile delivered at any gestation. Randomisation is stratified for maternal thrombophilia status and women are randomly assigned to 'standard high risk care' or 'standard high risk care' plus enoxaparin 40 mg from recruitment until 36 +0 weeks or delivery, whichever occurs sooner. Standard high risk care includes the use of aspirin 100 mg daily and calcium 1000-1500 mg daily (unless only had previous SGA with no preeclampsia). The primary outcome is preeclampsia and/or SGA <5 th customised birthweight centile. Analysis will be by intention to treat. The EPPI trial has more focussed and clinically relevant inclusion criteria than other randomised trials with a more restricted composite primary outcome. The inclusion of standard use of aspirin (and calcium) for all participants will help to ensure that any differences observed in outcome are likely to be related to enoxaparin use. These data will make a significant contribution to future meta-analyses and systematic reviews on the use of LMWH for the prevention of placental mediated conditions. ACTRN12609000699268 Australian New Zealand Clinical Trials Registry. Date registered 13/Aug/2009 (prospective registration).

Community transmission of type 2 poliovirus after cessation of trivalent oral polio vaccine in Bangladesh: an open-label cluster-randomised trial and modelling study.

PubMed

Taniuchi, Mami; Famulare, Michael; Zaman, Khalequ; Uddin, Md Jashim; Upfill-Brown, Alexander M; Ahmed, Tahmina; Saha, Parimalendu; Haque, Rashidul; Bandyopadhyay, Ananda S; Modlin, John F; Platts-Mills, James A; Houpt, Eric R; Yunus, Mohammed; Petri, William A

2017-10-01

Trivalent oral polio vaccine (tOPV) was replaced worldwide from April, 2016, by bivalent types 1 and 3 oral polio vaccine (bOPV) and one dose of inactivated polio vaccine (IPV) where available. The risk of transmission of type 2 poliovirus or Sabin 2 virus on re-introduction or resurgence of type 2 poliovirus after this switch is not understood completely. We aimed to assess the risk of Sabin 2 transmission after a polio vaccination campaign with a monovalent type 2 oral polio vaccine (mOPV2). We did an open-label cluster-randomised trial in villages in the Matlab region of Bangladesh. We randomly allocated villages (clusters) to either: tOPV at age 6 weeks, 10 weeks, and 14 weeks; or bOPV at age 6 weeks, 10 weeks, and 14 weeks and either one dose of IPV at age 14 weeks or two doses of IPV at age 14 weeks and 18 weeks. After completion of enrolment, we implemented an mOPV2 vaccination campaign that targeted 40% of children younger than 5 years, regardless of enrolment status. The primary outcome was Sabin 2 incidence in the 10 weeks after the campaign in per-protocol infants who did not receive mOPV2, as assessed by faecal shedding of Sabin 2 by reverse transcriptase quantitative PCR (RT-qPCR). The effect of previous immunity on incidence was also investigated with a dynamical model of poliovirus transmission to observe prevalence and incidence of Sabin 2 virus. This trial is registered at ClinicalTrials.gov, number NCT02477046. Between April 30, 2015, and Jan 14, 2016, individuals from 67 villages were enrolled to the study. 22 villages (300 infants) were randomly assigned tOPV, 23 villages (310 infants) were allocated bOPV and one dose of IPV, and 22 villages (329 infants) were assigned bOPV and two doses of IPV. Faecal shedding of Sabin 2 in infants who did not receive the mOPV2 challenge did not differ between children immunised with bOPV and one or two doses of IPV and those who received tOPV (15 of 252 [6%] vs six of 122 [4%]; odds ratio [OR] 1·29, 95% CI 0·45-3·72; p=0·310). However, faecal shedding of Sabin 2 in household contacts was increased significantly with bOPV and one or two doses of IPV compared with tOPV (17 of 751 [2%] vs three of 353 [1%]; OR 3·60, 95% CI 0·82-15·9; p=0·045). Dynamical modelling of within-household incidence showed that immunity in household contacts limited transmission. In this study, simulating 1 year of tOPV cessation, Sabin 2 transmission was higher in household contacts of mOPV2 recipients in villages receiving bOPV and either one or two doses of IPV, but transmission was not increased in the community as a whole as shown by the non-significant difference in incidence among infants. Dynamical modelling indicates that transmission risk will be higher with more time since cessation. Bill & Melinda Gates Foundation. Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Long-Term Safety and Tolerability of Valbenazine (NBI-98854) in Subjects with Tardive Dyskinesia and a Diagnosis of Schizophrenia or Mood Disorder

PubMed Central

Josiassen, Richard C.; Kane, John M.; Liang, Grace S.; Burke, Joshua; O’Brien, Christopher F.

2017-01-01

Background The short-term safety profile of once-daily valbenazine (NBI-98854) has been evaluated in several double-blind, placebo-controlled (DBPC) trials in adults with tardive dyskinesia (TD) who had a diagnosis of schizophrenia/schizoaffective (SCHZ) disorder or mood disorder. Studies with longer treatment duration (up to 48 weeks) were conducted to evaluate the long-term safety of this novel drug in subjects with TD. Methods The pooled long-term exposure (LTE) population included valbenazine-treated subjects from 3 studies: KINECT (NCT01688037: 6-week DBPC, 6-week open-label); KINECT 3 (NCT02274558: 6-week DBPC, 42-week blinded extension, 4-week drug-free follow-up); KINECT 4 (NCT02405091: 48-week open-label, 4-week drug-free follow-up). Safety assessments included adverse events (AEs), laboratory tests, vital signs, electrocardiograms (ECGs), and extrapyramidal symptom (EPS) scales. Psychiatric stability was monitored using the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS) (SCHZ subgroup), as well as the Montgomery-Åsberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) (mood subgroup). All data were analyzed descriptively. Results The LTE population included 430 subjects (KINECT, n = 46; KINECT 3, n = 220; KINECT 4, n = 164), 71.7% with SCHZ and 28.3% with a mood disorder; 85.5% were taking an antipsychotic (atypical only, 69.8%; typical only or typical + atypical, 15.7%). In the LTE population, treatment-emergent AEs (TEAEs) and discontinuations due to AEs were reported in 66.5% and 14.7% of subjects, respectively. The TEAE incidence was lower in the SCHZ subgroup (64.4%) than in the mood subgroup (71.9%). The 3 most common TEAEs in the SCHZ subgroup were urinary tract infection (UTI, 6.1%), headache (5.8%), and somnolence (5.2%). The 3 most common TEAEs in the mood subgroup were headache (12.4%), UTI (10.7%), and somnolence (9.1%). Mean score changes from baseline to end of treatment (Week 48) indicated that psychiatric stability was maintained in the SCHZ subgroup (PANSS Total, -3.4; PANSS Positive, -1.1; PANSS Negative, -0.1; PANSS General Psychopathology, -2.2; CDSS total, -0.4) and the mood subgroup (MADRS Total, 0.0; YMRS Total, -1.2). These scores remained generally stable during the 4-week drug-free follow-up periods. In the LTE population, mean changes in laboratory parameters, vital signs, ECG, and EPS scales were generally minimal and not clinically significant. Conclusion Valbenazine appeared to be well tolerated in adults with TD who received up to 48 weeks of treatment. In addition to long-term efficacy results (presented separately), these results suggest that valbenazine may be appropriate for the long-term management of TD regardless of underlying psychiatric diagnosis (SCHZ disorder or mood disorder). PMID:28839341

Long-Term Safety and Tolerability of Valbenazine (NBI-98854) in Subjects with Tardive Dyskinesia and a Diagnosis of Schizophrenia or Mood Disorder.

PubMed

Josiassen, Richard C; Kane, John M; Liang, Grace S; Burke, Joshua; O'Brien, Christopher F

2017-08-01

The short-term safety profile of once-daily valbenazine (NBI-98854) has been evaluated in several double-blind, placebo-controlled (DBPC) trials in adults with tardive dyskinesia (TD) who had a diagnosis of schizophrenia/schizoaffective (SCHZ) disorder or mood disorder. Studies with longer treatment duration (up to 48 weeks) were conducted to evaluate the long-term safety of this novel drug in subjects with TD. The pooled long-term exposure (LTE) population included valbenazine-treated subjects from 3 studies: KINECT (NCT01688037: 6-week DBPC, 6-week open-label); KINECT 3 (NCT02274558: 6-week DBPC, 42-week blinded extension, 4-week drug-free follow-up); KINECT 4 (NCT02405091: 48-week open-label, 4-week drug-free follow-up). Safety assessments included adverse events (AEs), laboratory tests, vital signs, electrocardiograms (ECGs), and extrapyramidal symptom (EPS) scales. Psychiatric stability was monitored using the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS) (SCHZ subgroup), as well as the Montgomery-Åsberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) (mood subgroup). All data were analyzed descriptively. The LTE population included 430 subjects (KINECT, n = 46; KINECT 3, n = 220; KINECT 4, n = 164), 71.7% with SCHZ and 28.3% with a mood disorder; 85.5% were taking an antipsychotic (atypical only, 69.8%; typical only or typical + atypical, 15.7%). In the LTE population, treatment-emergent AEs (TEAEs) and discontinuations due to AEs were reported in 66.5% and 14.7% of subjects, respectively. The TEAE incidence was lower in the SCHZ subgroup (64.4%) than in the mood subgroup (71.9%). The 3 most common TEAEs in the SCHZ subgroup were urinary tract infection (UTI, 6.1%), headache (5.8%), and somnolence (5.2%). The 3 most common TEAEs in the mood subgroup were headache (12.4%), UTI (10.7%), and somnolence (9.1%). Mean score changes from baseline to end of treatment (Week 48) indicated that psychiatric stability was maintained in the SCHZ subgroup (PANSS Total, -3.4; PANSS Positive, -1.1; PANSS Negative, -0.1; PANSS General Psychopathology, -2.2; CDSS total, -0.4) and the mood subgroup (MADRS Total, 0.0; YMRS Total, -1.2). These scores remained generally stable during the 4-week drug-free follow-up periods. In the LTE population, mean changes in laboratory parameters, vital signs, ECG, and EPS scales were generally minimal and not clinically significant. Valbenazine appeared to be well tolerated in adults with TD who received up to 48 weeks of treatment. In addition to long-term efficacy results (presented separately), these results suggest that valbenazine may be appropriate for the long-term management of TD regardless of underlying psychiatric diagnosis (SCHZ disorder or mood disorder).

Treatment of molluscum contagiosum with an East Indian sandalwood oil product.

PubMed

Haque, Malika; Coury, Daniel L

2017-11-22

To evaluate the safety and efficacy of an East Indian sandalwood oil (EISO) product as a topical treatment for molluscum contagiosum. Ten subjects ranging in age from 22 months to 29 years were recruited. Subjects were instructed to apply an EISO product to the lesions twice daily. Subjects were monitored every two to three weeks during the study and were questioned regarding local or systemic side effects. Assessment of response was recorded by counting lesions and documented by photographs. Nine of ten subjects (90%) experienced complete resolution of molluscum lesions within the twelve week study period. Response was unrelated to lesion size or number, how long the molluscum rash had been present, or patient age or gender. There were no complaints of side effects, skin irritation, pain, or other adverse events reported in any subjects. In this pilot open label study, an EISO product proved to be an effective treatment for molluscum contagiosum lesions with resolution of lesions typically occurring within twelve weeks of therapy.

Cevimeline.

PubMed

Weber, Juliane; Keating, Gillian M

2008-01-01

Cevimeline is an orally administered muscarinic receptor agonist that is indicated for the treatment of symptoms of dry mouth in patients with Sjogren's syndrome. Several well designed placebo-controlled trials demonstrated that 4-12 weeks' therapy with cevimeline 30 mg three times daily improved symptoms of dry mouth in patients with Sjogren's syndrome. Other symptoms, such as dry eye symptoms and overall dryness, also improved to a significantly greater extent with cevimeline than with placebo. Moreover, cevimeline significantly improved the salivary flow rate in patients with Sjogren's syndrome. Increased salivary flow was maintained in the longer term with cevimeline in patients with Sjogren's syndrome and symptoms of dry mouth, according to the results of an open-label 52-week study. From week 20 onwards, rates of patient and investigator satisfaction with the cevimeline dosage were > or =88%. Oral cevimeline 30 mg three times daily was generally well tolerated in patients with Sjogren's syndrome, with many of the most commonly reported adverse events reflecting the pharmacological action of the drug.

Efficacy and tolerability of itopride hydrochloride in patients with non-ulcer dyspepsia.

PubMed

Shenoy, K T; Veenasree; Leena, K B

2003-06-01

To document the clinical efficacy and tolerability of itopride hydrochloride in patients with non-ulcer dyspepsia an open-label, non-comparative study, was undertaken at the Medical College, Thiruvananthapuram, among patients with endoscopically confirmed diagnosis of non-ulcer dyspepsia or chronic gastritis. Itopride hydrochloride 50 mg (1 tablet) thrice a day for 2 weeks was administered among them. Relief of symptoms at the end of two weeks treatment, assessed as marked/complete, moderate, slight, none or worse; QT interval on ECG; adverse events; haemogram; serum chemistry for hepatic and renal functions. None had QT prolongation on ECG. At the end of 2 weeks' treatment, moderate to complete relief of symptoms was reported by 22 patients (73%), whereas 5 (17%) reproted slight improvement, and 3 (10%) reported no improvement. Clinical tolerability was excellent in 28 patients (93%) and good in 2 (7%). None of the patients had any prolongation of QT on ECG, nor did any patient show any abnormality in haemogram or serum chemistry during the treatment.

Douching with Water Works device for perceived vaginal odor with or without complaints of discharge in women with no infectious cause of vaginitis: a pilot study.

PubMed

Chatwani, Ashwin J; Hassan, Sarmina; Rahimi, Salma; Jeronis, Stacey; Dandolu, Vani

2006-01-01

To determine if douching with Water Works device for 1 month can (1) lower or eliminate perceived vaginal odor by subject; (2) have any effects on vaginal ecosystem. Ten women with perceived vaginal odor with or without discharge, douched every day for 4 weeks in an open-label, nonrandomized pilot study. Primary outcome measures included perceived vaginal odor by subject, lactobacilli score from Nugent slide, and acceptance of the Water Works douching system. Secondary outcome included the safety of using this douching device. At week 4, there was improvement in vaginal odor (P=.0006) and there was no significant change in lactobacilli score. Douching with Water Works device is associated with reduction or elimination of vaginal odor without adversely affecting the vaginal ecosystem.

Tracking the autochthonous carbon transfer in stream biofilm food webs.

PubMed

Risse-Buhl, Ute; Trefzger, Nicolai; Seifert, Anne-Gret; Schönborn, Wilfried; Gleixner, Gerd; Küsel, Kirsten

2012-01-01

Food webs in the rhithral zone rely mainly on allochthonous carbon from the riparian vegetation. However, autochthonous carbon might be more important in open canopy streams. In streams, most of the microbial activity occurs in biofilms, associated with the streambed. We followed the autochthonous carbon transfer toward bacteria and grazing protozoa within a stream biofilm food web. Biofilms that developed in a second-order stream (Thuringia, Germany) were incubated in flow channels under climate-controlled conditions. Six-week-old biofilms received either ¹³C- or ¹²C-labeled CO₂, and uptake into phospholipid fatty acids was followed. The dissolved inorganic carbon of the flow channel water became immediately labeled. In biofilms grown under 8-h light/16-h dark conditions, more than 50% of the labeled carbon was incorporated in biofilm algae, mainly filamentous cyanobacteria, pennate diatoms, and nonfilamentous green algae. A mean of 29% of the labeled carbon reached protozoan grazer. The testate amoeba Pseudodifflugia horrida was highly abundant in biofilms and seemed to be the most important grazer on biofilm bacteria and algae. Hence, stream biofilms dominated by cyanobacteria and algae seem to play an important role in the uptake of CO₂ and transfer of autochthonous carbon through the microbial food web.

Do nutrition labels influence healthier food choices? Analysis of label viewing behaviour and subsequent food purchases in a labelling intervention trial.

PubMed

Ni Mhurchu, Cliona; Eyles, Helen; Jiang, Yannan; Blakely, Tony

2018-02-01

There are few objective data on how nutrition labels are used in real-world shopping situations, or how they affect dietary choices and patterns. The Starlight study was a four-week randomised, controlled trial of the effects of three different types of nutrition labels on consumer food purchases: Traffic Light Labels, Health Star Rating labels, or Nutrition Information Panels (control). Smartphone technology allowed participants to scan barcodes of packaged foods and receive randomly allocated labels on their phone screen, and to record their food purchases. The study app therefore provided objectively recorded data on label viewing behaviour and food purchases over a four-week period. A post-hoc analysis of trial data was undertaken to assess frequency of label use, label use by food group, and association between label use and the healthiness of packaged food products purchased. Over the four-week intervention, study participants (n = 1255) viewed nutrition labels for and/or purchased 66,915 barcoded packaged products. Labels were viewed for 23% of all purchased products, with decreasing frequency over time. Shoppers were most likely to view labels for convenience foods, cereals, snack foods, bread and bakery products, and oils. They were least likely to view labels for sugar and honey products, eggs, fish, fruit and vegetables, and meat. Products for which participants viewed the label and subsequently purchased the product during the same shopping episode were significantly healthier than products where labels were viewed but the product was not subsequently purchased: mean difference in nutrient profile score -0.90 (95% CI -1.54 to -0.26). In a secondary analysis of a nutrition labelling intervention trial, there was a significant association between label use and the healthiness of products purchased. Nutrition label use may therefore lead to healthier food purchases. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

A multicenter study of topical azelaic acid 15% gel in combination with oral doxycycline as initial therapy and azelaic acid 15% gel as maintenance monotherapy.

PubMed

Thiboutot, Diane M; Fleischer, Alan B; Del Rosso, James Q; Rich, Phoebe

2009-07-01

This two-phase, multicenter study was undertaken to examine the safety and efficacy of combination therapy with oral doxycycline and topical azelaic acid (AzA) 15% gel in moderate-to-severe papulopustular rosacea and to determine the effect of subsequent maintenance monotherapy with AzA 15% gel alone. In the initial open-label, non-randomized phase of the study, subjects (n=172) received topical AzA 15% gel and oral doxycycline (100 mg), both twice daily, for < or = 12 weeks. In the second, double-blind study phase, subjects who had initially undergone at least four weeks of combination treatment in phase 1 and who achieved > or = 75% inflammatory lesion count reduction (n=136) were randomized to receive either AzA 15% gel or its vehicle twice daily for an additional 24 weeks. Assessments of efficacy were obtained at four-week intervals throughout both phases of the study and included change in inflammatory lesion count, investigator global assessment (IGA) of rosacea severity, and separate assessments of erythema and telangiectasia severity. At the last visit for each phase of the study, the investigator and participant each rated overall improvement, with the participant rating cosmetic acceptability and the investigator rating treatment as "success" or "failure" based on IGA score. During the second phase of the trial, the rate of relapse -- defined as either a 50% deterioration in the lesion count improvement from phase 1, an increase in erythema intolerable to the subject or maintenance therapy failure as judged by the investigator and/or the subject -- was obtained. Safety assessments were conducted for both phases of the study and included analysis of adverse events (AEs) and a rating of cutaneous tolerability by the subject. By week 12 of the open-label phase of the study, 81.4% of subjects had reached a 75% or greater reduction in inflammatory lesion count, and 64% of patients achieved treatment success. During the second study phase (maintenance phase), AzA 15% gel consistently provided a better maintenance response than vehicle, with maintenance of remission in 75% of patients over the six-month duration of the maintenance phase. Additionally AzA 15% gel showed a statistically significantly lower deterioration in absolute inflammatory lesion counts than did vehicle after 8, 16, 20 and 24 weeks of maintenance therapy. No serious treatment-related AEs were encountered in the study, and 98.5% of subjects were satisfied with the local tolerability of both AzA gel and vehicle.

S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer (TRICOLORE): a randomized, open-label, phase III, noninferiority trial.

PubMed

Yamada, Y; Denda, T; Gamoh, M; Iwanaga, I; Yuki, S; Shimodaira, H; Nakamura, M; Yamaguchi, T; Ohori, H; Kobayashi, K; Tsuda, M; Kobayashi, Y; Miyamoto, Y; Kotake, M; Shimada, K; Sato, A; Morita, S; Takahashi, S; Komatsu, Y; Ishioka, C

2018-03-01

Combination therapy with oral fluoropyrimidine and irinotecan has not yet been established as first-line treatment of metastatic colorectal cancer (mCRC). We carried out a randomized, open-label, phase III trial to determine whether S-1 and irinotecan plus bevacizumab is noninferior to mFOLFOX6 or CapeOX plus bevacizumab in terms of progression-free survival (PFS). Patients from 53 institutions who had previously untreated mCRC were randomly assigned (1 : 1) to receive either mFOLFOX6 or CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; a 3-week regimen: intravenous infusions of irinotecan 150 mg/m2 and bevacizumab 7.5 mg/kg on day 1, oral S-1 80 mg/m2 twice daily for 2 weeks, followed by a 1-week rest; or a 4-week regimen: irinotecan 100 mg/m2 and bevacizumab 5 mg/kg on days 1 and 15, S-1 80 mg/m2 twice daily for 2 weeks, followed by a 2-week rest). The primary end point was PFS. The noninferiority margin was 1.25; noninferiority would be established if the upper limit of the 95% confidence interval (CI) for the hazard ratio (HR) of the control group versus the experimental group was less than this margin. Between June 2012 and September 2014, 487 patients underwent randomization. Two hundred and forty-three patients assigned to the control group and 241 assigned to the experimental group were included in the primary analysis. Median PFS was 10.8 months (95% CI 9.6-11.6) in the control group and 14.0 months (95% CI 12.4-15.5) in the experimental group (HR 0.84, 95% CI 0.70-1.02; P < 0.0001 for noninferiority, P = 0.0815 for superiority). One hundred and fifty-seven patients (64.9%) in the control group and 140 (58.6%) in the experimental group had adverse events of grade 3 or higher. S-1 and irinotecan plus bevacizumab is noninferior to mFOLFOX6 or CapeOX plus bevacizumab with respect to PFS as first-line treatment of mCRC and could be a new standard treatment. UMIN000007834.

An instrument assessing satisfaction with iron chelation therapy: Psychometric testing from an open-label clinical trial.

PubMed

Rofail, Diana; Viala, Muriel; Gater, Adam; Abetz-Webb, Linda; Baladi, Jean-Francois; Cappellini, Maria Domenica

2010-08-01

The Satisfaction with Iron Chelation Therapy (SICT) instrument was developed based on a literature review, in-depth patient and clinician interviews, and cognitive debriefing interviews. An, open-label, single arm, multicenter trial evaluating the efficacy and safety of deferasirox in patients diagnosed with transfusion-dependent iron overload, provided an opportunity to assess the psychometric measurement properties of the instrument. Psychometric analyses were performed using data at baseline from 273 patients with a range of transfusion-dependent iron overload conditions who were participating in a multinational study. Responsiveness was further evaluated for all patients who also had subsequent satisfaction domain scores collected at week 4. Baseline SICT domain scores had acceptable floor and ceiling effects and internal consistency reliability (Cronbach's alpha: 0.75-0.85). Item discriminant and item convergent validity were both excellent although one item in each analysis did not meet the specified criterion. Small to moderate correlations were observed between SICT and Short Form 36 Health Survey (SF-36) domain scores. Patients with the highest levels of serum ferritin at baseline (>3100 ng/mL) were the least satisfied about the Perceived Effectiveness of ICT and vice versa. Satisfaction improved in all patients, although there were no clear differences observed between groups of patients defined according to changes in serum ferritin levels from baseline to week 4 (stable, improved, or worsened). The SICT domains are reliable and valid. Further testing using a more specific criterion (such as assessing patient global ratings of change in satisfaction domains that correspond to the SICT domains) could help to establish with greater confidence the responsiveness of the instrument.

Effects of saxagliptin add-on therapy to insulin on blood glycemic fluctuations in patients with type 2 diabetes: A randomized, control, open-labeled trial.

PubMed

Li, Feng-Fei; Jiang, Lan-Lan; Yan, Reng-Na; Zhu, Hong-Hong; Zhou, Pei-Hua; Zhang, Dan-Feng; Su, Xiao-Fei; Wu, Jin-Dan; Ye, Lei; Ma, Jian-Hua

2016-10-01

To investigate whether saxagliptin add-on therapy to continuous subcutaneous insulin infusion (CSII) further improve blood glycemic control than CSII therapy in patients with newly diagnosed type 2 diabetes (T2D). This was a single-center, randomized, control, open-labeled trial. Newly diagnosed T2D patients were recruited between February 2014 and December 2015. Subjects were divided into saxagliptin add-on therapy to CSII group (n = 31) and CSII therapy group (n = 38). The treatment was maintained for 4 weeks. Oral glucose tolerance test was performed at baseline. Serum samples were obtained before and 30 and 120 minutes after oral administration for glucose, insulin, and C-peptide determination. Continuous glucose monitoring (CGM) was performed before and endpoint. A total of 69 subjects were admitted. After 4-week therapy, CGM data showed that patients with saxagliptin add-on therapy exhibited further improvement of mean amplitude glycemic excursion (MAGE), the incremental area under curve of plasma glucose >7.8 and 10 mmol/L compared with that of control group. In addition, the hourly mean blood glucose concentrations, especially between 0000 and 0600 in patient with saxagliptin add-on therapy, were significantly lower compared with that of the control patients. Furthermore, patients in saxagliptin add-on group needed lower insulin dose to maintain euglycemic control. In addition, severe hypoglycemic episode was not observed from any group. Saxagliptin add-on therapy to insulin had the ability of further improve blood glycemic controlling, with lower insulin dose required by patients with T2D to maintain euglycemic controlling.

A pilot study on the effect of a symbiotic mixture in irritable bowel syndrome: an open-label, partially controlled, 6-month extension of a previously published trial.

PubMed

Bucci, C; Tremolaterra, F; Gallotta, S; Fortunato, A; Cappello, C; Ciacci, C; Iovino, P

2014-04-01

In recent years, the efficacy of probiotics has received considerable attention in the treatment for irritable bowel syndrome (IBS). In this regard, a symbiotic mixture (Probinul(®)) has shown beneficial effects. The aim of this study was to extend the previously published 4-week randomized, double-blinded, placebo-controlled study of this symbiotic mixture. This is an open-label prospective, partially controlled, 6-month extension period pilot study in which patients continued to receive the symbiotic mixture (Group 1) or were switched from placebo to symbiotic mixture (Group 2) using cyclic administration (last 2 weeks/month). The primary endpoints were the overall satisfactory relief of bloating and flatulence (assessed as proportions of responders). The secondary endpoints were evaluation of the symptom severity scores (bloating, flatulence, pain and urgency) and bowel function scores (frequency, consistency and incomplete evacuation). Twenty-six IBS patients completed the 6-month extension period (13 patients in Group 1 and 13 patients in Group 2). In the per-protocol analysis, the proportions of responders across time were not significantly different in the groups but in Group 2, there was an increased percentage of responders for flatulence (p = 0.07). In addition, the score of flatulence was reduced significantly during the 6-month treatment period in Group 2 (p < 0.05), while no other significant differences were detected. Treatment with this symbiotic mixture was associated with persistence of relief from flatulence or new reduction in flatulence in the present 6-month long extension study. These results need to be more comprehensively assessed in large, long-term, randomized, placebo-controlled studies.

Tocilizumab in patients with active rheumatoid arthritis and inadequate response to disease-modifying antirheumatic drugs or tumor necrosis factor inhibitors: subanalysis of Spanish results of an open-label study close to clinical practice.

PubMed

Álvaro-Gracia, José M; Fernández-Nebro, Antonio; García-López, Alicia; Guzmán, Manuel; Blanco, Francisco J; Navarro, Francisco J; Bustabad, Sagrario; Armendáriz, Yolanda; Román-Ivorra, José A

2014-01-01

To analyze the Spanish experience in an international study which evaluated tocilizumab in patients with rheumatoid arthritis (RA) and an inadequate response to conventional disease-modifying antirheumatic drugs (DMARDs) or tumor necrosis factor inhibitors (TNFis) in a clinical practice setting. Subanalysis of 170 patients with RA from Spain who participated in a phase IIIb, open-label, international clinical trial. Patients presented inadequate response to DMARDs or TNFis. They received 8mg/kg of tocilizumab every 4 weeks in combination with a DMARD or as monotherapy during 20 weeks. Safety and efficacy of tocilizumab were analyzed. Special emphasis was placed on differences between failure to a DMARD or to a TNFi and the need to switch to tocilizumab with or without a washout period in patients who had previously received TNFi. The most common adverse events were infections (25%), increased total cholesterol (38%) and transaminases (15%). Five patients discontinued the study due to an adverse event. After six months of tocilizumab treatment, 71/50/30% of patients had ACR 20/50/70 responses, respectively. A higher proportion of TNFi-naive patients presented an ACR20 response: 76% compared to 64% in the TNFi group with previous washout and 66% in the TNFi group without previous washout. Safety results were consistent with previous results in patients with RA and an inadequate response to DMARDs or TNFis. Tocilizumab is more effective in patients who did not respond to conventional DMARDs than in patients who did not respond to TNFis. Copyright © 2013 Elsevier España, S.L. All rights reserved.

An accelerated dose escalation with a grass pollen allergoid is safe and well-tolerated: a randomized open label phase II trial.

PubMed

Chaker, A M; Al-Kadah, B; Luther, U; Neumann, U; Wagenmann, M

2015-01-01

The number of injections in the dose escalation of subcutaneous immunotherapy (SCIT) is small for some currently used hypoallergenic allergoids, but can still be inconvenient to patients and can impair compliance. The aim of this trial was to compare safety and tolerability of an accelerated to the conventional dose escalation scheme of a grass pollen allergoid. In an open label phase II trial, 122 patients were 1:1 randomized for SCIT using a grass pollen allergoid with an accelerated dose escalation comprising only 4 weekly injections (Group I) or a conventional dose escalation including 7 weekly injections (Group II). Safety determination included the occurrence of local and systemic adverse events. Tolerability was assessed by patients and physicians. Treatment-related adverse events were observed in 22 (36.1 %) patients in Group I and 15 (24.6 %) in Group II. Local reactions were reported by 18 patients in Group I and 11 in Group II. Five Grade 1 systemic reactions (WAO classification) were observed in Group I and 2 in Group II. Grade 2 reactions occurred 3 times in Group I and 2 times in Group II. Tolerability was rated as "good" or "very good" by 53 (86.9 %) patients in Group I and 59 (100 %) in Group II by investigators. Forty-eight patients in Group I (80.0 %) and 54 in Group II (91.5 %) rated tolerability as "good" or "very good". The dose escalation of a grass pollen allergoid can be accelerated with safety and tolerability profiles comparable to the conventional dose escalation.

Extended release naltrexone injection is performed in the majority of opioid dependent patients receiving outpatient induction: a very low dose naltrexone and buprenorphine open label trial.

PubMed

Mannelli, Paolo; Wu, Li-Tzy; Peindl, Kathleen S; Swartz, Marvin S; Woody, George E

2014-05-01

The approval of extended release injectable naltrexone (XR-NTX; Vivitrol(®)) has introduced a new option for treating opioid addiction, but studies are needed to identify its place within the spectrum of available therapies. The absence of physiological opioid dependence is a necessary and challenging first step for starting XR-NTX. Outpatient detoxification gives poor results and inpatient detoxification is either unavailable or too brief for the physiological effects of opioids to resolve. Here we present findings from an open label study that tested whether the transition from opioid addiction to XR-NTX can be safely and effectively performed in an outpatient setting using very low dose naltrexone and buprenorphine. Twenty treatment seeking opioid addicted individuals were given increasing doses of naltrexone starting at 0.25mg with decreasing doses of buprenorphine starting at 4 mg during a 7-day outpatient XR-NTX induction procedure. Withdrawal discomfort, craving, drug use, and adverse events were assessed daily until the XR-NTX injection, then weekly over the next month. Fourteen of the 20 participants received XR-NTX and 13 completed weekly assessments. Withdrawal, craving, and opioid or other drug use were significantly lower during induction and after XR-NTX administration compared with baseline, and no serious adverse events were recorded. Outpatient transition to XR-NTX combining upward titration of very low dose naltrexone with downward titration of low dose buprenorphine was safe, well tolerated, and completed by most participants. Further studies with larger numbers of subjects are needed to see if this approach is useful for naltrexone induction. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

A Randomized Controlled Open-Label Pilot Study of Simvastatin Addition to Whole-Brain Radiation Therapy in Patients With Brain Metastases.

PubMed

El-Hamamsy, Manal; Elwakil, Hesham; Saad, Amr S; Shawki, May A

2016-10-27

Statins have been reported to have a potential radiosensitizing effect that has not been evaluated in clinical trials. The aim of this study was to evaluate the efficacy and safety of simvastatin in addition to whole-brain radiation therapy (WBRT) in patients with brain metastases (BM). A prospective randomized, controlled, open-label pilot study was conducted on 50 Egyptian patients with BM who were randomly assigned to receive 30-Gy WBRT (control group: 25 patients) or 30 Gy WBRT + simvastatin 80 mg/day for the WBRT period (simvastatin group: 25 patients). The primary outcome was radiological response at 4 weeks after WBRT. Secondary outcomes were 1-year progression-free survival (PFS), 1-year overall survival (OS), and health-related quality of life (HRQL) that was assessed using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and its brain module (BN-20), at baseline, after WBRT, and 4 weeks after WBRT. The addition of simvastatin was tolerated. Twenty-one patients were not evaluated for radiological response because of death (n = 16), noncompliance to follow-up (n = 4), and clinical deterioration (n = 1). Response rates were 60% and 78.6% (p = 0.427), 1-year PFS rates were 5.2% and 17.7% (p = 0.392), and 1-year OS rates were 12% and 8% (p = 0.880) for the control group and simvastatin group, respectively. Nonsignificant differences were found between the two arms regarding HRQL scales. The addition of simvastatin 80 mg/day did not improve the clinical outcomes of patients with BM receiving WBRT.

Long-term safety and efficacy of dalfampridine for walking impairment in patients with multiple sclerosis: Results of open-label extensions of two Phase 3 clinical trials

PubMed Central

Goodman, Andrew D; Bethoux, Francois; Brown, Theodore R; Schapiro, Randall T; Cohen, Ron; Marinucci, Lawrence N; Henney, Herbert R

2015-01-01

Background: In Phase 3 double-blind trials (MS-F203 and MS-F204), dalfampridine extended release tablets 10 mg twice daily (dalfampridine-ER; prolonged-release fampridine in Europe; fampridine modified or sustained release elsewhere) improved walking speed relative to placebo in patients with multiple sclerosis (MS). Objectives: Evaluation of long-term safety and efficacy of dalfampridine-ER in open-label extensions (MS-F203EXT, MS-F204EXT). Methods: Patients received dalfampridine-ER 10 mg twice daily; and had Timed 25-Foot Walk (T25FW) assessments at 2, 14 and 26 weeks, and then every 6 months. Subjects were categorized as dalfampridine-ER responders or non-responders, based on their treatment response in the double-blind parent trials that assessed T25FW. Results: We had 269 patients enter MS-F203EXT and 154 patients complete it; for a maximum exposure of 5 years. We had 214 patients enter MS-F204EXT and 146 complete it; for a maximum exposure of 3.3 years. No new safety signals emerged and dalfampridine-ER tolerability was consistent with the double-blind phase. Improvements in walking speed were lost after dalfampridine-ER was discontinued in the parent trial, but returned by the 2-week assessment after re-initiation of the drug. Throughout the extensions, mean improvement in walking speed declined, but remained improved, among the double-blind responders as compared with non-responders. Conclusions: The dalfamipridine-ER safety profile was consistent with the parent trials. Although walking speed decreased over time, dalfampridine-ER responders continued to show improved walking speed, which was sustained compared with non-responders. PMID:25583832

A preliminary path analysis of expectancy and patient-provider encounter in an open-label randomized controlled trial of spinal manipulation for cervicogenic headache.

PubMed

Haas, Mitchell; Aickin, Mikel; Vavrek, Darcy

2010-01-01

The purpose of this article was to present a preliminary model to identify the effects of expectancy of treatment success and the patient-provider encounter (PPE) on outcomes in an open-label randomized trial. Eighty participants with chronic cervicogenic headache (CGH) were randomized to 4 groups: 2 levels of treatment dose (8 or 16) and 2 levels of therapy from a chiropractor (spinal manipulation or light massage). Providers were instructed to have equal enthusiasm for all care. Structural equation modeling with standardized path coefficients (beta) was used in a path analysis to identify the effects of patient expectancy and the PPE on CGH pain. The model included monthly pain from baseline to 12 weeks. Expectancy and PPE were evaluated on Likert scales. The patient-provider encounter was measured as patient perception of chiropractor enthusiasm, confidence, and comfort with care. Baseline patient expectancy was balanced across groups. The PPE measures were balanced across groups and consistent over the 8-week treatment period. Treatment and baseline pain had the strongest effects on pain outcomes (|beta| = .46-.59). Expectations had little effect on pain (abs value(beta) < .15). The patient-provider encounter had a weak effect on pain (abs value(beta)= .03-.27) and on subsequent confidence in treatment success (abs value(beta)= .09 and .12). Encouraging equipoise in the PPE and balancing expectancy across treatment groups may protect against some confounding related to the absence of blinding in a randomized controlled trial of pain. In this trial, their effects were found to be small relative to the effects of treatment and baseline values. Copyright 2010 National University of Health Sciences. Published by Mosby, Inc. All rights reserved.

Open-label, dose-titration tolerability study of atomoxetine hydrochloride in Korean, Chinese, and Taiwanese adults with attention-deficit/hyperactivity disorder.

PubMed

Takahashi, Michihiro; Goto, Taro; Takita, Yasushi; Chung, Sang-Keun; Wang, Yufeng; Gau, Susan Shur-Fen

2014-03-01

The primary objective of this study was to assess the overall safety and tolerability of atomoxetine in Korean, Chinese, and Taiwanese adults with attention-deficit/hyperactivity disorder (ADHD). A total of 44 patients aged ≥18 years who met the Conners' Adult ADHD Diagnostic Interview for DSM-IV diagnostic criteria for ADHD were enrolled from China, Korea, and Taiwan. In this open-label, dose-escalation study, patients received atomoxetine orally once daily over a period of eight weeks, starting at 40 mg/day (one week) up to a maximum dosage of 120 mg/day. Tolerability was evaluated by rate of discontinuation due to adverse events. Safety was assessed by recording all adverse events, laboratory tests, vital signs, and electrocardiograms. ADHD symptoms were evaluated by the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) for efficacy assessment. Thirty-four patients (77.3%) completed the study. Atomoxetine was well tolerated with a discontinuation rate of 2.3% (1/44) due to adverse events. The most commonly reported adverse events were nausea, dizziness, and somnolence. The mean change from baseline to endpoint in CAARS-Inv:SV total ADHD symptom score was -12.5 (P < 0.001). A significant reduction in the CAARS-Inv:SV subscales (inattentive, hyperactive/impulsive, and ADHD index score, P < 0.001) was observed. This is the first atomoxetine clinical trial in adult patients with ADHD in China, Korea, and Taiwan. Atomoxetine was well tolerated in doses of up to 120 mg/day with no unknown safety concerns. Copyright © 2012 Blackwell Publishing Asia Pty Ltd.

An open-label randomized-controlled trial of low dose aspirin with an early screening test for pre-eclampsia and growth restriction (TEST): Trial protocol.

PubMed

Mone, Fionnuala; Mulcahy, Cecilia; McParland, Peter; Stanton, Alice; Culliton, Marie; Downey, Paul; McCormack, Dorothy; Tully, Elizabeth; Dicker, Patrick; Breathnach, Fionnuala; Malone, Fergal D; McAuliffe, Fionnuala M

2016-07-01

Pre-eclampsia remains a worldwide cause of maternal and perinatal morbidity and mortality. Low dose aspirin (LDA) can reduce the occurrence of pre-eclampsia in women with identifiable risk factors. Emerging screening tests can determine the maternal risk of developing placental disease, such as pre-eclampsia from the first trimester of pregnancy. The aim of this study is to determine if it is more beneficial in terms of efficacy and acceptability to routinely prescribe LDA to nulliparous low-risk women compared to test indicated LDA on the basis of a positive screening test for placental disease. We propose a three armed multi-center open-labeled randomized control trial of; (i) routine LDA, (ii) no aspirin, and (iii) LDA on the basis of a positive first trimester pre-eclampsia screening test. LDA (75mg once daily) shall be given from the first trimester until 36-week gestation. The primary outcome measures include; (i) the proportion of eligible women that agree to participate (acceptability), (ii) compliance with study protocol (acceptability and feasibility), (iii) the proportion of women in whom it is possible to obtain first trimester trans-abdominal uterine artery Doppler examination (feasibility) and (iv) the proportion of women with a completed screening test that are issued the screening result within one week of having the test performed (feasibility). This will be the first clinical trial to determine the efficacy and acceptability in low-risk women of taking routine LDA versus no aspirin versus LDA based on a positive first trimester screening test for the prevention of placental disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Psychosocial outcomes after initial treatment of erectile dysfunction with tadalafil once daily, tadalafil on demand or sildenafil citrate on demand: results from a randomized, open-label study.

PubMed

Hatzimouratidis, K; Buvat, J; Büttner, H; Vendeira, P A S; Moncada, I; Boehmer, M; Henneges, C; Boess, F G

2014-01-01

Initiation of ED treatment with a particular PDE5I may influence treatment-adherence and other outcomes. In this multicenter, open-label study, men with ED, naïve to PDE5I, were randomized to tadalafil 5 mg once-a-day (OaD; N=257), 10 mg on demand (PRN; N = 252) or sildenafil-citrate (sildenafil) 50 mg PRN (N = 261) for 8 weeks (dose adjustments allowed), followed by 16 weeks of pragmatic treatment (switching between PDE5I allowed). Primary outcomes (treatment-adherence) were reported previously. Here, we report effects on: Psychological and Interpersonal Relationship Scales, Self-Esteem and Relationship (SEAR) questionnaire, ED Inventory of Treatment Satisfaction (EDITS), International Index of Erectile Function (IIEF), Sexual Encounter Profile (SEP) and Global Assessment Questions (GAQ). Mixed-model for repeated measures and analysis of covariance were used to analyze changes from baseline; GAQ-responses were evaluated by logistic regression. Analyses were adjusted for treatment, country, ED-severity, baseline and baseline-by-treatment interaction. Patients randomized to tadalafil OaD or PRN reported greater improvement (least-square mean (s.e.) change) in Sexual Self-Confidence (OaD +0.90 (0.048), PRN +0.93 (0.050), vs +0.73 (0.049); P=0.006 and P=0.001) and Spontaneity (OaD +0.11 (0.035), PRN +0.13 (0.035), vs +0.02 (0.035); P = 0.044 and P = 0.010) compared with sildenafil. Improvements in GAQ and SEP responses, IIEF-EF, orgasmic function, sexual desire, overall satisfaction domains, SEAR and EDITS scores did not differ significantly between treatment groups.

Patient-controlled methylphenidate for cancer fatigue: a double-blind, randomized, placebo-controlled trial.

PubMed

Bruera, Eduardo; Valero, Vicente; Driver, Larry; Shen, Loren; Willey, Jie; Zhang, Tao; Palmer, J Lynn

2006-05-01

To evaluate the effectiveness of patient-controlled methylphenidate as compared with placebo in cancer patients with fatigue, as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F). Patients with a fatigue score of at least 4 on a scale of 0 to 10 (0 = no fatigue, 10 = worst possible fatigue) and hemoglobin level of at least 10 g/dL were included. Patients were randomly assigned to receive 5 mg methylphenidate or placebo every 2 hours as needed (maximum of four capsules a day), for 7 days. Patients completed a daily diary including study drug record and fatigue intensity. A research nurse telephoned patients daily to assess toxicity and fatigue level. All patients were offered open-label methylphenidate for 4 weeks. FACIT-F and the Edmonton Symptom Assessment System (ESAS) were assessed at baseline, and days 8, 15, and 36. The FACIT-F fatigue subscore on day 8 was considered the primary end point. Of 112 patients randomly assigned, 52 patients in the methylphenidate and 53 in the placebo group were assessable for analysis. Fatigue intensity improved significantly on day 8 in both the methylphenidate and placebo groups. However, there was no significant difference in fatigue improvement by FACIT-F (P = .31) or ESAS (P = .14) between groups. In open-label phase, fatigue intensity maintained low as compared with baseline. No significant toxicities were observed. Both methylphenidate and placebo resulted in significant symptom improvement. Methylphenidate was not significantly superior to placebo after 1 week of treatment. Longer study duration is justified. The role of daily telephone calls from a research nurse should be explored as a palliative care intervention.

Safety, pharmacokinetics and efficacy findings in an open-label, single-arm study of weekly paclitaxel plus lapatinib as first-line therapy for Japanese women with HER2-positive metastatic breast cancer.

PubMed

Inoue, Kenichi; Kuroi, Katsumasa; Shimizu, Satoru; Rai, Yoshiaki; Aogi, Kenjiro; Masuda, Norikazu; Nakayama, Takahiro; Iwata, Hiroji; Nishimura, Yuichiro; Armour, Alison; Sasaki, Yasutsuna

2015-12-01

Lapatinib is the human epidermal growth factor receptor 2 (HER2) targeting agent approved globally for HER2-positive metastatic breast cancer (MBC). The efficacy, safety and pharmacokinetics (PK) of lapatinib combined with paclitaxel (L+P) were investigated in this study, to establish clear evidence regarding the combination in Japanese patients. In this two-part, single-arm, open-label study, the tolerability of L+P as first-line treatment in Japanese patients with HER2-positive MBC was evaluated in six patients in the first part, and the safety, efficacy and PK were evaluated in a further six patients (making a total of twelve patients) in the second part. Eligible women were enrolled and received lapatinib 1500 mg once daily and paclitaxel 80 mg/m(2) weekly for at least 6 cycles. The only dose-limiting toxicity reported was Grade 3 diarrhea in one patient. The systemic exposure to maximum plasma concentration and area under the plasma concentration curve (AUC) for lapatinib, as well as the AUC of paclitaxel, were increased when combined. The most common adverse events (AEs) related to the study treatment were alopecia, diarrhea and decreased hemoglobin. The majority of drug-related AEs were Grade 1 or 2. The median overall survival was 35.6 months (95 % confidence interval 23.9, not reached). The response rate and clinical benefit rate were both 83 % (95 % confidence interval 51.6, 97.9). The L+P treatment was well tolerated in Japanese patients with HER2-positive MBC. Although the PK profiles of lapatinib and paclitaxel influenced each other, the magnitudes were not greatly different from those in non-Japanese patients.

Topical Coconut Oil in Very Preterm Infants: An Open-Label Randomised Controlled Trial.

PubMed

Strunk, Tobias; Pupala, Sameer; Hibbert, Julie; Doherty, Dorota; Patole, Sanjay

2018-01-01

The immature fragile skin of preterm infants represents an inadequate protective barrier. The emollient and anti-infective properties of coconut oil make it a potentially beneficial topical agent for this population. Our aim was to evaluate feasibility, safety, and the effects of topical coconut oil on skin condition in very preterm infants. An open-label randomised controlled trial in preterm infants <30 weeks' gestation was conducted. Enrolled infants were randomised to receive either routine care or topical coconut oil (5 mL/kg) twice daily for 21 days, starting within 24 h of birth. The neonatal skin condition was the primary outcome, and was assessed using the Neonatal Skin Condition Score (NSCS) on days 1, 7, 14, and 21. The number of coconut oil applications was recorded to assess clinical feasibility and all enrolled infants were monitored for adverse effects of topical coconut application, such as skin irritation. A total of 72 infants born <30 weeks' gestation were enrolled (36 infants per arm), with comparable demographic characteristics. Topical application of coconut oil was feasible and without adverse effects. The NSCS was maintained in the coconut oil group throughout the intervention period, but deteriorated from a median (IQR) of 3 (3-4) on day 1 to 4 (4-4) on day 21 in the control group (p = 0.01). There were no differences in common neonatal outcomes, including sepsis, necrotising enterocolitis, retinopathy of prematurity, chronic lung disease, and mortality. Topical coconut oil maintained a better skin condition in very preterm infants without adverse effects. This simple, safe, and affordable intervention warrants further investigation. © 2017 S. Karger AG, Basel.

An open-label tolerability study of BL-1020 antipsychotic: a novel gamma aminobutyric acid ester of perphenazine.

PubMed

Anand, Ravi; Geffen, Yona; Vasile, Daniel; Dan, Irina

2010-01-01

BL-1020, a novel gamma aminobutyric acid (GABA) ester of perphenazine, is a new oral antipsychotic with a strong affinity for dopamine and serotonin receptors. Unlike first- and second-generation antipsychotics, it has agonist activity at GABA(A). This is the first study to examine tolerability and safety of BL-1020 in schizophrenia. This was a phase-II, open-label, multicenter, 6-week study treating patients (n = 36) with chronic schizophrenia. Dosing started at 20 mg/d and increased over 7 days to 40 mg/d. Weekly assessments were conducted. All but 1 patient was titrated to 30 mg/d at day 4; on day 7, 30 were titrated to 40 mg/d. Four patients discontinued the study prematurely. There was no clinically relevant increase in vital signs, sedation, dizziness, or other central nervous system effects or electrocardiogram or laboratory abnormalities and a small increase in weight. Ten patients experienced extrapyramidal symptoms (EPS) requiring treatment with an anticholinergic; 4 patients were unable to reach maximum dose because of EPS. Extrapyramidal Symptom Rating Scale did not indicate clinically significant changes in EPS. The most common adverse event was insomnia (6 patients); other frequent adverse effects (all n = 3) were extrapyramidal disorder, headache, parkinsonism, tremor, and hyperprolactinemia. There was improvement on Positive and Negative Syndrome Scale and Clinical Global Impression of Change with 22 patients showing at least 20% decrease by end point on Positive and Negative Syndrome Scale and 31 patients showing at least minimal improvement on Clinical Global Impression of Change. These data suggest that 20 to 40 mg/d of BL-1020 is associated with clinically relevant improvement of psychosis with no worsening of EPS and support further testing in randomized controlled trials.

Green tea (Camellia sinensis) for patients with knee osteoarthritis: A randomized open-label active-controlled clinical trial.

PubMed

Hashempur, Mohammad Hashem; Sadrneshin, Sara; Mosavat, Seyed Hamdollah; Ashraf, Alireza

2018-02-01

Green tea is known as a dietary supplement and a novel functional food worldwide. Since there are increasing preclinical evidence about efficacy of green tea for treating osteoarthritis, this study has aimed at assessing its efficacy and safety for patients with knee osteoarthritis. This is a randomized open-label active-controlled clinical trial. As many as fifty adults with osteoarthritis of knee were randomly allocated to receive the green tea extract (in dosage form of tablet) plus diclofenac tablet as "intervention group"; or: diclofenac tablet alone as "control group" for a period of four weeks. Patients were assessed at the beginning of intervention, and then 4 weeks later, in terms of pain score via visual analogue scale (VAS), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire's total score in addition to its 3 sub-scores. Furthermore, they were asked about any adverse effects during intervention period. Mean differences of VAS pain, total WOMAC, and WOMAC physical function scores in green tea group showed a significant reduction, compared with the control group (P = 0.038, P = 0.006, and P = 0.004, respectively). However, No significant differences between the two groups were observed, regarding mean differences of WOMAC pain and stiffness scores of the enrolled patients (P = 0.163, and P = 0.150, respectively). Additionally, only 1 patient reported gastric upset [in control group]. It seems that green tea extract might well be considered as an adjunctive treatment both for control of pain and for the betterment of knee joint physical function in adults with osteoarthritis. However, further studies of longer duration and larger sample size are needed. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Maintenance percutaneous posterior nerve stimulation for refractory lower urinary tract symptoms in patients with multiple sclerosis: an open label, multicenter, prospective study.

PubMed

Zecca, C; Digesu, G A; Robshaw, P; Singh, A; Elneil, S; Gobbi, C

2014-03-01

Percutaneous tibial nerve stimulation is an effective second line therapy for lower urinary tract symptoms. Data on percutaneous tibial nerve stimulation maintenance treatment are scarce. In this study we evaluate its effectiveness and propose an algorithm of percutaneous tibial nerve stimulation maintenance treatment in patients with multiple sclerosis. In this prospective, multicenter, open label trial consecutive patients with multiple sclerosis and lower urinary tract symptoms unresponsive to medical therapy were treated with 12 weekly sessions of percutaneous tibial nerve stimulation. Responder patients (50% or greater improvement of lower urinary tract symptoms as measured by the patient perception of bladder condition questionnaire) entered a maintenance phase with individualized treatment frequency based on patient response. Lower urinary tract symptoms were assessed using a 3-day frequency volume chart, urodynamics and patient perception of bladder condition questionnaire. Treatment satisfaction was evaluated using a global response assessment scale and a treatment satisfaction visual analog scale. A total of 83 patients were included in the study and 74 (89%) responded to initial treatment. Persistent efficacy occurred in all initial responders after a mean treatment of 24 months. The greatest frequency of maintenance percutaneous tibial nerve stimulation was every 2 weeks. Lower urinary tract symptoms and patient treatment satisfaction improved with time compared to initial treatment (p <0.05). Bladder diary parameters and voiding parameters improved compared to baseline (p <0.05). Prolonged percutaneous tibial nerve stimulation treatment leads to a persistent improvement of lower urinary tract symptoms in patients with multiple sclerosis. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

White matter tract integrity is associated with antidepressant response to lurasidone in bipolar depression.

PubMed

Lan, Martin J; Rubin-Falcone, Harry; Motiwala, Fatima; Chen, Ying; Stewart, Jonathan W; Hellerstein, David J; Mann, J John; McGrath, Patrick J

2017-09-01

Patients with bipolar disorder spend the most time in the depressed phase, and that phase is associated with the most morbidity and mortality. Treatment of bipolar depression lacks a test to determine who will respond to treatment. White matter disruptions have been found in bipolar disorder. Previous reports suggest that white matter disruptions may be associated with resistance to antidepressant medication, but this has never been investigated in a prospective study using a Food and Drug Administration (FDA)-approved medication. Eighteen subjects with bipolar disorder who were in a major depressive episode and off all medications were recruited. Magnetic resonance imaging was acquired using a 64-direction diffusion tensor imaging sequence on a 3T scanner. Subjects were treated with 8 weeks of open-label lurasidone. The Montgomrey-Asberg Depression Rating Scale (MADRS) was completed weekly. Tract-Based Spatial Statistics were utilized to perform a regression analysis of fractional anisotropy (FA) data with treatment outcome as assessed by percent change in MADRS as a regressor while controlling for age and sex, using a threshold of P (threshold-free cluster enhancement-corrected) <.05. FA was positively correlated with antidepressant treatment response in multiple regions of the mean FA skeleton bilaterally, including tracts in the frontal and parietal lobes. Greater disruptions in the white matter tracts in bipolar disorder were associated with poorer antidepressant response to lurasidone. The disruptions may potentially indicate treatment with a different antidepressant medication class. These results are limited by the open-label study design, sample size and lack of a healthy control group. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

C2 Nerve Field Stimulation for the Treatment of Fibromyalgia: A Prospective, Double-blind, Randomized, Controlled Cross-over Study.

PubMed

Plazier, Mark; Ost, Jan; Stassijns, Gaëtane; De Ridder, Dirk; Vanneste, Sven

2015-01-01

Fibromyalgia is a condition characterized by widespread chronic pain. Due to the high prevalence and high costs, it has a substantial burden on society. Treatment results are diverse and only help a small subset of patients. C2 nerve field stimulation, aka occipital nerve stimulation, is helpful and a minimally invasive treatment for primary headache syndromes. Small C2 pilot studies seem to be beneficial in fibromyalgia. Forty patients were implanted with a subcutaneous electrode in the C2 dermatoma as part of a prospective, double-blind, randomized, controlled cross-over study followed by an open label follow up period of 6 months. The patients underwent 2 week periods of different doses of stimulation consisting of minimal (.1 mA), subthreshold, and suprathreshold (for paresthesias) in a randomized order. Twenty seven patients received a permanent implant and 25 completed the 6 month open label follow up period. During the 6 week trial phase of the study, patients had an overall decrease of 36% on the fibromyalgia impact questionnaire (FIQ), a decrease of 33% fibromyalgia pain and improvement of 42% on the impact on daily life activities and quality. These results imply an overall improvement in the disease burden, maintained at 6 months follow up, as well as an improvement in life quality of 50%. Seventy six percent of patients were satisfied or very satisfied with their treatment. There seems to be a dose-response curve, with increasing amplitudes leading to better clinical outcomes. Subcutaneous C2 nerve field stimulation seems to offer a safe and effective treatment option for selected medically intractable patients with fibromyalgia. Copyright © 2015 Elsevier Inc. All rights reserved.

Effects on agitation with rivastigmine patch monotherapy and combination therapy with memantine in mild to moderate Alzheimer's disease: a multicenter 24-week prospective randomized open-label study (the Korean EXelon Patch and combination with mEmantine Comparative Trial study).

PubMed

Yoon, Soo J; Choi, Seong H; Na, Hae R; Park, Kyung-Won; Kim, Eun-Joo; Han, Hyun J; Lee, Jae-Hong; Shim, Young S; Na, Duk L

2017-03-01

Memantine is known to be effective in the treatment of the behavioral symptoms of dementia, especially agitation in moderate to severe Alzheimer's disease (AD). However, memantine and rivastigmine patch combination therapy has not been well studied in determining treatment effectiveness with mild to moderate AD patients. This was a multicenter, 24-week, prospective, randomized, open-label study design. A total 147 AD patients with Mini-Mental State Examination scores from 10 to 20 were randomly assigned to rivastigmine patch monotherapy and combination therapy with memantine groups. Agitation symptoms, using the Korean Version of the Cohen Mansfield Agitation Inventory were evaluated at baseline and at study end. Suppression and emergence of agitation symptoms were also evaluated. We carried out factor analyses to evaluate the interrelationship of agitation symptoms and to investigate treatment response in these symptoms. Factor analyses showed two symptom clusters: factor A - aggressive agitated behaviors - versus factor B - non-aggressive agitated behaviors. The rivastigmine patch monotherapy group showed significantly decreased factor B scores and had a tendency of decreased Korean Version of the Cohen Mansfield Agitation Inventory total scores and factor A scores. Conversely, the combination therapy group showed significantly increased Korean Version of the Cohen Mansfield Agitation Inventory total scores and factor B scores. Neither monotherapy nor combination therapy reduced the emergence of new agitation symptoms. In this trial of mild to moderate AD patients, the rivastigmine patch monotherapy group experienced a reduction of non-aggressive agitated behaviors. However, combination therapy with memantine did not show any benefit on the agitation associated with mild to moderate AD. Geriatr Gerontol Int 2017; 17: 494-499. © 2016 Japan Geriatrics Society.

Daily Consumption of Virgin Coconut Oil Increases High-Density Lipoprotein Cholesterol Levels in Healthy Volunteers: A Randomized Crossover Trial.

PubMed

Chinwong, Surarong; Chinwong, Dujrudee; Mangklabruks, Ampica

2017-01-01

This open-label, randomized, controlled, crossover trial assessed the effect of daily virgin coconut oil (VCO) consumption on plasma lipoproteins levels and adverse events. The study population was 35 healthy Thai volunteers, aged 18-25. At entry, participants were randomly allocated to receive either (i) 15 mL VCO or (ii) 15 mL 2% carboxymethylcellulose (CMC) solution (as control), twice daily, for 8 weeks. After 8 weeks, participants had an 8-week washout period and then crossed over to take the alternative regimen for 8 weeks. Plasma lipoproteins levels were measured in participants at baseline, week-8, week-16, and week-24 follow-up visits. Results . Of 32 volunteers with complete follow-up (16 males and 16 females), daily VCO intake significantly increased high-density lipoprotein cholesterol by 5.72 mg/dL ( p = 0.001) compared to the control regimen. However, there was no difference in the change in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels between the two regimens. Mild diarrhea was reported by some volunteers when taking VCO, but no serious adverse events were reported. Conclusion . Daily consumption of 30 mL VCO in young healthy adults significantly increased high-density lipoprotein cholesterol. No major safety issues of taking VCO daily for 8 weeks were reported.

Daily Consumption of Virgin Coconut Oil Increases High-Density Lipoprotein Cholesterol Levels in Healthy Volunteers: A Randomized Crossover Trial

PubMed Central

2017-01-01

This open-label, randomized, controlled, crossover trial assessed the effect of daily virgin coconut oil (VCO) consumption on plasma lipoproteins levels and adverse events. The study population was 35 healthy Thai volunteers, aged 18–25. At entry, participants were randomly allocated to receive either (i) 15 mL VCO or (ii) 15 mL 2% carboxymethylcellulose (CMC) solution (as control), twice daily, for 8 weeks. After 8 weeks, participants had an 8-week washout period and then crossed over to take the alternative regimen for 8 weeks. Plasma lipoproteins levels were measured in participants at baseline, week-8, week-16, and week-24 follow-up visits. Results. Of 32 volunteers with complete follow-up (16 males and 16 females), daily VCO intake significantly increased high-density lipoprotein cholesterol by 5.72 mg/dL (p = 0.001) compared to the control regimen. However, there was no difference in the change in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels between the two regimens. Mild diarrhea was reported by some volunteers when taking VCO, but no serious adverse events were reported. Conclusion. Daily consumption of 30 mL VCO in young healthy adults significantly increased high-density lipoprotein cholesterol. No major safety issues of taking VCO daily for 8 weeks were reported. PMID:29387131

A Prospective Open-Label Study of Combined Treatment for Idiopathic Parkinson's Disease Using Acupuncture and Bee Venom Acupuncture as an Adjunctive Treatment.

PubMed

Doo, Kyeong-Hee; Lee, Ji-Hyun; Cho, Seung-Yeon; Jung, Woo-Sang; Moon, Sang-Kwan; Park, Jung-Mi; Ko, Chang-Nam; Kim, Ho; Park, Hi-Joon; Park, Seong-Uk

2015-10-01

The purpose of this study was to examine the effectiveness and safety of combined treatment using acupuncture and bee venom acupuncture (BVA) as an adjunctive treatment for idiopathic Parkinson's disease (PD). Eleven patients (7 men and 4 women) with idiopathic PD who had been receiving a stable dose of anti-parkinsonian medication for at least 4 weeks. Participants received conventional treatment for 12 weeks. Subsequently, they received additional treatment with acupuncture and BVA twice weekly for 12 weeks while still maintaining conventional treatment. All participants were assessed at baseline, 12 weeks, and 24 weeks by using the Unified Parkinson's Disease Rating Scale (UPDRS), the Parkinson's Disease Quality of Life Questionnaire (PDQL), the speed and number of steps required to walk 20 m, and the Beck Depression Inventory (BDI). Maximum excursion and directional control, measured by computerized dynamic posturography (Balance Master(®) System, NeuroCom, San Carlos, CA), were used to assess postural stability. Patients who underwent 12 weeks of twice-weekly combined treatment with acupuncture and BVA showed significant improvements in gait speed, PDQL score, activities of daily living (UPDRS part II), motor symptoms (UPDRS part III), and combined UPDRS part II+III scores compared with assessments after conventional treatment. Combined treatment with acupuncture and BVA showed promising results as a safe adjunctive therapy for PD.

Long‐term safety and efficacy of tofogliflozin as add‐on to insulin in patients with type 2 diabetes: Results from a 52‐week, multicentre, randomized, double‐blind, open‐label extension, Phase 4 study in Japan (J‐STEP/INS)

PubMed Central

Tamura, Masahiro; Senda, Masayuki; Gunji, Ryoji; Kaku, Kohei

2018-01-01

Aims To evaluate the long‐term safety and efficacy of tofogliflozin as an add‐on treatment to insulin over 52 weeks. Materials and methods This 52‐week, multicentre, Phase 4 study consisted of a 16‐week, randomized, double‐blind, placebo‐controlled phase and a 36‐week open label extension phase (NCT02201004). Japanese patients with type 2 diabetes mellitus, aged 20 to 75 years, with suboptimal glycaemic control (7.5%‐10.5%) receiving insulin monotherapy (basal‐bolus, bolus, premix [low and high] and basal) or receiving combination therapy with basal insulin and dipeptidyl peptidase‐4 inhibitor were eligible for participation. Patients who received tofogliflozin throughout the study (52 weeks) were referred to as the ‘tofo‐tofo group’ and patients who received placebo and tofogliflozin (36 weeks) were referred to as the ‘pla‐tofo group’. Results A total of 210 patients received treatment per randomization. Hypoglycaemia was the most common treatment‐emergent adverse event (AE) (42.9% in the tofo‐tofo group and 29.4% in the pla‐tofo group). Patients reported genital infection, urinary tract infection, excessive urination and AEs related to volume depletion (2.1%, 2.1%, 7.1% and 10.0% of patients in the tofo‐tofo group, and 0%, 1.5%, 2.9% and 7.4% of patients in the pla‐tofo group, respectively). Mean HbA1c and body weight at baseline (mean changes ± standard error from baseline to Week 52) in the tofo‐tofo and pla‐tofo groups were 8.53% (−0.76% ± 0.077) and 8.40% (−0.73% ± 0.102); 68.84 kg (−1.52 kg ± 0.207) and 72.24 kg (−2.13 kg ± 0.313), respectively. Conclusions This study demonstrates the safety and efficacy of tofogliflozin as add‐on to insulin therapy in type 2 diabetes mellitus patients, offering a new therapeutic solution to diabetes management. PMID:29316236

Growth and Puberty in a 2-Year Open-Label Study of Lisdexamfetamine Dimesylate in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder.

PubMed

Banaschewski, Tobias; Johnson, Mats; Nagy, Peter; Otero, Isabel Hernández; Soutullo, César A; Yan, Brian; Zuddas, Alessandro; Coghill, David R

2018-05-01

Stimulant medications for the treatment of attention-deficit/hyperactivity disorder have a history of safe and effective use; however, concerns exist that they may adversely affect growth trajectories in children and adolescents. The objective of this study was to evaluate the longer-term effects of lisdexamfetamine dimesylate on weight, height, body mass index and pubertal development in children and adolescents with attention-deficit/hyperactivity disorder. Children and adolescents aged 6-17 years with attention-deficit/hyperactivity disorder took open-label lisdexamfetamine dimesylate (30, 50 or 70 mg/day) in this open-label 2-year safety and efficacy study. Safety evaluations included treatment-emergent adverse events, measurement of weight, height and body mass index, and self-reported pubertal status using Tanner staging. The safety analysis population comprised all enrolled participants (N = 314) and 191 (60.8%) completed the study. Weight decrease was reported as a treatment-emergent adverse event in 63 participants (20.1%) and two participants (0.6%) discontinued the study as a result of treatment-emergent adverse events of weight decrease. Growth retardation of moderate intensity was reported as a treatment-emergent adverse event for two participants. From baseline to the last on-treatment assessment, there were increases in mean weight of 2.1 kg (standard deviation 5.83) and height of 6.1 cm (standard deviation 4.90), and a body mass index decrease of 0.5 kg/m 2 (standard deviation 1.72). Mean weight, height and body mass index z-scores decreased over the first 36 weeks of the study and then stabilised. Changes from baseline to the last on-treatment assessment in mean z-scores for weight, height and body mass index were significantly less than zero (- 0.51, - 0.24 and - 0.59, respectively; nominal p < 0.0001). The proportion of participants with a z-score of < - 1 ranged from 5.1% (baseline) to 22.1% (week 84) for weight, 8.2% (baseline) to 12.6% (week 96) for height, and 8.3% (baseline) to 28.8% (week 96) for body mass index. Thirteen participants (4.1%) shifted to a weight below the fifth percentile at the last on-treatment assessment from a higher weight category at baseline. At the last on-treatment assessment, most participants remained at their baseline Tanner stage or had shifted higher. Findings from this comprehensive examination of growth outcomes associated with lisdexamfetamine dimesylate treatment over 2 years were consistent with previous studies of stimulant medications. Whilst mean weight and height increased over the course of the study, there was a small but transient reduction in mean weight, height and body mass index z-scores. A small increase in the proportion of participants in the lowest weight and body mass index categories highlights the importance of the regular monitoring of weight and height. There was no evidence of delayed onset of puberty. CLINICALTRIALS. NCT01328756.

Combination therapy for type 2 diabetes: repaglinide plus rosiglitazone.

PubMed

Raskin, P; McGill, J; Saad, M F; Cappleman, J M; Kaye, W; Khutoryansky, N; Hale, P M

2004-04-01

This 24-week, randomized, multicentre, open-label, parallel-group clinical trial compared efficacy and safety of repaglinide monotherapy, rosiglitazone monotherapy, and combination therapy (repaglinide plus rosiglitazone) in Type 2 diabetes after unsatisfactory response to sulphonylurea or metformin monotherapy. Enrolled patients (n = 252) were adults having Type 2 diabetes for at least 1 year, with HbA(1c) values > 7.0% after previous monotherapy (sulphonylurea or metformin, >/= 50% maximal dose). Prior therapy was withdrawn for 2 weeks, followed by randomization to repaglinide, rosiglitazone, or repaglinide/rosiglitazone. Study treatments were initiated with a 12-week dose optimization period (doses optimized according to labelling), followed by a 12-week maintenance period. Efficacy endpoints were changes in HbA(1c) values (primary) or fasting plasma glucose values (secondary). Baseline HbA(1c) values were comparable (9.3% for repaglinide, 9.0% for rosiglitazone, 9.1% for combination). Mean changes in HbA(1c) values at the end of treatment were greater for repaglinide/rosiglitazone therapy (-1.43%) than for repaglinide (-0.17%) or rosiglitazone (-0.56%) monotherapy. Reductions of fasting plasma glucose values were also greater for combination therapy (-5.2 mmol/l, -94 mg/dl) than for repaglinide monotherapy (-3.0 mmol/l, -54 mg/dl) or rosiglitazone monotherapy (-3.7 mmol/l, -67 mg/dl). Minor hypoglycaemic events occurred in 9% of combination therapy patients, vs. 6% for repaglinide and 2% for rosiglitazone. Individual weight gains for combination therapy were correlated to HbA(1c) response. The combination therapy regimen was well tolerated. In patients previously showing unsatisfactory response to oral monotherapy, glycaemic reductions were greater for the repaglinide/rosiglitazone combination regimen than for use of either repaglinide or rosiglitazone alone.

Opicapone as Adjunct to Levodopa Therapy in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial.

PubMed

Lees, Andrew J; Ferreira, Joaquim; Rascol, Olivier; Poewe, Werner; Rocha, José-Francisco; McCrory, Michelle; Soares-da-Silva, Patricio

2017-02-01

Catechol O-methyltransferase (COMT) inhibitors are an established treatment for end-of-dose motor fluctuations associated with levodopa therapy in patients with Parkinson disease (PD). Current COMT inhibitors carry a high risk for toxic effects to hepatic cells or show moderate improvement. Opicapone was designed to be effective without the adverse effects. To evaluate the efficacy and safety of 25- and 50-mg/d dosages of opicapone compared with placebo as adjunct to levodopa therapy in patients with PD experiencing end-of-dose motor fluctuations. This phase 3 international, multicenter outpatient study evaluated a 25- and a 50-mg/d dosage of opicapone in a randomized, double-blind, 14- to 15-week, placebo-controlled clinical trial, followed by a 1-year open-label phase during which all patients received active treatment with opicapone. Patients with PD who experienced signs of end-of-dose deterioration and had a mean total awake off-time (state of akinesia or decreased mobility) of at least 1.5 hours, not including morning akinesia, were enrolled. Data were collected from March 18, 2011, through June 25, 2013. Data from the evaluable population were analyzed from July 31, 2013, to July 31, 2014. The primary efficacy outcome of the double-blind phase was the change from baseline in absolute off-time vs placebo based on patient diaries. The open-label phase focused on maintenance of treatment effect in off-time. A total of 427 patients (258 men [60.4%] and 169 women [39.6%]; mean [SD] age, 63.1 [8.8] years) were randomized to a 25-mg/d (n = 129) or a 50-mg/d (n = 154) dosage of opicapone or to placebo (n = 144). Of these, 376 patients completed the double-blind phase and entered the open-label phase, of whom 286 completed 1 year of open-label treatment. At the end of the double-blind phase, the least squares mean change (SE) in off-time was -64.5 (14.4) minutes for the placebo group, -101.7 (14.9) minutes for the 25-mg/d opicapone group, and -118.8 (13.8) minutes for the 50-mg/d opicapone group. The adjusted treatment difference vs placebo was significant for the 50-mg/d opicapone group (treatment effect, -54.3 [95% CI, -96.2 to -12.4] minutes; P = .008), but not for the 25-mg/d opicapone group (treatment effect, -37.2 [95% CI, -80.8 to 6.4] minutes; P = .11). The off-time reduction was sustained throughout the open-label phase (-126.3 minutes at 1-year open-label end point). The most common adverse events in the opicapone vs placebo groups were dyskinesia, constipation, and dry mouth. Fifty-one patients (11.9%) discontinued from the study during the double-blind phase. Treatment with a 50-mg once-daily dose of opicapone was associated with a significant reduction in mean daily off-time in levodopa-treated patients with PD and motor fluctuations, and this effect is maintained for at least 1 year. Opicapone was safe and well tolerated. clinicaltrials.gov Identifier: NCT01227655.

Color-Coded Labels Cued Nurses to Adhere to Central Line Connector Change.

PubMed

Morrison, Theresa Lynch; Laney, Christina; Foglesong, Jan; Brennaman, Laura

2016-01-01

This study examined nurses' adherence to policies regarding needleless connector changes using a novel, day-of-the-week, color-coded label compared with usual care that relied on electronic medical record (EMR) documentation. This was a prospective, comparative study. The study was performed on 4 medical-surgical units in a seasonally fluctuating, 715-bed healthcare system composed of 2 community hospitals. Convenience sample was composed of adults with central lines hospitalized for 4 or more days. At 4-day intervals, investigators observed bedside label use and EMR needleless connector change documentation. Control patients received standard care-needleless connector change with associated documentation in the EMR. Intervention patients, in addition to standard care, had a day-of-the-week, color-coded label placed on each needleless connector. To account for clustering within unit, multinomial logistic regression models using survey sampling methodology were used to conduct Wald χ tests. A multinominal odds ratio and 95% confidence interval (CI) provided an estimate of using labels that were provided on units relative to usual care documentation of needleless connector change in the EMR. In 335 central line observations, the units with labels (n = 205) had a 321% increase rate of documentation of needleless connector change in the EMR (odds ratio, 4.21; 95% CI, 1.76-10.10; P = .003) compared with the usual care control patients. For units with labels, when labels were present, placement of labels on needleless connectors increased the odds that nurses documented connector changes per policy (4.72; 95% CI, 2.02, 10.98; P = .003). Day-of-the-week, color-coded labels cued nurses to document central line needleless connector change in the EMR, which increased adherence to the needleless connector change policy. Providing day-of-the-week, color-coded needleless connector labels increased EMR documentation of timely needleless connector changes. Timely needleless connector changes may lower the incidence of central line-associated bloodstream infection.

Pilot Study of the 5-HT2AR Agonist Psilocybin in the Treatment of Tobacco Addiction

PubMed Central

Johnson, Matthew W.; Garcia-Romeu, Albert; Cosimano, Mary P.; Griffiths, Roland R.

2014-01-01

Despite suggestive early findings on the therapeutic use of hallucinogens in the treatment of substance use disorders, rigorous follow up has not been conducted. To determine the safety and feasibility of psilocybin as an adjunct to tobacco smoking cessation treatment we conducted an open-label pilot study administering moderate (20mg/70kg) and high (30mg/70kg) doses of psilocybin within a structured 15-week smoking cessation treatment protocol. Participants were 15 psychiatrically healthy nicotine-dependent smokers (10 males; mean age of 51 years), with a mean of 6 previous lifetime quit attempts, and smoking a mean of 19 cigarettes per day for a mean of 31 years at intake. Biomarkers assessing smoking status, and self-report measures of smoking behavior demonstrated that 12 of 15 participants (80%) showed seven-day point prevalence abstinence at 6-month follow-up. The observed smoking cessation rate substantially exceeds rates commonly reported for other behavioral and/or pharmacological therapies (typically <35%). Although the open-label design does not allow for definitive conclusions regarding the efficacy of psilocybin, these findings suggest psilocybin may be a potentially efficacious adjunct to current smoking cessation treatment models. The present study illustrates a framework for future research on the efficacy and mechanisms of hallucinogen-facilitated treatment of addiction. PMID:25213996

Increased colonic bile acid exposure: a relevant factor for symptoms and treatment in IBS.

PubMed

Bajor, Antal; Törnblom, Hans; Rudling, Mats; Ung, Kjell-Arne; Simrén, Magnus

2015-01-01

Bile acids may play a role in the pathogenesis of IBS. We investigated the potential effects of bile acids entering the colon and its role in the symptom pattern in IBS. We measured 75Se-labelled homocholic acid-taurine (75SeHCAT) retention, and serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor (FGF) 19 in patients with IBS (n=141) and control subjects (75SeHCAT n=29; C4 and FGF19 n=435). In patients with IBS stool frequency and form, as well as GI symptom severity were registered, and in a proportion of patients colonic transit time and rectal sensitivity were measured (n=66). An 8-week open-label treatment with colestipol was offered to patients with 75SeHCAT <20%, and the effect of treatment was evaluated with IBS severity scoring system and adequate relief of IBS symptoms. Compared with controls, patients with IBS had lower 75SeHCAT values (p=0.005), higher C4c levels (C4 corrected for cholesterol) (p<0.001), but similar FGF19 levels. Abnormal 75SeHCAT retention (<10%) was seen in 18% of patients, whereas 23% had elevated C4c levels. Patients with IBS with 75SeHCAT retention <10% had more frequent stools, accelerated colonic transit time, rectal hyposensitivity, a higher body mass index, higher C4c and lower FGF19 levels. Colestipol treatment improved IBS symptoms (IBS severity scoring system 220±109 vs. 277±106; p<0.01), and 15/27 patients fulfilled criteria for treatment response (adequate relief ≥50% of weeks 5-8). Increased colonic bile acid exposure influences bowel habit and colonic transit time in patients with IBS. A high response rate to open label treatment with colestipol supports this, but placebo-controlled studies are warranted. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Effects of an icon-based menu labelling initiative on consumer food choice.

PubMed

Kerins, Claire; Cunningham, Katie; Finucane, Francis M; Gibson, Irene; Jones, Jenni; Kelly, Colette

2017-01-01

The purpose of this study was to examine the impact of an icon-based menu labelling initiative on consumer buying behaviour. This quasi-experimental study recruited a convenience sample of eight food service establishments, all with at least one menu item meeting the heart healthy criteria. Data from sales of all menu items sold over an 8-week period were collated 4 weeks prior to and 4 weeks during the display of information icons related to healthy food choices on menus. The absolute change in menu item sales showed a non-significant trend towards an increase in healthier menu item selections. Furthermore, there was no association between the type of food service establishment and the percentage change in labelled menu item sales. The study did not find a statistically significant influence of the icon-based menu labels on consumer food choice. Given the limited amount of research that examines alternative menu labelling formats in real-world settings, more studies are necessary to confirm these results. Further research is needed to identify the optimal format, content and impact of menu labels on consumer behaviour.

Prescriber Compliance With Liver Monitoring Guidelines for Pazopanib in the Postapproval Setting: Results From a Distributed Research Network.

PubMed

Shantakumar, Sumitra; Nordstrom, Beth L; Hall, Susan A; Djousse, Luc; van Herk-Sukel, Myrthe P P; Fraeman, Kathy H; Gagnon, David R; Chagin, Karen; Nelson, Jeanenne J

2017-04-20

Pazopanib received US Food and Drug Administration approval in 2009 for advanced renal cell carcinoma. During clinical development, liver chemistry abnormalities and adverse hepatic events were observed, leading to a boxed warning for hepatotoxicity and detailed label prescriber guidelines for liver monitoring. As part of postapproval regulatory commitments, a cohort study was conducted to assess prescriber compliance with liver monitoring guidelines. Over a 4-year period, a distributed network approach was used across 3 databases: US Veterans Affairs Healthcare System, a US outpatient oncology community practice database, and the Dutch PHARMO Database Network. Measures of prescriber compliance were designed using the original pazopanib label guidelines for liver monitoring. Results from the VA (n = 288) and oncology databases (n = 283) indicate that prescriber liver chemistry monitoring was less than 100%: 73% to 74% compliance with baseline testing and 37% to 39% compliance with testing every 4 weeks. Compliance was highest near drug initiation and decreased over time. Among patients who should have had weekly testing, the compliance was 56% in both databases. The more serious elevations examined, including combinations of liver enzyme elevations meeting the laboratory definition of Hy's law were infrequent but always led to appropriate discontinuation of pazopanib. Only 4 patients were identified for analysis in the Dutch database; none had recorded baseline testing. In this population-based study, prescriber compliance was reasonable near pazopanib initiation but low during subsequent weeks of treatment. This study provides information from real-world community practice settings and offers feedback to regulators on the effectiveness of label monitoring guidelines.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

The Effect of Energy Labelling on Menus and a Social Marketing Campaign on Food-Purchasing Behaviours of University Students.

PubMed

Roy, Rajshri; Beattie-Bowers, Jack; Ang, Siew Min; Colagiuri, Stephen; Allman-Farinelli, Margaret

2016-08-05

This study assessed the impact of kilojoule (kJ) labelling alone or accompanied by a social marketing campaign on food sales and selection of less energy-dense meals by young adults from a university food outlet. There were two kJ labelling intervention phases each of five weeks: (1) kJ labelling alone (2) kJ labels with marketing materials ("8700 kJ campaign"). Food sales of labelled items were tracked during each intervention and five weeks after. Food sales during interventions were also compared with historical sales of foods in the same 10-week period in the previous year. A sub sample of young adults (n = 713; aged 19-24) were surveyed during both the interventions to assess awareness, influence, sentiment and anticipated future impact of kJ labels and the social marketing campaign respectively. There were no differences in sales between the kJ labelling with social marketing and the 5-weeks of labelling before and after. The percentage sale of chicken Caesar burger (3580 kJ, P = 0.01), steak and chips (4000 kJ, P = 0.02) and the grill burger (5500 kJ, P = 0.00) were lower in the year with menu labelling and social marketing campaign. Only 30 % students were initially aware of the kJ labels on the menu but 75 % of students were accepting of kJ labelling, after they were made aware. Respondents viewing the marketing campaign elements and then using kJ values on the menu selected meals with a lower mean energy content; constituting a reduction of 978 kJ (p < 0.01) even though the majority claimed that the 8700 kJ campaign would not impact their food choices. Point-of-purchase energy labelling may be an effective method to encourage better food choices when eating out among young adults. However, further efforts to increase awareness and provide education about energy requirements to prevent weight gain will be needed.

A preliminary open-label study of moclobemide treatment of pain disorder.

PubMed

Pirildar, Sebnem; Sezgin, Ulku; Elbi, Hayriye; Uyar, Meltem; Zileli, Berna

2003-01-01

Antidepressants appear to be useful in the treatment of pain disorders, although the exact underlying mechanisms are unknown. In this preliminary study, we examined the utility of moclobemide, a reversible inhibitor of monoamine oxidase, in the treatment of 14 patients with pain disorder. The drug was administered in doses up to 450 mg/day for 8 weeks. Assessments of perceived pain and psychological evaluations of patients were carried out weekly using visual assessment scores of pain, depression, anxiety, sleep, difficulty in concentration, dry mouth, sweating, and fatigue. The therapeutic effects of moclobemide on the sense of pain, depression, anxiety, sleepless, difficulty in concentration, dry mouth, sweating, and fatigue were analyzed using a repeated measures analysis of variance. Our findings suggest that moclobemide therapy may be an effective, useful option in the management of perceived pain, in addition to its beneficial effects on depression, somatization, and anxiety.

Douching With Water Works Device for Perceived Vaginal Odor With or Without Complaints of Discharge in Women With No Infectious Cause of Vaginitis: A Pilot Study

PubMed Central

Chatwani, Ashwin J.; Hassan, Sarmina; Rahimi, Salma; Jeronis, Stacey; Dandolu, Vani

2006-01-01

Objective. To determine if douching with Water Works device for 1 month can (1) lower or eliminate perceived vaginal odor by subject; (2) have any effects on vaginal ecosystem. Methods. Ten women with perceived vaginal odor with or without discharge, douched every day for 4 weeks in an open-label, nonrandomized pilot study. Primary outcome measures included perceived vaginal odor by subject, lactobacilli score from Nugent slide, and acceptance of the Water Works douching system. Secondary outcome included the safety of using this douching device. Results. At week 4, there was improvement in vaginal odor (P = .0006) and there was no significant change in lactobacilli score. Conclusion. Douching with Water Works device is associated with reduction or elimination of vaginal odor without adversely affecting the vaginal ecosystem. PMID:17485816

Dysthymic disorder: treatment with citalopram.

PubMed

Dunner, David L; Hendricksen, Helen E; Bea, Carolyn; Budech, Chris B; Friedman, S D

2002-01-01

We studied 15 patients with dysthymic disorder with open-label citalopram. The purpose of this study was to determine the dose range and safety of citalopram necessary for treatment of patients with dysthymic disorder and to attempt to increase doses in order to enhance remission of patients with dysthymic disorder when treated. Citalopram was well tolerated. The mean dose used in this 10-week study was 37.3 mg and the majority of patients responded to treatment. Various criteria for response and remission were employed. These findings are intended to give guidelines for a subsequent treatment study of dysthymic patients with citalopram using a double-blind placebo-controlled strategy. Copyright 2002 Wiley-Liss, Inc.

Tomato juice intake increases resting energy expenditure and improves hypertriglyceridemia in middle-aged women: an open-label, single-arm study.

PubMed

Hirose, Asuka; Terauchi, Masakazu; Tamura, Moe; Akiyoshi, Mihoko; Owa, Yoko; Kato, Kiyoko; Kubota, Toshiro

2015-04-08

Tomato-based food products have health-promoting and disease-preventing effects. Some tomato juice ingredients may have health benefits for middle-aged women, including women with menopausal symptoms and cardiovascular diseases. We investigated the net effect of tomato juice intake on several health parameters in women in this age group. An open-label, single-arm study was conducted, involving 95 women (40-60-years-old) who had at least one menopausal symptom. The participants refrained from foods and drinks rich in tomato and tomato-based products for 2 weeks prior to the study and during the 8 weeks of tomato juice consumption. After the run-in period, the women were asked to consume 200 mL of unsalted tomato juice, twice daily for 8 weeks. Their menopausal symptoms were evaluated using the Menopausal Symptom Scale (MSS), Hospital Anxiety and Depression Scale (HADS), and Athens Insomnia Scale (AIS) before the study, and at 4 and 8 weeks after study commencement. At the same times, body composition; blood pressure; heart rate; resting energy expenditures (REEs); and serum levels of triglyceride (TG), cholesterol, glucose, and hemoglobin A1c were measured. Ninety-three women (98%) completed the study. The following parameters showed significant changes, compared with baseline, at study weeks 4 and 8 (mean ± standard deviation at baseline, week 4, and week 8): (1) the MSS score improved (9.9 ± 5.2, 8.5 ± 5.0, 8.3 ± 5.0; P < 0.0001, repeated measures analysis of variance(ANOVA)), (2) the HADS-anxiety subscale score improved (5.3 ± 2.7, 4.8 ± 2.4, 4.9 ± 2.9; P = 0.041, Friedman test), (3) heart rate increased (62.6 ± 9.4 bpm, 64.4 ± 8.6 bpm, 63.8 ± 8.2 bpm; P = 0.028, Friedman test), (4) REE increased (1980 ± 368 kcal/day, 2108 ± 440 kcal/day, 2149 ± 470 kcal/day; P = 0.0030, repeated measures ANOVA), (5) serum TG level decreased in the subgroup of women (n = 22) who had high TG (150 mg/dL or higher) at baseline (237.8 ± 88.9 mg/dL, 166.7 ± 86.1 mg/dL, 170.9 ± 109.7 mg/dL; P = 0.0002, Friedman test). Tomato juice intake alleviated menopausal symptoms, including anxiety, increased REEs and heart rate, and lowered high baseline serum TG levels in middle-aged women. UMIN-CTR UMIN000011877 .

A 12-Month Open-Label Extension Study of the Safety and Tolerability of Lisdexamfetamine Dimesylate for Major Depressive Disorder in Adults.

PubMed

Richards, Cynthia; Iosifescu, Dan V; Mago, Rajnish; Sarkis, Elias; Geibel, Brooke; Dauphin, Matthew; McIntyre, Roger S; Weisler, Richard; Brawman-Mintzer, Olga; Gu, Joan; Madhoo, Manisha

2018-06-16

Psychostimulant augmentation is considered a potential treatment strategy for individuals with major depressive disorder who do not adequately respond to antidepressant monotherapy. The primary objective of this 12-month open-label extension study was to evaluate the safety and tolerability of lisdexamfetamine dimesylate (LDX) as augmentation therapy to an antidepressant in adults with major depressive disorder. Eligible adults who completed 1 of 3 short-term antecedent LDX augmentation of antidepressant monotherapy studies were treated with dose-optimized LDX (20-70 mg) for up to 52 weeks while continuing on the index antidepressant (escitalopram, sertraline, venlafaxine extended-release, or duloxetine) assigned during the antecedent short-term studies. Safety and tolerability assessments included the occurrence of treatment-emergent adverse events and vital sign changes. All 3 antecedent studies failed to meet the prespecified primary efficacy endpoint, so this open-label study was terminated early. Headache (15.5% [241/1559]), dry mouth (13.6% [212/1559]), insomnia (13.1% [204/1559]), and decreased appetite (12.1% [189/1559]) were the most frequently reported treatment-emergent adverse events. The greatest mean ± SD increases observed for systolic and diastolic blood pressure and for pulse were 2.6 ± 10.85 and 1.7 ± 7.94 mm Hg and 6.9 ± 10.27 bpm, respectively. Monitoring determined that less than 1% of participants experienced potentially clinically important changes in systolic blood pressure (10 [0.6%]), diastolic blood pressure (8 [0.5%]), or pulse (6 [0.4%]). The overall safety and tolerability of long-term LDX augmentation of antidepressant monotherapy was consistent with the profiles of the short-term antecedent studies, with no evidence of new safety signals.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Monovalent type-1 oral poliovirus vaccine given at short intervals in Pakistan: a randomised controlled, four-arm, open-label, non-inferiority trial.

PubMed

Mir, Fatima; Quadri, Farheen; Mach, Ondrej; Ahmed, Imran; Bhatti, Zaid; Khan, Asia; Rehman, Najeeb Ur; Durry, Elias; Salama, Maha; Oberste, Steven M; Weldon, William C; Sutter, Roland W; Zaidi, Anita K M

2015-08-01

Supplementary immunisation activities with oral poliovirus vaccines (OPVs) are usually separated by 4 week intervals; however, shorter intervals have been used in security-compromised areas and for rapid outbreak responses. We assessed the immunogenicity of monovalent type-1 oral poliovirus vaccine (mOPV1) given at shorter than usual intervals in Karachi, Pakistan. This was a multicentre, randomised, controlled, four-arm, open-label, non-inferiority trial done at five primary health-care centres in low-income communities in and around Karachi, Pakistan. Eligible participants were healthy newborn babies with a birthweight of at least 2·5 kg, for whom informed consent was provided by their parent or guardian, and lived less than 30 km from the study clinic. After receiving a birth dose of trivalent OPV, we enrolled and randomly assigned newborn babies (1:1:1:1) to receive two doses of mOPV1 with an interval of 1 week (mOPV1-1 week), 2 weeks (mOPV1-2 weeks), or 4 weeks (mOPV1-4 weeks) between doses, or two doses of bivalent OPV (bOPV) with an interval of 4 weeks between doses (bOPV-4 weeks). We gave the first study dose of OPV at age 6 weeks. We did the randomisation with a centrally generated, computerised allocation sequence with blocks of 16; participants' families and study physicians could not feasibly be masked to the allocations. Trial participants were excluded from local supplementary immunisation activities during the study period. The primary outcome was non-inferiority (within a 20% margin) between groups in seroconversion to type-1 poliovirus. The primary and safety analyses were done in the per-protocol population of infants who received all three doses of vaccine. This trial is registered with ClinicalTrials.gov, number NCT01586572, and is closed to new participants. Between March 1, 2012, and May 31, 2013, we enrolled 1009 newborn babies, and randomly assigned 829 (82%) to treatment. 554 (67%) of the 829 babies were included in the per-protocol analysis. Proportions of seroconversion to type-1 poliovirus were 107/135 (79%, 95% CI 72·4-86·1) with mOPV1-1 week, 108/135 (80%, 73·2-86·8) with mOPV1-2 weeks, 129/148 (87%, 80·9-92·0) with mOPV1-4 weeks, and 107/136 (79%, 71·8-85·6) with bOPV-4 weeks. Non-inferiority was shown between groups and no significant differences were noted. Ten participants died during the trial. Seven of these deaths occurred during the lead-in period before randomisation (two from diarrhoea, five from unknown causes). Three infants died from sepsis after random assignment. No deaths were attributed to the procedures or vaccines. Additionally, we noted no events of vaccine-associated paralysis. We identified no significant differences in responses to mOPV1 given with shorter intervals between doses than with the standard 4 week intervals. The short-interval strategy could be particularly beneficial when temporary windows of opportunity for safe access can be granted in areas of conflict--eg, during cease-fire periods. In such situations, we recommend shortening the interval between OPV doses to 7 days. World Health Organization. Copyright © 2015 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. Published by Elsevier Ltd.. All rights reserved.

Treatment with α-Lipoic Acid over 16 Weeks in Type 2 Diabetic Patients with Symptomatic Polyneuropathy Who Responded to Initial 4-Week High-Dose Loading.

PubMed

Garcia-Alcala, Hector; Santos Vichido, Celia Isabel; Islas Macedo, Silverio; Genestier-Tamborero, Christelle Nathalie; Minutti-Palacios, Marissa; Hirales Tamez, Omara; García, Carlos; Ziegler, Dan

2015-01-01

Effective treatment of diabetic sensorimotor polyneuropathy remains a challenge. To assess the efficacy and safety of α-lipoic acid (ALA) over 20 weeks, we conducted a multicenter randomized withdrawal open-label study, in which 45 patients with type 2 diabetes and symptomatic polyneuropathy were initially treated with ALA (600 mg tid) for 4 weeks (phase 1). Subsequently, responders were randomized to receive ALA (600 mg qd; n = 16) or to ALA withdrawal (n = 17) for 16 weeks (phase 2). During phase 1, the Total Symptom Score (TSS) decreased from 8.9 ± 1.8 points to 3.46 ± 2.0 points. During phase 2, TSS improved from 3.7 ± 1.9 points to 2.5 ± 2.5 points in the ALA treated group (p < 0.05) and remained unchanged in the ALA withdrawal group. The use of analgesic rescue medication was higher in the ALA withdrawal group than ALA treated group (p < 0.05). In conclusion, in type 2 diabetic patients with symptomatic polyneuropathy who responded to initial 4-week high-dose (600 mg tid) administration of ALA, subsequent treatment with ALA (600 mg qd) over 16 weeks improved neuropathic symptoms, whereas ALA withdrawal was associated with a higher use of rescue analgesic drugs. This trial is registered with ClinicalTrials.gov Identifier: NCT02439879.

Clinical events after transitioning from apixaban versus warfarin to warfarin at the end of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.

PubMed

Granger, Christopher B; Lopes, Renato D; Hanna, Michael; Ansell, Jack; Hylek, Elaine M; Alexander, John H; Thomas, Laine; Wang, Junyuan; Bahit, M Cecilia; Verheugt, Freek; Lawrence, Jack; Xavier, Denis; Wallentin, Lars

2015-01-01

We sought to assess the occurrence of events after blinded study drug discontinuation and transition to open-label vitamin K antagonist (VKA) in ARISTOTLE. At the end of ARISTOTLE, blinded study drug was stopped, and open-label VKA was recommended. For patients completing the trial on blinded study drug, a 2-day bridging period with apixaban or apixaban placebo was recommended (while beginning open-label VKA). Outcomes were assessed during the 30 days after stopping blinded study drug. Of the 6,809 patients in the apixaban group and 6,588 in the warfarin group who completed the trial on study drug, there were 21 strokes or systemic emboli (4.02%/year) and 26 major bleeding (4.97%/year) events in the apixaban group (transitioning to VKA) and 5 strokes or systemic emboli (0.99%/year) and 10 major bleeding (1.97%/year) events in the warfarin group (continuing on VKA), with most of the imbalance between groups being after the first week. Similar results were seen in the first 30 days of the trial where warfarin-naive patients starting warfarin had a higher rate of stroke or systemic emboli (5.41%/year) than warfarin-experienced patients (1.42%/year), a pattern not seen when starting apixaban. No similar increase in events with apixaban versus warfarin was seen during temporary or permanent study drug discontinuation during the trial. The excess in thrombotic and bleeding events in the apixaban group after study drug discontinuation appears to be related to an increased risk associated with the initiation of a VKA rather than a direct effect of apixaban. Whether ≥2 days of apixaban bridging improves outcomes during VKA transition is unknown and deserves further evaluation. Copyright © 2014 Elsevier Inc. All rights reserved.

Lanreotide autogel every 6 weeks compared with Lanreotide microparticles every 3 weeks in patients with well differentiated neuroendocrine tumors: a Phase III Study.

PubMed

Bajetta, Emilio; Procopio, Giuseppe; Catena, Laura; Martinetti, Antonia; De Dosso, Sara; Ricci, Sergio; Lecchi, Alberto S; Boscani, Paolo F; Iacobelli, Stefano; Carteni, Giacomo; De Braud, Filippo; Loli, Paola; Tartaglia, Andreas; Bajetta, Roberto; Ferrari, Leonardo

2006-11-15

The noninferiority of a 6-week dosing schedule of lanreotide Autogel (Lan ATG) at a dose of 120 mg compared with a 3-week dosing schedule of lanreotide microparticles (Lan MP) at a dose of 60 mg was investigated in patients with neuroendocrine tumors (NET). Patients who had sporadic, well differentiated NET with a low grade of malignancy were recruited for this open-label, Phase III, multicenter trial. Patients were randomized to receive either 3 deep subcutaneous injections of Lan ATG (120 mg, every 6 weeks) or 6 intramuscular injections of Lan MP (60 mg, every 3 weeks). Tumor markers, tumor size, and symptoms were assessed between baseline and Week 18. Success was classified as a response that ranged from disappearance to an increase <25% in tumor marker, tumor size, or symptom frequency. Sixty patients were randomized, and 46 patients completed the study. Both for tumor markers and for tumor size, Lan ATG was not inferior to Lan MP (55% and 59% of patients responded on tumor markers, respectively; 68% and 66% of patients responded on tumor size, respectively). There were too few symptomatic patients to compare carcinoid symptoms. Both treatments were tolerated well, and no safety concerns were identified. Lan ATG at a dose of 120 mg every 6 weeks was as effective for controlling NET as Lan MP at a dose of 60 mg every 3 weeks.

Ozone therapy as add-on treatment in fibromyalgia management by rectal insufflation: an open-label pilot study.

PubMed

Hidalgo-Tallón, Javier; Menéndez-Cepero, Silvia; Vilchez, Juan S; Rodríguez-López, Carmen M; Calandre, Elena P

2013-03-01

The objectives of this study were to evaluate the effectiveness and tolerability of ozone therapy by rectal insufflation as add-on therapy in fibromyalgia management. Patients with fibromyalgia received 24 sessions of ozone therapy during a 12-week period. At each session, the administered dose of ozone was 8 mg (200 mL of gas, at a concentration of 40 μg/mL). Ozone sessions were given 5 days a week during the first 2 weeks, twice a week from weeks 3-6, and weekly from weeks 7-12. Fibromyalgia Impact Questionnaire (FIQ) was the main outcome measure, and was administered at baseline and at weeks 4, 8, and 12. Secondary outcome measures, administered at baseline and at endpoint, were the Pittsburgh Sleep Quality Index, the Beck Depression Inventory, the State and Trait Anxiety Inventory, and the SF-12, the abbreviated form of the Short Form Health Survey. Emergent adverse reactions to treatment were recorded. FIQ total scores decreased significantly during the study period, with the decrease being observed in the first 4 weeks of the study. Significant improvement was also seen both in depression scores and in the Physical Summary Score of the SF-12. Transient meteorism after ozone therapy sessions was the most frequently reported side-effect. At the dose and number of sessions used in this study, ozone therapy by rectal insufflation seems to be beneficial for physical symptoms and depression of fibromyalgia.

Once-Weekly Administration of Sustained-Release Growth Hormone in Korean Prepubertal Children with Idiopathic Short Stature: A Randomized, Controlled Phase II Study.

PubMed

Hwang, Jin Soon; Lee, Hae Sang; Lee, Kee-Hyoung; Yoo, Han-Wook; Lee, Dae-Yeol; Suh, Byung-Kyu; Ko, Cheol Woo; Chung, Woo Yeong; Jin, Dong-Kyu; Shin, Choong Ho; Han, Heon-Seok; Han, Song; Kim, Ho-Seong

2018-06-20

To determine the optimal dose of LB03002, a sustained-release, once-weekly formulation of recombinant human growth hormone (rhGH), and to compare its efficacy and safety with daily rhGH in children with idiopathic short stature (ISS). This multicenter, randomized, open-label, phase II study included GH-naïve, prepubertal children with ISS, randomized to receive daily rhGH 0.37 mg/kg/week (control, n = 16), LB03002 0.5 mg/kg/week (n = 14), or LB03002 0.7 mg/kg/week (n = 16). The primary endpoint was height velocity (HV) change at week 26. At week 26, the least square (LS) means for HV change (cm/year) with control, LB03002 0.5 mg/kg/week, and LB03002 0.7 mg/kg/week were 5.08, 3.65, and 4.38, and the LS means for the change in height standard deviation score were 0.65, 0.49, and 0.58, respectively. The lower bound of the 90% confidence interval for the difference between LB03002 0.7 mg/kg/week and the control in the LS mean for HV change (-1.72) satisfied the noninferiority margin (-1.75). Adverse events were generally mild and short-lived. A once-weekly regimen of LB03002 0.7 mg/kg demonstrated noninferiority to the daily regimen of rhGH 0.37 mg/kg/week in terms of HV increments. LB03002 was well tolerated and its safety profile was comparable with that of daily rhGH. © 2018 S. Karger AG, Basel.

OpenMebius: an open source software for isotopically nonstationary 13C-based metabolic flux analysis.

PubMed

Kajihata, Shuichi; Furusawa, Chikara; Matsuda, Fumio; Shimizu, Hiroshi

2014-01-01

The in vivo measurement of metabolic flux by (13)C-based metabolic flux analysis ((13)C-MFA) provides valuable information regarding cell physiology. Bioinformatics tools have been developed to estimate metabolic flux distributions from the results of tracer isotopic labeling experiments using a (13)C-labeled carbon source. Metabolic flux is determined by nonlinear fitting of a metabolic model to the isotopic labeling enrichment of intracellular metabolites measured by mass spectrometry. Whereas (13)C-MFA is conventionally performed under isotopically constant conditions, isotopically nonstationary (13)C metabolic flux analysis (INST-(13)C-MFA) has recently been developed for flux analysis of cells with photosynthetic activity and cells at a quasi-steady metabolic state (e.g., primary cells or microorganisms under stationary phase). Here, the development of a novel open source software for INST-(13)C-MFA on the Windows platform is reported. OpenMebius (Open source software for Metabolic flux analysis) provides the function of autogenerating metabolic models for simulating isotopic labeling enrichment from a user-defined configuration worksheet. Analysis using simulated data demonstrated the applicability of OpenMebius for INST-(13)C-MFA. Confidence intervals determined by INST-(13)C-MFA were less than those determined by conventional methods, indicating the potential of INST-(13)C-MFA for precise metabolic flux analysis. OpenMebius is the open source software for the general application of INST-(13)C-MFA.

Ziprasidone as an adjuvant for clozapine- or olanzapine-associated medical morbidity in chronic schizophrenia

PubMed Central

Henderson, David C.; Fan, Xiaoduo; Copeland, Paul M.; Sharma, Bikash; Borba, Christina P.; Forstbauer, Sharon I.; Miley, Kate; Boxill, Ryan; Freudenreich, Oliver; Cather, Corey; Evins, A. Eden; Goff, Donald C.

2015-01-01

Objective This study sought to examine the effect of ziprasidone on olanzapine or clozapine associated medical morbidity such as insulin resistance, diabetes mellitus and impaired fasting glucose, obesity and hyperlipidemia in patients with schizophrenia or schizoaffective disorder. Method This was a six-week, open label trial of ziprasidone 160 mg/day added to a stable dose of olanzapine or clozapine in twenty-one schizophrenia or schizoaffective patients with diabetes mellitus, impaired fasting glucose, or insulin resistance. Results Ten olanzapine-treated subjects and eleven clozapine-treated subjects were enrolled in the study. There were no significant differences between the two groups at baseline for age, gender, education, ethnicity, BMI, cholesterol levels, or fasting glucose. At week six, there were no significant changes in weight, BMI, cholesterol levels, or fasting glucose. There was no significant difference in psychotic, negative or depressive symptoms. QTc significantly increased at week 2 but not at week 6. Conclusions The addition of 160 mg/day of ziprasidone was well tolerate but did not produce significant improvement in fasting glucose, insulin resistance, hyperlipidemia or lead to weight loss in olanzapine- or clozapine-treated subjects with schizophrenia or schizoaffective disorder. PMID:19283774

Evaluation of the efficacy, tolerability, and safety of an over-the-counter acne regimen containing benzoyl peroxide and salicylic acid in subjects with acne.

PubMed

Kircik, Leon H; Gwazdauskas, Jennifer; Butners, Victoria; Eastern, Joseph; Green, Lawrence J

2013-03-01

Benzoyl peroxide (BPO) is a widely used over-the-counter (OTC) topical acne treatment often used in combination with salicylic acid (SA) to achieve better comedone control than that achieved with BPO alone. MaxClarity™ is an OTC acne treatment system comprising BPO and SA in an aqueous foam delivery vehicle, VersaFoam AF™. This paper describes 2 open-label, single-arm studies conducted to assess the efficacy, safety, tolerability, and patient preference of MaxClarity in the treatment of mild, moderate, and severe acne. Subjects applied MaxClarity twice daily for 8 weeks in study 402 and for 12 weeks in study 405. Reductions in all lesion types were seen throughout both studies. At week 8 (study 402), there was a mean reduction from baseline of -56.9 ± 32.7% in total lesions in subjects with mild, moderate, or severe acne. At week 12 (study 405), there was a reduction from baseline of -61.6 ± 22.0% in total lesions in subjects with moderate or severe acne. Overall, both studies demonstrated that MaxClarity is a generally well tolerated and effective treatment for mild, moderate, and severe acne.

Time-to-onset and -resolution of adverse events before/after atomoxetine discontinuation in adult patients with ADHD.

PubMed

Upadhyaya, Himanshu; Tanaka, Yoko; Lipsius, Sarah; Kryzhanovskaya, Ludmila A; Lane, Jeannine R; Escobar, Rodrigo; Trzepacz, Paula T; Allen, Albert J

2015-01-01

Adults with attention-deficit/hyperactivity disorder treated with atomoxetine were examined for time-to-onset and -resolution of common treatment-emergent adverse events (TEAEs) and male sexual dysfunction, and for changes in blood pressure (BP) and heart rate (HR) upon atomoxetine discontinuation. 12-week open-label atomoxetine (40-100 mg/day) was followed by 12-week double-blind maintenance treatment (atomoxetine 80 or 100 mg/day). Responders were then randomized to atomoxetine (n = 266) or placebo (n = 258) for 25-week randomized withdrawal. Examined were (1) median time-to-onset and -resolution of TEAEs during atomoxetine treatment, and (2) within group, visitwise mean changes for sitting HR, systolic BP, and diastolic BP for the postrandomization placebo group. Common adverse events (AEs) appeared early, within week 1 of atomoxetine treatment. Some AEs resolve relatively rapidly, whereas others have a more lingering course of resolution (including male sexual side effects); median resolution times were 3 - 53 days. BP and HR increases during atomoxetine treatment returned to baseline upon atomoxetine discontinuation. Atomoxetine is associated with common AEs, with 3- to 53-day median resolution times. ClincialTrials.gov - NCT00700427.

Single-use autoinjector for once-weekly intramuscular injection of IFNβ-1a.

PubMed

Limmroth, Volker; Gerbershagen, Kathrin

2014-12-01

IFNβ products and glatiramer acetate are established treatment first-line options in long-term disease-modifying therapy of multiple sclerosis (MS). These self-injectable medications are used once weekly to once daily. Injection-related issues are common patient-cited reasons for nonadherence. Autoinjectors have been shown to support long-term adherence to injectable medications. The ability to self-inject in MS patients has been associated with a reduced risk of missed injections and drug discontinuation, and a beneficial effect on patient independence. The recently introduced easy-to-use prefilled once-weekly pen is a safe and effective device for intramuscular (IM) IFNβ-1a application and provides a convenient method for self-injection. We reviewed the available published evidence on the characteristics of this device. The once-weekly pen facilitates self-injection and was preferred over prefilled syringes by patients in a prospective open-label, multicenter Phase IIIb trial in MS patients who had been using IM IFNβ-1a in prefilled syringes. The simple and safe handling, shielded short needle, single-use disposable design and virtually painless injection by the device may contribute to adherence, quality of life and independence in patients using IM IFNβ-1a.

A nudge in a healthy direction. The effect of nutrition labels on food purchasing behaviors in university dining facilities.

PubMed

Cioffi, Catherine E; Levitsky, David A; Pacanowski, Carly R; Bertz, Fredrik

2015-09-01

Despite legislation that requires restaurants to post nutritional labels on their products or menu items, the scientific literature provides inconsistent support for the idea that adding labels to foods will change buying patterns. Lack of success of previous research may be that sample sizes have been too small and durations of studies too short. To assess the effect of nutrition labeling on pre-packaged food purchases in university dining facilities. Weekly sales data for a sample of pre-packaged food items were obtained and analyzed, spanning three semesters before and three semesters after nutritional labels were introduced on to the sample of foods. The labels summarized caloric content and nutrient composition information. Mean nutrient composition purchased were calculated for the sample of foods. Labeled food items were categorized as high-calorie, low-calorie, high-fat, or low-fat foods and analyzed for change as a function of the introduction of the labels. Data were obtained from all retail dining units located at Cornell University, Ithaca, NY where the pre-packaged food items were sold. Results indicated that the introduction of food labels resulted in a 7% reduction of the mean total kcals purchased per week (p < 0.001) from the labeled foods. Total fat purchased per week were also reduced by 7% (p < 0.001). Percent of sales from "low-calorie" and "low-fat" foods (p < 0.001) increased, while percent of sales from "high-calorie" and "high-fat" foods decreased (p < 0.001). The results suggest that nutrition labels on pre-packaged foods in a large university dining hall produces a small but significant reduction of labeled high calorie and high fat foods purchased and an increase in low calorie, low fat foods. Copyright © 2015 Elsevier Ltd. All rights reserved.

Efficacy and tolerability of fixed-combination brinzolamide/timolol in Latin American patients with open-angle glaucoma or ocular hypertension previously on brimonidine/timolol fixed combination.

PubMed

Alezzandrini, Arturo; Hubatsch, Douglas; Alfaro, Rene

2014-09-01

Fixed-combination glaucoma medications are commonly used to achieve target intraocular pressure (IOP) reduction in patients uncontrolled with monotherapy; however, ocular discomfort associated with eye drops can decrease adherence. This study assessed the efficacy and tolerability of twice-daily fixed-combination brinzolamide 1%/timolol 0.5% (BRINZ/TIM-FC) in Latin American patients transitioned from fixed-combination brimonidine 0.2%/timolol 0.5% (BRIM/TIM-FC) because of insufficient IOP control or treatment intolerance. This 8-week, open-label, prospective study was conducted at six sites in Argentina, Chile, and Mexico. Enrolled patients were aged ≥18 years with open-angle glaucoma (including primary, exfoliative, or pigment-dispersion glaucoma) or ocular hypertension with IOP of 19-35 mmHg in ≥1 eye at baseline (on BRIM/TIM-FC). Patients self-administered BRINZ/TIM-FC to both eyes at 8 a.m. and 8 p.m. daily for 8 weeks. The primary and secondary efficacy endpoints were mean IOP change from baseline at week 8 and percentage of patients achieving target IOP (≤18 mmHg) at week 8, respectively. Exploratory endpoints included patient and investigator preference for treatment at week 8. Adverse events (AEs) were assessed as the safety endpoint. Fifty patients (mean ± SD age, 66.7 ± 11.5 years) received BRINZ/TIM-FC, and 49 were included in the intent-to-treat population. Mean ± SD IOP was significantly reduced from baseline after 8 weeks of treatment with BRINZ/TIM-FC (-3.6 ± 3.0 mmHg; P < 0.0001, Wilcoxon signed-rank test; 17.1% reduction). Overall, 55.3% of patients achieved IOP ≤18 mmHg at week 8. Significantly more patients (89.4%) and investigators (95.7%) preferred BRINZ/TIM-FC to BRIM/TIM-FC (both P < 0.0001, exact binomial test). Of the 13 AEs observed, 8 were related to BRINZ/TIM-FC; the most common treatment-related AEs were eye irritation (n = 4) and abnormal sensation in the eye (n = 2). BRINZ/TIM-FC provides an effective and well-tolerated treatment option for patients transitioned from BRIM/TIM-FC.

Prolonged Follow-Up of Patients in the U.S. Multicenter Trial of Ursodeoxycholic Acid for Primary Biliary Cirrhosis

PubMed Central

Combes, Burton; Luketic, Velimir A.; Peters, Marion G.; Zetterman, Rowen K.; Garcia-Tsao, Guadalupe; Munoz, Santiago J.; Lin, Danyu; Flye, Nancy; Carithers, Robert L.

2013-01-01

OBJECTIVE Randomized, double-blind, placebo-controlled trials of ursodeoxycholic acid (UDCA) in patients with primary biliary cirrhosis (PBC) have not demonstrated improvement in survival during the placebo-controlled phases of these trials. Analyses purporting to demonstrate a survival advantage of UDCA are largely dependent on data obtained after the placebo phases were terminated, and placebo-treated patients were offered open-label UDCA. After completion of our 2-yr placebo-controlled trial of UDCA in which we observed no survival benefit for UDCA, we provided the patients with open-label UDCA to see if delay in providing UDCA for 2 yr had any effect on subsequent liver transplantation or death without liver transplantation. METHODS In our previously reported 2-yr placebo-controlled trial, 151 patients with PBC were randomized to receive either UDCA (n = 77) or placebo (n = 74). The number of patients who progressed to liver transplantation or death without transplantation were similar in both the groups, 12 (16%) in the UDCA-treated and 11 (15%) in placebo-treated patients. All the patients were then offered open-label UDCA, with 61 original UDCA and 56 original placebo-treated patients now taking UDCA in an extended open-label phase of the trial. RESULTS No significant differences were observed in the number of patients who underwent liver transplantation or died without liver transplantation in the open-label phase of the trial. Moreover, no difference in the time to these endpoints was seen over the period of observation of as long as 6 yr from the time of initial randomization. CONCLUSIONS Results of open-label extensions of previous conducted placebo-controlled trials of UDCA in PBC leave uncertain whether UDCA impacts significantly on liver transplantation and death without liver transplantation in patients with PBC. PMID:15046215

Effects of long-term treatment with rotigotine transdermal system on dyskinesia in patients with early-stage Parkinson's disease.

PubMed

Giladi, Nir; Ghys, Liesbet; Surmann, Erwin; Boroojerdi, Babak; Jankovic, Joseph

2014-12-01

In two 6-month, double-blind, placebo-controlled studies, rotigotine transdermal system was well-tolerated and efficacious monotherapy in early-stage PD. This post hoc analysis of the long-term open-label extensions (NCT00594165; NCT00599196) of these studies assessed incidence and severity of dyskinesia in participants treated with rotigotine, with or without concomitant levodopa, for up to 6 years. Open-label rotigotine was titrated to optimal dose (≤16 mg/24 h). Concomitant levodopa was permitted. Dyskinesia data, recorded using the Unified Parkinson's Disease Rating Scale Part IV, were pooled from the two open-label studies. Of 596 participants who received open-label rotigotine, 299 (50%) remained at trial closure; no patient discontinued due to dyskinesia. In the two studies, median exposure to rotigotine was 1910 days (∼5 years, 3 months), and 1564.5 days (∼4 years, 3 months). During up to 6 years of open-label rotigotine, 423/596 (71%) received levodopa. Dyskinesias were reported in 115/596 (19%) participants, 90/115 (78%) of who developed dyskinesia after levodopa was added; 25 reported dyskinesia in the absence of levodopa (includes patients who never received open-label levodopa, and those who reported dyskinesia before starting concomitant levodopa). Dyskinesia severity data were available for 107 of the 115 participants. In 56/107 (52%) participants, dyskinesia was considered 'not disabling' for all occurrences; the worst-case severity was 'mildly disabling' for 33/107 (31%), and 'moderately' or 'severely disabling' for 18/107 (17%; 3% of total participants). During treatment with rotigotine in patients with PD for up to 6 years the incidence of dyskinesia was low, and the dyskinesia was generally 'not disabling' or 'mildly disabling'. Copyright © 2014 Elsevier Ltd. All rights reserved.

Long-term Safety and Efficacy of Tapentadol Extended Release Following up to 2 Years of Treatment in Patients With Moderate to Severe, Chronic Pain: Results of an Open-label Extension Trial.

PubMed

Buynak, Robert; Rappaport, Stephen A; Rod, Kevin; Arsenault, Pierre; Heisig, Fabian; Rauschkolb, Christine; Etropolski, Mila

2015-11-01

Tapentadol extended release (ER) has demonstrated efficacy and safety for the management of moderate to severe, chronic pain in adults. This study evaluated the long-term safety and tolerability of tapentadol ER in patients with chronic osteoarthritis or low back pain. Patients were enrolled in this 1-year, open-label extension study after completing one of two 15-week, placebo-controlled studies of tapentadol ER and oxycodone controlled release (CR) for osteoarthritis knee pain (NCT00421928) or low back pain (NCT00449176), a 7-week crossover study between tapentadol immediate release and tapentadol ER for low back pain (NCT00594516), or a 1-year safety study of tapentadol ER and oxycodone CR for osteoarthritis or low back pain (NCT00361504). After titrating the drug to an optimal dose, patients received tapentadol ER (100-250 mg BID) for up to 1 year (after finishing treatment in the preceding studies); patients who were previously treated with tapentadol ER in the 1-year safety study received tapentadol ER continuously for up to 2 years in total. Of the 1,154 patients in the safety population, 82.7% were aged >65 years and 57.9% were female; 50.1% had mild baseline pain intensity. Mean (SD) pain intensity scores (11-point numerical rating scale) were 3.9 (2.38) at baseline (end of preceding study) and 3.7 (2.42) at end point, indicating that pain relief was maintained during the extension study. Improvements in measures of quality of life (eg, EuroQol-5 Dimension and the 36-item Short Form Health Survey [SF-36]) health status questionnaires) achieved during the preceding studies were maintained during the open-label extension study. Tapentadol ER was associated with a safety and tolerability profile comparable to that observed in the preceding studies. The most common treatment-emergent adverse events (incidence ≥10%; n = 1154) were headache (13.1%), nausea (11.8%), and constipation (11.1%). Similar efficacy and tolerability results were shown for patients who received up to 2 years of tapentadol ER treatment. Pain relief and improvements in quality of life achieved during the preceding studies were maintained throughout this extension study, during which tapentadol ER was well tolerated for the long-term treatment of chronic osteoarthritis or low back pain over up to 2 years of treatment. (ClinicalTrials.gov identifier: NCT00487435.). Copyright © 2015. Published by Elsevier Inc.

Effectiveness of lurasidone in schizophrenia or schizoaffective patients switched from other antipsychotics: a 6-month, open-label, extension study.

PubMed

Citrome, Leslie; Weiden, Peter J; McEvoy, Joseph P; Correll, Christoph U; Cucchiaro, Josephine; Hsu, Jay; Loebel, Antony

2014-08-01

To evaluate the long-term safety and tolerability of lurasidone in schizophrenia and schizoaffective disorder patients switched to lurasidone. Patients in this multicenter, 6-month open-label, flexible-dose, extension study had completed a core 6-week randomized trial in which clinically stable, but symptomatic, outpatients with schizophrenia or schizoaffective disorder were switched to lurasidone. Patients started the extension study on treatment with the same dose of lurasidone taken at study endpoint of the 6-week core study; following this, lurasidone was flexibly dosed (40-120 mg/day), if clinically indicated, starting on Day 7 of the extension study. The primary safety endpoints were the proportion of patients with treatment emergent adverse events (AEs), serious AEs, or who discontinued due to AEs. Secondary endpoints included metabolic variables and measures of extrapyramidal symptoms and akathisia, as well as the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity (CGI-S), and the Calgary Depression Scale for Schizophrenia (CDSS). The study was conducted from August 2010 to November 2011. Of the 198 patients who completed the 6-week core study, 149 (75.3%) entered the extension study and 148 received study medication. A total of 98 patients (65.8%) completed the 6-month extension study. Lurasidone 40, 80, and 120 mg were the modal daily doses for 19 (12.8%), 65 (43.9%), and 64 (43.2%) of patients, respectively. Overall mean (SD) daily lurasidone dose was 102.0 mg (77.1). The most commonly reported AEs were insomnia (13 patients [8.8%]), nausea (13 patients [8.8%]), akathisia (12 patients [8.1%]), and anxiety (9 patients [6.1%]). A total of 16 patients (10.8%) had at least one AE leading to discontinuation from the study. Consistent with prior studies of lurasidone, there was no signal for clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin. Movement disorder rating scales did not demonstrate meaningful changes. Treatment failure (defined as any occurrence of discontinuation due to insufficient clinical response, exacerbation of underlying disease, or AE) was observed for 19 patients (12.8% of patients entering) and median time to treatment failure was 58 days (95% CI 22-86). The discontinuation rate due to any cause was 50/148 (33.8%), and median time to discontinuation was 62 days (95% CI 30-75). The mean PANSS total score, mean CGI-S score, and mean CDSS score decreased consistently from core study baseline across extension visits, indicating an improvement in overall condition. In this 6-month, open-label extension study, treatment with lurasidone was generally well-tolerated with sustained improvement in efficacy measures observed in outpatients with schizophrenia or schizoaffective disorder who had switched to lurasidone from a broad range of antipsychotic agents.

Clinically Significant Symptom Reduction in Children with Attention-Deficit/Hyperactivity Disorder Treated with Micronutrients: An Open-Label Reversal Design Study

PubMed Central

Gordon, Heather A; Rucklidge, Julia J; Blampied, Neville M; Johnstone, Jeanette M

2015-01-01

Abstract Objective: The purpose of this study was to investigate the clinical effect and safety of a broad spectrum, 36 ingredient micronutrient (vitamins and minerals) in treating children with attention-deficit/hyperactivity disorder (ADHD). Methods: This open-label, on-off-on-off (reversal design) study followed 14 participants (8–12 years of age) with ADHD, diagnosed using standardized instruments, for 6 months with no dropouts. Following baseline assessment, including hematology and biochemistry screening, participants began an 8 week treatment phase with micronutrients titrated up to maximum dose (15 capsules/day). Treatment was withdrawn for 4 weeks, reinstated for a further 8 weeks, and then withdrawn for 4 weeks. Primary outcomes included the Conners' Parent Rating Scale, the Clinical Global Impressions Scale (CGI), and the Strengths and Difficulties Questionnaire – Parent version (SDQ). Secondary outcomes were mood and global functioning. Results: Modified Brinley plots revealed a reduction in ADHD symptoms, improved mood, and improved overall functioning during intervention phases, and deterioration in ADHD symptoms, mood, and overall functioning during the withdrawal phases. Reliable change analyses, Cohen's d and percent superiority effect sizes, 95% confidence intervals and t tests confirmed clinically and statistically significant change between the intervention and withdrawal phases, with large effect sizes observed pre- to post-exposure of micronutrients (d = 1.2–2.2) on ADHD symptoms during intervention phases. Seventy-one percent of participants showed at least a 30% decrease in ADHD symptoms by the end of the second treatment phase, and 79% were identified as “much improved” or “very much improved” at the end of the second phase (5 months) based on the clinician-rated CGI when considering functioning generally. The SDQ showed that these benefits occurred across other areas of functioning including emotional symptoms, conduct problems, and prosocial behaviours. The children's self-reports confirmed the improvements. Excellent adherence to treatment occurred throughout, side effects were mild and transitory, and no safety issues were identified through blood analyses. Conclusions: This study demonstrates the clinical benefit, feasibility, and safety of broad-spectrum micronutrients in the treatment of childhood ADHD. Replications utilizing double-blind placebo-controlled studies are warranted. Trial is registered with the Australia and New Zealand Clinical Trial Registry: ACTRN12612000645853 PMID:26682999

Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis.

PubMed

De Benedetti, Fabrizio; Brunner, Hermine I; Ruperto, Nicolino; Kenwright, Andrew; Wright, Stephen; Calvo, Inmaculada; Cuttica, Ruben; Ravelli, Angelo; Schneider, Rayfel; Woo, Patricia; Wouters, Carine; Xavier, Ricardo; Zemel, Lawrence; Baildam, Eileen; Burgos-Vargas, Ruben; Dolezalova, Pavla; Garay, Stella M; Merino, Rosa; Joos, Rik; Grom, Alexei; Wulffraat, Nico; Zuber, Zbigniew; Zulian, Francesco; Lovell, Daniel; Martini, Alberto

2012-12-20

Systemic juvenile idiopathic arthritis (JIA) is the most severe subtype of JIA; treatment options are limited. Interleukin-6 plays a pathogenic role in systemic JIA. We randomly assigned 112 children, 2 to 17 years of age, with active systemic JIA (duration of ≥6 months and inadequate responses to nonsteroidal antiinflammatory drugs and glucocorticoids) to the anti-interleukin-6 receptor antibody tocilizumab (at a dose of 8 mg per kilogram of body weight if the weight was ≥30 kg or 12 mg per kilogram if the weight was <30 kg) or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients meeting the predefined criteria for nonresponse were offered open-label tocilizumab. All patients could enter an open-label extension. At week 12, the primary end point (an absence of fever and an improvement of 30% or more on at least three of the six variables in the American College of Rheumatology [ACR] core set for JIA, with no more than one variable worsening by more than 30%) was met in significantly more patients in the tocilizumab group than in the placebo group (64 of 75 [85%] vs. 9 of 37 [24%], P<0.001). At week 52, 80% of the patients who received tocilizumab had at least 70% improvement with no fever, including 59% who had 90% improvement; in addition, 48% of the patients had no joints with active arthritis, and 52% had discontinued oral glucocorticoids. In the double-blind phase, 159 adverse events, including 60 infections (2 serious), occurred in the tocilizumab group, as compared with 38, including 15 infections, in the placebo group. In the double-blind and extension periods combined, 39 serious adverse events (0.25 per patient-year), including 18 serious infections (0.11 per patient-year), occurred in patients who received tocilizumab. Neutropenia developed in 19 patients (17 patients with grade 3 and 2 patients with grade 4), and 21 had aminotransferase levels that were more than 2.5 times the upper limit of the normal range. Tocilizumab was efficacious in severe, persistent systemic JIA. Adverse events were common and included infection, neutropenia, and increased aminotransferase levels. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00642460.).

PPAR-γ agonism as a modulator of mood: proof-of-concept for pioglitazone in bipolar depression.

PubMed

Kemp, David E; Schinagle, Martha; Gao, Keming; Conroy, Carla; Ganocy, Stephen J; Ismail-Beigi, Faramarz; Calabrese, Joseph R

2014-06-01

Insulin resistance and other cardio-metabolic risk factors predict increased risk of depression and decreased response to antidepressant and mood stabilizer treatments. This proof-of-concept study tested whether administration of an insulin-sensitizing peroxisome proliferator-activated receptor (PPAR)-γ agonist could reduce bipolar depression symptom severity. A secondary objective was to determine whether levels of highly sensitive C-reactive protein and interleukin (IL)-6 predicted treatment outcome. Patients (n = 34) with bipolar disorder (I, II, or not otherwise specified) and metabolic syndrome/insulin resistance who were currently depressed (Quick Inventory of Depressive Symptoms [QIDS] total score ≥11) despite an adequate trial of a mood stabilizer received open-label, adjunctive treatment with the PPAR-γ agonist pioglitazone (15-30 mg/day) for 8 weeks. The majority of participants (76 %, n = 26) were experiencing treatment-resistant bipolar depression, having already failed two mood stabilizers or the combination of a mood stabilizer and a conventional antidepressant. Supporting an association between insulin sensitization and depression severity, pioglitazone treatment was associated with a decrease in the total Inventory of Depressive Symptomatology (IDS-C30) score from 38.7 ± 8.2 at baseline to 21.2 ± 9.2 at week 8 (p < 0.001). Self-reported depressive symptom severity and clinician-rated anxiety symptom severity significantly improved over 8 weeks as measured by the QIDS (p < 0.001) and Structured Interview Guide for the Hamilton Anxiety Scale (p < 0.001), respectively. Functional improvement also occurred as measured by the change in total score on the Sheehan Disability Scale (-17.9 ± 3.6; p < 0.001). Insulin sensitivity increased from baseline to week 8 as measured by the Insulin Sensitivity Index derived from an oral glucose tolerance test (0.98 ± 0.3; p < 0.001). Higher baseline levels of IL-6 were associated with greater decrease in depression severity (parameter estimate β = -3.89, standard error [SE] = 1.47, p = 0.015). A positive correlation was observed between improvement in IDS-C30 score and change in IL-6 (r = 0.44, p < 0.01). Open-label administration of the PPAR-γ agonist pioglitazone was associated with improvement in depressive symptoms and reduced cardio-metabolic risk. Reduction in inflammation may represent a novel mechanism by which pioglitazone modulates mood. (ClinicalTrials.gov Identifier: NCT00835120).

Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial.

PubMed

Ellis, Paul; Barrett-Lee, Peter; Johnson, Lindsay; Cameron, David; Wardley, Andrew; O'Reilly, Susan; Verrill, Mark; Smith, Ian; Yarnold, John; Coleman, Robert; Earl, Helena; Canney, Peter; Twelves, Chris; Poole, Christopher; Bloomfield, David; Hopwood, Penelope; Johnston, Stephen; Dowsett, Mitchell; Bartlett, John M S; Ellis, Ian; Peckitt, Clare; Hall, Emma; Bliss, Judith M

2009-05-16

Incorporation of a taxane as adjuvant treatment for early breast cancer offers potential for further improvement of anthracycline-based treatment. The UK TACT study (CRUK01/001) investigated whether sequential docetaxel after anthracycline chemotherapy would improve patient outcome compared with standard chemotherapy of similar duration. In this multicentre, open-label, phase III, randomised controlled trial, 4162 women (aged >18 years) with node-positive or high-risk node-negative operable early breast cancer were randomly assigned by computer-generated permuted block randomisation to receive FEC (fluorouracil 600 mg/m(2), epirubicin 60 mg/m(2), cyclophosphamide 600 mg/m(2) at 3-weekly intervals) for four cycles followed by docetaxel (100 mg/m(2) at 3-weekly intervals) for four cycles (n=2073) or control (n=2089). For the control regimen, centres chose either FEC for eight cycles (n=1265) or epirubicin (100 mg/m(2) at 3-weekly intervals) for four cycles followed by CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), and fluorouracil 600 mg/m(2) at 4-weekly intervals) for four cycles (n=824). The primary endpoint was disease-free survival. Analysis was by intention to treat (ITT). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN79718493. All randomised patients were included in the ITT population. With a median follow-up of 62 months, disease-free survival events were seen in 517 of 2073 patients in the experimental group compared with 539 of 2089 controls (hazard ratio [HR] 0.95, 95% CI 0.85-1.08; p=0.44). 75.6% (95% CI 73.7-77.5) of patients in the experimental group and 74.3% (72.3-76.2) of controls were alive and disease-free at 5 years. The proportion of patients who reported any acute grade 3 or 4 adverse event was significantly greater in the experimental group than in the control group (p<0.0001); the most frequent events were neutropenia (937 events vs 797 events), leucopenia (507 vs 362), and lethargy (456 vs 272). This study did not show any overall gain from the addition of docetaxel to standard anthracycline chemotherapy. Exploration of predictive biomarker-defined subgroups might have the potential to better target the use of taxane-based therapy. Cancer Research UK (CRUK 01/001), Sanofi-Aventis, Pfizer, and Roche.

Effects of a structured 20-session slow-cortical-potential-based neurofeedback program on attentional performance in children and adolescents with attention-deficit hyperactivity disorder: retrospective analysis of an open-label pilot-approach and 6-month follow-up.

PubMed

Albrecht, Johanna S; Bubenzer-Busch, Sarah; Gallien, Anne; Knospe, Eva Lotte; Gaber, Tilman J; Zepf, Florian D

2017-01-01

The aim of this approach was to conduct a structured electroencephalography-based neurofeedback training program for children and adolescents with attention-deficit hyperactivity disorder (ADHD) using slow cortical potentials with an intensive first (almost daily sessions) and second phase of training (two sessions per week) and to assess aspects of attentional performance. A total of 24 young patients with ADHD participated in the 20-session training program. During phase I of training (2 weeks, 10 sessions), participants were trained on weekdays. During phase II, neurofeedback training occurred twice per week (5 weeks). The patients' inattention problems were measured at three assessment time points before (pre, T0) and after (post, T1) the training and at a 6-month follow-up (T2); the assessments included neuropsychological tests (Alertness and Divided Attention subtests of the Test for Attentional Performance; Sustained Attention Dots and Shifting Attentional Set subtests of the Amsterdam Neuropsychological Test) and questionnaire data (inattention subscales of the so-called Fremdbeurteilungsbogen für Hyperkinetische Störungen and Child Behavior Checklist/4-18 [CBCL/4-18]). All data were analyzed retrospectively. The mean auditive reaction time in a Divided Attention task decreased significantly from T0 to T1 (medium effect), which was persistent over time and also found for a T0-T2 comparison (larger effects). In the Sustained Attention Dots task, the mean reaction time was reduced from T0-T1 and T1-T2 (small effects), whereas in the Shifting Attentional Set task, patients were able to increase the number of trials from T1-T2 and significantly diminished the number of errors (T1-T2 & T0-T2, large effects). First positive but very small effects and preliminary results regarding different parameters of attentional performance were detected in young individuals with ADHD. The limitations of the obtained preliminary data are the rather small sample size, the lack of a control group/a placebo condition and the open-label approach because of the clinical setting and retrospective analysis. The value of the current approach lies in providing pilot data for future studies involving larger samples.

Patient-reported outcomes and health-care resource utilization in patients with psoriasis treated with etanercept: continuous versus interrupted treatment.

PubMed

Gelfand, Joel M; Kimball, Alexa B; Mostow, Eliot N; Chiou, Chiun-Fang; Patel, Vaishali; Xia, H Amy; Freundlich, Bruce; Stevens, Seth R

2008-01-01

The 24-week Etanercept Assessment of Safety and Effectiveness (EASE) study evaluated the effectiveness and tolerability of continuous versus interrupted etanercept treatment in patients with moderate to severe plaque psoriasis. The objective of this analysis was to assess patient-reported outcomes (PROs) and health-care resource utilization (HRU) data from the EASE study. Patients received open-label etanercept 50 mg twice weekly for 12 weeks and then received either continued or interrupted (single round of discontinuation and re-treatment with etanercept) etanercept 50 mg once weekly for the second 12 weeks. PROs included the following: 1) the patient global assessments of psoriasis, joint pain, and itching scores; 2) the Dermatology Life Quality Index; 3) the Medical Outcomes Study Short Form 36 vitality domain; 4) the Beck Depression Inventory; 5) the European Quality-of-Life Group Feeling Thermometer; and 6) a patient satisfaction survey. HRU was evaluated using the Economic Implications of Psoriasis patient questionnaire. Continuous treatment with etanercept 50 mg twice weekly for 12 weeks followed by 50 mg once weekly for 12 weeks produced sustained and clinically important improvements in PROs and reductions in HRU. Reductions in some outcome measures after treatment discontinuation at week 12 were observed in the interrupted group; however, most changes did not revert to baseline levels, consistent with some residual clinical effect, and re-treatment produced improvements similar to week 12 levels. Continuous etanercept treatment provided greater sustained improvements in PROs than interrupted therapy; however, interrupting etanercept therapy, if needed, has predictable and manageable effects.

Safety and efficacy of an 8-week regimen of grazoprevir plus ruzasvir plus uprifosbuvir compared with grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis C virus genotypes 1, 2, or 3 (C-CREST-1 and C-CREST-2, part A): two randomised, phase 2, open-label trials.

PubMed

Gane, Edward J; Pianko, Stephen; Roberts, Stuart K; Thompson, Alexander J; Zeuzem, Stefan; Zuckerman, Eli; Ben-Ari, Ziv; Foster, Graham R; Agarwal, Kosh; Laursen, Alex L; Gerstoft, Jan; Gao, Wei; Huang, Hsueh-Cheng; Fitzgerald, Brian; Fernsler, Doreen; Li, Jerry J; Grandhi, Anjana; Liu, Hong; Su, Feng-Hsiu; Wan, Shuyan; Zeng, Zhen; Chen, Huei-Ling; Dutko, Frank J; Nguyen, Bach-Yen T; Wahl, Janice; Robertson, Michael N; Barr, Eliav; Yeh, Wendy W; Plank, Rebeca M; Butterton, Joan R; Esteban, Rafael

2017-11-01

New hepatitis C virus (HCV) therapies with pan-genotypic efficacy are needed. The goals of part A of C-CREST-1 and C-CREST-2 were to compare the efficacies of two doses (300 mg or 450 mg once daily) of uprifosbuvir (MK-3682; NS5B inhibitor) in an 8-week regimen combined with grazoprevir (NS3/4A inhibitor; 100 mg once daily) and an NS5A inhibitor, either elbasvir (50 mg once daily) or ruzasvir (MK-8408; 60 mg once daily), and to evaluate the safety and tolerability of these combination regimens in individuals infected with genotypes 1, 2, or 3. Part A of these phase 2, randomised, multicentre, open-label, clinical trials enrolled participants from 11 countries, aged 18 years or older, chronically infected with HCV genotypes 1, 2, or 3, with HCV RNA of at least 10 000 IU/mL, without evidence of cirrhosis, who had not received previous treatment for HCV infection. Within each HCV genotype, participants were randomly assigned (1:1:1:1) with a block size of 4, to open-label treatment to one of four treatment groups: grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (300 mg/day); grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (450 mg/day); grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (300 mg/day); or grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (450 mg/day), according to a computer-generated allocation schedule. Randomisation was centrally implemented using an interactive voice response system and integrated web response system. The primary endpoint was the proportion of participants achieving sustained virological response at 12 weeks (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the end of all study therapy) in the per-protocol analysis set, which included all participants who were randomised and received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT02332707 and NCT02332720. 241 participants were randomised between Feb 18, 2015, and March 16, 2015. 240 participants completed 8 weeks of treatment and reached follow-up 12 weeks after the end of treatment. Of the four regimens, grazoprevir plus ruzasvir plus uprifosbuvir 450 mg had the most consistently high SVR12 (>90%) for participants infected with genotype 1 (21 [91%] of 23), genotype 2 (15 [94%] of 16), and genotype 3 (20 [91%] of 22). In particular, among those with genotype 2 infection, the grazoprevir plus ruzasvir plus uprifosbuvir 450 mg regimen had a higher SVR12 (15 [94%] of 16) than the grazoprevir plus ruzasvir plus uprifosbuvir 300 mg regimen (ten [71%] of 14), grazoprevir plus elbasvir plus uprifosbuvir 300 mg regimen (11 [69%] of 16), or grazoprevir plus elbasvir plus uprifosbuvir 450 mg regimen (nine [60%] of 15). Overall, the most common adverse events were headache (55 [23%] of 240), fatigue (47 [20%] of 240), and nausea (32 [13%] of 240). Two (<1%) of 240 participants had serious adverse events (pharyngeal abscess and keratitis), which were not considered drug related by the respective investigators. These results support further evaluation of the three-drug direct-acting antiviral agent regimen of grazoprevir 100 mg plus ruzasvir 60 mg plus uprifosbuvir 450 mg among a more diverse HCV-infected population, including those with compensated cirrhosis, previous treatment with an interferon-containing regimen, and HCV-HIV co-infection. Merck & Co, Inc. Copyright © 2017 Elsevier Ltd. All rights reserved.

Open-label pilot study on vitamin D₃ supplementation for antipsychotic-associated metabolic anomalies.

PubMed

Thakurathi, Neelam; Stock, Shannon; Oppenheim, Claire E; Borba, Christina P C; Vincenzi, Brenda; Seidman, Larry J; Stone, William S; Henderson, David C

2013-09-01

Previous studies have linked vitamin D deficiency to hypertension, dyslipidemia, diabetes mellitus, and cardiovascular disease. The aim of this study was to investigate the short-term effects of vitamin D₃ supplementation on weight and glucose and lipid metabolism in antipsychotic-treated patients. A total of 19 schizophrenic or schizoaffective patients (BMI>27 kg/m²) taking atypical antipsychotics were recruited and dispensed a 2000 IU daily dose of vitamin D₃. On comparing baseline with week 8 (study end) results, we found a statistically significant increase in vitamin D₃ and total vitamin D levels but no statistically significant changes in weight, glucose, or lipids measurements. Patients whose vitamin D₃ level at week 8 was 30 ng/ml or more achieved a significantly greater decrease in total cholesterol levels compared with those whose week 8 vitamin D₃ measurement was less than 30 ng/ml. These results suggest that a randomized trial with a longer follow-up period would be helpful in further evaluating the effects of vitamin D₃ on weight, lipid metabolism, and on components of metabolic syndrome in antipsychotic-treated patients.

Effect of Cystone® on urinary composition and stone formation over a one year period.

PubMed

Erickson, S B; Vrtiska, T J; Lieske, J C

2011-07-15

Kidney stones are a common problem for which inadequate prevention exists. We recruited ten recurrent kidney stone formers with documented calcium oxalate stones into a two phased study to assess safety and effectiveness of Cystone(®), an herbal treatment for prevention of kidney stones. The first phase was a randomized double-blinded 12 week cross over study assessing the effect of Cystone(®) vs. placebo on urinary supersaturation. The second phase was an open label one year study of Cystone(®) to determine if renal stone burden decreased, as assessed by quantitative and subjective assessment of CT. Results revealed no statistically significant effect of Cystone(®) on urinary composition short (6 weeks) or long (52 weeks) term. Average renal stone burden increased rather than decreased on Cystone(®). Therefore, this study does not support the efficacy of Cystone(®) to treat calcium oxalate stone formers. Future studies will be needed to assess effects on stone passage, or on other stone types. Copyright © 2011 Elsevier GmbH. All rights reserved.

Glucose sensor-augmented continuous subcutaneous insulin infusion in patients with diabetic gastroparesis: An open-label pilot prospective study

PubMed Central

Pasricha, Pankaj J.; Tonascia, James; Parkman, Henry P.; Hamilton, Frank; Herman, William H.; Basina, Marina; Buckingham, Bruce; Earle, Karen; Kirkeby, Kjersti; Hairston, Kristen; Bright, Tamis; Rothberg, Amy E.; Kraftson, Andrew T.; Siraj, Elias S.; Subauste, Angela; Lee, Linda A.; Abell, Thomas L.; McCallum, Richard W.; Sarosiek, Irene; Nguyen, Linda; Fass, Ronnie; Snape, William J.; Vaughn, Ivana A.; Miriel, Laura A.; Farrugia, Gianrico

2018-01-01

Erratic blood glucose levels can be a cause and consequence of delayed gastric emptying in patients with diabetes. It is unknown if better glycemic control increases risks of hypoglycemia or improves hemoglobin A1c levels and gastrointestinal symptoms in diabetic gastroparesis. This study investigated the safety and potential efficacy of continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) in poorly controlled diabetes with gastroparesis. Forty-five type 1 or 2 patients with diabetes and gastroparesis and hemoglobin A1c >8% from the NIDDK Gastroparesis Consortium enrolled in a 24 week open-label pilot prospective study of CSII plus CGM. The primary safety outcome was combined numbers of mild, moderate, and severe hypoglycemic events at screening and 24 weeks treatment. Secondary outcomes included glycemic excursions on CGM, hemoglobin A1c, gastroparesis symptoms, quality-of-life, and liquid meal tolerance. Combined mild, moderate, and severe hypoglycemic events occurred similarly during the screening/run-in (1.9/week) versus treatment (2.2/week) phases with a relative risk of 1.18 (95% CI 0.85–1.64, P = 0.33). CGM time in hypoglycemia (<70 mg/dL) decreased from 3.9% to 1.8% (P<0.0001), time in euglycemia (70–180 mg/dL) increased from 44.0% to 52.0% (P = 0.02), time in severe hyperglycemia (>300 mg/dL) decreased from 14.2% to 7.0% (P = 0.005), and hemoglobin A1c decreased from 9.4±1.4% to 8.3±1.3% (P = 0.001) on CSII plus CGM. Symptom scores decreased from 29.3±7.1 to 21.9±10.2 with lower nausea/vomiting, fullness/early satiety, and bloating/distention scores (P≤0.001). Quality-of-life scores improved from 2.4±1.1 to 3.1±1.1 (P<0.0001) and volumes of liquid nutrient meals tolerated increased from 420±258 to 487±312 mL (P = 0.05) at 24 weeks. In conclusion, CSII plus CGM appeared to be safe with minimal risks of hypoglycemic events and associated improvements in glycemic control, gastroparesis symptoms, quality-of-life, and meal tolerance in patients with poorly controlled diabetes and gastroparesis. This study supports the safety, feasibility, and potential benefits of improving glycemic control in diabetic gastroparesis. PMID:29652893

Masitinib in the treatment of active rheumatoid arthritis: results of a multicentre, open-label, dose-ranging, phase 2a study

PubMed Central

Tebib, Jacques; Mariette, Xavier; Bourgeois, Pierre; Flipo, René-Marc; Gaudin, Philippe; Le Loët, Xavier; Gineste, Paul; Guy, Laurent; Mansfield, Colin D; Moussy, Alain; Dubreuil, Patrice; Hermine, Olivier; Sibilia, Jean

2009-01-01

Introduction Since current treatment options for patients suffering from active rheumatoid arthritis (RA) remain inadequate, especially for those unresponsive to disease-modifying antirheumatic drugs (DMARDs), new and improved medication is needed. This study evaluates the safety and efficacy of masitinib (AB1010), a potent and selective protein tyrosine kinase inhibitor of c-KIT, in the monotherapy treatment of DMARD-refractory RA. Methods This was a multicentre, uncontrolled, open-label, randomised, dose-ranging, phase 2a trial. Masitinib was administered orally to 43 patients who had inadequate response to DMARDs, at initial randomised dosing levels of 3 and 6 mg/kg per day over a 12-week period. Dose adjustment was permitted based upon tolerability and response criteria. Efficacy was assessed via American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) responses, disease activity score using 28 joint counts (DAS28), index of improvement in RA (ACRn) and C-reactive protein (CRP) improvement, relative to baseline at week 12. Results Improvement was observed in all efficacy endpoints, including ACR20/50/70 scores of 54%, 26% and 8%, respectively, and a reduction in CRP level by greater than 50% for approximately half the population. This improvement was sustainable throughout an extension phase (> 84 weeks) and was also independent of initial DMARD resistance (anti-tumour necrosis factor-alpha and/or methotrexate). A relatively high patient withdrawal rate (37%) required the use of last observation carried forward (LOCF) data imputation. Incidence of adverse events was high (95%), although the majority were of mild or moderate severity with a considerable decline in frequency observed after 12 weeks of treatment. Two nonfatal serious adverse events were reported. Dose-response analyses tentatively indicate that an initial dosing level of 6.0 mg/kg per day administered orally in two daily intakes is the most appropriate, based upon potency and tolerability trends. Conclusions Treatment with masitinib improved DMARD-refractory active RA. Following an initial high incidence of mostly mild to moderate side effects during the first 12 weeks of treatment, masitinib appears to be generally well tolerated. This, together with evidence of a sustainable efficacy response, suggests that masitinib is suitable for long-term treatment regimens. Since this was the first study of masitinib in a nononcologic pathology, the relatively high patient withdrawal rate observed can be partly attributed to a highly cautious response to adverse events. There is sufficient compelling evidence to warrant further placebo-controlled investigation. Trial registration ClinicalTrials.gov NCT00831922. PMID:19549290

Changes in Psychological Parameters in Patients with Tension-type Headache Following Massage Therapy: A Pilot Study

PubMed Central

Moraska, Albert; Chandler, Clint

2009-01-01

Investigations into complementary and alternative medicine (CAM) approaches to address stress, depression, and anxiety of those experiencing chronic pain are rare. The objective of this pilot study was to assess the value of a structured massage therapy program, with a focus on myofascial trigger points, on psychological measures associated with tension-type headache. Participants were enrolled in an open-label trial using a baseline control with four 3-week phases: baseline, massage (two 3-week periods) and a follow-up phase. Eighteen subjects with episodic or chronic tension-type headache were enrolled and evaluated at 3-week intervals using the State-Trait Anxiety Inventory, Beck Depression Inventory, and the Perceived Stress Scale. The Daily Stress Inventory was administered over 7-day periods during baseline and the final week of massage. Twice weekly, 45-minute massage therapy sessions commenced following the baseline phase and continued for 6 weeks. A significant improvement in all psychological measures was detected over the timeframe of the study. Post hoc evaluation indicated improvement over baseline for depression and trait anxiety following 6 weeks of massage, but not 3 weeks. A reduction in the number of events deemed stressful as well as their respective impact was detected. This pilot study provides evidence for reduction of affective distress in a chronic pain population, suggesting the need for more rigorously controlled studies using massage therapy to address psychological measures associated with TTH. PMID:20046550

Safety and Immunogenicity of an Anti-Zika Virus DNA Vaccine - Preliminary Report.

PubMed

Tebas, Pablo; Roberts, Christine C; Muthumani, Kar; Reuschel, Emma L; Kudchodkar, Sagar B; Zaidi, Faraz I; White, Scott; Khan, Amir S; Racine, Trina; Choi, Hyeree; Boyer, Jean; Park, Young K; Trottier, Sylvie; Remigio, Celine; Krieger, Diane; Spruill, Susan E; Bagarazzi, Mark; Kobinger, Gary P; Weiner, David B; Maslow, Joel N

2017-10-04

Background Although Zika virus (ZIKV) infection is typically self-limiting, other associated complications such as congenital birth defects and the Guillain-Barré syndrome are well described. There are no approved vaccines against ZIKV infection. Methods In this phase 1, open-label clinical trial, we evaluated the safety and immunogenicity of a synthetic, consensus DNA vaccine (GLS-5700) encoding the ZIKV premembrane and envelope proteins in two groups of 20 participants each. The participants received either 1 mg or 2 mg of vaccine intradermally, with each injection followed by electroporation (the use of a pulsed electric field to introduce the DNA sequence into cells) at baseline, 4 weeks, and 12 weeks. Results The median age of the participants was 38 years, and 60% were women; 78% were white, and 22% black; in addition, 30% were Hispanic. At the interim analysis at 14 weeks (i.e., after the third dose of vaccine), no serious adverse events were reported. Local reactions at the vaccination site (e.g., injection-site pain, redness, swelling, and itching) occurred in approximately 50% of the participants. After the third dose of vaccine, binding antibodies (as measured on enzyme-linked immunosorbent assay) were detected in all the participants, with geometric mean titers of 1642 and 2871 in recipients of 1 mg and 2 mg of vaccine, respectively. Neutralizing antibodies developed in 62% of the samples on Vero-cell assay. On neuronal-cell assay, there was 90% inhibition of ZIKV infection in 70% of the serum samples and 50% inhibition in 95% of the samples. The intraperitoneal injection of postvaccination serum protected 103 of 112 IFNAR knockout mice (bred with deletion of genes encoding interferon-α and interferon-β receptors) (92%) that were challenged with a lethal dose of ZIKV-PR209 strain; none of the mice receiving baseline serum survived the challenge. Survival was independent of the neutralization titer. Conclusions In this phase 1, open-label clinical trial, a DNA vaccine elicited anti-ZIKV immune responses. Further studies are needed to better evaluate the safety and efficacy of the vaccine. (Funded by GeneOne Life Science and others; ZIKA-001 ClinicalTrials.gov number, NCT02809443 .).

A randomized, open-label, crossover study comparing the effects of oral versus transdermal estrogen therapy on serum androgens, thyroid hormones, and adrenal hormones in naturally menopausal women.

PubMed

Shifren, Jan L; Desindes, Sophie; McIlwain, Marilyn; Doros, Gheorghe; Mazer, Norman A

2007-01-01

To compare the changes induced by oral versus transdermal estrogen therapy on the total and free serum concentrations of testosterone (T), thyroxine (T4), and cortisol (C) and the concentrations of their serum binding globulins sex hormone-binding globulin, thyroxine-binding globulin, and cortisol-binding globulin in naturally menopausal women. Randomized, open-label, crossover. Interventions included a 6-week withdrawal from previous hormone therapy (baseline), followed in randomized order by 12 weeks of oral conjugated equine estrogens (CEE) (0.625 mg/d) and 12 weeks of transdermal estradiol (TD E2) (0.05 mg/d), with oral micronized progesterone (100 mg/d) given continuously during both transdermal estrogen therapy regimens. Twenty-seven women were enrolled in the study, and 25 completed both treatment periods. The mean(SD) percentage changes from baseline of sex hormone-binding globulin, total T, and free T with oral CEE were +132.1% (74.5%), +16.4% (43.8%), and -32.7% (25.9%), respectively, versus +12.0% (25.1%), +1.2% (43.7%), and +1.0% (45.0%) with TD E2. The mean (SD) percentage changes of thyroxine-binding globulin, total T4, and free T4 with oral CEE were +39.9% (20.1%), +28.4% (29.2%), and -10.4% (22.3%), respectively, versus +0.4% (11.1%), -0.7% (16.5%), and +0.2% (26.6%) with TD E2. The mean (SD) percentage changes of cortisol-binding globulin, total C, and free C with oral CEE were +18.0% (19.5%), +29.2% (46.3%), and +50.4% (126.5%), respectively, versus -2.2% (11.3%), -6.7% (30.8%), and +1.8% (77.1%) with TD E2. Concentrations of all hormones and binding globulins were significantly different (P < or = 0.003) during administration of oral versus transdermal estrogen therapy, except for free T4 and free C. Compared with oral CEE, TD E2 exerts minimal effects on the total and free concentrations of T, T4, and C and their binding proteins.

Aripiprazole in Pervasive Developmental Disorder Not Otherwise Specified and Asperger's Disorder: A 14-Week, Prospective, Open-Label Study

PubMed Central

Diener, Jonathan T.; Kohn, Arlene E.; Li, Lang; Erickson, Craig A.; Posey, David J.; McDougle, Christopher J.

2009-01-01

Abstract Objective The aim of this study was to determine the effectiveness and tolerability of aripiprazole for irritability in pervasive developmental disorder not otherwise specified (PDD-NOS) and Asperger's disorder. Method This is a 14-week, prospective, open-label investigation of aripiprazole in 25 children and adolescents diagnosed with PDD-NOS or Asperger's disorder. Primary outcome measures included the Clinical Global Impressions–Improvement (CGI-I) scale and the Irritability subscale of the Aberrant Behavior Checklist (ABC-I). Results Twenty-five subjects, ages 5–17 years (mean 8.6 years) received a mean final aripiprazole dosage of 7.8 mg/day (range 2.5–15 mg/day). Full-scale intelligence quotient (IQ) scores ranged from 48 to 122 (mean 84). Twenty-two (88%) of 25 subjects were responders in regard to interfering symptoms of irritability, including aggression, self-injury, and tantrums, with a final CGI-I of 1 or 2 (very much or much improved) and a 25% or greater improvement on the ABC-I. The final mean CGI-I was 1.6 (p ≤ 0.0001). ABC-I scores ranged from 18 to 43 (mean 29) at baseline, whereas scores at week 14 ranged from 0 to 27 (mean 8.1) (p ≤ 0.001). Aripiprazole was well tolerated. Mild extrapyramidal symptoms (EPS) were reported in 9 subjects. Age- and sex-normed body mass index (BMI) increased from a mean value of 20.3 at baseline to 21.1 at end point (p ≤ 0.04). Prolactin significantly decreased from a mean value of 9.3 at baseline to 2.9 at end point (p ≤ 0.0001). No subject exited the study due to a drug-related adverse event. Conclusions These preliminary data suggest that aripiprazole may be effective and well tolerated for severe irritability in pediatric patients with PDD-NOS or Asperger's disorder. Larger-scale placebo-controlled studies are needed to elucidate the efficacy and tolerability of aripiprazole in this understudied population. PMID:19519261

An Open-Label, Randomized Trial of Methylphenidate and Atomoxetine Treatment in Children with Attention-Deficit/Hyperactivity Disorder.

PubMed

Shang, Chi-Yung; Pan, Yi-Lei; Lin, Hsiang-Yuan; Huang, Lin-Wan; Gau, Susan Shur-Fen

2015-09-01

The efficacy of both methylphenidate and atomoxetine has been established in placebo-controlled trials. The present study aimed to directly compare the efficacy of methylphenidate and atomoxetine in improving symptoms among children with attention-deficit/hyperactivity disorder (ADHD). The study sample included 160 drug-naïve children and adolescents 7-16 years of age, with DSM-IV-defined ADHD, randomly assigned to osmotic-release oral system methylphenidate (OROS-methylphenidate) (n=80) and atomoxetine (n=80) in a 24 week, open-label, head-to-head clinical trial. The primary efficacy measure was the score of the ADHD Rating Scale-IV Parents Version: Investigator Administered and Scored (ADHD-RS-IV). The secondary efficacy measures included the Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) and Chinese Swanson, Nolan, and Pelham IV scale (SNAP-IV), based on the ratings of investigators, parents, teachers, and subjects. At week 24, mean changes in ADHD-RS-IV Inattention scores were 13.58 points (Cohen's d, -3.08) for OROS-methylphenidate and 12.65 points (Cohen's d, -3.05) for atomoxetine; and mean changes in ADHD-RS-IV Hyperactivity-Impulsivity scores were 10.16 points (Cohen's d, -1.75) for OROS-methylphenidate and 10.68 points (Cohen's d, -1.87) for atomoxetine. In terms of parent-, teacher-, and self-ratings on behavioral symptoms, both of the two treatment groups significantly decreased on the SNAP-IV scores at the end-point, with effect sizes ranging from 0.9 to 0.96 on the Inattention subscale and from 0.61 to 0.8 on the Hyperactivity/Impulsivity subscale for OROS-methylphenidate; and from 0.51 to 0.88 on the Inattention subscale and from 0.29 to 0.57 on the Hyperactivity/Impulsivity subscale for atomoxetine. No statistically significant differences between treatment groups were observed on the outcome measures. Vomiting, somnolence, and dizziness were reported more often for atomoxetine than for OROS-methylphenidate, whereas insomnia was reported more often for OROS-methylphenidate than for atomoxetine. After 24 weeks of treatment, OROS-methylphenidate and atomoxetine had comparable efficacy in reducing core ADHD symptoms in drug-naïve children and adolescents with ADHD.

Neo-adjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized, open-label, phase III trial (SAKK 75/08).

PubMed

Ruhstaller, T; Thuss-Patience, P; Hayoz, S; Schacher, S; Knorrenschild, J R; Schnider, A; Plasswilm, L; Budach, W; Eisterer, W; Hawle, H; Mariette, C; Hess, V; Mingrone, W; Montemurro, M; Girschikofsky, M; Schmidt, S C; Bitzer, M; Bedenne, L; Brauchli, P; Stahl, M

2018-04-04

This open-label, phase lll trial compared chemoradiation followed by surgery with or without neoadjuvant and adjuvant cetuximab in patients with resectable esophageal carcinoma. Patients were randomly assigned (1:1) to 2 cycles of chemotherapy (docetaxel 75 mg/m2, cisplatin 75 mg/m2) followed by chemoradiation (45 Gy, docetaxel 20 mg/m2 and cisplatin 25 mg/m2, weekly for 5 weeks) and surgery, with or without neoadjuvant cetuximab 250 mg/m2 weekly and adjuvant cetuximab 500 mg/m2 fortnightly for 3 months. The primary endpoint was progression-free survival (PFS). In total, 300 patients (median age, 61 years; 88% male; 63% adenocarcinoma; 85% cT3/4a, 90% cN+) were assigned to cetuximab (n = 149) or control (n = 151). The R0-resection rate was 95% for cetuximab versus 97% for control. Postoperative treatment-related mortality was 6% in both arms. Median PFS was 2.9 years (95% CI, 2.0 to not reached) with cetuximab and 2.0 years (95% CI, 1.5 to 2.8) with control (HR, 0.79; 95% CI, 0.58 to 1.07; P = .13). Median overall survival (OS) time was 5.1 years (95% CI, 3.7 to not reached) versus 3.0 years (95% CI, 2.2 to 4.2) for cetuximab and control, respectively (HR, 0.73; 95% CI, 0.52 to 1.01; P = .055). Time to loco-regional failure after R0-resection was significantly longer for cetuximab (HR 0.53; 95% CI, 0.31 to 0.90; P = .017); time to distant failure did not differ between arms (HR, 1.01; 95% CI, 0.64 to 1.59, P = .97). Cetuximab did not increase adverse events in neoadjuvant or postoperative settings. Adding cetuximab to multimodal therapy significantly improved loco-regional control, and led to clinically relevant, but not-significant improvements in PFS and OS in resectable esophageal carcinoma. NCT01107639.

PlenadrEMA: effect of dual-release versus conventional hydrocortisone on fatigue, measured by ecological momentary assessments: a study protocol for an open-label switch pilot study.

PubMed

Boesen, Victor Brun; Christoffersen, Thea; Watt, Torquil; Borresen, Stina Willemoes; Klose, Marianne; Feldt-Rasmussen, Ulla

2018-01-23

Patients with adrenal insufficiency have impaired health-related quality of life (QoL). The dual-release hydrocortisone preparation, Plenadren, has been developed to mimic the physiological cortisol release more closely than conventional hydrocortisone treatment. Plenadren has been shown to improve QoL, in particular fatigue, in patients with primary adrenal insufficiency. However, the effect has not been investigated in patients with secondary adrenal insufficiency; furthermore, no study has taken the diurnal variation of fatigue into account. To assess diurnal variations, it is necessary to use repeated daily measurements, such as ecological momentary assessments (EMAs). This study aims to evaluate EMAs of fatigue as outcome in future large-scale randomised clinical trials. The PlenadrEMA trial is an investigator-initiated open-label switch pilot trial of the effect of Plenadren versus conventional hydrocortisone on fatigue in patients with secondary adrenal insufficiency. The trial will include 30 participants. After 5 weeks on their usual hydrocortisone treatment, patients will be shifted to Plenadren for 16 weeks. Fatigue will be assessed using momentary versions of the Multidimensional Fatigue Inventory (MFI-20). Items will be administered to participants via a smartphone application four times daily during 20 days. Assessments will be performed before treatment shift and repeated after 12.5 weeks on Plenadren. The study will identify the best suited outcome for future randomised clinical trials, and in addition, estimate the variability and difference in fatigue between the two treatments to perform power calculations. The trial will be conducted in accordance with the Declaration of Helsinki and has been approved by the Regional Scientific Ethical Committee in Copenhagen (ID: H-1-2014-073). All patients will receive written and verbal information about the trial and will give informed consent before enrolment. Findings will be published in peer-reviewed journals and presented at international conferences. EudraCT201400203932. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Effects of fluoxetine on fine motor performance in dysthymia: an 8-week, nonrandomized, open-label study.

PubMed

Schrijvers, Didier; Maas, Yvonne J; Sabbe, Bernard G C

2009-01-01

Present findings on psychomotor retardation in dysthymia are inconsistent and changes in psychomotor performance during antidepressant treatment have not been investigated in this population to date. The present study aims to explore the psychomotor effects of an 8-week regimen of fluoxetine in dysthymic patients. Dysthymic patients (both inpatients and outpatients of the Psychiatric Hospital Sint-Norbertus, Duffel, Belgium), presenting over a period of 2 years, meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for dysthymia, and having Hamilton Depression Rating Scale scores of > or = 12 were enrolled. During 8 weeks of treatment with fluoxetine 20 mg/d, depression severity and graphic motor activity were assessed 4 times by recording the time (a reaction time [RT] and a movement time [MT]) participants needed to copy single lines and simple and complex figures. The patients' outcomes were compared with those of untreated, healthy controls, matched for sex and comparable age and education. The assessors were masked to treatment and group. Eighteen dysthymic patients (mean age, 40 years; male/female ratio, 4/14; mean weight, 70 kg; all white) were treated; 18 healthy controls (mean age, 40 years; male/female ratio, 4/14; mean weight, 72 kg; all white) were used as comparison. The overall patient group experienced significant psychomotor changes only in association with the complex figure-copying task (RT: F = 5.67, P < 0.05). In a subgroup analysis of 9 patients who clinically responded to treatment (ie, > 40% decrease in severity scores), significant improvements were observed only for the RT of the line- (F = 4.75, P < 0.05) and complex figure-copying task (F = 11.86, P < 0.01) and the MT of the simple figure-copying task (F = 7.57, P < 0.05), but not for the other psychomotor variables. Although some significant psychomotor changes were observed in a subgroup of clinically responsive dysthymic patients, the overall results of this small, nonrandomized, open-label study do not suggest a beneficial psychomotor effect associated with short-term fluoxetine treatment of dysthymia.

A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency.

PubMed

Burton, Barbara K; Balwani, Manisha; Feillet, François; Barić, Ivo; Burrow, T Andrew; Camarena Grande, Carmen; Coker, Mahmut; Consuelo-Sánchez, Alejandra; Deegan, Patrick; Di Rocco, Maja; Enns, Gregory M; Erbe, Richard; Ezgu, Fatih; Ficicioglu, Can; Furuya, Katryn N; Kane, John; Laukaitis, Christina; Mengel, Eugen; Neilan, Edward G; Nightingale, Scott; Peters, Heidi; Scarpa, Maurizio; Schwab, K Otfried; Smolka, Vratislav; Valayannopoulos, Vassili; Wood, Marnie; Goodman, Zachary; Yang, Yijun; Eckert, Stephen; Rojas-Caro, Sandra; Quinn, Anthony G

2015-09-10

Lysosomal acid lipase is an essential lipid-metabolizing enzyme that breaks down endocytosed lipid particles and regulates lipid metabolism. We conducted a phase 3 trial of enzyme-replacement therapy in children and adults with lysosomal acid lipase deficiency, an underappreciated cause of cirrhosis and severe dyslipidemia. In this multicenter, randomized, double-blind, placebo-controlled study involving 66 patients, we evaluated the safety and effectiveness of enzyme-replacement therapy with sebelipase alfa (administered intravenously at a dose of 1 mg per kilogram of body weight every other week); the placebo-controlled phase of the study was 20 weeks long and was followed by open-label treatment for all patients. The primary end point was normalization of the alanine aminotransferase level. Secondary end points included additional disease-related efficacy assessments, safety, and side-effect profile. Substantial disease burden at baseline included a very high level of low-density lipoprotein cholesterol (≥190 mg per deciliter) in 38 of 66 patients (58%) and cirrhosis in 10 of 32 patients (31%) who underwent biopsy. A total of 65 of the 66 patients who underwent randomization completed the double-blind portion of the trial and continued with open-label treatment. At 20 weeks, the alanine aminotransferase level was normal in 11 of 36 patients (31%) in the sebelipase alfa group and in 2 of 30 (7%) in the placebo group (P=0.03), with mean changes from baseline of -58 U per liter versus -7 U per liter (P<0.001). With respect to prespecified key secondary efficacy end points, we observed improvements in lipid levels and reduction in hepatic fat content (P<0.001 for all comparisons, except P=0.04 for triglycerides). The number of patients with adverse events was similar in the two groups; most events were mild and were considered by the investigator to be unrelated to treatment. Sebelipase alfa therapy resulted in a reduction in multiple disease-related hepatic and lipid abnormalities in children and adults with lysosomal acid lipase deficiency. (Funded by Synageva BioPharma and others; ARISE ClinicalTrials.gov number, NCT01757184.).

Rotigotine transdermal system as add-on to oral dopamine agonist in advanced Parkinson's disease: an open-label study.

PubMed

Kim, Jong-Min; Chung, Sun Ju; Kim, Jae Woo; Jeon, Beom Seok; Singh, Pritibha; Thierfelder, Stephan; Ikeda, Junji; Bauer, Lars

2015-02-28

Achieving optimal symptom control with minimal side effects is a major goal in clinical practice. Dual-agent dopamine receptor agonist (DA) therapy in Parkinson's disease (PD) may represent a promising approach to treatment, as the combination of different pharmacokinetic/pharmacological profiles may result in a lesser need for high dosages and, accordingly, may be well tolerated. The objective of the current study was to investigate safety and efficacy of rotigotine transdermal system as add-on to oral DA in patients with advanced PD inadequately controlled with levodopa and low-dose oral DA. PD0015 was an open-label, multinational study in patients with advanced-PD and sleep disturbance or early-morning motor impairment. Patients were titrated to optimal dose rotigotine (≤8 mg/24 h) over 1-4 weeks and maintained for 4-7 weeks (8-week treatment). Dosage of levodopa and oral DA (pramipexole ≤1.5 mg/day, ropinirole ≤6.0 mg/day) was stable. Primary variable was Clinical Global Impressions (CGI) item 4: side effects, assessing safety. Other variables included adverse events (AEs), Patient Global Impressions of Change (PGIC), Unified Parkinson's Disease Rating Scale (UPDRS) II and III, Parkinson's Disease Sleep Scale (PDSS-2), Pittsburgh Sleep Quality Index (PSQI), and "off" time. Of 90 patients who received rotigotine, 79 (88%) completed the study; 5 (6%) withdrew due to AEs. Most (83/89; 93%) had a CGI-4 score <3 indicating that rotigotine add-on therapy did not interfere with functioning; 6 (7%) experienced drug-related AEs that interfered with functioning (score ≥3). AEs occurring in ≥5% were application site pruritus (13%), dizziness (10%), orthostatic hypotension (10%), nausea (8%), dyskinesia (8%), and nasopharyngitis (6%). Numerical improvements in motor function (UPDRS III), activities of daily living (UPDRS II), sleep disturbances (PDSS-2, PSQI), and reduction in "off" time were observed. The majority (71/88; 81%) improved on PGIC. Addition of rotigotine transdermal system to low-dose oral DA in patients with advanced-PD was feasible and may be associated with clinical benefit. ClinicalTrials.gov identifier NCT01723904 . Trial registration date: November 6, 2012.

Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial.

PubMed

Dungan, Kathleen M; Povedano, Santiago Tofé; Forst, Thomas; González, José G González; Atisso, Charles; Sealls, Whitney; Fahrbach, Jessie L

2014-10-11

Dulaglutide and liraglutide, both glucagon-like peptide-1 (GLP-1) receptor agonists, improve glycaemic control and reduce weight in patients with type 2 diabetes. In a head-to-head trial, we compared the safety and efficacy of once-weekly dulaglutide with that of once-daily liraglutide in metformin-treated patients with uncontrolled type 2 diabetes. We did a phase 3, randomised, open-label, parallel-group study at 62 sites in nine countries between June 20, 2012, and Nov 25, 2013. Patients with inadequately controlled type 2 diabetes receiving metformin (≥1500 mg/day), aged 18 years or older, with glycated haemoglobin (HbA1c) 7·0% or greater (≥53 mmol/mol) and 10·0% or lower (≤86 mmol/mol), and body-mass index 45 kg/m(2) or lower were randomly assigned to receive once-weekly dulaglutide (1·5 mg) or once-daily liraglutide (1·8 mg). Randomisation was done according to a computer-generated random sequence with an interactive voice response system. Participants and investigators were not masked to treatment allocation. The primary outcome was non-inferiority (margin 0·4%) of dulaglutide compared with liraglutide for change in HbA1c (least-squares mean change from baseline) at 26 weeks. Safety data were collected for a further 4 weeks' follow-up. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01624259. We randomly assigned 599 patients to receive once-weekly dulaglutide (299 patients) or once-daily liraglutide (300 patients). 269 participants in each group completed treatment at week 26. Least-squares mean reduction in HbA1c was -1·42% (SE 0·05) in the dulaglutide group and -1·36% (0·05) in the liraglutide group. Mean treatment difference in HbA1c was -0·06% (95% CI -0·19 to 0·07, pnon-inferiority<0·0001) between the two groups. The most common gastrointestinal adverse events were nausea (61 [20%] in dulaglutide group vs 54 [18%] in liraglutide group), diarrhoea (36 [12%] vs 36 [12%]), dyspepsia (24 [8%] vs 18 [6%]), and vomiting (21 [7%] vs 25 [8%]), with similar rates of study or study drug discontinuation because of adverse events between the two groups (18 [6%] in each group). The hypoglycaemia rate was 0·34 (SE 1·44) and 0·52 (3·01) events per patient per year, respectively, and no severe hypoglycaemia was reported. Once-weekly dulaglutide is non-inferior to once-daily liraglutide for least-squares mean reduction in HbA1c, with a similar safety and tolerability profile. Eli Lilly and Company. Copyright © 2014 Elsevier Ltd. All rights reserved.

Peg-interferon plus nucleotide analogue treatment versus no treatment in patients with chronic hepatitis B with a low viral load: a randomised controlled, open-label trial.

PubMed

de Niet, Annikki; Jansen, Louis; Stelma, Femke; Willemse, Sophie B; Kuiken, Sjoerd D; Weijer, Sebastiaan; van Nieuwkerk, Carin M J; Zaaijer, Hans L; Molenkamp, Richard; Takkenberg, R Bart; Koot, Maarten; Verheij, Joanne; Beuers, Ulrich; Reesink, Hendrik W

2017-08-01

Antiviral treatment is currently not recommended for patients with chronic hepatitis B with a low viral load. However, they might benefit from acquiring a functional cure (hepatitis B surface antigen [HBsAg] loss with or without formation of antibodies against hepatitis B surface antigen [anti-HBs]). We assessed HBsAg loss during peg-interferon-alfa-2a (peg-IFN) and nucleotide analogue combination therapy in patients with chronic hepatitis B with a low viral load. In this randomised controlled, open-label trial, patients were enrolled from the Academic Medical Center (AMC), Amsterdam, Netherlands. Eligible patients were HBsAg positive and hepatitis B e antigen (HBeAg) negative for more than 6 months, could be treatment naive or treatment experienced, and had alanine aminotransferase (ALT) concentrations less than 5 × upper limit of normal (ULN). Participants were randomly assigned (1:1:1) by a computerised randomisation programme (ALEA Randomisation Service) to receive peg-IFN 180 μg/week plus adefovir 10 mg/day, peg-IFN 180 μg/week plus tenofovir disoproxil fumarate 245 mg/day, or no treatment for 48 weeks. The primary endpoint was the proportion of patients with serum HBsAg loss among those who received at least one dose of study drug or had at least one study visit (modified intention-to-treat population [mITT]). All patients have finished the initial study of 72 weeks and will be observed for up to 5 years of follow-up. This study is registered with ClinicalTrials.gov, number NCT00973219. Between Aug 4, 2009, and Oct 17, 2013, 167 patients were screened for enrolment, of whom 151 were randomly assigned (52 to peg-IFN plus adefovir, 51 to peg-IFN plus tenofovir, and 48 to no treatment). 46 participants in the peg-IFN plus adefovir group, 45 in the peg-IFN plus tenofovir group, and 43 in the no treatment group began treatment or observation and were included in the mITT population. At week 72, two (4%) patients in the peg-IFN plus adefovir group and two (4%) patients in the peg-IFN plus tenofovir group had achieved HBsAg loss, compared with none of the patients in the no treatment group (p=0·377). The most frequent adverse events (>30%) were fatigue, headache, fever, and myalgia, which were attributed to peg-IFN dosing. Two (4%) serious adverse events were reported in the peg-IFN plus adefovir group (admission to hospital for alcohol-related pancreatitis [week 6; n=1] and pregnancy, which was electively aborted [week 9; n=1]), three (7%) in the peg-IFN plus tenofovir group (admission to hospital after a suicide attempt during a severe depression [week 23; n=1], admission to hospital for abdominal pain [week 2; n=1], and an elective laminectomy [week 40; n=1]), and three (7%) in the no treatment group (admission to hospital for septic arthritis [week 72; n=1], endocarditis [week 5; n=1], and hyperthyroidism [week 20; n=1]). In patients with chronic hepatitis B with a low viral load, combination treatment (peg-IFN plus adefovir and peg-IFN plus tenofovir) did not result in significant HBsAg loss compared with no treatment, which does not support the use of combination treatment in this population of patients. Roche, Fonds NutsOhra. Copyright © 2017 Elsevier Ltd. All rights reserved.

Rescue Pharmacotherapy With Duloxetine for Selective Serotonin Reuptake Inhibitor Nonresponders in Late-Life Depression: Outcome and Tolerability

PubMed Central

Karp, Jordan F.; Whyte, Ellen M.; Lenze, Eric J.; Dew, Mary A.; Begley, Amy; Miller, Mark D.; Reynolds, Charles F.

2010-01-01

Background Up to 50% of depressed older adults either do not adequately respond to or are unable to tolerate treatment with a serotonin-specific reuptake inhibitor. On the basis of previous experience with serotonin-norepinephrine reuptake inhibitors, we predicted at least a 50% response rate to open-label treatment with duloxetine in subjects who were resistant to treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram. Method Community-dwelling subjects aged 65 years or older with current nonpsychotic major depressive disorder as established by the Structured Clinical Interview for DSM-IV received escitalopram under protocolized conditions between April 2004 and September 2006. Subjects who failed to meet response criteria or relapsed after achieving an initial response were subsequently switched to open treatment with duloxetine up to 120 mg/day. Side effects were assessed at every visit. Results Subjects (N = 40) switched to duloxetine had a mean (SD) age of 74.4 (7.0) years and a baseline (before escitalopram) 17-item Hamilton Rating Scale for Depression (HAM-D-17) score of 20.0 (3.5) and were predominantly female (65.0%) and white (82.5%). The mean (SD) maximum dose of duloxetine was 93.0 (27.8) mg/day. Subjects received this maximum dose for a median duration of 6.9 weeks. Fifty percent of subjects (N = 20) met criteria for full response, 17.5% (N = 7) were partial responders, and 32.5% (N = 13) did not respond. The median time to response was 12.0 weeks (95% CI = 8.4 to 14.6). Five of the subjects (12.5%) discontinued duloxetine because of intolerable side effects. Discussion These open-label data suggest that duloxetine at doses up to 120 mg/day is a well-tolerated and potentially effective treatment for older adults who fail to respond to an adequate trial of an SSRI. These results are preliminary, and future controlled studies are required to test the efficacy of rescue pharmacotherapy with duloxetine. Trial Registration clinicaltrials.gov Identifier: NCT00177671 PMID:18251622