Sample records for randomized open-label comparative
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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.
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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.
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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…
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Placebo Effects and the Common Cold: A Randomized Controlled Trial
Barrett, Bruce; Brown, Roger; Rakel, Dave; Rabago, David; Marchand, Lucille; Scheder, Jo; Mundt, Marlon; Thomas, Gay; Barlow, Shari
2011-01-01
PURPOSE We wanted to determine whether the severity and duration of illness caused by the common cold are influenced by randomized assignment to open-label pills, compared with conventional double-blind allocation to active and placebo pills, compared with no pills at all. METHODS We undertook a randomized controlled trial among a population with new-onset common cold. Study participants were allocated to 4 parallel groups: (1) those receiving no pills, (2) those blinded to placebo, (3) those blinded to echinacea, and (4) those given open-label echinacea. Primary outcomes were illness duration and area-under-the-curve global severity. Secondary outcomes included neutrophil count and interleukin 8 levels from nasal wash at intake and 2 days later. RESULTS Of 719 randomized study participants, 2 were lost and 4 exited early. Participants were 64% female, 88% white, and aged 12 to 80 years. Mean illness duration for each group was 7.03 days for those in the no-pill group, 6.87 days for those blinded to placebo, 6.34 days for those blinded to echinacea, and 6.76 days for those in the open-label echinacea group. Mean global severity scores for the 4 groups were no pills, 286; blinded to placebo, 264; blinded to echinacea, 236; and open-label echinacea, 258. Between-group differences were not statistically significant. Comparing the no-pill with blinded to placebo groups, differences (95% confidence interval [CI]) were −0.16 days (95% CI, −0.90 to 0.58 days) for illness duration and −22 severity points (95% CI, −70 to 26 points) for global severity. Comparing the group blinded to echinacea with the open-label echinacea group, differences were 0.42 days (95% CI, −0.28 to 1.12 days) and 22 severity points (95% CI, −19 to 63 points). Median change in interleukin 8 concentration and neutrophil cell count, respectively by group, were 30 pg/mL and 1 cell for the no-pill group, 39 pg/mL and 1 cell for the group binded to placebo, 58 pg/mL and 2 cells for the group blinded to echinacea, and 70 pg/mL and 1 cell for the group with open-label echinacea, also not statistically significant. Among the 120 participants who at intake rated echinacea’s effectiveness as greater than 50 on a 100-point scale for which 100 is extremely effective, illness duration was 2.58 days shorter (95% CI, −4.47 to −0.68 days) in those blinded to placebo rather than no pill, and mean global severity score was 26% lower but not significantly different (−97.0, 95% CI, −249.8 to 55.8 points). In this subgroup, neither duration nor severity differed significantly between the group blinded to echinacea and the open-label echinacea group. CONCLUSIONS Participants randomized to the no-pill group tended to have longer and more severe illnesses than those who received pills. For the subgroup who believed in echinacea and received pills, illnesses were substantively shorter and less severe, regardless of whether the pills contained echinacea. These findings support the general idea that beliefs and feelings about treatments may be important and perhaps should be taken into consideration when making medical decisions. PMID:21747102
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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
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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.
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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
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Kadowaki, Takashi; Kondo, Kazuoki; Sasaki, Noriyuki; Miyayama, Kyoko; Yokota, Shoko; Terata, Ryuji; Gouda, Maki
2017-09-01
To assess the efficacy and safety of teneligliptin as add-on to insulin monotherapy in patients with type 2 diabetes mellitus (T2DM). In a 16-week, double-blind period, 148 Japanese T2DM patients with inadequate glycemic control with insulin and diet/exercise therapies were randomized to placebo or teneligliptin 20 mg. In a subsequent 36-week, open-label period, all patients received teneligliptin once daily. The primary outcome measure was change in HbA1c at the end of the double-blind period. The difference between placebo and teneligliptin in change in HbA1c in the double-blind period (least squares mean ± SE) was -0.80% ± 0.11%; teneligliptin was superior (ANCOVA, P < 0.001). The HbA1c-lowering effect of teneligliptin was maintained throughout the open-label period. The incidence of adverse events was 53.5% with placebo and 44.2% with teneligliptin in the double-blind period, 66.7% in the placebo/teneligliptin group in the open-label period, and 77.9% in the teneligliptin/teneligliptin group over both double-blind/open-label periods. The incidence of hypoglycemic symptoms was 11.1% in the placebo/teneligliptin group in the open-label period and 27.3% in the teneligliptin/teneligliptin group over both double-blind/open-label periods. Teneligliptin was effective and well tolerated in Japanese T2DM patients with inadequate glycemic control. NCT02081599.
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Open-label placebo treatment in chronic low back pain: a randomized controlled trial
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
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Open-label placebo treatment in chronic low back pain: a randomized controlled trial.
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.
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Laurora, Irene; Wang, Yuan
2016-10-01
Extended-release (ER) naproxen sodium provides pain relief for up to 24 hours with a single dose (660 mg/day). Its pharmacokinetic profile after single and multiple dosing was compared to immediate release (IR) naproxen sodium in two randomized, open-label, crossover studies, under fasting and fed conditions. Eligible healthy subjects were randomized to ER naproxen sodium 660-mg tablet once daily or IR naproxen sodium 220-mg tablet twice daily (440 mg initially, followed by 220 mg 12 hours later). Primary variables: pharmacokinetic parameters after singleday administration (day 1) and at steady state after multiple-day administration (day 6). Total exposure was comparable for both treatments under fasting and fed conditions. After fasting: peak naproxen concentrations were slightly lower with ER naproxen sodium than with IR naproxen sodium but were reached at a similar time. Fed conditions: mean peak concentrations were comparable but reached after a longer time with ER vs. IR naproxen sodium. ER naproxen sodium was well tolerated, with a similar safety profile to IR naproxen sodium. The total exposure of ER naproxen sodium (660 mg) is comparable to IR naproxen sodium (220 mg) when administered at the maximum over the counter (OTC) dose of 660-mg daily dose on a single day and over multiple days. The rate of absorption is delayed under fed conditions.
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Deplanque, Gaël; Gervais, Radj; Vergnenegre, Alain; Falchero, Lionel; Souquet, Pierre-Jean; Chavaillon, Jean-Michel; Taviot, Bruno; Fraboulet, Ghislaine; Saal, Hakim; Robert, Caroline; Chosidow, Olivier
2016-06-01
Rash is a common epidermal growth factor receptor inhibitor-induced toxicity that can impair quality of life and treatment compliance. We sought to evaluate the efficacy of doxycycline in preventing erlotinib-induced rash (folliculitis) in patients with non-small-cell lung cancer. This open-label, randomized, prospective, phase II trial was conducted in 147 patients with locally advanced or metastatic non-small-cell lung cancer progressing after first-line chemotherapy, randomized for 4 months with erlotinib alone 150 mg/d per os (control arm) or combined with doxycycline 100 mg/d (doxycycline arm). Incidence and severity of rash, compliance, survival, and safety were assessed. Baseline characteristics of the 147 patients were well balanced in the intent-to-treat population. Folliculitis occurred in 71% of patients in the doxycycline arm and 81% in the control arm (P = .175). The severity of folliculitis and other skin lesions was lower in the doxycycline arm compared with the control arm. Other adverse events were reported at a similar frequency across arms. There was no significant difference in survival between treatment arms. The open-label design of the study and the duration of the treatment with doxycycline are limitations. Doxycycline did not reduce the incidence of erlotinib-induced folliculitis, but significantly reduced its severity. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
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2008-12-01
To determine whether ethyl-eicosapentaenoic acid (ethyl-EPA), an omega-3 fatty acid, improves the motor features of Huntington disease. Six-month multicenter, randomized, double-blind, placebo-controlled trial followed by a 6-month open-label phase without disclosing initial treatment assignments. Forty-one research sites in the United States and Canada. Three hundred sixteen adults with Huntington disease, enriched for a population with shorter trinucleotide (cytosine-adenine-guanine) repeat length expansions. Random assignment to placebo or ethyl-EPA, 1 g twice a day, followed by open-label treatment with ethyl-EPA. Six-month change in the Total Motor Score 4 component of the Unified Huntington's Disease Rating Scale analyzed for all research participants and those with shorter cytosine-adenine-guanine repeat length expansions (<45). At 6 months, the Total Motor Score 4 point change for patients receiving ethyl-EPA did not differ from that for those receiving placebo. No differences were found in measures of function, cognition, or global impression. Before public disclosure of the 6-month placebo-controlled results, 192 individuals completed the open-label phase. The Total Motor Score 4 change did not worsen for those who received active treatment for 12 continuous months compared with those who received active treatment for only 6 months (2.0-point worsening; P=.02). Ethyl-EPA was not beneficial in patients with Huntington disease during 6 months of placebo-controlled evaluation. Clinical Trial Registry clinicaltrials.gov Identifier: NCT00146211.
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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.
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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.
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Jin, Cai De; Kim, Moo Hyun; Bang, Junghee; Serebruany, Victor
The optimal dosing of novel oral P2Y12 receptor platelet inhibitors such as prasugrel or ticagrelor is unclear and especially challenging in East Asians. We hypothesize that half-dose prasugrel and ticagrelor may be sufficient for long-term maintenance management in Korean patients with the acute coronary syndrome (ACS) compared with conventional dosages. HOPE-TAILOR (Half Dose of Prasugrel and Ticagrelor in Platelet Response after Acute Coronary Syndromes) is a prospective, randomized, open-label, blinded, endpoint (PROBE) single-center, clinical trial. A total of 100 patients with ACS undergoing drug-eluting stent implantation will be randomly assigned to prasugrel, ticagrelor, or clopidogrel, and the patients in each treatment group will receive 1-month therapy with 100 mg q.d. aspirin plus prasugrel 10 mg q.d., ticagrelor 90 mg b.i.d., or clopidogrel 75 mg q.d., followed by half-dose prasugrel 5 mg q.d. or ticagrelor 45 mg b.i.d. for maintenance treatment but without clopidogrel dose reduction. The primary endpoint will be optimal platelet reactivity 3 months after coronary intervention, defined by VerifyNow Analyzer (PRU: 85-208) and vasodilator-stimulated phosphoprotein P2Y12 flow cytometry assay (platelet reactivity indices: 16-50%). Clinical outcomes will also be assessed, including major efficacy (composite of cardiac death, nonfatal myocardial infarction, repeat revascularization, or stroke) and safety (bleeding ≥2 according to the Bleeding Academic Research Consortium). HOPE-TAILOR is a prospective, randomized, open-label, blinded, endpoint study to explore the efficacy and safety of novel P2Y12 receptor inhibitors administered orally at half the dose in Korean patients with ACS. The results will be available late in 2017. © 2017 S. Karger AG, Basel.
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An Open-Label, Randomized Trial of Methylphenidate and Atomoxetine Treatment in Adults With ADHD.
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.
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Yao, James C; Pavel, Marianne; Lombard-Bohas, Catherine; Van Cutsem, Eric; Voi, Maurizio; Brandt, Ulrike; He, Wei; Chen, David; Capdevila, Jaume; de Vries, Elisabeth G E; Tomassetti, Paola; Hobday, Timothy; Pommier, Rodney; Öberg, Kjell
2016-11-10
Purpose Everolimus improved median progression-free survival by 6.4 months in patients with advanced pancreatic neuroendocrine tumors (NET) compared with placebo in the RADIANT-3 study. Here, we present the final overall survival (OS) data and data on the impact of biomarkers on OS from the RADIANT-3 study. Methods Patients with advanced, progressive, low- or intermediate-grade pancreatic NET were randomly assigned to everolimus 10 mg/day (n = 207) or placebo (n = 203). Crossover from placebo to open-label everolimus was allowed on disease progression. Ongoing patients were unblinded after final progression-free survival analysis and could transition to open-label everolimus at the investigator's discretion (extension phase). OS analysis was performed using a stratified log-rank test in the intent-to-treat population. The baseline levels of chromogranin A, neuron-specific enolase, and multiple soluble angiogenic biomarkers were determined and their impact on OS was explored. Results Of 410 patients who were enrolled between July 2007 and March 2014, 225 received open-label everolimus, including 172 patients (85%) randomly assigned initially to the placebo arm. Median OS was 44.0 months (95% CI, 35.6 to 51.8 months) for those randomly assigned to everolimus and 37.7 months (95% CI, 29.1 to 45.8 months) for those randomly assigned to placebo (hazard ratio, 0.94; 95% CI, 0.73 to 1.20; P = .30). Elevated baseline chromogranin A, neuron-specific enolase, placental growth factor, and soluble vascular endothelial growth factor receptor 1 levels were poor prognostic factors for OS. The most common adverse events included stomatitis, rash, and diarrhea. Conclusion Everolimus was associated with a median OS of 44 months in patients with advanced, progressive pancreatic NET, the longest OS reported in a phase III study for this population. Everolimus was associated with a survival benefit of 6.3 months, although this finding was not statistically significant. Crossover of patients likely confounded the OS results.
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ERIC Educational Resources Information Center
Borji, Rihab; Sahli, Sonia; Baccouch, Rym; Laatar, Rabeb; Kachouri, Hiba; Rebai, Haithem
2018-01-01
Background: This study aimed to compare the effectiveness of a hopping and jumping training programme (HJP) versus a sensorimotor rehabilitation programme (SRP) on postural performances in children with intellectual disability. Methods: Three groups of children with intellectual disability participated in the study: the HJP group, the SRP group…
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Fukuda, Sanae; Nojima, Junzo; Kajimoto, Osami; Yamaguti, Kouzi; Nakatomi, Yasuhito; Kuratsune, Hirohiko; Watanabe, Yasuyoshi
2016-07-08
The aim of this study was to evaluate the benefit of oral ubiquinol-10 supplementation in CFS patients using an open-label study and a randomized, double-blinded, placebo-controlled (RCT) study. Twenty patients with CFS were randomly enrolled in an 8-week open-label oral ubiquinol-10 (150 mg ubiquinol-10/day) study. The patients and the attending physicians were not blinded to the supplementation. Forty-three patients with CFS were randomly assigned to receive either ubiquinol-10 (150 mg/day) or placebo every day for 12 weeks. The patients and the attending physicians were blinded to the supplementation, and a total of 31 patients (N = 17 in the ubiquinol group and 14 in the placebo group) completed the study. The beneficial effects of ubiquinol-10 were observed in the open-label study we conducted prior to the RCT. The RCT results suggest that supplementation with ubiquinol-10 for 12 weeks is effective for improving several CFS symptoms. © 2016 BioFactors, 42(4):431-440, 2016. © 2016 International Union of Biochemistry and Molecular Biology.
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Eren, Makbule; Dinleyici, Ener C; Vandenplas, Yvan
2010-03-01
The purpose of this trial is to evaluate the clinical efficacy and cost/effectiveness of Saccharomyces boulardii compared with yogurt fluid (YF) in acute non-bloody diarrhea in children. This randomized, prospective open-label clinical trial includes 55 children (36 boys, 19 girls; mean age 21.2 +/- 28.2 months). Group A (N = 28) received lyophilized S. boulardii and group B (N = 27) received YF. The duration of diarrhea was shorter with S. boulardii but the hospital stay was reduced with YF, although these differences were not significant. However, diarrhea had resolved in significantly more children on day 3 in the S. boulardii group (48.5% versus 25.5%; P < 0.05). In outpatient cases, yogurt treatment was cheaper than S. boulardii whereas in hospitalized patients, treatment cost was similar. In conclusion, the effect of daily freshly prepared YF was comparable to S. boulardii in the treatment of acute non-bloody diarrhea in children. The duration of diarrhea was shorter in the S. boulardii group, expressed as a significantly higher number of patients with normal stools on day 3.
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Eren, Makbule; Dinleyici, Ener C.; Vandenplas, Yvan
2010-01-01
The purpose of this trial is to evaluate the clinical efficacy and cost/effectiveness of Saccharomyces boulardii compared with yogurt fluid (YF) in acute non-bloody diarrhea in children. This randomized, prospective open-label clinical trial includes 55 children (36 boys, 19 girls; mean age 21.2 ± 28.2 months). Group A (N = 28) received lyophilized S. boulardii and group B (N = 27) received YF. The duration of diarrhea was shorter with S. boulardii but the hospital stay was reduced with YF, although these differences were not significant. However, diarrhea had resolved in significantly more children on day 3 in the S. boulardii group (48.5% versus 25.5%; P < 0.05). In outpatient cases, yogurt treatment was cheaper than S. boulardii whereas in hospitalized patients, treatment cost was similar. In conclusion, the effect of daily freshly prepared YF was comparable to S. boulardii in the treatment of acute non-bloody diarrhea in children. The duration of diarrhea was shorter in the S. boulardii group, expressed as a significantly higher number of patients with normal stools on day 3. PMID:20207879
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Donepezil for cancer fatigue: a double-blind, randomized, placebo-controlled trial.
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.
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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.
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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
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Kuznetsova, Olga M; Tymofyeyev, Yevgen
2014-04-30
In open-label studies, partial predictability of permuted block randomization provides potential for selection bias. To lessen the selection bias in two-arm studies with equal allocation, a number of allocation procedures that limit the imbalance in treatment totals at a pre-specified level but do not require the exact balance at the ends of the blocks were developed. In studies with unequal allocation, however, the task of designing a randomization procedure that sets a pre-specified limit on imbalance in group totals is not resolved. Existing allocation procedures either do not preserve the allocation ratio at every allocation or do not include all allocation sequences that comply with the pre-specified imbalance threshold. Kuznetsova and Tymofyeyev described the brick tunnel randomization for studies with unequal allocation that preserves the allocation ratio at every step and, in the two-arm case, includes all sequences that satisfy the smallest possible imbalance threshold. This article introduces wide brick tunnel randomization for studies with unequal allocation that allows all allocation sequences with imbalance not exceeding any pre-specified threshold while preserving the allocation ratio at every step. In open-label studies, allowing a larger imbalance in treatment totals lowers selection bias because of the predictability of treatment assignments. The applications of the technique in two-arm and multi-arm open-label studies with unequal allocation are described. Copyright © 2013 John Wiley & Sons, Ltd.
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Xia, Qiangwei; Wang, Tiansong; Park, Yoonsuk; Lamont, Richard J.; Hackett, Murray
2009-01-01
Differential analysis of whole cell proteomes by mass spectrometry has largely been applied using various forms of stable isotope labeling. While metabolic stable isotope labeling has been the method of choice, it is often not possible to apply such an approach. Four different label free ways of calculating expression ratios in a classic “two-state” experiment are compared: signal intensity at the peptide level, signal intensity at the protein level, spectral counting at the peptide level, and spectral counting at the protein level. The quantitative data were mined from a dataset of 1245 qualitatively identified proteins, about 56% of the protein encoding open reading frames from Porphyromonas gingivalis, a Gram-negative intracellular pathogen being studied under extracellular and intracellular conditions. Two different control populations were compared against P. gingivalis internalized within a model human target cell line. The q-value statistic, a measure of false discovery rate previously applied to transcription microarrays, was applied to proteomics data. For spectral counting, the most logically consistent estimate of random error came from applying the locally weighted scatter plot smoothing procedure (LOWESS) to the most extreme ratios generated from a control technical replicate, thus setting upper and lower bounds for the region of experimentally observed random error. PMID:19337574
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Langhans, Linnea; Tvedskov, Tove F; Klausen, Thomas L; Jensen, Maj-Britt; Talman, Maj-Lis; Vejborg, Ilse; Benian, Cemil; Roslind, Anne; Hermansen, Jonas; Oturai, Peter S; Bentzon, Niels; Kroman, Niels
2017-07-01
To compare the rate of positive resection margins between radioactive seed localization (RSL) and wire-guided localization (WGL) after breast conserving surgery (BCS). WGL is the current standard for localization of nonpalpable breast lesions in BCS, but there are several difficulties related to the method. From January 1, 2014 to February 4, 2016, patients with nonpalpable invasive breast cancer or DCIS visible on ultrasound were enrolled in this randomized, multicenter, open-label clinical trial, and randomly assigned to RSL or WGL. The primary outcome was margin status after BCS. Secondary outcomes were duration of the surgical procedure, weight of surgical specimen, and patients' pain perception. Analyses were performed by intention-to-treat (ITT) and per protocol. Out of 444 eligible patients, 413 lesions representing 409 patients were randomized; 207 to RSL and 206 to WGL. Twenty-three did not meet inclusion criteria, chose to withdraw, or had a change in surgical management and were excluded. The remaining 390 lesions constituted the ITT population. Here, resection margins were positive in 23 cases (11.8%) in the RSL group compared with 26 cases (13.3%) in the WGL group (P = 0.65). The per-protocol analysis revealed no difference in margin status (P = 0.62). There were no significant differences in the duration of the surgical procedure (P = 0.12), weight of the surgical specimen (P = 0.54) or the patients' pain perception (P = 0.28). RSL offers a major logistic advantage, as localization can be done several days before surgery without any increase in positive resection margins compared with WGL.
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Chandramohan, S M; Gajbhiye, Raj Narenda; Agwarwal, Anil; Creedon, Erin; Schwiers, Michael L; Waggoner, Jason R; Tatla, Daljit
2013-08-01
Although stapling is an alternative to hand-suturing in gastrointestinal surgery, recent trials specifically designed to evaluate differences between the two in surgery time, anastomosis time, and return to bowel activity are lacking. This trial compared the outcomes of the two in subjects undergoing open gastrointestinal surgery. Adult subjects undergoing emergency or elective surgery requiring a single gastric, small, or large bowel anastomosis were enrolled into this open-label, prospective, randomized, interventional, parallel, multicenter, controlled trial. Randomization was assigned in a 1:1 ratio between the hand-sutured group (n = 138) and the stapled group (n = 142). Anastomosis time, surgery time, and time to bowel activity were collected and compared as primary endpoints. A total of 280 subjects were enrolled from April 2009 to September 2010. Only the time of anastomosis was significantly different between the two arms: 17.6 ± 1.90 min (stapled) and 20.6 ± 1.90 min (hand-sutured). This difference was deemed not clinically or economically meaningful. Safety outcomes and other secondary endpoints were similar between the two arms. Mechanical stapling is faster than hand-suturing for the construction of gastrointestinal anastomoses. Apart from this, stapling and hand-suturing are similar with respect to the outcomes measured in this trial.
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Aggarwal, Sunny; Upadhyay, Amit; Shah, Dheeraj; Teotia, Neeraj; Agarwal, Astha; Jaiswal, Vijay
2014-01-01
Background & objectives: Randomized controlled trials in developed countries have reported benefits of Lactobacillus GG (LGG) in the treatment of acute watery diarrhoea, but there is paucity of such data from India. The study was aimed to evaluate the efficacy and safety of Lactobacillus GG in the treatment of acute diarrhoea in children from a semi-urban city in north India. Methods: In this open labelled, randomized controlled trial 200 children with acute watery diarrhoea, aged between 6 months to 5 years visiting outpatient department and emergency room of a teaching hospital in north India were enrolled. The children were randomized into receiving either Lactobacillus GG in dose of 10 billion cfu/day for five days or no probiotic medication in addition to standard WHO management of diarrhoea. Primary outcomes were duration of diarrhoea and time to change in consistency of stools. Results: Median (inter quartile range) duration of diarrhoea was significantly shorter in children in LGG group [60 (54-72) h vs. 78 (72-90) h; P<0.001]. Also, there was faster improvement in stool consistency in children receiving Lactobacillus GG than control group [36 (30-36) h vs. 42 (36-48) h; P<0.001]. There was significant reduction in average number of stools per day in LGG group (P<0.001) compared to the control group. These benefits were seen irrespective of rotavirus positivity in stool tests. Interpretation & conclusions: Our results showed that the use of Lactobacillus GG in children with acute diarrhoea resulted in shorter duration and faster improvement in stool consistency as compared to the control group. PMID:24820831
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Nipanikar, Sanjay U; Gajare, Kamalakar V; Vaidya, Vidyadhar G; Kamthe, Amol B; Upasani, Sachin A; Kumbhar, Vidyadhar S
2017-01-01
The main objective of the present study was to assess efficacy and safety of AHPL/AYTOP/0113 cream, a polyherbal formulation in comparison with Framycetin sulphate cream in acute wounds. It was an open label, randomized, comparative, parallel group and multi-center clinical study. Total 47 subjects were randomly assigned to Group-A (AHPL/AYTOP/0113 cream) and 42 subjects were randomly assigned to Group-B (Framycetin sulphate cream). All the subjects were advised to apply study drug, thrice daily for 21 days or up to complete wound healing (whichever was earlier). All the subjects were called for follow up on days 2, 4, 7, 10, 14, 17 and 21 or up to the day of complete wound healing. Data describing quantitative measures are expressed as mean ± SD. Comparison of variables representing categorical data was performed using Chi-square test. Group-A subjects took significantly less ( P < 0.05) i.e., (mean) 7.77 days than (mean) 9.87 days of Group-B subjects for wound healing. At the end of the study, statistically significant better ( P < 0.05) results were observed in Group-A than Group-B in mean wound surface area, wound healing parameters and pain associated with wound. Excellent overall efficacy and tolerability was observed in subjects of both the groups. No adverse event or adverse drug reaction was noted in any subject of both the groups. AHPL/AYTOP/0113 cream proved to be superior to Framycetin sulphate cream in healing of acute wounds.
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Kantrowitz, Joshua T; Sharif, Zafar; Medalia, Alice; Keefe, Richard S E; Harvey, Philip; Bruder, Gerard; Barch, Deanna M; Choo, Tse; Lee, Seonjoo; Lieberman, Jeffrey A
2016-06-01
Small-scale studies of auditory processing cognitive remediation programs have demonstrated efficacy in schizophrenia. We describe a multicenter, rater-blinded, randomized, controlled study of auditory-focused cognitive remediation, conducted from June 24, 2010, to June 14, 2013, and approved by the local institutional review board at all sites. Prior to randomization, participants with schizophrenia (DSM-IV-TR) were stabilized on a standardized antipsychotic regimen (lurasidone [40-160 mg/d]), followed by randomization to adjunctive cognitive remediation: auditory focused (Brain Fitness) versus control (nonspecific video games), administered 1-2 times weekly for 30 sessions. Coprimary outcome measures included MATRICS Consensus Cognitive Battery (MCCB) and the University of California, San Diego, Performance-Based Skills Assessment-Brief scale. 120 participants were randomized and completed at least 1 auditory-focused cognitive remediation (n = 56) or video game control session (n = 64). 74 participants completed ≥ 25 sessions and postrandomization assessments. At study completion, the change from prestabilization was statistically significant for MCCB composite score (d = 0.42, P < .0001) across groups. Participants randomized to auditory-focused cognitive remediation had a trend-level higher mean MCCB composite score compared to participants randomized to control cognitive remediation (P = .08). After controlling for scores at the time of randomization, there were no significant between-treatment group differences at study completion. Auditory processing cognitive remediation combined with lurasidone did not lead to differential improvement over nonspecific video games. Across-group improvement from prestabilization baseline to study completion was observed, but since all participants were receiving lurasidone open label, it is difficult to interpret the source of these effects. Future studies comparing both pharmacologic and behavioral cognitive enhancers should consider a 2 × 2 design, using a control for both the medication and the cognitive remediation. ClinicalTrials.gov identifier: NCT01173874. © Copyright 2016 Physicians Postgraduate Press, Inc.
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Ioannides, D; Rigopoulos, D; Katsambas, A
2002-09-01
Topical application of isotretinoin and adapalene has proved effective in treating acne vulgaris. Both drugs demonstrate therapeutic advantages and less irritancy over tretinoin, the most widely used treatment for acne. They both act as retinoid agonists, but differ in their affinity profile for nuclear and cytosolic retinoic acid receptors. To compare the efficacy and tolerability of adapalene gel 0.1% and isotretinoin gel 0.05% in the treatment of acne vulgaris of the face, in a randomized open-label clinical trial. Eighty patients were enrolled and were instructed to apply adapalene gel 0.1% or isotretinoin gel 0.05% once daily over a 12-week treatment period. Efficacy determination included noninflammatory and inflammatory lesion counts by the investigator and global evaluation of improvement. Cutaneous tolerance was assessed by determining erythema, scaling and burning with pruritus. Adapalene and isotretinoin gels were highly effective in treating facial acne. Adapalene gel produced greater reductions in noninflammatory and inflammatory lesion counts than did isotretinoin gel, but differences between treatments were not statistically significant. Adapalene gel was significantly better tolerated than isotretinoin gel during the whole treatment period. The two gels studied demonstrated comparable efficacy. When adapalene and isotretinoin were compared, significantly lower skin irritation was noted with adapalene, indicating that adapalene may begin a new era of treatment with low-irritant retinoids.
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Aggrawal, Kapil; Satija, Naveen; Dasgupta, Gita; Dasgupta, Partha; Nain, Parul; Sahu, Aditya R.
2014-01-01
Background: Catechins and epicatechins are monomers of naturally occurring proanthocyanidins, which have been reported with free radical scavenging, antioxidant, antiinflammatory, antiallergic, and vasodilatory properties. Plant parts rich in proanthocyanidins have been used for years in treatment of various ano-rectal diseases. This study compares the efficacy of two herbal preparations, Daflon® 500 mg and Roidosanal®, in ameliorating the signs and symptoms associated with hemorrhoids. Objective: To evaluate the safety and to compare the efficacy of a herbal preparation, Roidosanal® versus Daflon® 500 mg, on signs and symptoms of hemorrhoidal disease. Materials and Methods: In this pilot, active controlled, open-labeled multicentre study, 73 patients with proctoscopy proven hemorrhoids (Grade I to III) were randomly assigned to receive either Roidosanal® (Gr R; n = 37) or Daflon® 500 mg (Gr D; n = 36), for 15 days, at three centers in India. Assessment of hemorrhoidal symptoms was carried out in all patients at different time points. Intent-to-treat analysis was performed for both primary and secondary endpoints. Results: Baseline characteristics were comparable between the two groups. Both products were found to be equally effective in improving the ano-rectal conditions in Grade I and Grade II hemorrhoids; however, Roidosanal® demonstrated better efficacy in patients with Grade III hemorrhoids. Hemorrhoids associated symptoms like bleeding, pain, etc., improved in both groups, although intergroup comparisons were comparable. Conclusion: Both Roidosanal® and Daflon® 500 mg were equally effective in resolving signs and symptoms of hemorrhoids. Roidosanal® can be tried as a safe and effective treatment option for treatment of hemorrhoids. Further randomized, double-blind and large multicentre studies are recommended. PMID:24948863
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Pathak, Garima; Upadhyay, Amit; Pathak, Umesh; Chawla, Deepak; Goel, Sneh P
2013-08-01
To compare the efficacy of phenobarbitone and phenytoin for treatment of neonatal seizures in term and near-term neonates. Open labeled randomized controlled trial. Neonatal intensive care unit of a level II unit from India, from November 2008 to September 2009. All term and late pre-term neonates admitted with clinically apparent seizures and not having any transient metabolic disorders (hypoglycemia or hypocalcemia) were randomly assigned. Phenobarbitone (n=54) or phenytoin (n=55) intravenously 20 mg/kg/dose over 20-30 min. Neonates whose seizures were not controlled by the assigned drug were then crossed over to be treated with other drug in same dose. Clinical control of seizures (seizure free period of 24 hours after giving anticonvulsant). Baseline characteristics including mean birthweight, gestation age and sex were comparable in both groups. Seizures were controlled in 8 of the 55 (14.5%) neonates who received phenytoin, as compared to 39 of 54 (72.2%) neonates who received phenobarbitone (P <0.001). In babies not responding to assigned drugs, after cross-over to the other drug, seizure control was achieved in 44/55 (80%) of the neonates assigned to receive phenytoin first as compared to 49/54 (91%) of those assigned to receive phenobarbitone first (P=0.014). After maximum dose of phenobarbitone seizures were controlled in 49/55(89%) in phenytoin group and 52/54 (96%) in phenobarbitone group (P<0.05). Phenobarbitone is more efficacious than phenytoin in control of clinical seizures in term or near-term neonates, irrespective of etiology. To evaluate serum vascular endothelial growth factor (VEGF) levels in children with acute lymphoblastic leukemia (ALL) during the induction phase of chemotherapy.
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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.
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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.
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Randomized open-label trial of baclofen for relapse prevention in alcohol dependence.
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.
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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.
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Pilot Study of Droxidopa With Carbidopa in Adults With ADHD.
Adler, Lenard A; Gorny, Stephen W
2015-04-23
We conducted a two-period (open-label and double-blind) pilot investigation of droxidopa, with and without carbidopa, for ADHD. Twenty adult ADHD patients received open-label droxidopa titrated from 200 to 600 mg 3 times per day (TID; Weeks 1-3), then open-label droxidopa plus carbidopa titrated from 25 or 50 mg TID (Weeks 4-6). In Weeks 7 to 8, patients were randomized to continued co-treatment or matching placebo substitution. Improvements in mean total Adult ADHD Investigator Symptom Report Scale (AISRS) scores were seen at Week 1 (p < .0001) and Week 3 (p < .0001). Improvements were maintained but not increased with carbidopa. Thirteen of 20 patients completed open-label treatment. In the double-blind period, mean total AISRS scores were similar between the co-treatment (n = 6) and placebo (n = 5) groups. No serious adverse events were reported. These preliminary findings indicate that droxidopa can improve adult ADHD symptoms. Further studies are warranted to examine the efficacy and safety of droxidopa in ADHD. © 2015 SAGE Publications.
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Garrigue, D; Godier, A; Glacet, A; Labreuche, J; Kipnis, E; Paris, C; Duhamel, A; Resch, E; Bauters, A; Machuron, F; Renom, P; Goldstein, P; Tavernier, B; Sailliol, A; Susen, S
2018-03-01
Essentials An immediate supply of plasma in case of trauma-induced coagulopathy is required. The Traucc trial compared French Lyophilised Plasma (FLyP) and Fresh Frozen Plasma (FFP). FLyP achieved higher fibrinogen concentrations compared with FFP. FLyP led to a more rapid coagulopathy improvement than FFP. Background Guidelines recommend beginning hemostatic resuscitation immediately in trauma patients. We aimed to investigate if French lyophilized plasma (FLyP) was more effective than fresh frozen plasma (FFP) for the initial management of trauma-induced coagulopathy. Methods In an open-label, phase 3, randomized trial (NCT02750150), we enrolled adult trauma patients requiring an emergency pack of 4 plasma units within 6 h of injury. We randomly assigned patients to receive 4-FLyP units or 4-FFP units. The primary endpoint was fibrinogen concentration at 45 min after randomization. Secondary outcomes included time to transfusion, changes in hemostatic parameters at different time-points, blood product requirements and 30-day in-hospital mortality. Results Forty-eight patients were randomized (FLyP, n = 24; FFP, n = 24). FLyP reduced the time from randomization to transfusion of first plasma unit compared with FFP (median[IQR],14[5-30] vs. 77[64-90] min). FLyP achieved a higher fibrinogen concentration 45 min after randomization compared with FFP (baseline-adjusted mean difference, 0.29 g L -1 ; 95% confidence interval [CI], 0.08-0.49) and a greater improvement in prothrombin time ratio, factor V and factor II. The between-group differences in coagulation parameters remained significant at 6 h. FLyP reduced fibrinogen concentrate requirements. Thirty-day in-hospital mortality rate was 22% with FLyP and 29% with FFP. Conclusion FLyP led to a more rapid, pronounced and extended increase in fibrinogen concentrations and coagulopathy improvement compared with FFP in the initial management of trauma patients. FLyP represents an attractive option for trauma management, especially when facing logistical issues such as combat casualties or mass casualties related to terror attacks or disasters. © 2017 International Society on Thrombosis and Haemostasis.
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Supan, Christian; Mombo-Ngoma, Ghyslain; Kombila, Maryvonne; Ospina Salazar, Carmen L; Held, Jana; Lell, Bertrand; Cantalloube, Cathy; Djeriou, Elhadj; Ogutu, Bernhards; Waitumbi, John; Otsula, Nekoye; Apollo, Duncan; Polhemus, Mark E; Kremsner, Peter G; Walsh, Douglas S
2017-08-01
Artemisinin-based combination therapies are recommended as first-line agents for treating uncomplicated Plasmodium falciparum malaria. Ferroquine, a 4-aminoquinolone, is a novel long-acting combination partner for fast-acting drugs like artesunate (AS). We did a small phase 2a, multicenter, open-label, safety-focused dose-ranging randomized study of ferroquine at three African hospitals: two Gabonese and one Kenyan. We recruited adult men with symptomatic uncomplicated P. falciparum monoinfection. Four escalating doses of ferroquine (100, 200, 400, and 600 mg) were assessed in sequence, versus an amodiaquine comparator. After a 2:1 randomization (block size three, equating to N = 12 for each ferroquine dose and N = 6 for each of four amodiaquine comparator groups) patients received daily for three consecutive days, either ferroquine + AS (200 mg/day) or amodiaquine (612 mg/day) + AS (200 mg/day). Safety, electrocardiograms, parasite clearance times, efficacy, and pharmacokinetics were assessed to day 28. Seventy-two patients were randomized. Ferroquine + AS showed generally mild increases (Grade 1 toxicity) in alanine aminotransferase (ALT) levels with a dose trend starting at 400 mg. There were two Grade 2 ALT events: one patient receiving 200 mg (3.8 upper limit of normal [ULN], day 7) and one receiving 600 mg (3.3 ULN, day 14), both without increased bilirubin. One ferroquine 100 mg + AS patient after one dose was withdrawn after developing a QTcF interval prolongation > 60 milliseconds over baseline. Parasitemias in all patients cleared quickly, with no recurrence through day 28. Hepatic, as well as cardiac, profiles should be monitored closely in future trials. (ClinicalTrials.gov: NCT00563914).
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Dominguez-Rodriguez, Alberto; Burillo-Putze, Guillermo; Garcia-Saiz, Maria Del Mar; Aldea-Perona, Ana; Harmand, Magali González-Colaço; Mirò, Oscar; Abreu-Gonzalez, Pedro
2017-04-01
Morphine has been used for several decades in cases of acute pulmonary edema (APE) due to the anxiolytic and vasodilatory properties of the drug. The non-specific depression of the central nervous system is probably the most significant factor for the changes in hemodynamics in APE. Retrospective studies have shown both negative and neutral effects in patients with APE and therefore some authors have suggested benzodiazepines as an alternative treatment. The use of intravenous morphine in the treatment of APE remains controversial. The MIdazolan versus MOrphine in APE trial (MIMO) is a multicenter, prospective, open-label, randomized study designed to evaluate the efficacy and safety of morphine in patients with APE. The MIMO trial will evaluate as a primary endpoint whether intravenous morphine administration improves clinical outcomes defined as in-hospital mortality. Secondary endpoint evaluation will be mechanical ventilation, cardiopulmonary resuscitation, intensive care unit admission rate, intensive care unit length of stay, and hospitalization length. In the emergency department, morphine is still used for APE in spite of poor scientific background data. The data from the MIMO trial will establish the effect-and especially the risk-when using morphine for APE.
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Deuse, Tobias; Bara, Christoph; Barten, Markus J; Hirt, Stephan W; Doesch, Andreas O; Knosalla, Christoph; Grinninger, Carola; Stypmann, Jörg; Garbade, Jens; Wimmer, Peter; May, Christoph; Porstner, Martina; Schulz, Uwe
2015-11-01
In recent years a series of trials has sought to define the optimal protocol for everolimus-based immunosuppression in heart transplantation, with the goal of minimizing exposure to calcineurin inhibitors (CNIs) and harnessing the non-immunosuppressive benefits of everolimus. Randomized studies have demonstrated that immunosuppressive potency can be maintained in heart transplant patients receiving everolimus despite marked CNI reduction, although very early CNI withdrawal may be inadvisable. A potential renal advantage has been shown for everolimus, but the optimal time for conversion and the adequate reduction in CNI exposure remain to be defined. Other reasons for use of everolimus include a substantial reduction in the risk of cytomegalovirus infection, and evidence for inhibition of cardiac allograft vasculopathy, a major cause of graft loss. The ongoing MANDELA study is a 12-month multicenter, randomized, open-label, parallel-group study in which efficacy, renal function and safety are compared in approximately 200 heart transplant patients. Patients receive CNI therapy, steroids and everolimus or mycophenolic acid during months 3 to 6 post-transplant, and are then randomized at month 6 post-transplant (i) to convert to CNI-free immunosuppression with everolimus and mycophenolic acid or (ii) to continue reduced-exposure CNI, with concomitant everolimus. Patients are then followed to month 18 post-transplant The rationale and expectations for the trial and its methodology are described herein. Copyright © 2015 Elsevier Inc. All rights reserved.
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Defining success in clinical trials--profiling pregabalin, the newest AED.
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.
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Cremolini, Chiara; Marmorino, Federica; Loupakis, Fotios; Masi, Gianluca; Antoniotti, Carlotta; Salvatore, Lisa; Schirripa, Marta; Boni, Luca; Zagonel, Vittorina; Lonardi, Sara; Aprile, Giuseppe; Tamburini, Emiliano; Ricci, Vincenzo; Ronzoni, Monica; Pietrantonio, Filippo; Valsuani, Chiara; Tomasello, Gianluca; Passardi, Alessandro; Allegrini, Giacomo; Di Donato, Samantha; Santini, Daniele; Falcone, Alfredo
2017-06-09
Chemotherapy plus bevacizumab is a standard first-line treatment for unresectable metastatic colorectal cancer patients. Different chemotherapy backbones may be chosen, including one to three drugs, based on patients' general conditions and comorbidities, treatments' objectives, and disease characteristics. TRIBE trial demonstrated a significant advantage in terms of progression-free survival and overall survival for FOLFOXIRI plus bevacizumab as compared with FOLFIRI plus bevacizumab. Based on recent evidence, the de-intensification of the upfront regimen after 4-6 months of treatment is nowadays regarded as a valuable option. Moreover, the prolonged inhibition of angiogenesis, and in particular the continuation of bevacizumab beyond the evidence of disease progression, is an efficacious strategy in the treatment of metastatic colorectal cancer patients. TRIBE-2 is a prospective, open-label, multicentric phase III randomized trial in which unresectable and previously untreated metastatic colorectal cancer patients are randomized to receive first-line FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression or FOLFOXIRI plus bevacizumab followed by the re-introduction of the same regimen after disease progression. The primary endpoint is to compare the efficacy of the two proposed treatment strategies in terms of Progression Free Survival 2. The TRIBE-2 study aims at answering the question whether the upfront use of FOLFOXIRI improves the clinical outcome of metastatic colorectal cancer patients, when compared with the pre-planned, sequential use of oxaliplatin-based and irinotecan-based doublets. Both proposed treatment strategies are designed to exploit the effectiveness of the prolonged inhibition of angiogenesis, alternating short (up to 4 months) induction periods and less intensive maintenance phases. TRIBE2 is registered at Clinicaltrials.gov: NCT02339116 . January 12, 2015. TRIBE-2 is registered at EUDRACT 2014-004436-19, October 10, 2014.
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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.
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Cardiovascular Safety of Droxidopa in Patients With Symptomatic Neurogenic Orthostatic Hypotension.
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.
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Katsunuma, Toshio; Fujisawa, Takao; Mizuho, Nagao; Akira, Akasawa; Nomura, Ichiro; Yamaoka, Akiko; Kondo, Hisashi; Masuda, Kei; Yamaguchi, Koichi; Terada, Akihiko; Ikeda, Masanori; Nishioka, Kenji; Adachi, Yuichi; Kurihara, Kazuyuki
2013-01-01
Few studies have examined the efficacy or safety of a transdermal β2 agonist as add-on medicationto long-term leukotriene receptor antagonist (LTRA) therapy in pediatric asthma patients. In this randomized, open-label, multicenter clinical trial, children aged 4-12 years on long-term LTRA therapy were treated with tulobuterol patches (1-2 mg daily) or oral sustained-release theophylline (usual dose, 4-5 mg_kg daily) for 4 weeks. LTRAs were continued throughout the trial. Outcomes included volume peak expiratory flow (% PEF), fractional exhaled nitric oxide (FeNO), clinical symptoms and adverse events. Thirty-three and 31 patients were treated with tulobuterol patches and theophylline, respectively. % PEF measured in the morning and before bedtime was significantly higher at all times in the treatment period compared with baseline in the tulobuterol patch group (p < 0.001), and was significantly higher in the tulobuterol patch group compared with the theophylline group. FeNO was similar and unchanged from baseline in both groups. There were no drug-related adverse events in either group. These results suggest that short-term use of a transdermal β2 agonist is an effective therapy for pediatric asthma without inducing airway inflammation in children on long-term LTRA therapy. © 2013 Japanese Society of Allergology.
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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.
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Levetiracetam versus lorazepam in status epilepticus: a randomized, open labeled pilot study.
Misra, U K; Kalita, J; Maurya, P K
2012-04-01
For the management of status epilepticus (SE), lorazepam (LOR) is recommended as the first and phenytoin or fosphenytoin as the second choice. Both these drugs have significant toxicity. Intravenous levetiracetam (LEV) has become available, but its efficacy and safety has not been reported in comparison to LOR. We report a randomized, open labeled pilot study comparing the efficacy and safety of LEV and LOR in SE. Consecutive patients with convulsive or subtle convulsive SE were randomized to LEV 20 mg/kg IV over 15 min or LOR 0.1 mg/kg over 2-4 min. Failure to control SE within 10 min of administration of one study drug was treated by the other study drug. The primary endpoint was clinical seizure cessation and secondary endpoints were 24 h freedom from seizure, hospital mortality, and adverse events. Our results are based on 79 patients. Both LEV and LOR were equally effective. In the first instance, the SE was controlled by LEV in 76.3% (29/38) and by LOR in 75.6% (31/41) of patients. In those resistant to the above regimen, LEV controlled SE in 70.0% (7/10) and LOR in 88.9% (8/9) patients. The 24-h freedom from seizure was also comparable: by LEV in 79.3% (23/29) and LOR in 67.7% (21/31). LOR was associated with significantly higher need of artificial ventilation and insignificantly higher frequency of hypotension. For the treatment of SE, LEV is an alternative to LOR and may be preferred in patients with respiratory compromise and hypotension.
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A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis.
Kowdley, Kris V; Luketic, Velimir; Chapman, Roger; Hirschfield, Gideon M; Poupon, Raoul; Schramm, Christoph; Vincent, Catherine; Rust, Christian; Parés, Albert; Mason, Andrew; Marschall, Hanns-Ulrich; Shapiro, David; Adorini, Luciano; Sciacca, Cathi; Beecher-Jones, Tessa; Böhm, Olaf; Pencek, Richard; Jones, David
2018-05-01
Obeticholic acid (OCA), a potent farnesoid X receptor agonist, was studied as monotherapy in an international, randomized, double-blind, placebo-controlled phase 2 study in patients with primary biliary cholangitis who were then followed for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of ursodeoxycholic acid, which is relevant for patients who are intolerant of ursodeoxycholic acid and at higher risk of disease progression. Patients were randomized and dosed with placebo (n = 23), OCA 10 mg (n = 20), or OCA 50 mg (n = 16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing). The primary endpoint was the percent change in alkaline phosphatase from baseline to the end of the double-blind phase of the study. Secondary and exploratory endpoints included change from baseline to month 3/early termination in markers of cholestasis, hepatocellular injury, and farnesoid X receptor activation. Efficacy and safety continue to be monitored through an ongoing 6-year open-label extension (N = 28). Alkaline phosphatase was reduced in both OCA groups (median% [Q1, Q3], OCA 10 mg -53.9% [-62.5, -29.3], OCA 50 mg -37.2% [-54.8, -24.6]) compared to placebo (-0.8% [-6.4, 8.7]; P < 0.0001) at the end of the study, with similar reductions observed through 6 years of open-label extension treatment. OCA improved many secondary and exploratory endpoints (including γ-glutamyl transpeptidase, alanine aminotransferase, conjugated bilirubin, and immunoglobulin M). Pruritus was the most common adverse event; 15% (OCA 10 mg) and 38% (OCA 50 mg) discontinued due to pruritus. OCA monotherapy significantly improved alkaline phosphatase and other biochemical markers predictive of improved long-term clinical outcomes. Pruritus increased dose-dependently with OCA treatment. Biochemical improvements were observed through 6 years of open-label extension treatment. (Hepatology 2018;67:1890-1902). © 2017 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.
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Switching from adalimumab to tofacitinib in the treatment of patients with rheumatoid arthritis.
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.
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Wasdell, Michael B; Jan, James E; Bomben, Melissa M; Freeman, Roger D; Rietveld, Wop J; Tai, Joseph; Hamilton, Donald; Weiss, Margaret D
2008-01-01
The purpose of this study was to determine the efficacy of controlled-release (CR) melatonin in the treatment of delayed sleep phase syndrome and impaired sleep maintenance of children with neurodevelopmental disabilities including autistic spectrum disorders. A randomized double-blind, placebo-controlled crossover trial of CR melatonin (5 mg) followed by a 3-month open-label study was conducted during which the dose was gradually increased until the therapy showed optimal beneficial effects. Sleep characteristics were measured by caregiver who completed somnologs and wrist actigraphs. Clinician rating of severity of the sleep disorder and improvement from baseline, along with caregiver ratings of global functioning and family stress were also obtained. Fifty-one children (age range 2-18 years) who did not respond to sleep hygiene intervention were enrolled. Fifty patients completed the crossover trial and 47 completed the open-label phase. Recordings of total night-time sleep and sleep latency showed significant improvement of approximately 30 min. Similarly, significant improvement was observed in clinician and parent ratings. There was additional improvement in the open-label somnolog measures of sleep efficiency and the longest sleep episode in the open-label phase. Overall, the therapy improved the sleep of 47 children and was effective in reducing family stress. Children with neurodevelopmental disabilities, who had treatment resistant chronic delayed sleep phase syndrome and impaired sleep maintenance, showed improvement in melatonin therapy.
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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
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Adherence to Preexposure Prophylaxis: Current, Emerging, and Anticipated Bases of Evidence
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
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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.
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Design, objectives, execution and reporting of published open-label extension studies.
Megan, Bowers; Pickering, Ruth M; Weatherall, Mark
2012-04-01
Open-label extension (OLE) studies following blinded randomized controlled trials (RCTs) of pharmaceuticals are increasingly being carried out but do not conform to regulatory standards and questions surround the validity of their evidence. OLE studies are usually discussed as a homogenous group, yet substantial differences in study design still meet the definition of an OLE. We describe published papers reporting OLE studies focussing on stated objectives, design, conduct and reporting. A search of Embase and Medline databases for 1996 to July 2008 revealed 268 papers reporting OLE studies that met our eligibility criteria. A random sample of 50 was selected for detailed review. Over 80% of the studies had efficacy stated as an objective. The most common methods of allocation at the start of the OLE were for all RCT participants to switch to one active treatment or for only participants on the new drug to continue, but in three studies all participants were re-randomized at the start of the OLE. Eligibility criteria and other selection factors resulted in on average of 74% of participants in the preceding RCT(s) enrolling in the OLE and only 57% completed it. Published OLE studies do not form a homogenous group with respect to design or retention of participants, and thus the validity of evidence from an OLE should be judged on an individual basis. The term 'open label' suggests bias through lack of blinding, but slippage in relation to the sample randomized in the preceding RCT may be the more important threat to validity. © 2010 Blackwell Publishing Ltd.
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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.
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Lichtenstein, Gary R; Travis, Simon; Danese, Silvio; D'Haens, Geert; Moro, Luigi; Jones, Richard; Huang, Michael; Ballard, E David; Bagin, Robert; Hardiman, Yun; Collazo, Raul; Sandborn, William J
2015-09-01
Cumulative safety and tolerability of budesonide MMX, a once-daily oral corticosteroid for inducing mild to moderate ulcerative colitis remission, was examined. Data from three randomized, double-blind, placebo-controlled, phase II or III studies [budesonide MMX 9 mg, 6 mg, or 3mg for 8 weeks]; one phase II study [randomisation to budesonide MMX 9 mg or placebo for 4 weeks, then open-label budesonide MMX 9 mg for 4 weeks]; and one open-label study [budesonide MMX 9 mg for 8 weeks] were pooled. Patients randomised to budesonide MMX 9 mg [n = 288], 6 mg [n = 254], or placebo [n = 293] had similar rates of adverse events [AEs] [27.1%, 24.8%, and 23.9%, respectively] and serious AEs [2.4%, 2.0%, and 2.7%, respectively]; treatment-related AEs and serious AEs were reported by 11.8% and 13.5%, and 5.9% and 2.2%, respectively, of patients receiving budesonide MMX 3mg [n = 17] or open-label budesonide MMX 9 mg [n = 89]. Mean morning plasma cortisol concentrations were normal from baseline to final visit across randomised groups; in patients receiving open-label budesonide, mean cortisol concentration was 129.9 nmol/l after 4 weeks, returning to normal concentrations at final visit. Budesonide MMX was not associated with an overall increased risk for glucocorticoid-related adverse effects. Budesonide MMX 9 mg was associated with normal mean cortisol concentrations at final visit and an AE incidence comparable to placebo. Overall, budesonide MMX was safe and well tolerated for inducing remission of patients with mild to moderate ulcerative colitis. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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Travis, Simon; Danese, Silvio; D’Haens, Geert; Moro, Luigi; Jones, Richard; Huang, Michael; Ballard, E. David; Bagin, Robert; Hardiman, Yun; Collazo, Raul; Sandborn, William J.
2015-01-01
Background and aims: Cumulative safety and tolerability of budesonide MMX, a once-daily oral corticosteroid for inducing mild to moderate ulcerative colitis remission, was examined. Methods: Data from three randomized, double-blind, placebo-controlled, phase II or III studies [budesonide MMX 9mg, 6mg, or 3mg for 8 weeks]; one phase II study [randomisation to budesonide MMX 9mg or placebo for 4 weeks, then open-label budesonide MMX 9mg for 4 weeks]; and one open-label study [budesonide MMX 9mg for 8 weeks] were pooled. Results: Patients randomised to budesonide MMX 9mg [n = 288], 6mg [n = 254], or placebo [n = 293] had similar rates of adverse events [AEs] [27.1%, 24.8%, and 23.9%, respectively] and serious AEs [2.4%, 2.0%, and 2.7%, respectively]; treatment-related AEs and serious AEs were reported by 11.8% and 13.5%, and 5.9% and 2.2%, respectively, of patients receiving budesonide MMX 3mg [n = 17] or open-label budesonide MMX 9mg [n = 89]. Mean morning plasma cortisol concentrations were normal from baseline to final visit across randomised groups; in patients receiving open-label budesonide, mean cortisol concentration was 129.9 nmol/l after 4 weeks, returning to normal concentrations at final visit. Budesonide MMX was not associated with an overall increased risk for glucocorticoid-related adverse effects. Conclusions: Budesonide MMX 9mg was associated with normal mean cortisol concentrations at final visit and an AE incidence comparable to placebo. Overall, budesonide MMX was safe and well tolerated for inducing remission of patients with mild to moderate ulcerative colitis. PMID:26094251
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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
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Gao, Xiang; Ndongo, Marie-Noella; Checchio, Tina M; Cook, Jack; Duncan, Barbara; LaBadie, Robert R
2015-01-01
The relative bioavailability and bioequivalence of 20-mg doses of a pediatric formulation of sildenafil extemporaneous preparation suspension (EP; 10 mg/mL), the sildenafil 20-mg intact tablet and the crushed sildenafil 20-mg tablet mixed with apple sauce were assessed in a single-dose, randomized, open-label, 3-way crossover study with 18 healthy adult volunteers. Blood samples were collected at predefined times and analyzed for sildenafil plasma concentrations. Natural log-transformed sildenafil pharmacokinetic parameters (Cmax , AUClast , and AUCinf ) were used to estimate relative bioavailability and construct 90% confidence intervals (CI) using a mixed-effects model. Bioequivalence was concluded among the three formulations with one exception, in which the EP suspension showed a 15% decrease in Cmax with a lower 90% CI of 76% compared with the intact tablet. The 15% decrease in sildenafil Cmax is not considered to be clinically relevant. Therefore, the EP suspension is considered to be an appropriate pediatric formulation. All 3 formulations were well tolerated in healthy adult volunteers. © 2014, The American College of Clinical Pharmacology.
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Baber, Usman; Dangas, George; Cohen, David J; Gibson, C Michael; Mehta, Shamir R; Angiolillo, Dominick J; Pocock, Stuart J; Krucoff, Mitchell W; Kastrati, Adnan; Ohman, E Magnus; Steg, Philippe Gabriel; Badimon, Juan; Zafar, M Urooj; Chandrasekhar, Jaya; Sartori, Samantha; Aquino, Melissa; Mehran, Roxana
2016-12-01
Dual antiplatelet therapy (DAPT) is necessary to prevent thrombosis yet increases bleeding after percutaneous coronary intervention (PCI) with drug-eluting stents (DES). Antiplatelet monotherapy with a potent P2Y 12 receptor antagonist may reduce bleeding while maintaining anti thrombotic efficacy compared with conventional DAPT. TWILIGHT is a randomized, double-blind placebo-controlled trial evaluating the comparative efficacy and safety of antiplatelet monotherapy versus DAPT in up to 9000 high-risk patients undergoing PCI with DES. Upon enrollment after successful PCI, all patients will be treated with open label low-dose aspirin (81-100 mg daily) plus ticagrelor (90 mg twice daily) for 3 months. Event-free patients will then be randomized in a double-blind fashion to low-dose aspirin versus matching placebo with continuation of open-label ticagrelor for an additional 12 months. The primary hypothesis is that a strategy of ticagrelor monotherapy will be superior with respect to the primary endpoint of bleeding academic research consortium type 2, 3 or 5, while maintaining non-inferiority for ischemic events compared with ticagrelor plus ASA. TWILIGHT is the largest study to date that is specifically designed and powered to demonstrate reductions in bleeding with ticagrelor monotherapy versus ticagrelor plus ASA beyond 3 months post-procedure in a high-risk PCI population treated with DES. The trial will provide novel insights with respect to the potential role of ticagrelor monotherapy as an alternative for long-term platelet inhibition in a broad population of patients undergoing PCI with DES. Copyright © 2016 Elsevier Inc. All rights reserved.
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Karlson, Björn W; Dellborg, Mikael; Gullestad, Lars; Aberg, Jan; Sugg, Jennifer; Herlitz, Johan
2014-01-01
Previous metoprolol studies in myocardial infarction patients were performed with immediate-release (IR) metoprolol. This study aims to evaluate if extended-release metoprolol CR/XL once daily gives a similar β-blockade over 24 h compared to multiple dosing of metoprolol IR. After 2 days of routine metoprolol treatment, 27 patients with suspected acute myocardial infarction were randomized to open-label treatment with metoprolol IR (50 mg four times daily or 100 mg twice daily) or metoprolol CR/XL 200 mg once daily for 3 days. Metoprolol CR/XL 200 mg once daily gave more pronounced suppression of peak heart rate, with lower peak and less variation in peak to trough plasma levels. There were no differences in AUC between the CR/XL and IR formulations, although the trough plasma metoprolol levels were comparable for metoprolol CR/XL 200 mg once daily and metoprolol IR 50 mg four times daily, but lower for metoprolol IR 100 mg twice daily. Both treatments were well tolerated. Metoprolol CR/XL 200 mg once daily showed lower peak and less variation in peak to trough plasma levels compared to multiple dosing of metoprolol IR with the same AUC. This was accompanied by a more uniform β-blockade over time, which was reflected by heart rate, and a more pronounced suppression of peak heart rate with similar tolerability. This suggests metoprolol CR/XL may be used as an alternative to metoprolol IR in patients with myocardial infarction. © 2013 S. Karger AG, Basel.
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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.
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ERIC Educational Resources Information Center
Braam, W.; Didden, R.; Smits, M.; Curfs, L.
2008-01-01
Background: While several small-number or open-label studies suggest that melatonin improves sleep in individuals with intellectual disabilities (ID) with chronic sleep disturbance, a larger randomized control trial is necessary to validate these promising results. Methods: The effectiveness of melatonin for the treatment of chronic sleep…
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Katakami, Naoto; Mita, Tomoya; Yoshii, Hidenori; Shiraiwa, Toshihiko; Yasuda, Tetsuyuki; Okada, Yosuke; Umayahara, Yutaka; Kaneto, Hideaki; Osonoi, Takeshi; Yamamoto, Tsunehiko; Kuribayashi, Nobuichi; Maeda, Kazuhisa; Yokoyama, Hiroki; Kosugi, Keisuke; Ohtoshi, Kentaro; Hayashi, Isao; Sumitani, Satoru; Tsugawa, Mamiko; Ohashi, Makoto; Taki, Hideki; Nakamura, Tadashi; Kawashima, Satoshi; Sato, Yasunori; Watada, Hirotaka; Shimomura, Iichiro
2017-10-01
Sodium-glucose co-transporter-2 (SGLT2) inhibitors are anti-diabetic agents that improve glycemic control with a low risk of hypoglycemia and ameliorate a variety of cardiovascular risk factors. The aim of the ongoing study described herein is to investigate the preventive effects of tofogliflozin, a potent and selective SGLT2 inhibitor, on the progression of atherosclerosis in subjects with type 2 diabetes (T2DM) using carotid intima-media thickness (IMT), an established marker of cardiovascular disease (CVD), as a marker. The Study of Using Tofogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA) trial is a prospective, randomized, open-label, blinded-endpoint, multicenter, and parallel-group comparative study. The aim was to recruit a total of 340 subjects with T2DM but no history of apparent CVD at 24 clinical sites and randomly allocate these to a tofogliflozin treatment group or a conventional treatment group using drugs other than SGLT2 inhibitors. As primary outcomes, changes in mean and maximum IMT of the common carotid artery during a 104-week treatment period will be measured by carotid echography. Secondary outcomes include changes in glycemic control, parameters related to β-cell function and diabetic nephropathy, the occurrence of CVD and adverse events, and biochemical measurements reflecting vascular function. This is the first study to address the effects of SGLT2 inhibitors on the progression of carotid IMT in subjects with T2DM without a history of CVD. The results will be available in the very near future, and these findings are expected to provide clinical data that will be helpful in the prevention of diabetic atherosclerosis and subsequent CVD. Kowa Co., Ltd. UMIN000017607.
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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.
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Rodda, C P; Benson, J E; Vincent, A J; Whitehead, C L; Polykov, A; Vollenhoven, B
2015-09-01
To determine whether maternal vitamin D supplementation, in the vitamin D deficient mother, prevents neonatal vitamin D deficiency. Open-label randomized controlled trial. Metropolitan Melbourne, Australia, tertiary hospital routine antenatal outpatient clinic. Seventy-eight women with singleton pregnancies with vitamin D deficiency/insufficiency (serum 25-OH Vit D < 75 nmol/l) at their first antenatal appointment at 12-16-week gestation were recruited. Participants were randomized to vitamin D supplementation (2000-4000 IU cholecalciferol) orally daily until delivery or no supplementation. The primary outcome was neonatal serum 25-OH vit D concentration at delivery. The secondary outcome was maternal serum 25-OH vit D concentration at delivery. Baseline mean maternal serum 25-OH vit D concentrations were similar (P = 0·9) between treatment (32 nmol/l, 95% confidence interval 26-39 nmol/l) and control groups (33 nmol/l, 95% CI 26-39 nmol/l). Umbilical cord serum 25-OH vit D concentrations at delivery were higher (P < 0·0001) in neonates of treatment group mothers (81 nmol/l, 95% CI; 70-91 nmol/l) compared with neonates of control group mothers (42 nmol/l, 95% CI; 34-50 nmol/l) with a strongly positive correlation between maternal serum 25-OH Vit D and umbilical cord serum 25-OH vit D concentrations at delivery (Spearman rank correlation coefficient 0·88; P < 0·0001). Mean maternal serum 25-OH Vit D concentrations at delivery were higher (P < 0·0001) in the treatment group (71 nmol/l, 95% CI; 62-81 nmol/l) compared with the control group (36 nmol/l, 95% CI; 29-42 nmol/l). Vitamin D supplementation of vitamin D deficient pregnant women prevents neonatal vitamin D deficiency. © 2015 John Wiley & Sons Ltd.
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Altamura, A C; Salvadori, Daniele; Madaro, Donato; Santini, Annalisa; Mundo, Emanuela
2003-09-01
The literature on the use of quetiapine for the treatment of bipolar disorder (BD) is limited to case reports, and there are no systematic studies on the efficacy of quetiapine in the prophylactic treatment of BD. The aim of the present study was to compare the efficacy of flexible doses of quetiapine and well established mood stabilizers in the maintenance treatment of BD. Twenty-eight DSM-IV BD outpatients were consecutively recruited into the study and were randomized to receive one of two open-label treatments, with quetiapine or classical mood stabilizers at flexible doses for 12 months. Clinical assessment was carried out using BPRS, CGI, YMRS and the 21-item HAM-D at baseline (T0) and every 2 months until the end of the study. ANOVAs with repeated measures were applied to the rating scale scores considering the time and the treatment group as main factors. All patients experienced a significant improvement on the BPRS, CGI and HAM-D scores, with no significant side-effects and a good compliance. This study should be considered preliminary given the small sample size investigated and the open-label design. If these results will be replicated on larger samples and in controlled studies, there could be relevant implications for the use of quetiapine as an alternative maintenance treatment for BD.
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Song, Yan; Chang, Ming; Suzuki, Akiyuki; Frost, Robert J A; Kelly, Anne; LaCreta, Frank; Frost, Charles
2016-07-01
These studies evaluate the relative bioavailability of crushed apixaban tablets and the effect of food on apixaban pharmacokinetic properties. An open-label, randomized, crossover study in 33 healthy adults compared the bioavailability of 2 × 5-mg apixaban tablets administered whole (reference), crushed and suspended in 30 mL of water, and crushed and mixed with 30 g of applesauce. A second open-label, randomized, crossover study in 22 healthy adults compared apixaban 1 × 5-mg tablet administered when fasted (reference) or immediately after consumption of a high-fat, high-calorie meal. Point estimates and 90% CIs for geometric mean ratios were generated for Cmax, AUC0-∞, and AUC0-t. Cmax and AUC met bioequivalence criteria for crushed tablets in water. Cmax and AUC decreased by 21.1% and 16.4%, respectively, with the lower bound of the CIs falling below the bioequivalence criteria for crushed tablets with applesauce. Similarly, administration of whole tablets with a high-fat, high-calorie meal reduced apixaban Cmax and AUC by 14.9% and 20.1%, respectively. The exposure reductions in both studies were considered not clinically significant. Apixaban tablets can be administered crushed or whole, with or without food. The results of these alternative methods of administration support their use in patients who have difficulty swallowing tablets. ClinicalTrials.gov identifiers: NCT02101112 and NCT01437839. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
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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).
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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
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Teichmann, Alexander; Apter, Dan; Emerich, Janusz; Greven, Klaus; Klasa-Mazurkiewicz, Dagmara; Melis, Giambi B; Spaczynski, Marek; Grubb, Gary S; Constantine, Ginger D; Spielmann, Daniele
2009-12-01
This Phase 3, randomized, open-label, multicenter study conducted at 44 sites in Europe evaluated the safety and efficacy of a continuous, daily regimen of levonorgestrel (LNG) 90 mcg/ethinyl estradiol (EE) 20 mcg compared with a 21-day, cyclic LNG 100 mcg/EE 20 mcg regimen. Three hundred twenty-three healthy women were randomized to continuous LNG 90 mcg/EE 20 mcg and 318 subjects to cyclic LNG 100 mcg/EE 20 mcg for 1 year (13 pill packs). Pearl index, adverse event (AE) incidence and bleeding profiles were assessed. No pregnancies occurred with the continuous oral contraceptive (OC) (Pearl index=0.00). As the study progressed, the percentage of women who achieved amenorrhea during each 28-day pill pack increased: 40% at pill pack 7, 53% at pill pack 13. The percentage of women with no bleeding [with or without spotting (defined as not requiring sanitary protection)] was 50%, 69% and 79% at pill packs 3, 7 and 13, respectively. The incidence of AEs was similar to that of the cyclic OC (except for metrorrhagia and vaginal bleeding in the first 6 months). Continuous LNG 90 mcg/EE 20 mcg was shown to be a safe and effective OC in this direct comparison to a cyclic OC. Suppression of menses and the potential for no bleeding requiring sanitary protection may be provided by this continuous, low-dose OC.
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Ni Mhurchu, Cliona; Volkova, Ekaterina; Jiang, Yannan; Eyles, Helen; Michie, Jo; Neal, Bruce; Blakely, Tony; Swinburn, Boyd; Rayner, Mike
2017-03-01
Background: Nutrition labeling is a prominent policy to promote healthy eating. Objective: We aimed to evaluate the effects of 2 interpretive nutrition labels compared with a noninterpretive label on consumer food purchases. Design: In this parallel-group randomized controlled trial, we enrolled household shoppers across New Zealand who owned smartphones and were aged ≥18 y. Eligible participants were randomly assigned (1:1:1) to receive either traffic light labels (TLLs), Health Star Rating labels (HSRs), or a control [nutrition information panel (NIP)]. Smartphone technology allowed participants to scan barcodes of packaged foods and to receive allocated labels on their smartphone screens. The primary outcome was the mean healthiness of all packaged food purchases over the 4-wk intervention period, which was measured by using the Food Standards Australia New Zealand Nutrient Profiling Scoring Criterion (NPSC). Results: Between October 2014 and November 2015, 1357 eligible shoppers were randomly assigned to TLL ( n = 459), HSR ( n = 443), or NIP ( n = 455) labels. Overall difference in the mean transformed NPSC score for the TLL group compared with the NIP group was -0.20 (95% CI: -0.94, 0.54; P = 0.60). The corresponding difference for HSR compared with NIP was -0.60 (95% CI: -1.35, 0.15; P = 0.12). In an exploratory per-protocol analysis of participants who used the labeling intervention more often than average ( n = 423, 31%), those who were assigned to TLL and HSR had significantly better NPSC scores [TLL compared with NIP: -1.33 (95% CI: -2.63, -0.04; P = 0.04); HSR compared with NIP: -1.70 (95% CI: -2.97, -0.43; P = 0.01)]. Shoppers who were randomly assigned to HSR and TLL also found the labels significantly more useful and easy to understand than the NIP (all P values <0.001). Conclusions: At the relatively low level of use observed in this trial, interpretive nutrition labels had no significant effect on food purchases. However, shoppers who used interpretive labels found them to be significantly more useful and easy to understand, and compared with frequent NIP users, frequent TLL and HSR users had significantly healthier food purchases. This trial was registered at the Australian New Zealand Clinical Trials Registry (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366446&isReview=true) as ACTRN12614000644662. © 2017 American Society for Nutrition.
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Shirinsky, Ivan V; Biryukova, Anastasia A; Shirinsky, Valery S
2017-12-01
Statins have been shown to reduce ocular inflammation in animal models of uveitis and to prevent development of uveitis in observational studies. There have been no experimental human studies evaluating statins' efficacy and safety in uveitis. In this study, we aimed to investigate efficacy and safety of simvastatin in patients with uveitis. For this single-center, open-label, randomized study, we enrolled patients with acute non-infectious uveitis. The patients were randomized to receive 40 mg simvastatin per day for 2 months in addition to conventional treatment or conventional treatment alone. The studied outcomes were the rate of steroid-sparing control of ocular inflammation, measures of ocular inflammation, intraocular pressure, and visual acuity. Fifty patients were enrolled in the study. Twenty-five patients were randomly assigned to receive simvastatin with conventional treatment and 25 to conventional treatment alone. Simvastatin was associated with significantly higher rates of steroid-sparing ocular inflammation control, decrease in anterior chamber inflammation, and improvement in visual acuity. The treatment was well tolerated, no serious adverse effects were observed. Our findings suggest that statins may have therapeutic potential in uveitis. These results need to be confirmed in double-blind, randomized, controlled studies.
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Assem, M; Elsabaawy, M; Abdelrashed, M; Elemam, S; Khodeer, S; Hamed, W; Abdelaziz, A; El-Azab, G
2016-03-01
Primary prevention of spontaneous bacterial peritonitis (SBP) is an important strategy to reduce morbidity and mortality in cirrhotic patients with ascites. Efficacy and safety of alternating rifaximin and norfloxacin as primary prophylaxis is questionable. Three hundred thirty-four cirrhotic patients with high SAAG (≥1.1) ascites, protein level in ascitic fluid less than 1.5 g/dL with advanced liver disease (Child-Pugh score >9 points with serum bilirubin level >3 mg/dL) or renal impairment (serum creatinine level >1.2 mg/dL, blood urea nitrogen level >25 mg/dL, or serum sodium level <130 mEq/L) were included in an open-label, randomized study aimed at comparing alternating use of norfloxacin and rifaximin vs. norfloxacin or rifaximin alone as primary prophylaxis for SBP. Both intention-to-treat and per-protocol efficacy analyses were done after 6 months of treatment by assessment of ascitic fluid neutrophil count. Safety analysis was done for all intention-to-treat populations. Alternating norfloxacin and rifaximin showed superior prophylaxis by intention-to-treat (74.7 vs. 56.4% vs. 68.3%, p < 0.048). Pairwise analysis showed that alternating regimen had lower probability to develop SBP when compared to a norfloxacin-based regimen in intention-to-treat (p = 0.016) and per protocol analysis (p = 0.039). There was no difference among the studied groups regarding the incidence and severity of adverse events reported. Alternating norfloxacin- and rifaximin-based primary prophylaxis for SBP showed higher efficacy with the same safety profile when compared with monotherapy of norfloxacin.
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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).
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Open-label extension studies: do they provide meaningful information on the safety of new drugs?
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.
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Efficacy of Lisdexamfetamine in Adults With Moderate to Severe Binge-Eating Disorder
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
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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
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Rex, Douglas K; Bhandari, Raj; Desta, Taddese; DeMicco, Michael; Schaeffer, Cynthia; Etzkorn, Kyle; Barish, Charles; Pruitt, Ronald; Cash, Brooks D; Quirk, Daniel; Tiongco, Felix; Sullivan, Shelby; Bernstein, David
2018-04-30
Remimazolam is an ultrashort-acting benzodiazepine. We performed a randomized double-blind comparison of remimazolam to placebo for outpatient colonoscopy. This study design was a requirement of the U.S. Food and Drug Administration. An additional group was randomized to open-label midazolam administered according to its package insert instructions (randomization ratio for remimazolam:placebo:midazolam was 30:6:10). Study medications were administered under the supervision of the endoscopist, without any involvement of an anesthesia specialist. Patients were given 50 to 75 μg of fentanyl before receiving study medications. Patients who failed to achieve adequate sedation in any arm were rescued with midazolam dosed at the investigator's discretion. The primary endpoint was a composite that required 3 criteria be met: completion of the colonoscopy, no need for rescue medication, and ≤5 doses of remimazolam or placebo in any 15-minute interval (≤3 doses of midazolam in any 12-minute interval in the open-label midazolam arm). There were 461 randomized patients in 12 U.S. sites. The primary endpoint was met for remimazolam, placebo, and midazolam in 91.3%, 1.7%, and 25.2% of patients, respectively (P< 0.0001 for remimazolam vs placebo). Patients administered remimazolam received less fentanyl, had faster recovery of neuropsychiatric function, were ready for discharge faster, and felt back to normal faster than patients with both placebo and midazolam. Hypotension was less frequent with remimazolam and hypoxia occurred in 1% of subjects with remimazolam or midazolam. There were no treatment-emergent serious adverse events. Remimazolam can be safely administered under the supervision of endoscopists for outpatient colonoscopy and allows faster recovery of neuropsychiatric function compared with placebo (midazolam rescue) and midazolam. Copyright © 2018 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.
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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.
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Ruff, Christian T; Giugliano, Robert P; Braunwald, Eugene; Mercuri, Michele; Curt, Valentin; Betcher, Joshua; Grip, Laura; Cange, Abby L; Crompton, Andrea E; Murphy, Sabina A; Deenadayalu, Naveen; Antman, Elliott M
2014-08-12
At the end of 2 previous trials, an excess of stroke and bleeding was observed in patients with AF randomized to a new oral anticoagulant (NOAC) who transitioned to a vitamin K antagonist (VKA). The ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) trial compared once-daily edoxaban to warfarin for stroke prevention in patients with AF. An end-of-trial transition plan was developed to minimize the risks of stroke due to inadequate anticoagulation and bleeding from excessive anticoagulation during this critical period. All patients on the blinded study drug at the trial's conclusion were included in this analysis. In pre-specified analyses, stroke, bleeding, and death that occurred through 30 days after the end-of-trial visit were stratified by randomized treatment allocation and open-label anticoagulant selected post-trial. Of the 13,642 patients taking the blinded study drug at the end of the trial, 9,304 (68.2%) were transitioned to open-label VKA and 4,258 patients (31.2%) to an NOAC. There were 21 strokes evenly distributed across the 3 randomized treatment arms: warfarin 7 (1.90%/year), edoxaban high dose 7 (1.89%/year), edoxaban low dose 7 (1.85%/year). Major bleeding was also similar across the 3 treatment arms: warfarin 11 (2.98%/year), edoxaban high dose 10 (2.69%/year), edoxaban low dose 18 (4.76%/year). In patients transitioned to VKA, 85% of patients had at least 1 INR ≥ 2 by day 14 after the transition and 99% by day 30. The ENGAGE AF-TIMI 48 transition plan protected patients from an excess of thrombotic and bleeding events and should be helpful in clinical practice when patients are transitioned between oral anticoagulants. (Global Study to Assess the Safety and Effectiveness of Edoxaban [DU-176b] vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation [EngageAFTIMI48]; NCT00781391). Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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Van Buren, Peter N.; Lewis, Julia B.; Dwyer, Jamie P.; Greene, Tom; Middleton, John; Sika, Mohammed; Umanath, Kausik; Abraham, Josephine D.; Arfeen, Shahabul S.; Bowline, Isai G.; Chernin, Gil; Fadem, Stephen Z.; Goral, Simin; Koury, Mark; Sinsakul, Marvin V.; Weiner, Daniel E.
2016-01-01
Background Phosphate binders are the cornerstone of hyperphosphatemia management in dialysis patients. Ferric citrate is an iron-based oral phosphate binder that effectively lowers serum phosphorus levels. Study Design 52-week, open-label, phase 3, randomized, controlled trial for safety-profile assessment. Setting & Participants Maintenance dialysis patients with serum phosphorus levels ≥6.0 mg/dL after washout of prior phosphate binders. Intervention 2:1 randomization to ferric citrate or active control (sevelamer carbonate and/or calcium acetate). Outcomes Changes in mineral bone disease, protein-energy wasting/inflammation, and occurrence of adverse events after 1 year. Measurements Serum calcium, intact parathyroid hormone, phosphorus, aluminum, white blood cell count, percentage of lymphocytes, serum urea nitrogen, and bicarbonate. Results There were 292 participants randomly assigned to ferric citrate, and 149, to active control. Groups were well matched. For mean changes from baseline, phosphorus levels decreased similarly in the ferric citrate and active control groups (−2.04 ± 1.99 [SD] vs −2.18 ± 2.25 mg/dL, respectively; P = 0.9); serum calcium levels increased similarly in the ferric citrate and active control groups (0.22 ± 0.90 vs 0.31 ± 0.95 mg/dL; P = 0.2). Hypercalcemia occurred in 4 participants receiving calcium acetate. Parathyroid hormone levels decreased similarly in the ferric citrate and active control groups (−167.1 ± 399.8 vs −152.7 ± 392.1 pg/mL; P = 0.8). Serum albumin, bicarbonate, serum urea nitrogen, white blood cell count and percentage of lymphocytes, and aluminum values were similar between ferric citrate and active control. Total and low-density lipoprotein cholesterol levels were lower in participants receiving sevelamer than those receiving ferric citrate and calcium acetate. Fewer participants randomly assigned to ferric citrate had serious adverse events compared with active control. Limitations Open-label study, few peritoneal dialysis patients. Conclusions Ferric citrate was associated with similar phosphorus control compared to active control, with similar effects on markers of bone and mineral metabolism in dialysis patients. There was no evidence of protein-energy wasting/inflammation or aluminum toxicity, and fewer participants randomly assigned to ferric citrate had serious adverse events. Ferric citrate is an effective phosphate binder with a safety profile comparable to sevelamer and calcium acetate. PMID:25958079
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Burri, Christian; Yeramian, Patrick D.; Merolle, Ada; Serge, Kazadi Kyanza; Mpanya, Alain; Lutumba, Pascal; Mesu, Victor Kande Betu Ku; Lubaki, Jean-Pierre Fina; Mpoto, Alfred Mpoo; Thompson, Mark; Munungu, Blaise Fungula; Josenando, Théophilo; Bernhard, Sonja C.; Olson, Carol A.; Blum, Johannes; Tidwell, Richard R.; Pohlig, Gabriele
2016-01-01
Background Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT. Methods The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent. Findings/Conclusion Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3. PMID:26881924
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Burri, Christian; Yeramian, Patrick D; Allen, James L; Merolle, Ada; Serge, Kazadi Kyanza; Mpanya, Alain; Lutumba, Pascal; Mesu, Victor Kande Betu Ku; Bilenge, Constantin Miaka Mia; Lubaki, Jean-Pierre Fina; Mpoto, Alfred Mpoo; Thompson, Mark; Munungu, Blaise Fungula; Manuel, Francisco; Josenando, Théophilo; Bernhard, Sonja C; Olson, Carol A; Blum, Johannes; Tidwell, Richard R; Pohlig, Gabriele
2016-02-01
Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT. The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent. Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3.
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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.
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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.
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Lariño-Noia, José; de la Iglesia, Daniel; Iglesias-García, Julio; Macías, Manuel; López Martín, Aurelio; Legaz, María Luisa; Vila, Juan; Reyes, Antonio; Abdulkader, Ihab; Domínguez-Muñoz, J Enrique
2018-04-24
the incidence of cystic pancreatic lesions (CPL) in the asymptomatic population is increasing. Achieving a preoperative diagnosis of CPL still remains a challenge. to evaluate the diagnostic accuracy of the cytological diagnosis of CPL from samples obtained by cytology brush versus standard endoscopic ultrasound fine needle aspiration (EUS-FNA). a multicenter, randomized, open-label trial was performed of EUS-cytology brush (EUS-EB) versus EUS-FNA for the cytological diagnosis of CPL. Patients that underwent EUS-FNA with a CPL > 15 mm were included and randomized into two groups: group I, EUS-EB; group II, EUS-FNA. The final diagnosis was based on the histological evaluation of surgical specimens and clinical parameters, imaging and a five year follow-up in non-operated patients. The main outcome was the diagnostic accuracy of both methods. Secondary outcomes were the diagnostic adequacy of specimens and the rate of adverse events. Data were compared using the Chi-squared test. An intention to treat (ITT) and per-protocol (PP) analysis were performed. sixty-five patients were included in the study, 31 in group I and 34 in group II. Three patients initially randomized to group I were changed to group II as it was impossible to obtain a sample using the brush. The mean size of the CPL was 28.2 mm (range 16-60 mm). The diagnostic accuracy of EUS-EB was not superior to EUS-FNA, neither in the ITT nor the PP analysis (44.8% vs 41.1%, p = 0.77 and 38.4% vs 45.9%, p = 0.55). EUS-EB does not improve the diagnostic accuracy of CPL in comparison with EUS-FNA.
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Gupta, Arun; Kumar, Sunil; Dole, Sanjeeva; Deshpande, Shailesh; Deshpande, Vaishali; Singh, Sudha; Sasibhushan, V
2017-01-01
Cyavanaprāśa (CP) is an Ayurvedic immune booster formulation that confers vigor and vitality while delaying the ageing process. Benefits of CP have been studied widely in adult population. Current study assessed beneficial effects of CP on health and immunity related parameters in healthy children. This study was a 6 month long two armed, randomized, open labeled, prospective clinical study. School going healthy children between ages of 5-12 years were randomized to receive orally daily either CP (approx. 6 g) followed by a cup of milk (100 - 200 ml) or cup of milk only twice a day while continuing with their normal/routine diet. Results were analyzed based on number of episodes, severity, duration of illness (infections and allergies) and number of absent days due to illness during the study duration and changes in levels of energy, physical fitness, strength, stamina and quality of life in children which were recorded in subject diary by their parents/Legally Acceptable Representative (LAR). 702 participants were randomized, out of which 627 completed the study (CP n = 313; Control n = 314). Results of immunity (episodes of infections or allergy related conditions) showed more than 2 times protection from immunity related illness in CP Group as compared to the control. CP also showed better percentage improvement in energy levels, physical fitness, strength, stamina and quality of life assessed through KIDSCREEN QOL-27 questionnaires in children. Regular consumption of CP for a period of six months could significantly improve immunity, energy levels, physical fitness, strength, stamina and quality of life in school going healthy children. Clinical Trail Registry of India vide CTRI/2015/02/005574, Dated 24 February 2015.
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Gupta, Arun; Kumar, Sunil; Dole, Sanjeeva; Deshpande, Shailesh; Deshpande, Vaishali; Singh, Sudha; Sasibhushan, V.
2017-01-01
Context: Cyavanaprāśa (CP) is an Ayurvedic immune booster formulation that confers vigor and vitality while delaying the ageing process. Benefits of CP have been studied widely in adult population. Objectives: Current study assessed beneficial effects of CP on health and immunity related parameters in healthy children. Methods: This study was a 6 month long two armed, randomized, open labeled, prospective clinical study. School going healthy children between ages of 5-12 years were randomized to receive orally daily either CP (approx. 6 g) followed by a cup of milk (100 – 200 ml) or cup of milk only twice a day while continuing with their normal/routine diet. Results were analyzed based on number of episodes, severity, duration of illness (infections and allergies) and number of absent days due to illness during the study duration and changes in levels of energy, physical fitness, strength, stamina and quality of life in children which were recorded in subject diary by their parents/Legally Acceptable Representative (LAR). Results: 702 participants were randomized, out of which 627 completed the study (CP n = 313; Control n = 314). Results of immunity (episodes of infections or allergy related conditions) showed more than 2 times protection from immunity related illness in CP Group as compared to the control. CP also showed better percentage improvement in energy levels, physical fitness, strength, stamina and quality of life assessed through KIDSCREEN QOL-27 questionnaires in children. Conclusion: Regular consumption of CP for a period of six months could significantly improve immunity, energy levels, physical fitness, strength, stamina and quality of life in school going healthy children. Study Registration: Clinical Trail Registry of India vide CTRI/2015/02/005574, Dated 24 February 2015. PMID:28867858
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Ducrot, Pauline; Julia, Chantal; Méjean, Caroline; Kesse-Guyot, Emmanuelle; Touvier, Mathilde; Fezeu, Léopold K; Hercberg, Serge; Péneau, Sandrine
2016-05-01
Despite growing evidence supporting the utility of front-of-pack nutrition labels in enabling consumer evaluation of food product healthiness, research on food choices is scarce. This study aims at comparing the impact of front-of-pack nutrition labels on consumers' purchasing intentions. Five-arm, open-label RCT. The study setting was a virtual web-based supermarket, with participants from the French NutriNet-Santé study. The eligibility requirement was grocery shopping involvement. The intervention was to simulate one shopping situation with front-of-pack nutrition labels affixed on food products (December 2014 to March 2015). Participants were randomly assigned to one of five exposure conditions using a central computer system: Guideline Daily Amounts, Multiple Traffic Lights, Five-Color Nutrition Label, Green Tick, or control (no front-of-pack exposure). Given the nature of the intervention, masking of participants was not performed. The primary outcome was the overall nutritional quality of the contents of the shopping cart, estimated using the United Kingdom Food Standards Agency nutrient profiling system. Secondary outcomes included energy and nutrient content of the shopping cart. Impact of the front-of-pack labels was also evaluated across sociodemographic subgroups based on age, educational level, income, and nutrition knowledge. A total of 11,981 participants were included in the analyses (April 2015). The Five-Color Nutrition Label significantly led to the highest overall nutritional quality of the shopping cart, as reflected by lower Food Standards Agency scores (M=8.72; SD=2.75), followed by Multiple Traffic Lights (M=8.97; SD=2.68) and Green Tick (M=8.99; SD=2.71), compared with the control (M=9.34; SD=2.57) (p<0.0001). The Five-Color Nutrition Label was the only front-of-pack format that led to a lower content in lipids, saturated fatty acids, and sodium of the shopping cart (all p<0.05). The impact of the different front-of-pack labels was similar across sociodemographic subgroups. The Five-Color Nutrition Label based on a color-coded and graded scale indicating overall nutritional quality is effective in promoting overall healthier food choices in all population subgroups. This study is registered at www.clinicaltrials.gov NCT02385838. Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.
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Aronson, Solomon; Levy, Jerrold H; Lumb, Philip D; Fontes, Manuel; Wang, Yamei; Crothers, Tracy A; Sulham, Katherine A; Navetta, Marco S
2014-06-01
To examine the impact of blood pressure control on hospital health resource utilization using data from the ECLIPSE trials. Post-hoc analysis of data from 3 prospective, open-label, randomized clinical trials (ECLIPSE trials). Sixty-one medical centers in the United States. Patients 18 years or older undergoing cardiac surgery. Clevidipine was compared with nitroglycerin, sodium nitroprusside, and nicardipine. The ECLIPSE trials included 3 individual randomized open-label studies comparing clevidipine to nitroglycerin, sodium nitroprusside, and nicardipine. Blood pressure control was assessed as the integral of the cumulative area under the curve (AUC) outside specified systolic blood pressure ranges, such that lower AUC represents less variability. This analysis examined surgery duration, time to extubation, as well as intensive care unit (ICU) and hospital length of stay (LOS) in patients with AUC≤10 mmHg×min/h compared to patients with AUC>10 mmHg×min/h. One thousand four hundred ten patients were included for analysis; 736 patients (52%) had an AUC≤10 mmHg×min/h, and 674 (48%) had an AUC>10 mmHg×min/h. The duration of surgery and ICU LOS were similar between groups. Time to extubation and postoperative LOS were both significantly shorter (p = 0.05 and p<0.0001, respectively) in patients with AUC≤10. Multivariate analysis demonstrates AUC≤10 was significantly and independently associated with decreased time to extubation (hazard ratio 1.132, p = 0.0261) and postoperative LOS (hazard ratio 1.221, p = 0.0006). Based on data derived from the ECLIPSE studies, increased perioperative BP variability is associated with delayed time to extubation and increased postoperative LOS. Copyright © 2014 Elsevier Inc. All rights reserved.
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Rosenthal, Richard N.; Ling, Walter; Casadonte, Paul; Vocci, Frank; Bailey, Genie L.; Kampman, Kyle; Patkar, Ashwin; Chavoustie, Steven; Blasey, Christine; Sigmon, Stacey; Beebe, Katherine L.
2015-01-01
Aims To evaluate safety and efficacy of buprenorphine implants (BI) versus placebo implants (PI) for the treatment of opioid dependence. A secondary aim compared BI to open-label sublingual buprenorphine/naloxone tablets (BNX). Design Randomized, double-blind, placebo-controlled trial. Subjects received either 4 buprenorphine implants (80 mg/implant) (n=114), 4 placebo implants (n=54), or open-label BNX (12–16 mg/d) (n=119). Setting 20 addiction treatment centers. Participants Adult outpatients (ages 18 to 65) with DSM-IV-TR opioid dependence. Measurements The primary efficacy endpoint was the percent of urine samples negative for opioids collected from weeks 1 to 24, examined as a cumulative distribution function (CDF). Findings The BI CDF was significantly different from placebo (P<.0001). Mean (95% CI) proportions of urines negative for opioids were: BI: 31.2% (25.3, 37.1) and PI: 13.4% (8.3, 18.6). BI subjects had a higher study completion rate relative to placebo (64% vs. 26%, P<.0001), lower clinician-rated (P<.0001) and patient-rated (P<.0001) withdrawal, lower patient-ratings of craving (P<.0001), and better subjects’ (P=.031) and clinicians’ (P=.022) global ratings of improvement. BI also resulted in significantly lower cocaine use (P=.0016). Minor implant-site reactions were comparable in the buprenorphine (27.2% [31/114]) and placebo groups (25.9% [14/54]). BI were non-inferior to BNX on percent urines negative for opioids [mean (95% CI): 33.5 (27.3, 39.6); CI for the difference of proportions, (−10.7, 6.2)]. Conclusions Compared with placebo, buprenorphine implants result in significantly less frequent opioid use, and are non-inferior to sublingual buprenorphine/naloxone tablets. PMID:23919595
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Rosenthal, Richard N; Ling, Walter; Casadonte, Paul; Vocci, Frank; Bailey, Genie L; Kampman, Kyle; Patkar, Ashwin; Chavoustie, Steven; Blasey, Christine; Sigmon, Stacey; Beebe, Katherine L
2013-12-01
To evaluate the safety and efficacy of buprenorphine implants (BI) versus placebo implants (PI) for the treatment of opioid dependence. A secondary aim compared BI to open-label sublingual buprenorphine/naloxone tablets (BNX). Randomized, double-blind, placebo-controlled trial. Subjects received either four buprenorphine implants (80 mg/implant) (n = 114), four placebo implants (n = 54) or open-label BNX (12-16 mg/day) (n = 119). Twenty addiction treatment centers. Adult out-patients (ages 18-65) with DSM-IV-TR opioid dependence. The primary efficacy end-point was the percentage of urine samples negative for opioids collected from weeks 1 to 24, examined as a cumulative distribution function (CDF). The BI CDF was significantly different from placebo (P < 0.0001). Mean [95% confidence interval (CI)] proportions of urines negative for opioids were: BI = 31.2% (25.3, 37.1) and PI = 13.4% (8.3, 18.6). BI subjects had a higher study completion rate relative to placebo (64 versus 26%, P < 0.0001), lower clinician-rated (P < 0.0001) and patient-rated (P < 0.0001) withdrawal, lower patient-ratings of craving (P < 0.0001) and better subjects' (P = 0.031) and clinicians' (P = 0.022) global ratings of improvement. BI also resulted in significantly lower cocaine use (P = 0.0016). Minor implant-site reactions were comparable in the buprenorphine [27.2% (31 of 114)] and placebo groups [25.9% (14 of 54)]. BI were non-inferior to BNX on percentage of urines negative for opioids [mean (95% CI) = 33.5 (27.3, 39.6); 95% CI for the difference of proportions = (-10.7, 6.2)]. Compared with placebo, buprenorphine implants result in significantly less frequent opioid use and are non-inferior to sublingual buprenorphine/naloxone tablets. © 2013 Society for the Study of Addiction.
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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
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Massicotte, Patricia; Julian, Jim A; Gent, Michael; Shields, Karen; Marzinotto, Velma; Szechtman, Barbara; Andrew, Maureen
2003-01-25
Venous thromboembolic events (VTE) are serious complications in children and for which the standard of care, unfractionated heparin followed by oral anticoagulation (UFH/OA), is problematic. The objective of REVIVE was to compare the efficacy and safety of a low molecular weight heparin (reviparin-sodium) to UFH/OA for the treatment of VTE in children. This multicenter, open-label study, with blinded central outcome adjudication, randomized patients with objectively confirmed VTE to receive either reviparin-sodium or UFH/OA. Dose adjustments were made using nomograms. The efficacy outcome was based on recurrent VTE and death due to VTE during the 3-month treatment period. The safety outcomes were major bleeding, minor bleeding and death. Due to slow patient accrual, REVIVE was closed prematurely. At 3 months, with reviparin-sodium, 2/36 patients (5.6%) had recurrent VTE or death compared to 4/40 patients (10.0%) receiving UFH/OA (odds ratio=0.53; 95% CI=(0.05, 4.00); Fisher's exact test: 2P=0.677). There were 7 major bleeds, 2/36 (5.6%) in the reviparin-sodium group and 5/40 (12.5%) in UFH/OA group (odds ratio=0.41; 95% confidence interval 0.04, 2.76); Fisher's exact test: P=0.435). There were 5 deaths during the study period, 1 (2.8%) in the reviparin-sodium group and 4 (10.0%) in the UFH/OA group. All five deaths were unrelated to VTE but one was due to an intracranial hemorrhage in the UFH/OA group. Although limited by small sample size, REVIVE provides valuable information on the incidence of recurrent VTE, major bleeding and problematic issues associated with therapy of VTE in children.
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de Jong, Jan; Sukbuntherng, Juthamas; Skee, Donna; Murphy, Joe; O'Brien, Susan; Byrd, John C; James, Danelle; Hellemans, Peter; Loury, David J; Jiao, Juhui; Chauhan, Vijay; Mannaert, Erik
2015-05-01
To assess ibrutinib pharmacokinetics under fasted and fed conditions, impact of food-intake timing, and the safety and tolerability. Three studies were analyzed. Study 1 was a randomized, open-label, single-dose, four-way crossover study in 44 healthy participants. Study 2 was a randomized, repeat-dose crossover study in 16 patients with previously treated chronic lymphocytic leukemia (CLL). Ibrutinib dose was 420 mg in both studies. Study 3 was an open-label, sequential study to assess the effect of a standard breakfast on ibrutinib 560 mg in eight healthy participants. Administration of single-dose ibrutinib under fasting conditions (study 1) resulted in approximately 60 % of exposure compared with drug intake either 30 min before, 30 min after (fed), or 2 h after a high-fat meal. Similar food effect was observed (study 3) when ibrutinib was given 30 min before meal. In CLL patients (study 2), the C max and AUC under fasting conditions were 43 and 61 %, respectively, relative to fed conditions. When administered once-daily in uncontrolled food-intake conditions (≥30 min before or 2 h after), exposures were slightly (≈30 %) lower than in fed condition. When corrected for repeated dosing, pharmacokinetic parameters in healthy participants and patients were comparable. Ibrutinib was generally well tolerated in all settings studied. Ibrutinib administered in fasted condition reduces exposure to approximately 60 % as compared with dosing in proximity to food-intake, regardless of timing/type of meal. Because repeated drug intake in fasted condition is unlikely, no food restrictions may be needed to administer ibrutinib.
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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.
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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
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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
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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.
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Cash, Brooks D; Pimentel, Mark; Rao, Satish S C; Weinstock, Leonard; Chang, Lin; Heimanson, Zeev; Lembo, Anthony
2017-09-01
Diarrhea-predominant irritable bowel syndrome (IBS-D) impairs patient quality of life (QOL). Rifaximin is an oral, nonsystemic antibiotic indicated for IBS-D. The objective of this secondary analysis was to evaluate rifaximin retreatment on IBS-related QOL in patients with IBS-D. Patients received open-label rifaximin 550 mg three times daily for 2 weeks. Clinical responders [simultaneously meeting weekly response criteria for abdominal pain (⩾30% improvement from baseline in mean weekly pain score) and stool consistency (⩾50% decrease from baseline in number of days/week with Bristol Stool Scale (BSS) type 6 or 7 stools) during ⩾2 of first 4 weeks posttreatment] who relapsed during an up to 18-week treatment-free observation phase were randomly assigned to receive two 2-week courses of double-blind rifaximin or placebo, separated by 10 weeks. A validated 34-item IBS-QOL questionnaire examined patient responses in 8 domains. The 2579 patients receiving open-label rifaximin experienced a mean improvement from baseline in IBS-QOL overall score of 54.9%. Responders to open-label rifaximin ( n = 1074 of 2438 evaluable; 44.1%) had significantly greater improvement from baseline in IBS-QOL overall and all eight subdomain scores, including dysphoria, food avoidance, interference with activity, body image, and sexual function versus nonresponders at 4 weeks posttreatment ( n = 1364; p < 0.001 for all comparisons). A significantly greater percentage of responders to open-label rifaximin achieved the minimally clinically important difference (MCID; ⩾14-point improvement from baseline) in the overall IBS-QOL score versus nonresponders [ n = 561 (52.2%) versus n = 287 (21.0%); p < 0.0001]. Among 636 patients with IBS-D relapse, the MCID in the overall IBS-QOL score was achieved by a significantly greater percentage of patients receiving double-blind rifaximin versus placebo (38.6% versus 29.6%, respectively; p = 0.009). Open-label and blinded retreatment with a short course (2 weeks) of rifaximin improved IBS-QOL in patients with IBS-D [ClinicalTrials.gov identifier: NCT01543178].
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Presenting numeric information with percentages and descriptive risk labels: A randomized trial
Sinayev, Aleksandr; Peters, Ellen; Tusler, Martin; Fraenkel, Liana
2015-01-01
Background Previous research demonstrated that providing (vs. not providing) numeric information about medications’ adverse effects (AEs) increased comprehension and willingness to use medication, but left open the question about which numeric format is best. Objective To determine which of four tested formats (percentage, frequency, percentage+risk label, frequency+risk label) maximizes comprehension and willingness to use medication across age and numeracy levels. Design In a cross-sectional internet survey (N=368; American Life Panel, 5/15/08–6/18/08), respondents were presented with a hypothetical prescription medication for high cholesterol. AE likelihoods were described using one of four tested formats. Main outcome measures were risk comprehension (ability to identify AE likelihood from a table) and willingness to use the medication (7-point scale; not likely=0, very likely=6). Results The percentage+risk label format resulted in the highest comprehension and willingness to use the medication compared to the other three formats (mean comprehension in percentage + risk label format=95% vs mean across the other three formats = 81%; mean willingness= 3.3 vs 2.95, respectively). Comprehension differences between percentage and frequency formats were smaller among the less numerate. Willingness to use medication depended less on age and numeracy when labels were used. Limitations Generalizability is limited by use of a sample that was older, more educated, and better off financially than national averages. Conclusions Providing numeric AE-likelihood information in a percentage format with risk labels is likely to increase risk comprehension and willingness to use a medication compared to other numeric formats. PMID:25952743
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Presenting Numeric Information with Percentages and Descriptive Risk Labels: A Randomized Trial.
Sinayev, Aleksandr; Peters, Ellen; Tusler, Martin; Fraenkel, Liana
2015-11-01
Previous research demonstrated that providing (v. not providing) numeric information about the adverse effects (AEs) of medications increased comprehension and willingness to use medication but left open the question about which numeric format is best. The objective was to determine which of 4 tested formats (percentage, frequency, percentage + risk label, frequency + risk label) maximizes comprehension and willingness to use medication across age and numeracy levels. In a cross-sectional internet survey (N = 368; American Life Panel, 15 May 2008 to 18 June 2008), respondents were presented with a hypothetical prescription medication for high cholesterol. AE likelihoods were described using 1 of 4 tested formats. Main outcome measures were risk comprehension (ability to identify AE likelihood from a table) and willingness to use the medication (7-point scale; not likely = 0, very likely = 6). The percentage + risk label format resulted in the highest comprehension and willingness to use the medication compared with the other 3 formats (mean comprehension in percentage + risk label format = 95% v. mean across the other 3 formats = 81%; mean willingness = 3.3 v. 2.95, respectively). Comprehension differences between percentage and frequency formats were smaller among the less numerate. Willingness to use medication depended less on age and numeracy when labels were used. Generalizability is limited by the use of a sample that was older, more educated, and better off financially than national averages. Providing numeric AE-likelihood information in a percentage format with risk labels is likely to increase risk comprehension and willingness to use a medication compared with other numeric formats. © The Author(s) 2015.
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Zhu, Qi; Burzykowski, Tomasz
2011-03-01
To reduce the influence of the between-spectra variability on the results of peptide quantification, one can consider the (18)O-labeling approach. Ideally, with such labeling technique, a mass shift of 4 Da of the isotopic distributions of peptides from the labeled sample is induced, which allows one to distinguish the two samples and to quantify the relative abundance of the peptides. It is worth noting, however, that the presence of small quantities of (16)O and (17)O atoms during the labeling step can cause incomplete labeling. In practice, ignoring incomplete labeling may result in the biased estimation of the relative abundance of the peptide in the compared samples. A Markov model was developed to address this issue (Zhu, Valkenborg, Burzykowski. J. Proteome Res. 9, 2669-2677, 2010). The model assumed that the peak intensities were normally distributed with heteroscedasticity using a power-of-the-mean variance funtion. Such a dependence has been observed in practice. Alternatively, we formulate the model within the Bayesian framework. This opens the possibility to further extend the model by the inclusion of random effects that can be used to capture the biological/technical variability of the peptide abundance. The operational characteristics of the model were investigated by applications to real-life mass-spectrometry data sets and a simulation study. © American Society for Mass Spectrometry, 2011
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Gottwald-Hostalek, Ulrike; Uhl, Wolfgang; Wolna, Peter; Kahaly, George J
2017-02-01
Small levothyroxine (L-T4) dose changes can lead to significant clinical effects. To ensure thyroid hormone levels are safely maintained, authorities are increasingly adopting stricter potency specifications for L-T4, the most stringent of these being 95-105% of the labeled dose over the whole shelf-life. Levothyroxine sodium (Euthyrox, Eutirox, Lévothyrox ) has been reformulated, and two studies performed, to ensure bioequivalence to the currently marketed formulation and dosage form proportionality of the new formulation. The bioequivalence study was an open-label, randomized, single-dose, two-period, two-sequence crossover comparing the highest dosage strengths of the currently marketed and the new L-T4 formulation at a total dose of 600 μg. The dosage form proportionality study was an open-label, randomized, three-period, six-sequence crossover, comparing 50 μg, 100 μg, and 200 μg L-T4 tablets, at a total dose of 600 μg. Blood samples were taken at predefined time intervals. Primary outcomes were area under the curve (AUC) and maximum concentration (C max ) of thyroxine (T4) in plasma. In the bioequivalence study, comparing the T4 profiles for the new and current formulation of L-T4, the geometric least square mean ratio of the baseline-adjusted AUC 0-72,adj was 99.3% (90% confidence interval [CI]: 95.6-103.2) and the C max,adj was 101.7% (90% CI: 98.8-104.6). Bioequivalence was established if the 90% CI lay within the predefined 0.9-1.11 limits. In the dosage form proportionality study, pairwise comparisons ranged from 99.3% to 104.8%, and all 95% CIs were within the predefined CI range (0.8-1.25): the three dose strengths were dosage form proportional. The new formulation of L-T4 meets the most stringent potency specification guidelines, and has been demonstrated to be bioequivalent to the current formulation and to show dosage form proportionality. The new formulation will enable patients to receive a dose fine tuned to their medical needs, contributing to improved safety in the use of L-T4.
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Pharmacoeconomic evidence of bosentan for pulmonary arterial hypertension.
Strange, Geoff; Keogh, Anne; Dalton, Brad; Gabbay, Eli
2011-06-01
In this article, we review randomized controlled trials, open-label trials and pharmacoeconomic models of bosentan for the management of patients with pulmonary arterial hypertension. Bosentan consistently improves WHO functional class and quality of life, slows clinical worsening and is associated with improved survival compared with historical treatment. Although head-to-head trials are scarce, data directly comparing bosentan with sildenafil indicate no clinically significant differences between treatments as measured by the 6-min walk distance alone. Compared with historical care, bosentan treatment, over a 15-30-year period, increases the number of quality-adjusted life years (3.49 years). Economic modeling suggests that the cost-effectiveness of bosentan is similar to that of ambrisentan (US$43,725-57,778 per quality-adjusted life year), not as cost effective as sildenafil (at 20 mg three-times daily) and more cost effective than iloprost. More randomized controlled trials of longer duration are required to confirm the results from these economic models.
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Dhakar, Ashok K; Dogra, Sunil; Vinay, Keshavamurthy; Sarangal, Rishu; Kanwar, Amrinder J; Singh, Mini P
2016-01-01
Initial reports of immunotherapy using intralesional Mycobacterium w (Mw) vaccine have documented its useful role in treatment of genital and extragenital warts. To compare the efficacy and safety of intralesional Mw vaccine versus cryotherapy in the treatment of refractory extragenital warts. This was a prospective, randomized, comparative study of 66 patients. The outcome was assessed in terms of complete clearance of warts and change in Dermatology Life Quality Index (DLQI) score. Complete clearance of treated warts was seen in 66.7% (20/30) and 65.5% (19/29) of patients in the Mw and cryotherapy groups, respectively (P = .769). Clearance of distant warts was significantly (P = .004) high in the Mw group. Improvement in DLQI was greater in the Mw group. Both treatment modalities were well tolerated, and no major side effects occurred. Mw vaccine and cryotherapy are equally efficacious in treatment of refractory extragenital warts. Mw vaccine has an added advantage of clearance of distant warts. © The Author(s) 2015.
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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.
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Beelen, D W; Elmaagacli, A; Müller, K D; Hirche, H; Schaefer, U W
1999-05-15
In a single-center open-label prospective study, a total of 134 marrow transplant recipients with hematologic malignancies were randomly assigned to a bacterial decontamination medication using metronidazole and ciprofloxacin (n = 68) or ciprofloxacin alone (n = 66) during 5 weeks posttransplant. The development of grades II to IV acute graft-versus-host disease (GVHD) was defined as the primary study endpoint. According to the intention-to-treat, 17 patients (25%) randomized to the combined decontamination medication and 33 patients (50%) randomized to ciprofloxacin alone developed grades II to IV GVHD (P <.002). The higher frequency of grades II to IV acute GVHD in patients randomized to ciprofloxacin alone resulted from a more than twofold increased number of patients developing liver or intestinal involvement with acute GVHD compared with patients randomized to the combined decontamination medication (P <.003). The influence of the study medication on grades II to IV acute GVHD was significant only in recipients of transplants from genotypically HLA-identical sibling donors (n = 80), whereas in recipients of transplants from donors other than HLA-identical siblings (n = 54), grades II to IV acute GVHD frequencies between the study arms were not significantly different. The combined decontamination was associated with a significant reduction of culture growth of intestinal anaerobic bacteria during 5 weeks posttransplant (P <. 00001). In addition, the number of cultures with growth of anaerobic bacteria (P <.005) as well as the median concentrations of anaerobic bacteria in the posttransplant period (P <.0001) were higher in patients contracting grades II to IV acute GVHD. Neither chronic GVHD nor overall survival was significantly different between the two study arms. In patients with HLA-identical sibling donors who were treated in early disease stages, the 5-year survival estimate was slightly, but not significant, higher after the combined decontamination medication (60% +/- 11%) compared with ciprofloxacin alone (46% +/- 9%). In conclusion, the present study provides evidence that antimicrobial chemotherapy targeted to intestinal anaerobic bacteria in marrow transplant recipients significantly reduces the severity of acute GVHD and supports the theory that the intestinal anaerobic bacterial microflora plays a role in the pathogenesis of acute GVHD after human marrow transplantation.
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Gnessi, Lucio; Bacarea, Vladimir; Marusteri, Marius; Piqué, Núria
2015-10-30
There is a strong rationale for the use of agents with film-forming protective properties, like xyloglucan, for the treatment of acute diarrhea. However, few data from clinical trials are available. A randomized, controlled, open-label, parallel group, multicentre, clinical trial was performed to evaluate the efficacy and safety of xyloglucan, in comparison with diosmectite and Saccharomyces in adult patients with acute diarrhea due to different causes. Patients were randomized to receive a 3-day treatment. Symptoms (stools type, nausea, vomiting, abdominal pain and flatulence) were assessed by a self-administered ad-hoc questionnaire 1, 3, 6, 12, 24, 48 and 72 h following the first dose administration. Adverse events were also recorded. A total of 150 patients (69.3 % women and 30.7 % men, mean age 47.3 ± 14.7 years) were included (n = 50 in each group). A faster onset of action was observed in the xyloglucan group compared with the diosmectite and S. bouliardii groups. At 6 h xyloglucan produced a statistically significant higher decrease in the mean number of type 6 and 7 stools compared with diosmectite (p = 0.031). Xyloglucan was the most efficient treatment in reducing the percentage of patients with nausea throughout the study period, particularly during the first hours (from 26 % at baseline to 4 % after 6 and 12 h). An important improvement of vomiting was observed in all three treatment groups. Xyloglucan was more effective than diosmectite and S. bouliardii in reducing abdominal pain, with a constant improvement observed throughout the study. The clinical evolution of flatulence followed similar patterns in the three groups, with continuous improvement of the symptom. All treatments were well tolerated, without reported adverse events. Xyloglucan is a fast, efficacious and safe option for the treatment of acute diarrhea. EudraCT number 2014-001814-24 (date: 2014-04-28) ISRCTN number: 90311828.
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High-dose levofloxacin in community-acquired pneumonia: a randomized, open-label study.
Lee, Jin Hwa; Kim, Seo Woo; Kim, Ji Hye; Ryu, Yon Ju; Chang, Jung Hyun
2012-09-01
The conventional treatment for community-acquired pneumonia (CAP) involves combination therapy consisting of a β-lactam penicillin or a cephalosporin with a macrolide. Alternatively, high-dose levofloxacin treatment has been used as single-agent therapy for treating CAP, covering atypical pathogens. This study compared the clinical efficacy and safety of high-dose levofloxacin with combined ceftriaxone and azithromycin for the treatment of CAP. This phase IV, prospective, randomized, open-label trial enrolled patients admitted to a tertiary referral hospital for CAP treatment from 2010 to 2011. Hospital admission was decided based on clinical judgement and the pneumonia severity index. Forty subjects were enrolled and assigned to two treatment arms using a random numbers table. The 20 subjects in the experimental group were given levofloxacin 750 mg intravenously once daily, followed by the same dose of oral levofloxacin at discharge when clinically improved and the 20 subjects in the control group were given ceftriaxone 2.0 g intravenously once daily plus oral azithromycin 500 mg for 3 consecutive days, followed by oral cefpodoxime 200 mg per day at discharge after clinical improvement. The primary outcome was the clinical success rate. Secondary outcomes were the microbiological success rate and adverse events during the study. Of the 40 subjects enrolled, 36 completed the study: 17 in the experimental group and 19 in the control group. The groups did not differ in terms of demographic factors or clinical findings at baseline. The clinical success rate (cured + improved) was 94% in the experimental (levofloxacin) group and 84% in the control group (p > 0.05). The microbiological success rate and overall adverse events were also similar in both groups. Single-agent, high-dose levofloxacin treatment exhibited excellent clinical and microbiological efficacy with a safety profile comparable to that of ceftriaxone plus azithromycin therapy. Large-scale clinical trials are required to verify these results. WHO International Clinical Trials Registry: KCT0000374; Daiichi-Sankyo Korea study code: T11-13-V1.
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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.
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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.
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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
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Kim, Soo Jin; Lee, Young-Ki; Oh, Jieun; Cho, AJin; Noh, Jung Woo
2017-09-15
The association between the dialysate calcium level and coronary artery calcification (CAC) has not yet been evaluated in hemodialysis patients. The objective of this study was to determine whether lowering the dialysate calcium levels would decrease the progression of coronary artery calcification (CAC) compared to using standard calcium dialysate. We conducted an open-label randomized trial with parallel groups. The patients were randomly assigned to either 12-month treatment with low calcium dialysate (LCD; 1.25mmol/L, n=36) or standard calcium dialysate (SCD; 1.5mmol/L, n=40). The primary outcome was the change in the CAC scores assessed by 64-slice multidetector computed tomography after 12months. During the treatment period, CAC scores increased in both groups, especially significant in LCD group (402.5±776.8, 580.5±1011.9, P=0.004). When we defined progressors as patients at second and third tertiles of CAC changes, progressor group had a higher proportion of LCD-treated patients than SCD-treated patients (P=0.0229). In multivariate analysis, LCD treatment is a significant risk factor for increase in CAC scores (odds ratio=5.720, 95% CI: 1.219-26.843, P=0.027). Use of LCD may accelerate the progression of CAC in patients with chronic hemodialysis over a 12-month period. Clinical Research Information Service [Internet]; Osong (Chungcheongbuk-do): Korea Centers for Disease Control and Prevention, Ministry of Health and Welfare (Republic of Korea), 2010: KCT0000942. Available from: https://cris.nih.go.kr/cris/search/search_result_st01_kren.jsp?seq=3572&sLeft=2&type=my. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.
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Yang, Guang; Li, Chunlin; Gong, Yanping; Li, Jian; Cheng, Xiaoling; Tian, Hui
2013-06-01
By delaying absorption of carbohydrates, acarbose can reduce preprandial hyperglycemia and delay the emergence of postprandial hyperglycemia. To evaluate whether acarbose can shorten the desirable time interval between insulin injection and meals, 60 elderly (≥60 years) patients with unsatisfactorily controlled type 2 diabetes mellitus despite insulin use were enrolled in a randomized, open-label study of 16 weeks' duration. Two groups (n=20 each) were randomized to receive isophane protamine biosynthetic human insulin 70/30 injections twice daily 30 min before meals plus acarbose 50 mg once daily (Group A) or three times daily (Group B) before meals, whereas the third group (n=20) received isophane protamine biosynthetic human insulin 70/30 injections twice daily immediately before meals plus acarbose 50 mg three times daily before meals (Group C). The required insulin dosage at study end was significantly less in Groups B and C than in Group A. Both continuous glucose monitoring data and the patients' self-monitoring data indicated that blood glucose variability parameters were significantly improved in Groups B and C in comparison with Group A, but there were no significant differences between Groups B and C. The incidence of hypoglycemia was low in all three groups. The absence of a significant difference in glucose variability between Groups B and C suggests that the addition of acarbose permitted adjustment of the insulin administration time from 30 min before meals to immediately before meals-which may be more convenient for patients-without affecting glycemic control.
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Borius, Pierre-Yves; Garnier, Stéphanie Ranque; Baumstarck, Karine; Castinetti, Frédéric; Donnet, Anne; Guedj, Eric; Cornu, Philippe; Blond, Serge; Salas, Sébastien; Régis, Jean
2017-08-02
Hypophysectomy performed by craniotomy or percutaneous techniques leads to complete pain relief in more than 70% to 80% of cases for opioid refractory cancer pain. Radiosurgery could be an interesting alternative approach to reduce complications. To assess the analgesic efficacy compared with standard of care is the primary goal. The secondary objectives are to assess ophthalmic and endocrine tolerance, drug consumption, quality of life, and mechanisms of analgesic action. The trial is multicenter, randomized, prospective, and open-label with 2 parallel groups. This concerns patients in palliative care suffering from nociceptive or mixed cancer pain, refractory to standard opioid therapy. Participants will be randomly assigned to the control group receiving standards of care for pain according to recommendations, or to the experimental group receiving a pituitary GammaKnife (Elekta, Stockholm, Sweden) radiosurgery (160 Gy delivered in pituitary gland) associated with standards of care. Evaluation assessments will be taken at baseline, day0, day4, day7, day14, day28, day45, month3, and month6. We could expect pain improvement in 70% to 90% of cases at day4. In addition we will assess the safety of pituitary radiosurgery in a vulnerable population. The secondary endpoints could show decay of opioid consumption, good patient satisfaction, and improvement of the quality of life. The design of this study is potentially the most appropriate to demonstrate the efficacy and safety of radiosurgery for this new indication. New recommendations could be obtained in order to improve pain relief and quality of life. Copyright © 2017 by the Congress of Neurological Surgeons
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Kosalaraksa, Pope; Mehlsen, Jesper; Vesikari, Timo; Forstén, Aino; Helm, Klaus; Van Damme, Pierre; Joura, Elmar A; Ciprero, Karen; Maansson, Roger; Luxembourg, Alain; Sobanjo-ter Meulen, Ajoke
2015-06-01
A 9-valent human papillomavirus (9vHPV) vaccine has recently been reported to be safe and highly efficacious against infection and disease related to HPV6/11/16/18/31/33/45/52/58. We evaluated the immunogenicity and safety of the 9vHPV vaccine administered concomitantly with REPEVAX (diphtheria, tetanus, acellular pertussis and inactivated poliomyelitis vaccine). This open-label, randomized, multicenter study enrolled 1054 males and females ages 11-15 years. Subjects were randomly assigned to each group in a 1:1 ratio. Subjects received a 0.5 mL dose of 9vHPV vaccine intramuscularly at day 1, months 2 and 6 and a 0.5 mL dose of REPEVAX either on day 1 (concomitant vaccination group; n = 526) or at month 1 (nonconcomitant vaccination group, n = 528). Serologic responses for each vaccine component were tested by 1-sided tests of noninferiority between groups. Systemic and injection-site adverse experiences (AEs) and serious AEs were monitored. Noninferiority of anti-HPV geometric mean titers and seroconversion rates for all 9vHPV antigens were demonstrated for the concomitant group compared with the nonconcomitant group. Seroconversion rates for the 9vHPV vaccine types were ≥99.8% in both groups at month 7. For REPEVAX, noninferiority of immune response was established for diphtheria, tetanus, all polio and pertussis antigens for both groups. There were no vaccine-related serious AEs. Overall, concomitant administration of 9vHPV vaccine and REPEVAX was generally well tolerated and did not interfere with the immune response to either vaccine. This strategy would minimize the number of visits required to deliver each vaccine individually.
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Huang, Charles Lung-Cheng; Hwang, Tzung-Jeng; Chen, Yi-Hsing; Huang, Guan-Hua; Hsieh, Ming H; Chen, Hsiu-Hsi; Hwu, Hai-Gwo
2015-05-01
To compare the efficacy and safety profile between intramuscular (IM) olanzapine and IM haloperidol plus IM lorazepam in acute schizophrenic patients with moderate to severe agitation. This was a prospective, randomized, open-label study. Acutely agitated patients with schizophrenia or schizoaffective disorder (n = 67) were randomized to receive 10 mg IM olanzapine (n = 37) or 5 mg IM haloperidol plus 2 mg IM lorazepam (n = 30). Agitation was measured with Positive and Negative Syndrome Scale Excited Component (PANSS-EC) and Agitation-Calmness Evaluation Scale (ACES) during the first 2 hours and at 24 hours after the first injection. Safety was assessed using the Simpson-Angus Scale and Barnes Akathisia Rating Scale and by recording adverse events at 24 hours following the first injection. The Clinical Global Impression-Severity scale was also rated. The PANSS-EC scores decreased significantly at 2 hours after the first injection in both groups (olanzapine: -10.2, p < 0.001; haloperidol + lorazepam: -9.9, p < 0.001). Haloperidol plus lorazepam was not inferior to olanzapine in reducing agitation at 2 hours. There were no significant differences in PANSS-EC or ACES scores between the two groups within 2 hours following the first injection. The frequencies of adverse events and changes in Clinical Global Impression-Severity, Simpson-Angus Scale, and Barnes Akathisia Rating Scale scores from baseline to 24 hours showed no significant differences between the groups. The findings suggest that IM haloperidol (5 mg) plus lorazepam (2 mg) is not inferior to IM olanzapine (10 mg) in the treatment of acute schizophrenic patients with moderate to severe agitation (ClinialTrials.gov identifier number NCT00797277). Copyright © 2015. Published by Elsevier B.V.
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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.
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Oh, Mi Sun; Yu, Kyung-Ho; Hong, Keun-Sik; Kang, Dong-Wha; Park, Jong-Moo; Bae, Hee-Joon; Koo, Jaseong; Lee, Juneyoung; Lee, Byung-Chul
2015-07-01
To assess the efficacy and safety of modest blood pressure (BP) reduction with valsartan within 48 h after symptom onset in patients with acute ischemic stroke and high BP. This was a multicenter, prospective, randomized, open-label, blinded-end-point trial. A total of 393 subjects were recruited at 28 centers and then randomly assigned in a 1:1 ratio to receive valsartan (n = 195) or no treatment (n = 198) for seven-days after presentation. The primary outcome was death or dependency, defined as a score of 3-6 on the modified Rankin Scale (mRS) at 90 days after symptom onset. Early neurological deterioration (END) within seven-days and 90-day major vascular events were also assessed. There were 372 patients who completed the 90-day follow-up. The valsartan group had 46 of 187 patients (24·6%) with a 90-day mRS 3-6, compared with 42 of 185 patients (22·6%) in the control group (odds ratio [OR], 1·11; 95% confidence interval [CI], 0·69-1·79; P = 0·667). The rate of major vascular events did not differ between groups (OR, 1·41; 95% CI, 0·44-4·49; P = 0·771). There was a significant increase of END in the valsartan group (OR, 2·43; 95% CI, 1·25-4·73; P = 0·008). Early reduction of BP with valsartan did not reduce death or dependency and major vascular events at 90 days, but increased the risk of END. © 2015 World Stroke Organization.
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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.
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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.
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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.
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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.
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Chen, Chun Lin; Desai-Krieger, Daksha; Ortiz, Stephan; Kerolous, Majid; Wright, Harold M.; Ghahramani, Parviz
2015-01-01
Combining different classes of antihypertensives is more effective for reducing blood pressure (BP) than increasing the dose of monotherapies. The aims of this phase I study were to investigate pharmacokinetic and pharmacodynamic interactions between nebivolol, a vasodilatory β1-selective blocker, and valsartan, an angiotensin II receptor blocker, and to assess safety and tolerability of the combination. This was a single-center, randomized, open-label, multiple-dose, 3-way crossover trial in 30 healthy adults aged 18–45 years. Participants were randomized into 1 of 6 treatment sequences (1:1:1:1:1:1) consisting of three 7-day treatment periods followed by a 7-day washout. Once-daily oral treatments comprised nebivolol (20 mg), valsartan (320 mg), and nebivolol–valsartan combination (20/320 mg). Outcomes included AUC0-τ,ss, Cmax,ss, Tmax,ss, changes in BP, pulse rate, plasma angiotensin II, plasma renin activity, 24-hour urinary aldosterone, and adverse events. Steady-state pharmacokinetic interactions were observed but deemed not clinically significant. Systolic and diastolic BP reduction was significantly greater with nebivolol–valsartan combination than with either monotherapy. The mean pulse rate associated with nebivolol and nebivolol–valsartan treatments was consistently lower than that associated with valsartan monotherapy. A sharp increase in mean day 7 plasma renin activity and plasma angiotensin II that occurred in valsartan-treated participants was significantly attenuated with concomitant nebivolol administration. Mean 24-hour urine aldosterone at day 7 was substantially decreased after combined treatment, as compared with either monotherapy. All treatments were safe and well tolerated. In conclusion, nebivolol and valsartan coadministration led to greater reductions in BP compared with either monotherapy; nebivolol and valsartan lower BP through complementary mechanisms. PMID:25853236
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Chen, Chun Lin; Desai-Krieger, Daksha; Ortiz, Stephan; Kerolous, Majid; Wright, Harold M; Ghahramani, Parviz
2015-01-01
Combining different classes of antihypertensives is more effective for reducing blood pressure (BP) than increasing the dose of monotherapies. The aims of this phase I study were to investigate pharmacokinetic and pharmacodynamic interactions between nebivolol, a vasodilatory β1-selective blocker, and valsartan, an angiotensin II receptor blocker, and to assess safety and tolerability of the combination. This was a single-center, randomized, open-label, multiple-dose, 3-way crossover trial in 30 healthy adults aged 18-45 years. Participants were randomized into 1 of 6 treatment sequences (1:1:1:1:1:1) consisting of three 7-day treatment periods followed by a 7-day washout. Once-daily oral treatments comprised nebivolol (20 mg), valsartan (320 mg), and nebivolol-valsartan combination (20/320 mg). Outcomes included AUC0-τ,ss, Cmax,ss, Tmax,ss, changes in BP, pulse rate, plasma angiotensin II, plasma renin activity, 24-hour urinary aldosterone, and adverse events. Steady-state pharmacokinetic interactions were observed but deemed not clinically significant. Systolic and diastolic BP reduction was significantly greater with nebivolol-valsartan combination than with either monotherapy. The mean pulse rate associated with nebivolol and nebivolol-valsartan treatments was consistently lower than that associated with valsartan monotherapy. A sharp increase in mean day 7 plasma renin activity and plasma angiotensin II that occurred in valsartan-treated participants was significantly attenuated with concomitant nebivolol administration. Mean 24-hour urine aldosterone at day 7 was substantially decreased after combined treatment, as compared with either monotherapy. All treatments were safe and well tolerated. In conclusion, nebivolol and valsartan coadministration led to greater reductions in BP compared with either monotherapy; nebivolol and valsartan lower BP through complementary mechanisms.
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Kadowaki, Takashi; Muto, Satsuki; Ouchi, Yoshiumi; Shimazaki, Ryutaro; Seino, Yutaka
2017-12-01
We examined the efficacy and safety of saxagliptin as an add-on to insulin in Japanese patients with type 2 diabetes mellitus. We randomized 240 patients with type 2 diabetes mellitus on insulin monotherapy to 5-mg saxagliptin or placebo as add-on therapy for a 16-week, double-blind period. All patients received 5-mg saxagliptin and insulin for an additional 36 weeks (open-label extension). Change in hemoglobin A1c (HbA1c) at Week 16 was the main endpoint. At Week 16, the adjusted change in HbA1c from baseline increased by 0.51% with placebo and decreased by 0.40% with saxagliptin (difference -0.92% [95% confidence interval -1.07%, -0.76%; p < 0.001]). In patients receiving saxagliptin, reductions in HbA1c at Week 16 were maintained to Week 52, while switching from placebo to saxagliptin resulted in a similar reduction in HbA1c. The incidence of hypoglycemia was not markedly increased with saxagliptin versus placebo in the double-blind period and did not increase substantially during the open-label extension period. The efficacy and safety of saxagliptin was similar between the elderly and non-elderly patient groups. Adding saxagliptin to ongoing insulin therapy improved glycemic control and was well tolerated in Japanese patients with type 2 diabetes.
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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.
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Doody, Kevin J; Broome, E Jason; Doody, Kathleen M
2016-04-01
The purpose of this study is to to compare the efficacy of intravaginal culture (IVC) of embryos in INVOcell™ (INVO Bioscience, MA, USA) to traditional in vitro fertilization (IVF) incubators in a laboratory setting using a mild pre-determined stimulation regimen based solely on anti-mullerian hormone (AMH) and body weight with minimal ultrasound monitoring. The primary endpoint examined was total quality blastocysts expressed as a percentage of total oocytes placed in incubation. Secondary endpoints included percentage of quality blastocysts transferred, pregnancy, and live birth rates. In this prospective randomized open-label controlled single-center study, 40 women aged <38 years of age with a body mass index (BMI) of <36 and an AMH of 1-3 ng/mL were randomized prior to trigger to receive either IVC or IVF. Controlled ovarian stimulation was administered with human menopausal gonadotropin (hMG) in a fixed gonadotropin-releasing hormone (GnRH) agonist cycle based solely on AMH and body weight. A single ultrasound-monitoring visit was performed on the 10th day of stimulation. One or two embryos were transferred following 5 days of culture. IVF produced a greater percentage of total quality embryos as compared to IVC (50.6 vs. 30.7 %, p = 0.0007, respectively). There was no significant difference between in IVF and IVC in the percentage of quality blastocysts transferred (97.5 vs. 84.9 %, p = 0.09) or live birth rate (60 % IVF, 55 % IVC). IVF was shown to be superior to IVC in creating quality blastocysts. However, both IVF and IVC produced identical blastocysts for transfer resulting in similar live birth rates. IVC using INVOcell™ is effective and may broaden access to fertility care in selected patient populations by ameliorating the need for a traditional IVF laboratory setting. Further studies will help elucidate the potential physiological, psychological, geographic, and financial impact of IVC on the delivery of fertility care.
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Role of ranitidine in negative symptoms of schizophrenia--an open label study.
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.
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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.
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Adenis, A.; Blay, J.-Y.; Bui-Nguyen, B.; Bouché, O.; Bertucci, F.; Isambert, N.; Bompas, E.; Chaigneau, L.; Domont, J.; Ray-Coquard, I.; Blésius, A.; Van Tine, B. A.; Bulusu, V. R.; Dubreuil, P.; Mansfield, C. D.; Acin, Y.; Moussy, A.; Hermine, O.; Le Cesne, A.
2014-01-01
Background Masitinib is a highly selective tyrosine kinase inhibitor with activity against the main oncogenic drivers of gastrointestinal stromal tumor (GIST). Masitinib was evaluated in patients with advanced GIST after imatinib failure or intolerance. Patients and methods Prospective, multicenter, randomized, open-label trial. Patients with inoperable, advanced imatinib-resistant GIST were randomized (1 : 1) to receive masitinib (12 mg/kg/day) or sunitinib (50 mg/day 4-weeks-on/2-weeks-off) until progression, intolerance, or refusal. Primary efficacy analysis was noncomparative, testing whether masitinib attained a median progression-free survival (PFS) (blind centrally reviewed RECIST) threshold of >3 months according to the lower bound of the 90% unilateral confidence interval (CI). Secondary analyses on overall survival (OS) and PFS were comparative with results presented according to a two-sided 95% CI. Results Forty-four patients were randomized to receive masitinib (n = 23) or sunitinib (n = 21). Median follow-up was 14 months. Patients receiving masitinib experienced less toxicity than those receiving sunitinib, with significantly lower occurrence of severe adverse events (52% versus 91%, respectively, P = 0.008). Median PFS (central RECIST) for the noncomparative primary analysis in the masitinib treatment arm was 3.71 months (90% CI 3.65). Secondary analyses showed that median OS was significantly longer for patients receiving masitinib followed by post-progression addition of sunitinib when compared against patients treated directly with sunitinib in second-line [hazard ratio (HR) = 0.27, 95% CI 0.09–0.85, P = 0.016]. This improvement was sustainable as evidenced by 26-month follow-up OS data (HR = 0.40, 95% CI 0.16–0.96, P = 0.033); an additional 12.4 months survival advantage being reported for the masitinib treatment arm. Risk of progression while under treatment with masitinib was in the same range as for sunitinib (HR = 1.1, 95% CI 0.6–2.2, P = 0.833). Conclusions Primary efficacy analysis ensured the masitinib treatment arm could satisfy a prespecified PFS threshold. Secondary efficacy analysis showed that masitinib followed by the standard of care generated a statistically significant survival benefit over standard of care. Encouraging median OS and safety data from this well-controlled and appropriately designed randomized trial indicate a positive benefit–risk ratio. Further development of masitinib in imatinib-resistant/intolerant patients with advanced GIST is warranted. PMID:25122671
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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.
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Psychiatric adverse events during treatment with brodalumab: Analysis of psoriasis clinical trials.
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.
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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
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Junge, Wolfgang; Heger-Mahn, Doris; Trummer, Dietmar; Merz, Martin
2013-09-01
Transdermal delivery of contraceptives offers several advantages over combined oral contraceptives (COCs), including effective absorption and the provision of relatively constant serum concentrations. Ethinyl estradiol (EE) and the progestin gestodene are well-absorbed through the skin and, therefore, well-suited for use in a transdermal contraceptive patch. The objective of this study was to investigate the impact of a once-weekly transparent, transdermal patch delivering low doses of EE and gestodene equivalent to a COC containing 0.02 mg EE and 0.06 mg gestodene on hemostasis parameters compared with a monophasic COC containing 0.03 mg EE and 0.15 mg levonorgestrel. In this single-center, open-label, randomized, crossover study, 30 women (aged 18-35 years) received three cycles of each treatment, separated by a two-cycle washout period. The primary outcome measure was the absolute change from baseline in prothrombin fragments 1 + 2 and D-dimer. For both treatments, prothrombin fragments 1 + 2 remained stable during the first treatment period, and increased only slightly in the second period (mean absolute change 0.025 and 0.028 nmol/L in the novel Bayer patch and COC groups, respectively). Increases in D-dimer were observed in both periods (mean absolute change 107.0 ± 147.2 ng/L for the novel Bayer patch and 113.7 ± 159.0 ng/L for the COC). There were no statistically significant treatment differences in prothrombin 1 + 2 or D-dimer (p = 0.667 and p = 0.884, respectively) and no statistically significant treatment sequence or period effects. A COC containing 0.03 mg EE and 0.15 mg levonorgestrel and the novel Bayer patch have comparable influence on hemostatic endpoints. Both treatments were well-tolerated by subjects.
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Tedesco-Silva, Helio; Peddi, V. Ram; Sánchez-Fructuoso, Ana; Marder, Brad A.; Russ, Graeme R.; Diekmann, Fritz; Flynn, Alison; Hahn, Carolyn M.; Li, Huihua; Tortorici, Michael A.; Schulman, Seth L.
2016-01-01
Background Calcineurin inhibitor–associated nephrotoxicity and other adverse events have prompted efforts to minimize/eliminate calcineurin inhibitor use in kidney transplant recipients. Methods This open-label, randomized, multinational study evaluated the effect of planned transition from tacrolimus to sirolimus on kidney function in renal allograft recipients. Patients received tacrolimus-based immunosuppression and then were randomized 3 to 5 months posttransplantation to transition to sirolimus or continue tacrolimus. The primary end point was percentage of patients with 5 mL/min per 1.73 m2 or greater improvement in estimated glomerular filtration rate from randomization to month 24. Results The on-therapy population included 195 patients (sirolimus, 86; tacrolimus, 109). No between-group difference was noted in percentage of patients with 5 mL/min per 1.73 m2 or greater estimated glomerular filtration rate improvement (sirolimus, 34%; tacrolimus, 42%; P = 0.239) at month 24. Sirolimus patients had higher rates of biopsy-confirmed acute rejection (8% vs 2%; P = 0.02), treatment discontinuation attributed to adverse events (21% vs 3%; P < 0.001), and lower rates of squamous cell carcinoma of the skin (0% vs 5%; P = 0.012). Conclusions Our findings suggest that renal function improvement at 24 months is similar for patients with early conversion to sirolimus after kidney transplantation versus those remaining on tacrolimus. PMID:27500260
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Fekaj, Enver; Gjata, Arben; Maxhuni, Mehmet
2013-09-22
In patients with obstructive jaundice, multi-organ dysfunction may develop. This trial is a prospective, open-label, randomized, and controlled study with the objective to evaluate the effect of ursodeoxycholic acid in liver functional restoration in patients with obstructive jaundice after endoscopic treatment. The aim of this study is to evaluate the effect of ursodeoxycholic acid in liver functional restoration of patients with obstructive jaundice after endoscopic treatment. The hypothesis of this trial is that patients with obstructive jaundice, in which will be administered UDCA, in the early phase after endoscopic intervention will have better and faster functional restoration of the liver than patients in the control group.Patients with obstructive jaundice, randomly, will be divided into two groups: (A) test group in which will be administered ursodeoxycholic acid twenty-four hours after endoscopic procedure and will last fourteen days, and (B) control group.Serum-testing will include determination of bilirubin, alanine transaminase, aspartate transaminase, gama-glutamil transpeptidase, alkaline phosphatase, albumin, and cholesterol levels. These parameters will be determined one day prior endoscopic procedure, and on the third, fifth, seventh, tenth, twelfth and fourteenth days after endoscopic intervention. This trial is a prospective, open-label, randomized, and controlled study to asses the effect of ursodeoxycholic acid in liver functional restoration of patients with obstructive jaundice in the early phase after endoscopic treatment.
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NASA Astrophysics Data System (ADS)
Wu, J.; Yao, W.; Zhang, J.; Li, Y.
2018-04-01
Labeling 3D point cloud data with traditional supervised learning methods requires considerable labelled samples, the collection of which is cost and time expensive. This work focuses on adopting domain adaption concept to transfer existing trained random forest classifiers (based on source domain) to new data scenes (target domain), which aims at reducing the dependence of accurate 3D semantic labeling in point clouds on training samples from the new data scene. Firstly, two random forest classifiers were firstly trained with existing samples previously collected for other data. They were different from each other by using two different decision tree construction algorithms: C4.5 with information gain ratio and CART with Gini index. Secondly, four random forest classifiers adapted to the target domain are derived through transferring each tree in the source random forest models with two types of operations: structure expansion and reduction-SER and structure transfer-STRUT. Finally, points in target domain are labelled by fusing the four newly derived random forest classifiers using weights of evidence based fusion model. To validate our method, experimental analysis was conducted using 3 datasets: one is used as the source domain data (Vaihingen data for 3D Semantic Labelling); another two are used as the target domain data from two cities in China (Jinmen city and Dunhuang city). Overall accuracies of 85.5 % and 83.3 % for 3D labelling were achieved for Jinmen city and Dunhuang city data respectively, with only 1/3 newly labelled samples compared to the cases without domain adaption.
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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.
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Boman, Kurt; Olofsson, Mona; Berggren, Peter; Sengupta, Partho P; Narula, Jagat
2014-08-01
The strategy using cardiological consultation in addition to the robot-assisted remote echocardiography at a distance was tested in a prospective, randomized open-label trial to evaluate its feasibility and to define its clinical value in a rural area. The present study involved 1 primary healthcare center in the north of Sweden, 135 miles from the hospital where the echocardiograms and the cardiology teleconsultation were performed long distance in real time. Nineteen patients were randomized to remote consultation and imaging, and 19 to the standard of care consultation. The total process time was significantly reduced in the former arm (median 114 days vs. 26.5 days; p < 0.001). The time from randomization until attaining a specialist consultation was also significantly reduced (p < 0.001). The patients' satisfaction was reassuring; they considered that the remote consultation strategy offered an increased rapidity of diagnosis and the likelihood of receiving faster management compared with the standard of care at the primary healthcare center. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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Uenishi, K; Tokiwa, M; Kato, S; Shiraki, M
2018-05-01
There were two errors in this article. 1. In the section "Ethical considerations", the registration number of the study was incorrectly given as UMIN000024492. The correct number is UMIN0000 20267. 2. The Acknowledgments paragraph was incomplete.
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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…
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Kim, Bong Hyun; Kim, Kyuseok; Nam, Hae Jeong
2017-01-31
Many previous studies of electroacupuncture used combined therapy of electroacupuncture and systemic manual acupuncture, so it was uncertain which treatment was effective. This study evaluated and compared the effects of systemic manual acupuncture, periauricular electroacupuncture and distal electroacupuncture for treating patients with tinnitus. A randomized, parallel, open-labeled exploratory trial was conducted. Subjects aged 20-75 years who had suffered from idiopathic tinnitus for > 2 weeks were recruited from May 2013 to April 2014. The subjects were divided into three groups by systemic manual acupuncture group (MA), periauricular electroacupuncture group (PE), and distal electroacupuncture group (DE). The groups were selected by random drawing. Nine acupoints (TE 17, TE21, SI19, GB2, GB8, ST36, ST37, TE3 and TE9), two periauricular acupoints (TE17 and TE21), and four distal acupoints (TE3, TE9, ST36, and ST37) were selected. The treatment sessions were performed twice weekly for a total of eight sessions over 4 weeks. Outcomes were the tinnitus handicap inventory (THI) score and the loud and uncomfortable visual analogue scales (VAS). Demographic and clinical characteristics of all participants were compared between the groups upon admission using one-way analysis of variance (ANOVA). One-way ANOVA was used to evaluate the THI, VAS loud , and VAS uncomfortable scores. The least significant difference test was used as a post-hoc test. Thirty-nine subjects were eligible and their data were analyzed. No difference in THI and VAS loudness scores was observed in between groups. The VAS uncomfortable scores decreased significantly in MA and DE compared with those in PE. Within the group, all three treatments showed some effect on THI, VAS loudness scores and VAS uncomfortable scores after treatment except DE in THI. There was no statistically significant difference between systemic manual acupuncture, periauricular electroacupuncture and distal electroacupuncture in tinnitus. However, all three treatments had some effect on tinnitus within the group before and after treatment. Systemic manual acupuncture and distal electroacupuncture have some effect on VAS uncomfortable . KCT0001991 by CRIS (Clinical Research Information Service), 2016-8-1, retrospectively registered.
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West, Mike; Boulanger, Bernard R; Fogarty, Charles; Tennenberg, Alan; Wiesinger, Barbara; Oross, Margaret; Wu, Shu-Chen; Fowler, Cynthia; Morgan, Nancy; Kahn, James B
2003-02-01
Therapy of nosocomial pneumonia is usually empiric and includes > or = 1 broad-spectrum antimicrobial agent. When considering the use of fluoroquinolones in these difficult-to-treat infections--in which drug delivery to the site of infection may be impaired or organisms with higher minimum inhibitory concentrations may be present--an agent should be chosen whose pharmacodynamics ensure maximal drug exposure. Use of the 750-mg dose of levofloxacin should enhance therapeutic benefit in patients with nosocomial pneumonia. The goal of this study was to compare the efficacy and safety of levofloxacin 750 mg and imipenem/cilastatin followed by ciprofloxacin in adult patients with nosocomial pneumonia. This was a multicenter, prospective, randomized, open-label trial conducted in North America. Patients were randomly assigned to 1 of 2 treatment arms: levofloxacin 750 mg QD given i.v. and then orally for 7 to 15 days or imipenem/cilastatin 500 mg to 1 g i.v. every 6 to 8 hours, followed by oral ciprofloxacin 750 mg every 12 hours for 7 to 15 days. Adjunctive antibacterial therapy was mandatory in patients with documented or suspected Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus infection. The primary predefined outcome measure was the clinical response (cure, improvement, failure, or unable to evaluate) in microbiologically evaluable patients 3 to 15 days after the end of therapy. The study enrolled 438 adult patients (315 men, 123 women; mean [SD] age, 55.7 [20.04] years). Two hundred twenty patients received levofloxacin, and 218 received the comparator regimen. Demographic and baseline clinical characteristics were similar in the intent-to-treat and clinically evaluable populations. In patients evaluable for microbiologic efficacy, clinical success (cure or improvement) was achieved in 58.1% (54/93) of patients who received levofloxacin, compared with 60.6% (57/94) of patients who received the comparator regimen (95% CI, -12.0 to 17.2). Similar clinical results were seen in patients evaluable for clinical efficacy and in the intent-to-treat population. In the 187 patients evaluable for microbiologic efficacy, eradication was achieved in 66.7% (62/93) of patients receiving levofloxacin and 60.6% (57/94) of patients receiving the comparator regimen (95% CI, -20.3 to 8.3). In this study, levofloxacin was at least as effective and was as well tolerated as imipenem/cilastatin followed by ciprofloxacin in adult patients with nosocomial pneumonia, as demonstrated by comparable clinical and microbiologic success rates.
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Leentjens, Jenneke; Quintin, Jessica; Gerretsen, Jelle; Kox, Matthijs; Pickkers, Peter; Netea, Mihai G.
2014-01-01
Rationale To prevent or combat infection, increasing the effectiveness of the immune response is highly desirable, especially in case of compromised immune system function. However, immunostimulatory therapies are scarce, expensive, and often have unwanted side-effects. β-glucans have been shown to exert immunostimulatory effects in vitro and in vivo in experimental animal models. Oral β-glucan is inexpensive and well-tolerated, and therefore may represent a promising immunostimulatory compound for human use. Methods We performed a randomized open-label intervention pilot-study in 15 healthy male volunteers. Subjects were randomized to either the β -glucan (n = 10) or the control group (n = 5). Subjects in the β-glucan group ingested β-glucan 1000 mg once daily for 7 days. Blood was sampled at various time-points to determine β-glucan serum levels, perform ex vivo stimulation of leukocytes, and analyze microbicidal activity. Results β-glucan was barely detectable in serum of volunteers at all time-points. Furthermore, neither cytokine production nor microbicidal activity of leukocytes were affected by orally administered β-glucan. Conclusion The present study does not support the use of oral β-glucan to enhance innate immune responses in humans. Trial Registration ClinicalTrials.gov NCT01727895 PMID:25268806
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Dhurat, Rachita; Chitallia, Jill; May, Theodor W; Jayaraaman, Ammani M; Madhukara, Jithendriya; Anandan, Subbu; Vaidya, Pradyumna; Klenk, Adolf
2017-01-01
Androgenetic alopecia is a condition with a high prevalence worldwide and affects both males and females. Currently, only 2 approved treatments exist: finasteride (males only) and minoxidil 2 or 5% solution (males and females). We conducted a randomized, open-label, multicenter noninferiority study to determine whether a caffeine-based 0.2% topical liquid would be no less effective than minoxidil 5% solution in males (n = 210) with androgenetic alopecia. The primary end point was the percentage change in the proportion of anagen hairs from baseline to 6 months using a frontal and occipital trichogram. At 6 months, the group of the 5% minoxidil solution showed a mean improvement in anagen ratio of the trichogram of 11.68%, and the group of the 0.2% caffeine solution had an anagen improvement of 10.59%. The difference of mean values between both groups was 1.09%. The statistical analysis was performed and reported in accordance with the CONSORT Guidelines 2010 for reporting of noninferiority and equivalence randomized trials. A caffeine-based topical liquid should be considered as not inferior to minoxidil 5% solution in men with androgenetic alopecia. © 2017 The Author(s) Published by S. Karger AG, Basel.
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Jain, Jay Prakash; Leong, F Joel; Chen, Lan; Kalluri, Sampath; Koradia, Vishal; Stein, Daniel S; Wolf, Marie-Christine; Sunkara, Gangadhar; Kota, Jagannath
2017-09-01
The artemether-lumefantrine combination requires food intake for the optimal absorption of lumefantrine. In an attempt to enhance the bioavailability of lumefantrine, new solid dispersion formulations (SDF) were developed, and the pharmacokinetics of two SDF variants were assessed in a randomized, open-label, sequential two-part study in healthy volunteers. In part 1, the relative bioavailability of the two SDF variants was compared with that of the conventional formulation after administration of a single dose of 480 mg under fasted conditions in three parallel cohorts. In part 2, the pharmacokinetics of lumefantrine from both SDF variants were evaluated after a single dose of 480 mg under fed conditions and a single dose of 960 mg under fasted conditions. The bioavailability of lumefantrine from SDF variant 1 and variant 2 increased up to ∼48-fold and ∼24-fold, respectively, relative to that of the conventional formulation. Both variants demonstrated a positive food effect and a less than proportional increase in exposure between the 480-mg and 960-mg doses. Most adverse events (AEs) were mild to moderate in severity and not suspected to be related to the study drug. All five drug-related AEs occurred in subjects taking SDF variant 2. No clinically significant treatment-emergent changes in vital signs, electrocardiograms, or laboratory blood assessments were noted. The solid dispersion formulation enhances the lumefantrine bioavailability to a significant extent, and SDF variant 1 is superior to SDF variant 2. Copyright © 2017 Jain et al.
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Bourbeau, Jean; Casan, Pere; Tognella, Silvia; Haidl, Peter; Texereau, Joëlle B; Kessler, Romain
2016-01-01
Most hospitalizations and costs related to COPD are due to exacerbations and insufficient disease management. The COPD patient Management European Trial (COMET) is investigating a home-based multicomponent COPD self-management program designed to reduce exacerbations and hospital admissions. Multicenter parallel randomized controlled, open-label superiority trial. Thirty-three hospitals in four European countries. A total of 345 patients with Global initiative for chronic Obstructive Lung Disease III/IV COPD. The program includes extensive patient coaching by health care professionals to improve self-management (eg, develop skills to better manage their disease), an e-health platform for reporting frequent health status updates, rapid intervention when necessary, and oxygen therapy monitoring. Comparator is the usual management as per the center's routine practice. Yearly number of hospital days for acute care, exacerbation number, quality of life, deaths, and costs.
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Armoiry, X; Kan, A; Melendez-Torres, G J; Court, R; Sutcliffe, P; Auguste, P; Madan, J; Counsell, C; Clarke, A
2018-05-01
Beta-interferon (IFN-β) and glatiramer acetate (GA) have been evaluated in people with clinically isolated syndrome (CIS) with the aim to delay a second clinical attack and a diagnosis of clinically definite multiple sclerosis (CDMS). We systematically reviewed trials evaluating the short- and long-term clinical effectiveness of these drugs in CIS. We searched multiple electronic databases. We selected randomised controlled studies (RCTs) conducted in CIS patients and where the interventions were IFN-β and GA. Main outcomes were time to CDMS, and discontinuation due to adverse events (AE). We compared interventions using random-effect network meta-analyses (NMA). We also reported outcomes from long-term open-label extension (OLE) studies. We identified five primary studies. Four had open-label extensions following double-blind periods comparing outcomes between early vs delayed DMT. Short-term clinical results (double-blind period) showed that all drugs delayed CDMS compared to placebo. Indirect comparisons did not suggest superiority of any one active drug over another. We could not undertake a NMA for discontinuation due to AE. Long-term clinical results (OLE studies) showed that the risk of developing CDMS was consistently reduced across studies after early DMT treatment compared to delayed DMT (HR = 0.64, 95% CI 0.55, 0.74). No data supported the benefit of DMTs in reducing the time to, and magnitude of, disability progression. Meta-analyses confirmed that IFN-β and GA delay time to CDMS compared to placebo. In the absence of evidence that early DMTs can reduce disability progression, future research is needed to better identify patients most likely to benefit from long-term DMTs.
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Hantoushzadeh, Sedigheh; Golshahi, Fateme; Javadian, Pouya; Khazardoost, Soghra; Aram, Shahnaz; Hashemi, Shahrzad; Mirarmandehi, Bahare; Borna, Sedigheh
2012-07-01
This study was performed to determine the comparative efficacy of probiotic yoghurt and clindamycin in the treatment of bacterial vaginosis in pregnant women in the third trimester. This randomized clinical trial was performed as an open-label study. 310 symptomatic patients with BV were recruited. Diagnosis of BV was through Amsel criteria. The patients were randomly assigned to receive either probiotic yoghurt (100 g twice a day/week) or orally administered clindamycin (300 mg twice a day/week). Ten patients in probiotic group and 9 subjects in clindamycin group had symptom recurrence (p > 0.05). 132 patients in probiotic group and 105 subjects in clindamycin group had pH decrease (p < 0.0001). 140 patients in probiotic group and 141 subjects in clindamycin group had complete symptomatic cure (p > 0.05). Twelve patients in probiotic group and seven subjects in clindamycin group had preterm birth. Nine women in probiotic group and five subjects in clindamycin group had PROM (p > 0.05). According to the obtained results, it may be concluded that probiotics would have a good efficacy in the treatment of bacterial vaginosis in pregnancy leading to decreased burden of subsequent preterm birth.
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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.
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Smith, Tristram; Aman, Michael G; Arnold, L Eugene; Silverman, Laura B; Lecavalier, Luc; Hollway, Jill; Tumuluru, Rameshwari; Hyman, Susan L; Buchan-Page, Kristin A; Hellings, Jessica; Rice, Robert R; Brown, Nicole V; Pan, Xueliang; Handen, Benjamin L
2016-10-01
The authors previously reported on a 2-by-2 randomized clinical trial of individual and combined treatment with atomoxetine (ATX) and parent training (PT) for attention-deficit/hyperactivity disorder (ADHD) symptoms and behavioral noncompliance in 128 5- to 14-year-old children with autism spectrum disorder. In the present report, they describe a 24-week extension of treatment responders and nonresponders. One-hundred seventeen participants from the acute trial (91%) entered the extension; 84 of these were in 2 subgroups: "treatment responders" (n = 43) from all 4 groups in the acute trial, seen monthly for 24 weeks, and "placebo nonresponders" (n = 41), treated with open-label ATX for 10 weeks. Participants originally assigned to PT continued PT during the extension; the remainder served as controls. Primary outcome measurements were the parent-rated Swanson, Nolan and Pelham ADHD scale and the Home Situations Questionnaire. Sixty percent (26 of 43) of treatment responders in the acute trial, including 68% of responders originally assigned to ATX, still met the response criteria at the end of the extension. The response rate of placebo nonresponders treated with 10-week open-label ATX was 37% (15 of 41), similar to the acute trial. Children receiving open-label ATX + PT were significantly more likely to be ADHD responders (53% versus 23%) and noncompliance responders (58% versus 14%) than those receiving open-label ATX alone. Most ATX responders maintained their responses during the extension. PT combined with ATX in the open-label trial appeared to improve ADHD and noncompliance outcomes more than ATX alone. Clinical trial registration information-Atomoxetine, Placebo and Parent Management Training in Autism (Strattera); http://clinicaltrials.gov; NCT00844753. Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
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Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis.
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.
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Webster, Lynn R; Brenner, Darren M; Barrett, Andrew C; Paterson, Craig; Bortey, Enoch; Forbes, William P
2015-01-01
Background Subcutaneous methylnaltrexone is efficacious and well tolerated for opioid-induced constipation (OIC) but may theoretically disrupt opioid-mediated analgesia. Methods Opioid use, pain intensity, and opioid withdrawal (Objective Opioid Withdrawal Scale [OOWS] and Subjective Opiate Withdrawal Scale [SOWS] scores) were reported in a randomized, double-blind trial with an open-label extension (RCT) and an open-label trial (OLT) evaluating safety in adults with chronic noncancer pain. In the RCT, patients taking ≥50 mg of oral morphine equivalents daily with <3 rescue-free bowel movements weekly received methyl naltrexone 12 mg once daily (n=150), every other day (n=148), or placebo (n=162) for 4 weeks, followed by open-label methylnaltrexone 12 mg (as needed [prn]; n=364) for 8 weeks. In the OLT, patients (n=1,034) on stable opioid doses with OIC received methylnaltrexone 12 mg prn for up to 48 weeks. Results Minimal fluctuations of median morphine equivalent dose from baseline (BL) were observed in the RCT double-blind period (BL, 154.8–161.0 mg/d; range, 137.1–168.0 mg/d), RCT open-label period (BL, 156.3–174.6; range, 144.0–180.0) and OLT (BL, 120 mg/d; range, 117.3–121.1 mg/d). No significant change from BL in pain intensity score occurred in any group at weeks 2 or 4 (both P≥0.1) of the RCT double-blind period, and scores remained stable during the open-label period and in the OLT (mean change, −0.2 to 0.1). Changes from BL in OOWS and SOWS scores during the double-blind period were not significantly impacted by methylnaltrexone exposure at weeks 2 or 4 (P>0.05 for all). Conclusion Methylnaltrexone did not affect opioid-mediated analgesia in patients with chronic noncancer pain and OIC. PMID:26586963
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Kantarjian, Hagop M.; Thomas, Xavier G.; Dmoszynska, Anna; Wierzbowska, Agnieszka; Mazur, Grzegorz; Mayer, Jiri; Gau, Jyh-Pyng; Chou, Wen-Chien; Buckstein, Rena; Cermak, Jaroslav; Kuo, Ching-Yuan; Oriol, Albert; Ravandi, Farhad; Faderl, Stefan; Delaunay, Jacques; Lysák, Daniel; Minden, Mark; Arthur, Christopher
2012-01-01
Purpose This multicenter, randomized, open-label, phase III trial compared the efficacy and safety of decitabine with treatment choice (TC) in older patients with newly diagnosed acute myeloid leukemia (AML) and poor- or intermediate-risk cytogenetics. Patients and Methods Patients (N = 485) age ≥ 65 years were randomly assigned 1:1 to receive decitabine 20 mg/m2 per day as a 1-hour intravenous infusion for five consecutive days every 4 weeks or TC (supportive care or cytarabine 20 mg/m2 per day as a subcutaneous injection for 10 consecutive days every 4 weeks). The primary end point was overall survival (OS); the secondary end point was the complete remission (CR) rate plus the CR rate without platelet recovery (CRp). Adverse events (AEs) were recorded. Results The primary analysis with 396 deaths (81.6%) showed a nonsignificant increase in median OS with decitabine (7.7 months; 95% CI, 6.2 to 9.2) versus TC (5.0 months; 95% CI, 4.3 to 6.3; P = .108; hazard ratio [HR], 0.85; 95% CI, 0.69 to 1.04). An unplanned analysis with 446 deaths (92%) indicated the same median OS (HR, 0.82; 95% CI, 0.68 to 0.99; nominal P = .037). The CR rate plus CRp was 17.8% with decitabine versus 7.8% with TC (odds ratio, 2.5; 95% CI, 1.4 to 4.8; P = .001). AEs were similar for decitabine and cytarabine, although patients received a median of four cycles of decitabine versus two cycles of TC. The most common drug-related AEs with decitabine were thrombocytopenia (27%) and neutropenia (24%). Conclusion In older patients with AML, decitabine improved response rates compared with standard therapies without major differences in safety. An unplanned survival analysis showed a benefit for decitabine, which was not observed at the time of the primary analysis. PMID:22689805
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Costa, Dorcas Lamounier; Costa, Carlos Henrique Nery; de Almeida, Roque Pacheco; de Melo, Enaldo Viera; de Carvalho, Sílvio Fernando Guimarães; Rabello, Ana; de Carvalho, Andréa Lucchesi; Sousa, Anastácio de Queiroz; Leite, Robério Dias; Lima, Simone Soares; Amaral, Thais Alves; Alves, Fabiana Piovesan; Rode, Joelle
2017-01-01
Background There is insufficient evidence to support visceral leishmaniasis (VL) treatment recommendations in Brazil and an urgent need to improve current treatments. Drug combinations may be an option. Methods A multicenter, randomized, open label, controlled trial was conducted in five sites in Brazil to evaluate efficacy and safety of (i) amphotericin B deoxycholate (AmphoB) (1 mg/kg/day for 14 days), (ii) liposomal amphotericin B (LAMB) (3 mg/kg/day for 7 days) and (iii) a combination of LAMB (10 mg/kg single dose) plus meglumine antimoniate (MA) (20 mg Sb+5/kg/day for 10 days), compared to (iv) standard treatment with MA (20 mg Sb+5/kg/day for 20 days). Patients, aged 6 months to 50 years, with confirmed VL and without HIV infection were enrolled in the study. Primary efficacy endpoint was clinical cure at 6 months. A planned efficacy and safety interim analysis led to trial interruption. Results 378 patients were randomized to the four treatment arms: MA (n = 112), AmphoB (n = 45), LAMB (n = 109), or LAMB plus MA (n = 112). A high toxicity of AmphoB prompted an unplanned interim safety analysis and this treatment arm was dropped. Per intention-to-treat protocol final analyses of the remaining 332 patients show cure rates at 6 months of 77.5% for MA, 87.2% for LAMB, and 83.9% for LAMB plus MA, without statistically significant differences between the experimental arms and comparator (LAMB: 9.7%; CI95% -0.28 to 19.68, p = 0.06; LAMB plus MA: 6.4%; CI95% -3.93 to 16.73; p = 0.222). LAMB monotherapy was safer than MA regarding frequency of treatment-related adverse events (AE) (p = 0.045), proportion of patients presenting at least one severe AE (p = 0.029), and the proportion of AEs resulting in definitive treatment discontinuation (p = 0.003). Conclusions Due to lower toxicity and acceptable efficacy, LAMB would be a more suitable first line treatment for VL than standard treatment. ClinicalTrials.gov identification number: NCT01310738. Trial registration ClinicalTrials.gov NCT01310738 PMID:28662034
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Werner, Gerald S; Martin-Yuste, Victoria; Hildick-Smith, David; Boudou, Nicolas; Sianos, Georgios; Gelev, Valery; Rumoroso, Jose Ramon; Erglis, Andrejs; Christiansen, Evald Høj; Escaned, Javier; di Mario, Carlo; Hovasse, Thomas; Teruel, Luis; Bufe, Alexander; Lauer, Bernward; Bogaerts, Kris; Goicolea, Javier; Spratt, James C; Gershlick, Anthony H; Galassi, Alfredo R; Louvard, Yves
2018-05-02
The clinical value of percutaneous coronary intervention (PCI) for chronic coronary total occlusions (CTOs) is not established by randomized trials. This study should compare the benefit of PCI vs. optimal medical therapy (OMT) on the health status in patients with at least one CTO. Three hundred and ninety-six patients were enrolled in a prospective randomized, multicentre, open-label, and controlled clinical trial to compare the treatment by PCI with OMT with a 2:1 randomization ratio. The primary endpoint was the change in health status assessed by the Seattle angina questionnaire (SAQ) between baseline and 12 months follow-up. Fifty-two percent of patients have multi-vessel disease in whom all significant non-occlusive lesions were treated before randomization. An intention-to-treat analysis was performed including 13.4% failed procedures in the PCI group and 7.3% cross-overs in the OMT group. At 12 months, a greater improvement of SAQ subscales was observed with PCI as compared with OMT for angina frequency [5.23, 95% confidence interval (CI) 1.75; 8.71; P = 0.003], and quality of life (6.62, 95% CI 1.78-11.46; P = 0.007), reaching the prespecified significance level of 0.01 for the primary endpoint. Physical limitation (P = 0.02) was also improved in the PCI group. Complete freedom from angina was more frequent with PCI 71.6% than OMT 57.8% (P = 0.008). There was no periprocedural death or myocardial infarction. At 12 months, major adverse cardiac events were comparable between the two groups. Percutaneous coronary intervention leads to a significant improvement of the health status in patients with stable angina and a CTO as compared with OMT alone. NCT01760083.
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Pontes, Caridad; Gratacós, Jordi; Torres, Ferran; Avendaño, Cristina; Sanz, Jesús; Vallano, Antoni; Juanola, Xavier; de Miguel, Eugenio; Sanmartí, Raimon; Calvo, Gonzalo
2015-08-20
Dose reduction schedules of tumor necrosis factor antagonists (anti-TNF) as maintenance therapy in patients with spondyloarthritis are used empirically in clinical practice, despite the lack of clinical trials providing evidence for this practice. To address this issue the Spanish Society of Rheumatology (SER) and Spanish Society of Clinical Pharmacology (SEFC) designed a 3-year multicenter, randomized, open-label, controlled clinical trial (2 years for inclusion and 1 year of follow-up). The study is expected to include 190 patients with axial spondyloarthritis on stable maintenance treatment (≥4 months) with any anti-TNF agent at doses recommended in the summary of product characteristics. Patients will be randomized to either a dose reduction arm or maintenance of the dosing regimen as per the official labelling recommendations. Randomization will be stratified according to the anti-TNF agent received before study inclusion. Patient follow-up, visit schedule, and examinations will be maintained as per normal clinical practice recommendations according to SER guidelines. The study aims to test the hypothesis of noninferiority of the dose reduction strategy compared with standard treatment. The first patients were recruited in July 2012, and study completion is scheduled for the end of April 2015. The REDES-TNF study is a pragmatic clinical trial that aims to provide evidence to support a medical decision now made empirically. The study results may help inform clinical decisions relevant to both patients and healthcare decision makers. EudraCT 2011-005871-18 (21 December 2011).
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Sokol, Serguei; Millard, Pierre; Portais, Jean-Charles
2012-03-01
The problem of stationary metabolic flux analysis based on isotope labelling experiments first appeared in the early 1950s and was basically solved in early 2000s. Several algorithms and software packages are available for this problem. However, the generic stochastic algorithms (simulated annealing or evolution algorithms) currently used in these software require a lot of time to achieve acceptable precision. For deterministic algorithms, a common drawback is the lack of convergence stability for ill-conditioned systems or when started from a random point. In this article, we present a new deterministic algorithm with significantly increased numerical stability and accuracy of flux estimation compared with commonly used algorithms. It requires relatively short CPU time (from several seconds to several minutes with a standard PC architecture) to estimate fluxes in the central carbon metabolism network of Escherichia coli. The software package influx_s implementing this algorithm is distributed under an OpenSource licence at http://metasys.insa-toulouse.fr/software/influx/. Supplementary data are available at Bioinformatics online.
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Wichianpitaya, Jirath; Taneepanichskul, Surasak
2013-01-01
Objective. To compare the efficacy of low-dose COC containing desogestrel (DSG) with drospirenone (DRSP) in the changes of premenstrual symptoms. Methods. In an open-label randomized controlled trial, 90 women with premenstrual syndrome who required COC were randomly recruited and allocated equally to receive either 6 cycles of 20 micrograms ethinyl estradiol (EE)/150 micrograms DSG (DSG group) or 20 micrograms EE/3 mg DRSP (DRSP group) in 24/4 extended regimen. Analysis of covariance and repeated analysis of variance were used to determine the difference of mean Women's Health Assessment Questionnaire (WHAQ) scores changes between groups, within group, and in premenstrual, menstrual, and postmenstrual phases. Results. Baseline characteristics and WHAQ scores were comparable. At the ends of the 3rd and the 6th cycles, mean WHAQ scores of all the 3 phases in DRSP group showed significant reduction and were significantly lower than those in DSG group. DSG group showed significant reduction in both premenstrual and menstrual phases after the 6th cycle. Adverse effects were comparable in both groups. In conclusion, low-dose COC containing either DSG or DRSP reduced premenstrual symptoms, but the latter showed greater efficacy and earlier reduction. PMID:23577032
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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…
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Khaledifar, Ali; Nasiri, Marzeih; Khaledifar, Borzoo; Khaledifar, Arsalan; Mokhtari, Ali
2017-03-01
Complementary medicine interventions are now successfully used to reduce stress as well as to stabilize hemodynamic indices within different procedures. The present study aimed to examine the effect of massage therapy and reflexotherapy on reducing stress in patients before coronary angiography. In this open-label clinical trial, 75 consecutive patients who were candidate for coronary angiography were randomly assigned to receive reflexotherapy (n = 25), or massage therapy (n = 25), or routine care (n = 25) before angiography. The Spielberger State-Trait Anxiety Inventory was used to determine the stress level of patients before and after interventions and vital signs were also measured. Improvement in diastolic blood pressure, heart rate, and respiratory rate was shown in the reflexotherapy group, and similar effects were observed following other interventions including massage therapy and routine resting program. In subjects who received reflexotherapy the level of stress decreased slightly compared with the other two groups. However, following interventions the level of stress in reflexotherapy group was shown to be lower than other study groups. Reflexotherapy before coronary angiography can help to stabilize vital sign as well as reduce the level of stress. The effect of massage therapy was limited to reducing stress.
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Sun, Caihong; Zou, Mingyang; Zhao, Dong; Xia, Wei; Wu, Lijie
2016-01-01
Autism spectrum disorders (ASD) are recognized as a major public health issue. Here, we evaluated the effects of folic acid intervention on methylation cycles and oxidative stress in autistic children enrolled in structured teaching. Sixty-six autistic children enrolled in this open-label trial and participated in three months of structured teaching. Forty-four children were treated with 400 μg folic acid (two times/daily) for a period of three months during their structured teaching (intervention group), while the remaining 22 children were not given any supplement for the duration of the study (control group). The Autism Treatment Evaluation Checklist (ATEC) and Psychoeducational Profile-third edition (PEP-3) were measured at the beginning and end of the treatment period. Folic acid, homocysteine, and glutathione metabolism in plasma were measured before and after treatment in 29 autistic children randomly selected from the intervention group and were compared with 29 age-matched unaffected children (typical developmental group). The results illustrated folic acid intervention improved autism symptoms towards sociability, cognitive verbal/preverbal, receptive language, and affective expression and communication. Furthermore, this treatment also improved the concentrations of folic acid, homocysteine, and normalized glutathione redox metabolism. Folic acid supplementation may have a certain role in the treatment of children with autism. PMID:27338456
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Sun, Caihong; Zou, Mingyang; Zhao, Dong; Xia, Wei; Wu, Lijie
2016-06-07
Autism spectrum disorders (ASD) are recognized as a major public health issue. Here, we evaluated the effects of folic acid intervention on methylation cycles and oxidative stress in autistic children enrolled in structured teaching. Sixty-six autistic children enrolled in this open-label trial and participated in three months of structured teaching. Forty-four children were treated with 400 μg folic acid (two times/daily) for a period of three months during their structured teaching (intervention group), while the remaining 22 children were not given any supplement for the duration of the study (control group). The Autism Treatment Evaluation Checklist (ATEC) and Psychoeducational Profile-third edition (PEP-3) were measured at the beginning and end of the treatment period. Folic acid, homocysteine, and glutathione metabolism in plasma were measured before and after treatment in 29 autistic children randomly selected from the intervention group and were compared with 29 age-matched unaffected children (typical developmental group). The results illustrated folic acid intervention improved autism symptoms towards sociability, cognitive verbal/preverbal, receptive language, and affective expression and communication. Furthermore, this treatment also improved the concentrations of folic acid, homocysteine, and normalized glutathione redox metabolism. Folic acid supplementation may have a certain role in the treatment of children with autism.
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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.
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Gruber, D; Skřivánek, A; Serrani, M; Lanius, V; Merz, M
2015-02-01
To investigate the bleeding pattern and cycle control parameters of a contraceptive patch containing 0.55 mg ethinyl estradiol (EE) and 2.1 mg gestodene (GSD) compared with a patch containing 0.6 mg EE and 6 mg norelgestromin (NGMN). In this phase III, open-label, randomized, parallel-group trial, healthy women aged 18-35 years (smokers aged 18-30 years) received either the EE/GSD patch (n=200) or the EE/NGMN patch (n=198). Treatment consisted of one patch per week for 3 weeks followed by a 7-day, patch-free interval for seven cycles. Bleeding control was assessed in two 90-day reference periods. In reference period 1, mean number of bleeding/spotting days was comparable across treatment groups (p>0.05). However, in reference period 2, there were fewer bleeding/spotting days in the EE/GSD patch group (15.7 versus 18.4; p<0.0001). Mean number of bleeding/spotting episodes was comparable across groups for both reference periods, but bleeding/spotting episodes were shorter for the EE/GSD patch than the EE/NGMN patch during reference period 1 (5.13 days versus 5.53 days, respectively; p<0.05) and reference period 2 (5.07 versus 5.66; p=0.0001). Both treatment groups showed a similar frequency of withdrawal bleeding episodes; however, across all seven cycles, the length of these episodes was consistently shorter with the EE/GSD patch (p<0.01). There were no notable treatment differences in intracyclic bleeding. Bleeding pattern and cycle control achieved with the EE/GSD patch was similar to that of the EE/NGMN patch. The paper presents data on the bleeding pattern and cycle control parameters of an investigational transdermal contraceptive patch containing EE and GSD compared with an approved contraceptive patch containing EE and NGMN. This descriptive study found that bleeding patterns associated with the EE/GSD patch were similar to those of an EE/NGMN patch providing higher EE exposure. Copyright © 2015 Elsevier Inc. All rights reserved.
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Kobeissy, Abdallah A; Hashash, Jana G; Jamali, Faek R; Skoury, Assaad M; Haddad, Reham; El-Samad, Sarah; Ladki, Rami; Aswad, Rola; Soweid, Assaad M
2012-01-01
AIM: To compare the efficacy of the proton-pump inhibitor, rabeprazole, with that of the H2-receptor antagonist, ranitidine, as on-demand therapy for relieving symptoms associated with non-erosive reflux disease (NERD). METHODS: This is a single center, prospective, randomized, open-label trial of on-demand therapy with rabeprazole (group A) vs ranitidine (group B) for 4 wk. Eighty-three patients who presented to the American University of Beirut Medical Center with persistent gastroesophageal reflux disease (GERD) symptoms and a normal upper gastrointestinal endoscopy were eligible for the study. Patients in group A (n = 44) were allowed a maximum rabeprazole dose of 20 mg twice daily, while those in group B (n = 39) were allowed a maximum ranitidine dose of 300 mg twice daily. Efficacy was assessed by patient evaluation of global symptom relief, scores of the SF-36 quality of life (QoL) questionnaires, total number of pills used, and number of medication-free days. RESULTS: Among the 83 patients who were enrolled in the study, 76 patients (40 in the rabeprazole group and 36 in the ranitidine group) completed the 4-wk trial. Baseline characteristics were comparable between both groups. After 4 wk, there was no significant difference in the subjective global symptom relief between the rabeprazole and the ranitidine groups (71.4% vs 65.4%, respectively; P = 0.9). There were no statistically significant differences between mean cumulative scores of the SF-36 QoL questionnaire for the two study groups (rabeprazole 22.40 ± 27.53 vs ranitidine 17.28 ± 37.06; P = 0.582). There was no significant difference in the mean number of pills used (rabeprazole 35.70 ± 29.75 vs ranitidine 32.86 ± 26.98; P = 0.66). There was also no statistically significant difference in the mean number of medication-free days between both groups. CONCLUSION: Rabeprazole has a comparable efficacy compared to ranitidine when given on-demand for the treatment of NERD. Both medications were associated with improved quality of life. PMID:22654431
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Kobeissy, Abdallah A; Hashash, Jana G; Jamali, Faek R; Skoury, Assaad M; Haddad, Reham; El-Samad, Sarah; Ladki, Rami; Aswad, Rola; Soweid, Assaad M
2012-05-21
To compare the efficacy of the proton-pump inhibitor, rabeprazole, with that of the H₂-receptor antagonist, ranitidine, as on-demand therapy for relieving symptoms associated with non-erosive reflux disease (NERD). This is a single center, prospective, randomized, open-label trial of on-demand therapy with rabeprazole (group A) vs ranitidine (group B) for 4 wk. Eighty-three patients who presented to the American University of Beirut Medical Center with persistent gastroesophageal reflux disease (GERD) symptoms and a normal upper gastrointestinal endoscopy were eligible for the study. Patients in group A (n = 44) were allowed a maximum rabeprazole dose of 20 mg twice daily, while those in group B (n = 39) were allowed a maximum ranitidine dose of 300 mg twice daily. Efficacy was assessed by patient evaluation of global symptom relief, scores of the SF-36 quality of life (QoL) questionnaires, total number of pills used, and number of medication-free days. Among the 83 patients who were enrolled in the study, 76 patients (40 in the rabeprazole group and 36 in the ranitidine group) completed the 4-wk trial. Baseline characteristics were comparable between both groups. After 4 wk, there was no significant difference in the subjective global symptom relief between the rabeprazole and the ranitidine groups (71.4% vs 65.4%, respectively; P = 0.9). There were no statistically significant differences between mean cumulative scores of the SF-36 QoL questionnaire for the two study groups (rabeprazole 22.40 ± 27.53 vs ranitidine 17.28 ± 37.06; P = 0.582). There was no significant difference in the mean number of pills used (rabeprazole 35.70 ± 29.75 vs ranitidine 32.86 ± 26.98; P = 0.66). There was also no statistically significant difference in the mean number of medication-free days between both groups. Rabeprazole has a comparable efficacy compared to ranitidine when given on-demand for the treatment of NERD. Both medications were associated with improved quality of life.
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Youssef, Nader N; Tron, Eduardo; Tolia, Vasundhara; Hamer-Maansson, Jennifer E; Lundborg, Per; Illueca, Marta
2014-11-01
To assess the overall exposure after a single dose of esomeprazole in children with gastroesophageal reflux disease (GERD). Oral esomeprazole administered as an intact capsule with 30 - 180 mL of water, or as an opened capsule mixed with as much as 1 tablespoon of applesauce followed by 30 - 180 mL of water. In this randomized, open-label study of children aged 1 - 11 years with endoscopically proven GERD, patients weighing 8 - < 20 kg were randomized to a single 5- or 10-mg oral dose of esomeprazole, and patients weighing >= 20 kg were randomized to a single 10- or 20-mg oral dose of esomeprazole. Esomeprazole exposure (AUC(0-∞)), AUC from zero to last measurable concentration (AUC(0-t)), maximum plasma concentration (C(max)), time to C(max) (t(max)), terminal-phase half-life, apparent oral clearance, and apparent volume of distribution were determined. 28 patients were randomized to receive esomeprazole: 14 patients weighing 8 to < 20 kg received esomeprazole 5 mg (n = 7) or 10 mg (n = 7), and 14 patients weighing ≥20 kg received esomeprazole 10 mg (n = 6) or 20 mg (n = 8). Children weighing 8 - < 20 kg had a 1.8-fold higher exposure with the 10-mg vs. 5-mg dose (AUC(0-∞), 1.32 vs. 0.73 μmol·h/L, respectively); children weighing ≥ 20 kg had a 4.4-fold higher exposure with the 20-mg vs. 10-mg dose (AUC(0-∞), 3.06 vs. 0.69 μmol·h/L). C(max) was 2.2-fold higher for the 10-mg vs. 5-mg dose (8 to < 20 kg) and 2.4-fold higher for the 20-mg vs.10-mg dose (>= 20 kg). The pharmacokinetics of single-dose esomeprazole were dose-dependent in children weighing >= 20 kg but not in children weighing 8 to < 20 kg.
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Kosiborod, Mikhail; Rasmussen, Henrik S; Lavin, Philip; Qunibi, Wajeh Y; Spinowitz, Bruce; Packham, David; Roger, Simon D; Yang, Alex; Lerma, Edgar; Singh, Bhupinder
2014-12-03
Hyperkalemia is a common electrolyte abnormality that may be difficult to manage because of a lack of effective therapies. Sodium zirconium cyclosilicate is a nonabsorbed cation exchanger that selectively binds potassium in the intestine. To evaluate the efficacy and safety of zirconium cyclosilicate for 28 days in patients with hyperkalemia. HARMONIZE was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial evaluating zirconium cyclosilicate in outpatients with hyperkalemia (serum potassium ≥5.1 mEq/L) recruited from 44 sites in the United States, Australia, and South Africa (March-August 2014). Patients (n = 258) received 10 g of zirconium cyclosilicate 3 times daily in the initial 48-hour open-label phase. Patients (n = 237) achieving normokalemia (3.5-5.0 mEq/L) were then randomized to receive zirconium cyclosilicate, 5 g (n = 45 patients), 10 g (n = 51), or 15 g (n = 56), or placebo (n = 85) daily for 28 days. The primary end point was mean serum potassium level in each zirconium cyclosilicate group vs placebo during days 8-29 of the randomized phase. In the open-label phase, serum potassium levels declined from 5.6 mEq/L at baseline to 4.5 mEq/L at 48 hours. Median time to normalization was 2.2 hours, with 84% of patients (95% CI, 79%-88%) achieving normokalemia by 24 hours and 98% (95% CI, 96%-99%) by 48 hours. In the randomized phase, serum potassium was significantly lower during days 8-29 with all 3 zirconium cyclosilicate doses vs placebo (4.8 mEq/L [95% CI, 4.6-4.9], 4.5 mEq/L [95% CI, 4.4-4.6], and 4.4 mEq/L [95% CI, 4.3-4.5] for 5 g, 10 g, and 15 g; 5.1 mEq/L [95% CI, 5.0-5.2] for placebo; P < .001 for all comparisons). The proportion of patients with mean potassium <5.1 mEq/L during days 8-29 was significantly higher in all zirconium cyclosilicate groups vs placebo (36/45 [80%], 45/50 [90%], and 51/54 [94%] for the 5-g, 10-g, and 15-g groups, vs 38/82 [46%] with placebo; P < .001 for each dose vs placebo). Adverse events were comparable between zirconium cyclosilicate and placebo, although edema was more common in the 15-g group (edema incidence: 2/85 [2%], 1/45 [2%], 3/51 [6%], and 8/56 [14%] patients in the placebo, 5-g, 10-g, and 15-g groups). Hypokalemia developed in 5/51 (10%) and 6/56 patients (11%) in the 10-g and 15-g zirconium cyclosilicate groups, vs none in the 5-g or placebo groups. Among outpatients with hyperkalemia, open-label sodium zirconium cyclosilicate reduced serum potassium to normal levels within 48 hours; compared with placebo, all 3 doses of zirconium cyclosilicate resulted in lower potassium levels and a higher proportion of patients with normal potassium levels for up to 28 days. Further studies are needed to evaluate the efficacy and safety of zirconium cyclosilicate beyond 4 weeks and to assess long-term clinical outcomes. clinicaltrials.gov Identifier: NCT02088073.
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Nakamura, Kazuhiko; Ihara, Eikichi; Akiho, Hirotada; Akahoshi, Kazuya; Harada, Naohiko; Ochiai, Toshiaki; Nakamura, Norimoto; Ogino, Haruei; Iwasa, Tsutomu; Aso, Akira; Iboshi, Yoichiro; Takayanagi, Ryoichi
2016-11-15
The ability of endoscopic submucosal dissection (ESD) to resect large early gastric cancers (EGCs) results in the need to treat large artificial gastric ulcers. This study assessed whether the combination therapy of rebamipide plus a proton pump inhibitor (PPI) offered benefits over PPI monotherapy. In this prospective, randomized, multicenter, open-label, and comparative study, patients who had undergone ESD for EGC or gastric adenoma were randomized into groups receiving either rabeprazole monotherapy (10 mg/day, n=64) or a combination of rabeprazole plus rebamipide (300 mg/day, n=66). The Scar stage (S stage) ratio after treatment was compared, and factors independently associated with ulcer healing were identified by using multivariate analyses. The S stage rates at 4 and 8 weeks were similar in the two groups, even in the subgroups of patients with large amounts of tissue resected and regardless of CYP2C19 genotype. Independent factors for ulcer healing were circumferential location of the tumor and resected tissue size; the type of treatment did not affect ulcer healing. Combination therapy with rebamipide and PPI had limited benefits compared with PPI monotherapy in the treatment of post-ESD gastric ulcer (UMIN Clinical Trials Registry, UMIN000007435).
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Nakamura, Kazuhiko; Ihara, Eikichi; Akiho, Hirotada; Akahoshi, Kazuya; Harada, Naohiko; Ochiai, Toshiaki; Nakamura, Norimoto; Ogino, Haruei; Iwasa, Tsutomu; Aso, Akira; Iboshi, Yoichiro; Takayanagi, Ryoichi
2016-01-01
Background/Aims The ability of endoscopic submucosal dissection (ESD) to resect large early gastric cancers (EGCs) results in the need to treat large artificial gastric ulcers. This study assessed whether the combination therapy of rebamipide plus a proton pump inhibitor (PPI) offered benefits over PPI monotherapy. Methods In this prospective, randomized, multicenter, open-label, and comparative study, patients who had undergone ESD for EGC or gastric adenoma were randomized into groups receiving either rabeprazole monotherapy (10 mg/day, n=64) or a combination of rabeprazole plus rebamipide (300 mg/day, n=66). The Scar stage (S stage) ratio after treatment was compared, and factors independently associated with ulcer healing were identified by using multivariate analyses. Results The S stage rates at 4 and 8 weeks were similar in the two groups, even in the subgroups of patients with large amounts of tissue resected and regardless of CYP2C19 genotype. Independent factors for ulcer healing were circumferential location of the tumor and resected tissue size; the type of treatment did not affect ulcer healing. Conclusions Combination therapy with rebamipide and PPI had limited benefits compared with PPI monotherapy in the treatment of post-ESD gastric ulcer (UMIN Clinical Trials Registry, UMIN000007435). PMID:27282261
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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.
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Simon, Steffen T; Kloke, Marianne; Alt-Epping, Bernd; Gärtner, Jan; Hellmich, Martin; Hein, Rebecca; Piel, Maren; Cornely, Oliver A; Nauck, Friedemann; Voltz, Raymond
2016-11-01
Episodic breathlessness is a frequent and burdensome symptom in cancer patients but pharmacological treatment is limited. To determine time to onset, efficacy, feasibility, and safety of transmucosal fentanyl in comparison to immediate-release morphine for the relief of episodic breathlessness. Phase II, investigator-initiated, multicenter, open-label, randomized, morphine-controlled, crossover trial with open-label titration of fentanyl buccal tablet (FBT) in inpatients with incurable cancer. The primary outcome was time to onset of meaningful breathlessness relief. Secondary outcomes were efficacy (breathlessness intensity difference at 10 and 30 minutes; sum of breathlessness intensity difference at 15 and 60 minutes), feasibility, and safety. Study was approved by local ethics committees. Twenty-five of 1341 patients were eligible, 10 patients agreed to participate (four female, mean age 58 ± 11, mean Karnofsky score 67 ± 11). Two patients died before final visits and two patients dropped-out because of disease progression leaving six patients for analysis with 61 episodes of breathlessness. Mean time to onset was for FBT 12.7 ± 10.0 and for immediate-release morphine 23.6 ± 15.1 minutes with a mean difference of -10.9 minutes (95% CI = -24.5 to 2.7, P = 0.094). Efficacy measures were predominately in favor for FBT. Both interventions were safe. Feasibility failed because of too much study demands for a very ill patient group. The description of a faster and greater relief of episodic breathlessness by transmucosal fentanyl versus morphine justifies further evaluation by a full-powered trial. Copyright © 2016. Published by Elsevier Inc.
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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.
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Hardy, Janet; Skerman, Helen; Glare, Paul; Philip, Jennifer; Hudson, Peter; Mitchell, Geoffrey; Martin, Peter; Spruyt, Odette; Currow, David; Yates, Patsy
2018-05-02
Nausea/vomiting (N/V) not related to anti-cancer treatment is common in patients with advanced cancer. The standard approach to management is to define a dominant cause, and treat with an antiemetic selected through pathophysiologic knowledge of emetic pathways. High rates of N/V control have been reported using both etiology-based guideline-driven antiemetic regimens and an empiric approach using single agents in uncontrolled studies. These different approaches had never been formally compared. This randomized, prospective, open label, dose-escalating study used readily available antiemetics in accordance with etiology-based guidelines or single agent therapy with haloperidol. Participants had a baseline average nausea score of ≥3/10. Response was defined as a ≥ 2/10 point reduction on a numerical rating scale of average nausea score with a final score < 3/10 at 72 h. Nausea scores and distress from nausea improved over time in the majority of the 185 patients randomized. For those who completed each treatment day, a greater response rate was seen in the guideline arm than the single agent arm at 24 h (49% vs 32%; p = 0.02), but not at 48 or 72 h. Response rates at 72 h in the intention to treat analysis were 49 and 53% respectively, with no significant difference between arms (0·04; 95% CI: -0·11, 0·19; p = 0·59). Over 80% of all participants reported an improved global impression of change. There were few adverse events worse than baseline in either arm. An etiology-based, guideline-directed approach to antiemetic therapy may offer more rapid benefit, but is no better than single agent treatment with haloperidol at 72 h. Australian New Zealand Clinical Trials Registry: ANZCTRN12610000481077 .
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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
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Ren, Hong; Li, Xiao; Ni, Zhao-Hui; Niu, Jian-Ying; Cao, Bin; Xu, Jie; Cheng, Hong; Tu, Xiao-Wen; Ren, Ai-Min; Hu, Ying; Xing, Chang-Ying; Liu, Ying-Hong; Li, Yan-Feng; Cen, Jun; Zhou, Rong; Xu, Xu-Dong; Qiu, Xiao-Hui; Chen, Nan
2017-03-01
To compare the efficacy and safety of short-course intravenous levofloxacin (LVFX) 750 mg with a conventional intravenous/oral regimen of LVFX 500 mg in patients from China with complicated urinary tract infections (cUTIs) and acute pyelonephritis (APN). This was a prospective, open-label, randomized, controlled, multicenter, non-inferiority clinical trial. Patients with cUTI and APN were randomly assigned to a short-course therapy group (intravenous LVFX at750 mg/day for 5 days) or a conventional therapy group (intravenous/oral regimen of LVFX at 500 mg/day for 7-14 days). The clinical, laboratory, and microbiological results were evaluated for efficacy and safety. The median dose of LVFX was 3555.4 mg in the short-course therapy group and 4874.2 mg in the conventional therapy group. Intention-to-treat analysis indicated the clinical effectiveness in the short-course therapy group (89.87%, 142/158) was non-inferior to that in the conventional therapy group (89.31%, 142/159). The microbiological effectiveness rates were also similar (short-course therapy: 89.55%, 60/67; conventional therapy: 86.30%, 63/73; p > 0.05). There were no significant differences in other parameters, including clinical and microbiological recurrence rates. The incidence of adverse effects and drug-related adverse effects were also similar for the short-course therapy group (21.95%, 36/164; 18.90%, 31/164) and the conventional therapy group (23.03%, 38/165; 15.76%, 26/165). Patients with cUTIs and APN who were given short-course LVFX therapy and conventional LVFX therapy had similar outcomes in clinical and microbiological efficacy, tolerance, and safety. The short-course therapy described here is a more convenient alternative to the conventional regimen with potential implication in anti-resistance and cost saving.
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Garg, Satish K; Mathieu, Chantal; Rais, Nadeem; Gao, Haitao; Tobian, Janet A; Gates, Jeffrey R; Ferguson, Jeffrey A; Webb, David M; Berclaz, Pierre-Yves
2009-09-01
Patients with type 1 diabetes require intensive insulin therapy for optimal glycemic control. AIR((R)) inhaled insulin (system from Eli Lilly and Company, Indianapolis, IN) (AIR is a registered trademark of Alkermes, Inc., Cambridge, MA) may be an efficacious and safe alternative to subcutaneously injected (SC) mealtime insulin. This was a Phase 3, 2-year, randomized, open-label, active-comparator, parallel-group study in 385 patients with type 1 diabetes who were randomly assigned to receive AIR insulin or SC insulin (regular human insulin or insulin lispro) at mealtimes. Both groups received insulin glargine once daily. Efficacy measures included mean change in hemoglobin A1C (A1C) from baseline to end point, eight-point self-monitored blood glucose profiles, and insulin dosage. Safety assessments included hypoglycemic events, pulmonary function tests, adverse events, and insulin antibody levels. In both treatment groups, only 20% of subjects reached the target of A1C <7.0%. A significant A1C difference of 0.44% was seen favoring SC insulin, with no difference between the groups in insulin doses or hypoglycemic events at end point. Patients in both treatment groups experienced progressive decreases in lung function, but larger (reversible) decrements in diffusing capacity of the lung for carbon monoxide (DL(CO)) were associated with AIR insulin treatment. Greater weight gain was seen with SC insulin treatment. The AIR inhaled insulin program was terminated by the sponsor prior to availability of any Phase 3 data for reasons unrelated to safety or efficacy. Despite early termination, this trial provides evidence that AIR insulin was less efficacious in lowering A1C and was associated with a greater decrease in DL(CO) and increased incidence of cough than SC insulin in patients with type 1 diabetes.
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Briand, Valérie; Bottero, Julie; Noël, Harold; Masse, Virginie; Cordel, Hugues; Guerra, José; Kossou, Hortense; Fayomi, Benjamin; Ayemonna, Paul; Fievet, Nadine; Massougbodji, Achille; Cot, Michel
2009-09-15
In the context of the increasing resistance to sulfadoxine-pyrimethamine (SP), we evaluated the efficacy of mefloquine (MQ) for intermittent preventive treatment during pregnancy (IPTp). A multicenter, open-label equivalence trial was conducted in Benin from July 2005 through April 2008. Women of all gravidities were randomized to receive SP (1500 mg of sulfadoxine and 75 mg of pyrimethamine) or 15 mg/kg MQ in a single intake twice during pregnancy. The primary end point was the proportion of low-birth-weight (LBW) infants (body weight, <2500 g; equivalence margin, 5%). A total of 1601 women were randomized to receive MQ (n=802)or SP (n=799).In the modified intention-to-treat analysis, which assessed only live singleton births, 59 (8%) of 735 women who were given MQ and 72 (9.8%) of 730 women who were given SP gave birth to LBW infants (difference between low birth weights in treatment groups, -1.8%; 95% confidence interval [CI], -4.8% to 1.1%]), establishing equivalence between the drugs. The per-protocol analysis showed consistent results. MQ was more efficacious than SP in preventing placental malaria (prevalence, 1.7% vs 4.4% of women; P = .005),clinical malaria (incidence rate, 26 cases/10,000 person-months vs. 68 cases/10,000 person-months; P = .007) and maternal anemia at delivery (as defined by a hemoglobin level <10 g/dL) (prevalence, 16% vs 20%; marginally significant at P = .09). Adverse events (mainly vomiting, dizziness, tiredness, and nausea) were more commonly associated with the use of MQ (prevalence, 78% vs 32%; P < 10(-3)) One woman in the MQ group had severe neuropsychiatric symptoms. MQ proved to be highly efficacious--both clinically and parasitologically--for use as IPTp. However, its low tolerability might impair its effectiveness and requires further investigations.
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von Au, Alexandra; Milloth, Eva; Diel, Ingo; Stefanovic, Stefan; Hennigs, Andre; Wallwiener, Markus; Heil, Joerg; Golatta, Michael; Rom, Joachim; Sohn, Christof; Schneeweiss, Andreas; Schuetz, Florian; Domschke, Christoph
2016-01-01
Patients with metastasized breast cancer often suffer from discomfort caused by metastatic bone disease. Thus, osteoprotection is an important part of therapy in breast cancer metastasized to bone, and bisphosphonates (BPs) are a major therapeutic option. In this study, our objectives were to compare the side effects of oral versus intravenous BP treatment and to assess their clinical effectiveness. In this prospective randomized, open-label, non-inferiority trial, we enrolled breast cancer patients with at least one bone metastasis and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned to one of the three treatment groups: A, 60 mg pamidronate intravenously q3w; B-iv, 900 mg clodronate intravenously q3w; and B-o, 2,400 mg oral clodronate daily. Assessments were performed at baseline and every 3 months thereafter. Between 1995 and 1999, 321 patients with confirmed bone metastases from breast cancer were included in the study. At first follow-up, gastrointestinal (GI) tract side effects were most common, and adverse effects on the GI tract were more frequent in the oral treatment group (P=0.002 and P<0.001, respectively). There were no statistically significant differences among the treatment cohorts for other documented side effects (skin, serum electrolytes, urinary tract, immune system, and others). No significant differences in clinical effectiveness of BP treatment, as assessed by pain score, were detected among the groups; however, pathologic fractures were more effectively prevented by intravenous than oral BP administration (P=0.03). Noncompliance rates were similar among the study cohorts. We conclude that oral BP treatment is significantly associated with higher rates of adverse GI side effects. Additionally, our data indicate that intravenous BP administration is more effective than oral treatment in prevention of pathologic fractures; hence, oral administration should be considered with caution.
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Auliac, J B; Chouaid, C; Greillier, L; Greiller, L; Monnet, I; Le Caer, H; Falchero, L; Corre, R; Descourt, R; Bota, S; Berard, H; Schott, R; Bizieux, A; Fournel, P; Labrunie, A; Marin, B; Vergnenegre, A
2014-09-01
Concomitant administration of erlotinib with standard chemotherapy does not appear to improve survival among patients with non-small-cell lung cancer (NSCLC), but preliminary studies suggest that sequential administration might be effective. To assess the efficacy and tolerability of second-line sequential administration of erlotinib and docetaxel in advanced NSCLC. In an open-label phase II trial, patients with advanced NSCLC, EGFR wild-type or unknown, PS 0-2, in whom initial cisplatin-based chemotherapy had failed were randomized to sequential erlotinib 150 mg/d (day 2-16)+docetaxel (75 mg/m(2) d1) (arm ED) or docetaxel (75 mg/m(2) d1) alone (arm D) (21-day cycle). The primary endpoint was the progression-free survival rate at 15 weeks (PFS 15). Secondary endpoints included PFS, overall survival (OS), the overall response rate (ORR) and tolerability. Based on a Simon optimal two-stage design, the ED strategy was rejected if the primary endpoint was below 33/66 patients at the end of the two Simon stages. 147 patients were randomized (median age: 60±8 years, PS 0/1/2: 44/83/20 patients; males: 78%). The ED strategy was rejected, with only 18 of 73 patients achieving PFS15 in arm ED at the end of stage 2 and 17 of 74 patients in arm D. In arms ED and D, respectively, median PFS was 2.2 and 2.5 months and median OS was 6.5 and 8.3 months. Sequential erlotinib and docetaxel was not more effective than docetaxel alone as second-line treatment for advanced NSCLC with wild-type or unknown EGFR status. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
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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.
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Li, Dai; Wang, Yu-Lu; Xu, Su-Mei; Li, Dan; Li, Xiao-Min; Pan, Jing; Xu, Ping-Sheng
2017-02-01
The present study was designed to evaluate the bioequivalence of a newly developed sildenafil citrate tablet 50 mg (Jinge®, Test) and a marketed counterpart (Viagra®, 100 mg, Reference) in healthy adult male Chinese volunteers. This single-dose, randomized, open-label, four-period, and two-treatment self-crossover study included two parts: fasting and postprandial studies. In each part of the study, the subjects were randomly assigned to receive test or reference products (100 mg sildenafil) in a 1 : 1 ratio, and then received the alternative products, following a 1-week washout period. Plasma sildenafil concentrations were analyzed by liquid chromatography-tandem mass spectrometry. Tolerability was assessed during the entire study period. 32 healthy volunteers (aged 19 - 30) were enrolled in the study; 31 volunteers completed the fasting study, while 32 volunteers completed the postprandial study. The test formulation was bioequivalent to the marketed formulation as the 90% CIs for the ratio of geometric means of Cmax (fasting: 98.79 - 119.61%; fed: 94.47 - 119.65%), AUClast (fasting: 98.70 - 109.71%; fed: 96.39 - 112.89%), and AUC∞ (fasting: 98.45 - 108.87%; fed: 96.36 - 112.74%) were within equivalence limits (80 - 125%) under both fasting and postprandial conditions. When sildenafil was given with high-fat meals, mean Cmax was reduced by 23%, and median tmax ranged from 0.75 to 1.50 hours (p ≤ 0.05). However, both AUClast and AUC∞ were comparable between fasting and postprandial conditions. No serious adverse events were found among the subjects. This study confirmed that test and reference sildenafil citrate tablets were bioequivalent under fasting and postprandial conditions. .
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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.
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Chandra, Richa; Ansah, Patrick; Sagara, Issaka; Sie, Ali; Tiono, Alfred B; Djimde, Abdoulaye A; Zhao, Qinying; Robbins, Jeffery; Penali, Louis K; Ogutu, Bernhards
2015-03-10
This randomized, open-label study was conducted to establish the non-inferiority of a combination of azithromycin (AZ) and chloroquine (CQ) to artemether-lumefantrine (AL) for treatment of uncomplicated malaria in children from six sites in sub-Saharan Africa. Children with uncomplicated Plasmodium falciparum malaria between six and 59 months of age were randomized 1:1 to either AZCQ (30 mg/kg AZ + 10 mg/kg CQ base) or AL per prescribing information for three days (Days 0, 1, 2). Each site could enrol in the study population once the treatment of uncomplicated malaria in five children five to 12 years of age was deemed to be effective and well tolerated. The primary efficacy evaluation was the proportion of subjects in both the modified intent-to-treat (MITT) and per-protocol (PP) populations with an adequate clinical and parasitological response (PCR corrected) at Day 28. Non-inferiority was concluded if the lower bound of the 95% confidence interval comparing the two groups was 10 percentage points or greater. A total of 255 children were enrolled in the efficacy analysis (AZCQ, n = 124; AL, n = 131). The PCR corrected clearance rates were 89% (AZCQ) versus 98% (AL) for MITT, a difference of -9.10 (95% confidence interval; -16.02, -2.18) and 93% (AZCQ) versus 99% (AL) for PP, a difference of -6.08 (-12.10, -0.05). Early and late treatment failures were more common in subjects receiving AZCQ. Adverse events were more common in subjects treated with AZCQ. Drug concentrations obtained at specified time points following AZCQ administration had a large coefficient of variation partially due to sparse sampling with sample collection time window. In this study, non-inferiority of AZCQ to AL was not demonstrated. ClinicalTrials.gov NCT00677833 .
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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]).
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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).
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Sethi, Sanjay; Fogarty, Charles; Hanania, Nicola A; Martinez, Fernando J; Rennard, Stephen; Fries, Michael; Orevillo, Chad; Darken, Patrick; St Rose, Earl; Strom, Shannon; Fischer, Tracy; Golden, Michael; Dwivedi, Sarvajna; Reisner, Colin
2016-11-17
Background: Co-Suspension™ Delivery Technology offers a novel pharmaceutical platform for inhaled drug therapy. This randomized, double-blind, placebo-controlled, single-dose study (NCT01349868) evaluated the efficacy of a range of doses for formoterol fumarate (FF) delivered using Co-Suspension delivery technology via a pressurized metered dose inhaler (MDI) versus placebo in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). Secondary objectives included determination of non-inferior efficacy and systemic exposure compared with open-label Foradil ® 12 μg (Foradil ® Aerolizer ® ; formoterol fumarate dry powder inhaler). Methods: Patients received each of the 6 study treatments (FF MDI [7.2, 9.6 and 19.2μg], placebo MDI and open-label Foradil ® [12 and 24µg]), separated by 3-10 days. Spirometry was performed 60 and 30 minutes prior to and at regular intervals up to 12 hours post-administration of study drug. The primary outcome measure was the change in forced expiratory volume in 1 second (FEV 1 ) area under the curve between 0 and 12 hours (AUC 0-12 ) relative to test day baseline. Results: A total of 50 patients were randomized to study treatment sequences. All doses of FF MDI demonstrated superiority to placebo ( p <0.0001) and non-inferiority to Foradil ® 12μg, on bronchodilator outcome measures. No serious adverse events were reported during the study. Conclusions: This study demonstrates non-inferiority of bronchodilator response and bioequivalent exposure of FF MDI 9.6μg to Foradil ® 12μg, with both agents exhibiting a similar safety profile in patients with moderate-to-severe COPD. This study supports the selection of FF MDI 9.6µg for further evaluation in Phase III trials.
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Okur, Onur; Tekgul, Zeki Tuncel; Erkan, Nazif
2017-10-01
The purpose of this study was to compare the effects of lateral abdominal transversus abdominis plane block (TAP block) and iliohypogastric/ilioinguinal nerve block (IHINB) under ultrasound guidance for postoperative pain management of inguinal hernia repair. Secondary purposes were to compare the complication rates of the two techniques and to examine the effects of TAP block and IHINB on chronic postoperative pain. This was a prospective randomized controlled open-label study. After approval of the Research Ethics Board, a total of 90 patients were allocated to three groups of 30 by simple randomized sampling as determined with a priori power analysis. Peripheral nerve blocks (TAP block or IHINB) were administered to patients following subarachnoid block according to their allocated group. Patient pain scores, additional analgesic requirements and complication rates were recorded periodically and compared. Pain scores were significantly lower in the study groups (p < 0.001, p < 0.001, p < 0.001, p = 0.002, p < 0.001, p < 0.001 for 1, 2, 4, 6, 24, and 48 h and at 1 and 6 months, respectively). First pain declaration times were significantly longer in the study groups (TAP block group [GT] 266.6 ± 119.7 min; IHINB group [GI] 247.2 ± 128.7 min; and control group [GC] 79.1 ± 66.2 min; p < 0.001). At 24 h, the numeric rating scale scores of GT were significantly lower than GI (p = 0.048). Additional analgesic requirements of GT and GI patients were found to be significantly lower than GC patients (p = 0.001, p < 0.001, p = 0.006, p = 0.002, p = 0.001, p < 0.001 for 1, 2, 4, 6, 24, and 48 h, respectively). We conclude that administration of TAP block or IHINB for patients undergoing inguinal herniorrhaphy reduces the intensity of both acute and chronic postoperative pain and additional analgesic requirements.
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Guang-Sheng, Fan; Mei-Lu, Bian; Li-Nan, Cheng; Xiao-Ming, Cao; Zi-Rong, Huang; Zi-Yan, Han; Xiao-Ping, Jing; Jian, Li; Shu-Ying, Wu; Cheng-Liang, Xiong; Zheng-Ai, Xiong; Tian-Fu, Yue
2010-01-01
To evaluate and compare the contraceptive efficacy, bleeding pattern, side effects and other positive effects of a combined oral contraceptive (COC) containing drospirenone (DRSP) [Yasmin] with those of a COC containing desogestrel (DSG) in healthy Chinese women. This was a randomized, open-label, controlled, multicentre study of 768 healthy Chinese women requiring contraception. The subjects were randomized to ethinylestradiol (EE) 30 microg/DRSP 3 mg (n = 573) or EE 30 microg/ DSG 150 microg (n = 195), at a ratio of 3 : 1. Each individual was treated for 13 cycles. Further visits were required at cycle 4, cycle 7, cycle 10 and cycle 13 of treatment. Weight, height and body mass index were evaluated at each visit. The Menstrual Distress Questionnaire (MDQ) was administered at baseline, visit 3 (cycle 7) and visit 5 (after cycle 13). Baseline characteristics were similar between the two groups (p > 0.05). The Pearl Index (method failure) for EE/DRSP was 0.208 per 100 women-years, which was lower than that for EE/DSG (0.601 per 100 women-years). There were no significant differences between the treatment groups with regard to bleeding patterns. According to the MDQ subscale, improvements in water retention and increases in appetite during the intermenstrual period and in water retention and general well-being during the menstrual period in the EE/DRSP group (-0.297, -0.057, 0.033 and 0.150, respectively) were significantly improved compared with the EE/DSG group (-0.108, 0.023, 0.231 and -0.023, respectively) [all p < 0.05]. Other values that improved in both groups, particularly improvement in breast pain and tenderness and skin condition, were more evident in the EE/DRSP group (18.0%, 89/494; 12.6%, 62/494) than in the EE/DSG group (11.3%, 19/168; 5.4%, 9/168). Mean weight increased in the EE/DSG group (0.57 kg) while there was a significant decrease in mean weight (-0.28 kg) in the EE/DRSP group (p < 0.01). Both EE/DRSP and EE/DSG have good contraceptive efficacy and a comparable bleeding pattern. EE/DRSP had a more favourable effect on weight and premenstrual symptoms than EE/DSG.
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Observing Protein & Energy Nutrition (OPEN) Study
The Observing Protein and Energy Nutrition (OPEN) Study was designed to assess dietary measurement error by comparing results from self-reported dietary intake data with four dietary biomarkers: doubly labeled water and urinary nitrogen, sodium, and potassium.
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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.
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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
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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.
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Cervigni, Mauro; Sommariva, Monica; Tenaglia, Raffaele; Porru, Daniele; Ostardo, Edoardo; Giammò, Alessandro; Trevisan, Silvia; Frangione, Valeria; Ciani, Oriana; Tarricone, Rosanna; Pappagallo, Giovanni L
2017-04-01
Intravesical instillation of hyaluronic acid (HA) plus chondroitin sulfate (CS) in women with bladder pain syndrome/interstitial cystitis (BPS/IC) has shown promising results. This study compared the efficacy, safety, and costs of intravesical HA/CS (Ialuril ® , IBSA) to dimethyl sulfoxide (DMSO). Randomized, open-label, multicenter study involving 110 women with BPS/IC. The allocation ratio (HA/CS:DMSO) was 2:1. Thirteen weekly instillations of HA (1.6%)/CS (2.0%) or 50% DMSO were given. Patients were evaluated at 3 (end-of-treatment) and 6 months. Primary endpoint was reduction in pain intensity at 6 months by visual analogue scale (VAS) versus baseline. Secondary efficacy measurements were quality of life and economic analyses. A significant reduction in pain intensity was observed at 6 months in both treatment groups versus baseline (P < 0.0001) in the intention-to-treat population. Treatment with HA/CS resulted in a greater reduction in pain intensity at 6 months compared with DMSO for the per-protocol population (mean VAS reduction 44.77 ± 25.07 vs. 28.89 ± 31.14, respectively; P = 0.0186). There were no significant differences between treatment groups in secondary outcomes. At least one adverse event was reported in 14.86% and 30.56% of patients in the HA/CS and DMSO groups, respectively. There were significantly fewer treatment-related adverse events for HA/CS versus DMSO (1.35% vs. 22.22%; P = 0.001). Considering direct healthcare costs, the incremental cost-effectiveness ratio of HA/CS versus DMSO fell between 3735€/quality-adjusted life years (QALY) and 8003€/QALY. Treatment with HA/CS appears to be as effective as DMSO with a potentially more favorable safety profile. Both treatments increased health-related quality of life, while HA/CS showed a more acceptable cost-effectiveness profile. © 2016 Wiley Periodicals, Inc.
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Haziza, Christelle; Weitkunat, Rolf; Magnette, John
2016-01-01
Introduction: Tobacco harm reduction aims to provide reduced risk alternatives to adult smokers who would otherwise continue smoking combustible cigarettes (CCs). This randomized, open-label, three-arm, parallel-group, single-center, short-term confinement study aimed to investigate the effects of exposure to selected harmful and potentially harmful constituents (HPHCs) of cigarette smoke in adult smokers who switched to a carbon-heated tobacco product (CHTP) compared with adult smokers who continued to smoke CCs and those who abstained from smoking for 5 days. Methods: Biomarkers of exposure to HPHCs, including nicotine and urinary excretion of mutagenic material, were measured in 24-hour urine and blood samples in 112 male and female Caucasian smokers switching from CCs to the CHTP ad libitum use. Puffing topography was assessed during product use. Results: Switching to the CHTP or smoking abstinence (SA) resulted in marked decreases from baseline to Day 5 in all biomarkers of exposure measured, including carboxyhemoglobin (43% and 55% decrease in the CHTP and SA groups, respectively). The urinary excretion of mutagenic material was also markedly decreased on Day 5 compared with baseline (89% and 87% decrease in the CHTP and SA groups, respectively). No changes in biomarkers of exposure to HPHCs or urinary mutagenic material were observed between baseline and Day 5 in the CC group. Conclusions: Our results provide clear evidence supporting a reduction in the level of exposure to HPHCs of tobacco smoke in smokers who switch to CHTP under controlled conditions, similar to that observed in SA. Implications: The reductions observed in biomarkers of exposure to HPHCs of tobacco smoke in this short-term study could potentially also reduce the incidence of cancer, cardiovascular and respiratory diseases in those smokers who switch to a heated tobacco product. PMID:26817490
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Bernardo-Escudero, Roberto; Alonso-Campero, Rosalba; Francisco-Doce, María Teresa de Jesús; Cortés-Fuentes, Myriam; Villa-Vargas, Miriam; Angeles-Uribe, Juan
2012-12-01
The study aimed to assess the pharmacokinetics of a new, modified-release metoclopramide tablet, and compare it to an immediate-release tablet. A single and multiple-dose, randomized, open-label, parallel, pharmacokinetic study was conducted. Investigational products were administered to 26 healthy Hispanic Mexican male volunteers for two consecutive days: either one 30 mg modified-release tablet every 24 h, or one 10 mg immediate-release tablet every 8 h. Blood samples were collected after the first and last doses of metoclopramide. Plasma metoclopramide concentrations were determined by high-performance liquid chromatography. Safety and tolerability were assessed through vital signs measurements, clinical evaluations, and spontaneous reports from study subjects. All 26 subjects were included in the analyses [mean (SD) age: 27 (8) years, range 18-50; BMI: 23.65 (2.22) kg/m², range 18.01-27.47)]. Peak plasmatic concentrations were not statistically different with both formulations, but occurred significantly later (p < 0.05) with the modified-release form [tmax: 3.15 (1.28) vs. 0.85 (0.32) h and tmax-ss: 2.92 (1.19) vs. 1.04 (0.43) h]. There was no difference noted in the average plasma concentrations [Cavgτ: 23.90 (7.90) vs. 20.64 (7.43) ng/mL after the first dose; and Cavg-ss: 31.14 (9.64) vs. 35.59 (12.29) ng/mL after the last dose, (p > 0.05)]. One adverse event was reported in the test group (diarrhea), and one in the reference group (headache). This study suggests that the 30 mg modified-release metoclopramide tablets show features compatible with slow-release formulations when compared to immediate-release tablets, and is suitable for once-a-day administration.
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Pentikis, Helen S; Adetoro, Nikki
2017-11-10
Bacterial vaginosis (BV) is the most common vaginal infection in reproductive-age women and a significant risk factor for sexually transmitted diseases and pregnancy complications. Standard 5- to 7-day antimicrobial treatments for BV are associated with high rates of recurrence and adverse events. SYM-1219 is a novel granule formulation containing 2 g of secnidazole, developed as an oral, single-dose BV treatment. Two phase 1, open-label, single-center, randomized, crossover trials (studies 102 and 103) assessed the pharmacokinetics and safety of SYM-1219 single doses (≥7-day washout between doses) in healthy, nonpregnant women aged 18 to 65 years inclusive. Study 102 compared SYM-1219 in applesauce in fasted vs fed states. Study 103 compared SYM-1219 (fasted) in pudding and yogurt vs applesauce. Studies 102 and 103 each dosed 24 subjects (mean [standard deviation] ages, 36 [1.8] and 40 [11.6] years, respectively). In both studies the 90% confidence intervals for all treatment comparisons of maximum plasma concentration, area under the concentration-time curve from 0 to last measurable concentration and to infinity, geometric mean ratios were within 80% to 125%, demonstrating bioequivalence. In both studies median fasted time to maximum plasma concentration was 4 hours (6 hours fed in study 102), and mean half-life ranged from 17 to 19 hours. Treatment-emergent adverse events occurred in 70.8% and 83.3% subjects in studies 102 and 103, respectively, most commonly headache (41.7% and 50.0%) and gastrointestinal treatment-emergent adverse events. The pharmacokinetics of SYM-1219 were similar in fed and fasted states and when administered in different foods. © 2017 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.
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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
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Hordinsky, Maria; Fleischer, Alan; Rivers, Jason K; Poulin, Yves; Belsito, Donald; Hultsch, Thomas
2010-08-01
Chronic hand dermatitis is common and difficult to treat. Our aim was to assess the efficacy of pimecrolimus cream 1% in mild-to-moderate chronic hand dermatitis. Adult patients (n = 652) were randomized to pimecrolimus 1% or vehicle cream twice daily with overnight occlusion for 6 weeks, followed by a 6-week open-label pimecrolimus treatment. Primary efficacy was 5-point Investigators' Global Assessment of prospectively selected 'target hand' as treatment success (Investigators' Global Assessment 0 or 1) and treatment failure. Pruritus relief was also assessed. Following double-blind phase treatment, target hand treatment success was achieved in 29.8 and 23.2% of the patients in the pimecrolimus and vehicle groups, respectively (p = 0.057). The proportion of patients experiencing pruritus relief was significantly higher in the pimecrolimus group compared to the vehicle group at all time points throughout the double-blind phase. The groups were comparable with respect to treating disease signs. Pruritus relief, however, was significantly greater in the pimecrolimus group. Copyright 2010 S. Karger AG, Basel.
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Toll, Benjamin A.; O’Malley, Stephanie S.; Katulak, Nicole A.; Wu, Ran; Dubin, Joel A.; Latimer, Amy; Meandzija, Boris; George, Tony P.; Jatlow, Peter; Cooney, Judith L.; Salovey, Peter
2008-01-01
Prospect theory suggests that because smoking cessation is a prevention behavior with a fairly certain outcome, gain-framed messages will be more persuasive than loss-framed messages when attempting to encourage smoking cessation. To test this hypothesis, the authors randomly assigned participants (N = 258) in a clinical trial to either a gain- or loss-framed condition, in which they received factually equivalent video and printed messages encouraging smoking cessation that emphasized either the benefits of quitting (gains) or the costs of continuing to smoke (losses), respectively. All participants received open label sustained-release bupropion (300 mg/day) for 7 weeks. In the intent-to-treat analysis, the difference between the experimental groups by either point prevalence or continuous abstinence was not statistically significant. Among 170 treatment completers, however, a significantly higher proportion of participants were continuously abstinent in the gain-framed condition as compared with the loss-framed condition. These data suggest that gain-framed messages may be more persuasive than loss-framed messages in promoting early success in smoking cessation for participants who are engaged in treatment. PMID:18072836
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Nestor, Mark; Andriessen, Anneke; Berman, Brian; Katz, Bruce E; Gilbert, Dore; Goldberg, David J; Gold, Michael H; Kirsner, Robert S; Lorenc, Paul Z
2017-08-01
Non-thermal laser therapy in dermatology, is a growing field in medical technology by which therapeutic effects are achieved by exposing tissues to specific wavelengths of light. The purpose of this review was to gain a better understanding of the science behind non-thermal laser and the evidence supporting its use in dermatology. A group of dermatologists and surgeons recently convened to review the evidence supporting the use of non-thermal laser for body sculpting, improving the appearance of cellulite, and treating onychomycosis. The use of non-thermal laser for body sculpting is supported by three randomized, double-blind, sham-controlled studies (N = 161), one prospective open-label study (N = 54), and two retrospective studies (N = 775). Non-thermal laser application for improving the appearance of cellulite is supported by one randomized, double-blind, sham-controlled study (N = 38). The use of non-thermal laser for the treatment of onychomycosis is supported by an analysis of three non-randomized, open-label studies demonstrating clinical improvement of nails (N = 292). Non-thermal laser is steadily moving into mainstream medical practice, such as dermatology. Although present studies have demonstrated the safety and efficacy of non-thermal laser for body sculpting, cellulite reduction and onychomycosis treatment, studies demonstrating the efficacy of non-thermal laser as a stand-alone procedure are still inadequate.
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USDA-ARS?s Scientific Manuscript database
Low-quality dietary protein intake and vitamin B-12 deficiency could interact to decrease methionine transmethylation and remethylation rates during pregnancy, and may affect epigenetic modifications of the fetal genome. The objective of this randomized, partially open-labeled intervention trial was...
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Yang, Wenying; Zhu, Lvyun; Meng, Bangzhu; Liu, Yu; Wang, Wenhui; Ye, Shandong; Sun, Li; Miao, Heng; Guo, Lian; Wang, Zhanjian; Lv, Xiaofeng; Li, Quanmin; Ji, Qiuhe; Zhao, Weigang; Yang, Gangyi
2016-01-01
The present study was to compare the efficacy and safety of subject-driven and investigator-driven titration of biphasic insulin aspart 30 (BIAsp 30) twice daily (BID). In this 20-week, randomized, open-label, two-group parallel, multicenter trial, Chinese patients with type 2 diabetes inadequately controlled by premixed/self-mixed human insulin were randomized 1:1 to subject-driven or investigator-driven titration of BIAsp 30 BID, in combination with metformin and/or α-glucosidase inhibitors. Dose adjustment was decided by patients in the subject-driven group after training, and by investigators in the investigator-driven group. Eligible adults (n = 344) were randomized in the study. The estimated glycated hemoglobin (HbA1c) reduction was 14.5 mmol/mol (1.33%) in the subject-driven group and 14.3 mmol/mol (1.31%) in the investigator-driven group. Non-inferiority of subject-titration vs investigator-titration in reducing HbA1c was confirmed, with estimated treatment difference -0.26 mmol/mol (95% confidence interval -2.05, 1.53) (-0.02%, 95% confidence interval -0.19, 0.14). Fasting plasma glucose, postprandial glucose increment and self-measured plasma glucose were improved in both groups without statistically significant differences. One severe hypoglycemic event was experienced by one subject in each group. A similar rate of nocturnal hypoglycemia (events/patient-year) was reported in the subject-driven (1.10) and investigator-driven (1.32) groups. There were 64.5 and 58.1% patients achieving HbA1c <53.0 mmol/mol (7.0%), and 51.2 and 45.9% patients achieving the HbA1c target without confirmed hypoglycemia throughout the trial in the subject-driven and investigator-driven groups, respectively. Subject-titration of BIAsp 30 BID was as efficacious and well-tolerated as investigator-titration. The present study supported patients to self-titrate BIAsp 30 BID under physicians' supervision.
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Falup-Pecurariu, Oana; Man, Sorin C; Neamtu, Mihai L; Chicin, Gratiana; Baciu, Ginel; Pitic, Carmen; Cara, Alexandra C; Neculau, Andrea E; Burlea, Marin; Brinza, Ileana L; Schnell, Cristina N; Sas, Valentina; Lupu, Valeriu V; François, Nancy; Swinnen, Kristien; Borys, Dorota
2017-03-04
Prophylactic paracetamol administration impacts vaccine immune response; this study ( www.clinicaltrials.gov : NCT01235949) is the first to assess PHiD-CV immunogenicity following prophylactic ibuprofen administration. In this phase IV, multicenter, open-label, randomized, controlled, non-inferiority study in Romania (November 2010-December 2012), healthy infants were randomized 3:3:3:1:1:1 to prophylactically receive immediate, delayed or no ibuprofen (IIBU, DIBU, NIBU) or paracetamol (IPARA, DPARA, NPARA) after each of 3 primary doses (PHiD-CV at age 3/4/5 months co-administered with DTPa-HBV-IPV/Hib at 3/5 and DTPa-IPV/Hib at 4 months) or booster dose (PHiD-CV and DTPa-HBV-IPV/Hib; 12-15 months). Non-inferiority of immune response one month post-primary vaccination in terms of percentage of infants with anti-pneumococcal antibody concentrations ≥0.2 µg/mL (primary objective) was demonstrated if the upper limit (UL) of the 98.25% confidence interval of difference between groups (NIBU vs IIBU, NIBU vs DIBU) was <10% for ≥7/10 serotypes. Immunogenicity and reactogenicity/safety were evaluated, including confirmatory analysis of difference in fever incidences post-primary vaccination in IBU or DIBU group compared to NIBU. Of 850 infants randomized, 812 were included in the total vaccinated cohort. Non-inferiority was demonstrated for both comparisons (UL was <10% for 9/10 vaccine serotypes; exceptions: 6B [NIBU], 23F [IIBU]). However, fever incidence post-primary vaccination in the IIBU and DIBU groups did not indicate a statistically significant reduction. Prophylactic administration (immediate or delayed) of paracetamol decreased fever incidence but seemed to reduce immune response to PHiD-CV, except when given only at booster. Twenty-seven serious adverse events were reported for 15 children; all resolved and were not vaccination-related.
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Clinical efficacy of edaravone for the treatment of amyotrophic lateral sclerosis.
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.
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Ketamine for cancer pain: what is the evidence?
Jonkman, Kelly; van de Donk, Tine; Dahan, Albert
2017-06-01
In this review, we assess the benefit of ketamine in the treatment of terminal cancer pain that is refractory to opioid treatment and/or complicated by neuropathy. While randomized controlled trials consistently show lack of clinical efficacy of ketamine in treating cancer pain, a large number of open-label studies and case series show benefit. Ketamine is an N-methyl-D-aspartate receptor antagonist that at low-dose has effective analgesic properties. In cancer pain, ketamine is usually prescribed as adjuvant to opioid therapy when pain becomes opioid resistant or when neuropathic pain symptoms dominate the clinical picture. A literature search revealed four randomized controlled trials that examined the benefit of oral, subcutaneous or intravenous ketamine in opioid refractory cancer pain. None showed clinically relevant benefit in relieving pain or reducing opioid consumption. This suggests absence of evidence of benefit for ketamine as adjuvant analgesic in cancer pain. These findings contrast the benefit from ketamine observed in a large number of open-label studies and (retrospective) case series. We relate the opposite outcomes to methodological issues. The complete picture is such that there is still insufficient evidence to state with certainty that ketamine is not effective in cancer pain.
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Bui, Eric; Nadal-Vicens, Mireya; M. Simon, Naomi
2012-01-01
Complicated grief (CG) is a common and often under-acknowledged cause of profound impairment experienced after the loss of a loved one. Although both clinical and basic research suggests that pharmacological agents might be of use in the treatment of CG, research on pharmacological approaches to this condition is still scarce. Three open-label trials and one randomized trial on bereavement-related depression suggest that tricyclic antidepressants may be effective, although they may be more efficacious for depressive symptoms than for grief-specific symptoms. Four open-label trials (total number of participants, 50) of selective serotonin reuptake inhibitors (SSRIs) have yielded results, providing very preliminary support that they might be effective in the treatment of CG, both as a standalone treatment and in conjunction with psychotherapeutic interventions. These more recent studies have shown an effect on both depression and grief-specific scales. Furthermore, therapeutic interventions for CG may be more effective in conjunction with SSRI administration. Given the small number of pharmacological studies to date, there is a need for randomized trials to test the potential efficacy of pharmacological agents in the treatment of CG. PMID:22754287
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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.
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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.
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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.
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2012-01-01
Introduction The Molecular Adsorbent Recycling System (MARS) is used to treat patients with liver failure. Observational data suggest that citrate anticoagulation during MARS is feasible. Comparative studies on the optimal anticoagulation regimen during MARS are lacking. The aim of the current study was to evaluate two heparin-free anticoagulation regimens. Methods We performed a prospective randomized open-label crossover study of regional citrate anticoagulation against no anticoagulation. Ten patients (age 55 ± 11 years) with liver failure undergoing MARS treatment were included. The primary endpoint was completion of MARS sessions. Secondary endpoints included treatment efficacy and safety. Longevity of MARS treatment was plotted as a Kaplan-Meier estimate. Fisher's exact test was used for contingency table analysis. Results Of a total of 27 6-hour sessions, four sessions had to be terminated prematurely, three due to occlusive clotting of the extracorporeal circuit and one due to uncontrollable bleeding from the vascular access site. All four events occurred in the group without anticoagulation. Between group comparison demonstrated citrate anticoagulation to significantly increase the likelihood of completed MARS treatment (Fisher's exact test, P 0.04). This translates into higher bilirubin reduction ratios when citrate was applied (reduction ratio 0.25 vs. 0.15, P 0.02). Systemic ionized calcium concentrations were significantly reduced during citrate anticoagulation (P < 0.001) but remained within a safe range. We observed no major adverse events. Conclusions Regional citrate anticoagulation in patients with liver failure is feasible. Citrate anticoagulation provides superior patency of the extracorporeal circuit. Avoidance of anticoagulation during MARS results in significant loss of treatment efficacy, due to treatment downtime. Additional studies are required to identify the optimal anticoagulation regimen for extracorporeal circulation in patients with liver failure. PMID:22305273
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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.
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Pettengell, Ruth; Coiffier, Bertrand; Egorov, Anton; Singer, Jack; Sivcheva, Lilia
2018-06-01
Pixantrone is recommended in relapsed and refractory non-Hodgkin lymphoma (NHL) or heavily pretreated NHL patients. Its conditional approval in Europe was based on results from the open-label, randomized, phase 3 PIX301 study, comparing pixantrone monotherapy with physician's choice of treatment in 140 patients with relapsed or refractory aggressive NHL. This post-hoc analysis of the PIX301 study investigated possible correlations between patient characteristics and clinical response in 17 patients (24%) treated with pixantrone who achieved a complete response (CR) or an unconfirmed complete response (CRu) at study end. These patients (10 male and 7 female) had a median age of 61 (range 41-75) years, and the most common diagnoses were diffuse large B-cell lymphoma (n = 10) and transformed indolent lymphoma (n = 4). Most had received two prior lines of therapy (n = 12). There was wide variation in the time from diagnosis to study entry (219-4777 days). Among the 17 patients who achieved a CR/CRu with pixantrone, 6 had stable or progressive disease as a response to their last regimen, 7 had a partial response, and 4 had a CR/CRu. Four patients from the pixantrone group survived without progression for more than 400 days. Prior response to previous therapies did not appear to affect long-term response to pixantrone. These observations suggest that pixantrone monotherapy in patients with multiply relapsed or refractory aggressive NHL who had received at least two prior therapies can be associated with durable responses and long-term remission, and this may be unrelated to the clinical response to the last therapy.
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Airhart, Sophia E; Shireman, Laura M; Risler, Linda J; Anderson, Gail D; Nagana Gowda, G A; Raftery, Daniel; Tian, Rong; Shen, Danny D; O'Brien, Kevin D
2017-01-01
The co-primary objectives of this study were to determine the human pharmacokinetics (PK) of oral NR and the effect of NR on whole blood nicotinamide adenine dinucleotide (NAD+) levels. Though mitochondrial dysfunction plays a critical role in the development and progression of heart failure, no mitochondria-targeted therapies have been translated into clinical practice. Recent murine studies have reported associations between imbalances in the NADH/NAD+ ratio with mitochondrial dysfunction in multiple tissues, including myocardium. Moreover, an NAD+ precursor, nicotinamide mononucleotide, improved cardiac function, while another NAD+ precursor, nicotinamide riboside (NR), improved mitochondrial function in muscle, liver and brown adipose. Thus, PK studies of NR in humans is critical for future clinical trials. In this non-randomized, open-label PK study of 8 healthy volunteers, 250 mg NR was orally administered on Days 1 and 2, then uptitrated to peak dose of 1000 mg twice daily on Days 7 and 8. On the morning of Day 9, subjects completed a 24-hour PK study after receiving 1000 mg NR at t = 0. Whole-blood levels of NR, clinical blood chemistry, and NAD+ levels were analyzed. Oral NR was well tolerated with no adverse events. Significant increases comparing baseline to mean concentrations at steady state (Cave,ss) were observed for both NR (p = 0.03) and NAD+ (p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R2 = 0.72, p = 0.008). Because NR increases circulating NAD+ in humans, NR may have potential as a therapy in patients with mitochondrial dysfunction due to genetic and/or acquired diseases.
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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.
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Airhart, Sophia E.; Shireman, Laura M.; Risler, Linda J.; Anderson, Gail D.; Nagana Gowda, G. A.; Raftery, Daniel; Tian, Rong; Shen, Danny D.; O’Brien, Kevin D.
2017-01-01
Objectives The co-primary objectives of this study were to determine the human pharmacokinetics (PK) of oral NR and the effect of NR on whole blood nicotinamide adenine dinucleotide (NAD+) levels. Background Though mitochondrial dysfunction plays a critical role in the development and progression of heart failure, no mitochondria-targeted therapies have been translated into clinical practice. Recent murine studies have reported associations between imbalances in the NADH/NAD+ ratio with mitochondrial dysfunction in multiple tissues, including myocardium. Moreover, an NAD+ precursor, nicotinamide mononucleotide, improved cardiac function, while another NAD+ precursor, nicotinamide riboside (NR), improved mitochondrial function in muscle, liver and brown adipose. Thus, PK studies of NR in humans is critical for future clinical trials. Methods In this non-randomized, open-label PK study of 8 healthy volunteers, 250 mg NR was orally administered on Days 1 and 2, then uptitrated to peak dose of 1000 mg twice daily on Days 7 and 8. On the morning of Day 9, subjects completed a 24-hour PK study after receiving 1000 mg NR at t = 0. Whole-blood levels of NR, clinical blood chemistry, and NAD+ levels were analyzed. Results Oral NR was well tolerated with no adverse events. Significant increases comparing baseline to mean concentrations at steady state (Cave,ss) were observed for both NR (p = 0.03) and NAD+ (p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R2 = 0.72, p = 0.008). Conclusions Because NR increases circulating NAD+ in humans, NR may have potential as a therapy in patients with mitochondrial dysfunction due to genetic and/or acquired diseases. PMID:29211728
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Ilkowitz, Jeniece Trast; Katikaneni, Ranjitha; Cantwell, Martin; Ramchandani, Neesha; Heptulla, Rubina A
2016-09-01
The closed-loop (CL) system delivers insulin in a glucose-responsive manner and optimal postprandial glycemic control is difficult to achieve with the algorithm and insulin available. We hypothesized that adjunctive therapy with liraglutide, a once-daily glucagon-like peptide-1 agonist, would be more effective in normalizing postprandial hyperglycemia versus insulin monotherapy in the CL system, in patients with type 1 diabetes. This was a randomized, controlled, open-label, crossover design trial comparing insulin monotherapy versus adjuvant subcutaneous liraglutide 1.2 mg and insulin, using the CL system in 15 patients. Blood glucose (BG), insulin, and glucagon concentrations were analyzed. The liraglutide arm was associated with overall decreased mean BG levels (P = .0002). The average BG levels from 8:00 pm (day 1) to 9:00 pm (day 2) were lower in the liraglutide arm (144.6 ± 36.31 vs 159.7 ± 50.88 mg/dl respectively; P = .0002). Two-hour postbreakfast and lunch BG profiles were better in the liraglutide arm (P < .05) and the insulin and glucagon assay values were lower (P < .0001). Postprandially, the area under the curve (AUC) for 2-hour postbreakfast and lunch BG levels were significant (P = .01, P = .03) and the AUC for glucagon, postbreakfast (P < .0001) and lunch (P < .05), was also significant. The incidence of hypoglycemia did not differ between arms (P = .83, Fisher's exact test). Overall, adjunct liraglutide therapy plus CL was well tolerated even with expected side effects. This is a proof-of-concept study showing liraglutide can be a potential adjunctive therapy in addition to CL with insulin to reduce postprandial hyperglycemia in type 1 diabetes. © 2016 Diabetes Technology Society.
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Memantine and constraint-induced aphasia therapy in chronic poststroke aphasia.
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.
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Responsive cortical stimulation for the treatment of medically intractable partial epilepsy.
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.
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Göke, R; Eschenbach, P; Dütting, E D
2015-06-01
This study compared the efficacy of vildagliptin and sitagliptin in lowering fasting plasma glucose (FPG) as single-pill combinations (SPCs) with metformin. The randomized crossover, open-label, active-controlled study design assessed the FPG-lowering abilities of a vildagliptin/metformin (50/1000 mg twice daily) SPC compared with a sitagliptin/metformin (50/1000 mg twice daily) SPC after 2 weeks of treatment in 99 type 2 diabetes patients uncontrolled by stable metformin therapy (1000-2000 mg/day). The change in FPG from baseline to day 14 was significantly greater (P < 0.02, Wilcoxon) with vildagliptin [-21.9 mg/dL (SD 27.0)] than with sitagliptin [-14.5 mg/dL (SD 23.0)]. After 14 days of treatment, the mean FPG was 137.8 mg/dL (SD 28.5) with vildagliptin and 140.1mg/dL (SD 26.5) with sitagliptin (P < 0.05, Wilcoxon). Both of these DPP-4 inhibitors, given as SPCs twice daily with metformin, lowered FPG after 14 days of treatment. However, vildagliptin produced a significantly greater reduction in FPG vs baseline compared with sitagliptin, which may translate into clinical relevance. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
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Ahrendt, Hans-Joachim; Nisand, Israel; Bastianelli, Carlo; Gómez, Maria Angeles; Gemzell-Danielsson, Kristina; Urdl, Wolfgang; Karskov, Birgit; Oeyen, Luc; Bitzer, Johannes; Page, Geert; Milsom, Ian
2006-12-01
This randomized multicenter, open-label, trial compared efficacy, acceptability, tolerability and compliance of NuvaRing with a combined oral contraceptive (COC), containing 30 microg of ethinyl estradiol (EE) and 3 mg of drospirenone. In this 13-cycle study, 983 women were randomized and treated (intent-to-treat population) with NuvaRing or COC. One in-treatment pregnancy occurred with NuvaRing (Pearl Index=0.25) (95% confidence interval [CI]: 0.006, 1.363) and four with the COC (Pearl Index=0.99) (95% CI: 0.269, 2.530). For both groups, compliance (89.2% NuvaRing, 85.5% COC) and satisfaction (84% NuvaRing; 87% COC) were high; the vast majority of women found NuvaRing easy to insert (96%) and remove (97%). Tolerability was similar; the most frequent adverse events with NuvaRing were related to ring use, whereas estrogen-related events were more common with the COC. NuvaRing has comparable efficacy and tolerability to a COC containing 30 microg of EE and 3 mg drospirenone. User acceptability of both methods was high.
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Safety and Immunogenicity of Sequential Rotavirus Vaccine Schedules
Libster, Romina; McNeal, Monica; Walter, Emmanuel B.; Shane, Andi L.; Winokur, Patricia; Cress, Gretchen; Berry, Andrea A.; Kotloff, Karen L.; Sarpong, Kwabena; Turley, Christine B.; Harrison, Christopher J.; Pahud, Barbara A.; Marbin, Jyothi; Dunn, John; El-Khorazaty, Jill; Barrett, Jill
2016-01-01
BACKGROUND AND OBJECTIVES: Although both licensed rotavirus vaccines are safe and effective, it is often not possible to complete the schedule by using the same vaccine formulation. The goal of this study was to investigate the noninferiority of the immune responses to the 2 licensed rotavirus vaccines when administered as a mixed schedule compared with administering a single vaccine formulation alone. METHODS: Randomized, multicenter, open-label study. Healthy infants (6–14 weeks of age) were randomized to receive rotavirus vaccines in 1 of 5 different schedules (2 using a single vaccine for all doses, and 3 using mixed schedules). The group receiving only the monovalent rotavirus vaccine received 2 doses of vaccine and the other 4 groups received 3 doses of vaccine. Serum for immunogenicity testing was obtained 1 month after the last vaccine dose and the proportion of seropositive children (rotavirus immunoglobulin A ≥20 U/mL) were compared in all the vaccine groups. RESULTS: Between March 2011 and September 2013, 1393 children were enrolled and randomized. Immune responses to all the sequential mixed vaccine schedules were shown to be noninferior when compared with the 2 single vaccine reference groups. The proportion of children seropositive to at least 1 vaccine antigen at 1 month after vaccination ranged from 77% to 96%, and was not significantly different among all the study groups. All schedules were well tolerated. CONCLUSIONS: Mixed schedules are safe and induced comparable immune responses when compared with the licensed rotavirus vaccines given alone. PMID:26823540
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Yotebieng, Marcel; Behets, Frieda; Kawende, Bienvenu; Ravelomanana, Noro Lantoniaina Rosa; Tabala, Martine; Okitolonda, Emile W
2017-04-26
Despite the rapid adoption of the World Health Organization's 2013 guidelines, children continue to be infected with HIV perinatally because of sub-optimal adherence to the continuum of HIV care in maternal and child health (MCH) clinics. To achieve the UNAIDS goal of eliminating mother-to-child HIV transmission, multiple, adaptive interventions need to be implemented to improve adherence to the HIV continuum. The aim of this open label, parallel, group randomized trial is to evaluate the effectiveness of Continuous Quality Improvement (CQI) interventions implemented at facility and health district levels to improve retention in care and virological suppression through 24 months postpartum among pregnant and breastfeeding women receiving ART in MCH clinics in Kinshasa, Democratic Republic of Congo. Prior to randomization, the current monitoring and evaluation system will be strengthened to enable collection of high quality individual patient-level data necessary for timely indicators production and program outcomes monitoring to inform CQI interventions. Following randomization, in health districts randomized to CQI, quality improvement (QI) teams will be established at the district level and at MCH clinics level. For 18 months, QI teams will be brought together quarterly to identify key bottlenecks in the care delivery system using data from the monitoring system, develop an action plan to address those bottlenecks, and implement the action plan at the level of their district or clinics. If proven to be effective, CQI as designed here, could be scaled up rapidly in resource-scarce settings to accelerate progress towards the goal of an AIDS free generation. The protocol was retrospectively registered on February 7, 2017. ClinicalTrials.gov Identifier: NCT03048669 .
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Efficacy of steroidal vs non-steroidal agents in oral lichen planus: a randomised, open-label study.
Singh, A R; Rai, A; Aftab, M; Jain, S; Singh, M
2017-01-01
This study compared the therapeutic efficacy of steroidal and non-steroidal agents for treating oral lichen planus. Forty patients with clinical and/or histologically proven oral lichen planus were randomly placed into four groups and treated with topical triamcinolone, oral dapsone, topical tacrolimus or topical retinoid for three months. Pre- and post-treatment symptoms and signs were scored for each patient. Patients in all treatment groups showed significant clinical improvement after three months (p 0.05) and for topical retinoid vs topical tacrolimus (p > 0.05). Non-steroidal drugs such as dapsone, tacrolimus and retinoid are as efficacious as steroidal drugs for treating oral lichen planus, and avoid the side effects associated with steroids.
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Effect of Terbinafine on Theophylline Pharmacokinetics in Healthy Volunteers
Trépanier, Eric F.; Nafziger, Anne N.; Amsden, Guy W.
1998-01-01
Twelve healthy volunteers were enrolled in an open-label, randomized, crossover study. Subjects received single doses of theophylline (5 mg/kg) with and without multiple-dose terbinafine, and 11 blood samples were collected over 24 h. The study phases were separated by a 4-week washout period. Theophylline serum data were modeled via noncompartmental analysis. When the control phase (i.e., no terbinafine) was compared to the treatment phase (terbinafine), theophylline exposure (the area under the serum concentration-time curve from time zero to infinity) increased by 16% (P = 0.03), oral clearance decreased by 14% (P = 0.04), and half-life increased by 24% (P = 0.002). No significant changes in other theophylline pharmacokinetic parameters were evident. PMID:9517954
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Evaluation of Bayesian Sequential Proportion Estimation Using Analyst Labels
NASA Technical Reports Server (NTRS)
Lennington, R. K.; Abotteen, K. M. (Principal Investigator)
1980-01-01
The author has identified the following significant results. A total of ten Large Area Crop Inventory Experiment Phase 3 blind sites and analyst-interpreter labels were used in a study to compare proportional estimates obtained by the Bayes sequential procedure with estimates obtained from simple random sampling and from Procedure 1. The analyst error rate using the Bayes technique was shown to be no greater than that for the simple random sampling. Also, the segment proportion estimates produced using this technique had smaller bias and mean squared errors than the estimates produced using either simple random sampling or Procedure 1.
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Elmer, Lawrence W; Surmann, Erwin; Boroojerdi, Babak; Jankovic, Joseph
2012-06-01
This prospective, open-label extension (SP702; NCT00594165) of a 6-month double-blind, randomized study investigated the long-term safety and tolerability of rotigotine transdermal system in early Parkinson's disease (PD). Patients with early-stage idiopathic PD received transdermal rotigotine for up to 6 years at optimal dose (up to 16 mg/24h). Adjunctive levodopa was allowed. Primary outcomes included adverse events (AEs) and extent of rotigotine exposure. Other outcomes included time to levodopa, incidence of dyskinesias, and efficacy using the Unified Parkinson's Disease Rating Scale (UPDRS) II+III total score. Of 217 patients entering the open-label study, 47% were still in the study upon closure; 24% withdrew because of AEs and 6% because of lack of efficacy. The median exposure to rotigotine was 1910 days (≈ 5 years, 3 months; range 1-2188 days). Most common AEs were somnolence (23% per patient-year), falls (17%), peripheral edema (14%), nausea (12%), and application site reactions (ASRs; 12%). 3% withdrew because of ASRs. 26% patients did not initiate levodopa; of those who did, fewer than half started levodopa in the first year. Dyskinesias were reported by 25% patients; the majority (83%) reported their first episode after initiating levodopa. Mean UPDRS II+III total scores remained below double-blind baseline for up to 2 years of open-label treatment. This is the longest interventional study of rotigotine conducted to date. Transdermal rotigotine was generally well tolerated for up to 6 years; AEs reported were similar to those observed in shorter studies and led to discontinuation in only 24% patients. Copyright © 2012 Elsevier Ltd. All rights reserved.
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Bruins Slot, Karsten M H; Berge, Eivind
2013-08-08
Anticoagulant treatment with vitamin K antagonists (VKAs) is aimed at preventing thromboembolic complications and has been the therapy of choice for most people with non-valvular atrial fibrillation (AF) for many decades. A new class of anticoagulants, the factor Xa inhibitors, appear to have several pharmacological and practical advantages over VKAs. To assess the effectiveness and safety of treatment with factor Xa inhibitors versus VKAs for the prevention of cerebral or systemic embolic events in people with AF. We searched the trials registers of the Cochrane Stroke Group and the Cochrane Heart Group (June 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 10), MEDLINE (1950 to April 2013) and EMBASE (1980 to April 2013). In an effort to identify further published, unpublished and ongoing trials we searched trials registers and Google Scholar (July 2012). We also screened reference lists and contacted pharmaceutical companies, authors and sponsors of relevant published trials. Randomised controlled trials that directly compared the effects of long-term treatment (more than four weeks) with factor Xa inhibitors and VKAs for the prevention of cerebral and systemic embolism in patients with AF. We included patients with and without a previous stroke or TIA. The primary efficacy outcome was the composite endpoint of all strokes and other systemic embolic events. Two authors independently assessed trial quality and the risk of bias, and extracted data. We calculated a weighted estimate of the typical treatment effect across trials using the odds ratio (OR) with 95% confidence interval (CI) by means of a fixed-effect model. However, in the case of moderate or high heterogeneity of treatment effects, we used a random-effects model to compare the overall treatment effects and performed a pre-specified sensitivity analysis excluding any fully open-label studies. We included data from 42,084 participants randomised into 10 trials. All participants had a confirmed diagnosis of AF (or atrial flutter) and were deemed by the randomising physician to be eligible for long-term anticoagulant treatment with a VKA (warfarin) with a target International Normalised Ratio (INR) of 2.0 to 3.0 in most patients. The included trials directly compared dose-adjusted warfarin with either apixaban, betrixaban, darexaban, edoxaban, idraparinux or rivaroxaban. Four trials were double-masked, five partially-masked (that is different doses of factor Xa inhibitor administered double-masked and warfarin administered open-label) and one was open-label. Median duration of follow-up ranged from 12 weeks to 1.9 years.The composite primary efficacy endpoint of all strokes (both ischaemic and haemorrhagic) and non-central nervous systemic embolic events was reported in nine of the included studies (40,777 participants). Treatment with a factor Xa inhibitor significantly decreased the number of strokes and systemic embolic events compared with dose-adjusted warfarin (OR 0.81, 95% CI 0.72 to 0.91). We also analysed both components of this composite endpoint separately: treatment with a factor Xa inhibitor significantly decreased both the number of ischaemic and haemorrhagic strokes (OR 0.78, 95% CI 0.69 to 0.89) and the number of systemic embolic events (OR 0.53, 95% CI 0.32 to 0.87).All of the included studies (42,078 participants) reported the number of major bleedings. Treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.89, 95% CI 0.81 to 0.98). There was, however, statistically significant and high heterogeneity (I² = 81%) and an analysis using a random-effects model did not show a statistically significant decrease in the number of major bleedings (OR 0.92, 95% CI 0.63 to 1.34). The pre-specified sensitivity analysis excluding open-label studies showed that treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.84, 95% CI 0.76 to 0.92) but moderate heterogeneity was still observed (I² = 65%). A similar sensitivity analysis using a random-effects model did not show a statistically significant decrease in the number of major bleedings in patients treated with factor Xa inhibitors (OR 0.78, 95% CI 0.57 to 1.05). Part of the observed heterogeneity can thus be explained by the increased risk of major bleedings in the factor Xa treatment arm in the single included open-label study, which studied idraparinux. Other heterogeneity might be explained by differences in baseline bleeding risks in the two largest trials of apixaban and rivaroxaban that we included in this review.Data on intracranial haemorrhages (ICHs) were reported in eight studies (39,638 participants). Treatment with a factor Xa inhibitor significantly reduced the risk of ICH compared with warfarin (OR 0.56, 95% CI 0.45 to 0.70). Again, we observed statistically significant heterogeneity (I² = 60%). The pre-specified sensitivity analysis excluding the open-label study showed that treatment with a factor Xa inhibitor significantly reduced the number of ICHs compared with warfarin (OR 0.51, 95% CI 0.41 to 0.64), without any sign of statistical heterogeneity (I² = 0%).The number of patients who died from any cause was reported in six studies (38,924 participants). Treatment with a factor Xa inhibitor significantly reduced the number of all-cause deaths compared with warfarin (OR 0.88, 95% 0.81 to 0.97). Factor Xa inhibitors significantly reduced the number of strokes and systemic embolic events compared with warfarin in patients with AF. Factor Xa inhibitors also seem to reduce the number of major bleedings and ICHs compared with warfarin, though the evidence for a reduction of major bleedings is somewhat less robust. There is currently no conclusive evidence to determine which factor Xa inhibitor is more effective and safer for long-term anticoagulant treatment of patients with AF as head-to-head studies of the different factor Xa inhibitors have not yet been performed.
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Mansour, Diana; Westhoff, Carolyn; Kher, Uma; Korver, Tjeerd
2017-04-01
To obtain more precise and detailed information regarding the bleeding patterns of nomegestrol acetate (NOMAC)/17β-estradiol (E2) and drospirenone/ethinyl estradiol (DRSP/EE) and to identify whether baseline demographic characteristics were associated with unscheduled bleeding, absent scheduled bleeding, or amenorrhea. This analysis pooled results from two pivotal open-label, randomized trials that compared bleeding patterns of NOMAC/E2 and DRSP/EE. In the two studies 4317 women aged 18-50 years from 24 countries across the Americas, Europe, and Asia underwent treatment. 2835 women taking NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen and 938 women taking DRSP/EE (3 mg/30 μg) in a 21/7-day regimen had at least 1 evaluable cycle for vaginal bleeding analyses. The frequency of absent scheduled bleeding was higher (p<.0001) for women using NOMAC/E2 than DRSP/EE across all 11 cycles (cycles 2-12), ranging between 17.6% and 31.6% and between 3.4% and 5.8%, respectively. For women who had absent scheduled bleeding in cycles 2, 3, or 4 the incidence of absent scheduled bleeding in subsequent cycles was high and ranged between approximately 50%-60% for NOMAC/E2 and approximately 40%-50% for DRSP/EE. Amenorrhea increased over time with both regimens, being higher with NOMAC/E2. Both absent scheduled bleeding and amenorrhea with NOMAC/E2 were more common in older women, overweight women, switchers, and smokers; unscheduled bleeding was more common in starters, but had no association with age, body mass index, and smoking. NOMAC/E2 is associated with a higher prevalence of absent scheduled bleeding compared with DRSP/EE. Absent scheduled bleeding and amenorrhea were associated with age, body weight, switching and smoking. Unscheduled bleeding was more common in starters. Information about the factors associated with bleeding patterns may help clinicians provide guidance to women considering use of the NOMAC/E2 oral contraceptive. Copyright © 2016 Elsevier Inc. All rights reserved.
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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.
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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
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Naylor, Jennifer C; Kilts, Jason D; Bradford, Daniel W; Strauss, Jennifer L; Capehart, Bruce P; Szabo, Steven T; Smith, Karen D; Dunn, Charlotte E; Conner, Kathryn M; Davidson, Jonathan R T; Wagner, Henry Ryan; Hamer, Robert M; Marx, Christine E
2015-05-01
Many individuals with post-traumatic stress disorder (PTSD) experience persistent symptoms despite pharmacological treatment with antidepressants. Several open-label monotherapy and adjunctive studies have suggested that aripiprazole (a second-generation antipsychotic) may have clinical utility in PTSD. However, there have been no randomized placebo-controlled trials of aripiprazole use for PTSD. We thus conducted a pilot randomized controlled trial of adjunctive aripiprazole versus placebo among Veterans with chronic PTSD serving in the US military since 11 September 2001 to assess the feasibility, safety, tolerability, and therapeutic potential of aripiprazole. Sixteen Veterans were randomized, and 14 completed at least 4 weeks of the study; 12 completed the entire 8-week trial. Outcome measures included the Clinician-Administered PTSD Scale (CAPS), PTSD Checklist, Beck Depression Inventory, Second Edition, and Positive and Negative Syndrome Scale scores. Aripiprazole was well-tolerated in this cohort, and improvements in CAPS, PTSD Checklist, Beck Depression Inventory, Second Edition, and Positive and Negative Syndrome Scale scores were as hypothesized. Although CAPS change scores did not reach statistical significance, aripiprazole outperformed placebo by 9 points on the CAPS in the last observation carried forward analysis compared with the placebo group (n = 7 per group), and by 20 points in the group randomized to aripiprazole that completed the entire study (n = 5) compared with the placebo group (n = 7). Results suggest promise for aripiprazole as an adjunctive strategy for the treatment of PTSD.
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Miskowiak, Kamilla W; Carvalho, André F; Vieta, Eduard; Kessing, Lars V
2016-10-01
Cognitive dysfunction is an emerging treatment target in bipolar disorder (BD). Several trials have assessed the efficacy of novel pharmacological and psychological treatments on cognition in BD but the findings are contradictory and unclear. A systematic search following the PRISMA guidelines was conducted on PubMed and PsychInfo. Eligible articles reported randomized, controlled or open-label trials investigating pharmacological or psychological treatments targeting cognitive dysfunction in BD. The quality of the identified randomized controlled trials (RCTs) was evaluated with the Cochrane Collaboration's Risk of Bias tool. We identified 19 eligible studies of which 13 were RCTs and six were open-label or non-randomized studies. The findings regarding efficacy on cognition were overall disappointing or preliminary, possibly due to several methodological challenges. For the RCTs, the risk of bias was high in nine cases, unclear in one case and low in three cases. Key reasons for the high risk of bias were lack of details on the randomization process, suboptimal handling of missing data and lack of a priori priority between cognition outcomes. Other challenges were the lack of consensus on whether and how to screen for cognitive impairment and on how to assess efficacy on cognition. In conclusion, methodological problems are likely to impede the success rates of cognition trials in BD. We recommend adherence to the CONSORT guidelines for RCTs, screening for cognitive impairment before inclusion of trial participants and selection of one primary cognition outcome. Future implementation of a 'neurocircuitry-based' biomarker model to evaluate neural target engagement is warranted. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.
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Duburcq, Thibault; Durand, Arthur; Tournoys, Antoine; Gnemmi, Viviane; Gmyr, Valery; Pattou, François; Jourdain, Mercedes; Tamion, Fabienne; Besnier, Emmanuel; Préau, Sebastien; Parmentier-Decrucq, Erika; Mathieu, Daniel; Poissy, Julien; Favory, Raphaël
2018-02-14
Sodium lactate seemed to improve fluid balance and avoid fluid overload. The objective of this study was to determine if these beneficial effects can be at least partly explained by an improvement in disseminated intravascular coagulation (DIC)-associated renal microvascular thrombosis. Ancillary work of an interventional randomized open label controlled experimental study. Fifteen female "Large White" pigs (2 months old) were challenged with intravenous infusion of E. coli endotoxin. Three groups of five animals were randomly assigned to receive different fluids: a treatment group received sodium lactate 11.2% (SL group); an isotonic control group received 0.9% NaCl (NC group); a hypertonic control group, with the same amount of osmoles and sodium than SL group, received sodium bicarbonate 8.4% (SB group). Glomerular filtration rate (GFR) markers, coagulation and inflammation parameters were measured over a 5-h period. Immediately after euthanasia, kidneys were withdrawn for histological study. Statistical analysis was performed with nonparametric tests and the Dunn correction for multiple comparisons. A p < 0.05 was considered significant. The direct immunofluorescence study revealed that the percentage of capillary sections thrombosed in glomerulus were significantly lesser in SL group [5 (0-28) %] compared to NC [64 (43-79) %, p = 0.01] and SB [64 (43-79), p = 0.03] groups. Alterations in platelet count and fibrinogen level occurred earlier and were significantly more pronounced in both control groups compared to SL group (p < 0.05 at 210 and 300 min). The increase in thrombin-antithrombin complexes was significantly higher in NC [754 (367-945) μg/mL; p = 0.03] and SB [463 (249-592) μg/mL; p = 0.03] groups than in SL group [176 (37-265) μg/mL]. At the end of the experiment, creatinine clearance was significantly higher in SL group [55.46 (30.07-67.85) mL/min] compared to NC group [1.52 (0.17-27.67) mL/min, p = 0.03]. In this study, we report that sodium lactate improves DIC-associated renal microvascular thrombosis and preserves GFR. These findings could at least partly explain the better fluid balance observed with sodium lactate infusion.
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Starman, James S; Bosse, Michael J; Cates, Casey A; Norton, H James
2012-03-01
Recombinant human bone morphogenetic protein-2 (BMP-2) is Food and Drug Administration-approved for use in acute open tibial shaft fractures. Some surgeons, however, also use BMP-2 in an "off-label" application for other acute fractures and for nonunion care. This retrospective study was performed to assess radiographic outcomes of off-label uses of BMP-2 for acute fractures and nonunions at our institution. All eligible off-label BMP-2 applications between 2004 and 2008 for acute fractures or nonunions were reviewed. Univariate and multivariate analyses were completed to identify patient and clinical factors that could predict radiographic success or failure of the procedure. One hundred sixteen of 145 BMP-2 applications in 104 of 128 patients met inclusion and exclusion criteria. The overall radiographic union rate was 66% (76 of 116). In the univariate analysis, five factors correlated with significantly higher union rate: volume of bone defect <4 cm3, >2 cortices in contact at the index procedure, male gender, body mass index <30, and history of closed fracture pattern. Within the multivariate analysis, factors independently predictive of radiographic union included open versus closed fracture, gender, and volume of bone defect. Off-label use of BMP-2 in acute fractures and nonunions resulted in a 66% success rate. It remains uncertain whether there is any clinical advantage to this approach, but it appears that female gender, open injury, and higher volumes of bone defect may be important negative prognostic factors for obtaining radiographic union. Appropriately powered prospective randomized trials are needed for further clarification, especially in light of the high cost of this treatment.
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Oh, Chang-Kwon; Huh, Kyu Ha; Lee, Jong Soo; Cho, Hong Rae; Kim, Yu Seun
2014-09-01
The purpose of this study was to compare once-daily tacrolimus with twice-daily tacrolimus in terms of safety, efficacy, and patient satisfaction. This prospective, randomized, open-label, multicenter study was conducted at three institutes. Patients in the investigational group were converted from tacrolimus twice daily to the same dose of extended-release tacrolimus once daily at 1 month post-transplantation, while patients in the control group were maintained on tacrolimus twice daily. The efficacies, safeties, and patient satisfaction for the two drugs at 6 months post-transplantation were compared. Sixty patients were enrolled and randomized to the investigational group (28 of 29 patients completed the study) or the control group (26 of 31 patients completed the study). At 6 months post-transplantation, composite efficacy failure rates including the incidences of biopsy-confirmed acute rejection in the investigational and control groups were 0% and 10.7%, respectively; patient survival was 100% in each group. No difference in estimated glomerular filtration rate values were observed at 6 months post-transplantation (p=0.97). The safety and satisfaction profile (immunosuppressant therapy barrier scale) of once-daily tacrolimus was comparable with that of twice-daily tacrolimus (p=0.35). Conversion from twice-daily tacrolimus to once-daily tacrolimus one month after transplantation is safe and effective.
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Sriprasert, Intira; Suerungruang, Suparerk; Athilarp, Porntip; Matanasarawoot, Anuchart
2015-01-01
This open-label randomized controlled trial was designed to compare the efficacy of acupuncture and combined oral contraceptive (COC) pill in treating moderate-to-severe primary dysmenorrhea. Fifty-two participants were randomly assigned to receive either acupuncture (n = 27) or COC (n = 25) for three menstrual cycles. Mefenamic acid was prescribed as a recue analgesic drug with both groups. The statistical approach used for efficacy and safety assessments was intention-to-treat analysis. By the end of the study, both treatments had resulted in significant improvement over baselines in all outcomes, that is, maximal dysmenorrhea pain scores, days suffering from dysmenorrhea, amount of rescue analgesic used, and quality of life assessed by SF-36 questionnaire. Over the three treatment cycles, COC caused greater reduction in maximal pain scores than acupuncture, while improvements in the remaining outcomes were comparable. Responders were defined as participants whose maximal dysmenorrhea pain scores decreased at least 33% below their baseline. Response rates following both interventions at the end of the study were not statistically different. Acupuncture commonly caused minimal local side effects but did not cause any hormone-related side effects as did COC. In conclusion, acupuncture is an alternative option for relieving dysmenorrhea, especially when COC is not a favorable choice. PMID:26346199
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Eberhart, Leopold; Geldner, Götz; Huljic, Susanne; Marggraf, Kerstin; Keller, Thomas; Koch, Tilo; Kranke, Peter
2018-06-01
To compare the effectiveness of 20:1 cafedrine/theodrenaline approved for use in Germany to ephedrine in the restoration of arterial blood pressure and on post-operative outcomes in patients with intra-operative arterial hypotension of any origin under standard clinical practice conditions. 'HYPOTENS' is a national, multi-center, prospective, open-label, two-armed, non-interventional study. Effectiveness and post-operative outcome following cafedrine/theodrenaline or ephedrine therapy will be evaluated in two cohorts of hypotensive patients. Cohort A includes patients aged ≥50 years with ASA-classification 2-4 undergoing non-emergency surgical procedures under general anesthesia. Cohort B comprises patients undergoing Cesarean section under spinal anesthesia. Participating surgical departments will be assigned to a treatment arm by routinely used anti-hypotensive agent. To minimize bias, matched department pairs will be compared in a stratified selection process. The composite primary end-point is the lower absolute deviation from individually determined target blood pressure (IDTBP) and the incidence of heart rate ≥100 beats/min in the first 15 min. Secondary end-points include incidence and degree of early post-operative delirium (cohort A), severity of fetal acidosis in the newborn (cohort B), upper absolute deviation from IDTBP, percentage increase in systolic blood pressure, and time to IDTBP. This open-label, non-interventional study design mirrors daily practice in the treatment of patients with intra-operative hypotension and ensures full treatment decision autonomy with respect to each patient's individual condition. Selection of participating sites by a randomization process addresses bias without interfering with the non-interventional nature of the study. First results are expected in 2018. ClinicalTrials.gov identifier: NCT02893241; DRKS identifier: DRKS00010740.
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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…
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Maeda-Yamamoto, Mari; Ema, Kaori; Monobe, Manami; Shibuichi, Ikuo; Shinoda, Yuki; Yamamoto, Tomohiro; Fujisawa, Takao
2009-09-01
We previously reported that 'benifuuki' green tea containing O-methylated catechin significantly relieved the symptoms of perennial or seasonal rhinitis compared with a placebo green tea that did not contain O-methylated catechin in randomized double-blind clinical trials. In this study we assessed the effects of 'benifuuki' green tea on clinical symptoms of seasonal allergic rhinitis. An open-label, single-dose, randomized, parallel-group study was performed on 38 subjects with Japanese cedar pollinosis. The subjects were randomly assigned to long-term (December 27, 2006-April 8, 2007, 1.5 months before pollen exposure) or short-term (February 15, 2007: after cedar pollen dispersal--April 8, 2007) drinking of a 'benifuuki' tea drink containing 34 mg O-methylated catechin per day. Each subject recorded their daily symptom scores in a diary. The primary efficacy variable was the mean weekly nasal symptom medication score during the study period. The nasal symptom medication score in the long-term intake group was significantly lower than that of the short-term intake group at the peak of pollen dispersal. The symptom scores for throat pain, nose-blowing, tears, and hindrance to activities of daily living were significantly better in the long-term group than the short-term group. In particular, the differences in the symptom scores for throat pain and nose-blowing between the 2 groups were marked. We conclude that drinking 'benifuuki' tea for 1.5 months prior to the cedar pollen season is effective in reducing symptom scores for Japanese cedar pollinosis.
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Kario, Kazuomi; Hoshide, Satoshi
2014-06-01
The ACS1 (Azilsartan Circadian and Sleep Pressure - the first study) is a multicenter, randomized, open-label, two parallel-group study carried out to investigate the efficacy of an 8-week oral treatment with azilsartan 20 mg in comparison with amlodipine 5 mg. The patients with stage I or II primary hypertension will be randomly assigned to either an azilsartan group (n=350) or an amlodipine group (n=350). The primary endpoint is a change in nocturnal systolic blood pressure (BP) as measured by ambulatory BP monitoring at the end of follow-up relative to the baseline level during the run-in period. In addition, we will carry out the same analysis after dividing four different nocturnal BP dipping statuses (extreme-dippers, dippers, nondipper, and risers). The findings of this study will help in establishing an appropriate antihypertensive treatment for hypertensive patients with a disrupted circadian BP rhythm.
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Hoshide, Satoshi
2014-01-01
Objective The ACS1 (Azilsartan Circadian and Sleep Pressure – the first study) is a multicenter, randomized, open-label, two parallel-group study carried out to investigate the efficacy of an 8-week oral treatment with azilsartan 20 mg in comparison with amlodipine 5 mg. Materials and methods The patients with stage I or II primary hypertension will be randomly assigned to either an azilsartan group (n=350) or an amlodipine group (n=350). The primary endpoint is a change in nocturnal systolic blood pressure (BP) as measured by ambulatory BP monitoring at the end of follow-up relative to the baseline level during the run-in period. In addition, we will carry out the same analysis after dividing four different nocturnal BP dipping statuses (extreme-dippers, dippers, nondipper, and risers). Conclusion The findings of this study will help in establishing an appropriate antihypertensive treatment for hypertensive patients with a disrupted circadian BP rhythm. PMID:24637789
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Swartz, Holly A; Zuckoff, Allan; Frank, Ellen; Spielvogle, Heather N; Shear, M Katherine; Fleming, M A Dana; Scott, John
2006-01-01
Major depression affects one out of five women during her lifetime. Depressed mothers with psychiatrically ill children represent an especially vulnerable population. Challenged by the demands of caring for ill children, these mothers often put their own needs last; consequently, their depressions remain untreated. This population is especially difficult to engage in treatment. We have developed a nine-session intervention, an engagement session followed by eight sessions of brief interpersonal psychotherapy designed to increase maternal participation in their own psychotherapy, resolve symptoms of maternal depression, and enhance relationships (IPT-MOMS). This open-label trial assesses the feasibility and acceptability of providing this treatment to depressed mothers. Thirteen mothers meeting DSM-IV criteria for major depression were recruited from a pediatric mental health clinic where their school-age children were receiving psychiatric treatment. Subjects (mothers) were treated openly with IPT-MOMS. Eighty-five percent (11/13) completed the study. Subjects were evaluated with the Hamilton Rating Scale for Depression, and completed self-report measures of quality of life and functioning at three time points: baseline, after treatment completion, and 6-months posttreatment. A signed rank test was used to compare measurement changes between assessment time points. Subjects showed significant improvement from baseline to posttreatment on measures of maternal symptoms and functioning. These gains were maintained at 6-month follow-up. Therapy was well tolerated and accepted by depressed mothers, who are typically difficult to engage in treatment. A high proportion of subjects completed treatment and experienced improvements in functioning. Future randomized clinical trials are needed to establish the efficacy of this approach.
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Clobazam : in patients with Lennox-Gastaut syndrome.
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.
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Camargo, Caio Lamunier de Abreu; Belda, Walter; Fagundes, Luiz Jorge; Romiti, Ricardo
2014-01-01
BACKGROUND Genital warts are caused by human papillomavirus infection and represent one of the most common sexually transmitted diseases. Many infections are transient but the virus may recur, persist, or become latent. To date, there is no effective antiviral treatment to eliminate HPV infection and most therapies are aimed at the destruction of visible lesions. Potassium hydroxide is a strong alkali that has been shown to be safe and effective for the treatment of genital warts and molluscum contagiosum. Cryotherapy is considered one of the most established treatments for genital warts. No comparative trials have been reported to date on the use of potassium hydroxide for genital warts. OBJECTIVE A prospective, open-label, randomized clinical trial was conducted to compare topical potassium hydroxide versus cryotherapy in the treatment of genital warts affecting immunocompetent, sexually active men. METHODS Over a period of 10 months, 48 patients were enrolled. They were randomly divided into two groups and selected on an alternative basis for either potassium hydroxide therapy or cryotherapy. While response to therapy did not differ substantially between both treatment modalities, side effects such as local pain and post-treatment hypopigmentation were considerably more prevalent in the groups treated using cryotherapy. RESULT In our study, potassium hydroxide therapy proved to be at least as effective as cryotherapy and offered the benefit of a better safety profile. CONCLUSION Topical 5% potassium hydroxide presents an effective, safe, and low-cost treatment modality for genital warts in men and should be included in the spectrum of therapies for genital warts. PMID:24770498
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Camargo, Caio Lamunier de Abreu; Belda Junior, Walter; Fagundes, Luiz Jorge; Romiti, Ricardo
2014-01-01
Genital warts are caused by human papillomavirus infection and represent one of the most common sexually transmitted diseases. Many infections are transient but the virus may recur, persist, or become latent. To date, there is no effective antiviral treatment to eliminate HPV infection and most therapies are aimed at the destruction of visible lesions. Potassium hydroxide is a strong alkali that has been shown to be safe and effective for the treatment of genital warts and molluscum contagiosum. Cryotherapy is considered one of the most established treatments for genital warts. No comparative trials have been reported to date on the use of potassium hydroxide for genital warts. A prospective, open-label, randomized clinical trial was conducted to compare topical potassium hydroxide versus cryotherapy in the treatment of genital warts affecting immunocompetent, sexually active men. Over a period of 10 months, 48 patients were enrolled. They were randomly divided into two groups and selected on an alternative basis for either potassium hydroxide therapy or cryotherapy. While response to therapy did not differ substantially between both treatment modalities, side effects such as local pain and post-treatment hypopigmentation were considerably more prevalent in the groups treated using cryotherapy. In our study, potassium hydroxide therapy proved to be at least as effective as cryotherapy and offered the benefit of a better safety profile. Topical 5% potassium hydroxide presents an effective, safe, and low-cost treatment modality for genital warts in men and should be included in the spectrum of therapies for genital warts.
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Haziza, Christelle; de La Bourdonnaye, Guillaume; Merlet, Sarah; Benzimra, Muriel; Ancerewicz, Jacek; Donelli, Andrea; Baker, Gizelle; Picavet, Patrick; Lüdicke, Frank
2016-11-01
Smoking conventional cigarettes (CCs) exposes smokers to harmful and potentially harmful constituents (HPHCs). The Tobacco Heating System 2.2 (THS 2.2), a candidate modified risk tobacco product, was developed to reduce or eliminate the formation of HPHCs, while preserving as much as possible the taste, sensory experience, nicotine delivery profile and ritual characteristics of CC. This randomized, controlled, open-label study in confinement for 5 day exposure aimed to demonstrate the reduction in exposure to selected HPHCs, to assess nicotine uptake and subjective effects, in participants switching to THS 2.2 (n = 80) compared to participants continuing smoking CCs (n = 40) and abstaining from smoking (n = 40). The subjects were randomized according to sex and daily CC consumption. The levels of biomarkers of exposure to HPHCs were significantly reduced in participants switching to THS 2.2, compared to CC use. More importantly, the magnitude of exposure reduction observed was close to that which was seen in participants who abstained from smoking for 5 days, while nicotine uptake was maintained. Reduction in urge-to-smoke was comparable between THS and CC groups, however THS 2.2 was slightly less satisfactory than CCs. The new, alternative tobacco product THS 2.2 was well tolerated. Copyright © 2016 Philip Morris Products S.A. Published by Elsevier Inc. All rights reserved.
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Akinyotu, Oriyomi; Bello, Folasade; Abdus-Salam, Rukiyat; Arowojolu, Ayodele
2018-05-02
To compare the effectiveness of mefloquine and sulphadoxine-pyrimethamine as intermittent preventive therapy for malaria among pregnant women with HIV. The present randomized, controlled, prospective, open-label study enrolled women with HIV who had reached at least 16 weeks of pregnancy attending prenatal clinics at secondary and tertiary health facilities in South West Nigeria between January 1 and August 31, 2016. Block randomization was used to assign patients to treatment with mefloquine or sulphadoxine-pyrimethamine for malaria prophylaxis. The primary outcome was malaria parasitemia at delivery. Data were compared with the χ 2 and t tests on a per-protocol basis. Of 142 women enrolled and randomized equally to each group, 131 (92.3%) completed the study (64 in the mefloquine group and 67 in the sulphadoxine-pyrimethamine group). Blood-sample malaria parasites were isolated from 6 (9%) and 5 (7%) patients in the mefloquine and sulphadoxine-pyrimethamine groups, respectively, at enrolment, and 6 (9%) and 9 (13%) patients in the mefloquine and sulphadoxine-pyrimethamine groups, respectively, at delivery; the differences between the groups was not significant at enrolment (P=0.693) or delivery (P=0.466). Outcomes following prophylactic use of mefloquine for intermittent preventive therapy for malaria among pregnant women with HIV were comparable to sulphadoxine-pyrimethamine treatment; mefloquine is a feasible alternative therapy. ClinicalTrials.gov: NCT02524444. © 2018 International Federation of Gynecology and Obstetrics.
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Cecchini, M; Warin, L
2016-03-01
Food labels are considered a crucial component of strategies tackling unhealthy diets and obesity. This study aims at assessing the effectiveness of food labelling in increasing the selection of healthier products and in reducing calorie intake. In addition, this study compares the relative effectiveness of traffic light schemes, Guideline Daily Amount and other food labelling schemes. A comprehensive set of databases were searched to identify randomized studies. Studies reporting homogeneous outcomes were pooled together and analysed through meta-analyses. Publication bias was evaluated with a funnel plot. Food labelling would increase the amount of people selecting a healthier food product by about 17.95% (confidence interval: +11.24% to +24.66%). Food labelling would also decrease calorie intake/choice by about 3.59% (confidence interval: -8.90% to +1.72%), but results are not statistically significant. Traffic light schemes are marginally more effective in increasing the selection of healthier options. Other food labels and Guideline Daily Amount follow. The available evidence did not allow studying the effects of single labelling schemes on calorie intake/choice. Findings of this study suggest that nutrition labelling may be an effective approach to empowering consumers in choosing healthier products. Interpretive labels, as traffic light labels, may be more effective. © 2015 World Obesity.
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Arns, Martijn; Bruder, Gerard; Hegerl, Ulrich; Spooner, Chris; Palmer, Donna M; Etkin, Amit; Fallahpour, Kamran; Gatt, Justine M; Hirshberg, Laurence; Gordon, Evian
2016-01-01
To determine whether EEG occipital alpha and frontal alpha asymmetry (FAA) distinguishes outpatients with major depression (MDD) from controls, predicts antidepressant treatment outcome, and to explore the role of gender. In the international Study to Predict Optimized Treatment in Depression (iSPOT-D), a multi-center, randomized, prospective open-label trial, 1008 MDD participants were randomized to escitalopram, sertraline or venlafaxine-extended release. The study also recruited 336 healthy controls. Treatment response was established after eight weeks and resting EEG was measured at baseline (two minutes eyes open and eyes closed). No differences in EEG alpha for occipital and frontal cortex, or for FAA, were found in MDD participants compared to controls. Alpha in the occipital and frontal cortex was not associated with treatment outcome. However, a gender and drug-class interaction effect was found for FAA. Relatively greater right frontal alpha (less cortical activity) in women only was associated with a favorable response to the Selective Serotonin Reuptake Inhibitors escitalopram and sertraline. No such effect was found for venlafaxine-extended release. FAA does not differentiate between MDD and controls, but is associated with antidepressant treatment response and remission in a gender and drug-class specific manner. Future studies investigating EEG alpha measures in depression should a-priori stratify by gender. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
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Random Deep Belief Networks for Recognizing Emotions from Speech Signals.
Wen, Guihua; Li, Huihui; Huang, Jubing; Li, Danyang; Xun, Eryang
2017-01-01
Now the human emotions can be recognized from speech signals using machine learning methods; however, they are challenged by the lower recognition accuracies in real applications due to lack of the rich representation ability. Deep belief networks (DBN) can automatically discover the multiple levels of representations in speech signals. To make full of its advantages, this paper presents an ensemble of random deep belief networks (RDBN) method for speech emotion recognition. It firstly extracts the low level features of the input speech signal and then applies them to construct lots of random subspaces. Each random subspace is then provided for DBN to yield the higher level features as the input of the classifier to output an emotion label. All outputted emotion labels are then fused through the majority voting to decide the final emotion label for the input speech signal. The conducted experimental results on benchmark speech emotion databases show that RDBN has better accuracy than the compared methods for speech emotion recognition.
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Random Deep Belief Networks for Recognizing Emotions from Speech Signals
Li, Huihui; Huang, Jubing; Li, Danyang; Xun, Eryang
2017-01-01
Now the human emotions can be recognized from speech signals using machine learning methods; however, they are challenged by the lower recognition accuracies in real applications due to lack of the rich representation ability. Deep belief networks (DBN) can automatically discover the multiple levels of representations in speech signals. To make full of its advantages, this paper presents an ensemble of random deep belief networks (RDBN) method for speech emotion recognition. It firstly extracts the low level features of the input speech signal and then applies them to construct lots of random subspaces. Each random subspace is then provided for DBN to yield the higher level features as the input of the classifier to output an emotion label. All outputted emotion labels are then fused through the majority voting to decide the final emotion label for the input speech signal. The conducted experimental results on benchmark speech emotion databases show that RDBN has better accuracy than the compared methods for speech emotion recognition. PMID:28356908
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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.
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Rintoul, Robert C; Ritchie, Andrew J; Edwards, John G; Waller, David A; Coonar, Aman S; Bennett, Maxine; Lovato, Eleonora; Hughes, Victoria; Fox-Rushby, Julia A; Sharples, Linda D
2014-09-20
Malignant pleural mesothelioma incidence continues to rise, with few available evidence-based therapeutic options. Results of previous non-randomised studies suggested that video-assisted thoracoscopic partial pleurectomy (VAT-PP) might improve symptom control and survival. We aimed to compare efficacy in terms of overall survival, and cost, of VAT-PP and talc pleurodesis in patients with malignant pleural mesothelioma. We undertook an open-label, parallel-group, randomised, controlled trial in patients aged 18 years or older with any subtype of confirmed or suspected mesothelioma with pleural effusion, recruited from 12 hospitals in the UK. Eligible patients were randomly assigned (1:1) to either VAT-PP or talc pleurodesis by computer-generated random numbers, stratified by European Organisation for Research and Treatment of Cancer risk category (high vs low). The primary outcome was overall survival at 1 year, analysed by intention to treat (all patients randomly assigned to a treatment group with a final diagnosis of mesothelioma). This trial is registered with ClinicalTrials.gov, number NCT00821860. Between Oct 24, 2003, and Jan 24, 2012, we randomly assigned 196 patients, of whom 175 (88 assigned to talc pleurodesis, 87 assigned to VAT-PP) had confirmed mesothelioma. Overall survival at 1 year was 52% (95% CI 41-62) in the VAT-PP group and 57% (46-66) in the talc pleurodesis group (hazard ratio 1·04 [95% CI 0·76-1·42]; p=0·81). Surgical complications were significantly more common after VAT-PP than after talc pleurodesis, occurring in 24 (31%) of 78 patients who completed VAT-PP versus ten (14%) of 73 patients who completed talc pleurodesis (p=0·019), as were respiratory complications (19 [24%] vs 11 [15%]; p=0·22) and air-leak beyond 10 days (five [6%] vs one [1%]; p=0·21), although not significantly so. Median hospital stay was longer at 7 days (IQR 5-11) in patients who received VAT-PP compared with 3 days (2-5) for those who received talc pleurodesis (p<0·0001). VAT-PP is not recommended to improve overall survival in patients with pleural effusion due to malignant pleural mesothelioma, and talc pleurodesis might be preferable considering the fewer complications and shorter hospital stay associated with this treatment. BUPA Foundation. Copyright © 2014 Elsevier Ltd. All rights reserved.
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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
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Laparoscopic Lavage for Perforated Diverticulitis With Purulent Peritonitis: A Randomized Trial.
Thornell, Anders; Angenete, Eva; Bisgaard, Thue; Bock, David; Burcharth, Jakob; Heath, Jane; Pommergaard, Hans-Christian; Rosenberg, Jacob; Stilling, Nikolaj; Skullman, Stefan; Haglind, Eva
2016-02-02
Perforated diverticulitis with purulent peritonitis has traditionally been treated with open colon resection and stoma formation with risk for reoperations, morbidity, and mortality. Laparoscopic lavage alone has been suggested as definitive treatment. To compare laparoscopic lavage with open colon resection and colostomy (Hartmann procedure) for perforated diverticulitis with purulent peritonitis. Randomized, controlled, multicenter, open-label trial. (ISRCTN registry number: ISRCTN82208287). 9 hospitals in Sweden and Denmark. Patients who have confirmed Hinchey grade III perforated diverticulitis with purulent peritonitis at diagnostic laparoscopy. Randomization between laparoscopic lavage and the Hartmann procedure. Primary outcome was the percentage of patients having 1 or more reoperations within 12 months. Key secondary outcomes were number of reoperations, hospital readmissions, total length of hospital stay during 12 months, and adverse events. A total of 43 and 40 patients were randomly assigned to laparoscopic lavage and the Hartmann procedure with a median (first, third quartiles) follow-up of 372 days (336, 394) and 378 days (226, 396), respectively. Fewer patients in the laparoscopic group (12 of 43; 27.9%) than in the Hartmann group (25 of 40; 62.5%) had at least 1 reoperation within 12 months (relative risk reduction, 59%; relative risk, 0.41 [95% CI, 0.23 to 0.72]; P = 0.004). Mortality and severe adverse events did not differ between groups. Total length of hospital stay (days) within 12 months was shorter for the laparoscopic group than the Hartmann group, with a reduction of 35% (relative risk, 0.65 [CI, 0.45 to 0.94]; P = 0.047). After 12 months, 3 patients in the laparoscopic group and 11 in the Hartmann group had a stoma. Not all patients presenting with suspected diverticulitis were enrolled. Laparoscopic lavage reduced the need for reoperations, had a similar safety profile to the Hartmann procedure, and may be an appropriate treatment of choice for acute perforated diverticulitis with purulent peritonitis. ALF; Sahlgrenska University Hospital, Gothenburg.
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Herzog, Rebecca; Boehm, Michael; Unterwurzacher, Markus; Wagner, Anja; Parapatics, Katja; Májek, Peter; Mueller, André C.; Lichtenauer, Anton; Bennett, Keiryn L.; Alper, Seth L.; Vychytil, Andreas; Aufricht, Christoph; Kratochwill, Klaus
2018-01-01
Peritoneal dialysis (PD) is a modality of renal replacement therapy in which the high volumes of available PD effluent (PDE) represents a rich source of biomarkers for monitoring disease and therapy. Although this information could help guide the management of PD patients, little is known about the potential of PDE to define pathomechanism-associated molecular signatures in PD. We therefore subjected PDE to a high-performance multiplex proteomic analysis after depletion of highly-abundant plasma proteins and enrichment of low-abundance proteins. A combination of label-free and isobaric labeling strategies was applied to PDE samples from PD patients (n = 20) treated in an open-label, randomized, two-period, cross-over clinical trial with standard PD fluid or with a novel PD fluid supplemented with alanyl-glutamine (AlaGln). With this workflow we identified 2506 unique proteins in the PDE proteome, greatly increasing coverage beyond the 171 previously-reported proteins. The proteins identified range from high abundance plasma proteins to low abundance cellular proteins, and are linked to larger numbers of biological processes and pathways, some of which are novel for PDE. Interestingly, proteins linked to membrane remodeling and fibrosis are overrepresented in PDE compared with plasma, whereas the proteins underrepresented in PDE suggest decreases in host defense, immune-competence and response to stress. Treatment with AlaGln-supplemented PD fluid is associated with reduced activity of membrane injury-associated mechanisms and with restoration of biological processes involved in stress responses and host defense. Our study represents the first application of the PDE proteome in a randomized controlled prospective clinical trial of PD. This novel proteomic workflow allowed detection of low abundance biomarkers to define pathomechanism-associated molecular signatures in PD and their alterations by a novel therapeutic intervention. PMID:29208752
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Thorndike, Anne N.; Riis, Jason; Levy, Douglas E.
2016-01-01
Population-level strategies to improve healthy food choices are needed for obesity prevention. We conducted a randomized controlled trial of 2,672 employees at Massachusetts General Hospital who were regular customers of the hospital cafeteria with all items labeled green (healthy), yellow (less healthy), or red (unhealthy) to determine if social norm (peer-comparison) feedback with or without financial incentives increased employees’ healthy food choices. Participants were randomized in 2012 to three arms: 1) monthly letter with social norm feedback about healthy food purchases, comparing employee to “all” and to “healthiest” customers (feedback-only); 2) monthly letter with social norm feedback plus small financial incentive for increasing green purchases (feedback-incentive); or 3) no contact (control). The main outcome was change in proportion of green-labeled purchases at end of 3-month intervention. Post-hoc analyses examined linear trends. At baseline, the proportion of green-labeled purchases (50%) did not differ between arms. At end of the 3-month intervention, the percentage increase in green-labeled purchases was larger in the feedback-incentive arm compared to control (2.2% vs. 0.1%, P=0.03), but the two intervention arms were not different. The rate of increase in green-labeled purchases was higher in both feedback-only (P=0.04) and feedback-incentive arms (P=0.004) compared to control. At end of a 3-month wash-out, there were no differences between control and intervention arms. Social norms plus small financial incentives increased employees’ healthy food choices over the short-term. Future research will be needed to assess the impact of this relatively low-cost intervention on employees’ food choices and weight over the long-term. Trial Registration: Clinical Trials.gov NCT01604499 PMID:26827617
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Thorndike, Anne N; Riis, Jason; Levy, Douglas E
2016-05-01
Population-level strategies to improve healthy food choices are needed for obesity prevention. We conducted a randomized controlled trial of 2672 employees at the Massachusetts General Hospital who were regular customers of the hospital cafeteria with all items labeled green (healthy), yellow (less healthy), or red (unhealthy) to determine if social norm (peer-comparison) feedback with or without financial incentives increased employees' healthy food choices. Participants were randomized in 2012 to three arms: 1) monthly letter with social norm feedback about healthy food purchases, comparing employee to "all" and to "healthiest" customers (feedback-only); 2) monthly letter with social norm feedback plus small financial incentive for increasing green purchases (feedback-incentive); or 3) no contact (control). The main outcome was change in proportion of green-labeled purchases at the end of 3-month intervention. Post-hoc analyses examined linear trends. At baseline, the proportion of green-labeled purchases (50%) did not differ between arms. At the end of the 3-month intervention, the percentage increase in green-labeled purchases was larger in the feedback-incentive arm compared to control (2.2% vs. 0.1%, P=0.03), but the two intervention arms were not different. The rate of increase in green-labeled purchases was higher in both feedback-only (P=0.04) and feedback-incentive arms (P=0.004) compared to control. At the end of a 3-month wash-out, there were no differences between control and intervention arms. Social norms plus small financial incentives increased employees' healthy food choices over the short-term. Future research will be needed to assess the impact of this relatively low-cost intervention on employees' food choices and weight over the long-term. Clinical Trials.gov: NCT01604499. Copyright © 2016 Elsevier Inc. All rights reserved.
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Kim, Min Jung; Park, Sung Chan; Park, Ji Won; Chang, Hee Jin; Kim, Dae Yong; Nam, Byung-Ho; Sohn, Dae Kyung; Oh, Jae Hwan
2018-02-01
The phase II randomized controlled trial aimed to compare the outcomes of robot-assisted surgery with those of laparoscopic surgery in the patients with rectal cancer. The feasibility of robot-assisted surgery over laparoscopic surgery for rectal cancer has not been established yet. Between February 21, 2012 and March 11, 2015, patients with rectal cancer (cT1-3NxM0) were enrolled. Patients were randomized 1:1 to either robot-assisted or laparoscopic surgery, and stratified per sex and administration of preoperative chemoradiotherapy. The primary outcome was the quality of total mesorectal excision (TME) specimen. Secondary outcomes were the circumferential and distal resection margins, the number of harvested lymph nodes, morbidity, bowel function recovery, and quality of life. A total of 163 patients were randomly assigned to the robot-assisted (n = 81) and laparoscopic (n = 82) surgery groups, and 139 patients were eligible for the analyses (73 vs 66, respectively). One patient (1.2%) in the robot-assisted group was converted to open surgery. The TME quality did not differ between the robot-assisted and laparoscopic groups (80.3% vs 78.1% complete TME, respectively; 18.2% vs 21.9% nearly complete TME, respectively; P = 0.599). The resection margins, number of harvested lymph nodes, morbidity, and bowel function recovery also were not significantly different. On analyzing quality of life, scores of the European Organization for Research and Treatment of Cancer Quality of Life (EORTC QLQ C30) and EORTC QLQ CR38 were similar in the 2 groups, but in the EORTC QLQ CR 38 questionnaire, sexual function 12 months postoperatively was better in the robot-assisted group than in the laparoscopic group (P = 0.03). Robot-assisted surgery in rectal cancer showed TME quality comparable with that of laparoscopic surgery, and it demonstrated similar postoperative morbidity, bowel function recovery, and quality of life.
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Freeman, Roy; Mathias, Christopher J.; Low, Phillip; Hewitt, L. Arthur; Kaufmann, Horacio
2015-01-01
Abstract— We evaluated whether droxidopa, a prodrug converted to norepinephrine, is beneficial in the treatment of symptomatic neurogenic orthostatic hypotension, which results from failure to generate an appropriate norepinephrine response to postural challenge. Patients with symptomatic neurogenic orthostatic hypotension and Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa titration (100–600 mg, 3× daily). Responders then received an additional 7-day open-label treatment at their individualized dose. Patients were subsequently randomized to continue with droxidopa or withdraw to placebo for 14 days. We then assessed patient-reported scores on the Orthostatic Hypotension Questionnaire and blood pressure measurements. Mean worsening of Orthostatic Hypotension Questionnaire dizziness/lightheadedness score from randomization to end of study (the primary outcome; N=101) was 1.9±3.2 with placebo and 1.3±2.8 units with droxidopa (P=0.509). Four of the other 5 Orthostatic Hypotension Questionnaire symptom scores and all 4 symptom-impact scores favored droxidopa, with statistical significance for the patient’s self-reported ability to perform activities requiring standing a short time (P=0.033) and standing a long time (P=0.028). Furthermore, a post hoc analysis of a predefined composite score of all symptoms (Orthostatic Hypotension Questionnaire composite) demonstrated a significant benefit for droxidopa (P=0.013). There was no significant difference between groups for standing systolic blood pressure (P=0.680). Droxidopa was well tolerated. In summary, this randomized withdrawal droxidopa study failed to meet its primary efficacy end point. Additional clinical trials are needed to confirm that droxidopa is beneficial in symptomatic neurogenic orthostatic hypotension, as suggested by the positive secondary outcomes of this trial. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00633880. PMID:25350981
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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.
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Toure, Offianan A; Assi, Serge B; N'Guessan, Tiacoh L; Adji, Gbessi E; Ako, Aristide B; Brou, Marie J; Ehouman, Marie F; Gnamien, Laeticia A; Coulibaly, M'Lanhoro A A; Coulibaly, Baba; Beourou, Sylvain; Bassinka, Issiaka; Soumahoro, Adama; Kadjo, Florence; Tano, Mea A
2014-11-19
Emergence of artemisinin resistance has raised concerns that the most potent anti-malarial drug may be under threat. Artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) are, respectively, the first- and second-line treatments for uncomplicated falciparum malaria in Côte d'Ivoire. Constant monitoring by National Malaria Control Programme (NMCP) of drug efficacy is an important tool in establishing rational anti-malarial drug policies in Côte d'Ivoire. In an open label, randomized controlled clinical trial, children and adults were randomized to receive AS-AQ or AL. Both drug regimens were given for three days, and follow-up was for 42 days. The primary endpoint was the 42-day cure rate and was defined as proportion of patients with PCR-corrected cure rate after 42 days of follow-up. A total of 383 patients who were attending the Anonkoua-koute (Abidjan), Petit Paris (Korhogo) and Libreville (Man) hospitals and presenting with symptomatic acute uncomplicated falciparum malaria were randomized to receive AS-AQ (188) and AL (195). The intention-to-treat analysis showed effectiveness rates of 94.7% and 96.4% for AS-AQ and AL, respectively on day 42. After adjustment for PCR, these rates were 96.8% and 99%, respectively. At day 42, in per-protocol analysis, Adequate clinical and parasitological response (ACPR) PCR uncorrected was 97.8% and 97.4% for AS-AQ and AL, respectively. The PCR adjusted ACPR was 100% for each combination and both regimens were well tolerated. This study has shown the high efficacy of AS-AQ in patients of all ages with acute uncomplicated falciparum malaria and AS-AQ was non-inferior to AL. Continuous efficacy monitoring is recommended.
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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.
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Hexsel, Doris; Soirefmann, Mariana; Porto, Manoela D; Schilling-Souza, Juliana; Siega, Carolina; Dal'Forno, Taciana
2014-05-01
Striae distensae (SD) is a common skin condition, with a prevalence ranging from 40% to 90%, depending on the population studied. To evaluate the efficacy of superficial dermabrasion and compare it with that of topical tretinoin cream in the treatment of narrow and early SD. Prospective, single-center, randomized, open-label study. Thirty-two women presenting with early, untreated SD (striae rubra) were included in this study. One group received 16 weekly sessions of superficial and localized dermabrasion, and the other used 0.05% tretinoin cream daily. Striae width and length were measured and compared between groups and over time. Global Aesthetic Improvement Scale scores and subject satisfaction were also assessed. Biopsies were performed for subjects who agreed to undergo this procedure, followed by histologic analyses of the skin samples. Both treatments were efficacious, with significant improvement in early SD from baseline, but there was no significant difference between the two treatments. Histologic assessment showed improvement in epidermal and dermal layers for the dermabrasion treatment group. Both treatments had similar efficacy, but superficial dermabrasion had a lower frequency of side effects and better adherence of the patients. © 2014 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc.
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Sakuraba, Atsushi; Sato, Toshiro; Morohoshi, Yuichi; Matsuoka, Katsuyoshi; Okamoto, Susumu; Inoue, Nagamu; Takaishi, Hiromasa; Ogata, Haruhiko; Iwao, Yasushi; Hibi, Toshifumi
2012-06-01
The effect of granulocyte and monocyte adsorption apheresis (GMA) on prevention of relapse of ulcerative colitis (UC) is not clear. This was a pilot open-labeled, prospective, randomized, unblinded study to compare the tolerability and efficacy of intermittent GMA (once every 2 weeks) with mercaptopurine to maintain remission of UC. Twenty-one patients with UC, who had achieved remission by induction therapies were randomly assigned to receive either intermittent GMA (N = 10) or oral mercaptopurine (0.5 mg/kg per day; N = 11). The study period was 24 months. The rate of the patients maintaining remission and the incidences of adverse effects were compared between the two groups. At 24 months, seven of 10 patients (70.0%) on intermittent GMA and seven of 11 patients (63.6%, P = 1.00) on oral mercaptopurine were still in remission. Three patients relapsed in each group. One patient taking mercaptopurine, but none receiving intermittent GMA, dropped out because of adverse effects. Intermittent therapy with GMA was well tolerated and a substantial proportion of patients maintained remission. Intermittent GMA therapy in maintaining remission of UC merits further investigation. © 2012 The Authors. Therapeutic Apheresis and Dialysis © 2012 International Society for Apheresis.
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Chosidow, O; Maurette, C; Dupuy, P
2003-01-01
Topical ketoconazole (KC) is considered a standard treatment for seborrheic dermatitis. In a placebo-controlled, double-blind clinical study, we demonstrated that antifungal ciclopiroxolamine (CIC) 1% cream was effective in mild to moderate facial seborrheic dermatitis. We report here the results of a randomized, open-labeled clinical study comparing CIC 1% cream and KC 2% foaming gel in patients with mild to moderate facial seborrheic dermatitis, using a non-inferiority trial design. Three hundred and three patients were enrolled, 154 patients in the CIC group and 149 patients in the KC group, and comprised the study population for intent-to-treat (ITT) analysis. The per protocol (PP) population comprised a total of 282 patients, 147 in the CIC group and 135 in the KC group. Patients were randomly allocated to apply either the CIC 1% cream twice a day for 28 days maximum (initial phase), followed by once a day for another 28 days (maintenance phase); or the KC 2% foaming gel twice a week at the initial phase, followed by once a week during the maintenance phase. Test lesions were defined as lesions localized to the nasolabial folds, alae nasi, and/or the eyebrows. The main efficacy parameter (endpoint) was the proportion of patients who presented a complete disappearance of both erythema and scaling on test lesions and pruritus on all lesions at the end of the initial phase (28 days or less). At baseline, both treatment groups were comparable in terms of demographic data and lesional status. At the end of the initial phase, responders were found to be non-inferior with CIC treatment compared with KC treatment in both study populations (ITT population: 37% CIC responders and 34% KC responders; in the PP population: 39 and 36% responders, respectively). The 95% confidence interval limit for differences were -7.99-13.56 in the ITT population, and -8.06-14.5 in the PP population. At the end of the maintenance phase, treatment response to CIC was greater than to KC in both ITT and PP populations (57 and 44% in both populations, respectively, p = 0.03). Local tolerance as well as global acceptability was better with CIC than with KC (p = 0.001, intergroup analysis). CIC 1% administered as a cream demonstrated to be non-inferior to KC 2% foaming gel in mild to moderate facial seborrheic dermatitis. Copyright 2003 S. Karger AG, Basel
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Vishwanathan, Karthick; Dickinson, Paul A; Bui, Khanh; Cassier, Philippe A; Greystoke, Alastair; Lisbon, Eleanor; Moreno, Victor; So, Karen; Thomas, Karen; Weilert, Doris; Yap, Timothy A; Plummer, Ruth
2018-04-01
Two phase 1, open-label studies assessed the impact of food or gastric pH modification (omeprazole) on the exposure and safety/tolerability of osimertinib and its metabolites. The food effect study was an open-label, 2-period crossover study in patients with advanced non-small-cell lung cancer, randomized into 2 treatment sequences: single-dose osimertinib 80 mg in a fed then fasted state or fasted then fed. The gastric pH study was an open-label, 2-period fixed sequence study assessing the effect of omeprazole on osimertinib exposure in healthy male volunteers. In period 1, volunteers received omeprazole 40 mg (days 1-4), then omeprazole 40 mg plus osimertinib 80 mg (day 5). In period 2, volunteers received osimertinib 80 mg alone (single dose). Blood samples were collected at prespecified time points for pharmacokinetic analyses. Safety/tolerability was also assessed. In the food effect study 38 patients were randomized to fed/fasted (n = 18) or fasted/fed (n = 20) sequences with all patients completing treatment. Coadministration with food did not affect osimertinib exposure (geometric least-squares mean ratios [90% confidence intervals]: 106.05% [94.82%, 118.60%] [area under the plasma concentration time curve from zero to 72 hours] and 92.75% [81.40%, 105.68%] [maximum plasma concentration]). In the gastric pH study (n = 68 received treatment, n = 47 completed the study), coadministration with omeprazole did not affect osimertinib exposure (geometric least-squares mean ratios 106.66% [100.26%, 113.46%] [area under the concentration-time curve], 101.65% [94.65%, 109.16%] [peak concentration]). Osimertinib was well tolerated in both studies. Osimertinib may be administered without regard to food. Dose restriction is not required in patients whose gastric pH may be altered by concomitant agents or medical conditions. ClinicalTrials.gov: NCT02224053, NCT02163733. © 2017, The American College of Clinical Pharmacology.
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Armodafinil for fatigue associated with menopause: an open-label trial.
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.
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Tahara, Shigeyuki; Murakami, Mami; Kaneko, Tomomi; Shimatsu, Akira
2017-07-28
A multicenter, open-label, phase 2 study was conducted to investigate the efficacy and safety of long-acting pasireotide formulation in Japanese patients with acromegaly or pituitary gigantism. Medically naïve or inadequately controlled patients (on somatostatin analogues or dopamine agonists) were included. Primary end point was the proportion of all patients who achieved biochemical control (mean growth hormone [GH] levels<2.5μg/L and normalized insulin-like growth factor-1 [IGF-1]) at month 3. Thirty-three patients (acromegaly, n=32; pituitary gigantism, n=1) were enrolled and randomized 1:1:1 to receive open-label pasireotide 20mg, 40mg, or 60mg. The median age was 52 years (range, 31-79) and 20 patients were males. At month 3, 18.2% of patients (6/33; 90% confidence interval: 8.2%, 32.8%) had biochemical control (21.2% [7/33] when including a patient with mean GH<2.5μg/L and IGF-1< lower limit of normal). Reductions in the median GH and IGF-1 levels observed at month 3 were maintained up to month 12; the median percent change from baseline to month 12 in GH and IGF-1 levels were -74.71% and -59.33%, respectively. Twenty-nine patients completed the 12-month core phase, 1 withdrew consent, and 3 discontinued treatment due to adverse events (AEs; diabetes mellitus, hyperglycemia, liver function abnormality, n=1 each). Almost all patients (97%; 32/33) experienced AEs; the most common AEs were nasopharyngitis (48.5%), hyperglycemia (42.4%), diabetes mellitus (24.2%), constipation (18.2%), and hypoglycemia (15.2%). Serious AEs were reported in 7 patients with the most common being hyperglycemia (n=2). Long-acting pasireotide demonstrated clinically relevant efficacy and was well tolerated in Japanese patients with acromegaly or pituitary gigantism.
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Smith, Kimberly Y; Tierney, Camlin; Mollan, Katie; Venuto, Charles S; Budhathoki, Chakra; Ma, Qing; Morse, Gene D; Sax, Paul; Katzenstein, David; Godfrey, Catherine; Fischl, Margaret; Daar, Eric S; Collier, Ann C
2014-02-01
We aimed to evaluate treatment responses to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) in initial antiretroviral regimens among women and men, and determine if treatment outcomes differ by sex. We performed a randomized trial of open-label ATV/r or EFV combined with abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) in 1857 human immunodeficiency virus type 1-infected, treatment-naive persons enrolled between September 2005 and November 2007 at 59 sites in the United States and Puerto Rico. Associations of sex with 3 primary study endpoints of time to virologic failure, safety, and tolerability events were analyzed using Cox proportional hazards models. Model-based population pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM version VII). Of 1857 participants, 322 were women. Women assigned to ATV/r had a higher risk of virologic failure with either nucleoside reverse transcriptase inhibitor backbone than women assigned to EFV, or men assigned to ATV/r. The effects of ATV/r and EFV upon safety and tolerability risk did not differ significantly by sex. With ABC/3TC, women had a significantly higher (32%) safety risk compared to men; with TDF/FTC, the safety risk was 20% larger for women compared to men, but not statistically significant. Women had slower ATV clearance and higher predose levels of ATV compared to men. Self-reported adherence did not differ significantly by sex. This is the first randomized clinical trial to identify a significantly earlier time to virologic failure in women randomized to ATV/r compared to women randomized to EFV. This finding has important clinical implications given that boosted protease inhibitors are often favored over EFV in women of childbearing potential. NCT00118898.
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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
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2007-01-01
Third-generation nonsteroidal aromatase inhibitors (AIs), letrozole and anastrozole, are superior to tamoxifen as initial therapy for early breast cancer but have not been directly compared in a head-to-head adjuvant trial. Cumulative evidence suggests that AIs are not equivalent in terms of potency of estrogen suppression and that there may be differences in clinical efficacy. Thus, with no data from head-to-head comparisons of the AIs as adjuvant therapy yet available, the question of whether there are efficacy differences between the AIs remains. To help answer this question, the Femara versus Anastrozole Clinical Evaluation (FACE) is a phase IIIb open-label, randomized, multicenter trial designed to test whether letrozole or anastrozole has superior efficacy as adjuvant treatment of postmenopausal women with hormone receptor (HR)- and lymph node-positive breast cancer. Eligible patients (target accrual, N = 4,000) are randomized to receive either letrozole 2.5 mg or anastrozole 1 mg daily for up to 5 years. The primary objective is to compare disease-free survival at 5 years. Secondary end points include safety, overall survival, time to distant metastases, and time to contralateral breast cancer. The FACE trial will determine whether or not letrozole offers a greater clinical benefit to postmenopausal women with HR+ early breast cancer at increased risk of early recurrence compared with anastrozole. PMID:17912637
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Mou, Shan; Li, Jialin; Yu, Zanzhe; Wang, Qin; Ni, Zhaohui
2013-02-01
An open-label, randomized, controlled, single-centre clinical trial to evaluate the effects of low-protein intake, with or without keto acid supplementation, on nutritional status and proteinuria, in patients with hepatitis B virus (HBV) and early stage chronic glomerulonephritis. Patients with chronic glomerulonephritis and HBV infection were randomized to receive a low-protein diet (0.6-0.8 g/kg ideal body weight [IBW] per day) either without (LP group) or with (sLP group) keto acid supplementation (0.1 g/kg IBW per day), for 12 months. Nutritional, clinical and safety parameters were recorded. The study included 17 patients (LP group n = 9; sLP group n = 8). Proteinuria and microalbuminuria were significantly lower in the sLP group at 6 and 12 months compared with baseline, and at 12 months compared with the LP group. There were no significant differences in serum creatinine level or estimated glomerular filtration rate. Nutritional parameters (serum albumin and prealbumin) were significantly improved at 12 months, compared with baseline, in the sLP group. Restriction of dietary protein intake to 0.6-0.8 g/kg IBW per day appears to have an acceptable safety profile. Supplementation with keto acids is associated with decreased urine protein excretion.
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Doi, Tokuhide; Akai, Masami; Fujino, Keiji; Iwaya, Tsutomu; Kurosawa, Hisashi; Hayashi, Kunihiko; Marui, Eiji
2008-04-01
To examine the effect of home-based exercise on knee osteoarthritis among Japanese in comparison with that of nonsteroidal antiinflammatory drugs (NSAIDs). An open-labeled, randomized, controlled, multiclinic trial compared home-based quadriceps exercise with NSAIDs. Treatments were basically evaluated after 8 wks and compared with the baseline scores. Outcomes were evaluated with a set of psychometric measurements including the Western Ontario and McMaster Universities Arthritis Index (WOMAC), 36-Item Short-Form Health Survey (SF-36), Japanese Knee Osteoarthritis Measure (JKOM), and pain with the visual analog scale. A total of 142 patients entered this trial to provide the baseline data. After 21 cases withdrew, the final number analyzed was 121 cases: 63 for the exercise group and 58 for the NSAIDs group. Between these two groups, there was no significant difference in gender, age, body height and weight, body mass index, or each score at baseline. The subjects in both groups showed improvements in all scores at the end of intervention. The difference in improvement rate of each score between the two groups was not statistically significant, though the mean rank score measured with JKOM in the exercise was slightly better than that of the NSAIDs. Home-based exercise using quadriceps strengthening improves knee osteoarthritis no less than NSAIDs.
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Haziza, Christelle; de La Bourdonnaye, Guillaume; Skiada, Dimitra; Ancerewicz, Jacek; Baker, Gizelle; Picavet, Patrick; Lüdicke, Frank
2016-11-30
The Tobacco Heating System (THS) 2.2, a candidate Modified Risk Tobacco Product (MRTP), is designed to heat tobacco without burning it. Tobacco is heated in order to reduce the formation of harmful and potentially harmful constituents (HPHC), and reduce the consequent exposure, compared with combustible cigarettes (CC). In this 5-day exposure, controlled, parallel-group, open-label clinical study, 160 smoking, healthy subjects were randomized to three groups and asked to: (1) switch from CCs to THS 2.2 (THS group; 80 participants); (2) continue to use their own non-menthol CC brand (CC group; 41 participants); or (3) to refrain from smoking (smoking abstinence (SA) group; 39 participants). Biomarkers of exposure, except those associated with nicotine exposure, were significantly reduced in the THS group compared with the CC group, and approached the levels observed in the SA group. Increased product consumption and total puff volume were reported in the THS group. However, exposure to nicotine was similar to CC at the end of the confinement period. Reduction in urge-to-smoke was comparable between the THS and CC groups and THS 2.2 product was well tolerated. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
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Miller, Suellen; Tudor, Carrie; Thorsten, Vanessa; Nyima; Kalyang; Sonam; Lhakpen; Droyoung; Quzong, Karma; Dekyi, Tsering; Hartwell, Ty; Wright, Linda L.; Varner, Michael W.
2009-01-01
The objective of this study was to compare a Tibetan traditional medicine (the uterotonic Zhi Byed 11 [ZB11]) to oral misoprostol for prophylaxis of postpartum hemorrhage (PPH). We conducted a double-blind randomized controlled trial at three hospitals in Lhasa, Tibet, People’s Republic of China. Women (N = 967) were randomized to either ZB11 or misoprostol groups. Postpartum blood loss was measured in a calibrated blood collection drape. The primary combined outcome was incidence of PPH, defined as measured blood loss (MBL) ≥ 500 mL, administration of open label uterotonics, or maternal death. We found that the rate of the combined outcome was lower among the misoprostol group (16.1% versus 21.8% for ZB11; P = .02). Frequency of PPH was lower with misoprostol (12.4% versus 17.4%; P = .02). There were no significant differences in MBL > 1000 mL or mean or median MBL. Fever was significantly more common in the misoprostol group (P = .03). The rate of combined outcome was significantly lower among women receiving misoprostol. However, other indices of obstetric hemorrhage were not significantly different. PMID:19249659
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Graham, Dan J; Lucas-Thompson, Rachel G; Mueller, Megan P; Jaeb, Melanie; Harnack, Lisa
2017-04-01
The present study investigated whether parent/child pairs would select more healthful foods when: (i) products were labelled with front-of-package (FOP) nutrition labels relative to packages without labels; (ii) products were labelled with colour-coded Multiple Traffic Light (MTL) FOP labels relative to monochromatic Facts up Front (FuF) FOP labels; and (iii) FOP labels were explained via in-aisle signage v. unexplained. Participants were randomly assigned to one of five conditions: (i) FuF labels with in-aisle signs explaining the labels; (ii) FuF labels, no signage; (iii) MTL labels with in-aisle signage; (iv) MTL labels, no signage; (v) control group, no labels/signage. Saturated fat, sodium, sugar and energy (calorie) content were compared across conditions. The study took place in a laboratory grocery aisle. Parent/child pairs (n 153) completed the study. Results did not support the hypothesis that MTL labels would lead to more healthful choices than FuF labels. The presence of FOP labels did little to improve the healthfulness of selected foods, with few exceptions (participants with v. without access to FOP labels selected lower-calorie cereals, participants with access to both FOP labels and in-aisle explanatory signage selected products with less saturated fat v. participants without explanatory signage). Neither MTL nor FuF FOP labels led to food choices with significantly lower saturated fat, sodium or sugar. In-aisle signs explaining the FOP labels were somewhat helpful to consumers in making more healthful dietary decisions. New FOP labelling programmes could benefit from campaigns to increase consumer awareness and understanding of the labels.
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Rossignol, Patrick; Dorval, Marc; Fay, Renaud; Ros, Joan Fort; Loughraieb, Nathalie; Moureau, Frédérique; Laville, Maurice
2013-06-01
Anticoagulation for chronic dialysis patients with contraindications to heparin administration is challenging. Current guidelines state that in patients with increased bleeding risks, strategies that can induce systemic anticoagulation should be avoided. Heparin-free dialysis using intermittent saline flushes is widely adopted as the method of choice for patients at risk of bleeding, although on-line blood predilution may also be used. A new dialyzer, Evodial (Gambro, Lund, Sweden), is grafted with unfractionated heparin during the manufacturing process and may allow safe and efficient heparin-free hemodialysis sessions. In the present trial, Evodial was compared to standard care with either saline flushes or blood predilution. The HepZero study is the first international (seven countries), multicenter (10 centers), randomized, controlled, open-label, non-inferiority (and if applicable subsequently, superiority) trial with two parallel groups, comprising 252 end-stage renal disease patients treated by maintenance hemodialysis for at least 3 months and requiring heparin-free dialysis treatments. Patients will be treated during a maximum of three heparin-free dialysis treatments with either saline flushes or blood predilution (control group), or Evodial. The first heparin-free dialysis treatment will be considered successful when there is: no complete occlusion of air traps or dialyzer rendering dialysis impossible; no additional saline flushes to prevent clotting; no change of dialyzer or blood lines because of clotting; and no premature termination (early rinse-back) because of clotting.The primary objectives of the study are to determine the effectiveness of the Evodial dialyzer, compared with standard care in terms of successful treatments during the first heparin-free dialysis. If the non-inferiority of Evodial is demonstrated then the superiority of Evodial over standard care will be tested. The HepZero study results may have major clinical implications for patient care. ClinicalTrials.gov NCT01318486.
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Kinoshita, Hidefumi; Nakagawa, Ken; Usui, Yukio; Iwamura, Masatsugu; Ito, Akihiro; Miyajima, Akira; Hoshi, Akio; Arai, Yoichi; Baba, Shiro; Matsuda, Tadashi
2015-08-01
Three-dimensional (3D) imaging systems have been introduced worldwide for surgical instrumentation. A difficulty of laparoscopic surgery involves converting two-dimensional (2D) images into 3D images and depth perception rearrangement. 3D imaging may remove the need for depth perception rearrangement and therefore have clinical benefits. We conducted a multicenter, open-label, randomized trial to compare the surgical outcome of 3D-high-definition (HD) resolution and 2D-HD imaging in laparoscopic radical prostatectomy (LRP), in order to determine whether an LRP under HD resolution 3D imaging is superior to that under HD resolution 2D imaging in perioperative outcome, feasibility, and fatigue. One-hundred twenty-two patients were randomly assigned to a 2D or 3D group. The primary outcome was time to perform vesicourethral anastomosis (VUA), which is technically demanding and may include a number of technical difficulties considered in laparoscopic surgeries. VUA time was not significantly shorter in the 3D group (26.7 min, mean) compared with the 2D group (30.1 min, mean) (p = 0.11, Student's t test). However, experienced surgeons and 3D-HD imaging were independent predictors for shorter VUA times (p = 0.000, p = 0.014, multivariate logistic regression analysis). Total pneumoperitoneum time was not different. No conversion case from 3D to 2D or LRP to open RP was observed. Fatigue was evaluated by a simulation sickness questionnaire and critical flicker frequency. Results were not different between the two groups. Subjective feasibility and satisfaction scores were significantly higher in the 3D group. Using a 3D imaging system in LRP may have only limited advantages in decreasing operation times over 2D imaging systems. However, the 3D system increased surgical feasibility and decreased surgeons' effort levels without inducing significant fatigue.
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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.
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Su, Qing; Liu, Chao; Zheng, Hongting; Zhu, Jun; Li, Peng Fei; Qian, Lei; Yang, Wen Ying
2017-06-01
Premixed insulins are recommended starter insulins in Chinese patients after oral antihyperglycemic medication (OAM) failure. In the present study, we compared the efficacy and safety of insulin lispro mix 25 (LM25) twice daily (b.i.d.) and insulin lispro mix 50 (LM50) b.i.d. as a starter insulin regimen in Chinese patients with type 2 diabetes mellitus (T2DM) who had inadequate glycemic control with OAMs. The primary efficacy outcome in the present open-label parallel randomized clinical trial was change in HbA1c from baseline to 26 weeks. Patients were randomized in a ratio of 1: 1 to LM25 (n = 80) or LM50 (n = 76). A mixed-effects model with repeated measures was used to analyze continuous variables. The Cochran-Mantel-Haenszel test with stratification factor was used to analyze categorical variables. At the end of the study, LM50 was more efficacious than LM25 in reducing mean HbA1c levels (least-squares [LS] mean difference 0.48; 95 % confidence interval [CI] 0.22, 0.74; P < 0.001). More subjects in the LM50 than LM25 group achieved HbA1c targets of <7.0 % (72.4 % vs 45.0 %; P = 0.001) or ≤6.5 % (52.6 % vs 20.0 %; P < 0.001). Furthermore, LM50 was more effective than LM25 at reducing HbA1c in patients with baseline HbA1c, blood glucose excursion, and postprandial glucose greater than or equal to median levels (P ≤ 0.001). The rate and incidence of hypoglycemic episodes and increase in weight at the end of the study were similar between treatment groups. In Chinese patients with T2DM, LM50 was more efficacious than LM25 as a starter insulin. © 2016 The Authors. Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.
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Ovulatory effects of three oral contraceptive regimens: a randomized, open-label, descriptive trial.
Seidman, Larry; Kroll, Robin; Howard, Brandon; Ricciotti, Nancy; Hsieh, Jennifer; Weiss, Herman
2015-06-01
This study describes ovarian activity suppression of a 21/7-active low-dose combined oral contraceptive (COC) regimen that included only ethinyl estradiol (EE) during the traditional hormone-free interval (HFI) and two commercially available 28-day regimens, a 24/4 and a 21/7 regimen. The randomized, open-label, parallel-group descriptive study was conducted at two US sites. Healthy, reproductive-aged women (n=146) were randomized to one of three groups for three consecutive 28-day cycles, as follows: treatment 1 (n=39 completed): 21/7-active COC [21 days of 150 mcg desogestrel (DSG)/20 mcg EE, followed by 7 days of 10 mcg EE (DSG/EE+7 days EE)], treatment 2 (n=39 completed): 24 days of 3mg drospirenone (DRSP)/20 mcg EE, followed by 4 placebo (PBO)-pill days (DRSP/EE+4 days PBO) and treatment 3 (n=42 completed): 21 days of 100 mcg levonorgestrel (LNG)/20 mcg EE, followed by 7 PBO-pill days (LNG/EE+7 days PBO). The primary outcome was ovarian activity suppression assessed by transvaginal ultrasound and serum hormone concentrations and classified using the Hoogland and Skouby (H/S) method. Ovarian activity rate (H/S grade 4 or 5) was low for all three treatments: 0% [95% confidence interval (CI) 0-2.8] for DSG/EE+7 days EE, 1% (95% CI 0.2-5.2) for DRSP/EE+4days PBO and 1% (95% CI 0-3.9) for LNG/EE+7 days PBO. All three treatments showed similar suppression of serum progesterone, 17β-estradiol, follicle-stimulating hormone and luteinizing hormone levels. The 21/7-active low-dose COC regimen (DSG/EE+7 days EE) showed ovarian activity suppression that was similar to the 24/4 (DRSP/EE+4 days PBO) and 21/7 (LNG/EE+7days PBO) regimens. The 21/7-active low-dose COC regimen (DSG/EE+7 days EE) that included only EE during the traditional HFI showed suppression of ovarian follicular activity that was similar to the 24/4 (DRSP/EE+4days PBO) and the 21/7 (LNG/EE+7 days PBO) comparator regimens. Copyright © 2015 Elsevier Inc. All rights reserved.
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Sedai, Suman; Garnavi, Rahil; Roy, Pallab; Xi Liang
2015-08-01
Multi-atlas segmentation first registers each atlas image to the target image and transfers the label of atlas image to the coordinate system of the target image. The transferred labels are then combined, using a label fusion algorithm. In this paper, we propose a novel label fusion method which aggregates discriminative learning and generative modeling for segmentation of cardiac MR images. First, a probabilistic Random Forest classifier is trained as a discriminative model to obtain the prior probability of a label at the given voxel of the target image. Then, a probability distribution of image patches is modeled using Gaussian Mixture Model for each label, providing the likelihood of the voxel belonging to the label. The final label posterior is obtained by combining the classification score and the likelihood score under Bayesian rule. Comparative study performed on MICCAI 2013 SATA Segmentation Challenge demonstrates that our proposed hybrid label fusion algorithm is accurate than other five state-of-the-art label fusion methods. The proposed method obtains dice similarity coefficient of 0.94 and 0.92 in segmenting epicardium and endocardium respectively. Moreover, our label fusion method achieves more accurate segmentation results compared to four other label fusion methods.
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Takács, István; Tóth, Béla E; Szekeres, László; Szabó, Boglárka; Bakos, Bence; Lakatos, Péter
2017-01-01
The comparative efficacy and safety profiles of selected daily 1000 IU, weekly 7000 IU and monthly 30,000 IU vitamin D 3 -not previously investigated-will be evaluated. Here, a prospective, randomized clinical trial, comparing efficacy and safety of a daily single dose of 1000 IU (group A) to a once-weekly 7000 IU dose (group B), or monthly 30,000 IU dose (group C) of vitamin D 3 . The present study is a controlled, randomized, open-label, multicenter clinical trial, 3 months in duration. Sixty-four adult subjects with vitamin D deficiency (25OHD<20 ng/ml), were included according to the inclusion and exclusion criteria. Dose-responses for increases in serum vitamin 25OHD were statistically equivalent for each of the three groups: A, B and C. Outcomes were 13.0 ± 1.5; 12.6 ± 1.1 and 12.9 ± 0.9 ng/ml increases in serum 25OHD per 1000 IU, daily, weekly and monthly, respectively. The treatment of subjects with selected doses restored 25OHD values to levels above 20 ng/ml in all groups. Treatment with distinct administration frequency of vitamin D 3 did not exhibit any differences in safety parameters. The daily, weekly and monthly administrations of daily equivalent of 1000 IU of vitamin D 3 provide equal efficacy and safety profiles.
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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.
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Chiari, Paolo; Giorgi, Sabina; Ugolini, Daniela; Montanari, Morena; Giudanella, Pietro; Gramantieri, Antonella; Collesi, Franca; Pau, Michelina; Smaldone, Maddalena; Matarasso, Maddalena; Mazzini, Cinzia; Russo, Francesca; Gazineo, Domenica; Fontana, Mirella; Taddia, Patrizia
2012-01-01
Randomized controlled trial on the effectiveness of Corpitolinol 60 in the prevention of pressure sores in surgical patients. The risk of pressure sores in surgical patients is widely recognised. The Corpitolinol 60 (Sanyréne®) applied on compressed areas seems to reduce the risk of pressure sores. To assess the efficacy of Corpitolinol 60 in preventing pressure sores in the operatory theatre. The open label randomized clinical trial was conducted in 5 operating theatres of Northen Italy. Patients were randomized to receive Corpitolinol 60 in areas undergoing compression. Experimental group and controls were treated with usual measures for preventing pressure sores. The lesions were staged according to NPUAP up to 24 hours after surgery. Three-hundred-one patients were randomized (155 in the Sanyréne® group and 143 controls). The main variables predictive of pressure sores risk (ASA class, sex, age, duration of the surgery, and BMI) were comparable across groups. At the end of the surgery 71 patients (23.8%) in the experimental group and 47 controls (30.8%) had a pressure sore (p 0.006; RR 1.81 IC95% 1.17-2.79). Twelve and 24 hours after surgery the differences between groups were not significant. The aim of reducing pressure sores was not reached for patients treated with Corpitolinol 60.
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Wongpakaran, R; Suansanae, T; Tan-Khum, T; Kraivichian, C; Ongarjsakulman, R; Suthisisang, C
2017-06-01
Psychopharmacologic therapy has so far focused on ameliorating disruptive behaviours to improve patient's function and quality of life. Due to the complicated neurobiological aetiology of autism spectrum disorder (ASD), a traditional pharmacist intervention may be insufficient to initiate the optimal care for this vulnerable population. We evaluate the impact of providing specialty psychiatry (PS) pharmacist intervention in identifying and resolving drug-related problems (DRPs) among children with ASD associated with disruptive behaviours. An eight-week-long, prospective, randomized open-label study was conducted. Children between 2.5 and 12 years of age with ASD and showing disruptive behaviours were included. They were randomly assigned to an intervention or a control group. Patients in the intervention group received pharmacist interventions delivered by a PS pharmacist, while those in control group were cared by a hospital pharmacist. The primary outcome was the number of patients who resolved of at least one DRP by the end of the study. The secondary outcome was to compare the mean Aberrant Behavior Checklist-Irritability (ABC-I) scores between the two groups. Twenty-five patients were randomly assigned to either an intervention or control group. At week 8, the total number of patients who resolved of at least one DRP was 13 (52%) in the intervention group and 4 (16%) in the control group, respectively (P=.016). Improper drug selection, medication non-adherence and subtherapeutic dosage were the most common DRPs. Mean ABC-I scores improved in the intervention group more than in the control group (9.8±5.6 vs 17.7±7.9; P<.001). To the best of our knowledge, this is the first study which demonstrated that PS pharmacist intervention is an effective strategy to resolve DRPs in patient with ASD. The reduction in common DRPs mostly resulted from the PS pharmacist interventions, including selection of antipsychotic agent, adjustment of dosage based on ABC-I scores and provision of individualized drug counselling. Reducing DRPs led to the improvement of any disruptive behaviour. In addition, multidisciplinary team should develop drug therapy protocols to promote the role of pharmacists in this setting. © 2017 John Wiley & Sons Ltd.
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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
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Shi, Y K; Wang, L; Han, B H; Li, W; Yu, P; Liu, Y P; Ding, C M; Song, X; Ma, Z Y; Ren, X L; Feng, J F; Zhang, H L; Chen, G Y; Han, X H; Wu, N; Yao, C; Song, Y; Zhang, S C; Song, W; Liu, X Q; Zhao, S J; Lin, Y C; Ye, X Q; Li, K; Shu, Y Q; Ding, L M; Tan, F L; Sun, Y
2017-10-01
Icotinib has been previously shown to be non-inferior to gefitinib in non-selected advanced non-small-cell lung cancer patients when given as second- or further-line treatment. In this open-label, randomized, phase 3 CONVINCE trial, we assessed the efficacy and safety of first-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance in lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation. Eligible participants were adults with stage IIIB/IV lung adenocarcinoma and exon 19/21 EGFR mutations. Participants were randomly allocated (1 : 1) to receive oral icotinib or 3-week cycle of cisplatin plus pemetrexed for up to four cycles; non-progressive patients after four cycles were maintained with pemetrexed until disease progression or intolerable toxicity. The primary end point was progression-free survival (PFS) assessed by independent response evaluation committee. Other end points included overall survival (OS) and safety. Between January 2013 and August 2014, 296 patients were randomized, and 285 patients were treated (148 to icotinib, 137 to chemotherapy). Independent response evaluation committee-assessed PFS was significantly longer in the icotinib group (11.2 versus 7.9 months; hazard ratio, 0.61, 95% confidence interval 0.43-0.87; P = 0.006). No significant difference for OS was observed between treatments in the overall population or in EGFR-mutated subgroups (exon 19 Del/21 L858R). The most common grade 3 or 4 adverse events (AEs) in the icotinib group were rash (14.8%) and diarrhea (7.4%), compared with nausea (45.9%), vomiting (29.2%), and neutropenia (10.9%) in the chemotherapy group. AEs (79.1% versus 94.2%; P < 0.001) and treatment-related AEs (54.1% versus 90.5%; P < 0.001) were significantly fewer in the icotinib group than in the chemotherapy group. First-line icotinib significantly improves PFS of advanced lung adenocarcinoma patients with EGFR mutation with a tolerable and manageable safety profile. Icotinib should be considered as a first-line treatment for this patient population. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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Nonlocal atlas-guided multi-channel forest learning for human brain labeling
DOE Office of Scientific and Technical Information (OSTI.GOV)
Ma, Guangkai; Gao, Yaozong; Wu, Guorong
Purpose: It is important for many quantitative brain studies to label meaningful anatomical regions in MR brain images. However, due to high complexity of brain structures and ambiguous boundaries between different anatomical regions, the anatomical labeling of MR brain images is still quite a challenging task. In many existing label fusion methods, appearance information is widely used. However, since local anatomy in the human brain is often complex, the appearance information alone is limited in characterizing each image point, especially for identifying the same anatomical structure across different subjects. Recent progress in computer vision suggests that the context features canmore » be very useful in identifying an object from a complex scene. In light of this, the authors propose a novel learning-based label fusion method by using both low-level appearance features (computed from the target image) and high-level context features (computed from warped atlases or tentative labeling maps of the target image). Methods: In particular, the authors employ a multi-channel random forest to learn the nonlinear relationship between these hybrid features and target labels (i.e., corresponding to certain anatomical structures). Specifically, at each of the iterations, the random forest will output tentative labeling maps of the target image, from which the authors compute spatial label context features and then use in combination with original appearance features of the target image to refine the labeling. Moreover, to accommodate the high inter-subject variations, the authors further extend their learning-based label fusion to a multi-atlas scenario, i.e., they train a random forest for each atlas and then obtain the final labeling result according to the consensus of results from all atlases. Results: The authors have comprehensively evaluated their method on both public LONI-LBPA40 and IXI datasets. To quantitatively evaluate the labeling accuracy, the authors use the dice similarity coefficient to measure the overlap degree. Their method achieves average overlaps of 82.56% on 54 regions of interest (ROIs) and 79.78% on 80 ROIs, respectively, which significantly outperform the baseline method (random forests), with the average overlaps of 72.48% on 54 ROIs and 72.09% on 80 ROIs, respectively. Conclusions: The proposed methods have achieved the highest labeling accuracy, compared to several state-of-the-art methods in the literature.« less
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Nonlocal atlas-guided multi-channel forest learning for human brain labeling
Ma, Guangkai; Gao, Yaozong; Wu, Guorong; Wu, Ligang; Shen, Dinggang
2016-01-01
Purpose: It is important for many quantitative brain studies to label meaningful anatomical regions in MR brain images. However, due to high complexity of brain structures and ambiguous boundaries between different anatomical regions, the anatomical labeling of MR brain images is still quite a challenging task. In many existing label fusion methods, appearance information is widely used. However, since local anatomy in the human brain is often complex, the appearance information alone is limited in characterizing each image point, especially for identifying the same anatomical structure across different subjects. Recent progress in computer vision suggests that the context features can be very useful in identifying an object from a complex scene. In light of this, the authors propose a novel learning-based label fusion method by using both low-level appearance features (computed from the target image) and high-level context features (computed from warped atlases or tentative labeling maps of the target image). Methods: In particular, the authors employ a multi-channel random forest to learn the nonlinear relationship between these hybrid features and target labels (i.e., corresponding to certain anatomical structures). Specifically, at each of the iterations, the random forest will output tentative labeling maps of the target image, from which the authors compute spatial label context features and then use in combination with original appearance features of the target image to refine the labeling. Moreover, to accommodate the high inter-subject variations, the authors further extend their learning-based label fusion to a multi-atlas scenario, i.e., they train a random forest for each atlas and then obtain the final labeling result according to the consensus of results from all atlases. Results: The authors have comprehensively evaluated their method on both public LONI_LBPA40 and IXI datasets. To quantitatively evaluate the labeling accuracy, the authors use the dice similarity coefficient to measure the overlap degree. Their method achieves average overlaps of 82.56% on 54 regions of interest (ROIs) and 79.78% on 80 ROIs, respectively, which significantly outperform the baseline method (random forests), with the average overlaps of 72.48% on 54 ROIs and 72.09% on 80 ROIs, respectively. Conclusions: The proposed methods have achieved the highest labeling accuracy, compared to several state-of-the-art methods in the literature. PMID:26843260
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Yoshimura, Shinichi; Uchida, Kazutaka; Daimon, Takashi; Takashima, Ryuzo; Kimura, Kazuhiro; Morimoto, Takeshi
2017-11-01
Several studies suggested that statins during hospitalization were associated with better disability outcomes in patients with acute ischemic stroke, but only 1 small randomized trial is available. We conducted a multicenter, open-label, randomized controlled trial in patients with acute ischemic strokes in 11 hospitals in Japan. Patients with acute ischemic stroke and dyslipidemia randomly received statins within 24 hours after admission in the early group or on the seventh day in the delayed group, in a 1:1 ratio. Statins were administered for 12 weeks. The primary outcome was patient disability assessed by modified Rankin Scale at 90 days. A total of 257 patients were randomized and analyzed (early 131, delayed 126). At 90 days, modified Rankin Scale score distribution did not differ between groups ( P =0.68), and the adjusted common odds ratio of the early statin group was 0.84 (95% confidence interval, 0.53-1.3; P =0.46) compared with the delayed statin group. There were 3 deaths at 90 days (2 in the early group, 1 in the delayed group) because of malignancy. Ischemic stroke recurred in 9 patients (6.9%) in the early group and 5 patients (4.0%) in the delayed group. The safety profile was similar between groups. Our randomized trial involving patients with acute ischemic stroke and dyslipidemia did not show any superiority of early statin therapy within 24 hours of admission compared with delayed statin therapy 7 days after admission to alleviate the degree of disability at 90 days after onset. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02549846. © 2017 American Heart Association, Inc.
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Lee, Joo Myung; Cho, Deok-Kyu; Hahn, Joo-Yong; Song, Young Bin; Park, Taek Kyu; Oh, Ju-Hyeon; Lee, Jin Bae; Doh, Joon-Hyung; Kim, Sang-Hyun; Yang, Jeong Hoon; Choi, Jin-Ho; Choi, Seung-Hyuck; Lee, Sang Hoon; Gwon, Hyeon-Cheol
2016-12-01
Dual antiplatelet therapy (DAPT) is a fundamental treatment that optimizes clinical outcomes after percutaneous coronary intervention, especially in patients with acute coronary syndrome (ACS). Although current international guidelines recommend DAPT for at least 12 months after implantation of a drug-eluting stent in patients with ACS, these recommendations are not based on randomized controlled trials dedicated to ACS population. The SMART-DATE trial is a prospective, multicenter, randomized, and open-label study to demonstrate the noninferiority of 6-month DAPT compared with 12 months or longer DAPT in patients with ACS undergoing percutaneous coronary intervention. A total of 2,700 patients will undergo prospective, random assignment to either of the DAPT duration groups. To minimize the bias from different stent devices, the type of stents will be randomly assigned (everolimus-eluting stents, zotarolimus-eluting stents, or biolimus A9-eluting stents). The primary end point is a composite of all-cause death, myocardial infarction, and cerebrovascular events at 18 months after the index procedure. The major secondary end points are definite/probable stent thrombosis defined by the Academic Research Consortium and bleeding defined by Bleeding Academic Research Consortium type 2-5. The SMART-DATE randomized trial is the first study exploring the safety of 6-month DAPT compared with conventional 12-month or longer DAPT dedicated to patients with ACS after second-generation drug-eluting stent implantation. Copyright © 2016 Elsevier Inc. All rights reserved.
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Ottoboni, Tom; Keller, Mary Rose; Cravets, Matt; Clendeninn, Neil; Quart, Barry
2018-01-01
Fosaprepitant, an intravenous (IV) aprepitant prodrug for chemotherapy-induced nausea and vomiting prophylaxis, is associated with systemic and infusion-site reactions attributed in part to its surfactant, polysorbate 80. HTX-019 is an IV aprepitant formulation free of polysorbate 80 and other synthetic surfactants. This open-label, single-dose, randomized, two-way crossover bioequivalence study compared pharmacokinetics and safety of HTX-019 and fosaprepitant. Healthy subjects received single-dose HTX-019 (130 mg) or fosaprepitant (150 mg) IV over 30 min, with ≥7-day washout between doses. Blood samples were evaluated for pharmacokinetics and bioequivalence; safety evaluation included treatment-emergent adverse events (TEAEs) and serious adverse events. Ninety-seven of one hundred enrolled subjects completed the study. Baseline characteristics were comparable between treatment sequences. For HTX-019, mean (percent coefficient of variation) area under the curve (AUC) from time 0 to time of last measurable plasma concentration (AUC 0-t ), AUC from time 0 to infinity (AUC 0-inf ), and plasma concentration at 12 h (C 12 h ) for HTX-019 were 43,729 h*ng/mL (32.7), 45,460 h*ng/mL (36.8), and 988.4 ng/mL (27.5), respectively; corresponding fosaprepitant values were 44,130 h*ng/mL (32.0), 46,163 h*ng/mL (36.6), and 1,022 ng/mL (28.5). Also, 90% CIs (94.186-101.354) were within bioequivalence bounds (80%-125%). Within 1 h following infusion start, one (1%) HTX-019 recipient reported one TEAE, while 20 (20%) fosaprepitant recipients reported 32 TEAEs. Dyspnea occurred in three fosaprepitant recipients (at <1 min in two subjects and at 18 min in one subject, considered study drug related) and one HTX-019 recipient (at 120 h, associated with a respiratory tract infection and considered not related to the study drug). No severe TEAEs, serious adverse events, or deaths occurred; all TEAEs resolved. HTX-019 was bioequivalent to fosaprepitant and may provide a safer alternative to fosaprepitant for chemotherapy-induced nausea and vomiting prophylaxis.
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Ottoboni, Tom; Keller, Mary Rose; Cravets, Matt; Clendeninn, Neil; Quart, Barry
2018-01-01
Introduction Fosaprepitant, an intravenous (IV) aprepitant prodrug for chemotherapy-induced nausea and vomiting prophylaxis, is associated with systemic and infusion-site reactions attributed in part to its surfactant, polysorbate 80. HTX-019 is an IV aprepitant formulation free of polysorbate 80 and other synthetic surfactants. Materials and methods This open-label, single-dose, randomized, two-way crossover bioequivalence study compared pharmacokinetics and safety of HTX-019 and fosaprepitant. Healthy subjects received single-dose HTX-019 (130 mg) or fosaprepitant (150 mg) IV over 30 min, with ≥7-day washout between doses. Blood samples were evaluated for pharmacokinetics and bioequivalence; safety evaluation included treatment-emergent adverse events (TEAEs) and serious adverse events. Ninety-seven of one hundred enrolled subjects completed the study. Results Baseline characteristics were comparable between treatment sequences. For HTX-019, mean (percent coefficient of variation) area under the curve (AUC) from time 0 to time of last measurable plasma concentration (AUC0−t), AUC from time 0 to infinity (AUC0−inf), and plasma concentration at 12 h (C12 h) for HTX-019 were 43,729 h*ng/mL (32.7), 45,460 h*ng/mL (36.8), and 988.4 ng/mL (27.5), respectively; corresponding fosaprepitant values were 44,130 h*ng/mL (32.0), 46,163 h*ng/mL (36.6), and 1,022 ng/mL (28.5). Also, 90% CIs (94.186–101.354) were within bioequivalence bounds (80%–125%). Within 1 h following infusion start, one (1%) HTX-019 recipient reported one TEAE, while 20 (20%) fosaprepitant recipients reported 32 TEAEs. Dyspnea occurred in three fosaprepitant recipients (at <1 min in two subjects and at 18 min in one subject, considered study drug related) and one HTX-019 recipient (at 120 h, associated with a respiratory tract infection and considered not related to the study drug). No severe TEAEs, serious adverse events, or deaths occurred; all TEAEs resolved. Conclusion HTX-019 was bioequivalent to fosaprepitant and may provide a safer alternative to fosaprepitant for chemotherapy-induced nausea and vomiting prophylaxis. PMID:29535504
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Anti-Dementia Drugs, Gait Performance and Mental Imagery of Gait: A Non-Randomized Open-Label Trial.
Beauchet, Olivier; Barden, John; Liu-Ambrose, Teresa; Chester, Victoria L; Annweiler, Cedric; Szturm, Tony; Grenier, Sébastien; Léonard, Guillaume; Bherer, Louis; Allali, Gilles
2016-09-01
Few studies have examined the effect of anti-dementia drugs (i.e., acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists) on gait performance. Past studies have focused on the stride time (i.e., gait cycle duration) but not on the mental imagery of gait. To compare mental imagery of gait and spatiotemporal gait parameters in patients with dementia [i.e., Alzheimer's disease (AD) and non-AD] before and after the use of anti-dementia drugs (i.e., acetylcholinesterase inhibitors and memantine) and in controls (i.e., patients with dementia who did not take anti-dementia drugs). A total of 112 patients (mean age 82.5 ± 4.2 years, 68.8 % female) with mild-to-moderate AD and non-AD dementia were included in this non-randomized open-label trial (n = 56 in the Intervention group, and n = 56 in the Control group matched for age, sex, and stage and type of dementia) nested in a cohort study (mean follow-up 238.5 ± 79.8 days). Mental imagery of gait was assessed with the actual and imagined Timed Up and Go tests (aTUG and iTUG) and the difference between aTUG and iTUG (i.e., delta-TUG). Spatiotemporal gait parameters were measured with the GAITRite(®) system during normal walking. Participants in the Intervention group had a longer iTUG time (p < 0.001) and a lower delta-TUG value (p = 0.001) at the follow-up compared with those in the Control group. There was a significant increase in iTUG (p = 0.001) and decrease in delta-TUG (p < 0.001) from baseline to the follow-up only in the Intervention group. Multiple linear regression showed that the use of anti-dementia drugs was associated with a longer iTUG time and a lower delta-TUG value (best performance, p < 0.002). Our findings showed an improvement in mental imagery of gait with the use of anti-dementia drugs, but no changes in actual gait performance. NCT01315704.
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Pulido, Federico; Ribera, Esteban; Lagarde, María; Pérez-Valero, Ignacio; Palacios, Rosario; Iribarren, José A; Payeras, Antoni; Domingo, Pere; Sanz, José; Cervero, Miguel; Curran, Adrián; Rodríguez-Gómez, Francisco J; Téllez, María J; Ryan, Pablo; Barrufet, Pilar; Knobel, Hernando; Rivero, Antonio; Alejos, Belén; Yllescas, María; Arribas, José R
2017-11-29
Our objective was to assess the therapeutic noninferiority of dual therapy with darunavir/ritonavir and lamivudine compared to triple therapy with darunavir/ritonavir plus 2 nucleos(t)ides for maintenance of human immunodeficiency virus type 1 (HIV-1) suppression. This was a multicenter, open-label, noninferiority trial (margin 12%). Patients with HIV-1 RNA <50 copies/mL for 6 months or longer on triple therapy with darunavir/ritonavir and 2 nucleos(t)ides (tenofovir disoproxil fumarate and emtricitabine or abacavir and lamivudine) and with no resistance were randomized to continue therapy (n = 128) or switch to darunavir/ritonavir and lamivudine (n = 129). The primary endpoint was the proportion of participants with HIV-RNA <50 copies/mL after 48 weeks of follow-up according to the snapshot algorithm. A total of 249 participants received study drugs (intention-to-treat exposed). The proportion of participants with HIV-RNA <50 copies/mL in the dual- and triple-therapy arms was 88.9% (112/126) and 92.7% (114/123; difference, -3.8%; 95% confidence interval, -11.0 to 3.4), respectively. Four participants in the dual-therapy arm and 2 in the triple-therapy arm developed protocol-defined virological failure. Switching to dual therapy was associated with a significant increase in total, low-density lipoprotein, and high-density lipoprotein (HDL) cholesterol, but not in the total-to-HDL cholesterol ratio. Serious adverse events and study drug discontinuations due to adverse events occurred in 4.8% vs 4.9%P = .97) and in 0.8% (1/126) vs 1.6% P = .55) in dual therapy vs triple therapy, respectively. Dual therapy with darunavir/ritonavir and lamivudine demonstrated noninferior therapeutic efficacy and similar tolerability compared to triple therapy. NCT02159599. © 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.
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Abedin, Mohammed Joynal; Sayeed, Abdullah Abu; Basher, Ariful; Maude, Richard J; Hoque, Gofranul; Faiz, M A
2012-06-01
Severe organophosphate compound (OPC) poisoning is an important clinical problem in many countries of the world. Unfortunately, little clinical research has been performed and little evidence exists with which to determine the best therapy. A study was therefore undertaken to determine the optimal dosing regimen for atropine in the treatment of OPC poisoning. An open-label randomized clinical trial was conducted in Chittagong Medical College Hospital, Chittagong, Bangladesh, on 156 hospitalized individuals with OPC poisoning from June to September 2006. The aim was to compare the efficacy and safety of conventional bolus doses with individualized incremental doses of atropine for atropinization followed by continuous atropine infusion for management of OPC poisoning. Inclusion criteria were patients with a clear history of OPC poisoning with clear clinical signs of toxicity, i.e. features of cholinergic crisis. The patients were observed for at least 96 h. Immediate outcome and complications were recorded. Out of 156 patients, 81 patients received conventional bolus dose atropine (group A) and 75 patients received rapidly incremental doses of atropine followed by infusion (group B). The mortality in group 'A' was 22.5% (18/80) and in group 'B' 8% (6/75) (p < 0.05). The mean duration of atropinization in group 'A' was 151.74 min compared to 23.90 min for group 'B' (p < 0.001). More patients in group A experienced atropine toxicity than in group 'B' (28.4% versus 12.0%, p < 0.05); intermediate syndrome was more common in group 'A' than in group 'B' (13.6% versus 4%, p < 0.05), and respiratory support was required more often for patients in group 'A' than in group 'B' (24.7% versus 8%, p < 0.05). Rapid incremental dose atropinization followed by atropine infusion reduces mortality and morbidity from OPC poisoning and shortens the length of hospital stay and recovery. Incremental atropine and infusion should become the treatment of choice for OPC poisoning. Given the paucity of existing evidence, further clinical studies should be performed to determine the optimal dosing regimen of atropine that most rapidly and safely achieves atropinization in these patients.
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Home, Philip D; Bergenstal, Richard M; Bolli, Geremia B; Ziemen, Monika; Rojeski, Maria; Espinasse, Melanie; Riddle, Matthew C
2015-12-01
Insulin therapy in type 1 diabetes still provides suboptimal outcomes. Insulin glargine 300 units/mL (Gla-300), with a flatter pharmacodynamic profile compared with insulin glargine 100 units/mL (Gla-100), is an approach to this problem. People with type 1 diabetes, using a mealtime and basal insulin regimen, were randomized open-label to Gla-300 or Gla-100 and to morning or evening injection, continuing the mealtime analog, and followed for 6 months. Participants (n = 549) were a mean age of 47 years and had a mean duration of diabetes of 21 years and BMI of 27.6 kg/m(2). The change in HbA1c (primary end point; baseline 8.1%) was equivalent in the two treatment groups (difference, 0.04% [95% CI -0.10 to 0.19]) (0.4 mmol/mol [-1.1 to 2.1]), and Gla-300 was thus noninferior. Similar results with wider 95% CIs were found for morning and evening injection times and for prebreakfast self-measured plasma glucose (SMPG) overall. Results were also similar for Gla-300 when morning and evening injection time was compared, including overlapping 8-point SMPG profiles. Hypoglycemia did not differ, except for the first 8 weeks of the study, when nocturnal confirmed or severe hypoglycemia was lower with Gla-300 (rate ratio 0.69 [95% CI 0.53-0.91]). Hypoglycemia with Gla-300 did not differ by time of injection. The basal insulin dose was somewhat higher at 6 months for Gla-300. The adverse event profile did not differ and was independent of the Gla-300 time of injection. Weight gain was lower with Gla-300. In long-duration type 1 diabetes, Gla-300 provides similar glucose control to Gla-100, with a lower risk of hypoglycemia after transfer from other insulins, independent of time of injection, and less weight gain. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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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.
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Braun, William E; Schold, Jesse D; Stephany, Brian R; Spirko, Rita A; Herts, Brian R
2014-05-01
The two largest studies of mammalian target of rapamycin inhibitor treatment of autosomal dominant polycystic kidney disease (ADPKD) demonstrated no clear benefit on the primary endpoint of total kidney volume (TKV) or on eGFR. The present study evaluated two levels of rapamycin on the 12-month change in (125)I-iothalamate GFR (iGFR) as the primary endpoint and TKV secondarily. In a 12-month open-label pilot study, 30 adult patients with ADPKD were randomly assigned to low-dose (LD) rapamycin (rapamycin trough blood level, 2-5 ng/ml) (LD group, n=10), standard-dose (STD) rapamycin trough level (>5-8 ng/ml) (STD group, n=10), or standard care (SC group, n=10). They were evaluated with iGFR and noncontrast computed tomography. Change in iGFR at 12 months was significantly higher in the LD group (7.7±12.5 ml/min per 1.73 m(2); n=9) than in the SC group (-11.2 ± 9.1 ml/min per 1.73 m(2); n=9) (LD versus SC: P<0.01). Change in iGFR at 12 months in the STD group (1.6 ± 12.1 ml/min per 1.73 m(2); n=8) was not significantly greater than that in the SC group (P=0.07), but it was in the combined treatment groups (LD+STD versus SC: P<0.01). Neither eGFR calculated by the CKD-Epidemiology Collaboration equation nor TKV (secondary endpoint) changed significantly from baseline to 12 months in any of the groups. On the basis of results of the mixed model, during the study, patients in the LD group had significantly lower trough blood levels of rapamycin (mean range ± SD, 2.40 ± 0.64 to 2.90 ± 1.20 ng/ml) compared with those in the STD group (3.93 ± 2.27 to 5.77 ± 1.06 ng/ml) (P<0.01). Patients with ADPKD receiving LD rapamycin demonstrated a significant increase in iGFR compared with those receiving standard care, without a significant effect on TKV after 12 months.
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The Current Indication for Pacemaker in Patients with Cardioinhibitory Vasovagal Syncope
da Silva, Rose Mary Ferreira Lisboa
2016-01-01
The most frequent cause of syncope is vasovagal reflex. It is associated with worse quality of life, depression, fatigue and physical injury. Recurrence of vasovagal syncope is an aggravating, reaching the rate of 69%. Initial step and pharmacological treatment may not work, especially in patients with recurrent syncope without prodrome. These patients can present cardioinhibitory response with asystole. Studies were designed to analyses the effectiveness of pacemaker for prevention of syncope. In this review, nonrandomized clinical trials, open-label randomized, double-blind randomized, placebo-controlled, and studies based on tilt test or Implantable Loop Recorder findings will be discussed. PMID:27651841
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Park-Hansen, Jesper; Holme, Susanne J V; Irmukhamedov, Akhmadjon; Carranza, Christian L; Greve, Anders M; Al-Farra, Gina; Riis, Robert G C; Nilsson, Brian; Clausen, Johan S R; Nørskov, Anne S; Kruuse, Christina R; Rostrup, Egill; Dominguez, Helena
2018-05-23
Open heart surgery is associated with high occurrence of atrial fibrillation (AF), subsequently increasing the risk of post-operative ischemic stroke. Concomitant with open heart surgery, a cardiac ablation procedure is commonly performed in patients with known AF, often followed by left atrial appendage closure with surgery (LAACS). However, the protective effect of LAACS on the risk of cerebral ischemia following cardiac surgery remains controversial. We have studied whether LAACS in addition to open heart surgery protects against post-operative ischemic brain injury regardless of a previous AF diagnosis. One hundred eighty-seven patients scheduled for open heart surgery were enrolled in a prospective, open-label clinical trial and randomized to concomitant LAACS vs. standard care. Randomization was stratified by usage of oral anticoagulation (OAC) planned to last at least 3 months after surgery. The primary endpoint was a composite of post-operative symptomatic ischemic stroke, transient ischemic attack or imaging findings of silent cerebral ischemic (SCI) lesions. During a mean follow-up of 3.7 years, 14 (16%) primary events occurred among patients receiving standard surgery vs. 5 (5%) in the group randomized to additional LAACS (hazard ratio 0.3; 95% CI: 0.1-0.8, p = 0.02). In per protocol analysis (n = 141), 14 (18%) primary events occurred in the control group vs. 4 (6%) in the LAACS group (hazard ratio 0.3; 95% CI: 0.1-1.0, p = 0.05). In a real-world setting, LAACS in addition to elective open-heart surgery was associated with lower risk of post-operative ischemic brain injury. The protective effect was not conditional on AF/OAC status at baseline. LAACS study, clinicaltrials.gov NCT02378116 , March 4th 2015, retrospectively registered.
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Wallace, Carol A; Giannini, Edward H; Spalding, Steven J; Hashkes, Philip J; O'Neil, Kathleen M; Zeft, Andrew S; Szer, Ilona S; Ringold, Sarah; Brunner, Hermine I; Schanberg, Laura E; Sundel, Robert P; Milojevic, Diana S; Punaro, Marilynn G; Chira, Peter; Gottlieb, Beth S; Higgins, Gloria C; Ilowite, Norman T; Kimura, Yukiko; Johnson, Anne; Huang, Bin; Lovell, Daniel J
2014-06-01
To determine the elapsed time while receiving aggressive therapy to the first observation of clinically inactive disease (CID), total duration of CID and potential predictors of this response in a cohort of children with recent onset of polyarticular juvenile idiopathic arthritis (poly-JIA). Eighty-five children were randomized blindly to methotrexate (MTX), etanercept, and rapidly tapered prednisolone (MEP) or MTX monotherapy and assessed for CID over 1 year of treatment. Patients who failed to achieve intermediary endpoints were switched to open-label MEP treatment. Fifty-eight (68.2%) of the 85 patients achieved CID at 1 or more visits including 18 who received blinded MEP, 11 while receiving MTX monotherapy, and 29 while receiving open-label MEP. Patients starting on MEP achieved CID earlier and had more study days in CID compared to those starting MTX, but the differences were not significantly different. Patients given MEP (more aggressive therapy) earlier in the disease course were statistically more likely to have a higher proportion of followup visits in CID than those with longer disease course at baseline. Those who achieved American College of Rheumatology Pediatric 70 response at 4 months had a significantly greater proportion of followup visits in CID, compared to those who failed to achieve this improvement (p < 0.0001). Of the 32 patients who met criteria for CID and then lost CID status, only 3 fulfilled the definition of disease flare. Shorter disease duration prior to treatment, a robust response at 4 months, and more aggressive therapy result in a higher likelihood and longer duration of CID in patients with poly-JIA. The original trial from which data for this analysis were obtained is registered on www.clinicaltrials.gov NCT 00443430.
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Fredriksen, Mats; Dahl, Alv A; Martinsen, Egil W; Klungsøyr, Ole; Haavik, Jan; Peleikis, Dawn E
2014-12-01
How to generalize from randomized placebo controlled trials of ADHD drug treatment in adults to 'real-world' clinical practice is intriguing. This open-labeled prospective observational study examined the effectiveness of long-term stimulant and non-stimulant medication in adult ADHD including dose, side-effects and comorbidity in a clinical setting. A specialized ADHD outpatient clinic gave previously non-medicated adults (n=250) with ADHD methylphenidate as first-line drug according to current guidelines. Patients who were non-tolerant or experiencing low efficacy were switched to amphetamine or atomoxetine. Primary outcomes were changes of ADHD-symptoms evaluated with the Adult ADHD Self-Report Scale (ASRS) and overall severity by the Global Assessment of Functioning (GAF). Secondary outcomes were measures of mental distress, and response on the Clinical-Global-Impressions-Improvement Scale. Data at baseline and follow-ups were compared in longitudinal mixed model analyses for time on-medication, dosage, comorbidity, and side-effects. As results, 232 patients (93%) completed examination at the 12 month endpoint, and 163 (70%) remained on medication. Compared with the patients who discontinued medication, those still on medication had greater percentage reduction in ASRS-scores (median 39%, versus 13%, P<0.001) and greater improvement of GAF (median 20% versus 4%, P<0.001) and secondary outcomes. Continued medication and higher cumulated doses showed significant associations to sustained improvement. Conversely, psychiatric comorbidity and side-effects were related to lower effectiveness and more frequent termination of medication. Taken together, one-year treatment with stimulants or atomoxetine was associated with a clinically significant reduction in ADHD symptoms and mental distress, and improvement of measured function. No serious adverse events were observed. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.
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Deltoid Injections of Risperidone Long-acting Injectable in Patients with Schizophrenia
Quiroz, Jorge A.; Rusch, Sarah; Thyssen, An; Kushner, Stuart
2011-01-01
Background Risperidone long-acting injectable was previously approved for treatment of schizophrenia as biweekly injections in the gluteal muscle only. We present data on local injection-site tolerability and safety of risperidone long-acting injectable and comparability of systemic exposure of deltoid versus gluteal injections. Methods Risperidone long-acting injectable was administered in an open-label, single-dose, two-way crossover study, with patients randomized to receive either 25mg gluteal/37.5mg deltoid crossover in two treatment periods or 50mg gluteal/50mg deltoid injections crossover; each treatment period was separated by an 85-day observation period (Study 1) and an open-label, multiple-dose study (4 sequential 37.5mg or 50mg deltoid injections every 2 weeks) (Study 2). The pharmacokinetic results from both the studies have already been published. Results In Study 1 (n=170), the majority of patients had no local injection-site findings, based on investigator and patient-rated evaluations. In Study 2 (n=53), seven of the 51 patients who received at least two deltoid injections discontinued (primary endpoint). However, none of the discontinuations were due to injection-site related reasons. The 90-percent upper confidence limit of the true proportion of injection-site issue withdrawals was 5.7 percent. No moderate or severe injection-site reactions were reported. Conclusion Intramuscular injections via the deltoid and gluteal sites are equivalent routes of administration of risperidone long-acting injectable with respect to local injection-site tolerability. The overall safety and tolerability profile of risperidone long-acting injectable was comparable when administered as an intramuscular injection in the deltoid (37.5mg and 50mg) and gluteal (25mg and 50mg) sites. PMID:21779538
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Meta-analysis of laparoscopic versus open repair of perforated peptic ulcer.
Antoniou, Stavros A; Antoniou, George A; Koch, Oliver O; Pointner, Rudolph; Granderath, Frank A
2013-01-01
Laparoscopic treatment of perforated peptic ulcer (PPU) has been introduced as an alternative procedure to open surgery. It has been postulated that the minimally invasive approach involves less operative stress and results in decreased morbidity and mortality. We conducted a meta-analysis of randomized trials to test this hypothesis. Medline, EMBASE, and the Cochrane Central Register of Randomized Trials databases were searched, with no date or language restrictions. Our literature search identified 4 randomized trials, with a cumulative number of 289 patients, that compared the laparoscopic approach with open sutured repair of perforated ulcer. Analysis of outcomes did not favor either approach in terms of morbidity, mortality, and reoperation rate, although odds ratios seemed to consistently support the laparoscopic approach. Results did not determine the comparative efficiency and safety of laparoscopic or open approach for PPU. In view of an increased interest in the laparoscopic approach, further randomized trials are considered essential to determine the relative effectiveness of laparoscopic and open repair of PPU.
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Meta-analysis of Laparoscopic Versus Open Repair of Perforated Peptic Ulcer
Antoniou, George A.; Koch, Oliver O.; Pointner, Rudolph; Granderath, Frank A.
2013-01-01
Background and Objectives: Laparoscopic treatment of perforated peptic ulcer (PPU) has been introduced as an alternative procedure to open surgery. It has been postulated that the minimally invasive approach involves less operative stress and results in decreased morbidity and mortality. Methods: We conducted a meta-analysis of randomized trials to test this hypothesis. Medline, EMBASE, and the Cochrane Central Register of Randomized Trials databases were searched, with no date or language restrictions. Results: Our literature search identified 4 randomized trials, with a cumulative number of 289 patients, that compared the laparoscopic approach with open sutured repair of perforated ulcer. Analysis of outcomes did not favor either approach in terms of morbidity, mortality, and reoperation rate, although odds ratios seemed to consistently support the laparoscopic approach. Results did not determine the comparative efficiency and safety of laparoscopic or open approach for PPU. Conclusion: In view of an increased interest in the laparoscopic approach, further randomized trials are considered essential to determine the relative effectiveness of laparoscopic and open repair of PPU. PMID:23743368
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George, Duncan; Gálvez, Verònica; Martin, Donel; Kumar, Divya; Leyden, John; Hadzi-Pavlovic, Dusan; Harper, Simon; Brodaty, Henry; Glue, Paul; Taylor, Rohan; Mitchell, Philip B; Loo, Colleen K
2017-11-01
To assess the efficacy and safety of subcutaneous ketamine for geriatric treatment-resistant depression. Secondary aims were to examine if repeated treatments were safe and more effective in inducing or prolonging remission than a single treatment. In this double-blind, controlled, multiple-crossover study with a 6-month follow-up (randomized controlled trial [RCT] phase), 16 participants (≥60 years) with treatment-resistant depression who relapsed after remission or did not remit in the RCT were administered an open-label phase. Up to five subcutaneous doses of ketamine (0.1, 0.2, 0.3, 0.4, and 0.5 mg/kg) were administered in separate sessions (≥1 week apart), with one active control (midazolam) randomly inserted (RCT phase). Twelve ketamine treatments were given in the open-label phase. Mood, hemodynamic, and psychotomimetic outcomes were assessed by blinded raters. Remitters in each phase were followed for 6 months. Seven of 14 RCT-phase completers remitted with ketamine treatment. Five remitted at doses below 0.5 mg/kg. Doses ≥ 0.2 mg/kg were significantly more effective than midazolam. Ketamine was well tolerated. Repeated treatments resulted in higher likelihood of remission or longer time to relapse. Results provide preliminary evidence for the efficacy and safety of ketamine in treating elderly depressed. Dose titration is recommended for optimizing antidepressant and safety outcomes on an individual basis. Subcutaneous injection is a practical method for giving ketamine. Repeated treatments may improve remission rates (clinicaltrials.gov; NCT01441505). Copyright © 2017 American Association for Geriatric Psychiatry. All rights reserved.
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An evidence-based review of pregabalin for the treatment of fibromyalgia.
Arnold, Lesley M; Choy, Ernest; Clauw, Daniel J; Oka, Hiroshi; Whalen, Ed; Semel, David; Pauer, Lynne; Knapp, Lloyd
2018-04-16
Pregabalin, an α2-δ agonist, is approved for the treatment of fibromyalgia (FM) in the United States, Japan, and 37 other countries. The purpose of this article was to provide an in-depth, evidence-based summary of pregabalin for FM as demonstrated in randomized, placebo-controlled clinical studies, including open-label extensions, meta-analyses, combination studies and post-hoc analyses of clinical study data. PubMed was searched using the term "pregabalin AND fibromyalgia" and the Cochrane Library with the term "pregabalin". Both searches were conducted on 2 March 2017 with no other date limits set. Eleven randomized, double-blind, placebo-controlled clinical studies were identified including parallel group, two-way crossover and randomized withdrawal designs. One was a neuroimaging study. Five open-label extensions were also identified. Evidence of efficacy was demonstrated across the studies identified with significant and clinically relevant improvements in pain, sleep quality and patient status. The safety and tolerability profile of pregabalin is consistent across all the studies identified, including in adolescents, with dizziness and somnolence the most common adverse events reported. These efficacy and safety data are supported by meta-analyses (13 studies). Pregabalin in combination with other pharmacotherapies (7 studies) is also efficacious. Post-hoc analyses have demonstrated the onset of pregabalin efficacy as early as 1-2 days after starting treatment, examined the effect of pregabalin on other aspects of sleep beyond quality, and shown it is effective irrespective of the presence of a wide variety of patient demographic and clinical characteristics. Pregabalin is a treatment option for FM; its clinical utility has been comprehensively demonstrated.
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Canakinumab: in patients with cryopyrin-associated periodic syndromes.
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.
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Probiotics in diverticular disease of the colon: an open label study.
Lamiki, Pepu; Tsuchiya, Junji; Pathak, Surajit; Okura, Ruichi; Solimene, Umberto; Jain, Shalini; Kawakita, Shichiro; Marotta, Francesco
2010-03-01
To investigate the effectiveness and safety of a symbiotic mixture in preventing recurrence of constipation-related abdominal pain in patients with uncomplicated diverticular disease of the colon. Forty-six consecutive patients (10 men, 36 women, mean age 62.5 years, range 49 to 77 years), previously affected by symptomatic uncomplicated diverticular disease of the colon, were enrolled in a 6-month follow-up study in a prospective, randomized, open-label study. The following symptoms were assessed at entry and through follow-up by using a quantitative scale: constipation, diarrhoea and abdominal pain. After recruitment, the patients were assigned to the following treatment: SCM-III symbiotic mixture, 10 ml three times a day. The colonization of ingested Lactobacillus acidophilus 145 and Bifidobacterium spp. 420 was assessed by species-specific PCR. Forty-five patients completed the study (97%). Thirty-one patients (68%) were still symptom free after the 6th month of treatment. Treatment with SCM-III was regarded as "effective" or "very effective" in more than 78% of the patients altogether (p<0.01 vs baseline values). The microbiological study showed that, as compared to baseline values, SCM-III enabled a significant increase of the lactobacilli and bifidobacteria counting and a trend decrease of clostridia. Genomic analysis confirmed the survivability of the ingested strain as long as treatment was given. The present symbiotic mixture seems to be effective in preventing recurrence of symptomatic uncomplicated diverticular disease of the colon, especially in those patients with constipation-predominant features.
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Qayyum, Aisha; Najmi, Muzammil Hasan; Abbas, Mateen
2013-11-01
Comparative bioavailability studies are conducted to establish the bioequivalence of generic formulation with that of branded reference formulation, providing confidence to clinicians to use these products interchangeably. This study was carried out to compare a locally manufactured formulation of flurbiprofen with that of a branded product. Twenty two healthy male adults received a single dose of flurbiprofen (100mg) either generic or branded product according to randomization scheme on each of 2 periods. Blood samples were collected and plasma flurbiprofen concentration was determined by a validated HPLC method. Pharmacokinetic parameters like AUC(0-t), AUC(0-oo), Cmax, Tmax, t½, Vd and clearance were determined. The 90% CI for the ratio of geometric means of test to reference product's pharmacokinetic variables was calculated. Pharmacokinetic parameters for two formulations were comparable. Ratio of means of AUC(0-24), AUC(0-oo) and Cmax for test to reference products and 90% CI for these ratios were within the acceptable range. The p-values calculated by TOST were much less than the specified value (p-0.05). ANOVA gave p-values which were more than the specified value (p-0.05) for sequence, subject, period and formulation. Test formulation of flurbiprofen (tablet Flurso) was found to meet the criteria for bioequivalence to branded product (tablet Ansaid) based on pharmacokinetic parameters.
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Amico, K Rivet; Wallace, Melissa; Bekker, Linda-Gail; Roux, Surita; Atujuna, Millicent; Sebastian, Elaine; Dye, Bonnie J; Elharrar, Vanessa; Grant, Robert M
2017-05-01
Placebo-controlled trials of pre-exposure prophylaxis (PrEP) have reported challenges with study-product uptake and use, with the greatest challenges reported in studies with young women in sub-Saharan Africa. We conducted a qualitative sub-study to explore experiences with open-label PrEP among young women in Cape Town, South Africa participating in HTPN 067/Alternative Dosing to Augment Pre-Exposure Prophylaxis Pill Taking (ADAPT). HPTN 067/ADAPT provided open label oral FTC/TDF PrEP to young women in Cape Town, South Africa who were randomized to daily and non-daily PrEP regimens. Following completion of study participation, women were invited into a qualitative sub-study including focus groups and in-depth interviews. Interviews and groups followed a semi-structured guide, were recorded, transcribed, and translated to English from isiXhosa, and coded using framework analysis. Sixty of the 179 women enrolled in HPTN 067/ADAPT participated in either a focus group (six groups for a total of 42 participants) or an in-depth interview (n = 18). This sample of mostly young, unmarried women identified facilitators of and barriers to PrEP use, as well as factors influencing study participation. Cross-cutting themes characterizing discourse suggested that women placed high value on contributing to the well-being of one's community (Ubuntu), experienced a degree of skepticism towards PrEP and the study more generally, and reported a wide range of approaches towards PrEP (ranging from active avoidance to high levels of persistence and adherence). A Mutuality Framework is proposed that identifies four dynamics (distrust, uncertainty, alignment, and mutuality) that represent distinct interactions between self, community and study and serve to contextualize women's experiences. Implications for better understanding PrEP use, and non-use, and intervention opportunities are discussed. In this sample of women, PrEP use in the context of an open-label research trial was heavily influenced by underlying beliefs about safety, reciprocity of contributions to community, and trust in transparency and integrity of the research. Greater attention to factors positioning women in the different dynamics of the proposed Mutuality Framework could direct intervention approaches in clinical trials, as well as open-label PrEP scale-up.
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Combination therapy for type 2 diabetes: repaglinide plus rosiglitazone.
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.
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Provenzano, Robert; Besarab, Anatole; Wright, Steven; Dua, Sohan; Zeig, Steven; Nguyen, Peter; Poole, Lona; Saikali, Khalil G; Saha, Gopal; Hemmerich, Stefan; Szczech, Lynda; Yu, K H Peony; Neff, Thomas B
2016-06-01
Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that promotes erythropoiesis through increasing endogenous erythropoietin, improving iron regulation, and reducing hepcidin. Phase 2, randomized (3:1), open-label, active-comparator, safety and efficacy study. Patients with stable end-stage renal disease treated with hemodialysis who previously had hemoglobin (Hb) levels maintained with epoetin alfa. Part 1: 6-week dose-ranging study in 54 individuals of thrice-weekly oral roxadustat doses versus continuation of intravenous epoetin alfa. Part 2: 19-week treatment in 90 individuals in 6 cohorts with various starting doses and adjustment rules (1.0-2.0mg/kg or tiered weight based) in individuals with a range of epoetin alfa responsiveness. Intravenous iron was prohibited. Primary end point was Hb level response, defined as end-of-treatment Hb level change (ΔHb) of -0.5g/dL or greater from baseline (part 1) and as mean Hb level ≥ 11.0g/dL during the last 4 treatment weeks (part 2). Hepcidin, iron parameters, cholesterol, and plasma erythropoietin (the latter in a subset). Baseline epoetin alfa doses were 138.3±51.3 (SD) and 136.3±47.7U/kg/wk in part 1 and 152.8±80.6 and 173.4±83.7U/kg/wk in part 2, in individuals randomly assigned to roxadustat and epoetin alfa, respectively. Hb level responder rates in part 1 were 79% in pooled roxadustat 1.5 to 2.0mg/kg compared to 33% in the epoetin alfa control arm (P=0.03). Hepcidin level reduction was greater at roxadustat 2.0mg/kg versus epoetin alfa (P<0.05). In part 2, the average roxadustat dose requirement for Hb level maintenance was ∼1.7mg/kg. The least-squares-mean ΔHb in roxadustat-treated individuals was comparable to that in epoetin alfa-treated individuals (about -0.5g/dL) and the least-squares-mean difference in ΔHb between both treatment arms was -0.03 (95% CI, -0.39 to 0.33) g/dL (mixed effect model-repeated measure). Roxadustat significantly reduced mean total cholesterol levels, not observed with epoetin alfa. No safety concerns were raised. Short treatment duration and small sample size. In this phase 2 study of anemia therapy in patients with end-stage renal disease on maintenance hemodialysis therapy, roxadustat was well tolerated and effectively maintained Hb levels. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
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Melin, Eva O; Svensson, Ralph; Gustavsson, Sven-Åke; Winberg, Agneta; Denward-Olah, Ewa; Landin-Olsson, Mona; Thulesius, Hans O
2016-04-27
Depression is linked with alexithymia, anxiety, high HbA1c concentrations, disturbances of cortisol secretion, increased prevalence of diabetes complications and all-cause mortality. The psycho-educational method 'affect school with script analysis' and the mind-body therapy 'basic body awareness treatment' will be trialled in patients with diabetes, high HbA1c concentrations and psychological symptoms. The primary outcome measure is change in symptoms of depression. Secondary outcome measures are changes in HbA1c concentrations, midnight salivary cortisol concentration, symptoms of alexithymia, anxiety, self-image measures, use of antidepressants, incidence of diabetes complications and mortality. Two studies will be performed. Study I is an open-labeled parallel-group study with a two-arm randomized controlled trial design. Patients are randomized to either affect school with script analysis or to basic body awareness treatment. According to power calculations, 64 persons are required in each intervention arm at the last follow-up session. Patients with type 1 or type 2 diabetes were recruited from one hospital diabetes outpatient clinic in 2009. The trial will be completed in 2016. Study II is a multicentre open-labeled parallel-group three-arm randomized controlled trial. Patients will be randomized to affect school with script analysis, to basic body awareness treatment, or to treatment as usual. Power calculations show that 70 persons are required in each arm at the last follow-up session. Patients with type 2 diabetes will be recruited from primary care. This study will start in 2016 and finish in 2023. For both studies, the inclusion criteria are: HbA1c concentration ≥62.5 mmol/mol; depression, alexithymia, anxiety or a negative self-image; age 18-59 years; and diabetes duration ≥1 year. The exclusion criteria are pregnancy, severe comorbidities, cognitive deficiencies or inadequate Swedish. Depression, anxiety, alexithymia and self-image are assessed using self-report instruments. HbA1c concentration, midnight salivary cortisol concentration, blood pressure, serum lipid concentrations and anthropometrics are measured. Data are collected from computerized medical records and the Swedish national diabetes and causes of death registers. Whether the "affect school with script analysis" will reduce psychological symptoms, increase emotional awareness and improve diabetes related factors will be tried, and compared to "basic body awareness treatment" and treatment as usual. ClinicalTrials.gov: NCT01714986.
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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.
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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.
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Cho, Eun Kyung; Park, Ji-Young; Lee, Kyung Hee; Song, Hong Suk; Min, Young Joo; Kim, Yeul Hong; Kang, Jin-Hyoung
2014-01-01
The aim of this study was to compare CKD-810 (test docetaxel) with Taxotere(®) (reference docetaxel) in terms of pharmacokinetics and safety for patients with advanced or metastatic carcinoma. A randomized, open-label, two-way crossover study was conducted in eligible patients. Patients received with reference or test drugs of 75 mg/m(2) docetaxel by intravenous infusion for 60 min in the first period and the alternative drug in the second period with a washout of 3 weeks. Plasma concentrations of docetaxel were determined by validated high-performance liquid chromatography coupled to tandem mass spectrometry detection. Pharmacokinetic parameters, including the maximum plasma concentration (C(max)) and the area under the concentration-time curve (AUC), were determined by non-compartmental analysis. A total of 44 patients were included in the study, 21 patients received test drug and 23 received reference drug for the first cycle. The C(max) of docetaxel was 2,658.77 ng/mL for test drug and 2,827.60 ng/mL for reference drug, and two drugs showed no difference with a statistical significance. Time to reach C(max) (T(max)) of CKD-810 (0.94 h) versus reference docetaxel (0.97 h) was also not significantly different. Other pharmacokinetic parameters including the plasma AUC, elimination half-life, and total body clearance exhibited similar values without a significant difference. The most common grade 3 or 4 toxicity was neutropenia (CKD-810 19.5 or 29.3 %; reference docetaxel 14.6 or 41.5 %). Febrile neutropenia was experienced by only one patient in each group. Two patients died of progression of disease during the study. Docetaxel anhydrous CKD-810 use with patients suffering advanced or metastatic solid malignancies was equivalent to reference docetaxel in terms of pharmacokinetic parameters and safety profile. Additionally, the test and reference drug met the regulatory criteria for pharmacokinetic equivalence.
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Queiroz-Telles, Flavio; Goldani, Luciano Z; Schlamm, Haran T; Goodrich, James M; Espinel-Ingroff, Ana; Shikanai-Yasuda, Maria A
2007-12-01
In previous studies, itraconazole was revealed to be an effective therapy and was considered to be the gold standard treatment for mild-to-moderate acute and chronic clinical forms of paracoccidioidomycosis. A pilot study was conducted to investigate the efficacy, safety, and tolerability of voriconazole for the long-term treatment of acute or chronic paracoccidioidomycosis, with itraconazole as the control treatment. A randomized, open-label study was conducted at 3 Brazilian tertiary care hospitals. Patients were randomized (at a 2 : 1 ratio) to receive oral therapy with voriconazole or itraconazole for 6 months. Patients receiving >or=1 dose of study drug were evaluated for safety; patients with confirmed paracoccidioidomycosis who completed >or=6 months of therapy (treatment-evaluable patients) were evaluated for treatment efficacy. Satisfactory global response was assessed at the end of treatment. Fifty-three patients were evaluated for treatment safety (35 received voriconazole, and 18 received itraconazole). Both drugs were well tolerated. The most common treatment-related adverse events in the voriconazole group included abnormal vision, chromatopsia, rash, and headache; the most common treatment-related adverse events in the itraconazole group included bradycardia, diarrhea, and headache. Liver function test values were slightly higher in patients receiving voriconazole than in those receiving itraconazole; 2 patients in the voriconazole group were withdrawn from treatment because of increased liver function test values. In the intent-to-treat populations, the satisfactory response rate (i.e., complete or partial global response) was 88.6% among the voriconazole group and 94.4% among the itraconazole group. The response rate among treatment-evaluable patients was 100% for both treatment groups; no relapses were observed after 8 weeks of follow-up. This is, to our knowledge, the first study to demonstrate that voriconazole is as well tolerated and effective as itraconazole for the long-term treatment of paracoccidioidomycosis.
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Gargano, Nicola; Madrid, Lola; Valentini, Giovanni; D'Alessandro, Umberto; Halidou, Tinto; Sirima, Sodiomon; Tshefu, Antoinette; Mtoro, Ali; Gesase, Samwel
2017-01-01
ABSTRACT Artemisinin combination therapies are considered the mainstay of malaria treatment, but pediatric-friendly formulations for the treatment of infants are scarce. We sought to evaluate the efficacy and safety of a new dispersible-tablet formulation of dihydroartemisinin/piperaquine phosphate (DHA/PQP) in comparison to the marketed tablet (Eurartesim) in the treatment of infants with uncomplicated Plasmodium falciparum malaria. Reported here are the results of a large phase II, randomized, open-label, multicenter trial conducted in African infants (6 to 12 months of age) from Mozambique, Burkina Faso, The Gambia, the Democratic Republic of the Congo, and Tanzania. Primary efficacy endpoint was the PCR-corrected adequate clinical and parasitological response (ACPR) at day 28. Analysis was performed for the intention-to-treat (ITT) and per-protocol (PP) populations. A total of 201 patients received the dispersible-tablet formulation, and 99 received the conventional one administered as crushed tablets. At day 28, the PCR-corrected ACPRs were 86.9% (ITT) and 98.3% (PP) in the dispersible-tablet group and 84.9% (ITT) and 100% (PP) in the crushed-tablet group. At day 42, these values were 85.9% (ITT) and 96.5% (PP) in the dispersible-tablet group and 82.8% (ITT) and 96.4% (PP) in the crushed-tablet group. The comparison between survival curves for time to new infections showed no statistically significant differences (P = 0.409). The safety and tolerability profile for the two groups was similar in terms of type and frequency of adverse events and was consistent with that expected in African infants with malaria. A standard 3-day treatment with the new dispersible DHA/PQP formulation is as efficacious as the currently used tablet in African infants and has a comparable safety profile. (This trial was registered at ClinicalTrials.gov under registration no. NCT01992900.) PMID:29061746
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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.
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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.
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Furlong, N J; Hulme, S A; O'Brien, S V; Hardy, K J
2003-11-01
This open-label randomized controlled clinical trial compared the effect on glycaemic control and weight gain of repaglinide vs. gliclazide combined with bedtime NPH insulin in patients with Type 2 diabetes inadequately controlled with oral hypoglycaemic therapy [HbA1c>7.0% (DCCT aligned assay, normal range 4.6-6.2%)]. Eighty subjects with Type 2 diabetes were randomized to 13 weeks' open-label treatment with repaglinide 4 mg t.i.d. or gliclazide 160 mg b.i.d. in combination with bedtime NPH insulin (initial dose 0.5 units/kg). The fasting blood glucose (FBG) target was < or =6.0 mmol/l. Baseline characteristics were similar for age, sex, weight, BMI, FBG and HbA1c. Glycaemic control improved similarly in both groups-insulin/gliclazide by (mean) 1.0%, from 9.2 to 8.2% (P=0.001) and by 0.9%, from 9.4 to 8.5% in the insulin/repaglinide group (P=0.005) (P=0.83 between groups). Weight gain averaged (mean +/- sem) 4.1 +/- 0.5 and 3.4 +/- 0.4 kg in the insulin/gliclazide and insulin/repaglinide groups, respectively (P<0.0001 for both groups from baseline) (P=0.29 between groups). The mean number of hypoglycaemic episodes experienced per patient was 2.95 +/- 0.82 (insulin/gliclazide) and 2.3 +/- 0.52 (insulin/repaglinide) (P=0.81 between groups). Both treatments were associated with significant improvements in Diabetes Treatment Satisfaction [Diabetes Treatment Satisfaction Questionnaire-potential range 0 (min) to 36 (max)]; in the insulin/gliclazide group, by 4.9 +/- 1.1 points to 33.3 +/- 0.6 (P<0.0001) and by 3.0 +/- 0.9 points to 34.6 +/- 0.4 (P=0.0006) in the insulin/repaglinide group (P=0.29 between groups). Over 13 weeks, both repaglinide and gliclazide, when combined with bedtime NPH insulin produce similar significant improvements in glycaemic control (-1%) and similar weight gain.
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Ardehali, Abbas; Esmailian, Fardad; Deng, Mario; Soltesz, Edward; Hsich, Eileen; Naka, Yoshifumi; Mancini, Donna; Camacho, Margarita; Zucker, Mark; Leprince, Pascal; Padera, Robert; Kobashigawa, Jon
2015-06-27
The Organ Care System is the only clinical platform for ex-vivo perfusion of human donor hearts. The system preserves the donor heart in a warm beating state during transport from the donor hospital to the recipient hospital. We aimed to assess the clinical outcomes of the Organ Care System compared with standard cold storage of human donor hearts for transplantation. We did this prospective, open-label, multicentre, randomised non-inferiority trial at ten heart-transplant centres in the USA and Europe. Eligible heart-transplant candidates (aged >18 years) were randomly assigned (1:1) to receive donor hearts preserved with either the Organ Care System or standard cold storage. Participants, investigators, and medical staff were not masked to group assignment. The primary endpoint was 30 day patient and graft survival, with a 10% non-inferiority margin. We did analyses in the intention-to-treat, as-treated, and per-protocol populations. This trial is registered with ClinicalTrials.gov, number NCT00855712. Between June 29, 2010, and Sept 16, 2013, we randomly assigned 130 patients to the Organ Care System group (n=67) or the standard cold storage group (n=63). 30 day patient and graft survival rates were 94% (n=63) in the Organ Care System group and 97% (n=61) in the standard cold storage group (difference 2·8%, one-sided 95% upper confidence bound 8·8; p=0·45). Eight (13%) patients in the Organ Care System group and nine (14%) patients in the standard cold storage group had cardiac-related serious adverse events. Heart transplantation using donor hearts adequately preserved with the Organ Care System or with standard cold storage yield similar short-term clinical outcomes. The metabolic assessment capability of the Organ Care System needs further study. TransMedics. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Arzimanoglou, Alexis; Ferreira, Jose A; Satlin, Andrew; Mendes, Shannon; Williams, Betsy; Critchley, David; Schuck, Edgar; Hussein, Ziad; Kumar, Dinesh; Dhadda, Shobha; Bibbiani, Francesco
2016-05-01
A good knowledge of safety and age group-specific pharmacokinetics (PK) of antiepileptic drugs (AEDs) in young pediatric patients is of great importance in clinical practice. This paper presents 6-month interim safety and PK from an ongoing 2-year open-label study (Study 303) of adjunctive rufinamide treatment in pediatric subjects ≥ 1 to < 4 years with inadequately controlled epilepsies of the Lennox-Gastaut syndrome (LGS) spectrum. Subjects (N = 37) were randomized to either rufinamide or any other approved AED chosen by the investigator as adjunctive therapy to the subject's existing regimen of 1-3 AEDs. Interim safety results showed that treatment-emergent adverse events (TEAEs) were similar between the rufinamide (22 [88.0%]) and any-other-AED group (9 [81.8%]), with most events considered mild or moderate. A population PK analysis was conducted including plasma rufinamide concentrations from Study 303 and two other study populations of LGS subjects ≥ 4 years. The rufinamide PK profile was dose independent. The apparent clearance (CL/F) estimated from the PK model was 2.19 L/h; it was found to increase significantly as a function of body weight. Coadministration of valproic acid significantly decreased rufinamide CL/F. CL/F was not significantly affected by other concomitant AEDs, age, gender, race, hepatic function, or renal function. No adjustments to body weight-based rufinamide dosing in subjects ≥ 1 to < 4 years are necessary. Rufinamide was safe and well tolerated in these pediatric subjects. Results from the interim analysis demonstrate that rufinamide's safety and PK profile is comparable in subjects ≥ 1 to < 4 and ≥ 4 years with LGS. Study 303 (clinicaltrials.gov: NCT01405053). Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.
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Gargano, Nicola; Madrid, Lola; Valentini, Giovanni; D'Alessandro, Umberto; Halidou, Tinto; Sirima, Sodiomon; Tshefu, Antoinette; Mtoro, Ali; Gesase, Samwel; Bassat, Quique
2018-01-01
Artemisinin combination therapies are considered the mainstay of malaria treatment, but pediatric-friendly formulations for the treatment of infants are scarce. We sought to evaluate the efficacy and safety of a new dispersible-tablet formulation of dihydroartemisinin/piperaquine phosphate (DHA/PQP) in comparison to the marketed tablet (Eurartesim) in the treatment of infants with uncomplicated Plasmodium falciparum malaria. Reported here are the results of a large phase II, randomized, open-label, multicenter trial conducted in African infants (6 to 12 months of age) from Mozambique, Burkina Faso, The Gambia, the Democratic Republic of the Congo, and Tanzania. Primary efficacy endpoint was the PCR-corrected adequate clinical and parasitological response (ACPR) at day 28. Analysis was performed for the intention-to-treat (ITT) and per-protocol (PP) populations. A total of 201 patients received the dispersible-tablet formulation, and 99 received the conventional one administered as crushed tablets. At day 28, the PCR-corrected ACPRs were 86.9% (ITT) and 98.3% (PP) in the dispersible-tablet group and 84.9% (ITT) and 100% (PP) in the crushed-tablet group. At day 42, these values were 85.9% (ITT) and 96.5% (PP) in the dispersible-tablet group and 82.8% (ITT) and 96.4% (PP) in the crushed-tablet group. The comparison between survival curves for time to new infections showed no statistically significant differences ( P = 0.409). The safety and tolerability profile for the two groups was similar in terms of type and frequency of adverse events and was consistent with that expected in African infants with malaria. A standard 3-day treatment with the new dispersible DHA/PQP formulation is as efficacious as the currently used tablet in African infants and has a comparable safety profile. (This trial was registered at ClinicalTrials.gov under registration no. NCT01992900.). Copyright © 2017 Gargano et al.
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Becerra, Carlos R; Yoshida, Kenichiro; Mizuguchi, Hirokazu; Patel, Manish; Von Hoff, Daniel
2017-06-01
TAS-102 (trifluridine/tipiracil) is composed of an antineoplastic thymidine-based nucleoside analogue trifluridine (FTD), and a thymidine phosphorylase inhibitor, tipiracil (TPI), at a molar ratio of 1:0.5 (weight ratio, 1:0.471). A phase 1 study evaluated relative bioavailability of TAS-102 tablets compared with an oral solution containing equivalent amounts of FTD and TPI. In an open-label, 2-sequence, 3-period, crossover bioavailability study (part 1), patients 18 years or older with advanced solid tumors were randomized to receive TAS-102 tablets (60 mg; 3 × 20-mg tablets) on day 1 and TAS-102 oral solution (60 mg) on days 8 and 15, or the opposite sequence. In an extension (part 2), all patients received TAS-102 tablets. Of the 46 patients treated in the crossover study, 38 were evaluable in the crossover bioavailability pharmacokinetic population. For area under the concentration-time curve (AUC) 0-∞ and AUC 0-last for FTD and TPI, and maximum plasma concentration (C max ) for TPI, the 90% confidence intervals (CIs) of the geometric mean ratios were within the 0.80 to 1.25 boundary for demonstration of bioequivalence; for FTD C max , the lower limit of the 90%CI was 0.786. The most frequently reported treatment-related grade 3 or 4 adverse events were neutropenia (7 patients) and decreased neutrophil count (3 patients). Although the lower limit of the 90%CI for the geometric mean ratio of FTD C max was slightly lower than 0.80, the bioavailability of the TAS-102 tablet is considered clinically similar to that of a TAS-102 oral solution. TAS-102 was well tolerated in this population of patients with advanced solid tumors. © 2016, The American College of Clinical Pharmacology.
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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.
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Tavera, Alejandro Tsuchiya; Montoya, María Cecilia Perrilliat; Calderón, Eduardo Federico Garduño García; Gorodezky, Gina; Wixtrom, Roger N
2012-07-01
TMDes (Registered Trademark of Ascentia Health, Inc., Rockford, Illinois), custom-fit ear inserts to aid in reducing temporomandibular disorder (TMD) pain, were evaluated in a prospective, three-month, open-label, three-arm, randomized, unblinded clinical trial, which included patients with TMD diagnoses (RDC/TMD) of myofascial pain, arthralgia, and/or disc displacement with reduction; and a screening VAS pain score of > 4. The three treatment groups included: TMDes (n = 60), stabilization splint (n = 64), and jaw exercise regimen (n = 28). The mean change in Craniomandibular Index (CMI) scores (reductions reflecting improvement) from baseline to one month were -27% (TMDes), -20% (stabilization splint), -12% (jaw exercise regimen), and from baseline to three months were -45%, -41%, -36%, reflecting statistically significant noninferiority (p = 0.0096) of the TMDes to the stabilization splint (primary efficacy endpoint). The TMDes produced significant (p < 0.0001) mean changes in VAS pain scores from baseline of -46% at one month and -58% at three months and demonstrated comparable efficacy and safety to the stabilization splint.
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Mizuno, Hiroyuki; Hoshide, Satoshi; Tomitani, Naoko; Kario, Kazuomi
2017-10-01
Data are sparse regarding ambulatory blood pressure (BP) reduction of up-titration from a standard dose to a high dose in both nifedipine controlled-release (CR) and amlodipine. This was a prospective, randomized, multicenter, open-label trial. Fifty-one uncontrolled hypertensives medicated by two or more antihypertensive drugs including a renin-angiotensin system inhibitor and a calcium antagonist were randomly assigned to either the nifedipine CR (80 mg)/candesartan (8 mg) group or the amlodipine (10 mg)/candesartan (8 mg) group. The changes in 24-hr BP were comparable between the groups. The nifedipine group demonstrated a significant decrease in their urinary albumin creatinine ratio, whereas the amlodipine group demonstrated a significant decrease in their NTproBNP level. However, there was no significant difference in any biomarkers between the two groups. Nifedipine showed an almost equal effect on ambulatory blood pressure as amlodipine. Their potentially differential effects on renal protection and NTproBNP should be tested in larger samples.
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Frenette, Catherine T; Morelli, Giuseppe; Shiffman, Mitchell L; Frederick, R Todd; Rubin, Raymond A; Fallon, Michael B; Cheng, Jason T; Cave, Matt; Khaderi, Saira A; Massoud, Omar; Pyrsopoulos, Nikolaos; Park, James S; Robinson, James M; Yamashita, Mason; Spada, Alfred P; Chan, Jean L; Hagerty, David T
2018-06-15
Caspase-mediated apoptosis and inflammation contribute to progression of liver disease. Emricasan is a pan-caspase inhibitor that reduced serum markers of apoptosis and liver inflammation in patients with hepatitis C and non-alcoholic steatohepatitis (NASH). We performed a multicenter study of 86 patients with cirrhosis (Child-Pugh class A or B; mean score, 6.9; 38% with alcohol-associated cirrhosis, 29% with HCV-associated cirrhosis, and 23% with NASH) and model for end-stage liver disease (MELD) scores of 11-18 (mean, 12.8). Patients were randomly assigned to groups given placebo (n=42) or emricasan (25 mg, n=44), twice daily for 3 months; subjects then received open-label emricasan (25 mg) twice-daily for 3 months. The primary endpoint was the change from baseline in serum levels of cleaved keratin 18 (CK-18) at month 3. Seventy-four patients completed the 3-month study period (40 given emricasan and 34 given placebo); 69 patients received open-label emricasan for 3 months afterward. At the 3-month timepoint, emricasan significantly reduced mean MELD (P=.003) and Child-Pugh (P=.003) scores in subjects with high MELD scores (15 or more), compared with placebo, with significant reductions in INR (95% CI, -0.2882 to -0.0866) and total bilirubin (95% CI, -1.5069 to -0.0823) vs placebo. There were no significant differences between emricasan and placebo groups in mean MELD (P=.466) or Child-Pugh (P=.124) scores overall at 3 months compared to placebo. Of patients with high MELD scores, 6/9 given emricasan (67%) had a reduction of 2 points or more at month 3, compared with 2/10 given placebo (20%). Serum levels of full-length CK-18 (P=.02) and caspase 3/7 (P<.001), but not cleaved CK-18 (P=.092), decreased significantly at 3 months in the emricasan vs placebo group. Emricasan was well tolerated, and adverse events were balanced between groups. Emricasan's effects were generally maintained or increased after 6 months of treatment. In a randomized trial of patients with cirrhosis, we found 3 months treatment with emricasan to improve liver function, compared with placebo, reducing MELD and Child-Pugh scores, INR, and total bilirubin in patients with MELD scores ≥15. ClinicalTrials.gov no: NCT002209456. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
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Bajaj, Jasmohan S; Kassam, Zain; Fagan, Andrew; Gavis, Edith A; Liu, Eric; Cox, I Jane; Kheradman, Raffi; Heuman, Douglas; Wang, Jessica; Gurry, Thomas; Williams, Roger; Sikaroodi, Masoumeh; Fuchs, Michael; Alm, Eric; John, Binu; Thacker, Leroy R; Riva, Antonio; Smith, Mark; Taylor-Robinson, Simon D; Gillevet, Patrick M
2017-12-01
Recurrent hepatic encephalopathy (HE) is a leading cause of readmission despite standard of care (SOC) associated with microbial dysbiosis. Fecal microbiota transplantation (FMT) may improve dysbiosis; however, it has not been studied in HE. We aimed to define whether FMT using a rationally derived stool donor is safe in recurrent HE compared to SOC alone. An open-label, randomized clinical trial with a 5-month follow-up in outpatient men with cirrhosis with recurrent HE on SOC was conducted with 1:1 randomization. FMT-randomized patients received 5 days of broad-spectrum antibiotic pretreatment, then a single FMT enema from the same donor with the optimal microbiota deficient in HE. Follow-up occurred on days 5, 6, 12, 35, and 150 postrandomization. The primary outcome was safety of FMT compared to SOC using FMT-related serious adverse events (SAEs). Secondary outcomes were adverse events, cognition, microbiota, and metabolomic changes. Participants in both arms were similar on all baseline criteria and were followed until study end. FMT with antibiotic pretreatment was well tolerated. Eight (80%) SOC participants had a total of 11 SAEs compared to 2 (20%) FMT participants with SAEs (both FMT unrelated; P = 0.02). Five SOC and no FMT participants developed further HE (P = 0.03). Cognition improved in the FMT, but not the SOC, group. Model for End-Stage Liver Disease (MELD) score transiently worsened postantibiotics, but reverted to baseline post-FMT. Postantibiotics, beneficial taxa, and microbial diversity reduction occurred with Proteobacteria expansion. However, FMT increased diversity and beneficial taxa. SOC microbiota and MELD score remained similar throughout. FMT from a rationally selected donor reduced hospitalizations, improved cognition, and dysbiosis in cirrhosis with recurrent HE. (Hepatology 2017;66:1727-1738). © 2017 by the American Association for the Study of Liver Diseases.
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Fuchs, Flávio D; Scala, Luiz César N; Vilela-Martin, José F; de Mello, Renato Bandeira; Mosele, Francisca; Whelton, Paul K; Poli-de-Figueiredo, Carlos E; de Alencastro, Paulo Ricardo; E Silva, Ricardo Pereira; Gus, Miguel; Bortolotto, Luiz Aparecido; Schlatter, Rosane; Cesarino, Evandro José; Castro, Iran; Neto, José A Figueiredo; Chaves, Hilton; Steffens, André Avelino; Alves, João Guilherme; Brandão, Andréa Araujo; de Sousa, Marcos R; Jardim, Paulo Cesar; Moreira, Leila B; Franco, Roberto Silva; Gomes, Marco Mota; Neto, Abrahão Afiune; Fuchs, Felipe Costa; Filho, Dario C Sobral; Nóbrega, Antônio C; Nobre, Fernando; Berwanger, Otávio; Fuchs, Sandra C
2016-04-01
To compare the blood pressure (BP)-lowering efficacy of a chlorthalidone/amiloride combination pill with losartan, during initial management of stage I hypertension. In a randomized, double-blind, controlled trial, 655 participants were followed for 18 months in 21 Brazilian academic centers. Trial participants were adult volunteers aged 30-70 years with stage I hypertension (BP 140-159 or 90-99 mmHg) following 3 months of a lifestyle intervention. Participants were randomized to 12.5/2.5 mg of chlorthalidone/amiloride (N = 333) or 50 mg of losartan (N = 322). If BP remained uncontrolled after 3 months, study medication dose was doubled, and if uncontrolled after 6 months, amlodipine (5 and 10 mg) and propranolol (40 and 80 mg twice daily) were added as open-label drugs in a progressive fashion. At the end of follow-up, 609 (93%) participants were evaluated. The difference in SBP during 18 months of follow-up was 2.3 (95% confidence interval: 1.2 to 3.3) mmHg favoring chlorthalidone/amiloride. Compared with those randomized to diuretic, more participants allocated to losartan had their initial dose doubled and more of them used add-on antihypertensive medication. Levels of blood glucose, glycosilated hemoglobin, and incidence of diabetes were no different between the two treatment groups. Serum potassium was lower and serum cholesterol was higher in the diuretic arm. Microalbuminuria tended to be higher in patients with diabetes allocated to losartan (28.5 ± 40.4 versus 16.2 ± 26.7 mg, P = 0.09). Treatment with a combination of chlorthalidone and amiloride compared with losartan yielded a greater reduction in BP. NCT00971165.
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Menezes, C N; Duarte, R; Dickens, C; Dix-Peek, T; Van Amsterdam, D; John, M-A; Ive, P; Maskew, M; Macphail, P; Fox, M P; Raal, F; Sanne, I; Crowther, N J
2013-04-01
Stavudine is being phased out because of its mitochondrial toxicity and tenofovir (TDF) is recommended as part of first-line highly active antiretroviral therapy (HAART) in South Africa. A prospective, open-label, randomized controlled trial comparing standard- and low-dose stavudine with TDF was performed to assess early differences in adipocyte mtDNA copy number, gene expression and metabolic parameters in Black South African HIV-infected patients. Sixty patients were randomized 1:1:1 to either standard-dose (30-40 mg) or low-dose (20-30 mg) stavudine or TDF (300 mg) each combined with lamivudine and efavirenz. Subcutaneous fat biopsies were obtained at weeks 0 and 4. Adipocyte mtDNA copies/cell and gene expression were measured using quantitative polymerase chain reaction (qPCR). Markers of inflammation and lipid and glucose metabolism were also assessed. A 29% and 32% decrease in the mean mtDNA copies/cell was noted in the standard-dose (P < 0.05) and low-dose stavudine (P < 0.005) arms, respectively, when compared with TDF at 4 weeks. Nuclear respiratory factor-1 (NRF1) and mitochondrial cytochrome B (MTCYB) gene expression levels were affected by stavudine, with a significantly (P < 0.05) greater fall in expression observed with the standard, but not the low dose compared with TDF. No significant differences were observed in markers of inflammation and lipid and glucose metabolism. These results demonstrate early mitochondrial depletion among Black South African patients receiving low and standard doses of stavudine, with preservation of gene expression levels, except for NRF1 and MTCYB, when compared with patients on TDF. © 2012 British HIV Association.
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Ni, Hsing-Chang; Hwang Gu, Shoou-Lian; Lin, Hsiang-Yuan; Lin, Yu-Ju; Yang, Li-Kuang; Huang, Hui-Chun; Gau, Susan Shur-Fen
2016-05-01
Intra-individual variability in reaction time (IIV-RT) is common in individuals with attention-deficit/hyperactivity disorder (ADHD). It can be improved by stimulants. However, the effects of atomoxetine on IIV-RT are inconclusive. We aimed to investigate the effects of atomoxetine on IIV-RT, and directly compared its efficacy with methylphenidate in adults with ADHD. An 8-10 week, open-label, head-to-head, randomized clinical trial was conducted in 52 drug-naïve adults with ADHD, who were randomly assigned to two treatment groups: immediate-release methylphenidate (n=26) thrice daily (10-20 mg per dose) and atomoxetine once daily (n=26) (0.5-1.2 mg/kg/day). IIV-RT, derived from the Conners' continuous performance test (CCPT), was represented by the Gaussian (reaction time standard error, RTSE) and ex-Gaussian models (sigma and tau). Other neuropsychological functions, including response errors and mean of reaction time, were also measured. Participants received CCPT assessments at baseline and week 8-10 (60.4±6.3 days). We found comparable improvements in performances of CCPT between the immediate-release methylphenidate- and atomoxetine-treated groups. Both medications significantly improved IIV-RT in terms of reducing tau values with comparable efficacy. In addition, both medications significantly improved inhibitory control by reducing commission errors. Our results provide evidence to support that atomoxetine could improve IIV-RT and inhibitory control, of comparable efficacy with immediate-release methylphenidate, in drug-naïve adults with ADHD. Shared and unique mechanisms underpinning these medication effects on IIV-RT awaits further investigation. © The Author(s) 2016.
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Sildenafil Citrate Therapy for Oligohydramnios: A Randomized Controlled Trial.
Maher, Mohammad Ahmed; Sayyed, Tarek Mohammad; Elkhouly, Nabih
2017-04-01
To compare sildenafil plus hydration with hydration alone in improving the amniotic fluid index and neonatal outcomes in pregnancies complicated by idiopathic oligohydramnios ( amniotic fluid index less than 5 cm without underlying maternal or fetal causes and with normal fetal growth). This was an open-label randomized trial for women carrying singleton pregnancies at 30 weeks of gestation or more with idiopathic oligohydramnios detected during routine ultrasonogram. Women received either oral sildenafil citrate (25 mg every 8 hours) plus intravenous infusion of 2 L isotonic solution or fluids only until delivery. The primary study outcome was the amniotic fluid volume at 6 weeks of follow-up or the final volume before delivery, whichever occurred first. Secondary outcomes were duration of pregnancy prolongation, mode of delivery, and select neonatal outcomes. The study was powered to detect a 45% difference between groups, so, at an α level of 0.05 and 80% power, a sample size of 167 women was required. From February 24, 2015, through April 2016, 196 women were screened and 184 were randomized. Follow-up was completed in 166 (90%): 82 in the sildenafil group and 84 in the hydration group. Baseline characteristics were similar between groups. The amniotic fluid volume was higher in the sildenafil group at the final assessment (11.5 compared with 5.4 cm, P=.02). The sildenafil group delivered later (38.3 compared with 36.0 weeks of gestation, P=.001), had a lower rate of cesarean delivery (28% compared with 73%), and their neonates were less likely to be admitted to the neonatal intensive care unit (11% compared with 41%, P=.001). Sildenafil citrate increases amniotic fluid volume in pregnancies complicated by oligohydramnios. ClinicalTrials.gov, www.clinicaltrials.gov, NCT02372487.
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Levin, Yotam; Kochba, Efrat; Shukarev, Georgi; Rusch, Sarah; Herrera-Taracena, Guillermo; van Damme, Pierre
2016-10-17
Influenza remains a significant problem in elderly despite widespread vaccination coverage. This randomized, phase-I study in elderly compared different strategies of improving vaccine immunogenicity. A total of 370 healthy participants (⩾65years) were randomized equally 1:1:1:1:1:1 to six influenza vaccine treatments (approximately 60-63 participants per treatment arm) at day 1 that consisted of three investigational virosomal vaccine formulations at doses of 7.5, 15, and 45μg HA antigen/strain administered intradermally (ID) by MicronJet600™ microneedle device (NanoPass Technologies) or intramuscularly (IM), and three comparator registered seasonal vaccines; Inflexal V™ (Janssen) and MF59 adjuvanted Fluad™ (Novartis) administered IM and Intanza™ (Sanofi Pasteur) administered ID via Soluvia™ prefilled microinjection system (BD). Serological evaluations were performed at days 22 and 90 and safety followed-up for 6months. Intradermal delivery of virosomal vaccine using MicronJet600™ resulted in significantly higher immunogenicity than the equivalent dose of virosomal Inflexal V™ administered intramuscularly across most of the parameters and strains, as well as in some of the readouts and strains as compared with the 45μg dose of virosomal vaccine formulation. Of 370 participants, 300 (81.1%) reported ⩾1 adverse event (AE); more participants reported solicited local AEs (72.2%) than solicited systemic AEs (12.2%). Intradermal delivery significantly improved influenza vaccine immunogenicity compared with intramuscular delivery. Triple dose (45μg) virosomal vaccine did not demonstrate any benefit on vaccine's immunogenicity over 15μg commercial presentation. All treatments were generally safe and well-tolerated. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.
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Pulmonary atelectasis during low stretch ventilation: "open lung" versus "lung rest" strategy.
Fanelli, Vito; Mascia, Luciana; Puntorieri, Valeria; Assenzio, Barbara; Elia, Vincenzo; Fornaro, Giancarlo; Martin, Erica L; Bosco, Martino; Delsedime, Luisa; Fiore, Tommaso; Grasso, Salvatore; Ranieri, V Marco
2009-03-01
Limiting tidal volume (VT) may minimize ventilator-induced lung injury (VILI). However, atelectasis induced by low VT ventilation may cause ultrastructural evidence of cell disruption. Apoptosis seems to be involved as protective mechanisms from VILI through the involvement of mitogen-activated protein kinases (MAPKs). We examined the hypothesis that atelectasis may influence the response to protective ventilation through MAPKs. Prospective randomized study. University animal laboratory. Adult male 129/Sv mice. Isolated, nonperfused lungs were randomized to VILI: VT of 20 mL/kg and positive end-expiratory pressure (PEEP) zero; low stretch/lung rest: VT of 6 mL/kg and 8-10 cm H2O of PEEP; low stretch/open lung: VT of 6 mL/kg, two recruitment maneuvers and 14-16 cm H2O of PEEP. Ventilator settings were adjusted using the stress index. Both low stretch strategies equally blunted the VILI-induced derangement of respiratory mechanics (static volume-pressure curve), lung histology (hematoxylin and eosin), and inflammatory mediators (interleukin-6, macrophage inflammatory protein-2 [enzyme-linked immunosorbent assay], and inhibitor of nuclear factor-kB[Western blot]). VILI caused nuclear swelling and membrane disruption of pulmonary cells (electron microscopy). Few pulmonary cells with chromatin condensation and fragmentation were seen during both low stretch strategies. However, although cell thickness during low stretch/open lung was uniform, low stretch/lung rest demonstrated thickening of epithelial cells and plasma membrane bleb formation. Compared with the low stretch/open lung, low stretch/lung rest caused a significant decrease in apoptotic cells (terminal deoxynucleotidyl transferase mediated deoxyuridine-triphosphatase nick end-labeling) and tissue expression of caspase-3 (Western blot). Both low stretch strategies attenuated the activation of MAPKs. Such reduction was larger during low stretch/open lung than during low stretch/lung rest (p < 0.001). Low stretch strategies provide similar attenuation of VILI. However, low stretch/lung rest strategy is associated to less apoptosis and more ultrastructural evidence of cell damage possibly through MAPKs-mediated pathway.
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Randomized, Controlled Trial of Therapy Interruption in Chronic HIV-1 Infection
Papasavvas, Emmanouil; Kostman, Jay R; Mounzer, Karam; Grant, Robert M; Gross, Robert; Gallo, Cele; Azzoni, Livio; Foulkes, Andrea; Thiel, Brian; Pistilli, Maxwell; Mackiewicz, Agnieszka; Shull, Jane; Montaner, Luis J
2004-01-01
Background Approaches to limiting exposure to antiretroviral therapy (ART) drugs are an active area of HIV therapy research. Here we present longitudinal follow-up of a randomized, open-label, single-center study of the immune, viral, and safety outcomes of structured therapy interruptions (TIs) in patients with chronically suppressed HIV-1 infection as compared to equal follow-up of patients on continuous therapy and including a final therapy interruption in both arms. Methods and Findings Forty-two chronically HIV-infected patients on suppressive ART with CD4 counts higher than 400 were randomized 1:1 to either (1) three successive fixed TIs of 2, 4, and 6 wk, with intervening resumption of therapy with resuppression for 4 wk before subsequent interruption, or (2) 40 wk of continuous therapy, with a final open-ended TI in both treatment groups. Main outcome was analysis of the time to viral rebound (>5,000 copies/ml) during the open-ended TI. Secondary outcomes included study-defined safety criteria, viral resistance, therapy failure, and retention of immune reconstitution. There was no difference between the groups in time to viral rebound during the open-ended TI (continuous therapy/single TI, median [interquartile range] = 4 [1–8] wk, n = 21; repeated TI, median [interquartile range] = 5 [4–8] wk, n = 21; p = 0.36). No differences in study-related adverse events, viral set point at 12 or 20 wk of open-ended interruption, viral resistance or therapy failure, retention of CD4 T cell numbers on ART, or retention of lymphoproliferative recall antigen responses were noted between groups. Importantly, resistance detected shortly after initial viremia following the open-ended TI did not result in a lack of resuppression to less than 50 copies/ml after reinitiation of the same drug regimen. Conclusion Cycles of 2- to 6-wk time-fixed TIs in patients with suppressed HIV infection failed to confer a clinically significant benefit with regard to viral suppression off ART. Also, secondary analysis showed no difference between the two strategies in terms of safety, retention of immune reconstitution, and clinical therapy failure. Based on these findings, we suggest that further clinical research on the long-term consequences of TI strategies to decrease drug exposure is warranted. PMID:15630469
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Gorski Findling, Mary T; Werth, Paul M; Musicus, Aviva A; Bragg, Marie A; Graham, Dan J; Elbel, Brian; Roberto, Christina A
2018-01-01
In 2011, a National Academy of Medicine report recommended that packaged food in the U.S. display a uniform front-of-package nutrition label, using a system such as a 0-3 star ranking. Few studies have directly compared this to other labels to determine which best informs consumers and encourages healthier purchases. In 2013, we randomized adult participants (N=1247) in an Internet-based survey to one of six conditions: no label control; single traffic light; multiple traffic light; Facts Up Front; NuVal; or 0-3 star ranking. We compared groups on purchase intentions and accuracy of participants' interpretation of food labels. There were no differences in the nutritional quality of hypothetical shopping baskets across conditions (p=0.845). All labels improved consumers' abilities to judge the nutritional quality of foods relative to no label, but the best designs varied by outcomes. NuVal and multiple traffic light labels led to the greatest accuracy identifying the healthier of two products (p<0.001), while the multiple traffic light also led to the most accurate estimates of saturated fat, sugar, and sodium (p<0.001). The single traffic light outperformed other labels when participants compared nutrient levels between similar products (p<0.03). Single/multiple traffic light and Facts Up Front labels led to the most accurate calories per serving estimations (p<0.001). Although front-of-package labels helped participants more accurately assess products' nutrition information relative to no label, no conditions shifted adults' purchase intentions. Results did not point to a clearly superior label design, but they suggest that a 3-star label might not be best for educating consumers. Copyright © 2017 Elsevier Inc. All rights reserved.
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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).
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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.
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Bone metabolism in renal transplant patients treated with cyclosporine or sirolimus.
Campistol, Josep M; Holt, David W; Epstein, Solomon; Gioud-Paquet, Martine; Rutault, Karine; Burke, James T
2005-09-01
Sirolimus is a new immunosuppressive agent used as treatment to prevent acute renal allograft rejection. One of the complications of renal transplantation and subsequent long-term immunosuppression is bone loss associated with osteoporosis and consequent fracture. Two open-label, randomized, phase 2 studies comparing sirolimus versus cyclosporine (CsA) included indices of bone metabolism as secondary end-points. Markers of bone turnover, serum osteocalcin and urinary N-telopeptides, were measured over a 1-year period in 115 patients receiving either CsA or sirolimus as a primary therapy in combination with azathioprine and glucocorticoids (study A) or mycophenolate mofetil (MMF) and glucocorticoids (study B). Urinary excretion of N-telopeptides and the concentrations of serum osteocalcin were consistently higher in the CsA-treated patients and significantly different at week 24 for N-telopeptides and at weeks 12, 24, and 52 for osteocalcin. In conclusion, future trials are warranted to test whether a sirolimus-based regimen conserves bone mineral density compared with a CsA-based regimen.
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Artesunate, artemether or quinine in severe Plasmodium falciparum malaria?
Checkley, Anna M; Whitty, Christopher J M
2007-04-01
Quinine and the artemisinin-derivative drugs artesunate and artemether are effective treatments for severe falciparum malaria. Trials comparing artemether with quinine have not demonstrated convincing evidence of a mortality advantage for artemether. The South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT), a multicenter, randomized, open-label trial in 1461 adults with severe malaria in Asia compared artesunate with quinine. Mortality was 15% in the artesunate group and 22% in the quinine group, a reduction of 34.7% (95% confidence interval: 18.5-47.6%) in the artesunate group, with almost all the benefit reported in those with high parasite counts. Artesunate should constitute first-line treatment for severe malaria in Asia. These results can probably be generalized to the treatment of severe malaria in adults from all areas, especially in those with hyperparasitemia. However, it is unclear whether these results can be generalized to children in Africa, who constitute the majority of those who die from severe malaria worldwide.
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Stauffer, Virginia L.; Baygani, Simin K.; Kinon, Bruce J.; Krikke-Workel, Judith O.
2014-01-01
Abstract This 6-week, multicenter, randomized withdrawal, placebo-controlled trial sought to determine whether symptoms of physical dependence occur after abrupt cessation of pomaglumetad methionil (LY2140023 monohydrate), a metabotropic glutamate 2/3 receptor agonist, in patients with schizophrenia. Eligible outpatients, 18 to 65 years old who required a modification or initiation of antipsychotic medication received 4 weeks of pomaglumetad methionil during open-label treatment and then were randomized, double-blind, to continue pomaglumetad methionil or receive placebo for 2 weeks. The primary outcome compared results of the 3-day moving mean of the total score on the Discontinuation Symptom Checklist-Modified Rickels for pomaglumetad methionil-treated patients with those on placebo during the randomized withdrawal phase. An electronic patient-reported outcome (ePRO) device was used daily to record these results. During the withdrawal phase, 103 patients were randomized, and 98 patients completed the trial. There was no statistically significant evidence of withdrawal symptoms associated with placebo compared with pomaglumetad methionil continuation as measured by Discontinuation Symptom Checklist-Modified Rickels (P = 0.170). The results are supported by secondary analyses with the clinician-rated, Clinical Institute Withdrawal Assessment of Alcohol Scale Revised, which showed no statistically significant differences between treatment groups. Using the ePRO device, 82.5% of the patients achieved 75% to 100% of compliance. No discontinuations due to worsening of schizophrenia, serious adverse events, deaths, or seizures were reported during either phase of the study. These findings suggest that there is no evidence of withdrawal symptoms associated with the abrupt discontinuation of pomaglumetad methionil and that an ePRO device can be successfully used in a multicenter schizophrenia trial. PMID:25006819
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Tashima, Karen T; Smeaton, Laura M; Fichtenbaum, Carl J; Andrade, Adriana; Eron, Joseph J; Gandhi, Rajesh T; Johnson, Victoria A; Klingman, Karin L; Ritz, Justin; Hodder, Sally; Santana, Jorge L; Wilkin, Timothy; Haubrich, Richard H
2015-12-15
Nucleoside reverse transcriptase inhibitors (NRTIs) are often included in antiretroviral regimens in treatment-experienced patients in the absence of data from randomized trials. To compare treatment success between participants who omit versus those who add NRTIs to an optimized antiretroviral regimen of 3 or more agents. Multicenter, randomized, controlled trial. (ClinicalTrials.gov: NCT00537394). Outpatient HIV clinics. Treatment-experienced patients with HIV infection and viral resistance. Open-label optimized regimens (not including NRTIs) were selected on the basis of treatment history and susceptibility testing. Participants were randomly assigned to omit or add NRTIs. The primary efficacy outcome was regimen failure through 48 weeks using a noninferiority margin of 15%. The primary safety outcome was time to initial episode of a severe sign, symptom, or laboratory abnormality before discontinuation of NRTI assignment. 360 participants were randomly assigned, and 93% completed a 48-week visit. The cumulative probability of regimen failure was 29.8% in the omit-NRTIs group versus 25.9% in the add-NRTIs group (difference, 3.2 percentage points [95% CI, -6.1 to 12.5 percentage points]). No significant between-group differences were found in the primary safety end points or the proportion of participants with HIV RNA level less than 50 copies/mL. No deaths occurred in the omit-NRTIs group compared with 7 deaths in the add-NRTIs group. Unblinded study design, and the study may not be applicable to resource-poor settings. Treatment-experienced patients with HIV infection starting a new optimized regimen can safely omit NRTIs without compromising virologic efficacy. Omitting NRTIs will reduce pill burden, cost, and toxicity in this patient population. National Institute of Allergy and Infectious Diseases, Boehringer Ingelheim, Janssen, Merck, ViiV Healthcare, Roche, and Monogram Biosciences (LabCorp).
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HIV salvage therapy does not require nucleoside reverse transcriptase inhibitors: a randomized trial
Tashima, Karen T; Smeaton, Laura M; Fichtenbaum, Carl J; Andrade, Adriana; Eron, Joseph J; Gandhi, Rajesh T; Johnson, Victoria A; Klingman, Karin L; Ritz, Justin; Hodder, Sally; Santana, Jorge L; Wilkin, Timothy; Haubrich, Richard H
2015-01-01
Background Nucleoside reverse transcriptase inhibitors (NRTIs) are often included in antiretroviral (ARV) regimens in treatment-experienced patients in the absence of data from randomized trials. Objective To compare treatment success between participants who omit versus Add NRTIs to an optimized ARV regimen of three or more agents. Design Multisite, randomized, controlled trial. Setting Outpatient HIV clinics. Participants HIV-infected patients with three-class ARV experience and/or viral resistance. Intervention Open-label optimized regimens (not including NRTIs) were selected based upon treatment history and susceptibility testing. Participants were randomized to Omit or Add NRTIs. Measurements The primary efficacy outcome was regimen failure through week 48, using a non-inferiority margin of 15%. The primary safety outcome was time to initial episode of severe sign/symptom or laboratory abnormality prior to discontinuation of NRTI assignment. Results 360 participants were randomized and 93% completed a week 48 visit. The cumulative probability of regimen failure was 29.8% in the Omit NRTI arm versus 25.9% in the Add NRTI arm (difference= 3.2%: 95% CI, −6.1 to 12.5). There were no significant differences in the primary safety endpoints or the proportion of participants with HIV RNA <50 copies/mL between arms. No deaths occurred in the Omit NRTIs arm, compared with 7 deaths in the Add NRTIs arm. Limitations Non-blinded study design and may not be applicable to resource poor settings. Conclusion HIV-infected treatment-experienced patients starting a new optimized regimen can safely omit NRTIs without compromising virologic efficacy. Omitting NRTIs will reduce pill burden, cost, and toxicity in this patient population. PMID:26595748
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Sohn, Hoon-Sang; Jeon, Yoon Sang; Lee, JuHan; Shin, Sang-Jin
2017-06-01
Recently, minimally invasive plate osteosynthesis (MIPO) has been widely used for the treatment of proximal humeral fractures. However, there is concern about whether the MIPO in comminuted proximal humeral fractures is also comparable to open plating. The purpose of this study was to compare the clinical and radiographic outcomes of open plating and MIPO for acute displaced proximal humeral fractures. In this prospective, randomized controlled study, 107 patients who had an acute proximal humeral fracture were randomized to either the open plating or MIPO techniques. Forty-five patients treated with open plating and 45 with the MIPO technique who were followed up at least 1year were evaluated. Shoulder functional assessment, operating time, several radiographic parameters, and complications were evaluated at final follow-up. The mean follow-up period was 15.0 months in the open plating and 14.3 months in the MIPO technique. There were no statistically significant differences in functional assessment scores and radiographic parameters between the two groups. High complications rates were found in 4-part fracture in both surgical methods The average operation time in the MIPO group were significantly lower compared to the open plating group (p<0.05). This study showed MIPO in proximal humerus fractures had similar clinical and radiographic outcomes compared to the open plating. However, the MIPO technique in proximal humerus fracture provided significantly shorter operation time than the open plating. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Nissim, Nir; Shahar, Yuval; Elovici, Yuval; Hripcsak, George; Moskovitch, Robert
2017-09-01
Labeling instances by domain experts for classification is often time consuming and expensive. To reduce such labeling efforts, we had proposed the application of active learning (AL) methods, introduced our CAESAR-ALE framework for classifying the severity of clinical conditions, and shown its significant reduction of labeling efforts. The use of any of three AL methods (one well known [SVM-Margin], and two that we introduced [Exploitation and Combination_XA]) significantly reduced (by 48% to 64%) condition labeling efforts, compared to standard passive (random instance-selection) SVM learning. Furthermore, our new AL methods achieved maximal accuracy using 12% fewer labeled cases than the SVM-Margin AL method. However, because labelers have varying levels of expertise, a major issue associated with learning methods, and AL methods in particular, is how to best to use the labeling provided by a committee of labelers. First, we wanted to know, based on the labelers' learning curves, whether using AL methods (versus standard passive learning methods) has an effect on the Intra-labeler variability (within the learning curve of each labeler) and inter-labeler variability (among the learning curves of different labelers). Then, we wanted to examine the effect of learning (either passively or actively) from the labels created by the majority consensus of a group of labelers. We used our CAESAR-ALE framework for classifying the severity of clinical conditions, the three AL methods and the passive learning method, as mentioned above, to induce the classifications models. We used a dataset of 516 clinical conditions and their severity labeling, represented by features aggregated from the medical records of 1.9 million patients treated at Columbia University Medical Center. We analyzed the variance of the classification performance within (intra-labeler), and especially among (inter-labeler) the classification models that were induced by using the labels provided by seven labelers. We also compared the performance of the passive and active learning models when using the consensus label. The AL methods: produced, for the models induced from each labeler, smoother Intra-labeler learning curves during the training phase, compared to the models produced when using the passive learning method. The mean standard deviation of the learning curves of the three AL methods over all labelers (mean: 0.0379; range: [0.0182 to 0.0496]), was significantly lower (p=0.049) than the Intra-labeler standard deviation when using the passive learning method (mean: 0.0484; range: [0.0275-0.0724). Using the AL methods resulted in a lower mean Inter-labeler AUC standard deviation among the AUC values of the labelers' different models during the training phase, compared to the variance of the induced models' AUC values when using passive learning. The Inter-labeler AUC standard deviation, using the passive learning method (0.039), was almost twice as high as the Inter-labeler standard deviation using our two new AL methods (0.02 and 0.019, respectively). The SVM-Margin AL method resulted in an Inter-labeler standard deviation (0.029) that was higher by almost 50% than that of our two AL methods The difference in the inter-labeler standard deviation between the passive learning method and the SVM-Margin learning method was significant (p=0.042). The difference between the SVM-Margin and Exploitation method was insignificant (p=0.29), as was the difference between the Combination_XA and Exploitation methods (p=0.67). Finally, using the consensus label led to a learning curve that had a higher mean intra-labeler variance, but resulted eventually in an AUC that was at least as high as the AUC achieved using the gold standard label and that was always higher than the expected mean AUC of a randomly selected labeler, regardless of the choice of learning method (including a passive learning method). Using a paired t-test, the difference between the intra-labeler AUC standard deviation when using the consensus label, versus that value when using the other two labeling strategies, was significant only when using the passive learning method (p=0.014), but not when using any of the three AL methods. The use of AL methods, (a) reduces intra-labeler variability in the performance of the induced models during the training phase, and thus reduces the risk of halting the process at a local minimum that is significantly different in performance from the rest of the learned models; and (b) reduces Inter-labeler performance variance, and thus reduces the dependence on the use of a particular labeler. In addition, the use of a consensus label, agreed upon by a rather uneven group of labelers, might be at least as good as using the gold standard labeler, who might not be available, and certainly better than randomly selecting one of the group's individual labelers. Finally, using the AL methods: when provided by the consensus label reduced the intra-labeler AUC variance during the learning phase, compared to using passive learning. Copyright © 2017 Elsevier B.V. All rights reserved.
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Nissim, Nir; Shahar, Yuval; Boland, Mary Regina; Tatonetti, Nicholas P; Elovici, Yuval; Hripcsak, George; Moskovitch, Robert
2018-01-01
Background and Objectives Labeling instances by domain experts for classification is often time consuming and expensive. To reduce such labeling efforts, we had proposed the application of active learning (AL) methods, introduced our CAESAR-ALE framework for classifying the severity of clinical conditions, and shown its significant reduction of labeling efforts. The use of any of three AL methods (one well known [SVM-Margin], and two that we introduced [Exploitation and Combination_XA]) significantly reduced (by 48% to 64%) condition labeling efforts, compared to standard passive (random instance-selection) SVM learning. Furthermore, our new AL methods achieved maximal accuracy using 12% fewer labeled cases than the SVM-Margin AL method. However, because labelers have varying levels of expertise, a major issue associated with learning methods, and AL methods in particular, is how to best to use the labeling provided by a committee of labelers. First, we wanted to know, based on the labelers’ learning curves, whether using AL methods (versus standard passive learning methods) has an effect on the Intra-labeler variability (within the learning curve of each labeler) and inter-labeler variability (among the learning curves of different labelers). Then, we wanted to examine the effect of learning (either passively or actively) from the labels created by the majority consensus of a group of labelers. Methods We used our CAESAR-ALE framework for classifying the severity of clinical conditions, the three AL methods and the passive learning method, as mentioned above, to induce the classifications models. We used a dataset of 516 clinical conditions and their severity labeling, represented by features aggregated from the medical records of 1.9 million patients treated at Columbia University Medical Center. We analyzed the variance of the classification performance within (intra-labeler), and especially among (inter-labeler) the classification models that were induced by using the labels provided by seven labelers. We also compared the performance of the passive and active learning models when using the consensus label. Results The AL methods produced, for the models induced from each labeler, smoother Intra-labeler learning curves during the training phase, compared to the models produced when using the passive learning method. The mean standard deviation of the learning curves of the three AL methods over all labelers (mean: 0.0379; range: [0.0182 to 0.0496]), was significantly lower (p = 0.049) than the Intra-labeler standard deviation when using the passive learning method (mean: 0.0484; range: [0.0275 to 0.0724). Using the AL methods resulted in a lower mean Inter-labeler AUC standard deviation among the AUC values of the labelers’ different models during the training phase, compared to the variance of the induced models’ AUC values when using passive learning. The Inter-labeler AUC standard deviation, using the passive learning method (0.039), was almost twice as high as the Inter-labeler standard deviation using our two new AL methods (0.02 and 0.019, respectively). The SVM-Margin AL method resulted in an Inter-labeler standard deviation (0.029) that was higher by almost 50% than that of our two AL methods. The difference in the inter-labeler standard deviation between the passive learning method and the SVM-Margin learning method was significant (p = 0.042). The difference between the SVM-Margin and Exploitation method was insignificant (p = 0.29), as was the difference between the Combination_XA and Exploitation methods (p = 0.67). Finally, using the consensus label led to a learning curve that had a higher mean intra-labeler variance, but resulted eventually in an AUC that was at least as high as the AUC achieved using the gold standard label and that was always higher than the expected mean AUC of a randomly selected labeler, regardless of the choice of learning method (including a passive learning method). Using a paired t-test, the difference between the intra-labeler AUC standard deviation when using the consensus label, versus that value when using the other two labeling strategies, was significant only when using the passive learning method (p = 0.014), but not when using any of the three AL methods. Conclusions The use of AL methods, (a) reduces intra-labeler variability in the performance of the induced models during the training phase, and thus reduces the risk of halting the process at a local minimum that is significantly different in performance from the rest of the learned models; and (b) reduces Inter-labeler performance variance, and thus reduces the dependence on the use of a particular labeler. In addition, the use of a consensus label, agreed upon by a rather uneven group of labelers, might be at least as good as using the gold standard labeler, who might not be available, and certainly better than randomly selecting one of the group’s individual labelers. Finally, using the AL methods when provided by the consensus label reduced the intra-labeler AUC variance during the learning phase, compared to using passive learning. PMID:28456512
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Iwamoto, Jun; Sato, Yoshihiro
2014-01-01
An open-label randomized controlled trial was conducted to clarify the effect of eldecalcitol (ED) on body balance and muscle power in postmenopausal osteoporotic women treated with bisphosphonates. A total of 106 postmenopausal women with osteoporosis (mean age 70.8 years) were randomly divided into two groups (n=53 in each group): a bisphosphonate group (control group) and a bisphosphonate plus ED group (ED group). Biochemical markers, unipedal standing time (body balance), and five-repetition chair-rising time (muscle power) were evaluated. The duration of the study was 6 months. Ninety-six women who completed the trial were included in the subsequent analyses. At baseline, the age, body mass index, bone mass indices, bone turnover markers, unipedal standing time, and chair-rising time did not differ significantly between the two groups. During the 6-month treatment period, bone turnover markers decreased significantly from the baseline values similarly in the two groups. Although no significant improvement in the unipedal standing time was seen in the ED group, compared with the control group, the chair-rising time decreased significantly in the ED group compared with the control group. The present study showed that ED improved the chair-rising time in terms of muscle power in postmenopausal osteoporotic women treated with bisphosphonates. PMID:24476669
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Janin, Annick; Monnet, Joelle
2014-04-01
The primary objective of this study was to compare the bioavailability of paracetamol, phenylephrine hydrochloride and guaifenesin in a new oral syrup with an established oral reference product. The secondary objective was to compare the safety of the new syrup and the reference product. This was a single-centre, open-label, randomized, reference-replicated, crossover study. Healthy adult volunteers received one dose of syrup and two separate doses of a reference oral liquid formulation in a randomized sequence over three study periods, with a washout interval of ≥ 7 days between study periods. Blood samples were taken regularly postdose and analysed for paracetamol, phenylephrine hydrochloride and guaifenesin concentrations; adverse events were recorded. This study enrolled 45 subjects. For paracetamol and guaifenesin, the syrup and reference product were considered to be bioequivalent. Bioequivalence was not shown for phenylephrine hydrochloride. All adverse events were mild or moderate, most of which were considered formulation related. The syrup did not reach bioequivalence with the reference product, as bioequivalence could not be shown for phenylephrine hydrochloride. This may be due to differences in the excipients between the two products. Both the syrup and the reference product had a good safety profile and were well tolerated.
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Roseman, Mary G; Joung, Hyun-Woo; Littlejohn, Emily I
2018-05-01
Front-of-package (FOP) labels are increasing in popularity on retail products. Reductive FOP labels provide nutrient-specific information, whereas evaluative FOP labels summarize nutrient information through icons. Better understanding of consumer behavior regarding FOP labels is beneficial to increasing consumer use of nutrition labeling when making grocery purchasing decisions. We aimed to determine FOP label format effectiveness in aiding consumers at assessing nutrient density of food products. In addition, we sought to determine relationships between FOP label use and attitude toward healthy eating, diet self-assessment, self-reported health and nutrition knowledge, and label and shopping behaviors. A between-subjects experimental design was employed. Participants were randomly assigned to one of four label conditions: Facts Up Front, Facts Up Front Extended, a binary symbol, and no-label control. One hundred sixty-one US primary grocery shoppers, aged 18 to 69 years. Participants were randomly invited to the online study. Participants in one of four label condition groups viewed three product categories (cereal, dairy, and snacks) with corresponding questions. Adults' nutrition assessment of food products based on different FOP label formats, along with label use and attitude toward healthy eating, diet self-assessment, self-reported health and nutrition knowledge, and label and shopping behaviors. Data analyses included descriptive statistics, χ 2 tests, and logistical regression. Significant outcomes were set to α=.05. Participants selected the more nutrient-dense product in the snack food category when it contained an FOP label. Subjective health and nutrition knowledge and frequency of selecting food for healthful reasons were associated with FOP label use (P<0.01 and P<0.05, respectively). Both Facts Up Front (reductive) and binary (evaluative) FOP labels appear effective for nutrition assessment of snack products compared with no label. Specific attitude and behavior factors were associated with label use. Copyright © 2018 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.
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Robson, Val; Dodd, Susanna; Thomas, Stephen
2009-03-01
This paper is a report of a study to compare a medical grade honey with conventional treatments on the healing rates of wounds healing by secondary intention. There is an increasing body of evidence to support the use of honey to treat wounds, but there is a lack of robust randomized trials on which clinicians can base their clinical judgement. A sample of 105 patients were involved in a single centre, open-label randomized controlled trial in which patients received either a conventional wound dressing or honey. Data were collected between September 2004 and May 2007. The median time to healing in the honey group was 100 days compared with 140 days in the control group. The healing rate at 12 weeks was equal to 46.2% in the honey group compared with 34.0% in the conventional group, and the difference in the healing rates (95% confidence interval, CI) at 12 weeks between the two groups was 12.2% (-13.6%, 37.9%). The unadjusted hazard ratio (95% CI) from a Cox regression was equal to 1.30 (0.77, 2.19), P = 0.321. When the treatment effect was adjusted for confounding factors (sex, wound type, age and wound area at start of treatment), the hazard ratio increased to 1.51 but was again not statistically significant. Wound area at start of treatment and sex are both highly statistically significant predictors of time to healing. These results support the proposition that there are clinical benefits from using honey in wound care, but further research is needed.
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Niikura, Ryota; Nagata, Naoyoshi; Yamada, Atsuo; Doyama, Hisashi; Shiratori, Yasutoshi; Nishida, Tsutomu; Kiyotoki, Shu; Yada, Tomoyuki; Fujita, Tomoki; Sumiyoshi, Tetsuya; Hasatani, Kenkei; Mikami, Tatsuya; Honda, Tetsuro; Mabe, Katsuhiro; Hara, Kazuo; Yamamoto, Katsumi; Takeda, Mariko; Takata, Munenori; Tanaka, Mototsugu; Shinozaki, Tomohiro; Fujishiro, Mitsuhiro; Koike, Kazuhiko
2018-04-03
The clinical benefit of early colonoscopy within 24 h of arrival in patients with severe acute lower gastrointestinal bleeding (ALGIB) remains controversial. This trial will compare early colonoscopy (performed within 24 h) versus elective colonoscopy (performed between 24 and 96 h) to examine the identification rate of stigmata of recent hemorrhage (SRH) in ALGIB patients. We hypothesize that, compared with elective colonoscopy, early colonoscopy increases the identification of SRH and subsequently improves clinical outcomes. This trial is an investigator-initiated, multicenter, randomized, open-label, parallel-group trial examining the superiority of early colonoscopy over elective colonoscopy (standard therapy) in ALGIB patients. The primary outcome measure is the identification of SRH. Secondary outcomes include 30-day rebleeding, success of endoscopic treatment, need for additional endoscopic examination, need for interventional radiology, need for surgery, need for transfusion during hospitalization, length of stay, 30-day thrombotic events, 30-day mortality, preparation-related adverse events, and colonoscopy-related adverse events. The sample size will enable detection of a 9% SRH rate in elective colonoscopy patients and a SRH rate of ≥ 26% in early colonoscopy patients with a risk of type I error of 5% and a power of 80%. This trial will provide high-quality data on the benefits and risks of early colonoscopy in ALGIB patients. UMIN-CTR Identifier, UMIN000021129 . Registered on 21 February 2016; ClinicalTrials.gov Identifier, NCT03098173 . Registered on 24 March 2017.
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Hegg, Roberto; Mattar, André; de Matos, João Nunes; Pedrini, José Luiz; Aleixo, Sabina Bandeira; Rocha, Roberto Odebrecht; Cramer, Renato Peixoto; van-Eyll-Rocha, Sylvie
2016-01-01
OBJECTIVES: To compare the efficacy and safety of two filgrastim formulations for controlling chemotherapy-induced neutropenia and to evaluate the non-inferiority of the test drug relative to the originator. METHODS: This phase III non-inferiority study had a randomized, multicenter, and open-label design. The patients were randomized at a ratio of 1:1 with a follow-up period of 6 weeks for each patient. In both study arms, filgrastim was administered subcutaneously at a daily dose of 5 mg/kg body weight. The primary endpoint was the rate of grade 4 neutropenia in the first treatment cycle. The secondary endpoints were the duration of grade 4 neutropenia, the generation of anti-filgrastim antibodies, and the rates of adverse events, laboratory abnormalities, febrile neutropenia, and neutropenia of any grade. RESULTS: The primary efficacy analysis demonstrated the non-inferiority of the test drug compared with the originator drug; the upper limit of the 90% confidence interval (CI) for the rate of neutropenia between the two groups (12.61%) was lower than the established margin of non-inferiority. The two treatments were similar with respect to the secondary endpoints and safety. CONCLUSION: The efficacy and safety profile of the test drug were similar to those of the originator product based on the rate of grade 4 neutropenia in the first treatment cycle. This study supports Anvisa's approval of the first biosimilar drug manufactured by the Brazilian industry (Fiprima®). PMID:27759847
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Effect of Trelagliptin on Quality of Life in Patients with Type 2 Diabetes Mellitus: Study Protocol.
Ishii, Hitoshi; Suzaki, Yuki; Miyata, Yuko
2017-12-01
Long-term glycemic control in type 2 diabetes is critical to prevent or delay the onset of macrovascular and microvascular complications. Medication adherence is an integral component of type 2 diabetes management. Minimizing the dosing frequency of antidiabetic drugs may reduce treatment burden for patients and improve medication adherence. This study has been proposed to assess the reduction in treatment burden during 12 weeks' administration of trelagliptin, a weekly dosing dipeptidyl peptidase-4 (DPP-4) inhibitor, compared with a daily dosing DPP-4 inhibitor in patients with type 2 diabetes. This is a multicenter, randomized, open-label, parallel-group, comparative study to be conducted at approximately 15 sites across Japan. A total of 240 patients are to be randomized 1:1 to receive trelagliptin or a daily DPP-4 inhibitor for 12 weeks. Efficacy and safety will be compared between the two groups. The primary endpoint is the change in total score for all items of the diabetes-therapy-related QOL questionnaire from treatment start to treatment end. The study will be conducted with the highest respect for the individual participants in accordance with the protocol, the Declaration of Helsinki, the Ethical Guidelines for Clinical Research, the ICH Consolidated Guideline for Good Clinical Practice, and applicable local laws and regulations. Takeda Pharmaceutical Company Limited. Japic CTI-173482.
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2017-10-01
does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE October 2017 2. REPORT TYPE...comes from a large open-label case series in Iraq and Afghanistan Veterans with mTBI and posttraumatic headaches and data from a placebo- controlled trial...will be accomplished by conducting a randomized placebo- controlled double blind trial of prazosin vs placebo in 160 Iraq/Afghanistan active-duty
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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.
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Duburcq, Thibault; Durand, Arthur; Dessein, Anne-Frédérique; Vamecq, Joseph; Vienne, Jean-Claude; Dobbelaere, Dries; Mention, Karine; Douillard, Claire; Maboudou, Patrice; Gmyr, Valery; Pattou, François; Jourdain, Mercé; Tamion, Fabienne; Poissy, Julien; Mathieu, Daniel; Favory, Raphaël
2017-05-19
Sodium lactate has been shown to improve hemodynamics and avoid fluid overload. The objective of this study was to confirm a beneficial effect on fluid balance with sodium lactate infusion and to specify whether the advantage of lactate is related to a negative chloride balance, its particular metabolism, or simply its energy load. This was an interventional, randomized, open-label, controlled experimental study. Fifteen female "large white" pigs (2 months old) were challenged with intravenous infusion of Escherichia coli endotoxin. Three groups of five animals were randomly assigned to receive different fluids: a treatment group received sodium lactate 11.2% (SL group); an isotonic control group received 0.9% NaCl (NC group); and a hypertonic control group, with the same amount of osmoles and sodium as the SL group, received sodium bicarbonate 8.4% (SB group). In order to provide the same energy load in the three groups, control groups were perfused with an equivalent energy supply. Statistical analysis was performed with non-parametric tests and the Dunn correction for multiple comparisons at p < 0.05. Fluid and chloride balance, hemodynamics, oxygenation markers, and microcirculatory parameters were measured over a 5-h period. Cumulative fluid balance was significantly lower in the SL group (550 (415-800) mL; median (interquartile range)) compared to the NC group (1100 (920-1640) mL, p = 0.01) and the SB group (935 (790-1220) mL, p = 0.03). Hemodynamics, cardiac efficiency, and microcirculation were significantly enhanced in the SL group, resulting in a significant improvement in oxygen delivery (SL group 417 (305-565) mL/min/m 2 at 300 min versus the NC (207 (119-272) mL/min/m 2 , p = 0.01) and the SB (278, (211-315) mL/min/m 2 , p = 0.03) groups). Oxygenation markers (arterial oxygen partial pressure (PaO 2 )/inspired oxygen fraction (FiO 2 ), mixed venous oxygen saturation (SvO 2 ), and venoarterial carbon dioxide tension difference (Pv-aCO 2 ) were enhanced with sodium lactate infusion. Chloride balance was equivalent in both hypertonic groups and significantly reduced compared to the NC group. Sodium lactate infusion improves fluid balance and hemodynamics. The advantage of lactate does not seem to be explained by its energy load or by the induced negative chloride balance with subsequent water movements.
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Riddle, M C; Yki-Järvinen, H; Bolli, G B; Ziemen, M; Muehlen-Bartmer, I; Cissokho, S; Home, P D
2015-09-01
To evaluate the maintenance of efficacy and safety of insulin glargine 300 U/ml (Gla-300) versus glargine 100 U/ml (Gla-100) in people with type 2 diabetes mellitus (T2DM) using basal plus meal-time insulin for 12 months in the EDITION 1 trial. EDITION 1 was a multicentre, randomized, open-label, two-arm, phase IIIa study. Participants completing the initial 6-month treatment period continued to receive Gla-300 or Gla-100, as previously randomized, once daily for a further 6-month open-label extension phase. Changes in glycated haemoglobin (HbA1c) and fasting plasma glucose concentrations, insulin dose, hypoglycaemic events and body weight were assessed. Of 807 participants enrolled in the initial phase, 89% (359/404) assigned to Gla-300 and 88% (355/403) assigned to Gla-100 completed 12 months. Glycaemic control was sustained in both groups (mean HbA1c: Gla-300, 7.24%; Gla-100, 7.42%), with more sustained HbA1c reduction for Gla-300 at 12 months: least squares mean difference Gla-300 vs Gla-100: HbA1c -0.17 [95% confidence interval (CI) -0.30 to -0.05]%. The mean daily basal insulin dose at 12 months was 1.03 U/kg for Gla-300 and 0.90 U/kg for Gla-100. Lower percentages of participants had ≥1 confirmed [≤3.9 mmol/l (≤70 mg/dl)] or severe hypoglycaemic event with Gla-300 than Gla-100 at any time of day [24 h; 86 vs 92%; relative risk 0.94 (95% CI 0.89-0.99)] and during the night [54 vs 65%; relative risk 0.84 (95% CI 0.75-0.94)], while the annualized rates of such hypoglycaemic events were similar. No between-treatment differences in adverse events were apparent. During 12 months of treatment of T2DM requiring basal and meal-time insulin, glycaemic control was better sustained and fewer individuals reported hypoglycaemia with Gla-300 than with Gla-100. The mean basal insulin dose was higher with Gla-300 compared with Gla-100, but total numbers of hypoglycaemic events and overall tolerability did not differ between treatments. © 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
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Weil, Arnold J; Masters, Elizabeth T; Barsdorf, Alexandra I; Bass, Almasa; Pixton, Glenn; Wilson, Jacquelyn G; Wolfram, Gernot
2017-10-17
The efficacy of ALO-02, an abuse-deterrent formulation containing extended-release oxycodone and sequestered naltrexone, in the treatment of chronic low back pain (CLBP) was studied in a 12-week randomized controlled trial. Primary efficacy endpoint results have been published previously (Rauck et al., 2015). The current paper focuses on patient-reported outcomes for health-related quality of life (HRQL), work productivity, and activity impairment that were assessed during this study. This was a double-blind, placebo-controlled, randomized withdrawal study in patients with moderate-to-severe CLBP. After a screening period (≤2 weeks), patients entered an open-label titration period (4-6 weeks). Treatment responders were then randomized to a double-blind placebo-controlled treatment period (12 weeks). HRQL was assessed using changes in the Short Form-36 v2 Health Survey (SF-36v2) and the EuroQol-5 Dimensions Health Questionnaire 3-Level version (EQ-5D-3L). Work productivity and regular activities were evaluated using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP). A total of 410 patients received ALO-02 during the open-label titration period, of which 280 (intent-to-treat (ITT) population) were treated during the double-blind placebo-controlled treatment period (placebo, n = 134; ALO-02, n = 146). Significant improvement was observed for all SF-36v2 subscales and component scores (p < 0.005) and the EQ-5D-3L summary index and visual analog scale (p < 0.0001) during the titration period. Improvement was also significant (p < 0.0001) for all WPAI:SHP outcomes except 'work time missed due to CLBP' for the titration period. Significant differences favoring ALO-02 compared with placebo were only observed for the SF-36v2 Bodily Pain subscale (p ≤ 0.0232; ITT population) during the double-blind treatment period and the overall study period (screening to the end of the double-blind treatment period). The percentage change in activity impairment due to low back pain subscale of the WPAI:SHP significantly favored ALO-02 compared with placebo for the ITT population when considering the overall study period (p = 0.0040). HRQL, work productivity, and activity impairment may be improved with ALO-02 treatment. ClinicalTrials.gov NCT01571362 , registered April 3, 2012.
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Labelling Polymers and Micellar Nanoparticles via Initiation, Propagation and Termination with ROMP
Thompson, Matthew P.; Randolph, Lyndsay M.; James, Carrie R.; Davalos, Ashley N.; Hahn, Michael E.
2014-01-01
In this paper we compare and contrast three approaches for labelling polymers with functional groups via ring-opening metathesis polymerization (ROMP). We explored the incorporation of functionality via initiation, termination and propagation employing an array of novel initiators, termination agents and monomers. The goal was to allow the generation of selectively labelled and well-defined polymers that would in turn lead to the formation of labelled nanomaterials. Norbornene analogues, prepared as functionalized monomers for ROMP, included fluorescent dyes (rhodamine, fluorescein, EDANS, and coumarin), quenchers (DABCYL), conjugatable moieties (NHS esters, pentafluorophenyl esters), and protected amines. In addition, a set of symmetrical olefins for terminally labelling polymers, and for the generation of initiators in situ is described. PMID:24855496
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Fron Chabouis, Hélène; Chabouis, Francis; Gillaizeau, Florence; Durieux, Pierre; Chatellier, Gilles; Ruse, N Dorin; Attal, Jean-Pierre
2014-01-01
Operative clinical trials are often small and open-label. Randomization is therefore very important. Stratification and minimization are two randomization options in such trials. The first aim of this study was to compare stratification and minimization in terms of predictability and balance in order to help investigators choose the most appropriate allocation method. Our second aim was to evaluate the influence of various parameters on the performance of these techniques. The created software generated patients according to chosen trial parameters (e.g., number of important prognostic factors, number of operators or centers, etc.) and computed predictability and balance indicators for several stratification and minimization methods over a given number of simulations. Block size and proportion of random allocations could be chosen. A reference trial was chosen (50 patients, 1 prognostic factor, and 2 operators) and eight other trials derived from this reference trial were modeled. Predictability and balance indicators were calculated from 10,000 simulations per trial. Minimization performed better with complex trials (e.g., smaller sample size, increasing number of prognostic factors, and operators); stratification imbalance increased when the number of strata increased. An inverse correlation between imbalance and predictability was observed. A compromise between predictability and imbalance still has to be found by the investigator but our software (HERMES) gives concrete reasons for choosing between stratification and minimization; it can be downloaded free of charge. This software will help investigators choose the appropriate randomization method in future two-arm trials.
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Albrecht, Mary; Mukherjee, A. Lisa; Tierney, Camlin; Morse, Gene D.; Dykes, Carrie; Klingman, Karin L.; Demeter, Lisa M.
2012-01-01
Background We devised an open-label, randomized trial to evaluate whether therapeutic drug monitoring (TDM) of protease inhibitors (PIs) and dose escalation based upon a normalized inhibitory quotient (NIQ), which integrates PI trough concentration and drug resistance, could improve virologic outcome in PI-experienced patients with treatment failure. Secondary analyses through 48 weeks are presented. Methods Eligible HIV-infected subjects with a screening viral load of ≥1000 copies/mL initiated a new PI-based regimen at entry and had NIQ performed at week 2. Subjects with an NIQ ≤1 were randomized at week 4 to a standard-of-care (SOC) arm or TDM arm featuring PI dose escalation. Results One hundred and eighty-three subjects were randomized. There was no significant treatment difference in change from randomization to week 48 in HIV-1 RNA [P = .13, median (25th, 75th percentile log10 copies/mL change): −0.03 (−0.74, 0.62) with TDM and 0.11 (−2.3, 0.82) with SOC]. In subgroup analysis, patients with ≥0.69 active PIs benefited from TDM compared to those with <0.69 active PIs (P = .05). Conclusions While the TDM strategy of PI dose escalation did not improve virologic response at week 48 overall, in subgroup analysis, TDM favorably impacted virologic outcome in subjects taking PI-based regimens with moderate antiviral activity. PMID:22044856
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Suppaphol, Sorasak; Worathanarat, Patarawan; Kawinwongkovit, Viroj; Pittayawutwinit, Preecha
2012-04-01
To compare the operative outcome of carpal tunnel release between limited open carpal tunnel release using direct vision and tunneling technique (group A) with standard open carpal tunnel release (group B). Twenty-eight patients were enrolled in the present study. A single blind randomized control trial study was conducted to compare the postoperative results between group A and B. The study parameters were Levine's symptom severity and functional score, grip and pinch strength, and average two-point discrimination. The postoperative results between two groups were comparable with no statistical significance. Only grip strength at three months follow up was significantly greater in group A than in group B. The limited open carpal tunnel release in the present study is effective comparable to the standard open carpal tunnel release. The others advantage of this technique are better cosmesis and improvement in grip strength at the three months postoperative period.
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Dhiman, K S; Adhoor, Veeranagouda S; Agarwal, Riju; Mehta, Amit J
2016-01-01
Primary open angle glaucoma is an insidious and chronic vision-threatening eye ailment due to neuro-retino-optic nerve degeneration, which may be due to the raised intraocular pressure (IOP) or due to independent factors. Management of glaucoma is mainly concentrated on lowering IOP that requires lifetime topical medication, different ocular medicaments for lowering of IOP, and surgical interventions, but it has its own limitations to control the progression of glaucomatous optic neuropathy (GON), and this is the reason behind the use of alternative neuroprotective adjuvants. To evaluate the neuroprotective effect of Ayurvedic line of management of progressive GON. Ingredients of trial drug Vara Fort powder ( Chakshushya Rasayana ) were procured from the Institute Pharmacy, except Swarnamakshika Bhasma , which was purchased from Dhootapapeshwar Pharmaceuticals. The patients fulfilling inclusion criteria, attending outpatient and inpatient departments, irrespective of their sex, race, religion, occupation, etc., were selected and divided into two groups with open-labeled randomization. In Group A, in addition to betaxolol (0.1%) or timolol (0.5%) (non-iobrim), Chakshushya Rasayana 6 g/day orally with Triphala Ghrita and honey along with Koshtha-Shuddhi (body-microchannel clearing treatment) protocol was tried. Nasya (oleation through nasal route) with Jeevantyadi Taila and Tarpana (eye satiation) with Go-Ghrita were also performed. In Group B (control), brimonidine (iobrim) 0.2% eye drop was used for 3 months. Significant improvement was observed in subjective parameters in Group A such as blurred vision, frequent change of presbyopic glasses, and delayed dark adaptation. Chakshushya Rasayana , if administered in a systematic approach along with a modern topical betaxolol or timolol eye drops, has a definite role in improving the lost retinal sensitivity as much as up to 12 dB in 3 months duration.
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Videla, Sebastián; Lahjou, Mounia; Vaqué, Anna; Sust, Mariano; Encabo, Mercedes; Soler, Lluis; Sans, Artur; Sicard, Eric; Gascón, Neus; Encina, Gregorio; Plata-Salamán, Carlos
2017-12-01
Co-crystal of tramadol-celecoxib (CTC) is a novel co-crystal molecule containing two active pharmaceutical ingredients under development by Esteve (E-58425) and Mundipharma Research (MR308). This Phase I study compared single-dose pharmacokinetics (PK) of CTC with those of the individual reference products [immediate-release (IR) tramadol and celecoxib] alone and in open combination. Healthy adults aged 18-55 years were orally administered four treatments under fasted conditions (separated by 7-day wash-out period): 200 mg IR CTC (equivalent to 88 mg tramadol and 112 mg celecoxib; Treatment 1); 100 mg IR tramadol (Treatment 2); 100 mg celecoxib (Treatment 3); and 100 mg IR tramadol and 100 mg celecoxib (Treatment 4). Treatment sequence was assigned using computer-generated randomization. PK parameters were calculated using noncompartmental analysis with parameters for CTC adjusted according to reference product dose (100 mg). Thirty-six subjects (28 male, mean age 36 years) participated. Tramadol PK parameters for Treatments-1, -2 and -4, respectively, were 263, 346 and 349 ng ml -1 (mean maximum plasma concentration); 3039, 2979 and 3119 ng h ml -1 (mean cumulative area under the plasma concentration-time curve); and 2.7, 1.8 and 1.8 h (median time to maximum plasma concentration). For Treatments 1, 3 and 4, the respective celecoxib PK parameters were 313, 449 and 284 ng ml -1 ; 2183, 3093 and 2856 ng h ml -1 ; and 1.5, 2.3 and 3.0 h. No unexpected adverse events were reported. PK parameters of each API in CTC were modified by co-crystallization compared with marketed formulations of tramadol, celecoxib, and their open combination. © 2017 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
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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.
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A randomized, multicenter, open-label study of poly-L-lactic acid for HIV-1 facial lipoatrophy.
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.
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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.
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Chiu, Hsin-Hui; Wu, Mei-Hwan; Wang, Jou-Kou; Lu, Chun-Wei; Chiu, Shuenn-Nan; Chen, Chun-An; Lin, Ming-Tai; Hu, Fu-Chang
2013-03-01
To assess the tolerability and efficacy of the investigational use of the angiotensin II receptor blocker losartan added to β-blockade (BB) to prevent progressive aortic root dilation in patients with Marfan syndrome (MFS). Between May 1, 2007, and September 31, 2011, 28 patients with MFS (11 males [39%]; mean ± SD age, 13.1±6.3 years) with recognized aortic root dilation (z score >2.0) and receiving BB (atenolol or propranolol) treatment were enrolled. They were randomized to receive BB (BB: 13 patients) or β-blockade and losartan (BB-L: 15 patients) for 35 months. In the BB-L group, aortic root dilation was reduced with treatment, and the annual dilation rate of the aortic root was significantly lower than that of the BB group (0.10 mm/yr vs 0.89 mm/yr; P=.02). The absolute aortic diameters at the sinus of Valsalva, annulus, and sinotubular junction showed similar trends, with a reduced rate of dilation in the BB-L group (P=.02, P=.03, and P=.03, respectively). Five patients (33%) treated with BB-L were noted to have a reduced aortic root diameter. However, the differences between the groups regarding changes in aortic stiffness and cross-sectional compliance were not statistically significant. This randomized, open-label, active controlled trial mostly based on a pediatric population demonstrated for the first time that losartan add-on BB therapy is safe and provides more effective protection to slow the progression of aortic root dilation than does BB treatment alone in patients with MFS. clinicaltrials.gov Identifier: NCT00651235. Copyright © 2013 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.
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Schlenk, Richard F; Lübbert, Michael; Benner, Axel; Lamparter, Alexander; Krauter, Jürgen; Herr, Wolfgang; Martin, Hans; Salih, Helmut R; Kündgen, Andrea; Horst, Heinz-A; Brossart, Peter; Götze, Katharina; Nachbaur, David; Wattad, Mohammed; Köhne, Claus-Henning; Fiedler, Walter; Bentz, Martin; Wulf, Gerald; Held, Gerhard; Hertenstein, Bernd; Salwender, Hans; Gaidzik, Verena I; Schlegelberger, Brigitte; Weber, Daniela; Döhner, Konstanze; Ganser, Arnold; Döhner, Hartmut
2016-12-01
The aim of this clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with chemotherapy and to assess the NPM1 status as biomarker for ATRA therapy in younger adult patients (18-60 years) with acute myeloid leukemia (AML). Patients were randomized for intensive chemotherapy with or without open-label ATRA (45 mg/m 2 , days 6-8; 15 mg/m 2 , days 9-21). Two cycles of induction therapy were followed by risk-adapted consolidation with high-dose cytarabine or allogeneic hematopoietic cell transplantation. Due to the open label character of the study, analysis was performed on an intention-to-treat (ITT) and a per-protocol (PP) basis. One thousand one hundred patients were randomized (556, STANDARD; 544, ATRA) with 38 patients treated vice versa. Median follow-up for survival was 5.2 years. ITT analyses revealed no difference between ATRA and STANDARD for the total cohort and for the subset of NPM1-mutated AML with respect to event-free (EFS; p = 0.93, p = 0.17) and overall survival (OS; p = 0.24 and p = 0.32, respectively). Pre-specified PP analyses revealed better EFS in NPM1-mutated AML (p = 0.05) and better OS in the total cohort (p = 0.03). Explorative subgroup analyses on an ITT basis revealed better OS (p = 0.05) in ATRA for genetic low-risk patients according to ELN recommendations. The clinical trial is registered at clinicaltrialsregister.eu (EudraCT Number: 2004-004321-95).
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Chen, Chung-Hsin; Pu, Yeong-Shiau
2018-06-01
To investigate the efficacy and safety profile of 12-month adjuvant androgen-deprivation therapy (ADT) following total-gland cryoablation (TGC) in patients with high-risk localized prostate cancer (HRLPC). This open-label randomized trial included 38 HRLPC patients who received TGC between July 2011 and March 2013. Within 4 weeks after TGC, subjects were randomly assigned (1:1) to either the 12-month adjuvant ADT or non-adjuvant ADT group. The primary outcome was biochemical failure measured by the Phoenix definition. Adverse events were measured at month 1, 2, 3, 6, 9 and 12. In addition, a cohort of 145 HRLPC patients was selected retrospectively for outcome validation. The adjuvant ADT and non-adjuvant ADT groups did't differ in peri-operative characters, such as age, preoperative PSA, tumor stages, Gleason score, prostate size and cryoprobe number. Four patients with adjuvant ADT withdrew from this trial for personal reasons (N = 2), elevated liver function (N = 1) and poorly controlled hyperglycemia (N = 1). In contrast, none in non-adjuvant ADT group experienced adverse events. Biochemical failures were identified in 5 (26%) patients in each group during a median follow-up duration of 45 months. The median times to biochemical failure were 25 and 5.5 months for adjuvant ADT and non-adjuvant ADT groups, respectively. Biochemical-failure survival curves converged 24 months after TGC. Univariable and multivariable analyses revealed adjuvant ADT was not associated with biochemical recurrences in the validation cohort. Adjuvant ADT does not reduce biochemical failure for HRPLC patients undergoing TGC. It should be further confirmed by a larger cohort. Copyright © 2018. Published by Elsevier Inc.
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Thudium, Karen; Gallo, Jorge; Bouillaud, Emmanuel; Sachs, Carolin; Eddy, Simantini; Cheung, Wing
2015-01-01
The mammalian target of rapamycin (mTOR) inhibitor everolimus has a well-established pharmacokinetics profile. We conducted a randomized, single-center, open-label, two-sequence, two-period crossover study of healthy volunteers to assess the relative bioavailability of everolimus administered as one 5 mg tablet or five 1 mg tablets. Subjects were randomized 1:1 to receive everolimus dosed as one 5 mg tablet or as five 1 mg tablets on day 1, followed by a washout period on days 8-14 and then the opposite formulation on day 15. Blood sampling for pharmacokinetic evaluation was performed at prespecified time points, with 17 samples taken for each treatment period. Primary variables for evaluation of relative bioavailability were area under the concentration-time curve from time zero to infinity (AUCinf) and maximum blood concentration (Cmax). Safety was assessed by reporting the incidence of adverse events (AEs). Twenty-two participants received everolimus as one 5 mg tablet followed by five 1 mg tablets (n=11) or the opposite sequence (n=11). The Cmax of five 1 mg tablets was 48% higher than that of one 5 mg tablet (geometric mean ratio, 1.48; 90% confidence interval [CI], 1.35-1.62). AUCinf was similar (geometric mean ratio, 1.08; 90% CI, 1.02-1.16), as were the extent of absorption and the distribution and elimination kinetics. AEs, all grade 1 or 2, were observed in 54.5% of subjects. Although the extent of absorption was similar, the Cmax of five 1 mg tablets was higher than that of one 5 mg tablet, suggesting these formulations lead to different peak blood concentrations and are not interchangeable at the dose tested.
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Davis, Gary L; Nelson, David R; Terrault, Norah; Pruett, Timothy L; Schiano, Thomas D; Fletcher, Courtney V; Sapan, Christine V; Riser, Laura N; Li, Yufeng; Whitley, Richard J; Gnann, John W
2005-08-01
Chronic hepatitis C is the most common indication for liver transplantation, but viral recurrence is universal and progressive graft injury occurs in most recipients. Our aim was to assess the safety, pharmacokinetics (PK), and antiviral effects of high doses of a human hepatitis C antibody enriched immune globulin product (HCIG) in patients undergoing liver transplantation for chronic hepatitis C. This was a multicenter, randomized, open-label, controlled trial conducted at 4 transplant centers in the United States. A total of 18 patients with chronic hepatitis C, who underwent liver transplantation, were randomized to receive low-dose HCIG (75 mg/kg) or high-dose HCIG (200 mg/kg), or no treatment. A total of 17 infusions of HCIG were administered in each treated patient over 14 weeks using a time-dependent dosing strategy based on the PK of anti-hepatitis B immune globulin in liver transplant recipients. Hepatitis C virus levels, liver enzymes, and liver biopsies were obtained serially throughout the study period. PK profiles of HCV antibodies were determined on days 4, 10, and 98. HCIG infusions were safe and tolerated. The infusion rate could not be maximized because of symptoms for 18% to 30% of the doses. The half-life of HCIG was extremely short immediately after transplantation but was gradually prolonged. In the high-dose group, serum alanine aminotransferase (ALT) levels normalized in most subjects and no patient developed hepatic fibrosis. However, serum HCV RNA levels were not suppressed at either dose. In conclusion, HCIG, an anti-HCV enriched immune globulin product, appears to be safe in patients with chronic hepatitis C undergoing liver transplantation. Further studies are required to determine whether the drug has beneficial effects in this group of patients.
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Zhang, Di; Ke, Li; Ni, Zhen; Chen, Yu; Zhang, Lin-Hui; Zhu, Shao-Hua; Li, Chan-Juan; Shang, Lei; Liang, Jie; Shi, Yong-Quan
2017-08-01
Due to increasing antimicrobial resistance, a bismuth-based quadruple regimen has been recommended as an alternative first-line therapy for Helicobacter pylori (H pylori) eradication. However, different results are varied greatly and the availability of bismuth was limited in some countries. We assessed the efficacy and safety of 14-day berberine-containing quadruple therapy as an alternative regimen for H pylori eradication. In a randomized, open-label, non-inferiority, phase IV trial between November 25, 2014, and October 15, 2015, 612 treatment-naive patients were randomly assigned to 14-day berberine-containing (n = 308) or 14-day bismuth-containing (n = 304) quadruple therapy. The primary outcomes were eradication rates determined by the C urea breath test (C-UBT) 28 days after the end of treatment. The secondary outcomes were adverse events and compliance. The baseline demographic data including age, gender, body mass index (BMI), general condition and severity score were not statistically different in both groups. The eradication rates in bismuth and berberine groups were 86.4% (266/308) and 90.1% (274/304) in intention-to-treat (ITT) analysis (P = .149), and 89.6% (266/297) and 91.3% (273/299) in per-protocol (PP) analysis (P = .470), respectively. No statistically significant difference was found in the overall incidence of adverse events between both groups (35.7% vs 28.6%, P = .060). Both regimens achieved the recommended efficacy for H pylori eradication. The berberine-containing quadruple regimen was not inferior to bismuth-containing quadruple regimen and can be recommended as an alternative regimen for H pylori eradication in the local region.
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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.
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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).
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Citerio, Giuseppe; Franzosi, Maria Grazia; Latini, Roberto; Masson, Serge; Barlera, Simona; Guzzetti, Stefano; Pesenti, Antonio
2009-04-06
Many studies have attempted to determine the "best" anaesthetic technique for neurosurgical procedures in patients without intracranial hypertension. So far, no study comparing intravenous (IA) with volatile-based neuroanaesthesia (VA) has been able to demonstrate major outcome differences nor a superiority of one of the two strategies in patients undergoing elective supratentorial neurosurgery. Therefore, current practice varies and includes the use of either volatile or intravenous anaesthetics in addition to narcotics. Actually the choice of the anaesthesiological strategy depends only on the anaesthetists' preferences or institutional policies. This trial, named NeuroMorfeo, aims to assess the equivalence between volatile and intravenous anaesthetics for neurosurgical procedures. NeuroMorfeo is a multicenter, randomized, open label, controlled trial, based on an equivalence design. Patients aged between 18 and 75 years, scheduled for elective craniotomy for supratentorial lesion without signs of intracranial hypertension, in good physical state (ASA I-III) and Glasgow Coma Scale (GCS) equal to 15, are randomly assigned to one of three anaesthesiological strategies (two VA arms, sevoflurane + fentanyl or sevoflurane + remifentanil, and one IA, propofol + remifentanil). The equivalence between intravenous and volatile-based neuroanaesthesia will be evaluated by comparing the intervals required to reach, after anaesthesia discontinuation, a modified Aldrete score > or = 9 (primary end-point). Two statistical comparisons have been planned: 1) sevoflurane + fentanyl vs. propofol + remifentanil; 2) sevoflurane + remifentanil vs. propofol + remifentanil. Secondary end-points include: an assessment of neurovegetative stress based on (a) measurement of urinary catecholamines and plasma and urinary cortisol and (b) estimate of sympathetic/parasympathetic balance by power spectrum analyses of electrocardiographic tracings recorded during anaesthesia; intraoperative adverse events; evaluation of surgical field; postoperative adverse events; patient's satisfaction and analysis of costs. 411 patients will be recruited in 14 Italian centers during an 18-month period. We presented the development phase of this anaesthesiological on-going trial. The recruitment started December 4th, 2007 and up to 4th, December 2008, 314 patients have been enrolled.
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Electronic versus traditional chest tube drainage following lobectomy: a randomized trial.
Lijkendijk, Marike; Licht, Peter B; Neckelmann, Kirsten
2015-12-01
Electronic drainage systems have shown superiority compared with traditional (water seal) drainage systems following lung resections, but the number of studies is limited. As part of a medico-technical evaluation, before change of practice to electronic drainage systems for routine thoracic surgery, we conducted a randomized controlled trial (RCT) investigating chest tube duration and length of hospitalization. Patients undergoing lobectomy were included in a prospective open label RCT. A strict algorithm was designed for early chest tube removal, and this decision was delegated to staff nurses. Data were analysed by Cox proportional hazard regression model adjusting for lung function, gender, age, BMI, video-assisted thoracic surgery (VATS) or open surgery and presence of incomplete fissure or pleural adhesions. Time was distinguished as possible (optimal) and actual time for chest tube removal, as well as length of hospitalization. A total of 105 patients were randomized. We found no significant difference between the electronic group and traditional group in optimal chest tube duration (HR = 0.83; 95% CI: 0.55-1.25; P = 0.367), actual chest tube duration (HR = 0.84; 95% CI: 0.55-1.26; P = 0.397) or length of hospital stay (HR = 0.91; 95% CI: 0.59-1.39; P = 0.651). No chest tubes had to be reinserted. Presence of pleural adhesions or an incomplete fissure was a significant predictor of chest tube duration (HR = 1.72; 95% CI: 1.15-2.77; P = 0.014). Electronic drainage systems did not reduce chest tube duration or length of hospitalization significantly compared with traditional water seal drainage when a strict algorithm for chest tube removal was used. This algorithm allowed delegation of chest tube removal to staff nurses, and in some patients chest tubes could be removed safely on the day of surgery. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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Lyophilized Kit for the Preparation of the PET Perfusion Agent [(68)Ga]-MAA.
Amor-Coarasa, Alejandro; Milera, Andrew; Carvajal, Denny; Gulec, Seza; McGoron, Anthony J
2014-01-01
Rapid developments in the field of medical imaging have opened new avenues for the use of positron emitting labeled microparticles. The radioisotope used in our research was (68)Ga, which is easy to obtain from a generator and has good nuclear properties for PET imaging. Methods. Commercially available macroaggregated albumin (MAA) microparticles were suspended in sterile saline, centrifuged to remove the free albumin and stannous chloride, relyophilized, and stored for later labeling with (68)Ga. Labeling was performed at different temperatures and times. (68)Ga purification settings were also tested and optimized. Labeling yield and purity of relyophilized MAA microparticles were compared with those that were not relyophilized. Results. MAA particles kept their original size distribution after relyophilization. Labeling yield was 98% at 75°C when a (68)Ga purification system was used, compared to 80% with unpurified (68)Ga. Radiochemical purity was over 97% up to 4 hours after the labeling. The relyophilized MAA and labeling method eliminate the need for centrifugation purification of the final product and simplify the labeling process. Animal experiments demonstrated the high in vivo stability of the obtained PET agent with more than 95% of the activity remaining in the lungs after 4 hours.
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Tunnecliff, Jacqueline; Weiner, John; Gaida, James E; Keating, Jennifer L; Morgan, Prue; Ilic, Dragan; Clearihan, Lyn; Davies, David; Sadasivan, Sivalal; Mohanty, Patitapaban; Ganesh, Shankar; Reynolds, John; Maloney, Stephen
2017-03-01
Our objective was to compare the change in research informed knowledge of health professionals and their intended practice following exposure to research information delivered by either Twitter or Facebook. This open label comparative design study randomized health professional clinicians to receive "practice points" on tendinopathy management via Twitter or Facebook. Evaluated outcomes included knowledge change and self-reported changes to clinical practice. Four hundred and ninety-four participants were randomized to 1 of 2 groups and 317 responders analyzed. Both groups demonstrated improvements in knowledge and reported changes to clinical practice. There was no statistical difference between groups for the outcomes of knowledge change (P = .728), changes to clinical practice (P = .11) or the increased use of research information (P = .89). Practice points were shared more by the Twitter group (P < .001); attrition was lower in the Facebook group (P < .001). Research information delivered by either Twitter or Facebook can improve clinician knowledge and promote behavior change. No differences in these outcomes were observed between the Twitter and Facebook groups. Brief social media posts are as effective as longer posts for improving knowledge and promoting behavior change. Twitter may be more useful in publicizing information and Facebook for encouraging course completion. © The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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VanEpps, Eric M; Roberto, Christina A
2016-11-01
California, New York, and the cities of San Francisco and Baltimore have introduced bills requiring health-related warning labels for sugar-sweetened beverages. This study measures the extent to which these warning labels influence adolescents' beliefs and hypothetical choices. Participants completed an online survey in which they chose a beverage in a hypothetical vending machine task, rated perceptions of different beverages, and indicated interest in coupons for beverages. Data were collected and analyzed in 2015. A total of 2,202 demographically diverse adolescents aged 12-18 years completed the online survey. Participants were randomly assigned to one of six conditions: (1) no warning label; (2) calorie label; (3-6) one of four text versions of a warning label (e.g. Drinking beverages with added sugar(s) contributes to obesity, diabetes, and tooth decay). Hypothetical choices, perceptions of beverages, interest in coupons, and endorsement of warning label policies were assessed. Controlling for frequency of beverage purchases, significantly fewer adolescents chose a sugar-sweetened beverage in three of the four warning label conditions (65%, 63%, and 61%) than in the no label (77%) condition. Adolescents in the four warning label conditions chose fewer sugar-sweetened beverage coupons and believed that sugar-sweetened beverages were less likely to help them lead a healthy life and had more added sugar compared with the no label condition. Health-related warning labels on sugar-sweetened beverages improved adolescents' recognition of the sugar content of such beverages and reduced hypothetical choices to buy sugar-sweetened beverages. Published by Elsevier Inc.
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Camenzind, Edoardo; Wijns, William; Mauri, Laura; Boersma, Eric; Parikh, Keyur; Kurowski, Volkhard; Gao, Runlin; Bode, Christoph; Greenwood, John P; Gershlick, Anthony; O'Neill, William; Serruys, Patrick W; Jorissen, Brenda; Steg, P Gabriel
2009-12-01
Drug-eluting stents (DES) reduce restenosis rates compared to bare-metal stents. Most trials using DES enrolled selected patient and lesion subtypes, and primary endpoint focused on angiographic metrics or relatively short-term outcomes. When DES are used in broader types of lesions and patients, important differences may emerge in long-term outcomes between stent types, particularly the incidence of late stent thrombosis. PROTECT is a randomized, open-label trial comparing the long-term safety of the zotarolimus-eluting stent and the sirolimus-eluting stent. The trial has enrolled 8,800 patients representative of those seen in routine clinical practice, undergoing elective, unplanned, or emergency procedures in native coronary arteries in 196 centers in 36 countries. Indications for the procedure and selection of target vessel and lesion characteristics were at the operator's discretion. Procedures could be staged, but no more than 4 target lesions could be treated per patient. Duration of dual antiplatelet therapy was prespecified to achieve similar lengths of treatment in both study arms. The shortest predefined duration was 3 months, as per the manufacturer's instructions. The primary outcome measure is the composite rate of definite and probable stent thrombosis at 3 years, centrally adjudicated using Academic Research Consortium definitions. The main secondary end points are 3-year all-cause mortality, cardiac death, large nonfatal myocardial infarction, and all myocardial infarctions. This large, international, randomized, controlled trial will provide important information on comparative rates of stent thrombosis between 2 different DES systems and safety as assessed by patient-relevant long-term clinical outcomes.
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Patil, Vijay Maruti; Noronha, Vanita; Joshi, Amit; Muddu, Vamshi Krishna; Dhumal, Sachin; Bhosale, Bharatsingh; Arya, Supreeta; Juvekar, Shashikant; Banavali, Shripad; D'Cruz, Anil; Bhattacharjee, Atanu; Prabhash, Kumar
2015-03-01
Cetuximab based treatment is the recommended chemotherapy for head and neck squamous cell cancers in the palliative setting. However, due to financial constraints, intravenous (IV) chemotherapy without cetuximab is commonly used in lesser developed countries. We believe that oral metronomic chemotherapy may be safer and more effective in this setting. We conducted an open label, superiority, parallel design, randomized phase II trial comparing oral MCT [daily celecoxib (200mg twice daily) and weekly methotrexate (15mg/m(2))] to intravenous single agent cisplatin (IP) (75mg/m(2)) given 3 weekly. Eligible patients had head and neck cancers requiring palliative chemotherapy with ECOG PS 0-2 and adequate organ functions who could not afford cetuximab. The primary end point was progression-free survival. 110 Patients were recruited between July 2011 to May 2013, 57 randomized to the MCT arm and 53 to the IP arm. Patients in the MCT arm had significantly longer PFS (median 101 days, 95% CI: 58.2-143.7 days) compared to the IP arm (median 66 days, 95% CI; 55.8-76.1 days) (p=0.014). The overall survival (OS) was also increased significantly in the MCT arm (median 249 days, 95% CI: 222.5-275.5 days) compared to the IP arm (median 152 days, 95% CI: 104.2-199.8 days) (p=0.02). There were fewer grade 3/4 adverse effects with MCT, which was not significant. (18.9% vs. 31.4%, P=0.14). Oral metronomic chemotherapy has significantly better PFS and OS than single agent platinum in the palliative setting. Copyright © 2014 Elsevier Ltd. All rights reserved.
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Enzyme replacement therapy of Fabry disease.
Clarke, Joe T R; Iwanochko, R Mark
2005-08-01
Fabry disease is an X-linked lysosomal storage disease caused by deficiency of the enzyme alpha-galactosidase A and results in pain, progressive renal impairment, cardiomyopathy, and cerebrovascular disease. The results of two major randomized, double-blind, placebo-controlled clinical trials and open-label extensions have shown that replacement of the deficient enzyme with either of two preparations of recombinant human alpha-galactosidase A, agalsidase-alfa, and agalsidase-beta is safe. Biweekly i.v. infusions of 0.2 mg/kg of agalsidase-alfa were associated with a significant decrease in pain and stabilization of renal function. Biweekly infusions of 1 mg/kg of agalsidase-beta were associated with virtually complete clearing of accumulated glycolipid substrate from renal and cutaneous capillary endothelial cells. Several smaller, open-label studies, along with observations made in the course of monitoring large numbers of patients on enzyme replacement therapy, indicated that treatment stabilizes renal function and produces significant improvements in myocardial mass and function. Treatment of Fabry disease by enzyme replacement has a significant impact on at least some serious complications of the disease.
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A case series on the effectiveness of lurasidone in patients with stuttering.
Charoensook, Janet; Maguire, Gerald A
2017-08-01
The prevalence of stuttering is approximately 1% of the population, affecting an estimated 3 million individuals in the United States. The dopamine hypothesis of stuttering explains that abnormally increased cerebral dopamine affects the balanced levels that maintain the basal ganglia circuits, which helps with timing cues in initiating speech. This is especially significant when considering treatment strategies. We report a reduction in stuttering with lurasidone, a potent D2 receptor antagonist with a relatively favorable adverse effects profile. We conducted a non-randomized, open-label study of lurasidone in patients with stuttering (N = 7). Patients self-reported stuttering severity, locus of control, and avoidance using the Subjective Screening of Stuttering (SSS) scale and were assessed with the Clinical Global Impression (CGI) Scale. We observed a notable, statistically significant improvement in all areas of stuttering, as rated by the SSS scale. According to the CGI-Improvement Scale, 2 patients were scored as "very much improved" and 5 were scored as "much improved." This open-label study of lurasidone in patients with stuttering showed improvement in subjective symptoms, in CGI scores, and on the SSS scale.
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Endrikat, Jan; Klipping, C; Cronin, M; Gerlinger, C; Ruebig, A; Schmidt, W; Düsterberg, B
2002-03-01
In this open label, randomized study we compared the influence of a dose-reduced oral contraceptive containing 20 microg ethinyl estradiol (EE) and 100 microg levonorgestrel (20 EE) with a reference preparation containing 30 microg EE and 150 microg levonorgestrel (30 EE) on hemostatic, lipids, and carbohydrate metabolism variables. Data from 48 volunteers were obtained. The direction of the change (increase or decrease) in most of the hemostatic variables were similar in both treatment groups. In particular, prothrombin fragment 1 + 2 increased during treatment, reaching a median percent change of 40% in the 20 EE group and of 17% in the 30 EE group after one year. D-Dimer fibrin split products remained virtually unchanged, with no change at Cycle 13. The median HDL2 cholesterol levels decreased by 26% in the 20 EE group and by 39.8% in 30 EE group (p = 0.0045 for group difference) after one year. The median one year change for LDL cholesterol was 3.23% in the 20 EE group, compared to 25% in the 30 EE group, for VLDL 11.1% compared to 38.8%, respectively, and for total triglycerides 10.0% compared to 37.5%, respectively. The median absolute change for the area under the curve (AUC)(0-3h) for glucose at treatment Cycle 13 was 41.25 mmol/L x min in the 20 EE group and 73.50 mmol/L x min in the 30 EE group. The AUC(0-3h) insulin at treatment Cycle 13 decreased in the 20 EE group by 1635.0 pmolL x min and increased in the 30 EE group by 11797.5 pmolL x min (p = 0.0491 for group difference). Both study treatments were safe and well tolerated by the volunteers. In conclusion, the balanced one-third dose reduction in this new oral contraceptive evoked similar effects on the hemostatic variables, but favorable results for the lipid and carbohydrate profiles.
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Randomized Controlled Trials to Define Viral Load Thresholds for Cytomegalovirus Pre-Emptive Therapy
Griffiths, Paul D.; Rothwell, Emily; Raza, Mohammed; Wilmore, Stephanie; Doyle, Tomas; Harber, Mark; O’Beirne, James; Mackinnon, Stephen; Jones, Gareth; Thorburn, Douglas; Mattes, Frank; Nebbia, Gaia; Atabani, Sowsan; Smith, Colette; Stanton, Anna; Emery, Vincent C.
2016-01-01
Background To help decide when to start and when to stop pre-emptive therapy for cytomegalovirus infection, we conducted two open-label randomized controlled trials in renal, liver and bone marrow transplant recipients in a single centre where pre-emptive therapy is indicated if viraemia exceeds 3000 genomes/ml (2520 IU/ml) of whole blood. Methods Patients with two consecutive viraemia episodes each below 3000 genomes/ml were randomized to continue monitoring or to immediate treatment (Part A). A separate group of patients with viral load greater than 3000 genomes/ml was randomized to stop pre-emptive therapy when two consecutive levels less than 200 genomes/ml (168 IU/ml) or less than 3000 genomes/ml were obtained (Part B). For both parts, the primary endpoint was the occurrence of a separate episode of viraemia requiring treatment because it was greater than 3000 genomes/ml. Results In Part A, the primary endpoint was not significantly different between the two arms; 18/32 (56%) in the monitor arm had viraemia greater than 3000 genomes/ml compared to 10/27 (37%) in the immediate treatment arm (p = 0.193). However, the time to developing an episode of viraemia greater than 3000 genomes/ml was significantly delayed among those randomized to immediate treatment (p = 0.022). In Part B, the primary endpoint was not significantly different between the two arms; 19/55 (35%) in the less than 200 genomes/ml arm subsequently had viraemia greater than 3000 genomes/ml compared to 23/51 (45%) among those randomized to stop treatment in the less than 3000 genomes/ml arm (p = 0.322). However, the duration of antiviral treatment was significantly shorter (p = 0.0012) in those randomized to stop treatment when viraemia was less than 3000 genomes/ml. Discussion The results illustrate that patients have continuing risks for CMV infection with limited time available for intervention. We see no need to alter current rules for stopping or starting pre-emptive therapy. PMID:27684379
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Waddington Cruz, Márcia; Amass, Leslie; Keohane, Denis; Schwartz, Jeffrey; Li, Huihua; Gundapaneni, Balarama
2016-09-01
Transthyretin hereditary amyloid polyneuropathy, also traditionally known as transthyretin familial amyloid polyneuropathy (ATTR-FAP), is a rare, relentless, fatal hereditary disorder. Tafamidis, an oral, non-NSAID, highly specific transthyretin stabilizer, demonstrated safety and efficacy in slowing neuropathy progression in early-stage ATTRV30M-FAP in a 1.5-year, randomized, double-blind, placebo-controlled trial, and 1-year open-label extension study, with a second long-term open-label extension study ongoing. Subgroup analysis of the effectiveness of tafamidis in the pivotal study and its open-label extensions revealed a relatively cohesive cohort of patients with mild neuropathy (i.e. Neuropathy Impairment Score for Lower Limbs [NIS-LL] ≤ 10) at the start of active treatment. Early treatment with tafamidis for up to 5.5 years (≥1 dose of tafamidis meglumine 20 mg once daily during the original trial or after switching from placebo in its extension) resulted in sustained delay in neurologic progression and long-term preservation of nutritional status in this cohort. Mean (95% CI) changes from baseline in NIS-LL and mBMI were 5.3 (1.6, 9.1) points and -7.8 (-44.3, 28.8) kg/m 2 × g/L at 5.5 years, respectively. No new safety issues or side effects were identified. These data represent the longest prospective evaluation of tafamidis to date, confirm a favorable safety profile, and underscore the long-term benefits of early intervention with tafamidis. ClincalTrials.gov Identifier: NCT00409175, NCT00791492, and NCT00925002.
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An open-label study of sodium oxybate in Spasmodic dysphonia.
Rumbach, Anna F; Blitzer, Andrew; Frucht, Steven J; Simonyan, Kristina
2017-06-01
Spasmodic dysphonia (SD) is a task-specific laryngeal dystonia that affects speech production. Co-occurring voice tremor (VT) often complicates the diagnosis and clinical management of SD. Treatment of SD and VT is largely limited to botulinum toxin injections into laryngeal musculature; other pharmacological options are not sufficiently developed. Open-label study. We conducted an open-label study in 23 SD and 22 SD/VT patients to examine the effects of sodium oxybate (Xyrem), an oral agent with therapeutic effects similar to those of alcohol in these patients. Blinded randomized analysis of voice and speech samples assessed symptom improvement before and after drug administration. Sodium oxybate significantly improved voice symptoms (P = .001) primarily by reducing the number of SD-characteristic voice breaks and severity of VT. Sodium oxybate further showed a trend for improving VT symptoms (P = .03) in a subset of patients who received successful botulinum toxin injections for the management of their SD symptoms. The drug's effects were observed approximately 30 to 40 minutes after its intake and lasted about 3.5 to 4 hours. Our study demonstrated that sodium oxybate reduced voice symptoms in 82.2% of alcohol-responsive SD patients both with and without co-occurring VT. Our findings suggest that the therapeutic mechanism of sodium oxybate in SD and SD/VT may be linked to that of alcohol, and as such, sodium oxybate might be beneficial for alcohol-responsive SD and SD/VT patients. 4 Laryngoscope, 127:1402-1407, 2017. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.
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MacGregor, E Anne; Pawsey, Stephen P; Campbell, John C; Hu, Xiaojun
2010-04-01
Triptans are a recommended first-line treatment for moderate to severe migraine. Using clinical trial data, we evaluated the safety and tolerability of frovatriptan as acute treatment (AT) and as short-term preventive (STP) therapy for menstrual migraine (MM). Data from 2 Phase III AT trials (AT1: randomized, placebo controlled, 1 attack; AT2: 12-months, noncomparative, open label) and 3 Phase IIIb STP trials in MM (MMP1 and MMP2: randomized, placebo controlled, double blind, 3 perimenstrual periods; MMP3: open label, noncomparative, 12 perimenstrual periods) were analyzed. In AT1, patients treated each attack with frovatriptan 2.5 mg, sumatriptan 100 mg, or placebo. In AT2, they used frovatriptan 2.5 mg. In MMP1 and MMP2, women administered frovatriptan 2.5 mg for 6 days during the perimenstrual period, taking a loading dose of 2 or 4 tablets on day 1, followed by once-daily or BID frovatriptan 2.5 mg, respectively; in MMP3, they used BID frovatriptan 2.5 mg. In AT1, which was previously published in part, group differences in adverse events (AEs) were analyzed using the Fisher exact test, and response rates were compared using logistic regression. Post hoc analyses of sustained pain-free status with no AEs (SNAE) and sustained pain response with no AEs (SPRNAE) were performed using a 2-sample test for equality of proportions without continuity correction. For AT2 and the STP studies, data were summarized using descriptive statistics. Results of individual safety analyses for the STP studies were previously reported; the present report includes new results from a pooled analysis of MMP1 and MMP2 and a new analysis of MMP3 in which AEs were coded using Medical Dictionary for Regulatory Activities version 8.0. AT1 included 1206 patients in the safety group; AT2 included 496. In the STP studies, safety data were collected for 1487 women. In AT1 and AT2, 85.6% and 88.3%, respectively, of enrolled patients were women. Overall, AEs were generally mild to moderate (AT studies: 82.3%-90.0%; STP studies: 78.9%89.5%). In AT1, 27.3% (131/480) of frovatriptan patients, 33.4% (161/482) of sumatriptan patients, and 14.8% (36/244) of placebo patients experienced an AE considered possibly or probably related to treatment (P < 0.001 for either drug vs placebo).There were no significant differences between frovatriptan and sumatriptan in SNAE at 4 to 24 hours or in SPRNAE at 2 to 24 hours or at 4 to 24 hours. In randomized, controlled STP trials for MM, AEs were reported by 57.8% (166/287, BID) and 63.4% (210/331, once daily) of frovatriptan users versus 62.8% (216/344) of placebo recipients. There were no consistent differences in AEs reported by patients with potential cardiovascular risk or in AEs related to the use of estrogencontaining contraceptives (ECCs). In randomized controlled trials and 12-month open-label studies, frovatriptan was well tolerated in these women during AT and STP therapy for MM. Subgroup analyses provide preliminary evidence of tolerability in women using ECCs and in women with comorbidities that do not contraindicate triptan use but may be suggestive of cardiovascular risk. 2010 Excerpta Medica Inc. All rights reserved.
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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.
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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.
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Meloni, Domenico
2015-05-28
The aim of the present survey was to investigate the correct enforcement of the Community rules on the labelling and marketing of bivalve and gastropod molluscs retailed in Sardinia, Italy between 2009 and 2013. A total of 1500 packages and labels for live bivalve and gastropod molluscs were considered. A total of 375 labels (25%) presented non-compliance concerning the wrong trade name and additional wrong or missing information. The highest percentage of anomalous labels has been detected in small-scale retail shops (35%) and open-air markets (25%) compared with the big retailing chains (20%). The 5% of packages were not in compliance with the European Community rules on packaging of bivalve and gastropod molluscs. The high percentage of non-compliance with the European regulations on labelling results is a strong limitation for the consumers and highlights the need to improve the control system about labelling of seafood products.
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Biaggioni, Italo; Freeman, Roy; Mathias, Christopher J; Low, Phillip; Hewitt, L Arthur; Kaufmann, Horacio
2015-01-01
We evaluated whether droxidopa, a prodrug converted to norepinephrine, is beneficial in the treatment of symptomatic neurogenic orthostatic hypotension, which results from failure to generate an appropriate norepinephrine response to postural challenge. Patients with symptomatic neurogenic orthostatic hypotension and Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa titration (100-600 mg, 3× daily). Responders then received an additional 7-day open-label treatment at their individualized dose. Patients were subsequently randomized to continue with droxidopa or withdraw to placebo for 14 days. We then assessed patient-reported scores on the Orthostatic Hypotension Questionnaire and blood pressure measurements. Mean worsening of Orthostatic Hypotension Questionnaire dizziness/lightheadedness score from randomization to end of study (the primary outcome; N=101) was 1.9±3.2 with placebo and 1.3±2.8 units with droxidopa (P=0.509). Four of the other 5 Orthostatic Hypotension Questionnaire symptom scores and all 4 symptom-impact scores favored droxidopa, with statistical significance for the patient's self-reported ability to perform activities requiring standing a short time (P=0.033) and standing a long time (P=0.028). Furthermore, a post hoc analysis of a predefined composite score of all symptoms (Orthostatic Hypotension Questionnaire composite) demonstrated a significant benefit for droxidopa (P=0.013). There was no significant difference between groups for standing systolic blood pressure (P=0.680). Droxidopa was well tolerated. In summary, this randomized withdrawal droxidopa study failed to meet its primary efficacy end point. Additional clinical trials are needed to confirm that droxidopa is beneficial in symptomatic neurogenic orthostatic hypotension, as suggested by the positive secondary outcomes of this trial. http://www.clinicaltrials.gov. Unique identifier: NCT00633880. © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wolters Kluwer.
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von Minckwitz, Gunter; Möbus, Volker; Schneeweiss, Andreas; Huober, Jens; Thomssen, Christoph; Untch, Michael; Jackisch, Christian; Diel, Ingo J; Elling, Dirk; Conrad, Bettina; Kreienberg, Rolf; Müller, Volkmar; Lück, Hans-Joachim; Bauerfeind, Ingo; Clemens, Michael; Schmidt, Marcus; Noeding, Stefanie; Forstbauer, Helmut; Barinoff, Jana; Belau, Antje; Nekljudova, Valentina; Harbeck, Nadia; Loibl, Sibylle
2013-10-01
Bisphosphonates prevent skeletal-related events in patients with metastatic breast cancer. Their effect in early breast cancer is controversial. Ibandronate is an orally and intravenously available amino-bisphosphonate with a favorable toxicity profile. It therefore qualifies as potential agent for adjuvant use. The GAIN (German Adjuvant Intergroup Node-Positive) study was an open-label, randomized, controlled phase III trial with a 2 × 2 factorial design. Patients with node-positive early breast cancer were randomly assigned 1:1 to two different dose-dense chemotherapy regimens and 2:1 to ibandronate 50 mg per day orally for 2 years or observation. In all, 2,640 patients and 728 events were estimated to be required to demonstrate an increase in disease-free survival (DFS) by ibandronate from 75% to 79.5% by using a two-sided α = .05 and 1-β of 80%. We report here the efficacy analysis for ibandronate, which was released by the independent data monitoring committee because the futility boundary was not crossed after 50% of the required DFS events were observed. Between June 2004 and August 2008, 2,015 patients were randomly assigned to ibandronate and 1,008 to observation. Patients randomly assigned to ibandronate showed no superior DFS or overall survival (OS) compared with patients randomly assigned to observation (DFS: hazard ratio, 0.945; 95% CI, 0.768 to 1.161; P = .589; OS: HR, 1.040; 95% CI, 0.763 to 1.419; P = .803). DFS was numerically longer if ibandronate was used in patients younger than 40 years or older than 60 years compared with patients age 40 to 59 years (test for interaction P = .093). Adjuvant treatment with oral ibandronate did not improve outcome of patients with high-risk early breast cancer who received dose-dense chemotherapy.
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Kröger, Nicolaus; Iacobelli, Simona; Franke, Georg-Nikolaus; Platzbecker, Uwe; Uddin, Ruzena; Hübel, Kai; Scheid, Christof; Weber, Thomas; Robin, Marie; Stelljes, Matthias; Afanasyev, Boris; Heim, Dominik; Deliliers, Giorgio Lambertenghi; Onida, Francesco; Dreger, Peter; Pini, Massimo; Guidi, Stefano; Volin, Liisa; Günther, Andreas; Bethge, Wolfgang; Poiré, Xavier; Kobbe, Guido; van Os, Marleen; Brand, Ronald; de Witte, Theo
2017-07-01
Purpose To compare a reduced-intensity conditioning regimen (RIC) with a myeloablative conditioning regimen (MAC) before allogeneic transplantation in patients with myelodysplastic syndrome (MDS) within a randomized trial. Patients and Methods Within the European Society of Blood and Marrow Transplantation, we conducted a prospective, multicenter, open-label, randomized phase III trial that compared a busulfan-based RIC with MAC in patients with MDS or secondary acute myeloid leukemia. A total of 129 patients were enrolled from 18 centers. Patients were randomly assigned in a 1:1 ratio and were stratified according to donor, age, and blast count. Results Engraftment was comparable between both groups. The CI of acute graft-versus-host disease II to IV was 32.3% after RIC and 37.5% after MAC ( P = .35). The CI of chronic graft-versus-host disease was 61.6% after RIC and 64.7% after MAC ( P = .76). The CI of nonrelapse mortality after 1 year was 17% (95% CI, 8% to 26%) after RIC and 25% (95% CI, 15% to 36%) after MAC ( P = .29). The CI of relapse at 2 years was 17% (95% CI, 8% to 26%) after RIC and 15% (95% CI, 6% to 24%) after MAC ( P = .6), which resulted in a 2-year relapse-free survival and overall survival of 62% (95% CI, 50% to 74%) and 76% (95% CI, 66% to 87%), respectively, after RIC, and 58% (95% CI, 46% to 71%) and 63% (95% CI, 51% to 75%), respectively, after MAC ( P = .58 and P = .08, respectively). Conclusion This prospective, randomized trial of the European Society of Blood and Marrow Transplantation provides evidence that RIC resulted in at least a 2-year relapse-free survival and overall survival similar to MAC in patients with MDS or secondary acute myeloid leukemia.
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Dupuy, Alain; Dunant, Ariane; Grob, Jean-Jacques
2005-08-01
High-protection sunscreens have been suspected to prompt people to increase sun exposure, and thus to increase skin cancer risk. We tested the influence of both the actual protection (sun protection factor [SPF]) and the information about protection (label) on sun-exposure behavior. Randomized controlled trial. Four French seaside resorts during summer 2001. A total of 367 healthy subjects during their 1-week holiday. Outcome was assessable in 98% of them. Subjects were offered free sunscreens, with randomization into the following study arms: (1) SPF 40 labeled as "high protection"; (2) SPF 40 labeled as "basic protection"; and (3) SPF 12 labeled as "basic protection." Arm 4, ie, SPF 12 labeled as "high protection," was not implemented for ethical reasons. Subjects were not aware of the real target of the study and were blinded to the SPF value. Duration of sunbathing exposure during 1 week. Secondary outcomes were occurrence of sunburns and amount of sunscreen used. Influences of SPF and label were assessed separately. Compared with the low-SPF group, the high-SPF group did not have longer sunbathing exposure (12.9 +/- 7.2 h/wk for high SPF vs 14.6 +/- 6.7 h/wk for low SPF; P = .06), experienced fewer sunburns (14% vs 24%; P = .049), and used less sunscreen (median, 30 g vs 109 g; P<.001). The label "high protection" or "basic protection" had no influence on these end points. In this adult population, higher SPF had no influence on duration of sun exposure and offered better protection against sunburns. Although higher SPF may increase sun exposure duration in specific populations, this effect cannot be viewed as a universal side effect of high-SPF sunscreens.
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Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity--an update.
Grunberg, Steven M; Osoba, David; Hesketh, Paul J; Gralla, Richard J; Borjeson, Sussanne; Rapoport, Bernardo L; du Bois, Andreas; Tonato, Maurizio
2005-02-01
Development of effective antiemetic therapy depends upon an understanding of both the antiemetic agents and the emetogenic challenges these agents are designed to address. New potential antiemetic agents should be studied in an orderly manner, proceeding from phase I to phase II open-label trials and then to randomized double-blind phase III trials comparing new agents and regimens to best standard therapy. Use of placebos in place of antiemetic therapy against highly or moderately emetogenic chemotherapy is unacceptable. Nausea and vomiting should be evaluated separately and for both the acute and delayed periods. Defining the emetogenicity of new antineoplastic agents is a challenge, since such data are often not reliably recorded during early drug development. A four-level classification system is proposed for emetogenicity of intravenous antineoplastic agents. A separate four-level classification system for emetogenicity of oral antineoplastic agents, which are often given over an extended period of time, is also proposed.
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NASA Astrophysics Data System (ADS)
Kyeyune-Nyombi, Eru; Morone, Flaviano; Liu, Wenwei; Li, Shuiqing; Gilchrist, M. Lane; Makse, Hernán A.
2018-01-01
Understanding the structural properties of random packings of jammed colloids requires an unprecedented high-resolution determination of the contact network providing mechanical stability to the packing. Here, we address the determination of the contact network by a novel strategy based on fluorophore signal exclusion of quantum dot nanoparticles from the contact points. We use fluorescence labeling schemes on particles inspired by biology and biointerface science in conjunction with fluorophore exclusion at the contact region. The method provides high-resolution contact network data that allows us to measure structural properties of the colloidal packing near marginal stability. We determine scaling laws of force distributions, soft modes, correlation functions, coordination number and free volume that define the universality class of jammed colloidal packings and can be compared with theoretical predictions. The contact detection method opens up further experimental testing at the interface of jamming and glass physics.
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Memantine in the Treatment of Executive Function Deficits in Adults With ADHD.
Biederman, Joseph; Fried, Ronna; Tarko, Laura; Surman, Craig; Spencer, Thomas; Pope, Amanda; Grossman, Rebecca; McDermott, Katie; Woodworth, K Yvonne; Faraone, Stephen V
2017-02-01
To evaluate the efficacy and safety of memantine hydrochloride as an adjunct to stimulant pharmacotherapy for treating executive function deficits (EFDs) in adults with ADHD. This was a 12-week, double-blind, placebo-controlled, randomized clinical trial of memantine added to open-label treatment with stimulant medication. Because of the small sample size, we considered a standardized mean difference (equivalent to effect size) of ≥0.5 and odds ratios ≥2 as indicators of trend improvements. Twelve participants received memantine and 14 received a placebo. Trend improvements favoring memantine were observed on Behavior Rating Inventory of Executive Functions-Adult Inhibition and Self-Monitor subscales when compared with Placebo. No significant changes were noted on the Cambridge Neuropsychological Test Automated Battery. Among adults with ADHD and EFDs, adjunct treatment with memantine to osmotic release oral system-methylphenidate (OROS-MPH) was associated with improvements in selective areas of executive functioning, supporting the need for further research.
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Bloom, R D; Trofe-Clark, J; Wiland, A; Alloway, R R
2013-01-01
An exploratory, post hoc analysis was performed using data from a prospective, multicenter, open-label, randomized, two-period (14 d per period), two-sequence, crossover, steady-state pharmacokinetic study comparing generic tacrolimus (Sandoz) vs. reference tacrolimus in stable renal transplant patients receiving their pre-study twice-daily dose. Pharmacokinetic parameters were compared in 68 patients according to gender, African American ethnicity, the presence or absence of diabetes, and use of steroids. The ratios of tacrolimus AUC0-12 h , Cmax , and C12 with generic vs. reference tacrolimus were calculated using the geometric mean (GM) of dose-normalized values at days 14 and 28. Mean (SD) tacrolimus dose at baseline was 5.7 (4.2) mg/d. There were no consistent differences in dose-normalized AUC0-12 h , C12 , Cmax, or tmax between the generic and reference preparations within subpopulations. The 90% confidence intervals (CI) for the ratios of dose-normalized AUC0-12 h and C12 with generic vs. reference tacrolimus were within 80-125% for all subpopulations, as were 90% CIs for Cmax other than for females, African Americans, and non-diabetics, which is not unexpected given the wide variability of tacrolimus Cmax and the small subpopulation sizes. These exploratory results suggest that this generic tacrolimus preparation would be expected to offer comparable bioavailability to the reference drug in these patient subpopulations. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Crowdsourcing reproducible seizure forecasting in human and canine epilepsy
Wagenaar, Joost; Abbot, Drew; Adkins, Phillip; Bosshard, Simone C.; Chen, Min; Tieng, Quang M.; He, Jialune; Muñoz-Almaraz, F. J.; Botella-Rocamora, Paloma; Pardo, Juan; Zamora-Martinez, Francisco; Hills, Michael; Wu, Wei; Korshunova, Iryna; Cukierski, Will; Vite, Charles; Patterson, Edward E.; Litt, Brian; Worrell, Gregory A.
2016-01-01
See Mormann and Andrzejak (doi:10.1093/brain/aww091) for a scientific commentary on this article. Accurate forecasting of epileptic seizures has the potential to transform clinical epilepsy care. However, progress toward reliable seizure forecasting has been hampered by lack of open access to long duration recordings with an adequate number of seizures for investigators to rigorously compare algorithms and results. A seizure forecasting competition was conducted on kaggle.com using open access chronic ambulatory intracranial electroencephalography from five canines with naturally occurring epilepsy and two humans undergoing prolonged wide bandwidth intracranial electroencephalographic monitoring. Data were provided to participants as 10-min interictal and preictal clips, with approximately half of the 60 GB data bundle labelled (interictal/preictal) for algorithm training and half unlabelled for evaluation. The contestants developed custom algorithms and uploaded their classifications (interictal/preictal) for the unknown testing data, and a randomly selected 40% of data segments were scored and results broadcasted on a public leader board. The contest ran from August to November 2014, and 654 participants submitted 17 856 classifications of the unlabelled test data. The top performing entry scored 0.84 area under the classification curve. Following the contest, additional held-out unlabelled data clips were provided to the top 10 participants and they submitted classifications for the new unseen data. The resulting area under the classification curves were well above chance forecasting, but did show a mean 6.54 ± 2.45% (min, max: 0.30, 20.2) decline in performance. The kaggle.com model using open access data and algorithms generated reproducible research that advanced seizure forecasting. The overall performance from multiple contestants on unseen data was better than a random predictor, and demonstrates the feasibility of seizure forecasting in canine and human epilepsy. PMID:27034258
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ERIC Educational Resources Information Center
Adler, Lenard A.; Spencer, Thomas J.; Williams, David W.; Moore, Rodney J.; Michelson, David
2008-01-01
Objective: Previously, data from 97 weeks of open-label atomoxetine treatment of adults with attention-deficit/hyperactivity disorder (ADHD) were reported. This final report of that study presents results from over 4 years of treatment. Method: Results were derived from the study of 384 patients (125 patients remaining in the open-label trial…
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Hoekman, Berend; Breitling, Rainer; Suits, Frank; Bischoff, Rainer; Horvatovich, Peter
2012-01-01
Data processing forms an integral part of biomarker discovery and contributes significantly to the ultimate result. To compare and evaluate various publicly available open source label-free data processing workflows, we developed msCompare, a modular framework that allows the arbitrary combination of different feature detection/quantification and alignment/matching algorithms in conjunction with a novel scoring method to evaluate their overall performance. We used msCompare to assess the performance of workflows built from modules of publicly available data processing packages such as SuperHirn, OpenMS, and MZmine and our in-house developed modules on peptide-spiked urine and trypsin-digested cerebrospinal fluid (CSF) samples. We found that the quality of results varied greatly among workflows, and interestingly, heterogeneous combinations of algorithms often performed better than the homogenous workflows. Our scoring method showed that the union of feature matrices of different workflows outperformed the original homogenous workflows in some cases. msCompare is open source software (https://trac.nbic.nl/mscompare), and we provide a web-based data processing service for our framework by integration into the Galaxy server of the Netherlands Bioinformatics Center (http://galaxy.nbic.nl/galaxy) to allow scientists to determine which combination of modules provides the most accurate processing for their particular LC-MS data sets. PMID:22318370
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DRY CUPPING IN CHILDREN WITH FUNCTIONAL CONSTIPATION: A RANDOMIZED OPEN LABEL CLINICAL TRIAL.
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.
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Impact of a soy drink on climacteric symptoms: an open-label, crossover, randomized clinical trial
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
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Zonisamide and renal calculi in patients with epilepsy: how big an issue?
Wroe, Stephen
2007-08-01
To determine the prevalence of renal calculi in patients treated with zonisamide during randomized, controlled and open-label clinical trials, and from post-marketing surveillance data. Reports of renal calculi from four placebo-controlled double-blind trials of zonisamide, their long-term open-label treatment extension phases, and the US/European zonisamide clinical trial programme were reviewed. One double-blind study and its extension included routine ultrasound screening to identify asymptomatic calculi. Post-marketing surveillance data were also investigated, as was concomitant treatment with topiramate. No symptomatic renal calculi were reported during four randomized double-blind, placebo-controlled trials involving 848 subjects (including 498 zonisamide recipients) treated for up to 3 months. In long-term extension studies with treatment for up to 24 months, symptomatic renal calculi were reported in 9/626 (1.4%) patients. Pooled safety data from all US/European clinical trials identified 15/1296 (1.2%) patients with symptomatic renal calculi during treatment for up to 8.7 years. Post-marketing surveillance revealed nine cases from 59 667 patient-years of exposure in the USA, and 14 from 709 294 patient-years of exposure in Japan; only one case occurred during concomitant topiramate and zonisamide treatment. No imbalance in electrolyte levels was found from 35 patients receiving such co-treatment in clinical trials. The available data suggest that the risk of developing renal calculi during zonisamide treatment is low. Data are insufficient to determine whether concomitant treatment with topiramate increases the risk of renal stones.
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Patel, C G; Kornhauser, D; Vachharajani, N; Komoroski, B; Brenner, E; Handschuh del Corral, M; Li, L; Boulton, D W
2011-07-01
To evaluate the pharmacokinetic interactions of the potent, selective, dipeptidyl peptidase-4 inhibitor, saxagliptin, in combination with metformin, glyburide or pioglitazone. To assess the effect of co-administration of saxagliptin with oral antidiabetic drugs (OADs) on the pharmacokinetics and tolerability of saxagliptin, 5-hydroxy saxagliptin, metformin, glyburide, pioglitazone and hydroxy-pioglitazone, analyses of variance were performed on maximum (peak) plasma drug concentration (C(max)), area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) [saxagliptin + metformin (study 1) and saxagliptin + glyburide (study 2)] and area under the concentration-time curve from time 0 to time t (AUC) [saxagliptin + pioglitazone (study 3)] for each analyte in the respective studies. Studies 1 and 2 were open-label, randomized, three-period, three-treatment, crossover studies, and study 3 was an open-label, non-randomized, sequential study in healthy subjects. Co-administration of saxagliptin with metformin, glyburide or pioglitazone did not result in clinically meaningful alterations in the pharmacokinetics of saxagliptin or its metabolite, 5-hydroxy saxagliptin. Following co-administration of saxagliptin, there were no clinically meaningful alterations in the pharmacokinetics of metformin, glyburide, pioglitazone or hydroxy-pioglitazone. Saxagliptin was generally safe and well tolerated when administered alone or in combination with metformin, glyburide or pioglitazone. Saxagliptin can be co-administered with metformin, glyburide or pioglitazone without a need for dose adjustment of either saxagliptin or these OADs. © 2011 Blackwell Publishing Ltd.
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Maat, Arija; Cahn, Wiepke; Gijsman, Harm J; Hovens, Johannes E; Kahn, René S; Aleman, André
2014-04-01
To date, only few studies have examined the impact of medication on social cognition and none have examined the effects of aripiprazole in this respect. The goal of this 8-week, randomized, multicenter, open-label study was to examine the effects of aripiprazole and risperidone on social cognition and neurocognition in individuals with schizophrenia. Eighty schizophrenia patients (DSM-IV-TR) aged 16-50 years were administered multiple computerized measures of social cognition and neurocognition including reaction times at baseline and the end of week 8. Social functioning was mapped with the Social Functioning scale and Quality of Life scale. The study ran from June 2005 to March 2011. Scores on social cognitive and neurocognitive tests improved with both treatments, as did reaction time. There were few differences between the two antipsychotics on (social) cognitive test-scores. The aripiprazole group performed better (more correct items) on symbol substitution (P=.003). Aripiprazole was also superior to risperidone on reaction time for emotional working memory and working memory (P=.006 and P=.023, respectively). Improvements on these tests were correlated with social functioning. In conclusion, aripiprazole and risperidone showed a similar impact on social cognitive test-scores. However, aripiprazole treatment produced a greater effect on patients' processing speed compared to risperidone, with these improvements being associated with concurrent improvements in social functioning. Further research on the long-term effects of aripiprazole on cognition is warranted. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.
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Hagiwara, Nobuhisa; Kawada-Watanabe, Erisa; Koyanagi, Ryo; Arashi, Hiroyuki; Yamaguchi, Junichi; Nakao, Koichi; Tobaru, Tetsuya; Tanaka, Hiroyuki; Oka, Toshiaki; Endoh, Yasuhiro; Saito, Katsumi; Uchida, Tatsuro; Matsui, Kunihiko; Ogawa, Hiroshi
2017-08-01
To elucidate the effects of intensive LDL-C lowering treatment with a standard dose of statin and ezetimibe in patients with dyslipidaemia and high risk of coronary events, targeting LDL-C less than 70 mg/dL (1.8 mmol/L), compared with standard LDL-C lowering lipid monotherapy targeting less than 100 mg/dL (2.6 mmol/L). The HIJ-PROPER study is a prospective, randomized, open-label trial to assess whether intensive LDL-C lowering with standard-dose pitavastatin plus ezetimibe reduces cardiovascular events more than standard LDL-C lowering with pitavastatin monotherapy in patients with acute coronary syndrome (ACS) and dyslipidaemia. Patients were randomized to intensive lowering (target LDL-C < 70 mg/dL [1.8 mmol/L]; pitavastatin plus ezetimibe) or standard lowering (target LDL-C 90 mg/dL to 100 mg/dL [2.3-2.6 mmol/L]; pitavastatin monotherapy). The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina, and ischaemia-driven revascularization. Between January 2010 and April 2013, 1734 patients were enroled at 19 hospitals in Japan. Patients were followed for at least 36 months. Median follow-up was 3.86 years. Mean follow-up LDL-C was 65.1 mg/dL (1.68 mmol/L) for pitavastatin plus ezetimibe and 84.6 mg/dL (2.19 mmol/L) for pitavastatin monotherapy. LDL-C lowering with statin plus ezetimibe did not reduce primary endpoint occurrence in comparison with standard statin monotherapy (283/864, 32.8% vs. 316/857, 36.9%; HR 0.89, 95% CI 0.76-1.04, P = 0.152). In, ACS patients with higher cholesterol absorption, represented by elevated pre-treatment sitosterol, was associated with significantly lower incidence of the primary endpoint in the statin plus ezetimibe group (HR 0.71, 95% CI 0.56-0.91). Although intensive lowering with standard pitavastatin plus ezetimibe showed no more cardiovascular benefit than standard pitavastatin monotherapy in ACS patients with dyslipidaemia, statin plus ezetimibe may be more effective than statin monotherapy in patients with higher cholesterol absorption; further confirmation is needed. UMIN000002742, registered as an International Standard Randomized Controlled Trial. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology
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Smith, Kimberly Y.; Tierney, Camlin; Mollan, Katie; Venuto, Charles S.; Budhathoki, Chakra; Ma, Qing; Morse, Gene D.; Sax, Paul; Katzenstein, David; Godfrey, Catherine; Fischl, Margaret; Daar, Eric S.; Collier, Ann C.; Bolivar, Hector H.; Navarro, Sandra; Koletar, Susan L.; Gochnour, Diane; Seefried, Edward; Hoffman, Julie; Feinberg, Judith; Saemann, Michelle; Patterson, Kristine; Pittard, Donna; Currin, David; Upton, Kerry; Saag, Michael; Ray, Graham; Johnson, Steven; Santos, Bartolo; Funk, Connie A.; Morgan, Michael; Jackson, Brenda; Tebas, Pablo; Thomas, Aleshia; Kim, Ge-Youl; Klebert, Michael K.; Santana, Jorge L.; Marrero, Santiago; Norris, Jane; Valle, Sandra; Cox, Gary Matthew; Silberman, Martha; Shaik, Sadia; Lopez, Ruben; Vasquez, Margie; Daskalakis, Demetre; Megill, Christina; Shore, Jessica; Taiwo, Babafemi; Goldman, Mitchell; Boston, Molly; Lennox, Jeffrey; del Rio, Carlos; Lane, Timothy W.; Epperson, Kim; Luetkemeyer, Annie; Payne, Mary; Gripshover, Barbara; Antosh, Dawn; Reid, Jane; Adams, Mary; Storey, Sheryl S.; Dunaway, Shelia B.; Gallant, Joel; Wiggins, Ilene; Smith, Kimberly Y.; Swiatek, Joan A.; Timpone, Joseph; Kumar, Princy; Moe, Ardis; Palmer, Maria; Gothing, Jon; Delaney, Joanne; Whitely, Kim; Anderson, Ann Marie; Hammer, Scott M.; Yin, Michael T.; Jain, Mamta; Petersen, Tianna; Corales, Roberto; Hurley, Christine; Henry, Keith; Bordenave, Bette; Youmans, Amanda; Albrecht, Mary; Pollard, Richard B.; Olusanya, Abimbola; Skolnik, Paul R.; Adams, Betsy; Tashima, Karen T.; Patterson, Helen; Ukwu, Michelle; Rogers, Lauren; Balfour, Henry H.; Fox, Kathy A.; Swindells, Susan; Van Meter, Frances; Robbins, Gregory; Burgett-Yandow, Nicole; Davis, Charles E.; Boyce, Colleen; O'Brien, William A.; Casey, Gerianne; Morse, Gene D.; Hsaio, Chiu-Bin; Meier, Jeffrey L.; Stapleton, Jack T.; Mildvan, Donna; Revuelta, Manuel; Currin, David; El Sadr, Wafaa; Loquere, Avelino; El-Daher, Nyef; Johnson, Tina; Gross, Robert; Maffei, Kathyrn; Hughes, Valery; Sturge, Glenn; McMahon, Deborah; Rutecki, Barbara; Wulfsohn, Michael; Cheng, Andrew; Dix, Lynn; Liao, Qiming
2014-01-01
Background. We aimed to evaluate treatment responses to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) in initial antiretroviral regimens among women and men, and determine if treatment outcomes differ by sex. Methods. We performed a randomized trial of open-label ATV/r or EFV combined with abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) in 1857 human immunodeficiency virus type 1–infected, treatment-naive persons enrolled between September 2005 and November 2007 at 59 sites in the United States and Puerto Rico. Associations of sex with 3 primary study endpoints of time to virologic failure, safety, and tolerability events were analyzed using Cox proportional hazards models. Model-based population pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM version VII). Results. Of 1857 participants, 322 were women. Women assigned to ATV/r had a higher risk of virologic failure with either nucleoside reverse transcriptase inhibitor backbone than women assigned to EFV, or men assigned to ATV/r. The effects of ATV/r and EFV upon safety and tolerability risk did not differ significantly by sex. With ABC/3TC, women had a significantly higher (32%) safety risk compared to men; with TDF/FTC, the safety risk was 20% larger for women compared to men, but not statistically significant. Women had slower ATV clearance and higher predose levels of ATV compared to men. Self-reported adherence did not differ significantly by sex. Conclusions. This is the first randomized clinical trial to identify a significantly earlier time to virologic failure in women randomized to ATV/r compared to women randomized to EFV. This finding has important clinical implications given that boosted protease inhibitors are often favored over EFV in women of childbearing potential. Clinical Trials Registration NCT00118898. PMID:24253247
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Rational dosages of nutrients have a prolonged effect on learning disabilities.
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.
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Seol, Young Mi; Kim, Hyo Jeong; Choi, Young Jin; Lee, Eun Mi; Kim, Yang Soo; Oh, Sung Yong; Koh, Su Jin; Baek, Jin Ho; Lee, Won Sik; Joo, Young Don; Lee, Hyun Gi; Yun, Eun Young; Chung, Joo Seop
2016-02-01
Palonosetron is the second-generation 5-hydroxytryptamine 3 receptor antagonist (5-HT3RA) that has shown better efficacy than the first-generation 5-HT3RA for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy (MEC). Granisetron transdermal delivery system (GTDS), a novel transdermal formulation, was developed to deliver granisetron continuously over 7 days. This study compared the efficacy and tolerability of the GTDS to palonosetron for the control of CINV following MEC. A total of 196 patients were randomized to GP or PG group. In this multicenter, randomized, open-label, cross-over, active-controlled, Phase IV study, GP group was assigned to receive transdermal granisetron (one GTDS patch, 7 days) in the first chemotherapy cycle, palonosetron (iv 0.25 mg/day, 1 days) in the second chemotherapy cycle before receiving MEC, and PG group was assigned to receive palonosetron in the first cycle and GTDS in the second cycle. Primary endpoint was the percentage of chemotherapy cycles achieving complete response (CR; defined as no emetic episodes and no rescue medication use) during the acute phase (0-24 h in post-chemotherapy; non-inferiority comparison with palonosetron). Total 333 cycles (165 in GTDS and 168 in palonosetron) were included in the per protocol analysis. The GTDS cycles showed non-inferiority to palonosetron cycles during the acute phase: CR was achieved by 124 (75.2 %) patients in the GTDS cycles and 134 (79.8 %) patients in the palonosetron cycles (treatment difference, -4.6 %; 95 % confidence interval, -13.6-4.4). There was no significant difference in CR rate during acute phase after the end of the first and second chemotherapy cycle between GP and PG group (p = 0.405, p = 0.074). Patients' satisfaction, assessed using Functional Living Index-Emesis (FLI-E), GTDS cycle were higher than those of palonosetron cycle in GP group (FLI-E score; median 1549.5 in GTDS cycle, median 1670.0 in palonosetron cycle). Both treatments were well tolerated and safe. Transdermal granisetron is a good alternative therapeutic option to palonosetron for preventing CINV after MEC.
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Ueda, Tamenobu; Kai, Hisashi; Imaizumi, Tsutomu
2012-07-01
The treatment of morning hypertension has not been established. We compared the efficacy and safety of a losartan/hydrochlorothiazide (HCTZ) combination and high-dose losartan in patients with morning hypertension. A prospective, randomized, open-labeled, parallel-group, multicenter trial enrolled 216 treated outpatients with morning hypertension evaluated by home blood pressure (BP) self-measurement. Patients were randomly assigned to receive a combination therapy of 50 mg losartan and 12.5 mg HCTZ (n=109) or a high-dose therapy with 100 mg losartan (n=107), each of which were administered once every morning. Primary efficacy end points were morning systolic BP (SBP) level and target BP achievement rate after 3 months of treatment. At baseline, BP levels were similar between the two therapy groups. Morning SBP was reduced from 150.3±10.1 to 131.5±11.5 mm Hg by combination therapy (P<0.001) and from 151.0±9.3 to 142.5±13.6 mm Hg by high-dose therapy (P<0.001). The morning SBP reduction was greater in the combination therapy group than in the high-dose therapy group (P<0.001). Combination therapy decreased evening SBP from 141.6±13.3 to 125.3±13.1 mm Hg (P<0.001), and high-dose therapy decreased evening SBP from 138.9±9.9 to 131.4±13.2 mm Hg (P<0.01). Although both therapies improved target BP achievement rates in the morning and evening (P<0.001 for both), combination therapy increased the achievement rates more than high-dose therapy (P<0.001 and P<0.05, respectively). In clinic measurements, combination therapy was superior to high-dose therapy in reducing SBP and improving the achievement rate (P<0.001 and P<0.01, respectively). Combination therapy decreased urine albumin excretion (P<0.05) whereas high-dose therapy reduced serum uric acid. Both therapies indicated strong adherence and few adverse effects (P<0.001). In conclusion, losartan/HCTZ combination therapy was more effective for controlling morning hypertension and reducing urine albumin than high-dose losartan.
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Hammerness, Paul; Petty, Carter; Faraone, Stephen V; Biederman, Joseph
2017-01-01
The purpose of this study was to examine the impact of stimulant treatment on risk for alcohol and illicit drug use in adolescents with ADHD. Analysis of data derived from a prospective open-label treatment study of adolescent ADHD ( n = 115, 76% male), and a historical, naturalistic sample of ADHD ( n = 44, 68% male) and non-ADHD youth ( n = 52, 73% male) of similar age and sex. Treatment consisted of extended-release methylphenidate in the clinical trial or naturalistic stimulant treatment. Self-report of alcohol and drug use was derived from a modified version of the Drug Use Screening Inventory. Rates of alcohol and drug use in the past year were significantly lower in the clinical trial compared with untreated and treated naturalistic ADHD comparators, and similar to rates in non-ADHD comparators. Well-monitored stimulant treatment may reduce the risk for alcohol and substance use in adolescent ADHD.
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Thyssen, An; Solanki, Bhavna; Treem, William
2012-07-01
A sprinkle capsule formulation containing enteric-coated, delayed-release rabeprazole granules is being developed for the treatment of children with gastrointestinal reflux disease. The granules are designed to be mixed with vehicles that facilitate delivery to children, who may be unable to swallow solid formulations. The primary objective of this study-conducted on the sponsor's initiative-was to compare the bioavailability of rabeprazole granules when mixed with various dosing vehicles (small amount of soft food or infant formula) with that of a rabeprazole suspension with inactive vehicle granules (reference), to determine which dosing vehicle can be used to deliver rabeprazole in children. Tolerability was also assessed. This single-center, single-dose, randomized, open-label, 5-period crossover study was conducted in 35 healthy adult subjects. In a randomized sequence, fasting subjects received a single dose of 10-mg rabeprazole granules per treatment period, mixed with small amounts of 1 of 5 dosing vehicles (a strawberry-flavored suspension of rabeprazole granules with inactive vehicle granules reconstituted with water, yogurt [1 tablespoon], applesauce [1 tablespoon], or infant formula [5 mL], or a suspension of rabeprazole granules with inactive vehicle tablet reconstituted with water). Full plasma pharmacokinetic (PK) profiles of rabeprazole and its thioether metabolite were collected; concentrations were estimated via LC-MS/MS. PK properties were estimated using noncompartmental methods; 90% CIs around least squares mean test-to-reference ratios were calculated for C(max) and AUC values. All treatment-emergent adverse events (TEAEs) were recorded and assessed for severity (mild, moderate, or severe) and relationship to study drug. A total of 35 subjects were enrolled (mean age, 38 years; 54.3% female; 100% white; mean weight, 71.4 kg). Thirty-four subjects completed the study. Rabeprazole and rabeprazole thioether plasma PK properties were comparable between all of the dosing vehicles tested. Median T(max) was 2.5 to 3.0 hours, and mean elimination half-life was 1.27 to 1.43 hours. The 90%CIs for the least squares mean ratios for rabeprazole and rabeprazole thioether exposure were within the 80% to 125% bioequivalence limits for all relevant comparisons. All TEAEs were of mild or moderate intensity, with headache being the most commonly reported; 21 subjects (60%) experienced TEAEs during the study. No deaths or serious AEs were reported during the study; 1 subject experienced a TEAE (urinary tract infection) that led to the discontinuation of treatment. In these healthy adult subjects, the bioavailability of rabeprazole granules was comparable between all of the dosing vehicles tested, and rabeprazole was well tolerated. Soft food suitable for young children or infant formula may be appropriate for use as dosing vehicles for rabeprazole granules. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.
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Devarajan, T V; Venkataraman, S; Kandasamy, Narayanan; Oomman, Abraham; Boorugu, Hari Kishan; Karuppiah, S K P; Balat, Dushyant
2017-01-01
Modern sulfonylureas like glimepiride offer effective glycemic control with extrapancreatic benefits and good tolerability. The objective of the present study was to evaluate and compare safety and efficacy of glimepiride and sitagliptin in combination with metformin in patients with type 2 diabetes mellitus (T2DM). In this open-label, randomized, comparative, multicenter study, a total of 305 T2DM patients who were either drug naïve or uncontrolled on metformin were randomized to glimepiride 1 or 2 mg/sustained-release metformin 1000 mg once daily (glimepiride group, n = 202) or sitagliptin 50 mg/metformin 500 mg twice daily (sitagliptin group, n = 103) for 12 weeks. Primary endpoint was change in glycosylated hemoglobin (HbA1c). Secondary endpoints were change in fasting plasma glucose (FPG), postprandial plasma glucose (PPG), body mass index (BMI) and to assess overall safety profile. At 12 weeks, there was a statistically significant difference in the mean HbA1c reduction in glimepiride group (0.42%) as compared to sitagliptin group (0.30%) ( P = 0.001). Mean reduction in FPG and PPG was also statistically significant in the glimepiride group as compared to the sitagliptin group ( P = 0.008). There was no significant difference in terms of change in BMI (0.07 ± 0.39 kg/m 2 vs. 0.08 ± 0.31 kg/m 2 ) in glimepiride and sitagliptin groups, respectively, ( P = 0.644) between both the groups. The incidences of hypoglycemic events were also comparable among both the groups. In T2DM patients, glimepiride/metformin combination exhibited significant reduction in glycemic parameters as compared to sitagliptin/metformin combination. Moreover, there was no significant difference between both the groups in terms of change in BMI and incidence of hypoglycemia.
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Cicero, Arrigo F G; Derosa, Giuseppe; Manca, Marco; Bove, Marilisa; Borghi, Claudio; Gaddi, Antonio V
2007-08-01
In the setting of a six-month, open-label clinical trial, 141 consecutively enrolled, hypertensive, overweight patients were randomized to the oral ingestion of psyllium powder or guar gum 3.5 gr t.i.d., to be taken 20 min before the main two meals, or to standard diet. Both fibers improved significantly BMI, FPG, FPI, HOMA Index, HbA1c, LDL-C, and ApoB. Psyllium supplementation only exerted a significant improvement in plasma TG concentration, in SBP and DBP. In our study, six-month supplementation with psyllium fiber, but not with guar fiber nor standard diet, appears to significantly reduce both SBP and DBP in hypertensive overweight subjects.
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Franckle, Rebecca L; Levy, Douglas E; Macias-Navarro, Lorena; Rimm, Eric B; Thorndike, Anne N
2018-06-01
The objective of the present study was to test the effectiveness of financial incentives and traffic-light labels to reduce purchases of sugar-sweetened beverages in a community supermarket. In this randomized controlled trial, after a 2-month baseline period (February-March 2014), in-store traffic-light labels were posted to indicate healthy (green), less healthy (yellow) or unhealthy (red) beverages. During the subsequent five months (April-August 2014), participants in the intervention arm were eligible to earn a $US 25 in-store gift card each month they refrained from purchasing red-labelled beverages. Urban supermarket in Chelsea, MA, USA, a low-income Latino community. Participants were customers of this supermarket who had at least one child living at home. A total of 148 customers (n 77 in the intervention group and n 71 in the control group) were included in the final analyses. Outcomes were monthly in-store purchases tracked using a store loyalty card and self-reported consumption of red-labelled beverages. Compared with control participants, the proportion of intervention participants who purchased any red-labelled beverages decreased by 9 % more per month (P=0·002). More intervention than control participants reduced their consumption of red-labelled beverages (-23 % v. -2 % for consuming ≥1 red beverage/week, P=0·01). Overall, financial incentives paired with in-store traffic-light labels modestly reduced purchase and consumption of sugar-sweetened beverages by customers of a community supermarket.
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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
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Navani, Neal; Nankivell, Matthew; Lawrence, David R; Lock, Sara; Makker, Himender; Baldwin, David R; Stephens, Richard J; Parmar, Mahesh K; Spiro, Stephen G; Morris, Stephen; Janes, Sam M
2015-01-01
Summary Background The diagnosis and staging of lung cancer is an important process that identifies treatment options and guides disease prognosis. We aimed to assess endobronchial ultrasound-guided transbronchial needle aspiration as an initial investigation technique for patients with suspected lung cancer. Methods In this open-label, multicentre, pragmatic, randomised controlled trial, we recruited patients who had undergone a CT scan and had suspected stage I to IIIA lung cancer, from six UK centres and randomly assigned them to either endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) or conventional diagnosis and staging (CDS), for further investigation and staging. If a target node could not be accessed by EBUS-TBNA, then endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was allowed as an alternative procedure. Randomisation was stratified according to the presence of mediastinal lymph nodes measuring 1 cm or more in the short axis and by recruiting centre. We used a telephone randomisation method with permuted blocks of four generated by a computer. Because of the nature of the intervention, masking of participants and consenting investigators was not possible. The primary endpoint was the time-to-treatment decision after completion of the diagnostic and staging investigations and analysis was by intention-to-diagnose. This trial is registered with ClinicalTrials.gov, number NCT00652769. Findings Between June 10, 2008, and July 4, 2011, we randomly allocated 133 patients to treatment: 66 to EBUS-TBNA and 67 to CDS (one later withdrew consent). Two patients from the EBUS-TBNA group underwent EUS-FNA. The median time to treatment decision was shorter with EBUS-TBNA (14 days; 95% CI 14–15) than with CDS (29 days; 23–35) resulting in a hazard ratio of 1·98, (1·39–2·82, p<0·0001). One patient in each group had a pneumothorax from a CT-guided biopsy sample; the patient from the CDS group needed intercostal drainage and was admitted to hospital. Interpretation Transbronchial needle aspiration guided by endobronchial ultrasound should be considered as the initial investigation for patients with suspected lung cancer, because it reduces the time to treatment decision compared with conventional diagnosis and staging techniques. Funding UK Medical Research Council. PMID:25660225
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Lal, Himal; Poder, Airi; Campora, Laura; Geeraerts, Brecht; Oostvogels, Lidia; Vanden Abeele, Carline; Heineman, Thomas C
2018-01-02
In phase III trials, 2 doses of a herpes zoster (HZ) subunit vaccine (HZ/su; 50 µg varicella-zoster virus glycoprotein E [gE] and AS01 B Adjuvant System) administered 2-months apart in older adults (≥50 and ≥70 years) demonstrated >90% efficacy in preventing HZ and had a clinically acceptable safety profile. Here we report immunogenicity, reactogenicity and safety following administration of 2 HZ/su doses at intervals longer than 2 months. In this Phase III, open-label trial conducted in the US and Estonia, 354 adults ≥50 years were randomized 1:1:1 to receive 2 HZ/su doses 2, 6, or 12 months apart. gE-specific humoral immune responses were evaluated at pre-vaccination, 1 and 12 months post-dose 2. Co-primary objectives were to compare immune responses to HZ/su 1 month post-dose 2 when given 6-months or 12-months apart to those administered 2-months apart. For each participant, safety information was collected from dose 1 to 12 months post-dose 2. 346 participants completed the study and 343 were included in the according-to-protocol cohort for immunogenicity. One month post-dose 2, vaccine response rates were 96.5% (97.5% confidence interval [CI]: 90.4; 99.2) and 94.5% (97.5% CI: 87.6; 98.3) for the 0, 6- and 0, 12-month schedules, respectively, both schedules meeting the pre-defined criterion. Non-inferiority of anti-gE geometric mean concentrations was demonstrated for HZ/su administered on 0, 6-month compared to a 0, 2-month schedule; however, HZ/su administered on a 0, 12-month schedule did not meet the non-inferiority criterion. Injection site pain was the most commonly reported solicited adverse event (AE). 26 participants each reported at least 1 serious AE; none were assessed as related to vaccination. Immune responses to HZ/su administered at 0, 6-month were non-inferior to those elicited by a 0, 2-month schedule. HZ/su exhibited a clinically acceptable safety profile for all dosing intervals. Clinicaltrials.gov (NCT01751165). Copyright © 2017. Published by Elsevier Ltd.
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Ease of use and patient preference injection simulation study comparing two prefilled insulin pens.
Clark, Paula E; Valentine, Virginia; Bodie, Jennifer N; Sarwat, Samiha
2010-07-01
To determine patient ease of use and preference for the Humalog KwikPen* (prefilled insulin lispro [Humalog dagger] pen, Eli Lilly and Company, Indianapolis, IN, USA) (insulin lispro pen) versus the Next Generation FlexPen double dagger (prefilled insulin aspart [NovoRapid section sign ] pen, Novo Nordisk A/S, Bagsvaerd, Denmark) (insulin aspart pen). This was a randomized, open-label, 2-period, 8-sequence crossover study in insulin pen-naïve patients with diabetes. Randomized patients (N = 367) received device training, then simulated low- (15 U) and high- (60 U) dose insulin injections with an appliance. Patients rated pens using an ease of use questionnaire and were asked separately for final pen preferences. The Insulin Device 'Ease of Use' Battery is a 10-item questionnaire with a 7-point scale (higher scores reflect greater ease of use). The primary objective was to determine pen preference for 'easy to press to inject my dose' (by comparing composite scores [low- plus high-dose]). Secondary objectives were to determine pen preference on select questionnaire items (from composite scores), final pen preference, and summary responses for all questionnaire items. On the primary endpoint, 'easy to press to inject my dose,' a statistically significant majority of patients with a preference chose the insulin lispro pen over the insulin aspart pen (68.4%, 95% CI = 62.7-73.6%). Statistically significant majorities of patients with a preference also favored the insulin lispro pen on secondary items: 'easy to hold in my hand when I inject' (64.9%, 95% CI = 58.8-70.7%), 'easy to use when I am in a public place' (67.5%, 95% CI = 61.0-73.6%), and 'overall easy to use' (69.9%, 95% CI = 63.9-75.4%). A statistically significant majority of patients had a final preference for the insulin lispro pen (67.3%, 95% CI = 62.2-72.1%). Among pen-naïve patients with diabetes who had a preference, the majority preferred the insulin lispro pen over the insulin aspart pen with regard to ease of use. Study limitations included open-label design and injection simulation, use of an unvalidated questionnaire, and enrollment of mostly insulin-naïve patients.
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Klipping, Christine; Marr, Joachim
2005-06-01
To compare the effect of ethinyl estradiol 20 microg/drospirenone 3 mg (EE 20 microg/DRSP 3 mg) administered according to a 24/4 regimen with ethinyl estradiol 20 microg/desogestrel 150 microg (EE 20 microg/DSG 150 microg) administered according to the conventional 21/7 regimen on lipid, carbohydrate and hemostatic parameters. In this open-label study, healthy women were randomized to EE 20 microg/DRSP 3 mg or EE 20 microg/DSG 150 microg for seven cycles. Mean differences in high-density lipoprotein (HDL)- and low-density lipoprotein (LDL)-cholesterol levels at cycle 7 compared to baseline were assessed. Secondary variables included changes in other lipid, hemostatic and carbohydrate parameters. Both treatments increased HDL-cholesterol, but decreased LDL-cholesterol by a comparable extent. Although slightly elevated in both groups, blood glucose and C-peptide levels measured during oral glucose tolerance tests were within normal reference ranges at cycle 7. Overall, the differences in lipid, hemostatic or carbohydrate parameters were not significant between the two treatments. EE 20 microg/DRSP 3 mg has a good safety profile comparable with EE 20 microg/DSG 150 microg.
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Bruins Slot, Karsten Mh; Berge, Eivind
2018-03-06
Factor Xa inhibitors and vitamin K antagonists (VKAs) are now recommended in treatment guidelines for preventing stroke and systemic embolic events in people with atrial fibrillation (AF). This is an update of a Cochrane review previously published in 2013. To assess the effectiveness and safety of treatment with factor Xa inhibitors versus VKAs for preventing cerebral or systemic embolic events in people with AF. We searched the trials registers of the Cochrane Stroke Group and the Cochrane Heart Group (September 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (August 2017), MEDLINE (1950 to April 2017), and Embase (1980 to April 2017). We also contacted pharmaceutical companies, authors and sponsors of relevant published trials. We used outcome data from marketing authorisation applications of apixaban, edoxaban and rivaroxaban that were submitted to regulatory authorities in Europe and the USA. We included randomised controlled trials (RCTs) that directly compared the effects of long-term treatment (lasting more than four weeks) with factor Xa inhibitors versus VKAs for preventing cerebral and systemic embolism in people with AF. The primary efficacy outcome was the composite endpoint of all strokes and systemic embolic events. Two review authors independently extracted data, and assessed the quality of the trials and the risk of bias. We calculated a weighted estimate of the typical treatment effect across trials using the odds ratio (OR) with 95% confidence interval (CI) by means of a fixed-effect model. In case of moderate or high heterogeneity of treatment effects, we used a random-effects model to compare the overall treatment effects. We also performed a pre-specified sensitivity analysis excluding any open-label studies. We included data from 67,688 participants randomised into 13 RCTs. The included trials directly compared dose-adjusted warfarin with either apixaban, betrixaban, darexaban, edoxaban, idraparinux, idrabiotaparinux, or rivaroxaban. The majority of the included data (approximately 90%) was from apixaban, edoxaban, and rivaroxaban.The composite primary efficacy endpoint of all strokes (both ischaemic and haemorrhagic) and non-central nervous systemic embolic events was reported in all of the included studies. Treatment with a factor Xa inhibitor significantly decreased the number of strokes and systemic embolic events compared with dose-adjusted warfarin in participants with AF (OR 0.89, 95% CI 0.82 to 0.97; 13 studies; 67,477 participants; high-quality evidence).Treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.78, 95% CI 0.73 to 0.84; 13 studies; 67,396 participants; moderate-quality evidence). There was, however, statistically significant and high heterogeneity (I 2 = 83%). When we repeated this analysis using a random-effects model, it did not show a statistically significant decrease in the number of major bleedings (OR 0.88, 95% CI 0.66 to 1.17). A pre-specified sensitivity analysis excluding all open-label studies showed that treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.75, 95% CI 0.69 to 0.81), but high heterogeneity was also observed in this analysis (I 2 = 72%). The same sensitivity analysis using a random-effects model also showed a statistically significant decrease in the number of major bleedings in participants treated with factor Xa inhibitors (OR 0.76, 95% CI 0.60 to 0.96).Treatment with a factor Xa inhibitor significantly reduced the risk of intracranial haemorrhages (ICHs) compared with warfarin (OR 0.50, 95% CI 0.42 to 0.59; 12 studies; 66,259 participants; high-quality evidence). We observed moderate, but statistically significant heterogeneity (I 2 = 55%). The pre-specified sensitivity analysis excluding open-label studies showed that treatment with a factor Xa inhibitor significantly reduced the number of ICHs compared with warfarin (OR 0.47, 95% CI 0.40 to 0.56), with low, non-statistically significant heterogeneity (I 2 = 27%).Treatment with a factor Xa inhibitor also significantly reduced the number of all-cause deaths compared with warfarin (OR 0.89, 95% 0.83 to 0.95; 10 studies; 65,624 participants; moderate-quality evidence). Treatment with factor Xa inhibitors significantly reduced the number of strokes and systemic embolic events compared with warfarin in people with AF. The absolute effect of factor Xa inhibitors compared with warfarin treatment was, however, rather small. Factor Xa inhibitors also reduced the number of ICHs, all-cause deaths and major bleedings compared with warfarin, although the evidence for a reduction in the latter is less robust.
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Ilowite, Norman T.; Prather, Kristi; Lokhnygina, Yuliya; Schanberg, Laura E.; Elder, Melissa; Milojevic, Diana; Verbsky, James W.; Spalding, Steven J.; Kimura, Yukiko; Imundo, Lisa F.; Punaro, Marilynn G.; Sherry, David D.; Tarvin, Stacey E.; Zemel, Lawrence S.; Birmingham, James D.; Gottlieb, Beth S.; Miller, Michael L.; O'Neil, Kathleen; Ruth, Natasha M.; Wallace, Carol A.; Singer, Nora G.; Sandborg, Christy I.
2015-01-01
Background Interleukin-1 plays a pivotal role in in the pathogenesis of systemic juvenile idiopathic arthritis (sJIA). We assessed the efficacy and safety of rilonacept (IL-1 trap), an IL-1 inhibitor, in a randomized, double-blind, placebo-controlled trial. Methods An initial 4-week double-blind placebo phase was incorporated into a 24-week randomized multi-center design, followed by an open label phase. We randomized 71 children with at least 2 active joints 1:1 to 2 arms of the study. Patients in the rilonacept arm received rilonacept (4.4mg/kg loading dose followed by 2.2mg/kg weekly, subcutaneously) from day 0; patients in the placebo arm received placebo for 4 weeks followed by a loading dose of rilonacept at week 4 followed by weekly maintenance doses. The primary endpoint was time to response, using adapted JIA ACR30 response criteria coupled with absence of fever and taper of systemic corticosteroids using pre-specified criteria. Results Time to response was shorter in the rilonacept arm than in the placebo arm (Chi-square 7.235, P=.007). Secondary analysis showed 20/35 (57%) of patients in the rilonacept arm responded at week 4 compared to 9/33 (27%) in the placebo arm (P=.016) using the same response criteria. Exacerbation of sJIA (4) was the most common SAE. More patients in the rilonacept arm had elevated liver transaminases, including more than three times the upper limits of normal, as compared to those in the placebo arm. Adverse events were similar in the two arms of the study. Conclusions Rilonacept was generally well tolerated and demonstrated efficacy in active sJIA. PMID:24839206
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Battelino, Tadej; Nimri, Revital; Dovc, Klemen; Phillip, Moshe; Bratina, Natasa
2017-06-01
To investigate whether predictive low glucose management (PLGM) of the MiniMed 640G system significantly reduces the rate of hypoglycemia compared with the sensor-augmented insulin pump in children with type 1 diabetes. This randomized, two-arm, parallel, controlled, two-center open-label study included 100 children and adolescents with type 1 diabetes and glycated hemoglobin A 1c ≤10% (≤86 mmol/mol) and using continuous subcutaneous insulin infusion. Patients were randomly assigned to either an intervention group with PLGM features enabled (PLGM ON) or a control group (PLGM OFF), in a 1:1 ratio, all using the same type of sensor-augmented insulin pump. The primary end point was the number of hypoglycemic events below 65 mg/dL (3.6 mmol/L), based on sensor glucose readings, during a 14-day study treatment. The analysis was performed by intention to treat for all randomized patients. The number of hypoglycemic events below 65 mg/dL (3.6 mmol/L) was significantly smaller in the PLGM ON compared with the PLGM OFF group (mean ± SD 4.4 ± 4.5 and 7.4 ± 6.3, respectively; P = 0.008). This was also true when calculated separately for night ( P = 0.025) and day ( P = 0.022). No severe hypoglycemic events occurred; however, there was a significant increase in time spent above 140 mg/dL (7.8 mmol/L) in the PLGM ON group ( P = 0.0165). The PLGM insulin suspension was associated with a significantly reduced number of hypoglycemic events. Although this was achieved at the expense of increased time in moderate hyperglycemia, there were no serious adverse effects in young patients with type 1 diabetes. © 2017 by the American Diabetes Association.
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Schädler, Dirk; Pausch, Christine; Heise, Daniel; Meier-Hellmann, Andreas; Brederlau, Jörg; Weiler, Norbert; Marx, Gernot; Putensen, Christian; Spies, Claudia; Jörres, Achim; Quintel, Michael; Engel, Christoph; Kellum, John A; Kuhlmann, Martin K
2017-01-01
We report on the effect of hemoadsorption therapy to reduce cytokines in septic patients with respiratory failure. This was a randomized, controlled, open-label, multicenter trial. Mechanically ventilated patients with severe sepsis or septic shock and acute lung injury or acute respiratory distress syndrome were eligible for study inclusion. Patients were randomly assigned to either therapy with CytoSorb hemoperfusion for 6 hours per day for up to 7 consecutive days (treatment), or no hemoperfusion (control). Primary outcome was change in normalized IL-6-serum concentrations during study day 1 and 7. 97 of the 100 randomized patients were analyzed. We were not able to detect differences in systemic plasma IL-6 levels between the two groups (n = 75; p = 0.15). Significant IL-6 elimination, averaging between 5 and 18% per blood pass throughout the entire treatment period was recorded. In the unadjusted analysis, 60-day-mortality was significantly higher in the treatment group (44.7%) compared to the control group (26.0%; p = 0.039). The proportion of patients receiving renal replacement therapy at the time of enrollment was higher in the treatment group (31.9%) when compared to the control group (16.3%). After adjustment for patient morbidity and baseline imbalances, no association of hemoperfusion with mortality was found (p = 0.19). In this patient population with predominantly septic shock and multiple organ failure, hemoadsorption removed IL-6 but this did not lead to lower plasma IL-6-levels. We did not detect statistically significant differences in the secondary outcomes multiple organ dysfunction score, ventilation time and time course of oxygenation.
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Chi, Chia-Yu; Khanh, Truong Huu; Thoa, Le Phan Kim; Tseng, Fan-Chen; Wang, Shih-Min; Thinh, Le Quoc; Lin, Chia-Chun; Wu, Han-Chieh; Wang, Jen-Ren; Hung, Nguyen Thanh; Thuong, Tang Chi; Chang, Chung-Ming; Su, Ih-Jen; Liu, Ching-Chuan
2013-07-01
Enterovirus 71-induced brainstem encephalitis with pulmonary edema and/or neurogenic shock (stage 3B) is associated with rapid mortality in children. In a small pilot study, we found that milrinone reduced early mortality compared with historical controls. This prospective, randomized control trial was designed to provide more definitive evidence of the ability of milrinone to reduce the 1-week mortality of stage 3B enterovirus 71 infections. Prospective, unicenter, open-label, randomized, controlled study. Inpatient ward of a large tertiary teaching hospital in Ho Chi Minh City, Vietnam. Children (≤ 18 yr old) admitted with proven enterovirus 71-induced pulmonary edema and/or neurogenic shock. Patients were randomly assigned to receive intravenous milrinone (0.5 μg/kg/min) (n = 22) or conventional management (n = 19). Both groups received dopamine or dobutamine and intravenous immunoglobulin. The primary endpoint was 1-week mortality. The secondary endpoints included length of ventilator dependence and hospital stay and adverse events. The median age was 2 years with a predominance of boys in both groups. The 1-week mortality was significantly lower, 18.2% (4/22) in the milrinone compared with 57.9% (11/19) in the conventional management group (relative risk = 0.314 [95% CI, 0.12-0.83], p = 0.01). The median duration of ventilator-free days was longer in the milrinone treatment group (p = 0.01). There was no apparent neurologic sequela in the survivors in either group, and no drug-related adverse events were documented. Milrinone significantly reduced the 1-week mortality of enterovirus 71-induced pulmonary edema and/or neurogenic shock without adverse effects. Further studies are needed to determine whether milrinone might be useful to prevent progression of earlier stages of brainstem encephalitis.
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Mandelbrot, Laurent; Kieffer, François; Sitta, Rémi; Laurichesse-Delmas, Hélène; Winer, Norbert; Mesnard, Louis; Berrebi, Alain; Le Bouar, Gwenaëlle; Bory, Jean-Paul; Cordier, Anne-Gaëlle; Ville, Yves; Perrotin, Franck; Jouannic, Jean-Marie; Biquard, Florence; d'Ercole, Claude; Houfflin-Debarge, Véronique; Villena, Isabelle; Thiébaut, Rodolphe
2018-06-02
The efficacy of prophylaxis to prevent prenatal toxoplasmosis transmission is controversial, without any previous randomized clinical trial. In France, spiramycin (S) is usually prescribed for maternal seroconversions. A more potent pyrimethamine + sulfadiazine (PS) regimen is used to treat congenital toxoplasmosis and is offered in some countries as prophylaxis. To compare the efficacy and tolerance of PS vs S to reduce placental transmission. A randomized, open-label trial in 36 French centers, comparing pyrimethamine (50 mg qd) + sulfadiazine (1g tid) with folinic acid vs spiramycin (1g tid) following toxoplasmosis seroconversion. 143 women were randomized from 11/2010 to 01/2014. An amniocentesis was later performed in 131 cases, with a positive T. gondii PCR in 7/67 (10.4%) in the PS group vs. 13/64 (20.3%) in the S group. Cerebral ultrasound anomalies appeared in 0/73 fetuses in the PS group, vs 6/70 in the S group (p=0.01). Two of these pregnancies were terminated. Transmission rates, excluding 18 children with undefined status, were 12/65 in the PS group (18.5%), vs 18/60 in the S group (30%, p = 0.147), equivalent to an Odds ratio = 0.53 (95% CI 0.23-1.22) and which after adjustment tended to be stronger (p=0.03 for interaction) when treatment started within 3 weeks of seroconversion (95% CI 0.00-1.63). Two women had severe rashes, both with PS. There was a trend towards lower transmission with PS, but it did not reach statistical significance, possibly for lack of statistical power because enrollment was discontinued. There were also no fetal cerebral toxoplasmosis lesions in the PS group. These promising results encourage further research on chemoprophylaxis to prevent congenital toxoplasmosis. Copyright © 2018. Published by Elsevier Inc.
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Harada, Tasuku; Kosaka, Saori; Elliesen, Joerg; Yasuda, Masanobu; Ito, Makoto; Momoeda, Mikio
2017-11-01
To investigate the efficacy and safety of ethinylestradiol 20 μg/drospirenone 3 mg in a flexible extended regimen (Flexible MIB ) compared with placebo to treat endometriosis-associated pelvic pain (EAPP). A phase 3, randomized, double-blind, placebo-controlled, parallel-group study, consisting of a 24-week double-blind treatment phase followed by a 28-week open-label extension phase with an unblinded reference arm. Thirty-two centers. A total of 312 patients with endometriosis. Patients were randomized to Flexible MIB , placebo, or dienogest. The Flexible MIB and placebo arms received 1 tablet per day continuously for 120 days, with a 4-day tablet-free interval either after 120 days or after ≥3 consecutive days of spotting and/or bleeding on days 25-120. After 24 weeks, placebo recipients were changed to Flexible MIB . Patients randomized to dienogest received 2 mg/d for 52 weeks in an unblinded reference arm. Absolute change in the most severe EAPP based on visual analog scale scores from the baseline observation phase to the end of the double-blind treatment phase. Compared with placebo, Flexible MIB significantly reduced the most severe EAPP (mean difference in visual analog scale score: -26.3 mm). Flexible MIB also improved other endometriosis-associated pain and gynecologic findings and reduced the size of endometriomas. Flexible MIB improved EAPP and was well tolerated, suggesting it may be a new alternative for managing endometriosis. NCT01697111. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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The legibility of prescription medication labelling in Canada
Ahrens, Kristina; Krishnamoorthy, Abinaya; Gold, Deborah; Rojas-Fernandez, Carlos H.
2014-01-01
Introduction: The legibility of medication labelling is a concern for all Canadians, because poor or illegible labelling may lead to miscommunication of medication information and poor patient outcomes. There are currently few guidelines and no regulations regarding print standards on medication labels. This study analyzed sample prescription labels from Ontario, Canada, and compared them with print legibility guidelines (both generic and specific to medication labels). Methods: Cluster sampling was used to randomly select a total of 45 pharmacies in the tri-cities of Kitchener, Waterloo and Cambridge. Pharmacies were asked to supply a regular label with a hypothetical prescription. The print characteristics of patient-critical information were compared against the recommendations for prescription labels by pharmaceutical and health organizations and for print accessibility by nongovernmental organizations. Results: More than 90% of labels followed the guidelines for font style, contrast, print colour and nonglossy paper. However, only 44% of the medication instructions met the minimum guideline of 12-point print size, and none of the drug or patient names met this standard. Only 5% of the labels were judged to make the best use of space, and 51% used left alignment. None of the instructions were in sentence case, as is recommended. Discussion: We found discrepancies between guidelines and current labels in print size, justification, spacing and methods of emphasis. Conclusion: Improvements in pharmacy labelling are possible without moving to new technologies or changing the size of labels and would be expected to enhance patient outcomes. PMID:24847371
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3D exemplar-based random walks for tooth segmentation from cone-beam computed tomography images
DOE Office of Scientific and Technical Information (OSTI.GOV)
Pei, Yuru, E-mail: peiyuru@cis.pku.edu.cn; Ai, Xin
Purpose: Tooth segmentation is an essential step in acquiring patient-specific dental geometries from cone-beam computed tomography (CBCT) images. Tooth segmentation from CBCT images is still a challenging task considering the comparatively low image quality caused by the limited radiation dose, as well as structural ambiguities from intercuspation and nearby alveolar bones. The goal of this paper is to present and discuss the latest accomplishments in semisupervised tooth segmentation with adaptive 3D shape constraints. Methods: The authors propose a 3D exemplar-based random walk method of tooth segmentation from CBCT images. The proposed method integrates semisupervised label propagation and regularization by 3Dmore » exemplar registration. To begin with, the pure random walk method is to get an initial segmentation of the teeth, which tends to be erroneous because of the structural ambiguity of CBCT images. And then, as an iterative refinement, the authors conduct a regularization by using 3D exemplar registration, as well as label propagation by random walks with soft constraints, to improve the tooth segmentation. In the first stage of the iteration, 3D exemplars with well-defined topologies are adapted to fit the tooth contours, which are obtained from the random walks based segmentation. The soft constraints on voxel labeling are defined by shape-based foreground dentine probability acquired by the exemplar registration, as well as the appearance-based probability from a support vector machine (SVM) classifier. In the second stage, the labels of the volume-of-interest (VOI) are updated by the random walks with soft constraints. The two stages are optimized iteratively. Instead of the one-shot label propagation in the VOI, an iterative refinement process can achieve a reliable tooth segmentation by virtue of exemplar-based random walks with adaptive soft constraints. Results: The proposed method was applied for tooth segmentation of twenty clinically captured CBCT images. Three metrics, including the Dice similarity coefficient (DSC), the Jaccard similarity coefficient (JSC), and the mean surface deviation (MSD), were used to quantitatively analyze the segmentation of anterior teeth including incisors and canines, premolars, and molars. The segmentation of the anterior teeth achieved a DSC up to 98%, a JSC of 97%, and an MSD of 0.11 mm compared with manual segmentation. For the premolars, the average values of DSC, JSC, and MSD were 98%, 96%, and 0.12 mm, respectively. The proposed method yielded a DSC of 95%, a JSC of 89%, and an MSD of 0.26 mm for molars. Aside from the interactive definition of label priors by the user, automatic tooth segmentation can be achieved in an average of 1.18 min. Conclusions: The proposed technique enables an efficient and reliable tooth segmentation from CBCT images. This study makes it clinically practical to segment teeth from CBCT images, thus facilitating pre- and interoperative uses of dental morphologies in maxillofacial and orthodontic treatments.« less
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3D exemplar-based random walks for tooth segmentation from cone-beam computed tomography images.
Pei, Yuru; Ai, Xingsheng; Zha, Hongbin; Xu, Tianmin; Ma, Gengyu
2016-09-01
Tooth segmentation is an essential step in acquiring patient-specific dental geometries from cone-beam computed tomography (CBCT) images. Tooth segmentation from CBCT images is still a challenging task considering the comparatively low image quality caused by the limited radiation dose, as well as structural ambiguities from intercuspation and nearby alveolar bones. The goal of this paper is to present and discuss the latest accomplishments in semisupervised tooth segmentation with adaptive 3D shape constraints. The authors propose a 3D exemplar-based random walk method of tooth segmentation from CBCT images. The proposed method integrates semisupervised label propagation and regularization by 3D exemplar registration. To begin with, the pure random walk method is to get an initial segmentation of the teeth, which tends to be erroneous because of the structural ambiguity of CBCT images. And then, as an iterative refinement, the authors conduct a regularization by using 3D exemplar registration, as well as label propagation by random walks with soft constraints, to improve the tooth segmentation. In the first stage of the iteration, 3D exemplars with well-defined topologies are adapted to fit the tooth contours, which are obtained from the random walks based segmentation. The soft constraints on voxel labeling are defined by shape-based foreground dentine probability acquired by the exemplar registration, as well as the appearance-based probability from a support vector machine (SVM) classifier. In the second stage, the labels of the volume-of-interest (VOI) are updated by the random walks with soft constraints. The two stages are optimized iteratively. Instead of the one-shot label propagation in the VOI, an iterative refinement process can achieve a reliable tooth segmentation by virtue of exemplar-based random walks with adaptive soft constraints. The proposed method was applied for tooth segmentation of twenty clinically captured CBCT images. Three metrics, including the Dice similarity coefficient (DSC), the Jaccard similarity coefficient (JSC), and the mean surface deviation (MSD), were used to quantitatively analyze the segmentation of anterior teeth including incisors and canines, premolars, and molars. The segmentation of the anterior teeth achieved a DSC up to 98%, a JSC of 97%, and an MSD of 0.11 mm compared with manual segmentation. For the premolars, the average values of DSC, JSC, and MSD were 98%, 96%, and 0.12 mm, respectively. The proposed method yielded a DSC of 95%, a JSC of 89%, and an MSD of 0.26 mm for molars. Aside from the interactive definition of label priors by the user, automatic tooth segmentation can be achieved in an average of 1.18 min. The proposed technique enables an efficient and reliable tooth segmentation from CBCT images. This study makes it clinically practical to segment teeth from CBCT images, thus facilitating pre- and interoperative uses of dental morphologies in maxillofacial and orthodontic treatments.
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Lyophilized Kit for the Preparation of the PET Perfusion Agent [68Ga]-MAA
Amor-Coarasa, Alejandro; Milera, Andrew; Gulec, Seza; McGoron, Anthony J.
2014-01-01
Rapid developments in the field of medical imaging have opened new avenues for the use of positron emitting labeled microparticles. The radioisotope used in our research was 68Ga, which is easy to obtain from a generator and has good nuclear properties for PET imaging. Methods. Commercially available macroaggregated albumin (MAA) microparticles were suspended in sterile saline, centrifuged to remove the free albumin and stannous chloride, relyophilized, and stored for later labeling with 68Ga. Labeling was performed at different temperatures and times. 68Ga purification settings were also tested and optimized. Labeling yield and purity of relyophilized MAA microparticles were compared with those that were not relyophilized. Results. MAA particles kept their original size distribution after relyophilization. Labeling yield was 98% at 75°C when a 68Ga purification system was used, compared to 80% with unpurified 68Ga. Radiochemical purity was over 97% up to 4 hours after the labeling. The relyophilized MAA and labeling method eliminate the need for centrifugation purification of the final product and simplify the labeling process. Animal experiments demonstrated the high in vivo stability of the obtained PET agent with more than 95% of the activity remaining in the lungs after 4 hours. PMID:24800071
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A review of escitalopram and citalopram in child and adolescent depression.
Carandang, Carlo; Jabbal, Rekha; Macbride, Angela; Elbe, Dean
2011-11-01
To review the basic pharmacology and published literature regarding escitalopram and citalopram in child and adolescent depression. A LITERATURE REVIEW WAS CONDUCTED USING THE SEARCH TERMS: 'escitalopram', 'citalopram', 'depression', 'randomized controlled trial', 'open label trial' and limits set to: Human trials, English Language and All Child (Age 0-18). Additional articles were identified from reference information and poster presentation data. Three prospective, randomized controlled trials (RCT) were found for escitalopram in pediatric depression, and two RCTs were found for citalopram. One RCT each for escitalopram and citalopram showed superiority over placebo on the primary out come measure. Adverse effects in escitalopram and citalopram trials were generally mild to moderate. Suicidality was not assessed systematically in all RCTs reviewed, but did not appear to be elevated over placebo in escitalopram RCTs. One trial reported numerically higher suicide related events for citalopram compared to placebo (14 vs. 5, p=0.06). At present, escitalopram and citalopram should be considered a second-line option for adolescent depression. The US Food and Drug Administration approval of escitalopram for treatment of adolescent depression was based on a single positive RCT. This is less evidence than typically required for approval of a drug for a new indication.
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Efficacy of citalopram and moclobemide in patients with social phobia: some preliminary findings.
Atmaca, Murad; Kuloglu, Murat; Tezcan, Ertan; Unal, Ahmet
2002-12-01
The efficacy of irreversible and reversible monoamine oxidase inhibitors (MAOIs) in the treatment of social phobia (SP) is well established. Recently, selective serotonin reuptake inhibitors (SSRIs) have been used more frequently. In the present study, the efficacy and side-effect profile of citalopram, an SSRI, and moclobemide, the only MAOI used in Turkey, were compared. The 71 patients diagnosed with SP according to DSM-III-R were randomly assigned to two subgroups; citalopram (n = 36) or moclobemide (n = 35). The study was an 8-week, randomized, open-label, rater-blinded, parallel-group trial. All patients were assessed by Hamilton anxiety rating (HAM-A), Liebowitz social anxiety (LSAS), clinical global impression-severity of illness (CGI-SI) and clinical global impression-improvement (CGI-I) scales. There was a similar percentage of responders (citalopram 75%, n = 27 and moclobemide 74.3%, n = 26), with a >50% or greater reduction in LSAS total score and ratings of "very much" or "much improved" on the CGI-I. None of the patients withdrew from the study. The results of the present study suggest that citalopram has shown promising results in patients with SP. Copyright 2002 John Wiley & Sons, Ltd.
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Xue, Xiaobin; Song, Yun; Yu, Xiaojie; Fan, Qiang; Tang, Jiyou; Chen, Xu
2018-02-01
This study aimed to compare olanzapine and haloperidol efficacies in the treatment of acute psychiatric symptoms due to amphetamine-type stimulants (ATSs). The Zelen II design method was used; 124 patients with acute mental disorders due to amphetamine were randomly divided into olanzapine group (n = 63) and haloperidol group (n = 61). Then, a 4-week open-label medical therapy was performed. Clinical Global Impression Scale Item 2 was employed to evaluate the onset time; meanwhile, Brief Psychiatric Rating Scale (BPRS) was used at baseline and at posttreatment weeks 1, 2, and 4. Moreover, adverse reactions during the treatment were recorded. Onset time in the olanzapine group was significantly earlier than in the haloperidol group; BPRS scores in the olanzapine group were significantly lower than haloperidol group values at 1 and 2 weeks of treatment. The overall effective rates had no statistically significant difference. Short-term olanzapine and haloperidol treatments had equivalent efficacies in the treatment of acute symptoms of mental disorders due to ATSs; however, olanzapine administration resulted in relatively earlier disease onset, with less adverse reactions.
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Deshmukh, Saylee; Vyas, Mahesh K; Dwivedi, R R; Vyas, Hitesh A
2016-01-01
Non-communicable diseases are expected to kill more people in the 21 st century which are the resultant of deranged lifestyle such as unhealthy dietary habits and wrong behavioral pattern. In Ayurveda, Ahara Vidhi (dietary rules) and Vihara (conducts) are described in detail which can be included under the heading of lifestyle. Agnimandya (indigestion) is considered as the root cause of all diseases like diabetes mellitus, obesity etc., which are few among the top ten lifestyle disorders. The present study is aimed at establishment of relationship between disturbances in lifestyle and Agnimandya and role of lifestyle modification in correcting the state of Agnimandya . The present study was carried out on 33 patients diagnosed with Agnimandya having disturbed lifestyle. Patients were divided into two groups with simple random sampling method. In Group A, lifestyle modification was advised with placebo capsules of wheat flour, while in Group B, patients were treated with 2 g of Shatapushpadya Churna for 2 weeks. Both the groups showed statistically highly significant results on majority of the symptoms of Agnimandya , however, Group A provided better effect than Group B. Lifestyle has definite role in the manifestation and treatment of Agnimandya .
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Relative bioavailability of an extemporaneous ondansetron 4-mg capsule formulation versus solution.
Lam, Y W Francis; Javors, Martin A; Ait-Daoud, Nassima; Roache, John D; Johnson, Bankole A
2004-04-01
To compare the relative bioavailability of an extemporaneous ondansetron capsule formulation with that of an identical dose of the commercially available solution formulation. Open-label, randomized, two-way crossover study. University-affiliated research laboratory. Sixteen (eight men, eight women) healthy, nonsmoking volunteers. Participants were randomly assigned to receive a 4-mg dose of either the commercially available ondansetron solution or the extemporaneous ondansetron capsule formulation. Blood sampling was performed over 12 hours after dosing. After a washout period of at least 3 days, each participant was switched to the alternate formulation, and blood sampling was repeated. Ondansetron was well absorbed after administration of both formulations, with the solution achieving a faster rate of drug absorption over the first hour of dosing. After the peak plasma concentration was achieved, the plasma concentration-time curves of both formulations declined at a similar steady rate. There were no significant differences in pharmacokinetic parameters between the two formulations, and the relative bioavailability of the capsule versus the solution formulation was 101%. Similar concentration-time curves and pharmacokinetic parameters were achieved with the two formulations. The commercially available solution would be a useful alternative formulation for administration of low-dose ondansetron in research and clinical settings.
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Perspectives: Nanofibers and nanowires for disordered photonics
NASA Astrophysics Data System (ADS)
Pisignano, Dario; Persano, Luana; Camposeo, Andrea
2017-03-01
As building blocks of microscopically non-homogeneous materials, semiconductor nanowires and polymer nanofibers are emerging component materials for disordered photonics, with unique properties of light emission and scattering. Effects found in assemblies of nanowires and nanofibers include broadband reflection, significant localization of light, strong and collective multiple scattering, enhanced absorption of incident photons, synergistic effects with plasmonic particles, and random lasing. We highlight recent related discoveries, with a focus on material aspects. The control of spatial correlations in complex assemblies during deposition, the coupling of modes with efficient transmission channels provided by nanofiber waveguides, and the embedment of random architectures into individually coded nanowires will allow the potential of these photonic materials to be fully exploited, unconventional physics to be highlighted, and next-generation optical devices to be achieved. The prospects opened by this technology include enhanced random lasing and mode-locking, multi-directionally guided coupling to sensors and receivers, and low-cost encrypting miniatures for encoders and labels.
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NASA Astrophysics Data System (ADS)
Piao, Daqing; Davis, Carole A.; Hurst, Robert E.; Slaton, Joel W.
2017-02-01
Bladder cancer is one of the most expensive cancers to manage due to frequent recurrences requiring life-long surveillance and treatment. A near-infrared labeled 2-deoxy-d-glucose probe IRDye800CW-DG targeting glucose metabolism pathway has shown to enhance the sensitivity of diagnosing several types of cancers as tested on tumor models not including bladder tumor. This pilot study has explored differential uptake of intravesically administered IRDye800CW-DG in an orthotopic rat bladder tumor model. Twenty-five female Fischer rats were randomly grouped to four conditions: no-tumor-control (n=3), no-tumor-control intravesically instilled with IRDye800CWDG (n=6), rats bearing GFP-labeled AY-27 rat bladder urothelial cell carcinoma cells and washed with saline (n=5), and rats bearing AY-27 tumors and intravesically instilled with IRDye800CW-DG (n=11). Near-infrared fluorescence was measured from the opened bladder wall of anesthetized rat at an excitation wavelength of 750nm and an emission wavelength of 776nm, by using an in-house fluorescence imaging system. There is no statistically significant difference of the peak fluorescence intensity among the no-tumor-control bladders (n=3), the no-tumorcontrol bladders instilled with IRDye800CW-DG (n=6), and the GFP-labeled AY-27 treated bladders washed by saline (n=5). When compared to that of the no-tumor-control bladders instilled with IRDye800CW-DG (n=6), the fluorescence intensity of GFP-labeled AY-27 treated bladders instilled with IRDye800CW-DG and with histology confirmed neoplastic bladder tissue (n=11) was remarkably more intense (3.34 fold of over the former) and was also statistically significant (p<0.0001). The differential uptake of IRDye800CW-DG by the neoplastic urinary bladder tissues suggests the potential for cystoscopy-adaptation to enhance diagnosis and guiding surgical management of flat urinary bladder cancer.
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English, Joey D.; Yavagal, Dileep R.; Gupta, Rishi; Janardhan, Vallabh; Zaidat, Osama O.; Xavier, Andrew R.; Nogueira, Raul G.; Kirmani, Jawad F.; Jovin, Tudor G.
2016-01-01
Five landmark multicenter, prospective, randomized, open-label, blinded end point clinical trials have recently demonstrated significant clinical benefit of endovascular therapy with mechanical thrombectomy in acute ischemic stroke (AIS) patients presenting with proximal intracranial large vessel occlusions. The Society of Vascular and Interventional Neurology (SVIN) appointed an expert writing committee to summarize this new evidence and make recommendations on how these data should guide emergency endovascular therapy for AIS patients. PMID:27051410
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Gross, Oliver; Friede, Tim; Hilgers, Reinhard; Görlitz, Anke; Gavénis, Karsten; Ahmed, Raees; Dürr, Ulrike
2012-01-01
Introduction. Retrospective observational data show that ACE-inhibitor therapy delays renal failure and improves life expectancy in Alport patients with proteinuria. The EARLY PRO-TECT Alport trial assesses the safety and efficacy of early therapy onset with ramipril in pediatric Alport patients. Methods and analysis. This double-blind, randomized, placebo-controlled, multicenter phase III trial (NCT01485978; EudraCT-number 2010-024300-10) includes 120 pediatric patients aged 24 months to 18 years with early stages of Alport syndrome (isolated hematuria or microalbuminuria). From March 2012, up to 80 patients will be randomized 1:1 to ramipril or placebo. In the event of disease progression during 3-year treatment, patients are unblinded and ramipril is initiated, if applicable. Approximately 40 patients receive open-label ramipril contributing to the safety database. Primary end-points are "time to progression to next disease level" and "incidence of adverse drug events before disease progression." Treatment effect estimates from the randomized comparison and Alport registry data will be combined in supportive analyses to maximize evidence. Conclusion. Without this trial, ACE inhibitors may become standard off-label treatment in Alport syndrome without satisfactory evidence base. The results are expected to be of relevance for therapy of all pediatric patients with kidney disease, and the trial protocol might serve as a model for other rare pediatric glomerulopathies.
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Affect labeling enhances exposure effectiveness for public speaking anxiety.
Niles, Andrea N; Craske, Michelle G; Lieberman, Matthew D; Hur, Christopher
2015-05-01
Exposure is an effective treatment for anxiety but many patients do not respond fully. Affect labeling (labeling emotional experience) attenuates emotional responding. The current project examined whether affect labeling enhances exposure effectiveness in participants with public speaking anxiety. Participants were randomized to exposure with or without affect labeling. Physiological arousal and self-reported fear were assessed before and after exposure and compared between groups. Consistent with hypotheses, participants assigned to Affect Labeling, especially those who used more labels during exposure, showed greater reduction in physiological activation than Control participants. No effect was found for self-report measures. Also, greater emotion regulation deficits at baseline predicted more benefit in physiological arousal from exposure combined with affect labeling than exposure alone. The current research provides evidence that behavioral strategies that target prefrontal-amygdala circuitry can improve treatment effectiveness for anxiety and these effects are particularly pronounced for patients with the greatest deficits in emotion regulation. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Matsuda, Shuichi; Ogasawara, Takashi; Sugimoto, Shunsuke; Kato, Shinpei; Umezawa, Hiroki; Yano, Toshiaki; Kasamatsu, Norio
2016-06-01
The nursing- and healthcare-associated pneumonia guideline, proposed by the Japan Respiratory Society, recommends that patients at risk of exposure to drug-resistant pathogens, classified as treatment category C, be treated with antipseudomonal antibiotics. This study aimed to prove the non-inferiority of empirical therapy in our hospital compared with guideline-concordant therapy. This was a randomized controlled trial conducted from December 2011 to December 2012. Patients were randomized to the Guideline group receiving guideline-concordant therapy, and the Empiric group treated with sulbactam/ampicillin or ceftriaxone. The primary endpoint was in-hospital relapse of pneumonia and mortality within 30 days, with a predefined non-inferiority margin of 10%. The secondary endpoints included duration, adverse effects, and cost of antibiotic therapy. One hundred and eleven patients were assigned to the Guideline group (n = 55) and the Empiric group (n = 56; 3 of which were excluded). The incidence of relapse and death within 30 days was similar in the Guideline and the Empiric groups (31% vs. 26%, risk difference -4.5%, 95% CI -21.5% to 12.5%). While the duration of antibiotic therapy was slightly shorter in the Guideline group than in the Empiric group (7 vs. 8 days), there were no significant differences in adverse effects or cost. The efficacy of empiric therapy was comparable to guideline-concordant therapy, although non-inferiority was not proven. The administration of broad-spectrum antibiotics to patients at risk of exposure to drug-resistant pathogens may not necessarily improve the prognosis. UMIN000006792. Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
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Fu, Dong-Jing; Turkoz, Ibrahim; Walling, David; Lindenmayer, Jean-Pierre; Schooler, Nina R; Alphs, Larry
2018-02-01
Evaluate the effect of paliperidone palmitate once-monthly (PP1M) injectable on the specific functioning domains of the Personal and Social Performance (PSP) scale in patients with schizoaffective disorder (SCA) participating in a long-term study. This study (NCT01193153) included both in- and outpatient subjects with SCA experiencing an acute exacerbation of psychotic and mood symptoms. Subjects were treated with PP1M either as monotherapy or in combination with antidepressants or mood stabilizers during a 25-week open-label (OL) phase. Stabilized subjects were randomly assigned 1:1 (PP1M or placebo) into a 15-month double-blind (DB) relapse-prevention period. Functioning of the randomized subjects during OL and DB phases was evaluated using the PSP scale (four domains: socially useful activities, personal/social relationships, self-care, and disturbing/aggressive behaviors). Three statistical approaches were utilized to analyze PSP scores to assess robustness and consistency of findings. No adjustments were made for multiplicity. 334 of 667 enrolled subjects were stabilized with PP1M, randomly assigned to PP1M (n=164) or placebo (n=170) in the DB phase, and included in this analysis. Improvements in all PSP domain scores were observed during the OL phase and were maintained during the DB phase with PP1M, but decreased with placebo. Differences compared to placebo were significant in all four PSP domains during the DB phase (P≤0.008). The analysis in this study showed that PP1M improves functioning, as measured by the four PSP domain scores, in symptomatic subjects with SCA. Functioning was maintained compared with placebo. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.
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Yamaue, Hiroki; Shimizu, Atsushi; Hagiwara, Yasuhiro; Sho, Masayuki; Yanagimoto, Hiroaki; Nakamori, Shoji; Ueno, Hideki; Ishii, Hiroshi; Kitano, Masayuki; Sugimori, Kazuya; Maguchi, Hiroyuki; Ohkawa, Shinichi; Imaoka, Hiroshi; Hashimoto, Daisuke; Ueda, Kazuki; Nebiki, Hiroko; Nagakawa, Tatsuya; Isayama, Hiroyuki; Yokota, Isao; Ohashi, Yasuo; Shirasaka, Tetsuhiko
2017-04-01
Non-inferiority for overall survival (OS) following alternate-day treatment with the oral anticancer drug S-1 compared with standard daily treatment was assessed in Japanese patients with unresectable advanced pancreatic cancer in a multicenter, randomized, phase II study. This trial was registered at the UMIN Clinical Trials Registry (no. 000008604). Chemotherapy-naïve patients with locally advanced or metastatic pancreatic cancer were randomly assigned 2:1 to treatment with alternate-day (twice daily on alternate days from days 1 through 42 of a 42-day cycle) or daily (twice daily on days 1 through 28 of a 42-day cycle) treatment with S-1. The primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), time to treatment failure, response rate, quality of life assessments, and safety. A total of 190 patients were enrolled, of which 185 were included in the final analysis (alternate-day: 121; daily: 64). Median OS was 9.4 for the alternate-day group and 10.4 months for the daily group [hazard ratio (HR), 1.19; 95% credible interval, 0.86 to 1.64], indicating that non-inferiority of alternate-day treatment to daily treatment was not demonstrated. Median PFS was 3.0 for the alternate-day group and 4.2 months for the daily group (HR, 1.65; 95% credible interval, 1.20-2.29). The incidence of anorexia, fatigue, neutrophils, pigmentation, and pneumonitis was lower in alternate-day treatment compared with daily treatment. S-1 for advanced pancreatic cancer should be taken daily as recommended, based on the decreased OS and PFS and marginal improvement in safety observed in the alternate-day group.
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Lee, Hyun Jik; Chung, Moon Jae; Park, Jeong Yup; Park, Seung Woo; Nam, Chung Mo; Song, Si Young; Bang, Seungmin
2017-08-01
A biliary self-expandable metal stent (SEMS) is commonly used to relieve malignant biliary obstruction. The aim of this study was to compare the efficacy of a conventional uncovered SEMS with that of a newly developed uncovered double bare metal stent in reducing the risk of stent occlusion caused by tumor ingrowth. We performed a prospective, open-labeled, randomized trial in 71 patients at Severance Hospital, Yonsei University College of Medicine from June 2013 to June 2014. Patients with inoperable malignant biliary obstruction were included and randomized to receive an uncovered single bare metal stent (SBSs; S&G Biotech Inc.), an uncovered single bare metal stent (SBSt; Taewoong Medical), or an uncovered double bare metal stent (DBS; S&G Biotech Inc.). The mean age was 66.6 years (range, 35-83), and 42 (59.2%) were male. The mean duration of stent patency was 212 days (±152) in the DBS group (n = 24) compared with 124 days (±98) in the SBSs group (n = 23; P = 0.022 for noninferiority) and 116 days (±79) in the SBSt group (n = 24; P = 0.010 for noninferiority). There were no differences in the incidences of early and delayed complications or migration. The newly developed DBS is noninferior to the conventional uncovered SEMSs on duration of stent patency and tumor ingrowth occurred less frequently in the DBS group. This might decrease the need for reintervention and offer a better quality of life. The trial is registered with Clinicaltrials.gov no: NCT01869894.
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Tamura, Kazuo; Kawai, Yasukazu; Kiguchi, Toru; Okamoto, Masataka; Kaneko, Masahiko; Maemondo, Makoto; Gemba, Kenichi; Fujimaki, Katsumichi; Kirito, Keita; Goto, Tetsuya; Fujisaki, Tomoaki; Takeda, Kenji; Nakajima, Akihiro; Ueda, Takanori
2016-10-01
Control of serum uric acid (sUA) levels is very important during chemotherapy in patients with malignant tumors, as the risks of tumor lysis syndrome (TLS) and renal events are increased with increasing levels of sUA. We investigated the efficacy and safety of febuxostat, a potent non-purine xanthine oxidase inhibitor, compared with allopurinol for prevention of hyperuricemia in patients with malignant tumors, including solid tumors, receiving chemotherapy in Japan. An allopurinol-controlled multicenter, open-label, randomized, parallel-group comparative study was carried out. Patients with malignant tumors receiving chemotherapy, who had an intermediate risk of TLS or a high risk of TLS and were not scheduled to be treated with rasburicase, were enrolled and then randomized to febuxostat (60 mg/day) or allopurinol (300 or 200 mg/day). All patients started to take the study drug 24 h before chemotherapy. The primary objective was to confirm the non-inferiority of febuxostat to allopurinol based on the area under the curve (AUC) of sUA for a 6-day treatment period. Forty-nine and 51 patients took febuxostat and allopurinol, respectively. sUA decreased over time after initiation of study treatment. The least squares mean difference of the AUC of sUA between the treatment groups was -33.61 mg h/dL, and the 95 % confidence interval was -70.67 to 3.45, demonstrating the non-inferiority of febuxostat to allopurinol. No differences were noted in safety outcomes between the treatment groups. Febuxostat demonstrated an efficacy and safety similar to allopurinol in patients with malignant tumors receiving chemotherapy. http://www.clinicaltrials.jp ; Identifier: JapicCTI-132398.
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Kripp, Melanie; Prasnikar, Nicole; Vehling-Kaiser, Ursula; Quidde, Julia; Al-Batran, Salah-Eddin; Stein, Alexander; Neben, Kai; Hannig, Carla Verena; Tessen, Hans Werner; Trarbach, Tanja; Hinke, Axel; Hofheinz, Ralf-Dieter
2017-12-01
Dermatologic toxicities, especially akne-like skin rash, are the most common side-effects associated with anti-epidermal growth factor receptor (EGFR) therapy. Preemptive treatment with oral tetracyclines is recommended as a standard. Topical prophylactic options have thus far not been compared to tetracyclines. In the current study, we sought to establish an alternative topical treatment. In this multicentre, randomized, open-label phase II study patients with (K)Ras-wildtype colorectal cancer receiving panitumumab were randomized (1:1) to receive either doxycycline 100 mg b.i.d. (standard arm) or erythromycin ointment 2% followed by doxycycline in case of insufficient activity. The primary endpoint was the percentage of patients developing no skin toxicity ≥ grade 2 at any time during the first 8 weeks of panitumumab treatment. Skin toxicity was assessed using the NCI CTCAE v 4.0. Secondary endpoints comprised the assessment of skin toxicity using a more thorough grading system (WoMo score), evaluation of skin-related (DLQI) and global quality of life (EORTC QLQ C30). In total, 88 patients were included in this trial. 69% of the patients in the erythromycin arm suffered from skin toxicity of grade ≥ 2 versus 63% in the standard arm ( P = n.s .). However, as per WoMo score significantly more patients in the erythromycin arm developed moderate or severe skin toxicity at earlier time points. Skin related and overall quality of life was comparable between both arms. Based on this data erythromycin cannot be regarded as an alternative to doxycycline as prevention of EGFR-related skin toxicity.
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Schöffski, Patrick; Chawla, Sant; Maki, Robert G; Italiano, Antoine; Gelderblom, Hans; Choy, Edwin; Grignani, Giovanni; Camargo, Veridiana; Bauer, Sebastian; Rha, Sun Young; Blay, Jean-Yves; Hohenberger, Peter; D'Adamo, David; Guo, Matthew; Chmielowski, Bartosz; Le Cesne, Axel; Demetri, George D; Patel, Shreyaskumar R
2016-04-16
A non-randomised, phase 2 study showed activity and tolerability of eribulin in advanced or metastatic soft-tissue sarcoma. In this phase 3 study, we aimed to compare overall survival in patients with advanced or metastatic soft-tissue sarcoma who received eribulin with that in patients who received dacarbazine (an active control). We did this randomised, open-label, phase 3 study across 110 study sites in 22 countries. We enrolled patients aged 18 years or older with intermediate-grade or high-grade advanced liposarcoma or leiomyosarcoma who had received at least two previous systemic regimens for advanced disease (including an anthracycline). Using an interactive voice and web response system, an independent statistician randomly assigned (1:1) patients to receive eribulin mesilate (1·4 mg/m(2) intravenously on days 1 and 8) or dacarbazine (850 mg/m(2), 1000 mg/m(2), or 1200 mg/m(2) [dose dependent on centre and clinician] intravenously on day 1) every 21 days until disease progression. Randomisation was stratified by disease type, geographical region, and number of previous regimens for advanced soft-tissue sarcoma and in blocks of six. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT01327885, and is closed to recruitment, but treatment and follow-up continue. Between March 10, 2011 and May 22, 2013, we randomly assigned patients to eribulin (n=228) or dacarbazine (n=224). Overall survival was significantly improved in patients assigned to eribulin compared with those assigned to dacarbazine (median 13·5 months [95% CI 10·9-15·6] vs 11·5 months [9·6-13·0]; hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·0169). Treatment-emergent adverse events occurred in 224 (99%) of 226 patients who received eribulin and 218 (97%) of 224 who received dacarbazine. Grade 3 or higher adverse events were more common in patients who received eribulin (152 [67%]) than in those who received dacarbazine (126 [56%]), as were deaths (10 [4%] vs 3 [1%]); one death (in the eribulin group) was considered treatment-related by the investigators. Overall survival was improved in patients assigned to eribulin compared with those assigned to an active control, suggesting that eribulin could be a treatment option for advanced soft-tissue sarcoma. Eisai. Copyright © 2016 Elsevier Ltd. All rights reserved.
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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.
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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.
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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.
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Waddington Cruz, Márcia; Amass, Leslie; Keohane, Denis; Schwartz, Jeffrey; Li, Huihua; Gundapaneni, Balarama
2016-01-01
Abstract Transthyretin hereditary amyloid polyneuropathy, also traditionally known as transthyretin familial amyloid polyneuropathy (ATTR-FAP), is a rare, relentless, fatal hereditary disorder. Tafamidis, an oral, non-NSAID, highly specific transthyretin stabilizer, demonstrated safety and efficacy in slowing neuropathy progression in early-stage ATTRV30M-FAP in a 1.5-year, randomized, double-blind, placebo-controlled trial, and 1-year open-label extension study, with a second long-term open-label extension study ongoing. Subgroup analysis of the effectiveness of tafamidis in the pivotal study and its open-label extensions revealed a relatively cohesive cohort of patients with mild neuropathy (i.e. Neuropathy Impairment Score for Lower Limbs [NIS-LL] ≤ 10) at the start of active treatment. Early treatment with tafamidis for up to 5.5 years (≥1 dose of tafamidis meglumine 20 mg once daily during the original trial or after switching from placebo in its extension) resulted in sustained delay in neurologic progression and long-term preservation of nutritional status in this cohort. Mean (95% CI) changes from baseline in NIS-LL and mBMI were 5.3 (1.6, 9.1) points and −7.8 (−44.3, 28.8) kg/m2 × g/L at 5.5 years, respectively. No new safety issues or side effects were identified. These data represent the longest prospective evaluation of tafamidis to date, confirm a favorable safety profile, and underscore the long-term benefits of early intervention with tafamidis. Trial Registration: ClincalTrials.gov Identifier: NCT00409175, NCT00791492, and NCT00925002. PMID:27494299
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Giladi, Nir; Boroojerdi, Babak; Surmann, Erwin
2013-09-01
This open-label extension (SP716; NCT00599196) of a 6-month, double-blind, randomized study (SP513) investigated the safety and tolerability of rotigotine transdermal system over up to ~6 years in patients with Parkinson's disease (PD; early-stage PD at double-blind enrollment). Eligible patients completing the 6-month study received optimal dose open-label rotigotine (≤ 16 mg/24 h) for up to ~6 years. Adjunctive levodopa was permitted. Primary outcomes included adverse events (AEs) and extent of rotigotine exposure. Analysis of adjunctive levodopa use, dyskinesias [unified Parkinson's disease rating scale (UPDRS) IV], and efficacy (UPDRS II + III total score) were also assessed. Of 381 patients enrolled in the open-label extension, 52 % were still in the study at time of closure; 24 % withdrew because of AEs and 6 % because of lack of efficacy. Patients received rotigotine for a median duration of 1,564.5 days (~4 years, 3 months; range 5-2, 145 days). 69 % of patients started supplemental levodopa; median time to levodopa was 485 days (~1 year, 4 months). Most common AEs (% per patient-year) were somnolence (18 %), application site reactions (12 %), nausea (9 %), peripheral edema (7 %), and fall (7 %). AEs indicative of impulsive-compulsive behavior were recorded in 25 (7 %) patients. Dyskinesias were experienced by 65 (17 %) patients; the majority [47 of 65 (72 %)] reported first dyskinesia after starting levodopa. Mean UPDRS II + III total scores remained below double-blind baseline for 4 years (assessment of all patients). In conclusion, rotigotine was generally well tolerated for up to ~6 years in patients with early-stage PD. The AEs reported were in line with previous studies of rotigotine transdermal system, with typical dopaminergic side effects and application site reactions seen.
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Label propagation algorithm for community detection based on node importance and label influence
NASA Astrophysics Data System (ADS)
Zhang, Xian-Kun; Ren, Jing; Song, Chen; Jia, Jia; Zhang, Qian
2017-09-01
Recently, the detection of high-quality community has become a hot spot in the research of social network. Label propagation algorithm (LPA) has been widely concerned since it has the advantages of linear time complexity and is unnecessary to define objective function and the number of community in advance. However, LPA has the shortcomings of uncertainty and randomness in the label propagation process, which affects the accuracy and stability of the community. For large-scale social network, this paper proposes a novel label propagation algorithm for community detection based on node importance and label influence (LPA_NI). The experiments with comparative algorithms on real-world networks and synthetic networks have shown that LPA_NI can significantly improve the quality of community detection and shorten the iteration period. Also, it has better accuracy and stability in the case of similar complexity.
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Khandpur, Neha; Graham, Dan J; Roberto, Christina A
2017-07-01
Proposed variations to Nutrition Facts Labels (NFL) have included the display of added sugars (AS) content, but its impact on consumer understanding is poorly understood. To examine the degree to which different formats for displaying AS influence consumer understanding, perceptions, and purchase intentions. Randomized-controlled online experiment. A sample of 2509 U.S adults. Participants were randomized to 1 of 8 conditions and viewed 10 food or beverage images with either: (1) no label (control); (2) the current NFL (without AS); (3) the proposed NFL without AS; or the proposed NFL with AS in (4) grams, (5) grams and teaspoons, (6) grams and percent Daily Value (%DV), (7) grams with high/medium/low text, or (8) grams with high/medium/low text and %DV. ANCOVAs compared scores on quizzes that assessed the accuracy of judgments about AS, overall nutrition understanding and purchase intentions. Presenting AS in grams plus high/medium/low text with and without %DV led to the highest AS understanding scores (85% and 83% correct, respectively) compared to 70% correct when AS was not on the label or was displayed in grams only (74% correct). Displaying AS in teaspoons did not significantly improve understanding beyond grams alone. Consumers were best able to determine which of two products was healthier when AS was presented as %DV (68% correct) versus displayed in grams alone (60% correct), but %DV did not differ from high/medium/low text or teaspoons. None of the labels influenced purchase intentions relative to no label. Displaying AS on the NFL in grams with high/medium/low text, %DV, or the combination of the two, improved consumer understanding more than presenting it in grams or teaspoons. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Averaging in SU(2) open quantum random walk
NASA Astrophysics Data System (ADS)
Clement, Ampadu
2014-03-01
We study the average position and the symmetry of the distribution in the SU(2) open quantum random walk (OQRW). We show that the average position in the central limit theorem (CLT) is non-uniform compared with the average position in the non-CLT. The symmetry of distribution is shown to be even in the CLT.
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Comparison of levofloxacin versus moxifloxacin for multidrug-resistant tuberculosis.
Koh, Won-Jung; Lee, Seung Heon; Kang, Young Ae; Lee, Chang-Hoon; Choi, Jae Chol; Lee, Jae Ho; Jang, Seung Hun; Yoo, Kwang Ha; Jung, Ki Hwan; Kim, Ki Uk; Choi, Sang Bong; Ryu, Yon Ju; Chan Kim, Kyung; Um, Soojung; Kwon, Yong Soo; Kim, Yee Hyung; Choi, Won-Il; Jeon, Kyeongman; Hwang, Yong Il; Kim, Se Joong; Lee, Young Seok; Heo, Eun Young; Lee, Juhee; Ki, Yeo Woon; Shim, Tae Sun; Yim, Jae-Joon
2013-10-01
Levofloxacin (LFX) and moxifloxacin (MXF) are the two most frequently recommended fluoroquinolones for treatment of patients with multidrug-resistant tuberculosis (MDR-TB). However, studies comparing the effectiveness of LFX and MXF among patients with MDR-TB are lacking. To compare the effectiveness of LFX and MXF in terms of culture conversion after 3 months of treatment for MDR-TB. In this prospective multicenter randomized open label trial, we randomly assigned 182 patients with MDR-TB (sensitive to LFX and MXF) to receive either LFX (750 mg/day; 90 patients) or MXF (400 mg/day; 92 patients) with a background drug regimen. The primary outcome was the proportion of patients who achieved sputum culture conversion at 3 months of treatment. Secondary outcomes were time to culture conversion and time to smear conversion, with data censored at 3 months, and the proportions of adverse drug reactions. At 3 months of treatment, 68 (88.3%) of the 77 patients in the LFX group and 67 (90.5%) of the 74 in the MXF group showed conversion to negative sputum cultures (odds ratio for LFX compared with MXF, 0.78; 95% confidence interval, 0.27-2.20). Adverse drug reactions were reported in six patients (7.7%) in the LFX group and four (5.2%) in the MXF group (P = 0.75). The choice of LFX or MXF for treatment of patients with MDR-TB may not affect sputum culture conversion at 3 months of treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 01055145).
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Yang, Tao; Hou, Jiong; Li, Jinbao; Zhang, Xu; Zhu, Xiaoyan; Ni, Wen; Mao, Yanfei; Deng, Xiaoming
2013-05-01
Tracheal intubation with conventional laryngoscopy requires many trials until beginners are sufficiently skilled in intubating patients safely. To facilitate intubation, the authors used retrograde light-guided laryngoscopy (RLGL) and compared its feasibility with conventional direct laryngoscopy (DL). Twenty operators participated in a prospective, randomized, open-label, parallel-arm study. These operators intubated 205 patients randomly according to a computer-generated procedure by using either DL or RLGL (five intubations with each technique). The primary outcome was the success rate of tracheal intubation. The authors evaluated the success rate of tracheal intubation, the time to glottic exposure and tracheal intubation, and the Cormack and Lehane grades. Compared with DL, the success rate was greater in the RLGL group for all five intubations (72% vs. 47%; rate difference, 25%; 95% CI [11.84-38.16%], P < 0.001). This was associated with a shorter time to glottic exposure (median [25th and 75th percentile]; 27 [15; 42] vs. 45 [30; 73] s, P < 0.001), shorter intubation time (66 [44; 120] vs. 120 [69; 120] s, P < 0.001), and decreased throat soreness (mean ± SD; visual analog scale, 2.1 ± 0.9 vs. 3.7 ± 1.0 cm, P = 0.001) in the RLGL group compared to the DL group. RLGL is an alternative intubation technique. In our study, it enables beginners to intubate patients more successfully and quickly than conventional DL.
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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.
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Takeuchi, Tsutomu; Yamamoto, Kazuhiko; Yamanaka, Hisashi; Ishiguro, Naoki; Tanaka, Yoshiya; Eguchi, Katsumi; Watanabe, Akira; Origasa, Hideki; Kobayashi, Mariko; Shoji, Toshiharu; Togo, Osamu; Miyasaka, Nobuyuki; Koike, Takao
2016-07-01
To compare the efficacy and safety of certolizumab pegol (CZP) with and without loading dose (LD) in a post-hoc analysis of two Japanese clinical studies. Data from the double-blind trials (DBT) J-RAPID and HIKARI, and their open-label extension (OLE) studies, were used. Patients randomized to CZP 200 mg every 2 weeks (Q2W) groups starting with LD (400 mg Weeks 0/2/4; LD group; J-RAPID: n = 82, HIKARI: n = 116) and patients randomized to placebo groups who subsequently started CZP Q2W without LD in the OLEs (No-LD group; J-RAPID: n = 61, HIKARI: n = 99) were analyzed. Efficacy and pharmacokinetics were assessed during 24 weeks. Adverse events were reported from all studies. In both trials, the LD groups showed more rapid initial ACR20/50/70 kinetics, and maintained higher ACR50/70 responses until 24 weeks, compared with the No-LD groups. Anti-CZP antibody development was less frequent in the LD groups (J-RAPID: 1.2% versus 4.9%; HIKARI: 17.2% versus 27.3%). Similar safety profiles were reported between LD and No-LD groups (any AEs: 281.8 versus 315.7 [J-RAPID], 282.6 versus 321.3 [HIKARI] [incidence rate/100 patient-years]). Despite limitations, including comparing DBT and OLE studies, these results suggest that a CZP LD improves clinical response in active rheumatoid arthritis without altering the safety profile.
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Schulze, Laura; Feffer, Kfir; Lozano, Christopher; Giacobbe, Peter; Daskalakis, Zafiris J; Blumberger, Daniel M; Downar, Jonathan
Repetitive transcranial magnetic stimulation (rTMS) shows efficacy in the treatment of major depressive episodes (MDEs), but can require ≥4-6 weeks for maximal effect. Recent studies suggest that multiple daily sessions of rTMS can accelerate response without reducing therapeutic efficacy. However, it is unresolved whether therapeutic effects track cumulative number of pulses, or cumulative number of sessions. This open-label study reviewed clinical outcomes over a 20-30 session course of high-frequency bilateral dorsomedial prefrontal cortex (DMPFC)-rTMS among patients receiving 6000 pulses/day delivered either in twice-daily sessions 80 min apart (at 20 Hz) or single, longer, once-daily sessions (at 10 Hz). A retrospective chart review identified 130 MDD patients who underwent 20-30 daily sessions of bilateral DMPFC-rTMS (Once-daily, n = 65; Twice-daily, n = 65) at a single Canadian clinic. Mixed-effects modeling revealed significantly faster improvement (group-by-time interaction) for twice-daily versus once-daily DMPFC-rTMS. Across both groups, the pace of improvement showed a consistent relationship with number of cumulative sessions, but not with cumulative number of pulses. Although the twice-daily group completed treatment in half as many days, final clinical outcomes did not differ significantly between groups on dichotomous measures (response/remission rates: once-daily, 35.4%/33.8%; twice-daily, 41.5%/35.4%), or continuous measures, or on overall response distribution. Twice-daily rTMS appears feasible, tolerable, and capable of achieving comparable results to once-daily rTMS, while also reducing course length approximately twofold. Therapeutic gains tracked the cumulative number of sessions, not pulses. Future randomized studies comparing once-daily to multiple-daily rTMS sessions, while controlling for number of pulses, may be warranted. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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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.
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Jotwani, Vasantha; Scherzer, Rebecca; Glidden, David V; Mehrotra, Megha; Defechereux, Patricia; Liu, Albert; Gandhi, Monica; Bennett, Michael; Coca, Steven G; Parikh, Chirag R; Grant, Robert M; Shlipak, Michael G
2018-06-01
Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is becoming increasingly adopted for HIV prevention. Tenofovir can cause proximal tubular damage and chronic kidney disease in HIV-infected persons, but little is known regarding its nephrotoxic potential among HIV-uninfected persons. In this study, we evaluated the effects of PrEP on urine levels of the following: α1-microglobulin (α1m), a marker of impaired tubular reabsorption; albuminuria, a measure of glomerular injury; and total proteinuria. The Iniciativa Profilaxis Pre-Exposicion (iPrEx) study randomized HIV-seronegative men and transgender women who have sex with men to oral TDF/FTC or placebo. The iPrEx open-label extension (iPrEx-OLE) study enrolled former PrEP trial participants to receive open-label TDF/FTC. A cross-sectional analysis compared urine biomarker levels by study arm in iPrEx (N = 100 treatment arm, N = 100 placebo arm). Then, urine biomarker levels were compared before and after PrEP initiation in 109 participants of iPrEx-OLE. In iPrEx, there were no significant differences in urine α1m, albuminuria, or proteinuria by treatment arm. In iPrEx-OLE, after 24 weeks on PrEP, urine α1m and proteinuria increased by 21% [95% confidence interval (CI): 10 to 33] and 18% (95% CI: 8 to 28), respectively. The prevalence of detectable α1m increased from 44% to 65% (P < 0.001) and estimated glomerular filtration rate declined by 4 mL/min/1.73 m (P < 0.001). There was no significant change in albuminuria (6%; 95% CI: -7% to 20%). PrEP with TDF/FTC was associated with a statistically significant rise in urine α1m and proteinuria after 6 months, suggesting that PrEP may result in subclinical tubule dysfunction.
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OpenCL based machine learning labeling of biomedical datasets
NASA Astrophysics Data System (ADS)
Amoros, Oscar; Escalera, Sergio; Puig, Anna
2011-03-01
In this paper, we propose a two-stage labeling method of large biomedical datasets through a parallel approach in a single GPU. Diagnostic methods, structures volume measurements, and visualization systems are of major importance for surgery planning, intra-operative imaging and image-guided surgery. In all cases, to provide an automatic and interactive method to label or to tag different structures contained into input data becomes imperative. Several approaches to label or segment biomedical datasets has been proposed to discriminate different anatomical structures in an output tagged dataset. Among existing methods, supervised learning methods for segmentation have been devised to easily analyze biomedical datasets by a non-expert user. However, they still have some problems concerning practical application, such as slow learning and testing speeds. In addition, recent technological developments have led to widespread availability of multi-core CPUs and GPUs, as well as new software languages, such as NVIDIA's CUDA and OpenCL, allowing to apply parallel programming paradigms in conventional personal computers. Adaboost classifier is one of the most widely applied methods for labeling in the Machine Learning community. In a first stage, Adaboost trains a binary classifier from a set of pre-labeled samples described by a set of features. This binary classifier is defined as a weighted combination of weak classifiers. Each weak classifier is a simple decision function estimated on a single feature value. Then, at the testing stage, each weak classifier is independently applied on the features of a set of unlabeled samples. In this work, we propose an alternative representation of the Adaboost binary classifier. We use this proposed representation to define a new GPU-based parallelized Adaboost testing stage using OpenCL. We provide numerical experiments based on large available data sets and we compare our results to CPU-based strategies in terms of time and labeling speeds.
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2015-01-01
The aim of the present survey was to investigate the correct enforcement of the Community rules on the labelling and marketing of bivalve and gastropod molluscs retailed in Sardinia, Italy between 2009 and 2013. A total of 1500 packages and labels for live bivalve and gastropod molluscs were considered. A total of 375 labels (25%) presented non-compliance concerning the wrong trade name and additional wrong or missing information. The highest percentage of anomalous labels has been detected in small-scale retail shops (35%) and open-air markets (25%) compared with the big retailing chains (20%). The 5% of packages were not in compliance with the European Community rules on packaging of bivalve and gastropod molluscs. The high percentage of non-compliance with the European regulations on labelling results is a strong limitation for the consumers and highlights the need to improve the control system about labelling of seafood products. PMID:27800397
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Kabata, Paweł; Jastrzębski, Tomasz; Kąkol, Michał; Król, Karolina; Bobowicz, Maciej; Kosowska, Anna; Jaśkiewicz, Janusz
2015-02-01
Preoperative nutrition is beneficial for malnourished cancer patients. Yet, there is little evidence whether or not it should be given to nonmalnourished patients. The aim of this study was to assess the need to introduce preoperative nutritional support in patients without malnutrition at qualification for surgery. This was a prospective, two-arm, randomized, controlled, open-label study. Patients in interventional group received nutritional supplementation for 14 days before surgery, while control group kept on to their everyday diet. Each patient's nutritional status was assessed twice--at qualification (weight loss in 6 months, laboratory parameters: albumin, total protein, transferrin, and total lymphocyte count) and 1 day before surgery (change in body weight and laboratory parameters). After surgery, all patients were followed up for 30 days for postoperative complications. Fifty-four patients in interventional and 48 in control group were analyzed. In postoperative period, patients in control group suffered from significantly higher (p < 0.001) number of serious complications compared with patients receiving nutritional supplementation. Moreover, levels of all laboratory parameters declined significantly (p < 0.001) in these patients, while in interventional arm were stable (albumin and total protein) or raised (transferrin and total lymphocyte count). Preoperative nutritional support should be introduced for nonmalnourished patients as it helps to maintain proper nutritional status and reduce number and severity of postoperative complications compared with patients without such support.
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Alloway, R R; Sadaka, B; Trofe-Clark, J; Wiland, A; Bloom, R D
2012-10-01
Pharmacokinetic analyses comparing generic tacrolimus preparations versus the reference drug in kidney transplant patients are lacking. A prospective, multicenter, open-label, randomized, two-period (14 days per period), two-sequence, crossover and steady-state pharmacokinetic study was undertaken to compare twice-daily generic tacrolimus (Sandoz) versus reference tacrolimus (Prograf®) in stable renal transplant patients. AUC(0-12h) and peak concentration (C(max) ) were calculated from 12 h pharmacokinetic profiles at the end of each period (days 14 and 28). Of 71 patients enrolled, 68 provided evaluable pharmacokinetic data. The ratios of geometric means were 1.02 (90% CI 97-108%, p = 0.486) for AUC(0-12h) and 1.09 (90% CI 101-118%, p = 0.057) for C(max) . Mean (SD) C(0) was 7.3(1.8) ng/mL for generic tacrolimus versus 7.0(2.1) ng/mL for reference tacrolimus based on data from days 14 and 28. Correlations between 12 h trough levels and AUC were r = 0.917 for generic tacrolimus and r = 0.887 for reference drug at day 28. These data indicate that generic tacrolimus (Sandoz) has a similar pharmacokinetic profile to the reference drug and is bioequivalent in kidney transplant recipients according to US Food and Drug Administration and European Medicines Agency guidelines. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.
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Alloway, R R; Sadaka, B; Trofe-Clark, J; Wiland, A; Bloom, R D
2012-01-01
Pharmacokinetic analyses comparing generic tacrolimus preparations versus the reference drug in kidney transplant patients are lacking. A prospective, multicenter, open-label, randomized, two-period (14 days per period), two-sequence, crossover and steady-state pharmacokinetic study was undertaken to compare twice-daily generic tacrolimus (Sandoz) versus reference tacrolimus (Prograf®) in stable renal transplant patients. AUC0–12h and peak concentration (Cmax) were calculated from 12 h pharmacokinetic profiles at the end of each period (days 14 and 28). Of 71 patients enrolled, 68 provided evaluable pharmacokinetic data. The ratios of geometric means were 1.02 (90% CI 97–108%, p = 0.486) for AUC0–12h and 1.09 (90% CI 101–118%, p = 0.057) for Cmax. Mean (SD) C0 was 7.3(1.8) ng/mL for generic tacrolimus versus 7.0(2.1) ng/mL for reference tacrolimus based on data from days 14 and 28. Correlations between 12 h trough levels and AUC were r = 0.917 for generic tacrolimus and r = 0.887 for reference drug at day 28. These data indicate that generic tacrolimus (Sandoz) has a similar pharmacokinetic profile to the reference drug and is bioequivalent in kidney transplant recipients according to US Food and Drug Administration and European Medicines Agency guidelines. PMID:22759200
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Parabiaghi, A; Tettamanti, M; D'Avanzo, B; Barbato, A
2016-01-01
To determine whether the prescription of aripiprazole, compared with olanzapine and haloperidol, was associated with a lower frequency of metabolic syndrome (MS) and treatment discontinuation at 1 year. Patients were randomly assigned to be treated open-label and according to usual clinical practice with either aripiprazole, olanzapine, or haloperidol and followed up for 1 year. Three hundred out-patients with persistent schizophrenia were recruited in 35 mental health services. The intention-to-treat (ITT) analysis found no significant differences in the rate of MS between aripiprazole (37%), olanzapine (47%), and haloperidol (42%). Treatment discontinuation for any cause was higher for aripiprazole (52%) than for olanzapine (33%; OR, 0.41; P = 0.004), or haloperidol (37%; OR, 0.51; P = 0.030). No significant difference was found between olanzapine and haloperidol. Time to discontinuation for any cause was longer for olanzapine than for aripiprazole (HR, 0.55; P < 0.001). No significant differences were found between haloperidol and aripiprazole, or between olanzapine and haloperidol. The prescription of aripiprazole did not significantly reduce the rates of MS, but its treatment retention was worse. Aripiprazole cannot be considered the safest and most effective drug for maintenance treatment of schizophrenia in routine care, although it may have a place in antipsychotic therapy. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Treatment of type 2 diabetes with a combination regimen of repaglinide plus pioglitazone.
Jovanovic, Lois; Hassman, David R; Gooch, Brent; Jain, Rajeev; Greco, Susan; Khutoryansky, Naum; Hale, Paula M
2004-02-01
The efficacy and safety of combination therapy (repaglinide plus pioglitazone) was compared to repaglinide or pioglitazone in 24-week treatment of type 2 diabetes. This randomized, multicenter, open-label, parallel-group study enrolled 246 adults (age 24-85) who had shown inadequate response in previous sulfonylurea or metformin monotherapy (HbA(1c) > 7%). Prior therapy was withdrawn for 2 weeks, followed by randomization to repaglinide, pioglitazone, or repaglinide/pioglitazone. In the first 12 weeks of treatment, repaglinide doses were optimized, followed by 12 weeks of maintenance therapy. Pioglitazone dosage was fixed at 30 mg per day. Baseline HbA(1c) values were comparable (9.0% for repaglinide, 9.1% for pioglitazone, 9.3% for combination). Mean changes in HbA(1c) values at the end of treatment were -1.76% for repaglinide/pioglitazone, -0.18% for repaglinide, +0.32% for pioglitazone. Fasting plasma glucose reductions were -82 mg/dl for combination therapy, -34 mg/dl for repaglinide, -18 mg/dl for pioglitazone. Minor hypoglycemia occurred in 5% of patients for the combination, 8% for repaglinide, and 3% for pioglitazone. Weight gains for combination therapy were correlated to individual HbA(1c) reductions. In summary, for patients who had previously failed oral antidiabetic monotherapy, the combination repaglinide/pioglitazone had acceptable safety, with greater reductions of glycemic parameters than therapy using either agent alone.
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Siriswangvat, Suksiri; Sansanayudh, Nakarin; Nathisuwan, Surakit; Panomvana, Duangchit
2010-10-01
Emerging data suggests that several proton pump inhibitors (PPIs), including omeprazole, might interfere with the antiplatelet action of clopidogrel. However, there is a lack of data for rabeprazole. This study aimed to investigate and compare the impact of omeprazole and rabeprazole on the antiplatelet action of clopidogrel among patients with coronary artery disease (CAD). A prospective, randomized, open-labeled study was conducted among 87 CAD patients receiving clopidogrel and aspirin. Forty three and 44 patients were randomized to receive omeprazole 20 mg and rabeprazole 20 mg once daily, respectively, for at least 2 weeks. Adenosine 5-diphosphate 20 µmol/L-induced platelet aggregation was performed before and after PPIs treatment. Mean maximal platelet aggregation (MPA) before and after PPIs treatment of both groups were compared. At baseline, there were no significant differences in the mean MPA between the omeprazole and rabeprazole groups (40.68 ± 18.82% vs 36.42 ± 21.39%; P=0.326). After a 2-week treatment with PPIs, the mean MPA in both groups significantly increased from baseline and there were no differences between the omeprazole and rabeprazole groups (55.73 ± 19.66% vs 48.46 ± 18.80%; P=0.141). Both omeprazole and rabeprazole decreased the antiplatelet effect of clopidogrel. Use of these agents resulted in a similar degree of interference on clopidogrel's action, as measured by ADP-induced platelet aggregation.
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Pagel, Judith-Irina; Hulde, Nikolai; Kammerer, Tobias; Schwarz, Michaela; Chappell, Daniel; Burges, Alexander; Hofmann-Kiefer, Klaus; Rehm, Markus
2017-07-10
This study aims to investigate the effects of a modified, balanced crystalloid including phosphate in a perioperative setting in order to maintain a stable electrolyte and acid-base homeostasis in the patient. This is a single-centre, open-label, randomized controlled trial involving two parallel groups of female patients comparing a perioperative infusion regime with sodium glycerophosphate and Jonosteril® (treatment group) or Jonosteril® (comparator) alone. The primary endpoint is to maintain a stable concentration of weak acids [A - ] according to the Stewart approach of acid-base balance. Secondary endpoints are measurement of serum phosphate levels, other acid-base parameters such as the strong ion difference (SID), the onset and severity of postoperative nausea and vomiting (PONV), electrolyte levels and their excretion in the urine, monitoring of renal function and glycocalyx components, haemodynamics, amounts of catecholamines and other vasopressors used and the safety of the infusion regime. Perioperative fluid replacement with the use of currently available crystalloid preparations still fail to maintain a stable acid-base balance and experts agree that common balanced solutions are still not ideal. This study aims to investigate the effectivity and safety of a new crystalloid solution by adding sodium glycerophosphate to a standardized crystalloid preparation in order to maintain a balanced perioperative acid-base homeostasis. EudraCT number 201002422520 . Registered on 30 November 2010.
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Bookhart, Brahim K; Haskell, Lloyd; Bamber, Luke; Wang, Maria; Schein, Jeff; Mody, Samir H
2014-10-01
Venous thromboembolism (VTE) (deep vein thrombosis [DVT] and pulmonary embolism [(PE]) represents a substantial economic burden to the healthcare system. Using data from the randomized EINSTEIN DVT and PE trials, this North American sub-group analysis investigated the potential of rivaroxaban to reduce the length of initial hospitalization in patients with acute symptomatic DVT or PE. A post-hoc analysis of hospitalization and length-of-stay (LOS) data was conducted in the North American sub-set of patients from the randomized, open-label EINSTEIN trial program. Patients received either rivaroxaban (15 mg twice daily for 3 weeks followed by 20 mg once daily; n = 405) or dose-adjusted subcutaneous enoxaparin overlapping with (guideline-recommended 'bridging' therapy) and followed by a vitamin K antagonist (VKA) (international normalized ratio = 2.0-3.0; n = 401). The open-label study design allowed for the comparison of LOS between treatment arms under conditions reflecting normal clinical practice. LOS was evaluated using investigator records of dates of admission and discharge. Analyses were carried out in the intention-to-treat population using parametric tests. Costs were applied to the LOS based on weighted mean cost per day for DVT and PE diagnoses obtained from the Healthcare Cost and Utilization Project dataset. Of 382 patients hospitalized, 321 (84%), had acute symptomatic PE; few DVT patients required hospitalization. Similar rates of VTE patients were hospitalized in the rivaroxaban and enoxaparin/VKA treatment groups, 189/405 (47%) and 193/401 (48%), respectively. In hospitalized VTE patients, rivaroxaban treatment produced a 1.6-day mean reduction in LOS (median = 1 day) compared with enoxaparin/VKA (mean = 4.5 vs 6.1; median = 3 vs 4), translating to total costs that were $3419 lower in rivaroxaban-treated patients. In hospitalized North American patients with VTE, treatment with rivaroxaban produced a statistically significant reduction in LOS. When treating DVT and PE patients, clinicians should consider newer anti-coagulants with less complex treatment regimens.
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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.
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Loebermann, Micha; Kollaritsch, Herwig; Ziegler, Tom; Rendi-Wagner, Pamela; Chambonneau, Laurent; Dumas, Rafaele; Lafrenz, Michael
2004-07-01
Travelers are often advised to receive both the typhoid fever and hepatitis A virus (HAV) vaccines, particularly when going to areas where the 2 diseases are endemic. Thus, combined administration of these vaccines could make immunization more acceptable by reducing the number of injections needed. This study compared the safety profiles and immunogenicity of 3 batches of a combined typhoid fever/HAV vaccine administered using a dual-chamber bypass syringe. This randomized, open-label study was conducted at 2 university-based travel clinics in Germany and Austria. Subjects received a single IM injection from 1 of 3 batches of the combined vaccine. Blood samples were drawn immediately before and 28 days after vaccination to evaluate the response to the 2 antigens by assessing geometric mean titers (GMTs) and rates of seroconversion and seroprotection. Subjects recorded all adverse events (AEs) occurring during the study period in a diary. Six hundred ten healthy adults were enrolled in the study. Twenty-eight days after vaccination, 90.6% of the study population had protective typhoid Vi antibody titers (> or = 1 microg/mL) and 100% had protective HAV antibody titers (> or = 20 mIU/mL). Seroconversion rates and GMTs were not significantly different between the 3 batches. There were no differences with regard to local or systemic AEs between the 3 batches of vaccine. There were no immediate adverse reactions (within 30 minutes of vaccination) and no serious AEs related to vaccination. Of 609 evaluable subjects (1 was lost to follow-up after the first visit), 555 (91.1%) experienced > or = 1 local reaction within the first 7 days after vaccination, mainly pain at the injection site (550 [90.3%]), but only 26 (4.3%) described this pain as severe. Vaccine-related headache and mild to moderate asthenia were each reported by 54 subjects (8.9%). Symptoms resolved spontaneously in all cases. The 3 batches of the combined typhoid fever/HAV vaccine administered by dual-chamber bypass syringe were equally well tolerated and effective in healthy adults, and did not differ significantly in terms of GMTs or seroconversion rates.
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Choi, YoonJung; Lee, SeungHwan; Cho, Sang-Min; Kang, Won-Ho; Nam, Kyu-Yeol; Jang, In-Jin; Yu, Kyung-Sang
2016-01-01
A fixed-dose combination (FDC) of amlodipine and losartan has been used to reduce blood pressure in patients whose hypertension is not sufficiently controlled with either drug alone. The aim of this study was to evaluate the pharmacokinetic (PK) characteristics and tolerability of an FDC of 6.94 mg amlodipine besylate (5 mg as amlodipine)/50 mg losartan potassium compared to an FDC of 5 mg amlodipine camsylate/50 mg losartan potassium in healthy subjects. A randomized, open-label, single-dose, two-period, two-sequence crossover study was conducted on 46 healthy male subjects. Blood concentrations were measured by liquid chromatography-tandem mass spectrometry. Blood samples were collected up to 144 hours post dose for each period. PK parameters were calculated in each treatment group using a noncompartmental method. The 90% confidence intervals (CIs) of the geometric mean ratios of the two treatments for the maximum plasma concentration ( C max ) and the area under the concentration curve from time zero to the last quantifiable time point (AUC 0-t ) were estimated. Tolerability assessments were performed for all subjects who received the drug at least once. The PK profiles of the two treatments were similar. For amlodipine, the geometric mean ratios (90% CIs) of amlodipine besylate to amlodipine camsylate for the C max and AUC 0-t were 0.98 (0.94-1.01) and 0.97 (0.93-1.01), respectively. The corresponding values for losartan were 0.91 (0.81-1.02) and 1.05 (0.98-1.12), respectively. The incidence of adverse events was not significantly different between the two treatments, and both were well tolerated. An FDC of 6.94 mg amlodipine besylate (5 mg as amlodipine)/50 mg losartan potassium produced similar results to an FDC of 5 mg amlodipine camsylate/50 mg losartan potassium treatment with respect to the PK parameters of amlodipine and losartan based on C max and AUC 0-t values. The amlodipine besylate/losartan potassium combination was well tolerated by healthy male subjects.
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Very high volume hemofiltration with the Cascade system in septic shock patients.
Quenot, Jean-Pierre; Binquet, Christine; Vinsonneau, Christophe; Barbar, Saber-David; Vinault, Sandrine; Deckert, Valerie; Lemaire, Stéphanie; Hassain, Ali Ait; Bruyère, Rémi; Souweine, Bertrand; Lagrost, Laurent; Adrie, Christophe
2015-12-01
We compared hemodynamic and biological effects of the Cascade system, which uses very high volume hemofiltration (HVHF) (120 mL kg(-1) h(-1)), with those of usual care in patients with septic shock. Multicenter, prospective, randomized, open-label trial in three intensive care units (ICU). Adults with septic shock with administration of epinephrine/norepinephrine were eligible. Patients were randomized to usual care plus HVHF (Cascade group), or usual care alone (control group). Primary end point was the number of catecholamine-free days up to 28 days after randomization. Secondary end points were number of days free of mechanical ventilation, renal replacement therapy (RRT) or ICU up to 90 days, and 7-, 28-, and 90-day mortality. We included 60 patients (29 Cascade, 31 usual care). Baseline characteristics were comparable. Median number of catecholamine-free days was 22 [IQR 11-23] vs 20 [0-25] for Cascade vs control; there was no significant difference even after adjustment. There was no significant difference in number of mechanical ventilation-free days or ICU requirement. Median number of RRT-free days was 85 [46-90] vs 74 [0-90] for Cascade vs control groups, p = 0.42. By multivariate analysis, the number of RRT-free days was significantly higher in the Cascade group (up to 25 days higher after adjustment). There was no difference in mortality at 7, 28, or 90 days. Very HVHF using the Cascade system can safely be used in patients presenting with septic shock, but it was not associated with a reduction in the need for catecholamines during the first 28 days.
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Bernstein, Richard A; Kamel, Hooman; Granger, Christopher B; Kowal, Robert C; Ziegler, Paul D; Schwamm, Lee H
2017-08-01
Approximately 20% of ischemic strokes are associated with clinically apparent atrial fibrillation (AF). Regardless of stroke etiology, detection of AF in patients with ischemic strokes often changes antithrombotic treatment from anti-platelet to oral anticoagulation therapy. The role and the optimum duration of cardiac monitoring to detect AF in patients with strokes presumed due to large vessel atherosclerosis or small vessel disease is unknown. This manuscript describes the design and rationale of the STROKE-AF trial. STROKE-AF is a randomized, controlled, open-label, post-market clinical trial. Detection of AF will be evaluated using continuous arrhythmia monitoring with an insertable cardiac monitor (ICM) compared with standard of care follow-up in patients with stroke (within the prior 10 days) that is presumed due to large vessel cervical or intracranial atherosclerosis, or to small vessel disease. Approximately 500 patients will be enrolled at approximately 40 centers in the United States. Patients will be randomized 1:1 to arrhythmia monitoring with an ICM (continuous monitoring arm) or standard of care follow-up (control arm). Subjects will be followed for ≥12 months and up to 3 years. The primary objective is to compare the incidence rate of detected AF through 12 months of follow-up between the two arms. This trial will provide information on the value of ICMs to detect subclinical AF in patients with stroke presumed due to large vessel atherosclerosis or small vessel disease, which will have implications for guiding treatment with oral anticoagulation for secondary stroke prevention. Copyright © 2017 Elsevier Inc. All rights reserved.
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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.
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Apixaban and dalteparin in active malignancy associated venous thromboembolism. The ADAM VTE Trial.
McBane Ii, Robert; Loprinzi, Charles L; Ashrani, Aneel; Perez-Botero, Juliana; Leon Ferre, Roberto A; Henkin, Stanislav; Lenz, Charles J; Le-Rademacher, Jennifer G; Wysokinski, Waldemar E
2017-10-05
Currently, low molecular weight heparin (LMWH) is the guideline endorsed treatment of patients with cancer associated venous thromboembolism (VTE). While apixaban is approved for the treatment of acute VTE, there are limited data supporting its use in cancer patients. The rationale and design of this investigator initiated Phase IV, multicenter, randomized, open label, superiority trial assessing the safety of apixaban versus dalteparin for cancer associated VTE is provided (ADAM-VTE; NCT02585713). The main aim of the ADAM-VTE trial is to test the hypothesis that apixaban is associated with a significantly lower rate of major bleeding compared to dalteparin in the treatment of cancer patients with acute VTE. The primary safety outcome is rate of major bleeding. Secondary efficacy objective is to assess the rates of recurrent VTE or arterial thromboembolism. Cancer patients with acute VTE (n=300) are randomized to receive apixaban (10 mg twice daily for 7 days followed by 5 mg twice daily thereafter) or dalteparin (200 IU/Kg daily for 30 days followed by 150 IU/kg daily thereafter) for 6 months. Stratification factors used for randomization include cancer stage and cancer specific risk of venous thromboembolism using the Khorana score. Participating centers are chosen from the Academic and Community Cancer Research United (ACCRU) consortium comprised of 90 oncology practices in the United States and Canada. Based on the hypothesis to be tested, we anticipate that these trial results will provide evidence supporting apixaban as an effective treatment of cancer associated VTE at lower rates of major bleeding compared to LMWH.
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Motta, Massimo; Russo, Cristina; Vacante, Marco; Liardo, Rocco Luca Emanuele; Reitano, Francesca; Cammalleri, Lisa; Costanzo, Mario; Benfatto, Giuseppe; Frazzetto, Paola; Mondati, Enrico; Malaguarnera, Michele; Pennisi, Giovanni
2011-01-01
Elderly neoplastic patients frequently may show hypertension and hyperuricemia, before and after chemotherapeutic treatments. The purpose of this study was to evaluate the efficacy of losartan which is an antihypertensive drug with uricosuric properties vs. amlodipine in hypertensive neoplastic elderly patients. This was an open-labeled, randomized, comparative trial. The study was performed as a 30-day study. Seventy patients with cancer were randomly assigned to receive losartan or amlodipine. Blood pressure (BP), blood urea nitrogen (BUN) levels, creatinine, serum and urinary uric acid, creatinine and uric acid clearance were determined before and after chemotherapy. One day after chemotherapy in losartan group vs. amlodipine group we observed a significant difference in urinary uric acid (p<0.001) of 18 mg/24 h vs. 40 mg/24 h. Thirty days after chemotherapy we observed a significant difference in azotemia of 0.0 mg/dl vs. 3.8 mg/dl (p<0.001), serum uric acid of 0.05 mg/dl vs. 0.49 mg/dl (p<0.001), urinary uric acid (p<0.001) of 23 mg/24 h vs. 0.0 mg/24 h, GFR of 2 ml/min/1.73 m(2) vs. -8 ml/min/1.73 m(2) (p<0.05) and systolic BP (SBP) of 3.6 mmHg vs. 0.8 mmHg (p<0.05). The findings of the present study support the effective role of losartan compared to amlodipine in treating hypertension and hyperuricemia in elderly patients under chemotherapeutic treatment. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
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Lin, Yi-Hua; Liao, Xi-Ning; Fan, Li-Li; Qu, Yue-Jin
2017-01-01
Background The systemic inflammation is associated with clinical outcome and mortality in chronic obstructive pulmonary disease (COPD) patients. To investigate the effects of tiotropium (Tio) and/or budesonide/formoterol (Bud/Form) on systemic inflammation biomarkers in stable COPD patients of group D, a randomized, open-label clinical trial was conducted. Methods Eligible participants (n = 324) were randomized and received either Tio 18ug once daily (group I), Bud/Form 160/4.5ug twice daily (group II), Bud/Form 320/9ug twice daily (group III), or Tio 18ug once daily with Bud/Form 160/4.5ug twice daily (group IV) for 6 months. Systemic inflammation biomarkers were measured before randomization and during the treatment, including C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-8 (IL-8), serum amyloid A (SAA), tumor necrosis factor-α (TNF-α), fibrinogen (Fib), and white blood cell (WBC). Results After 6-month treatment, CRP levels in group II, group III and group IV changed by a median (interquartile range) of -1.25 (-3.29, 1.18) mg/L, -1.13 (-2.55, 0.77) mg/L, and -1.56 (-4.64, 0.22) mg/L respectively, all of which with statistical differences compared with group I. In addition, there were no treatment differences in terms of IL-8, SAA, TNF-α, Fib and WBC levels. Conclusions A long-term treatment with Bud/Form alone or together with Tio can attenuate circulating CRP levels in COPD patients of group D, compared with Tio alone. PMID:28832630