placebo-controlled study designed: Topics by Science.gov

Sample records for placebo-controlled study designed

Are There Scenarios When the Use of Non-Placebo-Control Groups in Experimental Trial Designs Increase Expected Value to Society?

PubMed

Uyei, Jennifer; Braithwaite, R Scott

2016-01-01

Despite the benefits of the placebo-controlled trial design, it is limited by its inability to quantify total benefits and harms. Such trials, for example, are not designed to detect an intervention's placebo or nocebo effects, which if detected could alter the benefit-to-harm balance and change a decision to adopt or reject an intervention. In this article, we explore scenarios in which alternative experimental trial designs, which differ in the type of control used, influence expected value across a range of pretest assumptions and study sample sizes. We developed a decision model to compare 3 trial designs and their implications for decision making: 2-arm placebo-controlled trial ("placebo-control"), 2-arm intervention v. do nothing trial ("null-control"), and an innovative 3-arm trial design: intervention v. do nothing v. placebo trial ("novel design"). Four scenarios were explored regarding particular attributes of a hypothetical intervention: 1) all benefits and no harm, 2) no biological effect, 3) only biological effects, and 4) surreptitious harm (no biological benefit or nocebo effect). Scenario 1: When sample sizes were very small, the null-control was preferred, but as sample sizes increased, expected value of all 3 designs converged. Scenario 2: The null-control was preferred regardless of sample size when the ratio of placebo to nocebo effect was >1; otherwise, the placebo-control was preferred. Scenario 3: When sample size was very small, the placebo-control was preferred when benefits outweighed harms, but the novel design was preferred when harms outweighed benefits. Scenario 4: The placebo-control was preferred when harms outweighed placebo benefits; otherwise, preference went to the null-control. Scenarios are hypothetical, study designs have not been tested in a real-world setting, blinding is not possible in all designs, and some may argue the novel design poses ethical concerns. We identified scenarios in which alternative experimental study designs would confer greater expected value than the placebo-controlled trial design. The likelihood and prevalence of such situations warrant further study. © The Author(s) 2015.
Importance of placebo effect in cough clinical trials.

PubMed

Eccles, Ron

2010-01-01

Cough is a unique symptom because, unlike sneeze and other symptoms, it can be under voluntary control and this complicates clinical trials on cough medicines. All over-the-counter cough medicines (OTC) are very effective treatments because of their placebo effect. The placebo effect is enhanced by expectancy related to advertising, brand, packaging, and formulation. This placebo effect creates a problem for the conduct of clinical trials on OTC cough medicines that attempt to demonstrate the efficacy of a pharmacological agent above that of any placebo effect. Up to 85% of the efficacy of some cough medicines can be attributed to a placebo effect. The placebo effect apparent in clinical trials consists of several components: natural recovery, regression of cough response toward mean, demulcent effect, effect of sweetness, voluntary control, and effects related to expectancy and meaning of the treatment. The placebo effect has been studied most in the pain model, and placebo analgesia is reported to depend on the activation of endogenous opioid systems in the brain; this model may be applicable to cough. A balanced placebo design may help to control for the placebo effect, but this trial design may not be acceptable due to deception of patients. The placebo effect in clinical trials may be controlled by use of a crossover design, where feasible, and the changes in the magnitude of the placebo effect in this study design are discussed.
Does EEG-Neurofeedback Improve Neurocognitive Functioning in Children with Attention-Deficit/Hyperactivity Disorder? A Systematic Review and a Double-Blind Placebo-Controlled Study

ERIC Educational Resources Information Center

Vollebregt, Madelon A.; van Dongen-Boomsma, Martine; Buitelaar, Jan K.; Slaats-Willemse, Dorine

2014-01-01

Background: The number of placebo-controlled randomized studies relating to EEG-neurofeedback and its effect on neurocognition in attention-deficient/hyperactivity disorder (ADHD) is limited. For this reason, a double blind, randomized, placebo-controlled study was designed to assess the effects of EEG-neurofeedback on neurocognitive functioning…
Use of placebo controls in the evaluation of surgery: systematic review

PubMed Central

Judge, Andrew; Hopewell, Sally; Collins, Gary S; Dean, Benjamin J F; Rombach, Ines; Brindley, David; Savulescu, Julian; Beard, David J; Carr, Andrew J

2014-01-01

Objective To investigate whether placebo controls should be used in the evaluation of surgical interventions. Design Systematic review. Data sources We searched Medline, Embase, and the Cochrane Controlled Trials Register from their inception to November 2013. Study selection Randomised clinical trials comparing any surgical intervention with placebo. Surgery was defined as any procedure that both changes the anatomy and requires a skin incision or use of endoscopic techniques. Data extraction Three reviewers (KW, BJFD, IR) independently identified the relevant trials and extracted data on study details, outcomes, and harms from included studies. Results In 39 out of 53 (74%) trials there was improvement in the placebo arm and in 27 (51%) trials the effect of placebo did not differ from that of surgery. In 26 (49%) trials, surgery was superior to placebo but the magnitude of the effect of the surgical intervention over that of the placebo was generally small. Serious adverse events were reported in the placebo arm in 18 trials (34%) and in the surgical arm in 22 trials (41.5%); in four trials authors did not specify in which arm the events occurred. However, in many studies adverse events were unrelated to the intervention or associated with the severity of the condition. The existing placebo controlled trials investigated only less invasive procedures that did not involve laparotomy, thoracotomy, craniotomy, or extensive tissue dissection. Conclusions Placebo controlled trial is a powerful, feasible way of showing the efficacy of surgical procedures. The risks of adverse effects associated with the placebo are small. In half of the studies, the results provide evidence against continued use of the investigated surgical procedures. Without well designed placebo controlled trials of surgery, ineffective treatment may continue unchallenged. PMID:24850821
Design of clinical trials of antidepressants: should a placebo control arm be included?

PubMed

Fritze, J; Möller, H J

2001-01-01

There is no doubt that available antidepressants are efficacious and effective. Nevertheless, more effective drugs with improved tolerability are needed. With this need in mind, some protagonists claim that future antidepressants should be proved superior to, or at least as effective as, established antidepressants, making placebo control methodologically dispensable in clinical trials. Moreover, the use of placebo control is criticised as unethical because it might result in effective treatment being withheld. There are, however, a number of methodological reasons why placebo control is indispensable for the proof of efficacy of antidepressants. Comparing investigational antidepressants only with standard antidepressants and not placebo yields ambiguous results that are difficult to interpret, be it in superiority or equivalence testing, and this method of assessment requires larger sample sizes than those required with the use of placebo control. Experimental methodology not adhering to the optimal study design is ethically questionable. Restricting the testing of investigational antidepressants only to superiority over standard antidepressants is an obstacle to therapeutic progress in terms of tolerability and the detection of innovative mechanisms of action from which certain subgroups of future patients might benefit. The use of a methodology that requires larger samples for testing of superiority or equivalence is also ethically questionable. In view of the high placebo response rates in trials of antidepressants, placebo treatment does not mean withholding effective treatment. Accepting the necessity of the clinical evaluation of new, potentially ineffective antidepressants implicitly means accepting placebo control as ethically justified. Three- or multi-arm comparisons including placebo and an active reference represent the optimal study design.
Surgical “Placebo” Controls

PubMed Central

Tenery, Robert; Rakatansky, Herbert; Riddick, Frank A.; Goldrich, Michael S.; Morse, Leonard J.; O’Bannon, John M.; Ray, Priscilla; Smalley, Sherie; Weiss, Matthew; Kao, Audiey; Morin, Karine; Maixner, Andrew; Seiden, Sam

2002-01-01

Objective To set ethical guidelines on the use of surgical placebo controls in the design of surgical trials. Background Data Ethical concerns recently arose from surgical trials where subjects in the control arm underwent surgical procedures that had the appearance of a therapeutic intervention, but during which the essential therapeutic maneuver was omitted. Although there are ethical guidelines on the use of a placebo in drug trials, little attention has been paid to the use of a surgical placebo control in surgical trials. Methods The Council on Ethical and Judicial Affairs developed ethical guidelines based on a wide literature search and consultation with experts. Results Surgical placebo controls should be limited to studies of new surgical procedures aimed at treating diseases that are not amenable to other surgical therapies, and are reasonably anticipated to be susceptible to substantial placebo effects. If the standard nonsurgical treatment is efficacious and acceptable to the patient, then it must be offered as part of the study design. Conclusions Surgical placebo controls should be used only when no other trial design will yield the requisite data and should always be accompanied by a rigorous informed consent process and a careful consideration of the related risks and benefits. The recommended ethical guidelines were adopted as AMA ethics policy and are now incorporated in the AMA’s Code of Medical Ethics. PMID:11807373
How informative are open-label studies for youth with bipolar disorder? A meta-analysis comparing open-label versus randomized, placebo-controlled clinical trials.

PubMed

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

2012-03-01

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

PubMed

Weimer, Katja; Enck, Paul

2014-01-01

Many study designs and design variants have been developed in the past to either overcome or enhance drug-placebo differences in clinical trials or to identify and characterize placebo responders in experimental studies. They share many commonalities as well as differences that are discussed here: the role of deception and ethical restrictions, habituation effects and the control of the natural course of disease, assay sensitivity testing and effective blinding, acceptability and motivation of patients and volunteers, and the development of individualized medicine. These are fostered by two opposite strategies: utilizing the beneficial aspects of the placebo response-and avoiding its negative counterpart, the nocebo effect-in medical routine for the benefit of patients, and minimizing-by controlling-the negative aspects of the placebo effect during drug development.
Efficient assessment of efficacy in post-traumatic peripheral neuropathic pain patients: pregabalin in a randomized, placebo-controlled, crossover study

PubMed Central

Jenkins, Tim M; Smart, Trevor S; Hackman, Frances; Cooke, Carol; Tan, Keith KC

2012-01-01

Background: Detecting the efficacy of novel analgesic agents in neuropathic pain is challenging. There is a critical need for study designs with the desirable characteristics of assay sensitivity, low placebo response, reliable pain recordings, low cost, short duration of exposure to test drug and placebo, and relevant and recruitable population. Methods: We designed a proof-of-concept, double-blind, randomized, placebo-controlled, crossover study in patients with post-traumatic peripheral neuropathic pain (PTNP) to evaluate whether such a study design had the potential to detect efficacious agents. Pregabalin, known to be efficacious in neuropathic pain, was used as the active analgesic. We also assessed physical activity throughout the study. Results: Twenty-five adults (20–70 years of age) with PTNP for ≥3 months entered a screening week and were then randomized to one of the two following treatment sequences: (1) pregabalin followed by placebo or (2) placebo followed by pregabalin. These 2-week treatment periods were separated by a 2-week washout period. Patients on pregabalin treatment received escalating doses to a final dosage of 300 mg/day (days 5–15). In an attempt to minimize placebo response, patients received placebo treatment during the screening week and the 2-week washout period. Average daily pain scores (primary endpoint) were significantly reduced for pregabalin versus placebo, with a mean treatment difference of −0.81 (95% confidence interval: −1.45 to −0.17; P = 0.015). Conclusion: The efficacy of pregabalin was similar to that identified in a large, parallel group trial in PTNP. Therefore, this efficient crossover study design has potential utility for future proof-of-concept studies in neuropathic pain. PMID:22888270
Improving the quality of randomized controlled trials in Chinese herbal medicine, part II: control group design.

PubMed

Bian, Zhao-Xiang; Moher, David; Dagenais, Simon; Li, You-Ping; Liu, Liang; Wu, Tai-Xiang; Miao, Jiang-Xia

2006-03-01

To discuss the types of control groups in randomized controlled trials (RCTs) of Chinese herbal medicine (CHM), and to provide suggestions for improving the design of control group in future clinical studies in this therapeutic area. A search of the Cochrane Library was conducted in July 2005 to identify RCTs of CHM, and 66 RCTs with CHM for type 2 diabetes mellitus were obtained as the basis for further analysis. Of 66 RCTs with CHM for type 2 diabetes mellitus, 61 (92.4%) trials had both a treatment group and a control group. Twenty-seven (40.9%) RCTs compared CHM plus conventional drug vs conventional drug, 24 (36.4%) compared CHM vs conventional drug, 5 (7.6%) compared CHM vs placebo, 3 (4.5%) compared CHM plus conventional drug vs conventional drug plus placebo, 3 (4.5%) compared CHM plus conventional drug vs other CHM, 1 (1.5%) compared CHM vs no treatment, 1 (1.5%) compared CHM plus placebo vs conventional drug plus placebo, 1 (1.5%) compared CHM vs CHM plus conventional drug vs conventional drug vs placebo, and 1 (1.5%) compared CHM vs conventional drug vs CHM plus conventional drug. A variety of control groups were used in RCTs of CHM for type 2 diabetes mellitus, including placebo, active, and no treatment control groups. Justification for selecting particular types of control groups were not provided in the trials reviewed in this study. Different control groups may be appropriate according to the study objectives, and several factors should be considered prior to selecting control groups in future RCTs of CHM. (1) Investigators of CHM who design clinical trials should understand the rationale for selecting different types of control groups; (2) Control groups for RCTs should be selected according to study objectives; (3) Active control groups should select interventions for comparisons that have the strongest evidence of efficacy and prescribe them as recommended; (4) Placebo control groups should select a placebo that mimics the physical characteristics of test intervention as closely as possible and is completely inert; (5) No treatment control groups should only be used when withholding treatment is ethical and objectives outcomes will not be subject to bias due to absent blinding; (6) Crossover control groups may be appropriate in chronic and stable conditions.
Predictive factors for the placebo effect in clinical trials for dry eye: a pooled analysis of three clinical trials.

PubMed

Imanaka, Takahiro; Sato, Izumi; Tanaka, Shiro; Kawakami, Koji

2017-11-01

Placebo effect is one of the methodological difficulties in dry eye clinical trials. If we could elucidate the tendencies of the placebo response and find predictors, we could reduce the placebo response in clinical trials for dry eye. In this study, we investigated the predictive factors for the placebo effect in dry eye clinical trials. A total of 205 patients with dry eye assigned to the placebo arms of three placebo-controlled randomised clinical trials were analysed by simple and multivariable regression analysis. The corneal fluorescein (FL) staining score and dry eye symptoms were studied at week 4. The variables of interest included gender, age, complications of Sjögren's syndrome, Schirmer's test I value, tear break-up time and conjunctival hyperaemia score. We also conducted a stratified analysis according to the patients' age. Among all the studied endpoints, the baseline scores were significantly related to the corresponding placebo response. In addition, for the FL score and the dryness score, age was a significant predictor of the placebo response (p=0.04 and p<0.0001, respectively). Stratified analysis by age showed that patients more than 40 years of age are more likely to have a stronger placebo response in the FL and dryness scores. The baseline scores and age were predictive factors of the placebo response in frequently used endpoints, such as FL score or dryness symptoms. These patient characteristics can be controlled by study design, and our findings enable the design of more efficient placebo-controlled studies with good statistical power. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Placebo Response in Repetitive Transcranial Magnetic Stimulation Trials of Treatment of Auditory Hallucinations in Schizophrenia: A Meta-Analysis

PubMed Central

Dollfus, Sonia; Lecardeur, Laurent; Morello, Rémy; Etard, Olivier

2016-01-01

Several meta-analyses have assessed the response of patients with schizophrenia with auditory verbal hallucinations (AVH) to treatment with repetitive transcranial magnetic stimulation (rTMS); however, the placebo response has never been explored. Typically observed in a therapeutic trial, the placebo effect may have a major influence on the effectiveness of rTMS. The purpose of this meta-analysis is to evaluate the magnitude of the placebo effect observed in controlled studies of rTMS treatment of AVH, and to determine factors that can impact the magnitude of this placebo effect, such as study design considerations and the type of sham used. The study included twenty-one articles concerning 303 patients treated by sham rTMS. A meta-analytic method was applied to obtain a combined, weighted effect size, Hedges’s g. The mean weighted effect size of the placebo effect across these 21 studies was 0.29 (P < .001). Comparison of the parallel and crossover studies revealed distinct results for each study design; placebo has a significant effect size in the 13 parallel studies (g = 0.44, P < 10−4), but not in the 8 crossover studies (g = 0.06, P = .52). In meta-analysis of the 13 parallel studies, the 45° position coil showed the highest effect size. Our results demonstrate that placebo effect should be considered a major source of bias in the assessment of rTMS efficacy. These results fundamentally inform the design of further controlled studies, particularly with respect to studies of rTMS treatment in psychiatry. PMID:26089351
Genetics and the Placebo Effect: the Placebome

PubMed Central

Hall, Kathryn T.; Loscalzo, Joseph; Kaptchuk, Ted J.

2015-01-01

Placebos are indispensable controls in randomized clinical trials (RCTs), and placebo responses significantly contribute to routine clinical outcomes. Recent neurophysiological studies reveal neurotransmitter pathways that mediate placebo effects. Evidence that genetic variations in these pathways can modify placebo effects raises the possibility of using genetic screening to identify placebo responders and thereby increase RCT efficacy and improve therapeutic care. Furthermore, the possibility of interaction between placebo and drug molecular pathways warrants consideration in RCT design. The study of genomic effects on placebo response, “the placebome”, is in its infancy. Here, we review evidence from placebo studies and RCTs to identify putative genes in the placebome, examine evidence for placebo-drug interactions, and discuss implications for RCTs and clinical care. PMID:25883069
Attitudes toward placebo-controlled clinical trials among depressed patients in Japan.

PubMed

Sugawara, Norio; Ishioka, Masamichi; Tsuchimine, Shoko; Tsuruga, Koji; Sato, Yasushi; Tarakita, Natsumi; Furukori, Hanako; Kudo, Shuhei; Tomita, Tetsu; Nakagami, Taku; Yasui-Furukori, Norio

2018-01-01

Placebo-controlled clinical trials are the standard in the design of clinical studies for the licensing of new drugs. Medical and ethical concerns regarding placebo use still exist in clinical trials of depressed patients. The aim of this study was to investigate the attitudes toward placebo-controlled clinical trials and to assess factors related to the willingness to participate in such trials among depressed patients in Japan. A total of 206 depressed patients aged 49.5 ± 15.7 years (mean ± SD) who were admitted to three psychiatric hospitals were recruited for a cross-sectional study from June 2015 to March 2016. After a thorough explanation of the placebo, the study participants completed a brief 14-item questionnaire developed to evaluate patients' attitudes regarding possible participation in placebo-controlled clinical trials. The Quick Inventory of Depressive Symptomatology was also administered to assess depressive symptoms. The results indicated that 47% of the patients would be willing to participate in a placebo-controlled clinical trial. Expectations for the improvement of disease, desire to receive more medical care, encouragement by family or friends, and desire to support the development of new drugs were associated with the willingness to participate in such trials, whereas a belief that additional time would be required for medical examinations and fear of exacerbation of symptoms due to placebo use were associated with non-participation. Patients were asked about possible participation in placebo-controlled clinical trials. Less than half of the respondents were willing to participate in placebo-controlled clinical trials. Attitudes toward participation in a placebo-controlled clinical trial need to be considered when deciding whether to conduct such a trial. Copyright © 2017. Published by Elsevier B.V.
Etoricoxib - preemptive and postoperative analgesia (EPPA) in patients with laparotomy or thoracotomy - design and protocols

PubMed Central

2010-01-01

Background and Objective Our objective was to report on the design and essentials of the Etoricoxib protocol- Preemptive and Postoperative Analgesia (EPPA) Trial, investigating whether preemptive analgesia with cox-2 inhibitors is more efficacious than placebo in patients who receive either laparotomy or thoracotomy. Design and Methods The study is a 2 × 2 factorial armed, double blinded, bicentric, randomised placebo-controlled trial comparing (a) etoricoxib and (b) placebo in a pre- and postoperative setting. The total observation period is 6 months. According to a power analysis, 120 patients scheduled for abdominal or thoracic surgery will randomly be allocated to either the preemptive or the postoperative treatment group. These two groups are each divided into two arms. Preemptive group patients receive etoricoxib prior to surgery and either etoricoxib again or placebo postoperatively. Postoperative group patients receive placebo prior to surgery and either placebo again or etoricoxib after surgery (2 × 2 factorial study design). The Main Outcome Measure is the cumulative use of morphine within the first 48 hours after surgery (measured by patient controlled analgesia PCA). Secondary outcome parameters include a broad range of tests including sensoric perception and genetic polymorphisms. Discussion The results of this study will provide information on the analgesic effectiveness of etoricoxib in preemptive analgesia and will give hints on possible preventive effects of persistent pain. Trial registration NCT00716833 PMID:20504378
Working Memory Training in Young Children with ADHD: A Randomized Placebo-Controlled Trial

ERIC Educational Resources Information Center

Dongen-Boomsma, Martine; Vollebregt, Madelon A.; Buitelaar, Jan K.; Slaats-Willemse, Dorine

2014-01-01

Background: Until now, working memory training has not reached sufficient evidence as effective treatment for ADHD core symptoms in children with ADHD; for young children with ADHD, no studies are available. To this end, a triple-blind, randomized, placebo-controlled study was designed to assess the efficacy of Cogmed Working Memory Training…
Developing a placebo-controlled trial in surgery: issues of design, acceptability and feasibility.

PubMed

Campbell, M K; Entwistle, V A; Cuthbertson, B H; Skea, Z C; Sutherland, A G; McDonald, A M; Norrie, J D; Carlson, R V; Bridgman, S

2011-02-21

Surgical placebos are controversial. This in-depth study explored the design, acceptability, and feasibility issues relevant to designing a surgical placebo-controlled trial for the evaluation of the clinical and cost effectiveness of arthroscopic lavage for the management of people with osteoarthritis of the knee in the UK. Two surgeon focus groups at a UK national meeting for orthopaedic surgeons and one regional surgeon focus group (41 surgeons); plenary discussion at a UK national meeting for orthopaedic anaesthetists (130 anaesthetists); three focus groups with anaesthetists (one national, two regional; 58 anaesthetists); two focus groups with members of the patient organisation Arthritis Care (7 participants); telephone interviews with people on consultant waiting lists from two UK regional centres (15 participants); interviews with Chairs of UK ethics committees (6 individuals); postal surveys of members of the British Association of Surgeons of the Knee (382 surgeons) and members of the British Society of Orthopaedic Anaesthetists (398 anaesthetists); two centre pilot (49 patients assessed). There was widespread acceptance that evaluation of arthroscopic lavage had to be conducted with a placebo control if scientific rigour was not to be compromised. The choice of placebo surgical procedure (three small incisions) proved easier than the method of anaesthesia (general anaesthesia). General anaesthesia, while an excellent mimic, was more intrusive and raised concerns among some stakeholders and caused extensive discussion with local decision-makers when seeking formal approval for the pilot.Patients were willing to participate in a pilot with a placebo arm; although some patients when allocated to surgery became apprehensive about the possibility of receiving placebo, and withdrew. Placebo surgery was undertaken successfully. Our study illustrated the opposing and often strongly held opinions about surgical placebos, the ethical issues underpinning this controversy, and the challenges that exist even when ethics committee approval has been granted. It showed that a placebo-controlled trial could be conducted in principle, albeit with difficulty. It also highlighted that not only does a placebo-controlled trial in surgery have to be ethically and scientifically acceptable but that it also must be a feasible course of action. The place of placebo-controlled surgical trials more generally is likely to be limited and require specific circumstances to be met. Suggested criteria are presented. The trial was assigned ISRCTN02328576 through http://controlled-trials.com/ in June 2006. The first patient was randomised to the pilot in July 2007.
Developing a placebo-controlled trial in surgery: Issues of design, acceptability and feasibility

PubMed Central

2011-01-01

Background Surgical placebos are controversial. This in-depth study explored the design, acceptability, and feasibility issues relevant to designing a surgical placebo-controlled trial for the evaluation of the clinical and cost effectiveness of arthroscopic lavage for the management of people with osteoarthritis of the knee in the UK. Methods Two surgeon focus groups at a UK national meeting for orthopaedic surgeons and one regional surgeon focus group (41 surgeons); plenary discussion at a UK national meeting for orthopaedic anaesthetists (130 anaesthetists); three focus groups with anaesthetists (one national, two regional; 58 anaesthetists); two focus groups with members of the patient organisation Arthritis Care (7 participants); telephone interviews with people on consultant waiting lists from two UK regional centres (15 participants); interviews with Chairs of UK ethics committees (6 individuals); postal surveys of members of the British Association of Surgeons of the Knee (382 surgeons) and members of the British Society of Orthopaedic Anaesthetists (398 anaesthetists); two centre pilot (49 patients assessed). Results There was widespread acceptance that evaluation of arthroscopic lavage had to be conducted with a placebo control if scientific rigour was not to be compromised. The choice of placebo surgical procedure (three small incisions) proved easier than the method of anaesthesia (general anaesthesia). General anaesthesia, while an excellent mimic, was more intrusive and raised concerns among some stakeholders and caused extensive discussion with local decision-makers when seeking formal approval for the pilot. Patients were willing to participate in a pilot with a placebo arm; although some patients when allocated to surgery became apprehensive about the possibility of receiving placebo, and withdrew. Placebo surgery was undertaken successfully. Conclusions Our study illustrated the opposing and often strongly held opinions about surgical placebos, the ethical issues underpinning this controversy, and the challenges that exist even when ethics committee approval has been granted. It showed that a placebo-controlled trial could be conducted in principle, albeit with difficulty. It also highlighted that not only does a placebo-controlled trial in surgery have to be ethically and scientifically acceptable but that it also must be a feasible course of action. The place of placebo-controlled surgical trials more generally is likely to be limited and require specific circumstances to be met. Suggested criteria are presented. Trial registration number The trial was assigned ISRCTN02328576 through http://controlled-trials.com/ in June 2006. The first patient was randomised to the pilot in July 2007. PMID:21338481
Web-Based Positive Psychology Interventions: A Reexamination of Effectiveness.

PubMed

Woodworth, Rosalind J; O'Brien-Malone, Angela; Diamond, Mark R; Schüz, Benjamin

2017-03-01

Seligman, Steen, Park, and Peterson (2005) suggested that positive psychology interventions (PPIs) contain specific, powerful, therapeutic ingredients that effect greater increases in happiness and reductions in depression than a placebo control. This study reexamined the three PPIs that Seligman et al. found to be most effective when delivered over the internet. Three PPIs and a placebo control, identical with the interventions used by Seligman et al., were examined in a web-based, randomized assignment design. Mixed-design analysis of variance and multilevel modeling showed that all interventions, including the placebo, led to significant increases in happiness and reductions in depression. The effects of PPIs were indistinguishable from those of the placebo control. Using web-based delivery, both PPIs and theoretically neutral placebos can increase happiness and reduce depression in self-selected populations. Possible explanations include that non-specific factors common to most therapeutic treatments are responsible for the observed changes, or that cultural or other context-related variables operate to account for the divergent findings. © 2016 Wiley Periodicals, Inc.
Caffeine withdrawal and high-intensity endurance cycling performance.

PubMed

Irwin, Christopher; Desbrow, Ben; Ellis, Aleisha; O'Keeffe, Brooke; Grant, Gary; Leveritt, Michael

2011-03-01

In this study, we investigated the impact of a controlled 4-day caffeine withdrawal period on the effect of an acute caffeine dose on endurance exercise performance. Twelve well-trained and familiarized male cyclists, who were caffeine consumers (from coffee and a range of other sources), were recruited for the study. A double-blind placebo-controlled cross-over design was employed, involving four experimental trials. Participants abstained from dietary caffeine sources for 4 days before the trials and ingested capsules (one in the morning and one in the afternoon) containing either placebo or caffeine (1.5 mg · kg(-1) body weight · day(-1)). On day 5, capsules containing placebo or caffeine (3 mg · kg(-1) body weight) were ingested 90 min before completing a time trial, equivalent to one hour of cycling at 75% peak sustainable power output. Hence the study was designed to incorporate placebo-placebo, placebo-caffeine, caffeine-placebo, and caffeine-caffeine conditions. Performance time was significantly improved after acute caffeine ingestion by 1:49 ± 1:41 min (3.0%, P = 0.021) following a withdrawal period (placebo-placebo vs. placebo-caffeine), and by 2:07 ± 1:28 min (3.6%, P = 0.002) following the non-withdrawal period (caffeine-placebo vs. caffeine-caffeine). No significant difference was detected between the two acute caffeine trials (placebo-caffeine vs. caffeine-caffeine). Average heart rate throughout exercise was significantly higher following acute caffeine administration compared with placebo. No differences were observed in ratings of perceived exertion between trials. A 3 mg · kg(-1) dose of caffeine significantly improves exercise performance irrespective of whether a 4-day withdrawal period is imposed on habitual caffeine users.

Investigating methotrexate toxicity within a randomized double-blinded, placebo-controlled trial: rationale and design of the Cardiovascular Inflammation Reduction Trial-Adverse Events (CIRT-AE) Study

USDA-ARS?s Scientific Manuscript database

Background: The role of low dose methotrexate (LDM) in potential serious toxicities remains unclear despite its common use. Prior observational studies investigating LDM toxicity compared LDM to other active drugs. Prior placebo-controlled clinical trials of LDM in inflammatory conditions were not l...
A randomized, double-blind, placebo controlled, parallel group, efficacy study of alpha BRAIN® administered orally.

PubMed

Solomon, Todd M; Leech, Jarrett; deBros, Guy B; Murphy, Cynthia A; Budson, Andrew E; Vassey, Elizabeth A; Solomon, Paul R

2016-03-01

Alpha BRAIN® is a nootropic supplement that purports to enhance cognitive functioning in healthy adults. The goal of this study was to investigate the efficacy of this self-described cognitive enhancing nootropic on cognitive functioning in a group of healthy adults by utilizing a randomized, double blind, placebo-controlled design. A total of 63-treatment naïve individuals between 18 and 35 years of age completed the randomized, double-blind, placebo controlled trial. All participants completed a 2-week placebo run in before receiving active product, Alpha BRAIN® or new placebo, for 6 weeks. Participants undertook a battery of neuropsychological tests at randomization and at study completion. Primary outcome measures included a battery of neuropsychological tests and measures of sleep. Compared with placebo, Alpha BRAIN® significantly improved on tasks of delayed verbal recall and executive functioning. Results also indicated significant time-by-group interaction in delayed verbal recall for the Alpha BRAIN® group. The use of Alpha BRAIN® for 6 weeks significantly improved recent verbal memory when compared with controls, in a group of healthy adults. While the outcome of the study is encouraging, this is the first randomized controlled trial of Alpha BRAIN®, and the results merit further study. Copyright © 2016 John Wiley & Sons, Ltd.
Double-Blind, Placebo-Controlled, Crossover Study of the Efficacy and Safety of Lisdexamfetamine Dimesylate in College Students with ADHD

ERIC Educational Resources Information Center

DuPaul, George J.; Weyandt, Lisa L.; Rossi, Joseph S.; Vilardo, Brigid A.; O'Dell, Sean M.; Carson, Kristen M.; Verdi, Genevieve; Swentosky, Anthony

2012-01-01

Objective: To evaluate stimulant medication on symptoms and functioning for college students with ADHD using double-blind, placebo-controlled, crossover design. Method: Participants included 24 college students with ADHD and 26 college students without psychopathology. Lisdexamfetamine dimesylate (LDX) was examined for ADHD participants over five…
Systematic Review and Meta-analysis: Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis

PubMed Central

Zou, Guangyong; Parker, Claire E.; Macdonald, John K.; Mosli, Mahmoud H.; Khanna, Reena; Shackelton, Lisa M.; Vandervoort, Margaret K.; AlAmeel, Turki; Al Beshir, Mohammad; AlMadi, Majid; Al-Taweel, Talal; Atkinson, Nathan S. S.; Biswas, Sujata; Chapman, Thomas P.; Dulai, Parambir S.; Glaire, Mark A.; Hoekman, Daniel; Koutsoumpas, Andreas; Minas, Elizabeth; Samaan, Mark A.; Travis, Simon; D’Haens, Geert; Levesque, Barrett G.; Sandborn, William J.; Feagan, Brian G.

2016-01-01

Background and Aims: Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis [UC] clinical trials, and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them. Methods: MEDLINE, EMBASE, and the Cochrane Library were searched from inception through April 2014 for placebo-controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant, or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool. Results: In all, 51 trials [48 induction and 10 maintenance phases] were identified. Placebo response and remission rates were pooled according to random-effects models, and mixed-effects meta-regression models were used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10% (95% confidence interval [CI] 7-13%) and 33% [95% CI 29-37%], respectively. Corresponding values for maintenance trials were 19% [95% CI 11-30%] and 22% [95% CI 17-28%]. Trials enrolling patients with more active disease confirmed by endoscopy [endoscopy subscore ≥ 2] were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits. Conclusions: Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials. PMID:26746169
Pentoxifylline for the treatment of nonalcoholic fatty liver disease: a meta-analysis of randomized double-blind, placebo-controlled studies.

PubMed

Zeng, Tao; Zhang, Cui-Li; Zhao, Xiu-Lan; Xie, Ke-Qin

2014-06-01

Pentoxifylline has been used to treat nonalcoholic fatty liver diseases (NAFLDs) due to its anti-tumor necrosis factor-α effects. We conducted a meta-analysis of randomized, double-blinded, placebo-controlled trials to investigate the effect of pentoxifylline on the biochemical and histological parameters of NAFLD patients. A comprehensive literature search was conducted in the database including PubMed, Embase, ISI web of knowledge, the Cochrane Library, and Google Scholar to identify randomized, double-blind, placebo-controlled clinical trials about the effects of pentoxifylline on NAFLD. The pooled weighted mean difference (WMD) with 95% confidence interval (CI) was calculated to compare the effects of pentoxifylline and placebo. Five well-designed studies were retrieved. Pooled results showed that pentoxifylline significantly reduced the serum alanine transaminase activity (WMD=-27.97; 95% CI: -42.59, -13.34) and aspartate transaminase activity (WMD=-13.97; 95% CI: -23.31, -4.63) in NAFLD patients compared with placebo. In addition, pentoxifylline significantly improved steatosis (WMD=-0.68; 95% CI: -1.01, -0.34), lobular inflammation (WMD=-0.49; 95% CI: -0.86, -0.12), and fibrosis (WMD=-0.60; 95% CI: -0.99, -0.21). Furthermore, pentoxifylline also led to significant reduction in BMI (WMD=-0.51; 95% CI: -0.96, -0.06) and fasting glucose (WMD=-8.97; 95% CI: -14.52, -3.42), but did not significantly affect the serum tumor necrosis factor α and adiponectin levels when compared with placebo. Pentoxifylline could reduce the aminotransferase activities and improve the histological parameters in NAFLD patients. Large well-designed, randomized, placebo-controlled studies are needed to confirm these results.
The challenges of control groups, placebos and blinding in clinical trials of dietary interventions.

PubMed

Staudacher, Heidi M; Irving, Peter M; Lomer, Miranda C E; Whelan, Kevin

2017-08-01

High-quality placebo-controlled evidence for food, nutrient or dietary advice interventions is vital for verifying the role of diet in optimising health or for the management of disease. This could be argued to be especially important where the benefits of dietary intervention are coupled with potential risks such as compromising nutrient intake, particularly in the case of exclusion diets. The objective of the present paper is to explore the challenges associated with clinical trials in dietary research, review the types of controls used and present the advantages and disadvantages of each, including issues regarding placebos and blinding. Placebo-controlled trials in nutrient interventions are relatively straightforward, as in general placebos can be easily produced. However, the challenges associated with conducting placebo-controlled food interventions and dietary advice interventions are protean, and this has led to a paucity of placebo-controlled food and dietary advice trials compared with drug trials. This review appraises the types of controls used in dietary intervention trials and provides recommendations and nine essential criteria for the design and development of sham diets for use in studies evaluating the effect of dietary advice, along with practical guidance regarding their evaluation. The rationale for these criteria predominantly relate to avoiding altering the outcome of interest in those delivered the sham intervention in these types of studies, while not compromising blinding.
Ethics of placebo-controlled clinical trials in multiple sclerosis: a reassessment.

PubMed

Polman, C H; Reingold, S C; Barkhof, F; Calabresi, P A; Clanet, M; Cohen, J A; Cutter, G R; Freedman, M S; Kappos, L; Lublin, F D; McFarland, H F; Metz, L M; Miller, A E; Montalban, X; O'Connor, P W; Panitch, H; Richert, J R; Petkau, J; Schwid, S R; Sormani, M P; Thompson, A J; Weinshenker, B G; Wolinsky, J S

2008-03-25

The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in "resource-restricted" environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes.
Investigating methotrexate toxicity within a randomized double-blinded, placebo-controlled trial: Rationale and design of the Cardiovascular Inflammation Reduction Trial-Adverse Events (CIRT-AE) Study.

PubMed

Sparks, Jeffrey A; Barbhaiya, Medha; Karlson, Elizabeth W; Ritter, Susan Y; Raychaudhuri, Soumya; Corrigan, Cassandra C; Lu, Fengxin; Selhub, Jacob; Chasman, Daniel I; Paynter, Nina P; Ridker, Paul M; Solomon, Daniel H

2017-08-01

The role of low dose methotrexate (LDM) in potential serious toxicities remains unclear despite its common use. Prior observational studies investigating LDM toxicity compared LDM to other active drugs. Prior placebo-controlled clinical trials of LDM in inflammatory conditions were not large enough to investigate toxicity. The Cardiovascular Inflammation Reduction Trial (CIRT) is an ongoing NIH-funded, randomized, double-blind, placebo-controlled trial of LDM in the secondary prevention of cardiovascular disease. We describe here the rationale and design of the CIRT-Adverse Events (CIRT-AE) ancillary study which aims to investigate adverse events within CIRT. CIRT will randomize up to 7000 participants with cardiovascular disease and no systemic rheumatic disease to either LDM (target dose: 15-20mg/week) or placebo for an average follow-up period of 3-5 years; subjects in both treatment arms receive folic acid 1mg daily for 6 days each week. The primary endpoints of CIRT include recurrent cardio vascular events, incident diabetes, and all-cause mortality, and the ancillary CIRT-AE study has been designed to adjudicate other clinically important adverse events including hepatic, gastrointestinal, respiratory, hematologic, infectious, mucocutaneous, oncologic, renal, neurologic, and musculoskeletal outcomes. Methotrexate polyglutamate levels and genome-wide single nucleotide polymorphisms will be examined for association with adverse events. CIRT-AE will comprehensively evaluate potential LDM toxicities among subjects with cardiovascular disease within the context of a large, ongoing, double-blind, placebo-controlled trial. This information may lead to a personalized approach to monitoring LDM in clinical practice. Copyright © 2017 Elsevier Inc. All rights reserved.
A two-way enriched clinical trial design: combining advantages of placebo lead-in and randomized withdrawal.

PubMed

Ivanova, Anastasia; Tamura, Roy N

2015-12-01

A new clinical trial design, designated the two-way enriched design (TED), is introduced, which augments the standard randomized placebo-controlled trial with second-stage enrichment designs in placebo non-responders and drug responders. The trial is run in two stages. In the first stage, patients are randomized between drug and placebo. In the second stage, placebo non-responders are re-randomized between drug and placebo and drug responders are re-randomized between drug and placebo. All first-stage data, and second-stage data from first-stage placebo non-responders and first-stage drug responders, are utilized in the efficacy analysis. The authors developed one, two and three degrees of freedom score tests for treatment effect in the TED and give formulae for asymptotic power and for sample size computations. The authors compute the optimal allocation ratio between drug and placebo in the first stage for the TED and compare the operating characteristics of the design to the standard parallel clinical trial, placebo lead-in and randomized withdrawal designs. Two motivating examples from different disease areas are presented to illustrate the possible design considerations. © The Author(s) 2011.
Response to Placebo in Clinical Epilepsy Trials - Old Ideas and New Insights

PubMed Central

Goldenholz, Daniel M.; Goldenholz, Shira R

2016-01-01

Randomized placebo controlled trials are a mainstay of modern clinical epilepsy research; the success or failure of innovative therapies depends on proving superiority to a placebo. Consequently, understanding what drives response to placebo (including the “placebo effect”) may facilitate evaluation of new therapies. In this review, part one will explore observations about placebos specific to epilepsy, including the relatively higher placebo response in children, apparent increase in placebo response over the past several decades, geographic variation in placebo effect, relationship to baseline epilepsy characteristics, influence of nocebo on clinical trials, the possible increase in (SUDEP) in placebo arms of trials, and patterns that placebo responses appear to follow in individual patients. Part two will discuss the principal causes of placebo responses, including regression to the mean, anticipation, classical conditioning, the Hawthorne effect, expectations from symbols, and the natural history of disease. Included in part two will be a brief overview of recent advances using simulations from large datasets that have afforded new insights into causes of epilepsy related placebo responses. In part three, new developments in study design will be explored, including sequential parallel comparison, two-way enriched design, time to pre-randomization, delayed start, and cohort reduction techniques. PMID:26921852
Reducing placebo exposure in trials: Considerations from the Research Roundtable in Epilepsy.

PubMed

Fureman, Brandy E; Friedman, Daniel; Baulac, Michel; Glauser, Tracy; Moreno, Jonathan; Dixon-Salazar, Tracy; Bagiella, Emilia; Connor, Jason; Ferry, Jim; Farrell, Kathleen; Fountain, Nathan B; French, Jacqueline A

2017-10-03

The randomized controlled trial is the unequivocal gold standard for demonstrating clinical efficacy and safety of investigational therapies. Recently there have been concerns raised about prolonged exposure to placebo and ineffective therapy during the course of an add-on regulatory trial for new antiepileptic drug approval (typically ∼6 months in duration), due to the potential risks of continued uncontrolled epilepsy for that period. The first meeting of the Research Roundtable in Epilepsy on May 19-20, 2016, focused on "Reducing placebo exposure in epilepsy clinical trials," with a goal of considering new designs for epilepsy regulatory trials that may be added to the overall development plan to make it, as a whole, safer for participants while still providing rigorous evidence of effect. This topic was motivated in part by data from a meta-analysis showing a 3- to 5-fold increased rate of sudden unexpected death in epilepsy in participants randomized to placebo or ineffective doses of new antiepileptic drugs. The meeting agenda included rationale and discussion of different trial designs, including active-control add-on trials, placebo add-on to background therapy with adjustment, time to event designs, adaptive designs, platform trials with pooled placebo control, a pharmacokinetic/pharmacodynamic approach to reducing placebo exposure, and shorter trials when drug tolerance has been ruled out. The merits and limitations of each design were discussed and are reviewed here. © 2017 American Academy of Neurology.
Design, formulation and sensory evaluation of a polyphenol-rich food placebo: an example of aronia juice for food intervention studies.

PubMed

Kardum, Nevena; Konic Ristic, Aleksandra; Zec, Manja; Kojadinovic, Milica; Petrovic-Oggiano, Gordana; Zekovic, Milica; Kroon, Paul A; Glibetić, Maria

2017-09-01

Products suitable for use as controls in food interventions designed to demonstrate the role of minor components are largely lacking. In the present study, we aimed to develop a formulation to be used as a placebo in a clinical trial designed to assess the effects of aronia juice polyphenols on platelet function. Three formulations with the same nutrient composition as aronia juice were prepared by mixing various nutrients, artificial colours and flavours with water. The similarity of formulations to aronia juice in terms of taste, colour, smell and texture was assessed by six food panellists. The final placebo was tested for its impact on platelet function, biochemical and anthropometric parameters in a 4-week long study. No significant changes in platelet function, or in several cardiovascular and safety markers were recorded. Formulation suitable for use as a placebo for dietary intervention studies using aronia juice has been developed and demonstrated to be well tolerated in humans.
Randomized trial of the effect of drug presentation on asthma outcomes: the American Lung Association Asthma Clinical Research Centers.

PubMed

Wise, Robert A; Bartlett, Susan J; Brown, Ellen D; Castro, Mario; Cohen, Rubin; Holbrook, Janet T; Irvin, Charles G; Rand, Cynthia S; Sockrider, Marianna M; Sugar, Elizabeth A

2009-09-01

Information that enhances expectations about drug effectiveness improves the response to placebos for pain. Although asthma symptoms often improve with placebo, it is not known whether the response to placebo or active treatment can be augmented by increasing expectation of benefit. The study objective was to determine whether response to placebo or a leukotriene antagonist (montelukast) can be augmented by messages that increase expectation of benefit. A randomized 20-center controlled trial enrolled 601 asthmatic patients with poor symptom control who were assigned to one of 5 study groups. Participants were randomly assigned to one of 4 treatment groups in a factorial design (ie, placebo with enhanced messages, placebo with neutral messages, montelukast with enhanced messages, or montelukast with neutral messages) or to usual care. Assignment to study drug was double masked, assignment to message content was single masked, and usual care was not masked. The enhanced message aimed to increase expectation of benefit from the drug. The primary outcome was mean change in daily peak flow over 4 weeks. Secondary outcomes included lung function and asthma symptom control. Peak flow and other lung function measures were not improved in participants assigned to the enhanced message groups versus the neutral messages groups for either montelukast or placebo; no differences were noted between the neutral placebo and usual care groups. Placebo-treated participants had improved asthma control with the enhanced message but not montelukast-treated participants; the neutral placebo group did have improved asthma control compared with the usual care group after adjusting for baseline difference. Headaches were more common in participants provided messages that mentioned headache as a montelukast side effect. Optimistic drug presentation augments the placebo effect for patient-reported outcomes (asthma control) but not lung function. However, the effect of montelukast was not enhanced by optimistic messages regarding treatment effectiveness.
Systematic Review and Meta-analysis: Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis.

PubMed

Jairath, Vipul; Zou, Guangyong; Parker, Claire E; Macdonald, John K; Mosli, Mahmoud H; Khanna, Reena; Shackelton, Lisa M; Vandervoort, Margaret K; AlAmeel, Turki; Al Beshir, Mohammad; AlMadi, Majid; Al-Taweel, Talal; Atkinson, Nathan S S; Biswas, Sujata; Chapman, Thomas P; Dulai, Parambir S; Glaire, Mark A; Hoekman, Daniel; Koutsoumpas, Andreas; Minas, Elizabeth; Samaan, Mark A; Travis, Simon; D'Haens, Geert; Levesque, Barrett G; Sandborn, William J; Feagan, Brian G

2016-05-01

Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis [UC] clinical trials, and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them. MEDLINE, EMBASE, and the Cochrane Library were searched from inception through April 2014 for placebo-controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant, or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool. In all, 51 trials [48 induction and 10 maintenance phases] were identified. Placebo response and remission rates were pooled according to random-effects models, and mixed-effects meta-regression models were used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10% (95% confidence interval [CI] 7-13%) and 33% [95% CI 29-37%], respectively. Corresponding values for maintenance trials were 19% [95% CI 11-30%] and 22% [95% CI 17-28%]. Trials enrolling patients with more active disease confirmed by endoscopy [endoscopy subscore ≥ 2] were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits. Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials. Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Prevalence and factors associated with use of placebo control groups in randomized controlled trials in psoriasis: a cross-sectional study.

PubMed

Katz, Kenneth A; Karlawish, Jason H; Chiang, David S; Bognet, Rachel A; Propert, Katherine J; Margolis, David J

2006-11-01

The ethics and science of using placebo control groups in clinical trials have been widely debated. Few studies, however, have examined factors associated with choice of control group. Our aim was to assess the prevalence of use of placebo controls in randomized controlled trials in psoriasis and to identify factors associated with use of placebo controls in these trials. This is a cross-sectional study of randomized controlled trials in psoriasis published from January 1, 2001 to December 20, 2005 and indexed in the Cochrane Central Register of Controlled Trials. We extracted data on types of control groups used, design issues (number of patients enrolled, primary end point), disease characteristics (psoriasis type and severity), and extrascientific issues (trial location, funding source, and year of publication). We used bivariable and multivariable logistic regression to determine factors associated with use of a placebo control group. Of 194 citations, 187 were available for review. One hundred thirty-five trials from 134 articles in 38 journals met inclusion criteria. Eighty-three trials (61.5%) enrolling 8171 subjects (41.7%) used active controls only, and 52 trials (38.5%) enrolling 11,406 subjects (58.3%) used placebo controls. Adjusted for trial location and funding source, trials significantly more likely to have used placebo controls included those conducted in the United States (odds ratio [OR], 5.79; 95% confidence interval [CI], 2.45-13.68; P < .001) and those funded by pharmaceutical companies (OR, 2.61; 95% CI, 1.19-5.73; P = .02). Predicted frequencies of placebo use ranged from 77.6% (industry-funded, conducted trials in the United States) to 18.6% (non-industry-funded trials not conducted in the United States). Our searches may not have identified all published trials, and we did not have access to data from unpublished trials. Use of placebo controls has been more common in psoriasis trials conducted in the United States and funded by pharmaceutical companies. The findings suggest that ethical and scientific issues related to choice of control group in psoriasis trials are interpreted markedly differently depending on trial location and funding source.
The paradox of sham therapy and placebo effect in osteopathy

PubMed Central

Cerritelli, Francesco; Verzella, Marco; Cicchitti, Luca; D’Alessandro, Giandomenico; Vanacore, Nicola

2016-01-01

Abstract Background: Placebo, defined as “false treatment,” is a common gold-standard method to assess the validity of a therapy both in pharmacological trials and manual medicine research where placebo is also referred to as “sham therapy.” In the medical literature, guidelines have been proposed on how to conduct robust placebo-controlled trials, but mainly in a drug-based scenario. In contrast, there are not precise guidelines on how to conduct a placebo-controlled in manual medicine trials (particularly osteopathy). The aim of the present systematic review was to report how and what type of sham methods, dosage, operator characteristics, and patient types were used in osteopathic clinical trials and, eventually, assess sham clinical effectiveness. Methods: A systematic Cochrane-based review was conducted by analyzing the osteopathic trials that used both manual and nonmanual placebo control. Searches were conducted on 8 databases from journal inception to December 2015 using a pragmatic literature search approach. Two independent reviewers conducted the study selection and data extraction for each study. The risk of bias was evaluated according to the Cochrane methods. Results: A total of 64 studies were eligible for analysis collecting a total of 5024 participants. More than half (43 studies) used a manual placebo; 9 studies used a nonmanual placebo; and 12 studies used both manual and nonmanual placebo. Data showed lack of reporting sham therapy information across studies. Risk of bias analysis demonstrated a high risk of bias for allocation, blinding of personnel and participants, selective, and other bias. To explore the clinical effects of sham therapies used, a quantitative analysis was planned. However, due to the high heterogeneity of sham approaches used no further analyses were performed. Conclusion: High heterogeneity regarding placebo used between studies, lack of reporting information on placebo methods and within-study variability between sham and real treatment procedures suggest prudence in reading and interpreting study findings in manual osteopathic randomized controlled trials (RCTs). Efforts must be made to promote guidelines to design the most reliable placebo for manual RCTs as a means of increasing the internal validity and improve external validity of findings. PMID:27583913
The paradox of sham therapy and placebo effect in osteopathy: A systematic review.

PubMed

Cerritelli, Francesco; Verzella, Marco; Cicchitti, Luca; D'Alessandro, Giandomenico; Vanacore, Nicola

2016-08-01

Placebo, defined as "false treatment," is a common gold-standard method to assess the validity of a therapy both in pharmacological trials and manual medicine research where placebo is also referred to as "sham therapy." In the medical literature, guidelines have been proposed on how to conduct robust placebo-controlled trials, but mainly in a drug-based scenario. In contrast, there are not precise guidelines on how to conduct a placebo-controlled in manual medicine trials (particularly osteopathy). The aim of the present systematic review was to report how and what type of sham methods, dosage, operator characteristics, and patient types were used in osteopathic clinical trials and, eventually, assess sham clinical effectiveness. A systematic Cochrane-based review was conducted by analyzing the osteopathic trials that used both manual and nonmanual placebo control. Searches were conducted on 8 databases from journal inception to December 2015 using a pragmatic literature search approach. Two independent reviewers conducted the study selection and data extraction for each study. The risk of bias was evaluated according to the Cochrane methods. A total of 64 studies were eligible for analysis collecting a total of 5024 participants. More than half (43 studies) used a manual placebo; 9 studies used a nonmanual placebo; and 12 studies used both manual and nonmanual placebo. Data showed lack of reporting sham therapy information across studies. Risk of bias analysis demonstrated a high risk of bias for allocation, blinding of personnel and participants, selective, and other bias. To explore the clinical effects of sham therapies used, a quantitative analysis was planned. However, due to the high heterogeneity of sham approaches used no further analyses were performed. High heterogeneity regarding placebo used between studies, lack of reporting information on placebo methods and within-study variability between sham and real treatment procedures suggest prudence in reading and interpreting study findings in manual osteopathic randomized controlled trials (RCTs). Efforts must be made to promote guidelines to design the most reliable placebo for manual RCTs as a means of increasing the internal validity and improve external validity of findings.
Antidepressant Efficacy of the Antimuscarinic Drug Scopolamine

PubMed Central

Furey, Maura L.; Drevets, Wayne C.

2010-01-01

Context The need for improved therapeutic agents that more quickly and effectively treat depression is critical. In a pilot study we evaluated the role of the cholinergic system in cognitive symptoms of depression and unexpectedly observed rapid reductions in depression severity following the administration of the antimuscarinic drug scopolamine hydrobromide (4 μg/kg intravenously) compared with placebo (P=.002). Subsequently a clinical trial was designed to assess more specifically the antidepressant efficacy of scopolamine. Objective To evaluate scopolamine as a potential antidepressant agent. Design Two studies were conducted: a double-blind, placebo-controlled, dose-finding study followed by a double-blind, placebo-controlled, crossover clinical trial. Setting The National Institute of Mental Health. Patients Currently depressed outpatients aged 18 to 50 years meeting DSM-IV criteria for recurrent major depressive disorder or bipolar disorder. Of 39 eligible patients, 19 were randomized and 18 completed the trial. Interventions Multiple sessions including intravenous infusions of placebo or scopolamine hydrobromide (4 μg/kg). Individuals were randomized to a placebo/ scopolamine or scopolamine/placebo sequence (series of 3 placebo sessions and series of 3 scopolamine sessions). Sessions occurred 3 to 5 days apart. Main Outcome Measures Psychiatric evaluations using the Montgomery-Asberg Depression Rating Scale and the Hamilton Anxiety Rating Scale were performed to assess antidepressant and antianxiety responses to scopolamine. Results The placebo/scopolamine group showed no significant change during placebo infusion vs baseline; reductions in depression and anxiety rating scale scores (P<.001 for both) were observed after the administration of scopolamine compared with placebo. The scopolamine/placebo group also showed reductions in depression and anxiety rating scale scores (P<.001 for both) after the administration of scopolamine, relative to baseline, and these effects persisted as they received placebo. In both groups, improvement was significant at the first evaluation after scopolamine administration (P≤.002). Conclusion Rapid, robust antidepressant responses to the antimuscarinic scopolamine occurred in currently depressed patients who predominantly had poor prognoses. PMID:17015814
Glutamine supplementation in cystic fibrosis: A randomized placebo-controlled trial.

PubMed

Forrester, Doug L; Knox, Alan J; Smyth, Alan R; Barr, Helen L; Simms, Rebecca; Pacey, Sarah J; Pavord, Ian D; Honeybourne, David; Dewar, Jane; Clayton, Andy; Fogarty, Andrew W

2016-03-01

Pulmonary infection and malnutrition in cystic fibrosis are associated with decreased survival. Glutamine has a possible anti-microbial effect, with a specific impact against Pseudomonas aeruginosa. We aimed to test the hypothesis that oral glutamine supplementation (21 g/day) for 8 weeks in adults with cystic fibrosis would decrease pulmonary inflammation and improve clinical status. The study design was a randomized double-blind placebo-controlled study design with an iso-nitrogenous placebo. The primary analysis was intention to treat, and the primary outcome was change in induced sputum neutrophils. Thirty-nine individuals were recruited and thirty-six completed the study. Glutamine supplementation had no impact on any of the outcome measures in the intention-to-treat analysis. In the per protocol analysis, glutamine supplementation was associated with an increase in induced sputum neutrophils (P = 0.046), total cells (P = 0.03), and in Pseudomonas isolation agar colony forming units (P = 0.04) compared to placebo. There was no effect of glutamine supplementation on markers of pulmonary inflammation in the intention-to-treat analysis. © 2015 Wiley Periodicals, Inc.
Verbal working memory-related functional connectivity alterations in boys with attention-deficit/hyperactivity disorder and the effects of methylphenidate.

PubMed

Wu, Zhao-Min; Bralten, Janita; An, Li; Cao, Qing-Jiu; Cao, Xiao-Hua; Sun, Li; Liu, Lu; Yang, Li; Mennes, Maarten; Zang, Yu-Feng; Franke, Barbara; Hoogman, Martine; Wang, Yu-Feng

2017-08-01

Few studies have investigated verbal working memory-related functional connectivity patterns in participants with attention-deficit/hyperactivity disorder (ADHD). Thus, we aimed to compare working memory-related functional connectivity patterns in healthy children and those with ADHD, and study effects of methylphenidate (MPH). Twenty-two boys with ADHD were scanned twice, under either MPH (single dose, 10 mg) or placebo, in a randomised, cross-over, counterbalanced placebo-controlled design. Thirty healthy boys were scanned once. We used fMRI during a numerical n-back task to examine functional connectivity patterns in case-control and MPH-placebo comparisons, using independent component analysis. There was no significant difference in behavioural performance between children with ADHD, treated with MPH or placebo, and healthy controls. Compared with controls, participants with ADHD under placebo showed increased functional connectivity within fronto-parietal and auditory networks, and decreased functional connectivity within the executive control network. MPH normalized the altered functional connectivity pattern and significantly enhanced functional connectivity within the executive control network, though in non-overlapping areas. Our study contributes to the identification of the neural substrates of working memory. Single dose of MPH normalized the altered brain functional connectivity network, but had no enhancing effect on (non-impaired) behavioural performance.

Effects of Risperidone on Cognitive-Motor Performance and Motor Movements in Chronically Medicated Children

ERIC Educational Resources Information Center

Aman, Michael G.; Hollway, Jill A.; Leone, Sarah; Masty, Jessica; Lindsay, Ronald; Nash, Patricia; Arnold, L. Eugene

2009-01-01

This study was designed to explore the placebo-controlled effects of risperidone on cognitive-motor processes, dyskinetic movements, and behavior in children receiving maintenance risperidone therapy. Sixteen children aged 4-14 years with disruptive behavior were randomly assigned to drug order in a crossover study of risperidone and placebo for 2…
Homeopathy for Perennial Asthma in Adolescents: Pilot Feasibility Study Testing a Randomised Withdrawal Design.

PubMed

Mitchiguian Hotta, Livia; Cardinalli Adler, Ubiratan; de Toledo Cesar, Amarilys; Martinez, Edson Zangiacomi; Demarzo, Marcelo Marcos Piva

2018-05-01

Previous findings from a pragmatic trial suggest that usual care compared with usual care plus individualised homeopathy is not a feasible design to address homeopathic interventions for asthma. The main purpose of this article was to investigate the feasibility of the randomised withdrawal design as a strategy to assess the effectiveness of a standardised clinical-pharmaceutical homeopathic protocol ( Organon.modus ) on perennial asthma in adolescents. Randomised withdrawal, double-blind, parallel, placebo-controlled, 12-week study. 12 to 17 years old adolescents, with the diagnosis of perennial asthma, using inhalatory beclomethasone (plus fenoterol for wheezing episodes), who achieved 3 months of well-controlled asthma, after a variable period of individualised homeopathic treatment according to Organon.modus protocol. a secondary care medical specialist centre. continuation with the individualised homeopathic medicine or with indistinguishable placebo during 12 weeks of beclomethasone step-down. number of days of well-controlled asthma. Secondary measures: number of days of fenoterol use, number of visits to an emergency service (without hospitalisation) and percentage of patients excluded due to an exacerbation characterising a partly controlled asthma. Tolerability was assessed by Adverse Events, registered at every visit. Nineteen patients were randomised to continue treatment with homeopathy and 21 with placebo. Effectiveness measures for the homeopathy and placebo groups respectively were median number of days of good clinical control: 84 versus 30 ( p = 0.18); median number of days of fenoterol use per patient: 3 versus 5 ( p = 0.41); visits to an emergency room: 1 versus 6 ( p = 0.35); percentage of exclusion due to partly controlled asthma: 36.8% versus 71.4% ( p = 0.05). Few Adverse Events were reported. This pilot study supports the feasibility of the double-blind randomised withdrawal design in studies investigating homeopathy on teenage asthma, when performed by specialists following a standardised clinical-pharmaceutical homeopathic protocol. RBR-6XTS8Z. The Faculty of Homeopathy.
Heartburn treatment in primary care: randomised, double blind study for 8 weeks

PubMed Central

Hatlebakk, Jan G; Hyggen, Arild; Madsen, Per H; Walle, Per O; Schulz, Tom; Mowinckel, Petter; Bernklev, Tomm; Berstad, Arnold

1999-01-01

Objective To compare the effects and tolerability of omeprazole and cisapride with that of placebo for control of heartburn in primary care patients. Design Randomised, double blind, placebo controlled study. Setting 65 primary care practices in Norway. Participants 483 untreated patients with complaints of heartburn ⩾3 days a week, with at most grade 1 reflux oesophagitis. Interventions Omeprazole 20 mg once daily, cisapride 20 mg twice daily, or placebo for 8 weeks. Main outcome measures Adequate control of heartburn, defined as ⩽1 day of the past 7 days with no more than mild heartburn, after 4 weeks of treatment. Results In the all patients treated analysis, adequate control of heartburn was achieved in 71% of patients taking omeprazole, 22% taking cisapride, and 18% taking placebo after 4 weeks of treatment (omeprazole v cisapride and placebo, P<0.0001; cisapride v placebo, non-significant). Results were comparable in patients with or without reflux oesophagitis. In patients treated with omeprazole only, symptom control was achieved significantly more often in patients positive for Helicobacter pylori. Antacid use was 2-3 times greater in patients taking cisapride or placebo than in those taking omeprazole. Relief of non-reflux symptoms did not significantly differ between the three groups. Significantly more patients taking cisapride reported adverse events than those taking omeprazole or placebo. Conclusions Omeprazole 20 mg once daily was highly effective in relieving heartburn whereas cisapride 20 mg twice daily was not significantly more effective than placebo. Key messagesIn primary care patients, heartburn is commonly treated empiricallyMost randomised clinical trials of treatment for heartburn have been conducted in specialist care, and documentation for empirical treatment is limitedOmeprazole was significantly more effective than cisapride or placebo in controlling heartburn and other symptoms of gastro-oesophageal reflux after 2, 4, and 8 weeks, whereas cisapride did not differ significantly from placeboOmeprazole should be considered as a first choice for empirical treatment of heartburn in primary care PMID:10463897
Preventing AVF thrombosis: the rationale and design of the Omega-3 fatty acids (Fish Oils) and Aspirin in Vascular access OUtcomes in REnal Disease (FAVOURED) study.

PubMed

Irish, Ashley; Dogra, Gursharan; Mori, Trevor; Beller, Elaine; Heritier, Stephane; Hawley, Carmel; Kerr, Peter; Robertson, Amanda; Rosman, Johan; Paul-Brent, Peta-Anne; Starfield, Melissa; Polkinghorne, Kevan; Cass, Alan

2009-01-21

Haemodialysis (HD) is critically dependent on the availability of adequate access to the systemic circulation, ideally via a native arteriovenous fistula (AVF). The Primary failure rate of an AVF ranges between 20-54%, due to thrombosis or failure of maturation. There remains limited evidence for the use of anti-platelet agents and uncertainty as to choice of agent(s) for the prevention of AVF thrombosis. We present the study protocol for a randomised, double-blind, placebo-controlled, clinical trial examining whether the use of the anti-platelet agents, aspirin and omega-3 fatty acids, either alone or in combination, will effectively reduce the risk of early thrombosis in de novo AVF. The study population is adult patients with stage IV or V chronic kidney disease (CKD) currently on HD or where HD is planned to start within 6 months in whom a planned upper or lower arm AVF is to be the primary HD access. Using a factorial-design trial, patients will be randomised to aspirin or matching placebo, and also to omega-3 fatty acids or matching placebo, resulting in four treatment groups (aspirin placebo/omega-3 fatty acid placebo, aspirin/omega-3 fatty acid placebo, aspirin placebo/omega-3 fatty acid, aspirin/omega-3 fatty acid). Randomisation will be achieved using a dynamic balancing method over the two stratification factors of study site and upper versus lower arm AVF. The medication will be commenced pre-operatively and continued for 3 months post surgery. The primary outcome is patency of the AVF at three months after randomisation. Secondary outcome measures will include functional patency at six and twelve months, primary patency time, secondary (assisted) patency time, and adverse events, particularly bleeding. This multicentre Australian and New Zealand study has been designed to determine whether the outcome of surgery to create de novo AVF can be improved by the use of aspirin and/or omega-3 fatty acids. Recently a placebo-controlled trial has shown that clopidogrel is effective in safely preventing primary AVF thrombosis, but ineffective at increasing functional patency. Our study presents significant differences in the anti-platelet agents used, the study design, and surgical and patient demographics that should contribute further evidence regarding the efficacy of anti-platelet agents. Australia & New Zealand Clinical Trials Register (ACTRN12607000569404).
Randomised placebo-controlled trials of surgery: ethical analysis and guidelines.

PubMed

Savulescu, Julian; Wartolowska, Karolina; Carr, Andy

2016-12-01

Use of a placebo control in surgical trials is a divisive issue. We argue that, in principle, placebo controls for surgery are necessary in the same way as for medicine. However, there are important differences between these types of trial, which both increase justification and limit application of surgical studies. We propose that surgical randomised placebo-controlled trials are ethical if certain conditions are fulfilled: (1) the presence of equipoise, defined as a lack of unbiased evidence for efficacy of an intervention; (2) clinically important research question; (3) the risk to patients is minimised and reasonable; (4) there is uncertainty about treatment allocation rather than deception; (5) there is preliminary evidence for efficacy, which justifies a placebo-controlled design; and (6) ideally, the placebo procedure should have some direct benefit to the patient, for example, as a diagnostic tool. Placebo-controlled trials in surgery will most often be justified when surgery is performed to improve function or relieve symptoms and when objective outcomes are not available, while the risk of mortality or significant morbidity is low. In line with medical placebo-controlled trials, the surgical trial (1) should be sufficiently powered and (2) standardised so that its results are valid, (3) consent should be valid, (4) the standard treatment or rescue medication should be provided if possible, and (5) after the trial, the patients should be told which treatment they received and there should be provision for post-trial care if the study may result in long-term negative effects. We comment and contrast our guidelines with those of the American Medical Association. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Utilizing placebo mechanisms for dose reduction in pharmacotherapy.

PubMed

Doering, Bettina K; Rief, Winfried

2012-03-01

The knowledge and systematic application of the placebo effect remains limited, although its importance to the treatment of various medical conditions has increasingly been recognized. A possible application of the placebo effect to pharmacotherapy is seen in conditioning processes that aim at a placebo-controlled dose reduction of drugs while maintaining the efficacy of the medical treatment. The pairing of a placebo and a pharmacological agent may achieve satisfactory treatment outcomes in combination with a lower dose of medication. This procedure includes classic and instrumental conditioning processes that involve both conscious and non-conscious information processing. Although recent studies have gathered preliminary evidence for the efficacy of placebo-controlled dose reduction (e.g. in psoriasis and attention deficit hyperactivity disorder [ADHD]), they have also illustrated the difficulties that are inherent to this approach. We critically review previous approaches and discuss designs for clinical trials that seem appropriate to the investigation of conditioned placebo effects in pharmacotherapy. Copyright Â© 2011 Elsevier Ltd. All rights reserved.
The effect of Neuragen PN® on Neuropathic pain: A randomized, double blind, placebo controlled clinical trial

PubMed Central

2010-01-01

Background A double blind, randomized, placebo controlled study to evaluate the safety and efficacy of the naturally derived topical oil, "Neuragen PN®" for the treatment of neuropathic pain. Methods Sixty participants with plantar cutaneous (foot sole) pain due to all cause peripheral neuropathy were recruited from the community. Each subject was randomly assigned to receive one of two treatments (Neuragen PN® or placebo) per week in a crossover design. The primary outcome measure was acute spontaneous pain level as reported on a visual analog scale. Results There was an overall pain reduction for both treatments from pre to post application. As compared to the placebo, Neuragen PN® led to significantly (p < .05) greater pain reduction. Fifty six of sixty subjects (93.3%) receiving Neuragen PN® reported pain reduction within 30 minutes. This reduction within 30 minutes occurred in only twenty one of sixty (35.0%) subjects receiving the placebo. In a break out analysis of the diabetic only subgroup, 94% of subjects in the Neuragen PN® group achieved pain reduction within 30 minutes vs 11.0% of the placebo group. No adverse events were observed. Conclusions This randomized, placebo controlled, clinical trial with crossover design revealed that the naturally derived oil, Neuragen PN®, provided significant relief from neuropathic pain in an all cause neuropathy group. Participants with diabetes within this group experienced similar pain relief. Trial registration ISRCTN registered: ISRCTN13226601 PMID:20487567
The Effect of Light-Intensity Cycling on Mood and Working Memory in Response to a Randomized, Placebo-Controlled Design.

PubMed

Lindheimer, Jacob B; OʼConnor, Patrick J; McCully, Kevin K; Dishman, Rod K

Prior attempts to measure psychological responses to exercise are potentially limited by a failure to account for participants' expectations, the absence of a valid exercise placebo, and demand characteristics. The purpose of this study was to explore the main and interactive effects of a manipulation designed to increase expectations about the psychological benefits of an acute bout of active, light-intensity (treatment), and passive (placebo) cycling on mood and cognition. Demand characteristics were attenuated during recruitment, informed consent, and interactions with test administrators by communicating to participants that the study purpose was to assess the effects of active and passive cycling on respiration, heart rate, and muscle activation. A repeated-measures, randomized, placebo-controlled design (n = 60) was used with cycling (active, passive) and information (informed, not informed) as between-subjects factors. State anxiety, feelings of energy, and working memory (percent accuracy and reaction time for correct responses) were measured at baseline (time 1), immediately after cycling (time 2) and 20 minutes after cycling (time 3). Most participants did not guess the purpose of the study (~92%) or expect a reduction in state anxiety (85%) or an increase in energy (80%) or cognitive performance (~93%). Mood and cognitive performance were not improved by active or passive cycling (all p values ≥ .12). The methods used here to disguise the experimental hypotheses provide a potential framework for reducing demand characteristics and placebo responses in future investigations of psychological responses to exercise.
Placebo use in vaccine trials: Recommendations of a WHO expert panel

PubMed Central

Rid, Annette; Saxena, Abha; Baqui, Abdhullah H.; Bhan, Anant; Bines, Julie; Bouesseau, Marie-Charlotte; Caplan, Arthur; Colgrove, James; Dhai, Ames; Gomez-Diaz, Rita; Green, Shane K.; Kang, Gagandeep; Lagos, Rosanna; Loh, Patricia; London, Alex John; Mulholland, Kim; Neels, Pieter; Pitisuttithum, Punee; Sarr, Samba Cor; Selgelid, Michael; Sheehan, Mark; Smith, Peter G.

2014-01-01

Vaccines are among the most cost-effective interventions against infectious diseases. Many candidate vaccines targeting neglected diseases in low- and middle-income countries are now progressing to large-scale clinical testing. However, controversy surrounds the appropriate design of vaccine trials and, in particular, the use of unvaccinated controls (with or without placebo) when an efficacious vaccine already exists. This paper specifies four situations in which placebo use may be acceptable, provided that the study question cannot be answered in an active-controlled trial design; the risks of delaying or foregoing an efficacious vaccine are mitigated; the risks of using a placebo control are justified by the social and public health value of the research; and the research is responsive to local health needs. The four situations are: (1) developing a locally affordable vaccine, (2) evaluating the local safety and efficacy of an existing vaccine, (3) testing a new vaccine when an existing vaccine is considered inappropriate for local use (e.g. based on epidemiologic or demographic factors), and (4) determining the local burden of disease. PMID:24768580
Ankle manual therapy for individuals with post-acute ankle sprains: description of a randomized, placebo-controlled clinical trial

PubMed Central

2010-01-01

Background Ankle sprains are common within the general population and can result in prolonged disablement. Limited talocrural dorsiflexion range of motion (DF ROM) is a common consequence of ankle sprain. Limited talocrural DF ROM may contribute to persistent symptoms, disability, and an elevated risk for re-injury. As a result, many health care practitioners use hands-on passive procedures with the intention of improving talocrural joint DF ROM in individuals following ankle sprains. Dosage of passive hands-on procedures involves a continuum of treatment speeds. Recent evidence suggests both slow- and fast-speed treatments may be effective to address disablement following ankle sprains. However, these interventions have yet to be longitudinally compared against a placebo study condition. Methods/Design We developed a randomized, placebo-controlled clinical trial designed to test the hypotheses that hands-on treatment procedures administered to individuals following ankle sprains during the post-acute injury period can improve short-, intermediate-, and long-term disablement, as well as reduce the risk for re-injury. Discussion This study is designed to measure the clinical effects of hands-on passive stretching treatment procedures directed to the talocrural joint that vary in treatment speed during the post-acute injury period, compared to hands-on placebo control intervention. Trial Registration http://www.clinicaltrials.gov identifier NCT00888498. PMID:20958995
Assessment of the Reporting Quality of Placebo-controlled Randomized Trials on the Treatment of Type 2 Diabetes With Traditional Chinese Medicine in Mainland China: A PRISMA-Compliant Systematic Review.

PubMed

Zhao, Xiyan; Zhen, Zhong; Guo, Jing; Zhao, Tianyu; Ye, Ru; Guo, Yu; Chen, Hongdong; Lian, Fengmei; Tong, Xiaolin

2016-01-01

Placebo-controlled randomized trials are often used to evaluate the absolute effect of new treatments and are considered gold standard for clinical trials. No studies, however, have yet been conducted evaluating the reporting quality of placebo-controlled randomized trials. The current study aims to assess the reporting quality of placebo-controlled randomized trials on treatment of diabetes with Traditional Chinese Medicine (TCM) in Mainland China and to provide recommendations for improvements.China National Knowledge Infrastructure database, Wanfang database, China Biology Medicine database, and VIP database were searched for placebo-controlled randomized trials on treatment of diabetes with TCM. Review, animal experiment, and randomized controlled trials without placebo control were excluded. According to Consolidated Standards of Reporting Trials (CONSORT) 2010 checklists items, each item was given a yes or no depending on whether it was reported or not.A total of 68 articles were included. The reporting percentage in each article ranged from 24.3% to 73%, and 30.9% articles reported more than 50% of the items. Seven of the 37 items were reported more than 90% of the items, whereas 7 items were not mentioned at all. The average reporting for "title and abstract," "introduction," "methods," "results," "discussion," and "other information" was 43.4%, 78.7%, 40.1%, 49.9%, 71.1%, and 17.2%, respectively. The percentage of each section had increased after 2010. In addition, the reporting of multiple study centers, funding, placebo species, informed consent forms, and ethical approvals were 14.7%, 50%, 36.85%, 33.8%, and 4.4%, respectively.Although a scoring system was created according to the CONSORT 2010 checklist, it was not designed as an assessment tool. According to CONSORT 2010, the reporting quality of placebo-controlled randomized trials on the treatment of diabetes with TCM improved after 2010. Future improvements, however, are still needed, particularly in methods sections.
Twelve Months of Nightly Zolpidem Does Not Lead to Dose Escalation: A Prospective Placebo-Controlled Study

PubMed Central

Roehrs, Timothy A.; Randall, Surilla; Harris, Erica; Maan, Renee; Roth, Thomas

2011-01-01

Study Objectives: To assess hypnotic self-administration and likelihood of dose escalation over 12 months of nightly use of zolpidem versus placebo in primary insomniacs. Design: Randomized, double-blind, placebo-controlled, clinical trial. Setting: Outpatient with tri-monthly one-week, sleep laboratory assessments. Participants: Thirty-three primary insomniacs, without psychiatric disorders or drug and alcohol abuse, 32–64 yrs old, 14 men and 19 women. Interventions: Participants were randomized to take zolpidem 10 mg (n = 17) or placebo (n = 16) nightly for 12 months. In probes during month 1, 4, and 12, after sampling color-coded placebo or zolpidem capsules on 2 nights, color-coded zolpidem or placebo was chosen on 5 consecutive nights and 1, 2, or 3 of the chosen capsules (5 mg each) could be self-administered on a given choice night. Results: Zolpidem was chosen more nights than placebo (80% of nights) and number of nights zolpidem was chosen did not differ over the 12 months. More zolpidem than placebo capsules were self-administered, and the total number of placebo or zolpidem capsules self-administered did not differ as a function of duration of use. In contrast, the total number of placebo capsules self-administered by the placebo group increased across time. The nightly capsule self-administration on zolpidem nights did not differ from that on placebo nights and neither nightly self-administration rates increased over the 12 months. An average 9.3 mg nightly dose was self-administered. Conclusions: Zolpidem was preferred to placebo, but its self-administration did not increase with 12 months of use. Chronic hypnotic use by primary insomniacs does not lead to dose escalation. Clinical Trial Registration: Safety and Efficacy of Chronic Hypnotic Use; # NCT01006525; http://www.clinicaltrials.gov/ Citation: Roehrs TA; Randall S; Harris E; Maan R; Roth T. Twelve months of nightly zolpidem does not lead to dose escalation: a prospective placebo-controlled study. SLEEP 2011;34(2):207–212. PMID:21286241
Rhodiola rosea therapy for major depressive disorder: a study protocol for a randomized, double-blind, placebo- controlled trial

PubMed Central

Mao, Jun J; Li, Qing S.; Soeller, Irene; Xie, Sharon X; Amsterdam, Jay D.

2014-01-01

Background Rhodiola rosea (R. rosea), a botanical of both western and traditional Chinese medicine, has been used as a folk remedy for improving stamina and reducing stress. However, few controlled clinical trials have examined the safety and efficacy of R. rosea for the treatment of major depressive disorder (MDD). This study seeks to evaluate the safety and efficacy of R. rosea in a 12-week, randomized, double-blind, placebo-controlled, parallel group study design. Methods / Design Subjects with MDD not receiving antidepressant therapy will be randomized to either R. rosea extract 340–1,360 mg daily; sertraline 50–200 mg daily, or placebo for 12 weeks. The primary outcome measure will be change over time in the mean 17-item Hamilton Depression Rating score. Secondary outcome measures will include safety and quality of life ratings. Statistical procedures will include mixed-effects models to assess efficacy for primary and secondary outcomes. Discussion This study will provide valuable preliminary information on the safety and efficacy data of R. rosea versus conventional antidepressant therapy of MDD. It will also inform additional hypotheses and study design of future, fully powered, phase III clinical trials with R. rosea to determine its safety and efficacy in MDD. PMID:25610752
Immediate Effects of Core Stabilization Exercise on β-Endorphin and Cortisol Levels Among Patients With Chronic Nonspecific Low Back Pain: A Randomized Crossover Design.

PubMed

Paungmali, Aatit; Joseph, Leonard Henry; Punturee, Khanittha; Sitilertpisan, Patraporn; Pirunsan, Ubon; Uthaikhup, Sureeporn

The main objective of the study was to measure the levels of plasma β-endorphin (PB) and plasma cortisol (PC) under lumbar core stabilization exercise (LCSE), placebo and control conditions in patients with chronic nonspecific low back pain. Twenty-four participants with chronic nonspecific low back pain participated in a randomized, placebo-controlled, crossover design study. There were 3 experimental exercise conditions: control condition (positioning in crook lying and rest), placebo condition (passive cycling in crook lying using automatic cycler), and LCSE on a Pilates device tested with a 48-hour interval between sessions by concealed randomization. A blood sample was collected before and after the exercise conditions. Plasma β-endorphin and PC were measured through enzyme-linked immunosorbent assay and electrochemiluminescence in a Cobas E411 auto analyzer. A significant difference in PB level was identified before and after the LCSE condition (P < .05), whereas no significant differences were noted in control and placebo exercise conditions. Also, the trend of elevation of PB under the LCSE was significantly different compared with the placebo and control conditions (P < .01). In contrast, the PC level remained unchanged in all 3 conditions. The findings of this study indicate that LCSE could possibly influence PB but not PC level among patients with chronic nonspecific low back pain. The mechanism of action of the pain-relieving effect of LCSE might be related to an endogenous opioid mechanism as part of its effects and might not be involved with a stress-induced analgesia mechanism. Copyright © 2018. Published by Elsevier Inc.
Chinese herbal medicine (Ma Zi Ren Wan) for functional constipation: study protocol for a prospective, double-blinded, double-dummy, randomized controlled trial

PubMed Central

2013-01-01

Background Functional constipation is a common clinical complaint. Although the effectiveness of Ma Zi Ren Wan for alleviating functional constipation symptoms has been proven in a previous randomized placebo-controlled study, further evidence is needed to make clinical recommendations about Chinese herbal medicine. In particular, a comparison with conventional western medicine for functional constipation patients is needed. Methods/Design This is a prospective, double-blinded, double dummy, randomized, controlled trial. After a 2-week run-in period, eligible patients (Rome III) with excessive traditional Chinese medicine syndrome will randomly be assigned to the Chinese medicine arm (Ma Zi Ren Wan and western medicine placebo), western medicine arm (senna and Chinese medicine placebo) or placebo arm (Chinese medicine placebo and western medicine placebo). Patients will undergo an 8-week treatment and an 8-week follow-up. The primary outcome is the responder rate for complete spontaneous bowel movement (CSBM) during treatment. Patients with a mean increase of CSBM ≧1/week in comparison with their baselines are defined as responders. The secondary outcomes include responder rate during follow-up, changes of colonic transit as measured with radio-opaque markers, individual and global symptom assessments, and reported adverse effects. Discussion This study is the first study to compare a Chinese Herbal Medicine (Ma Zi Ren Wan) with a laxative that is commonly used in the clinical practice of western medicine, and with a placebo. This study will complete the investigation of Ma Zi Ren Wan for functional constipation, and should, therefore, suggest recommendations for clinical practice. Furthermore, the process of first conducting a systematic review, then implementing a dose determination study followed by a placebo-control trial, and finally, comparing traditional Chinese medicine with an active conventional medicine in a controlled trial can be a reference to other researches on Chinese medicine interventions in the future. Trial registration NCT01695850 PMID:24180235
The placebo effect.

PubMed

Margo, C E

1999-01-01

Placebos have been traditionally regarded as deceptive therapies and have not been understood in the broader context of social symbols and of interpersonal factors that surround the healing process itself. Although the power of inert substances to heal is well recognized, the placebo effect also influences the outcome of conventional therapies. The role of the placebo in modern medicine is poorly defined because of a lack of a common understanding of what the placebo effect is and because of the negative connotions associated with its use. The response rate to placebo varies by illness. The natural course of disease and patient or physician bias can be misinterpreted as a placebo response. In research, the placebo effect is therapeutic noise to be removed by placebo-controlled trials. Few studies are designed to measure the placebo response rate directly. Placebos are a reminder of how little is known about mind-body interaction. The placebo effect may be one of the most versatile and underused therapeutic tools at the disposal of physicians.
On Suggestibility and Placebo: A Follow-Up Study.

PubMed

Lifshitz, Michael; Sheiner, Eli O; Olson, Jay A; Thériault, Rémi; Raz, Amir

2017-04-01

Identifying what makes some people respond well to placebos remains a major challenge. Here, we attempt to replicate an earlier study in which we found a relationship between hypnotic suggestibility and subjective ratings of relaxation following the ingestion of a placebo sedative (Sheiner, Lifshitz, & Raz, 2016). To assess the reliability of this effect, we tested 34 participants using a similar design. Participants ingested a placebo capsule in one of two conditions: (1) relaxation, wherein we described the capsule as a herbal sedative, or (2) control, wherein we described the capsule as inert. To index placebo response, we collected measures of blood pressure and heart rate, as well as self-report ratings of relaxation and drowsiness. Despite using a similar experimental design as in our earlier study, we were unable to replicate the correlation between hypnotic suggestibility and placebo response. Furthermore, whereas in our former experiment we observed a change in subjective ratings of relaxation but no change in physiological measures, here we found that heart rate dropped in the relaxation condition while subjective ratings remained unchanged. Even within a consistent context of relaxation, therefore, our present results indicate that placebos may induce effects that are fickle, tenuous, and unreliable. Although we had low statistical power, our findings tentatively accord with the notion that placebo response likely involves a complex, multifaceted interaction between traits, expectancies, and contexts.
Efficacy of Eight Months of Nightly Zolpidem: A Prospective Placebo-Controlled Study

PubMed Central

Randall, Surilla; Roehrs, Timothy A.; Roth, Thomas

2012-01-01

Study Objectives: To evaluate the long-term (8 months) efficacy of zolpidem in adults with chronic primary insomnia using polysomnography. Design: Randomized, double-blind, placebo-controlled clinical trial. Setting: Sleep disorders and research center. Participants: Healthy participants (n = 91), ages 23-70, meeting DSM-IV-TR criteria for primary insomnia. Interventions: Nightly zolpidem, 10 mg (5 mg for patients > 60 yrs) or placebo 30 minutes before bedtime for 8 months. Measurements and Results: Polysomnographic sleep parameters and morning subject assessments of sleep on 2 nights in months 1 and 8. Relative to placebo, zolpidem significantly increased overall total sleep time and sleep efficiency, reduced sleep latency and wake after sleep onset when assessed at months 1 and 8. Overall, subjective evaluations of efficacy were not shown among treatment groups. Conclusions: In adults with primary insomnia, nightly zolpidem administration remained efficacious across 8 months of nightly use. Clinical Trial Information: ClinicalTrials.gov Identifier: NCT01006525; Trial Name: Safety and Efficacy of Chronic Hypnotic Use; http://clinicaltrials.gov/ct2/show/NCT01006525. Citation: Randall S; Roehrs TA; Roth T. Efficacy of eight months of nightly zolpidem: a prospective placebo-controlled study. SLEEP 2012;35(11):1551-1557. PMID:23115404
A Randomized, Double-Blind, Crossover Comparison of MK-0929 and Placebo in the Treatment of Adults with ADHD

ERIC Educational Resources Information Center

Rivkin, Anna; Alexander, Robert C.; Knighton, Jennifer; Hutson, Pete H.; Wang, Xiaojing J.; Snavely, Duane B.; Rosah, Thomas; Watt, Alan P.; Reimherr, Fred W.; Adler, Lenard A.

2012-01-01

Objective: Preclinical models, receptor localization, and genetic linkage data support the role of D4 receptors in the etiology of ADHD. This proof-of-concept study was designed to evaluate MK-0929, a selective D4 receptor antagonist as treatment for adult ADHD. Method: A randomized, double-blind, placebo-controlled, crossover study was conducted…
A Placebo Double-Blind Pilot Study of Dextromethorphan for Problematic Behaviors in Children with Autism

ERIC Educational Resources Information Center

Woodard, Cooper; Groden, June; Goodwin, Matthew; Bodfish, James

2007-01-01

We used a mixed group/single-case, double-blind, placebo-controlled, ABAB design to examine the safety and efficacy of the glutamate antagonist dextromethorphan for the treatment of problematic behaviors and core symptoms in eight children diagnosed with autism. All participants had increased levels of irritability at baseline as measured by the…

The Explicit Learning of New Names for Known Objects Is Improved by Dexamphetamine

ERIC Educational Resources Information Center

Whiting, Emma; Chenery, Helen J.; Chalk, Jonathan; Darnell, Ross; Copland, David A.

2008-01-01

A randomised, double-blind, placebo-controlled, between subjects study design (N=37) was used to investigate the effects of dexamphetamine on explicit new name learning. Participants ingested 10 mg of dexamphetamine or placebo daily over 5 consecutive mornings before learning new names for 50 familiar objects plus fillers. The dexamphetamine group…
Effects of Transdermal Testosterone on Natriuretic Peptide Levels in Women: A Randomized Placebo-Controlled Pilot Study

PubMed Central

Lin, Eleanor; McCabe, Elizabeth; Newton-Cheh, Christopher; Bloch, Kenneth; Buys, Emmanuel; Wang, Thomas; Miller, Karen K.

2011-01-01

Objective To investigate whether testosterone administration alters natriuretic peptide levels in women. Design Three-month, double-blind, randomized, placebo-controlled study. Setting Clinical research center. Patients 51 women with hypoandrogenemia due to hypopituitarism. Intervention Transdermal testosterone (300 mcg daily) or placebo patch. Main Outcome Measure N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Results NT-proBNP levels decreased in the transdermal testosterone group compared with placebo over three months (p = 0.009). The difference between groups remained significant after controlling for baseline age, systolic blood pressure, body mass index, and homeostasis model of assessment-insulin resistance (p = 0.008). Change in NT-proBNP over three months was inversely associated with change in free testosterone levels (ρ = −0.41, p = 0.01). Conclusions Testosterone administration to women results in decreased natriuretic peptide levels, suggesting that testosterone may be an inverse regulator of the natriuretic peptide system. Clinical Trials Registration Number NCT00027430 PMID:22137497
Rationale and design of a double-blind, placebo-controlled, randomized trial to evaluate the safety and efficacy of nimodipine in preventing cognitive impairment in ischemic cerebrovascular events (NICE)

PubMed Central

2012-01-01

Background Stroke is the second most common cause of mortality and the leading cause of neurological disability, cognitive impairment and dementia worldwide. Nimodipine is a dihydropyridinic calcium antagonist with a role in neuroprotection, making it a promising therapy for vascular cognitive impairment and dementia. Methods/design The NICE study is a multicenter, randomized, double-blind, placebo-controlled study being carried out in 23 centers in China. The study population includes patients aged 30–80 who have suffered an ischemic stroke (≤7 days). Participants are randomly allocated to nimodipine (90 mg/d) or placebo (90 mg/d). The primary efficacy is to evaluate the level of mild cognitive impairment following treatment of an ischemic stroke with nimodipine or placebo for 6 months. Safety is being assessed by observing side effects of nimodipine. Assuming a relative risk reduction of 22%, at least 656 patients are required in this study to obtain statistical power of 90%. The first patient was recruited in November 2010. Discussion Previous studies suggested that nimodipine could improve cognitive function in vascular dementia and Alzheimer’s disease dementia. It is unclear that at which time-point intervention with nimodipine should occur. Therefore, the NICE study is designed to evaluate the benefits and safety of nimodipine, which was adminstered within seven days, in preventing/treating mild cognitive impairment following ischemic stroke. PMID:22950711
Lubiprostone plus PEG electrolytes versus placebo plus PEG electrolytes for outpatient colonoscopy preparation: a randomized, double-blind placebo-controlled trial.

PubMed

Sofi, Aijaz A; Nawras, Ali T; Pai, Chetan; Samuels, Qiana; Silverman, Ann L

2015-01-01

Bowel preparation using large volume of polyethylene glycol (PEG) solutions is often poorly tolerated. Therefore, there are ongoing efforts to develop an alternative bowel cleansing regimen that should be equally effective and better tolerated. The aim of this study was to assess the efficacy of lubiprostone (versus placebo) plus PEG as a bowel cleansing preparation for colonoscopy. Our study was a randomized, double-blind placebo-controlled design. Patients scheduled for screening colonoscopy were randomized 1:1 to lubiprostone (group 1) or placebo (group 2) plus 1 gallon of PEG. The primary endpoints were patient's tolerability and endoscopist's evaluation of the preparation quality. The secondary endpoint was to determine any reduction in the amount of PEG consumed in the lubiprostone group compared with the placebo group. One hundred twenty-three patients completed the study and were included in the analysis. There was no difference in overall cleanliness. The volume of PEG was similar in both the groups. The volume of PEG approached significance as a predictor of improved score for both the groups (P = 0.054). Lubiprostone plus PEG was similar to placebo plus PEG in colon cleansing and volume of PEG consumed. The volume of PEG consumed showed a trend toward improving the quality of the colon cleansing.
Ankle manual therapy for individuals with post-acute ankle sprains: description of a randomized, placebo-controlled clinical trial.

PubMed

Davenport, Todd E; Kulig, Kornelia; Fisher, Beth E

2010-10-19

Ankle sprains are common within the general population and can result in prolonged disablement. Limited talocrural dorsiflexion range of motion (DF ROM) is a common consequence of ankle sprain. Limited talocrural DF ROM may contribute to persistent symptoms, disability, and an elevated risk for re-injury. As a result, many health care practitioners use hands-on passive procedures with the intention of improving talocrural joint DF ROM in individuals following ankle sprains. Dosage of passive hands-on procedures involves a continuum of treatment speeds. Recent evidence suggests both slow- and fast-speed treatments may be effective to address disablement following ankle sprains. However, these interventions have yet to be longitudinally compared against a placebo study condition. We developed a randomized, placebo-controlled clinical trial designed to test the hypotheses that hands-on treatment procedures administered to individuals following ankle sprains during the post-acute injury period can improve short-, intermediate-, and long-term disablement, as well as reduce the risk for re-injury. This study is designed to measure the clinical effects of hands-on passive stretching treatment procedures directed to the talocrural joint that vary in treatment speed during the post-acute injury period, compared to hands-on placebo control intervention. http://www.clinicaltrials.gov identifier NCT00888498.
Arnica Ointment 10% Does Not Improve Upper Blepharoplasty Outcome: A Randomized, Placebo-Controlled Trial.

PubMed

van Exsel, Denise C E; Pool, Shariselle M W; van Uchelen, Jeroen H; Edens, Mireille A; van der Lei, Berend; Melenhorst, Wynand B W H

2016-07-01

It has been suggested that arnica can reduce postoperative edema and ecchymosis associated with cosmetic surgical procedures and improve outcome. Despite a high incidence of arnica use among upper blepharoplasty patients, evidence to support its treatment effect is lacking. The authors performed a randomized, double-blind, placebo-controlled trial to investigate the efficacy of arnica ointment after upper blepharoplasty. One hundred thirty-six bilateral upper blepharoplasty patients were randomized between arnica ointment 10% and placebo ointment. In both study arms, one periorbital area was designated as the treatment side (either arnica or placebo ointment), and the contralateral side served as an untreated (no ointment) internal control. As the primary endpoint, the overall periorbital appearance as based on light photography and judged by a medical and nonmedical panel, was assessed after 3 days, 7 days, and 6 weeks. Secondary endpoints were swelling, ecchymosis, erythema, pain, and patient satisfaction with recovery and outcome. There was no significant difference between arnica and placebo in overall judgment of periorbital appearance 3 days, 7 days, and 6 weeks after surgery. Furthermore, swelling, ecchymosis, erythema, pain, and patient satisfaction with recovery and outcome did not differ between arnica and placebo. Postoperative outcome in untreated eyelids was not different from eyelids treated with either arnica or placebo on any of the studied outcome measures. The authors' study demonstrates that topical arnica ointment after upper blepharoplasty does not improve postoperative outcome. Therapeutic, II.
Adjunctive treatment with lodenafil carbonate for erectile dysfunction in outpatients with schizophrenia and spectrum: a randomized, double-blind, crossover, placebo-controlled trial.

PubMed

Nunes, Luciana Vargas Alves; Lacaz, Fernando Sargo; Bressan, Rodrigo Affonseca; Nunes, Sandra Odebrecht Vargas Alves; Mari, Jair de Jesus

2013-04-01

INTRODUCTION.: Evidence is accumulating to support the presence of erectile dysfunction in patients with schizophrenia. This dysregulation may be amenable to therapeutic intervention to improve adherence and quality of life of patients who suffer from schizophrenia and schizoaffective disorders. AIM.: We aimed to evaluate the use of adjunctive medication lodenafil for the treatment of erectile dysfunction in outpatients with schizophrenia and spectrum. METHODS.: The design was a randomized, double-blind, crossover, placebo-controlled trial with lodenafil and it was carried at the Schizophrenia Outpatients Program. MAIN OUTCOME MEASURES.: The measures used to assess sexual dysfunction were Arizona Sexual Experiences Scale (ASEX) and International Index of Erectile Function (IIEF). The Positive and Negative Syndrome Scale (PANSS) and the Quality of Life Scale (QLS) were also used. The measures included the levels of prolactin, estradiol, luteinizing hormone, sex hormone-binding globulin, free testosterone, and total testosterone at baseline and end point. Lodenafil and placebo pills were used by the patients for 16 weeks. RESULTS.: Fifty male outpatients fulfilled the criteria and 94% of the participants completed the study. Lodenafil and placebo produced improvement in ASEX, IIEF scale, PANSS, and QLS, and there was no statistical difference between lodenafil and placebo groups in all sexual domains in the results of PANSS and QLS and in the results of hormone levels. CONCLUSION.: These results indicate that both lodenafil and placebo were effective in the treatment of erectile dysfunction for schizophrenia. Placebo effect is very important in patients with schizophrenia and this study showed the importance of discussing sexuality and trying to treat these patients. Further studies designed to test treatments of erectile dysfunction in patients who suffer from schizophrenia are necessary. © 2013 International Society for Sexual Medicine.
Trial of Propranolol in Children and Youth with ASD and Predictors of Response

DTIC Science & Technology

2017-07-01

youth) predicts treatment response. The design for both aims will be a double-blinded, placebo- controlled trial, 12 weeks in duration, with...the youth) predicts treatment response. The design for both aims will be a double-blinded, placebo- controlled trial, 12 weeks in duration, with...Department of the Army position, policy or decision unless so designated by other documentation. REPORT DOCUMENTATION PAGE Form Approved OMB No. 0704
Efficacy and safety of teneligliptin, a novel dipeptidyl peptidase-4 inhibitor, in Korean patients with type 2 diabetes mellitus: a 24-week multicentre, randomized, double-blind, placebo-controlled phase III trial.

PubMed

Hong, S; Park, C-Y; Han, K A; Chung, C H; Ku, B J; Jang, H C; Ahn, C W; Lee, M-K; Moon, M K; Son, H S; Lee, C B; Cho, Y-W; Park, S-W

2016-05-01

We assessed the 24-week efficacy and safety of teneligliptin, a novel dipeptidyl peptidase-4 inhibitor, in Korean patients with type 2 diabetes mellitus (T2DM) that was inadequately controlled with diet and exercise. The present study was designed as a multicentre, randomized, double-blind, placebo-controlled, parallel-group, phase III study. Patients (n = 142) were randomized 2 : 1 into two different treatment groups as follows: 99 received teneligliptin (20 mg) and 43 received placebo. The primary endpoint was change in glycated haemoglobin (HbA1c) level from baseline to week 24. Teneligliptin significantly reduced the HbA1c level from baseline compared with placebo after 24 weeks. At week 24, the differences between changes in HbA1c and fasting plasma glucose (FBG) in the teneligliptin and placebo groups were -0.94% [least-squares (LS) mean -1.22, -0.65] and -1.21 mmol/l (-1.72, -0.70), respectively (all p < 0.001). The incidence of hypoglycaemia and adverse events were not significantly different between the two groups. This phase III, randomized, placebo-controlled study provides evidence of the safety and efficacy of 24 weeks of treatment with teneligliptin as a monotherapy in Korean patients with T2DM. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
Microcurrent transcutaneous electric nerve stimulation in painful diabetic neuropathy: a randomized placebo-controlled study.

PubMed

Gossrau, Gudrun; Wähner, Michael; Kuschke, Marion; Konrad, Birgit; Reichmann, Heinz; Wiedemann, Bärbel; Sabatowski, Rainer

2011-06-01

Diabetes is a common health care problem in western countries. Painful diabetic neuropathy (PDN) might be one of the consequences of long ongoing diabetes; it is estimated that approximately 20% of European diabetic patients suffer from PDN. Transcutaneous electrical nerve stimulation (TENS) is often used as additional pain treatment. However, recent studies show inconsistent results. We aimed to assess the effect of micro-TENS in reducing neuropathic pain in patients with PDN in a placebo-controlled, single-blinded, and randomized design. DESIGN/SETTING/PATIENTS/OUTCOME MEASURES: 22 diabetic patients have been treated with a micro-TENS therapy and 19 patients have been treated with a placebo therapy. Treatment duration was 4 weeks with three therapeutical settings per week. Standardized questionnaires (Pain Disability Index [PDI], neuropathic pain score [NPS], Center for Epidemiologic Studies Depression Scale [CES-D]) were used to assess pain intensity, pain disability, as well as quality of life at baseline at the end of the treatment period and 4 weeks after treatment termination. Patients with a minimum of 30% reduction in NPS were defined as therapy responders. After 4 weeks of treatment, 6/21 patients in the verum group vs 10/19 patients in the placebo group responded to therapy. The median PDI score after 4 weeks of treatment showed a reduction of 23% in the verum vs 25% in the placebo group. The differences did not reach statistical significance. The pain reduction with the applied transcutaneous electrotherapy regimen is not superior to a placebo treatment. Wiley Periodicals, Inc.
Dietary supplementation with rice bran fermented with Lentinus edodes increases interferon-γ activity without causing adverse effects: a randomized, double-blind, placebo-controlled, parallel-group study.

PubMed

Choi, Ji-Young; Paik, Doo-Jin; Kwon, Dae Young; Park, Yongsoon

2014-04-22

The purpose of this study was to investigate the hypothesis that dietary supplementation with rice bran fermented with Lentinus edodes (rice bran exo-biopolymer, RBEP), a substance known to contain arabinoxylan, enhances natural killer (NK) cell activity and modulates cytokine production in healthy adults. This study was designed in a randomized, double-blind, placebo-controlled, and parallel-group format. Eighty healthy participants with white blood cell counts of 4,000-8,000 cells/μL were randomly assigned to take six capsules per day of either 3 g RBEP or 3 g placebo for 8 weeks. Three participants in the placebo group were excluded after initiation of the protocol; no severe adverse effects from RBEP supplementation were reported. NK cell activity of peripheral blood mononuclear cells was measured using nonradioactive cytotoxicity assay kits and serum cytokine concentrations included interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-4, IL-10, and IL-12 were measured by Bio-Plex cytokine assay kit. This study was registered with the Clinical Research Information Service (KCT0000536). Supplementation of RBEP significantly increased IFN-γ production compared with the placebo group (P = 0.012). However, RBEP supplementation did not affect either NK cell activity or cytokine levels, including IL-2, IL-4, IL-10, IL-12, and TNF-α, compared with the placebo group. The data obtained in this study indicate that RBEP supplementation increases IFN-γ secretion without causing significant adverse effects, and thus may be beneficial to healthy individuals. This new rice bran-derived product may therefore be potentially useful to include in the formulation of solid and liquid foods designed for treatment and prevention of pathological states associated with defective immune responses.
Efficacy of maropitant for preventing vomiting associated with motion sickness in dogs.

PubMed

Benchaoui, H A; Siedek, E M; De La Puente-Redondo, V A; Tilt, N; Rowan, T G; Clemence, R G

2007-09-29

Maropitant is a neurokinin-1 inhibitor that acts to prevent and treat vomiting by blocking stimuli to the final common pathway in the emetic centre of the brain. The field efficacy and safety of a single oral dose of maropitant were investigated for the prevention of vomiting in dogs with a history of motion sickness resulting from transportation by car in two blinded, placebo-controlled studies. In an exploratory study designed as a two-way crossover trial with 17 dogs, 10 of the dogs given the placebo vomited during a car journey but only three of the dogs vomited under maropitant treatment. In a larger multicentred parallel design study, 69 of 105 dogs treated with the placebo vomited during the journey compared with 15 of 106 dogs treated with maropitant (P < 0.0001).
Pharmacological interventions for self-injurious behaviour in adults with intellectual disabilities: Abridged republication of a Cochrane systematic review.

PubMed

Gormez, A; Rana, F; Varghese, S

2014-07-01

We aimed to determine clinical effectiveness of pharmacological interventions for self-injurious behaviour in adults with intellectual disability. We searched the following databases: CENTRAL; MEDLINE; EMBASE; PsycINFO; CINAHL; SCI; SSCI; Conference Proceedings Citation Index - Science; Conference Proceedings Citation Index - Social Science and Humanities; ZETOC; World Cat .We also searched ClinicalTrials.gov,ICTRP and the reference lists of included trials. We included randomised controlled trials that examined drug interventions versus placebo for self-injurious behaviour. We found five double-blind, placebo-controlled trials, which included a total of 50 people. Four trials compared the effects of naltrexone versus placebo and one trial clomipramine versus placebo. We did not identify any relevant placebo-controlled trials for other drugs. We presented a narrative summary, as meta-analysis was not appropriate due to differences in study designs, differences between interventions and heterogeneous outcome measures. There was weak evidence in included trials that any active drug was more effective than placebo for people with intellectual disability demonstrating self-injurious behaviour. Due to sparse data, an absence of power and statistical significance, and high risk of bias for four of the included trials, we are unable to reach any definite conclusions about the relative benefits of naltrexone or clomipramine compared to placebo. © The Author(s) 2014.
An exploration of the relationship between placebo and homeopathy and the implications for clinical trial design

PubMed Central

Haresnape, Claire

2013-01-01

Placebo appears to be a real neurobiological phenomenon that has evolved through the selection pressure to be able to heal ourselves. The complex language and social structures of humans means that we can attribute meaning to therapeutic encounters with culturally sanctioned authority figures and we can use our attachment to such figures to generate hope for recovery. Different mechanisms may be involved in the neurobiological aspect of placebo including anxiety, learning, conditioning as well as individual genetic variation. Examination of the published work shows that while some trials do seem to indicate a specific mode of action for homeopathic remedies other trials do not and this is an issue that needs to be addressed at the trial design stage. A clinical trial that includes both a placebo group and a non-participating control arm is the most powerful design for separating the non-specific and polymorphic placebo effect from the specific effects of trial medication. The control variables in a trial of homeopathic medication should also include the process of consultation as this may assume a meaning for the individual that can also be associated with a placebo effect. PMID:24040505
Effect of a plaster containing DHEP and heparin in acute ankle sprains with oedema: a randomized, double-blind, placebo-controlled, clinical study.

PubMed

Coudreuse, J-M; de Vathaire, F

2010-09-01

Ankle sprains are the most frequent injuries in sport and daily life, and are usually treated with anti-inflammatory drugs or compounds that have an effect on microcirculation. The efficacy and tolerability of a novel plaster containing both diclofenac epolamine (DHEP) and heparin in the treatment of acute painful ankle sprains with oedema was investigated in a randomized, double-blind, placebo-controlled study. This study, carried out in 32 French medical centres, enrolled 233 patients (148 male and 86 female, aged 18-65 years) with an ankle sprain that had occurred within the previous 48 hours. Patients were treated once daily with DHEP heparin or placebo plaster for 7 days. Reduction in ankle joint swelling measured by submalleolar circumference was the primary efficacy endpoint; secondary endpoints were pain (at rest, in active mobilization, by passive stretch and by pressure), functional disability and global judgement of efficacy and tolerability. DHEP heparin-treated patients experienced a significantly greater reduction in joint swelling compared with placebo (p = 0.005). The reduction in pain was also in favour of DHEP heparin patients, with significantly lower pain in DHEP heparin-treated than placebo-treated patients within 3 hours of the first application (p < 0.05). Only two patients in the DHEP heparin plaster group and six in the placebo group experienced minor adverse events, all of which resolved spontaneously. By design, the study was limited to a placebo-controlled comparison, and there was no test for possible selection bias (subsequently ruled out by choice of efficacy parameters and measures) that may have resulted in a baseline imbalance between patient groups. Results confirm the efficacy of DHEP heparin plaster compared with placebo for the treatment of painful ankle sprain with oedema. Prompt control of pain and oedema may shorten the time to initiation of a rehabilitation programme, thus reducing the risk of ankle disability recurrence and the development of chronic injury.
D-camphor-crataegus berry extract combination increases blood pressure and cognitive functioning in the elderly - a randomized, placebo controlled double blind study.

PubMed

Werner, Natalie S; Duschek, Stefan; Schandry, Rainer

2009-12-01

The present study investigated whether the D-camphor-crataegus berry extract combination Korodin elevates blood pressure and enhances cognitive performance in the elderly population. Eighty women aged between 50 and 80 years were examined based on a randomized, placebo controlled double blind design. Blood pressure was measured sphygmomanometrically and through continuous noninvasive recording. Cognitive performance was assessed by means of two tests measuring general information processing capacity and visuomotor speed. The administration of the drug led to a short term increase in blood pressure as well as in cognitive performance as compared to placebo. Potential physiological mechanisms of action mediating this effect, including hemodynamic alterations, sympathetic stimulation as well as improvement of cerebral metabolism are discussed.
Prolonged remission from hepatic encephalopathy with rifaximin: results of a placebo crossover analysis

PubMed Central

Bajaj, J S; Barrett, A C; Bortey, E; Paterson, C; Forbes, W P

2015-01-01

Background Rifaximin therapy reduced risk of hepatic encephalopathy (HE) recurrence and HE-related hospitalisations during a 6-month, randomised, placebo-controlled trial (RCT) and a 24-month open-label maintenance (OLM) study. However, the impact of crossover from placebo to rifaximin therapy is unclear. Aim To study the impact of crossing over from placebo to rifaximin treatment on breakthrough HE and hospitalisation rates using a within-subjects design. Methods Adults with cirrhosis and history of overt HE episodes, currently in HE remission, received placebo during the RCT and crossed over to rifaximin 550 mg twice daily during the OLM study. Rate of breakthrough overt HE episodes, hospitalisations and incidence and rate of adverse events (AEs) were analysed during RCT and first 6 months of OLM. Results Of 82 patients randomised to placebo in the RCT who crossed over to the OLM study, 39 experienced an HE episode during the RCT compared with 14 during the OLM study (P < 0.0001). Significantly lower rates of HE events were observed with rifaximin treatment compared with placebo treatment (P < 0.0001). Rates of HE-related hospitalisation were numerically lower during rifaximin treatment compared with placebo treatment, although not significant. Rates of most common AEs, serious AEs and infection-related AEs were similar between the two treatments. Conclusions This analysis confirms the repeatability of results from the RCT on safety and efficacy of rifaximin 550 mg twice daily in reducing the risk of hepatic encephalopathy recurrence, and suggests these findings are translatable outside of a rigorous, controlled trial setting. PMID:25339518
Examining the nootropic effects of a special extract of Bacopa monniera on human cognitive functioning: 90 day double-blind placebo-controlled randomized trial.

PubMed

Stough, Con; Downey, Luke A; Lloyd, Jenny; Silber, Beata; Redman, Stephanie; Hutchison, Chris; Wesnes, Keith; Nathan, Pradeep J

2008-12-01

While Ayurvedic medicine has touted the cognitive enhancing effects of Bacopa monniera for centuries, there is a need for double-blind placebo-controlled investigations. One hundred and seven healthy participants were recruited for this double-blind placebo-controlled independent group design investigation. Sixty-two participants completed the study with 80% treatment compliance. Neuropsychological testing using the Cognitive Drug Research cognitive assessment system was conducted at baseline and after 90 days of treatment with a special extract of Bacopa monniera (2 x 150 mg KeenMind) or placebo. The Bacopa monniera product significantly improved performance on the 'Working Memory' factor, more specifically spatial working memory accuracy. The number of false-positives recorded in the Rapid visual information processing task was also reduced for the Bacopa monniera group following the treatment period. The current study provides support for the two other published studies reporting cognitive enhancing effects in healthy humans after a 90 day administration of the Bacopa monniera extract. Further studies are required to ascertain the effective dosage range, the time required to attain therapeutic levels and the effects over a longer term of administration. (c) 2008 John Wiley & Sons, Ltd.
Design Dilemma: The Debate over Using Placebos in Cancer Clinical Trials

Cancer.gov

Many patients and researchers assert that in cancer clinical trials, placebos are inappropriate and that all participants should receive active treatment. But with the emergence of molecularly targeted anticancer agents, some cancer researchers believe placebo-controlled trials are now feasible and, in some cases, necessary.
QUETIAPINE IMPROVES RESPONSE INHIBITION IN ALCOHOL DEPENDENT PATIENTS: A PLACEBO-CONTROLLED PILOT STUDY

PubMed Central

Moallem, Nathasha; Ray, Lara A.

2013-01-01

Rationale Quetiapine has been shown to be a promising medication for the treatment of alcoholism. As an atypical antipsychotic medication with antagonist activity at D1 and D2, 5-HT1A and 5-HT2A, H1 and α1 and α2 receptors, quetiapine has been found to decrease impulsivity in other psychiatric disorders but its effects on impulsivity have not been studied in alcohol dependent patients. Objective This study seeks to test the effects of quetiapine on a specific dimension of impulsivity, namely response inhibition. This pilot study seeks to further elucidate the mechanisms of action of quetiapine for alcohol use disorders. Method A total of 20 non-treatment seeking alcohol dependent individuals were randomized to one of the following conditions in a double-blind, placebo-controlled design: (1) quetiapine (400 mg/day); or (2) matched placebo. Participants completed two counterbalanced intravenous placebo-alcohol administration sessions as well as behavioral measure of response inhibition (i.e. stop signal task) pre and post placebo-alcohol administration sessions. Results Analyses revealed a significant effect of quetiapine in improving response inhibition as measured by the stop signal task. These results provide preliminary evidence suggesting that quetiapine improves response inhibition in alcohol dependent patients, as compared to placebo. Conclusion This pilot study contributes a novel putative mechanism of action of quetiapine in alcoholism, namely an improvement in response inhibition. PMID:22037407

Libertas: rationale and study design of a multicentre, Phase II, double-blind, randomised, placebo-controlled investigation to evaluate the efficacy, safety and tolerability of locally applied NRL001 in patients with faecal incontinence.

PubMed

Siproudhis, L; Jones, D; Shing, R Ng Kwet; Walker, D; Scholefield, J H

2014-03-01

Faecal incontinence affects up to 8% of adults. Associated social isolation and subsequent depression can have devastating effects on quality of life (QoL). Faecal incontinence is an underreported health problem as the social isolation and stigma that patients experience makes it difficult for sufferers to discuss their condition with a physician. There have been few well-designed, placebo-controlled clinical trials of treatment for faecal incontinence and little clinical evidence is available to inform the most appropriate management strategies. Libertas, a robustly designed study will investigate the efficacy and safety of NRL001 (1R,2S-methoxamine), an α1 -adrenoceptor agonist, in the treatment of faecal incontinence. Libertas is a multicentre, Phase II, double-blind, randomised, placebo-controlled, parallel group study. Patient recruitment took place across 55 study centres in Europe. Patients suffering with faecal incontinence were randomised into four groups (approximately 110 each) to receive once daily self-administered doses of NRL001 (5, 7.5 or 10 mg or placebo in a suppository formulation) for 8 weeks. The primary objective of Libertas is to assess the impact of once daily administration of NRL001 on the severity and frequency of incontinence episodes as assessed by the Wexner score at 4 weeks, compared with placebo. Secondary outcomes include measures of efficacy of NRL001 compared with placebo following 8 weeks treatment; safety and tolerability; evaluation of plasma pharmacokinetics; establishment of any pharmacokinetic/pharmacodynamic relationship to adverse events; dose-response relationship; the efficacy of NRL001 therapy at 4 and 8 weeks assessed by the Vaizey score; and QoL using the Faecal Incontinence Quality of Life and the EQ-5D-5L Healthcare Questionnaires following 4 and 8 weeks NRL001 therapy. Overall patient satisfaction with the treatment will also be evaluated. This is the first randomised controlled study to investigate the efficacy and safety of a selective α1 -adrenoceptor agonist for the treatment of faecal incontinence. Furthermore, this is the first time the impact of NRL001 on assessments of QoL, health outcomes and patient satisfaction will be assessed. Innovative strategies were developed to meet the challenge of recruiting patients for this study, for example, media advertising, posters and mailshots as allowed by each study centre. Colorectal Disease © 2014 The Association of Coloproctology of Great Britain and Ireland.
The administration to Indonesians of monosodium L-glutamate in Indonesian foods: an assessment of adverse reactions in a randomized double-blind, crossover, placebo-controlled study.

PubMed

Prawirohardjono, W; Dwiprahasto, I; Astuti, I; Hadiwandowo, S; Kristin, E; Muhammad, M; Kelly, M F

2000-04-01

Monosodium L-glutamate (MSG) has been suggested to cause postprandial symptoms after the ingestion of Chinese or oriental meals. Therefore, we examined whether such symptoms could be elicited in Indonesians ingesting levels of MSG typically found in Indonesian cuisine. Healthy volunteers (n = 52) were treated with capsules of placebo or MSG (1.5 and 3.0 g/person) as part of a standardized Indonesian breakfast. The study used a rigorous, randomized, double-blind, crossover design. The occurrence of symptoms after MSG ingestion did not differ from that after consumption of the placebo.
Quantifying the placebo effect in psychological outcomes of exercise training: a meta-analysis of randomized trials.

PubMed

Lindheimer, Jacob B; O'Connor, Patrick J; Dishman, Rod K

2015-05-01

The placebo effect could account for some or all of the psychological benefits attributed to exercise training. The magnitude of the placebo effect in psychological outcomes of randomized controlled exercise training trials has not been quantified. The aim of this investigation was to estimate the magnitude of the population placebo effect in psychological outcomes from placebo conditions used in exercise training studies and compare it to the observed effect of exercise training. Articles published before 1 July 2013 were located using Google Scholar, MEDLINE, PsycINFO, and The Cochrane Library. To be included in the analysis, studies were required to have (1) a design that randomly assigned participants to exercise training, placebo, and control conditions and (2) an assessment of a subjective (i.e., anxiety, depression, energy, fatigue) or an objective (i.e., cognitive) psychological outcome. Meta-analytic and multi-level modeling techniques were used to analyze effects from nine studies involving 661 participants. Hedges' d effect sizes were calculated, and random effects models were used to estimate the overall magnitude of the placebo and exercise training effects. After adjusting for nesting effects, the placebo mean effect size was 0.20 (95% confidence interval [CI] -0.02, 0.41) and the observed effect of exercise training was 0.37 (95% CI 0.11, 0.63). A small body of research suggests both that (1) the placebo effect is approximately half of the observed psychological benefits of exercise training and (2) there is an urgent need for creative research specifically aimed at better understanding the role of the placebo effect in the mental health consequences of exercise training.
Placebos in clinical practice and research.

PubMed Central

De Deyn, P P; D'Hooge, R

1996-01-01

The main current application of placebo is in clinical research. The term placebo effect refers to diverse non-specific, desired or non-desired effects of substances or procedures and interactions between patient and therapist. Unpredictability of the placebo effect necessitates placebo-controlled designs for most trials. Therapeutic and diagnostic use of placebo is ethically acceptable only in few well-defined cases. While "therapeutic" application of placebo almost invariably implies deception, this is not the case for its use in research. Conflicts may exist between the therapist's Hippocratic and scientific obligations. The authors provide examples in neuropsychiatry, illustrating that objective scientific data and well-considered guidelines may solve the ethical dilemma. Placebo control might even be considered an ethical obligation but some provisos should be kept in mind: (a) no adequate therapy for the disease should exist and/or (presumed) active therapy should have serious side-effects; (b) placebo treatment should not last too long; (c) placebo treatment should not inflict unacceptable risks, and (d) the experimental subject should be adequately informed and informed consent given. PMID:8798935
A double-blind randomized placebo-controlled feasibility study evaluating individualized homeopathy in managing pain of knee osteoarthritis.

PubMed

Koley, Munmun; Saha, Subhranil; Ghosh, Shubhamoy

2015-07-01

Few homeopathic complexes seemed to produce significant effects in osteoarthritis; still, individualized homeopathy remained untested. We evaluated the feasibility of conducting an efficacy trial of individualized homeopathy in osteoarthritis. A prospective, parallel-arm, double-blind, randomized, placebo-controlled pilot study was conducted from January to October 2014 involving 60 patients (homeopathy, n = 30; placebo, n = 30) who were suffering from acute painful episodes of knee osteoarthritis and visiting the outpatient clinic of Mahesh Bhattacharyya Homeopathic Medical College and Hospital, West Bengal, India. Statistically significant reduction was achieved in 3 visual analog scales (measuring pain, stiffness, and loss of function) and Osteoarthritis Research Society International scores in both groups over 2 weeks (P < .05); however, group differences were not significant (P > .05). Overall, homeopathy did not appear to be superior to placebo; still, further rigorous evaluation in this design involving a larger sample size seems feasible in future. Clinical Trials Registry, India (CTRI/2014/05/004589). © The Author(s) 2015.
Using instrumental variables to disentangle treatment and placebo effects in blinded and unblinded randomized clinical trials influenced by unmeasured confounders

NASA Astrophysics Data System (ADS)

Chaibub Neto, Elias

2016-11-01

Clinical trials traditionally employ blinding as a design mechanism to reduce the influence of placebo effects. In practice, however, it can be difficult or impossible to blind study participants and unblinded trials are common in medical research. Here we show how instrumental variables can be used to quantify and disentangle treatment and placebo effects in randomized clinical trials comparing control and active treatments in the presence of confounders. The key idea is to use randomization to separately manipulate treatment assignment and psychological encouragement conversations/interactions that increase the participants’ desire for improved symptoms. The proposed approach is able to improve the estimation of treatment effects in blinded studies and, most importantly, opens the doors to account for placebo effects in unblinded trials.
Dietary Soy Supplement on Fibromyalgia Symptoms: A Randomized, Double-Blind, Placebo-Controlled, Early Phase Trial

PubMed Central

Wahner-Roedler, Dietlind L.; Thompson, Jeffrey M.; Luedtke, Connie A.; King, Susan M.; Cha, Stephen S.; Elkin, Peter L.; Bruce, Barbara K.; Townsend, Cynthia O.; Bergeson, Jody R.; Eickhoff, Andrea L.; Loehrer, Laura L.; Sood, Amit; Bauer, Brent A.

2011-01-01

Most patients with fibromyalgia use complementary and alternative medicine (CAM). Properly designed controlled trials are necessary to assess the effectiveness of these practices. This study was a randomized, double-blind, placebo-controlled, early phase trial. Fifty patients seen at a fibromyalgia outpatient treatment program were randomly assigned to a daily soy or placebo (casein) shake. Outcome measures were scores of the Fibromyalgia Impact Questionnaire (FIQ) and the Center for Epidemiologic Studies Depression Scale (CES-D) at baseline and after 6 weeks of intervention. Analysis was with standard statistics based on the null hypothesis, and separation test for early phase CAM comparative trials. Twenty-eight patients completed the study. Use of standard statistics with intent-to-treat analysis showed that total FIQ scores decreased by 14% in the soy group (P = .02) and by 18% in the placebo group (P < .001). The difference in change in scores between the groups was not significant (P = .16). With the same analysis, CES-D scores decreased in the soy group by 16% (P = .004) and in the placebo group by 15% (P = .05). The change in scores was similar in the groups (P = .83). Results of statistical analysis using the separation test and intent-to-treat analysis revealed no benefit of soy compared with placebo. Shakes that contain soy and shakes that contain casein, when combined with a multidisciplinary fibromyalgia treatment program, provide a decrease in fibromyalgia symptoms. Separation between the effects of soy and casein (control) shakes did not favor the intervention. Therefore, large-sample studies using soy for patients with fibromyalgia are probably not indicated. PMID:18990724
Placebo analgesia is not due to compliance or habituation: EEG and behavioural evidence.

PubMed

Watson, Alison; El-Deredy, Wael; Vogt, Brent A; Jones, Anthony K P

2007-05-28

This study was designed to resolve whether experimental placebo responses are due to either increased compliance or habituation. We stimulated both forearms and recorded laser-evoked potentials from 18 healthy volunteers treated on one arm with a sham analgesic cream and an inactive cream on the other (treatment group), and 13 volunteers with an inactive cream on both arms (controls). The treatment group showed a significant reduction in the pain ratings and laser-evoked potentials with both the sham and inactive creams. The control group showed no evidence of habituation to the laser stimulus. The results indicate that the reduction in pain during experimental placebo response is unlikely to be due to sensory habituation or compliance with the experimental instructions.
Comparison of psychological placebo and waiting list control conditions in the assessment of cognitive behavioral therapy for the treatment of generalized anxiety disorder: a meta-analysis

PubMed Central

ZHU, Zhipei; ZHANG, Li; JIANG, Jiangling; LI, Wei; CAO, Xinyi; ZHOU, Zhirui; ZHANG, Tiansong; LI, Chunbo

2014-01-01

Background There is ongoing debate about the efficacy of placebos in the treatment of mental disorders. In randomized control trials (RCTs) about the treatment of generalized anxiety disorder, the administration of a psychological placebo or placement on a waiting list are the two most common control conditions. But there has never been a systematic comparison of the clinical effect of these different strategies. Aim Compare the change in symptom severity among individuals treated with cognitive behavioral therapy, provided a psychological placebo, or placed on a waiting list using data from RCTs on generalized anxiety disorder. Methods The following databases were searched for RCTs on generalized anxiety disorder: PubMed, PsycInfo, EMBASE, The Cochrane Library, CNKI, Chongqing VIP, Wanfang, Chinese Biological Medical Literature Database, and Taiwan Electronic Periodical Services. Studies were selected based on pre-defined inclusion and exclusion criteria and the quality of each included study – based on the risk of bias and the level of evidence – was formally assessed. Meta-analysis was conducted using RevMan5.3 and network meta-analyses comparing the three groups were conducted using R. Results Twelve studies with a combined sample size of 531 were included in the analysis. Compared to either control method (placebo or waiting list), cognitive behavioral therapy was more effective for generalized anxiety disorder. Provision of a psychological placebo was associated with a significantly greater reduction of symptoms than placement on a waiting list. Eight of the studies were classified as ‘high risk of bias’, and the overall level of evidence was classified as ‘moderate’, indicating that further research could change the overall results of the meta-analysis. Conclusions RCTs about the treatment of generalized anxiety disorders are generally of moderate quality; they indicate the superiority of CBT but the results cannot, as yet, be considered robust. There is evidence of a non-negligible treatment effect of psychological placebos used as control conditions in research studies. This effect should be considered when designing and interpreting the results of randomized controlled trials about the effectiveness of psychotherapeutic interventions. PMID:25642106
Comparison of psychological placebo and waiting list control conditions in the assessment of cognitive behavioral therapy for the treatment of generalized anxiety disorder: a meta-analysis.

PubMed

Zhu, Zhipei; Zhang, Li; Jiang, Jiangling; Li, Wei; Cao, Xinyi; Zhou, Zhirui; Zhang, Tiansong; Li, Chunbo

2014-12-01

There is ongoing debate about the efficacy of placebos in the treatment of mental disorders. In randomized control trials (RCTs) about the treatment of generalized anxiety disorder, the administration of a psychological placebo or placement on a waiting list are the two most common control conditions. But there has never been a systematic comparison of the clinical effect of these different strategies. Compare the change in symptom severity among individuals treated with cognitive behavioral therapy, provided a psychological placebo, or placed on a waiting list using data from RCTs on generalized anxiety disorder. The following databases were searched for RCTs on generalized anxiety disorder: PubMed, PsycInfo, EMBASE, The Cochrane Library, CNKI, Chongqing VIP, Wanfang, Chinese Biological Medical Literature Database, and Taiwan Electronic Periodical Services. Studies were selected based on pre-defined inclusion and exclusion criteria and the quality of each included study - based on the risk of bias and the level of evidence - was formally assessed. Meta-analysis was conducted using RevMan5.3 and network meta-analyses comparing the three groups were conducted using R. Twelve studies with a combined sample size of 531 were included in the analysis. Compared to either control method (placebo or waiting list), cognitive behavioral therapy was more effective for generalized anxiety disorder. Provision of a psychological placebo was associated with a significantly greater reduction of symptoms than placement on a waiting list. Eight of the studies were classified as 'high risk of bias', and the overall level of evidence was classified as 'moderate', indicating that further research could change the overall results of the meta-analysis. RCTs about the treatment of generalized anxiety disorders are generally of moderate quality; they indicate the superiority of CBT but the results cannot, as yet, be considered robust. There is evidence of a non-negligible treatment effect of psychological placebos used as control conditions in research studies. This effect should be considered when designing and interpreting the results of randomized controlled trials about the effectiveness of psychotherapeutic interventions.
The Placebo Response in Pediatric Abdominal Pain-Related Functional Gastrointestinal Disorders: A Systematic Review and Meta-Analysis.

PubMed

Hoekman, Daniël R; Zeevenhooven, Judith; van Etten-Jamaludin, Faridi S; Douwes Dekker, Iuke; Benninga, Marc A; Tabbers, Merit M; Vlieger, Arine M

2017-03-01

To investigate the magnitude and determinants of the placebo response in studies with pediatric abdominal pain-related functional gastrointestinal disorders. The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL were searched for systematic reviews and randomized placebo-controlled trials concerning children 4-18 years of age with an abdominal pain-related functional gastrointestinal disorder. The primary outcome was the pooled proportion of subjects assigned to placebo with improvement as defined by the authors. The effect of trial characteristics on the magnitude of the placebo response was investigated using univariate meta-regression analysis. Twenty-one trials were identified. The pooled proportion of subjects with improvement was 41% (95% CI, 34%-49%; 17 studies) and with no pain was 17% (95% CI, 8%-32%; 7 studies). The pooled standardized mean difference on the Faces Pain Scales compared with baseline was -0.73 (95% CI, -1.04 to -0.42; 8 studies). There was significant heterogeneity across studies with respect to both outcomes. Lower dosing frequency (P = .04), positive study (P = .03), longer duration of treatment (P < .001), and higher placebo dropout (P < .001) were associated with higher report of no pain. Response on Faces Pain Scales was greater in studies conducted in the Middle East (P = .002), in studies that did not report the randomization schedule (P = .02), and in studies with a higher percentage of females (P = .04). Approximately 41% of children with abdominal pain-related functional gastrointestinal disorders improve on placebo. Several trial characteristics are correlated significantly with the proportion of patients with no pain on placebo and with the magnitude of the placebo response on Faces Pain Scales. These data could be valuable for the design of future studies. Copyright © 2016 Elsevier Inc. All rights reserved.
The Pervasive Problem With Placebos in Psychology: Why Active Control Groups Are Not Sufficient to Rule Out Placebo Effects.

PubMed

Boot, Walter R; Simons, Daniel J; Stothart, Cary; Stutts, Cassie

2013-07-01

To draw causal conclusions about the efficacy of a psychological intervention, researchers must compare the treatment condition with a control group that accounts for improvements caused by factors other than the treatment. Using an active control helps to control for the possibility that improvement by the experimental group resulted from a placebo effect. Although active control groups are superior to "no-contact" controls, only when the active control group has the same expectation of improvement as the experimental group can we attribute differential improvements to the potency of the treatment. Despite the need to match expectations between treatment and control groups, almost no psychological interventions do so. This failure to control for expectations is not a minor omission-it is a fundamental design flaw that potentially undermines any causal inference. We illustrate these principles with a detailed example from the video-game-training literature showing how the use of an active control group does not eliminate expectation differences. The problem permeates other interventions as well, including those targeting mental health, cognition, and educational achievement. Fortunately, measuring expectations and adopting alternative experimental designs makes it possible to control for placebo effects, thereby increasing confidence in the causal efficacy of psychological interventions. © The Author(s) 2013.
Effect of acupuncture and instruction on physiological recovery from maximal exercise: a balanced-placebo controlled trial.

PubMed

Urroz, Paola; Colagiuri, Ben; Smith, Caroline A; Yeung, Alan; Cheema, Birinder S

2016-07-18

This study aimed to investigate the effect of acupuncture administered immediately following a graded exercise test (GXT) on physiological measures of recovery and determine if instruction (expectancy) affected the responses. A balanced-placebo 2 × 2 factorial design was used with treatment (real vs placebo acupuncture) and instruction (told real vs told placebo acupuncture) as factors; a no-treatment control group was also included to compare the treatment responses to no treatment. Recreationally active, acupuncture naïve young adults (n = 60) performed a GXT to exhaustion on a cycle ergometer (15 W/min). Heart rate, blood pressure, oxygen consumption, respiratory rate and blood lactate were collected during the test and during 60 min of supine recovery on a plinth. An experienced acupuncturist delivered real or placebo acupuncture within 6 min of completing the GXT (total treatment time = 20 min). Real acupuncture points included Neiguan (PC6), Zusanli (ST36), Lieque (LU7), and Tanzhang (REN17), while placebo acupuncture was delivered using the Park sham needle placed 1-2 cm away from each real acupuncture point. The control group received no intervention. Linear and quadratic trend analyses over time indicated no significant differences between groups on any dependent variable. However, analysis of specific timepoints (every 10 min of the 60 min recovery) revealed that participants who received some form of treatment had a lower heart rate than participants in the no treatment control group (p = 0.042) at 20 min post-exercise. Further, a significant treatment by instruction interaction effect for heart rate was also found at 50 min (p = 0.042) and 60 min (p = 0.013) post-exercise, indicating that the differences between real and placebo acupuncture were affected by expectancy manipulation. No other significant effects were noted. However, it was interesting to note that participants who believed they were given real acupuncture reported quicker perceived recovery independent of actual treatment (p = 0.006) suggesting that instruction about treatment influenced perceived recovery. In summary, due to limited evidence, the current study does not support the acute use of acupuncture for exercise recovery. However, importantly, the current study demonstrates that a balanced-placebo design is viable for testing acupuncture and expectancy effects, and this methodology could therefore be implemented in future studies. ACTRN12612001015831 (Date registered: 20/09/2012).
Efficacy and tolerability of Hairgain in individuals with hair loss: a placebo-controlled, double-blind study.

PubMed

Thom, E

2001-01-01

This randomized, placebo-controlled, double-blind study was designed to investigate the efficacy and tolerability of a new agent for the treatment of hair loss, based on a marine protein, minerals and vitamins. Sixty subjects with hair loss of different aetiologies participated in the 6-month blinded phase of the study. Objective assessments indicated that the treatment was effective and subjective assessments showed a statistically significant positive effect of treatment. Exposure to the active preparation for a further 6 months in an open phase indicated a further improvement in hair growth. Exposure of the patients previously treated with placebo to the active preparation for 12 months gave similar results. Tolerability was good and no side-effects were reported. The product investigated may provide an alternative to pharmacotherapy for the treatment of hair-loss problems in individuals with androgenic alopecia.
Melatonin increases reactive aggression in humans.

PubMed

Liu, Jinting; Zhong, Ru; Xiong, Wei; Liu, Haibo; Eisenegger, Christoph; Zhou, Xiaolin

2017-10-01

Melatonin, a hormone released preferentially by the pineal gland during the night, affects circadian rhythms and aging processes. As animal studies have shown that melatonin increases resident-intruder aggression, this study aimed to investigate the impact of melatonin treatment on human aggression. In a double-blind, randomized, placebo-controlled between-participant design, 63 healthy male volunteers completed the Taylor Aggression Paradigm (TAP) after oral administration of melatonin or placebo. We found that when given the opportunity to administer high or low punishments to an opponent, participants who ingested melatonin selected the high punishment more often than those who ingested placebo. The increased reactive aggression under melatonin administration remained after controlling for inhibitory ability, trait aggression, trait impulsiveness, circadian preference, perceptual sensibility to noise, and changes in subjective sleepiness and emotional states. This study provides novel and direct evidence for the involvement of melatonin in human social processes.
Creativity on tap? Effects of alcohol intoxication on creative cognition

PubMed Central

Benedek, Mathias; Panzierer, Lisa; Jauk, Emanuel; Neubauer, Aljoscha C.

2017-01-01

Anecdotal reports link alcohol intoxication to creativity, while cognitive research highlights the crucial role of cognitive control for creative thought. This study examined the effects of mild alcohol intoxication on creative cognition in a placebo-controlled design. Participants completed executive and creative cognition tasks before and after consuming either alcoholic beer (BAC of 0.03) or non-alcoholic beer (placebo). Alcohol impaired executive control, but improved performance in the Remote Associates Test, and did not affect divergent thinking ability. The findings indicate that certain aspects of creative cognition benefit from mild attenuations of cognitive control, and contribute to the growing evidence that higher cognitive control is not always associated with better cognitive performance. PMID:28705663
Parental Attitudes About Placebo Use in Children.

PubMed

Faria, Vanda; Kossowsky, Joe; Petkov, Mike P; Kaptchuk, Ted J; Kirsch, Irving; Lebel, Alyssa; Borsook, David

2017-02-01

To assess parental attitudes regarding placebo use in pediatric randomized controlled trials and clinical care. Parents with children under age 18 years living in the US completed and submitted an online survey between September and November 2014. Among all 1300 participants, 1000 (76.9%; 538 mothers and 462 fathers) met the study inclusion criteria. The majority of surveyed parents considered the use of placebos acceptable in some pediatric care situations (86%) and some pediatric trials (91.5%), whereas only 5.7% of parents found the use of placebos in children always unacceptable. The clinical use of placebo was considered acceptable by a majority of parents for only 7 (mostly psychological) of the 17 conditions presented. Respondents' judgment about acceptability was influenced by the doctors' opinions about the therapeutic benefits of placebo treatment, the conditions for pediatric placebo use, transparency, safety, and purity of placebos. Most surveyed parents accepted the idea of using placebos in pediatric trials and within the clinic for some conditions without the practice of deception and with the creation of guidelines for ethical and safe use. This study suggests a need to reconsider pediatric trial design and clinical therapy in the light of generally positive parental support of appropriate placebo use. Copyright © 2016 Elsevier Inc. All rights reserved.
Methylphenidate and emotional-motivational processing in attention-deficit/hyperactivity disorder.

PubMed

Conzelmann, Annette; Woidich, Eva; Mucha, Ronald F; Weyers, Peter; Müller, Mathias; Lesch, Klaus-Peter; Jacob, Christian P; Pauli, Paul

2016-08-01

In line with the assumption that emotional-motivational deficits are one core dysfunction in ADHD, in one of our previous studies we observed a reduced reactivity towards pleasant pictures in adult ADHD patients as compared to controls. This was indicated by a lack of attenuation of the startle reflex specifically during pleasant pictures in ADHD patients. The first choice medical agents in ADHD, methylphenidate (MPH), is discussed to normalize these dysfunctions. However, experimental evidence in the sense of double-blind placebo-controlled study designs is lacking. Therefore, we investigated 61 adult ADHD patients twice, one time with placebo and one time with MPH with the same experimental design as in our study previously and assessed emotion processing during the presentation of pleasant, neutral and unpleasant pictures. We obtained startle reflex data as well as valence and arousal ratings in association with the pictures. As previously shown, ADHD patients showed a diminished startle attenuation during pleasant pictures while startle potentiation during unpleasant pictures was normal. Valence and arousal ratings unsuspiciously increased with increasing pleasantness and arousal of the pictures, respectively. There were no significant influences of MPH. The study replicates that ADHD patients show a reduced reactivity towards pleasant stimuli. MPH did not normalize this dysfunction. Possibly, MPH only influences emotions during more complex behavioural tasks that involve executive functions in adults with ADHD. Our results emphasize the importance for the use of double-blind placebo-controlled designs in psychopharmacological research.
Effect of Pumpkin Seed Oil on Hair Growth in Men with Androgenetic Alopecia: A Randomized, Double-Blind, Placebo-Controlled Trial

PubMed Central

Jeong, Dong Wook; Choi, Eun Jung; Kim, Yun Jin; Lee, Jeong Gyu; Yi, Yu Hyeon; Cha, Hyeong Soo

2014-01-01

Pumpkin seed oil (PSO) has been shown to block the action of 5-alpha reductase and to have antiandrogenic effects on rats. This randomized, placebo-controlled, double-blind study was designed to investigate the efficacy and tolerability of PSO for treatment of hair growth in male patients with mild to moderate androgenetic alopecia (AGA). 76 male patients with AGA received 400 mg of PSO per day or a placebo for 24 weeks. Change over time in scalp hair growth was evaluated by four outcomes: assessment of standardized clinical photographs by a blinded investigator; patient self-assessment scores; scalp hair thickness; and scalp hair counts. Reports of adverse events were collected throughout the study. After 24 weeks of treatment, self-rated improvement score and self-rated satisfaction scores in the PSO-treated group were higher than in the placebo group (P = 0.013, 0.003). The PSO-treated group had more hair after treatment than at baseline, compared to the placebo group (P < 0.001). Mean hair count increases of 40% were observed in PSO-treated men at 24 weeks, whereas increases of 10% were observed in placebo-treated men (P < 0.001). Adverse effects were not different in the two groups. PMID:24864154
Prolonged remission from hepatic encephalopathy with rifaximin: results of a placebo crossover analysis.

PubMed

Bajaj, J S; Barrett, A C; Bortey, E; Paterson, C; Forbes, W P

2015-01-01

Rifaximin therapy reduced risk of hepatic encephalopathy (HE) recurrence and HE-related hospitalisations during a 6-month, randomised, placebo-controlled trial (RCT) and a 24-month open-label maintenance (OLM) study. However, the impact of crossover from placebo to rifaximin therapy is unclear. To study the impact of crossing over from placebo to rifaximin treatment on breakthrough HE and hospitalisation rates using a within-subjects design. Adults with cirrhosis and history of overt HE episodes, currently in HE remission, received placebo during the RCT and crossed over to rifaximin 550 mg twice daily during the OLM study. Rate of breakthrough overt HE episodes, hospitalisations and incidence and rate of adverse events (AEs) were analysed during RCT and first 6 months of OLM. Of 82 patients randomised to placebo in the RCT who crossed over to the OLM study, 39 experienced an HE episode during the RCT compared with 14 during the OLM study (P < 0.0001). Significantly lower rates of HE events were observed with rifaximin treatment compared with placebo treatment (P < 0.0001). Rates of HE-related hospitalisation were numerically lower during rifaximin treatment compared with placebo treatment, although not significant. Rates of most common AEs, serious AEs and infection-related AEs were similar between the two treatments. This analysis confirms the repeatability of results from the RCT on safety and efficacy of rifaximin 550 mg twice daily in reducing the risk of hepatic encephalopathy recurrence, and suggests these findings are translatable outside of a rigorous, controlled trial setting. © 2014 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso-occlusive crises in patients with sickle cell disease: a phase III randomized, placebo-controlled, double-blind study of the Gardos channel blocker senicapoc (ICA-17043).

PubMed

Ataga, Kenneth I; Reid, Marvin; Ballas, Samir K; Yasin, Zahida; Bigelow, Carolyn; James, Luther St; Smith, Wally R; Galacteros, Frederic; Kutlar, Abdullah; Hull, James H; Stocker, Jonathan W

2011-04-01

Red blood cell (RBC) hydration is regulated in part by the Ca(2+) -activated K(+) efflux (Gardos) channel. Senicapoc selectively blocks potassium efflux through the Gardos channel, reducing RBC dehydration and haemolysis, and increasing haemoglobin levels in sickle cell disease (SCD). This randomized, placebo-controlled trial was designed to determine the safety and clinical efficacy of senicapoc in SCD patients. One hundred and forty-five patients were randomized to receive senicapoc and 144 patients to receive placebo for 52 weeks. Consistent with a previous study, patients in the senicapoc group had significantly increased haematocrit, haemoglobin, and decreased numbers of both dense erythrocytes and reticulocytes when compared to the placebo group. The unblinded Data Monitoring Committee terminated this study early due to a lack of efficacy when it determined that, despite improvements in anaemia and haemolysis, no significant improvement in the rate of sickle cell painful crises was observed in patients treated with senicapoc compared to those on placebo (0·38 vs. 0·31, respectively). Comparisons of the times to first, second and third crises between the senicapoc and placebo groups were not statistically significant. Nausea and urinary tract infections occurred more frequently in the senicapoc group than placebo. Serious adverse events were similar in the two groups. © 2011 Blackwell Publishing Ltd.
Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials

PubMed Central

Panés, Julian; Sandborn, William J; Schreiber, Stefan; Sands, Bruce E; Vermeire, Séverine; D'Haens, Geert; Panaccione, Remo; Higgins, Peter D R; Colombel, Jean-Frederic; Feagan, Brian G; Chan, Gary; Moscariello, Michele; Wang, Wenjin; Niezychowski, Wojciech; Marren, Amy; Healey, Paul; Maller, Eric

2017-01-01

Objective Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for IBD. We evaluated the efficacy and safety of tofacitinib for induction and maintenance treatment in patients with moderate-to-severe Crohn's disease (CD). Design We conducted two randomised, double-blind, placebo-controlled, multicentre phase IIb studies. Adult patients with moderate-to-severe CD were randomised to receive induction treatment with placebo, tofacitinib 5 or 10 mg twice daily for 8 weeks. Those achieving clinical response-100 or remission were re-randomised to maintenance treatment with placebo, tofacitinib 5 or 10 mg twice daily for 26 weeks. Primary endpoints were clinical remission at the end of the induction study, and clinical response-100 or remission at the end of the maintenance study. Results 180/280 patients randomised in the induction study were enrolled in the maintenance study. At week 8 of induction, the proportion of patients with clinical remission was 43.5% and 43.0% with 5 and 10 mg twice daily, respectively, compared with 36.7% in the placebo group (p=0.325 and 0.392 for 5 and 10 mg twice daily vs placebo). At week 26 of maintenance, the proportion of patients with clinical response-100 or remission was 55.8% with tofacitinib 10 mg twice daily compared with 39.5% with tofacitinib 5 mg twice daily and 38.1% with placebo (p=0.130 for 10 mg twice daily vs placebo). Compared with placebo, the change in C-reactive protein from baseline was statistically significant (p<0.0001) with 10 mg twice daily after both induction and maintenance treatments. Conclusions Primary efficacy endpoints were not significantly different from placebo, although there was evidence of a minor treatment effect. No new safety signals were observed for tofacitinib. Trial registration numbers NCT01393626 and NCT01393899. PMID:28209624
Effects of a Standardized Bacopa monnieri Extract on Cognitive Performance, Anxiety, and Depression in the Elderly: A Randomized, Double-Blind, Placebo-Controlled Trial

PubMed Central

Gregory, William L.; Leo, Michael; Kraemer, Dale; Bone, Kerry; Oken, Barry

2008-01-01

Abstract Objectives Study aims were to evaluate effects of Bacopa monnieri whole plant standardized dry extract on cognitive function and affect and its safety and tolerability in healthy elderly study participants. Design The study was a randomized, double-blind, placebo-controlled clinical trial with a placebo run-in of 6 weeks and a treatment period of 12 weeks. Setting/location Volunteers were recruited from the community to a clinic in Portland, Oregon by public notification. Subjects Fifty-four (54) participants, 65 or older (mean 73.5 years), without clinical signs of dementia, were recruited and randomized to Bacopa or placebo. Forty-eight (48) completed the study with 24 in each group. Interventions Standardized B. monnieri extract 300 mg/day or a similar placebo tablet orally for 12 weeks. Outcome measures The primary outcome variable was the delayed recall score from the Rey Auditory Verbal Learning Test (AVLT). Other cognitive measures were the Stroop Task assessing the ability to ignore irrelevant information, the Divided Attention Task (DAT), and the Wechsler Adult Intelligence Scale (WAIS) letter-digit test of immediate working memory. Affective measures were the State-Trait Anxiety Inventory, Center for Epidemiologic Studies Depression scale (CESD)-10 depression scale, and the Profile of Mood States. Vital signs were also monitored. Results Controlling for baseline cognitive deficit using the Blessed Orientation–Memory–Concentration test, Bacopa participants had enhanced AVLT delayed word recall memory scores relative to placebo. Stroop results were similarly significant, with the Bacopa group improving and the placebo group unchanged. CESD-10 depression scores, combined state plus trait anxiety scores, and heart rate decreased over time for the Bacopa group but increased for the placebo group. No effects were found on the DAT, WAIS digit task, mood, or blood pressure. The dose was well tolerated with few adverse events (Bacopa n = 9, placebo n = 10), primarily stomach upset. Conclusions This study provides further evidence that B. monnieri has potential for safely enhancing cognitive performance in the aging. PMID:18611150
A double-blind, placebo-controlled study to assess the effect of a probiotic mixture on symptoms and inflammatory markers in women with diarrhea-predominant IBS.

PubMed

Hod, K; Sperber, A D; Ron, Y; Boaz, M; Dickman, R; Berliner, S; Halpern, Z; Maharshak, N; Dekel, R

2017-07-01

Micro-inflammation is considered an element in the pathogenesis of irritable bowel syndrome (IBS). High-sensitivity C reactive protein (hs-CRP) was previously shown to be higher in IBS compared to healthy controls, albeit within the normal range. Since probiotics may suppress micro-inflammation in the gut, we tested if they reduce symptoms and inflammatory markers (hs-CRP and fecal calprotectin (FC) in diarrhea-predominant IBS (IBS-D). The aim of this study was to assess the clinical and laboratory effects of BIO-25, a multispecies probiotic, in women with IBS-D. A double-blind, placebo-controlled study. Following a 2-week run-in, eligible women were assigned at random to a probiotic capsule or an indistinguishable placebo, twice daily for 8 weeks. IBS symptoms and stool consistency were rated daily by Visual Analogue Scales (VAS) and the Bristol Stool Scale (BSS). High-sensitivity C reactive protein was tested at baseline, 4 and 8 weeks. FC was tested at baseline and 8 weeks. One hundred and seventy-two IBS-D patients were recruited and 107 eligible patients were allocated to the intervention (n=54) or placebo (n=53) group. All symptoms improved in both groups with no significant difference between them in symptom improvement, hs-CRP or FC levels. An 8-week treatment with BIO-25 improved symptoms in women with IBS-D, but was not superior to placebo. This rigorously designed and executed study supports the findings of other studies that did not demonstrate superiority of probiotics over placebo in IBS. High quality clinical studies are necessary to examine the efficacy of other specific probiotics in IBS-D patients since data are still conflicting. © 2017 John Wiley & Sons Ltd.
A randomized double-blind, placebo-controlled trial of minocycline in children and adolescents with fragile x syndrome.

PubMed

Leigh, Mary Jacena S; Nguyen, Danh V; Mu, Yi; Winarni, Tri I; Schneider, Andrea; Chechi, Tasleem; Polussa, Jonathan; Doucet, Paul; Tassone, Flora; Rivera, Susan M; Hessl, David; Hagerman, Randi J

2013-04-01

Minocycline rescued synaptic abnormalities and improved behavior in the fragile X mouse model. Previous open-label human studies demonstrated benefits in individuals with fragile X syndrome (FXS); however, its efficacy in patients with FXS has not been assessed in a controlled trial. Randomized, double-blind, placebo-controlled, crossover trial in individuals with FXS, aged 3.5 years to 16 years (n = 55, mean age 9.2 [SD, 3.6] years). Participants were randomized to minocycline or placebo for 3 months and then switched to the other treatment. Sixty-nine subjects were screened and 66 were randomized. Fifty-five subjects (83.3%) completed at least the first period and 48 (72.7%) completed the full trial. Intention-to-treat analysis demonstrated significantly greater improvements in one primary outcome, Clinical Global Impression Scale-Improvement after minocycline compared with placebo (2.49 ± 0.13 and 2.97 ± 0.13, respectively, p = .0173) and greater improvement in ad hoc analysis of anxiety and mood-related behaviors on the Visual Analog Scale (minocycline: 5.26 cm ± 0.46 cm, placebo: 4.05 cm ± 0.46 cm; p = .0488). Side effects were not significantly different during the minocycline and placebo treatments. No serious adverse events occurred on minocycline. Results may be potentially biased by study design weaknesses, including unblinding of subjects when they completed the study, drug-related side effects unblinding, and preliminary efficacy analysis results known to investigators. Minocycline treatment for 3 months in children with FXS resulted in greater global improvement than placebo. Treatment for 3 months appears safe; however, longer trials are indicated to further assess benefits, side effects, and factors associated with a clinical response to minocycline.
A Randomized Double-Blind, Placebo-Controlled Trial of Minocycline in Children and Adolescents with Fragile X Syndrome

PubMed Central

Leigh, Mary Jacena S.; Nguyen, Danh V.; Mu, Yi; Winarni, Tri I.; Schneider, Andrea; Chechi, Tasleem; Polussa, Jonathan; Doucet, Paul; Tassone, Flora; Rivera, Susan M.; Hessl, David; Hagerman, Randi J.

2013-01-01

Objective Minocycline rescued synaptic abnormalities and improved behavior in the fragile X mouse model. Prior open-label human studies demonstrated benefits in individuals with fragile X syndrome (FXS); however, its efficacy in patients with FXS has not been assessed in a controlled trial. Method Randomized, double-blind, placebo-controlled, crossover trial in individuals with FXS, ages 3.5-16 years (n=55, mean age 9.2 (SD 3.6 years)). Participants were randomized to minocycline or placebo for three months, then switched to the other treatment. Results Sixty-nine subjects were screened and 66 were randomized. Fifty-five subjects (83.3%) completed at least the first period and 48 (72.7%) completed the full trial. Intention-to-treat analysis demonstrated significantly greater improvements in one primary outcome, Clinical Global Impression Scale-Improvement after minocycline compared to placebo (2.49 ±0.13, 2.97 ±0.13, respectively, p 0.0173) and greater improvement in ad hoc analysis of anxiety and mood-related behaviors on the Visual Analoge Scale (minocycline 5.26 cm ±0.46 cm, placebo 4.05 cm±0.46cm; p 0.0488). Side effects were not significantly different during the minocycline and placebo treatments. No serious adverse events occurred on minocycline. Results may be potentially biased by study design weaknesses, including unblinding of subjects when they completed the study, drug-related side effects unblinding and preliminary efficacy analysis results known to investigators. Conclusion Minocycline treatment for three months in children with FXS resulted in greater global improvement than placebo. Treatment for three months appears safe; however, longer trials are indicated to further assess benefits, side effects, and factors associated with a clinical response to minocycline. PMID:23572165
No evidence for differential dose effects of hydrocortisone on intrusive memories in female patients with complex post-traumatic stress disorder--a randomized, double-blind, placebo-controlled, crossover study.

PubMed

Ludäscher, Petra; Schmahl, Christian; Feldmann, Robert E; Kleindienst, Nikolaus; Schneider, Miriam; Bohus, Martin

2015-10-01

Post-traumatic stress disorder is characterized by intrusive traumatic memories. Presently, a controversial debate is ongoing regarding whether reduced cortisol secretion in post-traumatic stress disorder promotes an automatic retrieval of trauma-associated memories. Hence, a pharmacological elevation of cortisol was proposed to decrease post-traumatic stress disorder symptoms, particularly intrusions. The present study investigated the impact of two different doses of hydrocortisone on automatic memory retrieval using a randomized, double-blind, placebo-controlled, crossover study in 30 inpatients with post-traumatic stress disorder. All participants were female and received various psychotropic medications. They were randomly assigned to one of two groups within a crossover design: they received either 1 week placebo followed by 1 week hydrocortisone 10/d, followed by 1 week placebo, followed by hydrocortisone 30 mg/d (15 participants) or 1 week hydrocortisone 30 mg/d, followed by 1 week placebo, followed by 1 week hydrocortisone 10 mg/d, followed by 1 week placebo (15 participants). The outcome measures were the frequency and the intensity of intrusions, the overall symptomatology of post-traumatic stress disorder and the general psychopathology. We did not find any differences in the frequency and the intensity of post-traumatic stress disorder-related intrusions between the 10 mg hydrocortisone, the 30 mg hydrocortisone and the placebo condition. All effect sizes for the hydrocortisone condition vs. placebo were very small. Additionally, the overall symptomatology of post-traumatic stress disorder and the general psychopathology did not differ between the hydrocortisone therapies and placebo. Our results do not show any effect of the hydrocortisone administration on intrusions in complex post-traumatic stress disorder. © The Author(s) 2015.
What motivates Parkinson's disease patients to enter clinical trials?

PubMed

Valadas, Anabela; Coelho, Miguel; Mestre, Tiago; Guedes, Leonor Correia; Finisterra, Maria; Noronha, Ana; Rosa, Mário M; Sampaio, Cristina; Ferreira, Joaquim J

2011-11-01

Limited data is available regarding motivations and concerns of Parkinson's disease (PD) patients when participating in clinical trials (CTs). Knowledge of these factors may improve the recruitment and quality of future trials. To assess the motivations and concerns of PD patients concerning participation in CTs and to evaluate the extent to which patients understand informed consent materials and placebo effect concept. Cross-sectional study in PD patients enrolled in CTs between 2002 and 2007. Two questionnaires designed for placebo-controlled and active-controlled studies were mailed to patients. From the 93/127 replied questionnaires (response rate: 73.2%) 91 were evaluable. Fifty-nine percent of the participants were women with a mean age of 66.8 years. The main reasons for participating in CTs were to help the advance of science (63.7%), to gain access to a better treatment (56.0%), and to benefit others (51.6%). Risk of adverse events (49.5%) and negative effects of treatment (35.2%) were the major concerns. Ninety percent reported they had understood the informed consent. Of 80 patients included in placebo-controlled studies, 63.9% understood the placebo effect concept. Globally, 66% of patients would participate in another CT and 41.6% in a placebo-controlled trial. The main motivations of PD patients to participate in CTs were the benefit to the patient himself and to others. The major concern was safety. PD patients understood the informed consent, but more educational efforts must be made to explain the placebo effect. Most PD patients were very positive toward CTs and would participate in another trial. Copyright © 2011 Elsevier Ltd. All rights reserved.
Once daily controlled-release pregabalin in the treatment of patients with fibromyalgia: a phase III, double-blind, randomized withdrawal, placebo-controlled study.

PubMed

Arnold, Lesley M; Arsenault, Pierre; Huffman, Cynthia; Patrick, Jeffrey L; Messig, Michael; Chew, Marci L; Sanin, Luis; Scavone, Joseph M; Pauer, Lynne; Clair, Andrew G

2014-10-01

Safety and efficacy of a once daily controlled-released (CR) formulation of pregabalin was evaluated in patients with fibromyalgia using a placebo-controlled, randomized withdrawal design. This multicenter study included 6 week single-blind pregabalin CR treatment followed by 13 week double-blind treatment with placebo or pregabalin CR. The starting dose of 165 mg/day was escalated during the first 3 weeks, up to 495 mg/day based on efficacy and tolerability. Patients with ≥50% reduction in average daily pain score at the end of the single-blind phase were randomized to continue pregabalin CR at the optimized dose (330-495 mg/day) or to placebo. The primary endpoint was time to loss of therapeutic response (LTR), defined as <30% pain reduction relative to single-blind baseline or discontinuation owing to lack of efficacy or adverse event (AE). Secondary endpoints included measures of pain severity, global assessment, functional status, tiredness/fatigue, and sleep. ClinicalTrials.gov NCT01271933. A total of 441 patients entered the single-blind phase, and 63 were randomized to pregabalin CR and 58 to placebo. The median time to LTR (Kaplan-Meier analysis) was significantly longer in the pregabalin CR group than placebo (58 vs. 22 days, p = 0.02). By trial end, 34/63 (54.0%) pregabalin CR and 41/58 (70.7%) placebo patients experienced LTR. Significantly more patients reported 'benefit from treatment' (Benefit, Satisfaction, and Willingness to Continue Scale) in the pregabalin CR group; no other secondary endpoints were statistically significant. Most AEs were mild to moderate in severity (most frequent: dizziness, somnolence). The percentage of pregabalin CR patients discontinuing because of AEs was 12.2% and 4.8% in the single-blind and double-blind phases, respectively (placebo, 0%). Time to LTR was significantly longer with pregabalin CR versus placebo in fibromyalgia patients who initially showed improvement with pregabalin CR, indicating maintenance of response. Pregabalin CR was well tolerated in most patients. Generalizability may be limited by study duration and selective population.
Design of clinical trials evaluating dietary interventions in patients with functional gastrointestinal disorders.

PubMed

Yao, Chu K; Gibson, Peter R; Shepherd, Susan J

2013-05-01

Clear guiding principles for the design and conduct of dietary intervention trials in functional gastrointestinal disorders (FGID) are lacking. This narrative review examines the specific challenges associated with the design and reporting in dietary intervention trials. Dietary intervention trials need to address the collinearity between food, nutrients, and bioactive components that obscure the relationship between food and their effects in the gut. Randomized, double-blinded, placebo-controlled studies remain the gold standard for dietary trials, but are limited by difficulties in adequate masking of study food or inappropriate choice of placebo food/diets. Provision of study diets as the preferred delivery method can somewhat address these limitations, although allowing good adherence compared with education-based dietary interventions. Issues associated with participant expectancies and dietary behaviors can alter the true effectiveness of a diet. In addition, failure to adjust for or report baseline intake of nutrients of interest can reduce their magnitude of benefit. Bias in subjective reports and choice of measurement tools can preclude accurate assessment of food-intake data. In the design of elimination and rechallenge studies, sufficient time period and adequate exclusion of dietary triggers are essential to ensure symptoms are well-controlled before rechallenging. The route and frequency of challenging, design of test food, and/or placebo should match the aims of the rechallenge phase. Long-term efficacy data of such therapeutic diets has been poorly documented in most studies. Standardized guidelines that address many of the challenges outlined above are suggested to strengthen the quality of evidence for dietary therapies in FGID.
Do randomized clinical trials with inadequate blinding report enhanced placebo effects for intervention groups and nocebo effects for placebo groups? A protocol for a meta-epidemiological study of PDE-5 inhibitors

PubMed Central

2012-01-01

Background Patients’ expectations of treatment effects may contribute to positive (placebo) and negative (nocebo) outcomes. The effect of patient expectations may be pronounced in subjectively assessed conditions, such as male erectile dysfunction. The aim of this project is to examine the magnitude of expectancy in trials of phosphodiesterase-5 inhibitors. We hypothesize that randomized controlled trials with inadequate blinding will report enhanced placebo effects for intervention groups and nocebo effects for placebo groups, compared with adequately blinded studies. Methods/design We will quantify the magnitude of expectancy by comparing the effect estimates of trials with inadequate and adequate blinding. Blinding will be assessed using four domains from the Cochrane ‘risk-of-bias’ tool: allocation concealment; blinding of patient; caregiver; and outcome assessor. Our secondary aim is to identify factors that can modify expectations, such as prior experience with the intervention and drug side effects. We will perform an electronic search using a combination of controlled vocabulary and free text words in the following databases: MEDLINE, EMBASE, CENTRAL, and a clinical trials register. We will include randomized controlled trials, with either parallel or crossover design, that compare one phosphodiesterase-5 inhibitor with a placebo. The study’s primary aim should be to investigate the efficacy of phosphodiesterase-5 inhibitors for treating male erectile dysfunction. Screening will take place at two levels: abstracts and titles, followed by full text reports. Two reviewers will independently extract data on the primary outcome and assess risk of bias. We will meta-analyze treatment effects, if appropriate, to assess the magnitude of enhanced placebo effects and nocebo effects in intervention and placebo groups, respectively. We will explore possible mediators of placebo and nocebo effects with subgroup and meta-regression analyses. Discussion Treatments may confer significant costs and risk of adverse effects; it is important, therefore, to determine whether the effects of treatments are larger than expectancy alone. If treatment expectations can be used in a non-deceptive way to produce clinically advantageous outcomes, then it may be possible to incorporate such mechanisms into evidence-based healthcare decision-making. PMID:23151403
Nicotine Gum and Behavioral Treatment: A Placebo Controlled Trial.

ERIC Educational Resources Information Center

Hall, Sharon M.; And Others

1987-01-01

Assigned 139 subjects to intensive behavioral or to low-contact smoking treatment and to 2-milligram nicotine gum or to placebo gum in a 2x2 factorial design. Nicotine gum produced higher abstinence rates than did placebo. Subjects receiving low-contact condition plus nicotine gum had excellent abstinence rates at both 26 weeks and 52 weeks.…
[Treatment of cyclical mastodynia using an extract of Vitex agnus castus: results of a double-blind comparison with a placebo].

PubMed

Halaska, M; Raus, K; Bĕles, P; Martan, A; Paithner, K G

1998-10-01

The aim of study presented here was to gather the data about the tolerability and efficacy of Vitex agnus castus (VACS) extract. The study was designed as double-blind, placebo controlled in two parallel groups (each 50 patients). Treatment phase lasted 3 consequent menstrual cycles (2 x 30 drops/day = 1.8 ml of VASC) or placebo. Mastalgia during at least 5 days of the cycle before the treatment was the strict inclusion condition. For assessment of the efficacy visual analogue scale was used. Altogether 97 patients were included into the statistical analysis (VACS: n = 48, placebo: n = 49). Intensity of breast pain diminished quicker with VACS group. The tolerability was satisfactory. We found VACS to be useful in the treatment of cyclical breast pain in women.
Naproxen or Estradiol for Bleeding and Spotting with the Levonorgestrel Intrauterine System: A Randomized Controlled Trial

PubMed Central

MADDEN, Tessa; PROEHL, Sarah; ALLSWORTH, Jenifer E.; SECURA, Gina M.; PEIPERT, Jeffrey F.

2011-01-01

Objective To evaluate whether oral naproxen or transdermal estradiol decreases bleeding and spotting in women initiating the levonorgestrel-releasing intrauterine system (LNG-IUS). Study Design We conducted a randomized controlled trial of naproxen, estradiol, or placebo administered over the first 12 weeks of LNG-IUS use. Participants completed a written bleeding diary. We imputed missing values and performed an intention-to-treat analysis. Results There were 129 women randomized to naproxen (n=42), estradiol (n=44), or placebo (n=43). The naproxen group was more likely to be in the lowest quartile of bleeding and spotting days compared to placebo, 42.9% versus 16.3% (p=0.03). In the multivariable analysis, the naproxen group had a 10% reduction in bleeding and spotting days (RRadj 0.90, 95%CI 0.84–0.97) compared to placebo. More frequent bleeding and spotting was observed in the estradiol group (RRadj 1.25, 95%CI 1.17–1.34). Conclusions Administration of naproxen resulted in a reduction in bleeding and spotting days compared to placebo. (150 words) PMID:22055339
Efficacy and tolerability of ramelteon in a double-blind, placebo-controlled, crossover study in Japanese patients with chronic primary insomnia.

PubMed

Kohsaka, Masako; Kanemura, Takashi; Taniguchi, Mitsutaka; Kuwahara, Hiroo; Mikami, Akira; Kamikawa, Kunihisa; Uno, Hideki; Ogawa, Atsushi; Murasaki, Mitsukuni; Sugita, Yoshiro

2011-10-01

The aim of this study was to evaluate the efficacy and safety of ramelteon 4, 8, 16 or 32 mg and placebo in Japanese patients with chronic insomnia using a randomized, double-blind, five-period crossover design. A total of 65 Japanese patients with chronic primary insomnia received ramelteon or placebo for two nights each in sleep laboratories. Changes in sleep parameters were assessed objectively by polysomnography and subjectively by postsleep questionnaires. Safety and tolerability was evaluated by assessment of the occurrence of adverse events, next-day residual effects and laboratory and ECG investigations. Ramelteon 8 and 32 mg significantly shortened the mean latency to persistent sleep in comparison with placebo, and there was a statistically significant trend for linear dose-response for this sleep parameter. Overall changes in sleep architecture were modest (<3% changes vs placebo), with increases in stage 1 and decreases in stage 3/4. Ramelteon was well tolerated, the most common adverse effect being somnolence, which was similar to placebo at doses up to 8 mg, but increased with higher doses. Next-day residual effects occurred no more frequently with ramelteon at any dose than with placebo. When compared with sleep latency data from a similarly-designed US study, there was no evidence of any ethnic differences in the efficacy of ramelteon between Japanese and US patients. Overall, ramelteon 8 mg showed the most favorable balance between sleep-promoting effects and tolerability. The unique efficacy profile of ramelteon, promoting sleep initiation without affecting other sleep parameters, may be due to its circadian shifting effect.
Double-blind, randomized, controlled trial of rasagiline as monotherapy in early Parkinson's disease patients.

PubMed

Stern, Matthew B; Marek, Kenneth L; Friedman, Joseph; Hauser, Robert A; LeWitt, Peter A; Tarsy, Daniel; Olanow, C Warren

2004-08-01

Rasagiline (N-propargyl-1(R)-aminoindan) mesylate is a potent, selective, and irreversible monoamine oxidase-B inhibitor. This study was designed to evaluate the safety, tolerability, and preliminary efficacy of rasagiline monotherapy in early Parkinson's disease (PD) patients not receiving levodopa. The study was performed as a multicenter, parallel-group, double-blind, randomized, placebo-controlled, 10-week study. Fifty-six PD patients were randomly assigned to rasagiline mesylate 1, 2, or 4 mg once daily, or placebo. A 3-week dose-escalation period was followed by a 7-week maintenance phase. At week 10, the mean (+/-SE) changes from baseline in total Unified Parkinson's Disease Rating Scale (UPDRS) score were -1.8 (+/-1.3), -3.6 (+/-1.7), -3.6 (+/-1.2), and -0.5 (+/-0.8) in the rasagiline 1, 2, and 4 mg/day and placebo groups, respectively. Analysis of responders showed that 28% of patients (12 of 43) receiving rasagiline had an improvement in total UPDRS score of greater than 30%, compared with none of the patients receiving placebo (P < 0.05, Fisher's exact test). The frequency and types of adverse events reported by rasagiline-treated and placebo-treated patients were similar. These results suggest that rasagiline monotherapy is well tolerated and efficacious in early PD. Copyright 2004 Movement Disorder Society
Patients’ Perspectives of Enrollment in Research Without Consent- The Patients’ Experiences in Emergency Research- ProTECT Study (PEER-ProTECT)

PubMed Central

Dickert, Neal W; Scicluna, Victoria M; Baren, Jill M; Biros, Michelle H; Fleischman, Ross J; Govindarajan, Prasanthi R; Jones, Elizabeth B; Pancioli, Arthur M; Wright, David W; Pentz, Rebecca D

2016-01-01

Objective Research in acute illness often requires an exception from informed consent (EFIC). Few studies have assessed the views of patients enrolled in EFIC trials. This study was designed to assess the views of patients and their surrogates of EFIC enrollment in a randomized, placebo-controlled trial of an investigational agent for traumatic brain injury. Design Interactive interview study. Setting Nested within the Progesterone for the Treatment of Traumatic Brain Injury (ProTECT III) trial, a Phase III randomized controlled trial in acute traumatic brain injury (TBI). Participants Patients and surrogates (for patients incapable of being interviewed) enrolled in ProTECT III under EFIC at 12 sites. Measurements Interviews focused on respondents’ acceptance of EFIC enrollment in ProTECT, use of placebo and randomization, understanding of major study elements, and views regarding regulatory protections. Descriptive statistical analysis was performed; textual data were analyzed thematically. Main Results 85 individuals were interviewed. 84% had positive attitudes toward ProTECT III inclusion. 78% found their inclusion under EFIC acceptable, and 72% found use of EFIC in ProTECT III acceptable in general. Only 2 respondents clearly disagreed with both personal and general EFIC enrollment. The most common concerns (26%) related to absence of consent. 80% and 92% were accepting of placebo use and randomization, respectively. Though there were few black respondents (n=11), they were less accepting of personal EFIC enrollment than white respondents (55% vs 83%, p= 0.0494). Conclusions Acceptance of EFIC in this placebo-controlled trial of an investigational agent was high and exceeded acceptance among community consultation participants. EFIC enrollment appears generally consistent with patients’ preferences. PMID:25574795
Comparison of the Anti-Adhesion Activity of Three Different Cranberry Extracts on Uropathogenic P-fimbriated Escherichia coli: a Randomized, Double-blind, Placebo Controlled, Ex Vivo, Acute Study.

PubMed

Howell, Amy; Souza, Dan; Roller, Marc; Fromentin, Emilie

2015-07-01

Research suggests that cranberry (Vaccinium macrocarpon) helps maintain urinary tract health. Bacterial adhesion to the uroepithelium is the initial step in the progression to development of a urinary tract infection. The bacterial anti-adhesion activity of cranberry proanthocyanidins (PACs) has been demonstrated in vitro. Three different cranberry extracts were developed containing a standardized level of 36 mg of PACs. This randomized, double-blind, placebo controlled, ex vivo, acute study was designed to compare the anti-adhesion activity exhibited by human urine following consumption of three different cranberry extracts on uropathogenic P-fimbriated Escherichia coli in healthy men and women. All three cranberry extracts significantly increased anti-adhesion activity in urine. from 6 to 12 hours after intake of a single dose standardized to deliver 36 mg of PACs (as measured by the BL-DMAC method), versus placebo.
Bromelain and cardiovascular risk factors in diabetes: An exploratory randomized, placebo controlled, double blind clinical trial.

PubMed

Ley, Chit Moy; Ni, Qing; Liao, Xing; Gao, Huai-Lin; Robinson, Nicola

2016-10-01

To assess whether the dietary supplement (bromelain) has the potential to reduce plasma fibrinogen and other cardiovascular disease (CVD) risk factors in patients with diabetes. This randomized placebo controlled, double blind, parallel design, efficacy study was carried out in China and investigated the effect of 12 weeks of bromelain (1,050 mg/day) on plasma fibrinogen. This randomized controlled trial (RCT) recruited 68 Chinese diabetic patients [32 males and 36 females; Han origin, mean age of 61.26 years (standard deviation (SD), 12.62 years)] with at least one CVD risk factor. Patients were randomized into either bromelain or placebo group. While bromelain group received bromelain capsule, the placebo group received placebo capsule which consisted inert ingredient and has no treatment effect. Subjects were required to take 1,050 mg (3×350 mg) of either bromelain or starch-filled placebo capsules, two to be taken (2×350 mg) after breakfast and another (350 mg) after dinner, daily for 12 weeks. Plasma fibrinogen, CVD risk factors and anthropometric indicators were determined at baseline and at 12 weeks. The change in the fibrinogen level in the bromelain group at the end of the study showed a mean reduction of 0.13 g/L (standard deviation (SD) 0.86g/L) compared with the mean reduction of 0.36 g/L (SD 0.96 g/L) for the placebo group. However, there was no significant difference in the mean change in fibrinogen between the placebo and bromelain groups (mean difference=0.23g/L (SD 0.22 g/L), =0.291). Similarly, the difference in mean change in other CVD risk factors (blood lipids, blood pressure), blood glucose, C-reactive protein and anthropometric measures between the bromelain and placebo groups was also not statistically significant. Statistical differences in fibrinogen between bromelain and placebo groups before the trial despite randomization may have influenced the results of this study. This RCT failed to show a beneficial effect in reducing fibrinogen or influencing other selected CVD risk factors but suggests other avenues for subsequent research on bromelain.
Creativity on tap? Effects of alcohol intoxication on creative cognition.

PubMed

Benedek, Mathias; Panzierer, Lisa; Jauk, Emanuel; Neubauer, Aljoscha C

2017-11-01

Anecdotal reports link alcohol intoxication to creativity, while cognitive research highlights the crucial role of cognitive control for creative thought. This study examined the effects of mild alcohol intoxication on creative cognition in a placebo-controlled design. Participants completed executive and creative cognition tasks before and after consuming either alcoholic beer (BAC of 0.03) or non-alcoholic beer (placebo). Alcohol impaired executive control, but improved performance in the Remote Associates Test, and did not affect divergent thinking ability. The findings indicate that certain aspects of creative cognition benefit from mild attenuations of cognitive control, and contribute to the growing evidence that higher cognitive control is not always associated with better cognitive performance. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

A Double-Blinded, Randomized, Placebo-Controlled Clinical Trial of Aminophylline to Prevent Acute Kidney Injury in Children following Congenital Heart Surgery with Cardiopulmonary Bypass

PubMed Central

Axelrod, David M.; Sutherland, Scott M.; Anglemyer, Andrew; Grimm, Paul C.; Roth, Stephen J.

2015-01-01

Objective Acute kidney injury (AKI) occurs commonly in children following congenital cardiac surgery with cardiopulmonary bypass (CPB) and has been associated with increased morbidity and mortality. Aminophylline, a methylxanthine nonselective adenosine receptor antagonist, has been effective in the management of AKI in certain populations. This study sought to determine if post-operative administration of aminophylline attenuates AKI in children undergoing congenital cardiac surgery with CPB. Design Single-center, double-blinded, placebo-controlled, randomized clinical trial (RCT). Setting Tertiary center, pediatric cardiovascular intensive care unit. Patients 144 children after congenital heart surgery with CPB. Interventions Seventy-two patients were randomized to receive aminophylline and 72 patients received placebo. Study drug was administered every six hours for 72 hours. Measurements and Main Results The primary outcome variable was development of any AKI, defined by the serum creatinine criteria of the Kidney Diseases: Improving Global Outcomes (KDIGO) criteria. Secondary outcomes included the development of severe AKI, time between CVICU admission and first successful extubation, percent fluid overload, total fluid balance, urine output, bioelectrical impedance, and serum neutrophil gelatinase-associated lipocalin (NGAL). The unadjusted rate and severity of AKI were not different between groups; 43/72 (60%) of the treatment group and 36/72 (50%) of the placebo group developed AKI (p=0.32). Stage 2/3 AKI occurred in 23/72 (32%) of the treatment group and 15/72 (21%) of the placebo group (p=0.18). Secondary outcome measures also demonstrated no significant difference between treatment and placebo groups. Aminophylline administration was safe; no deaths occurred in either group, and rates of adverse events were similar (14% in the treatment group versus 18% in the placebo group, p =0.30). Conclusions In this placebo-controlled RCT, we found no effect of aminophylline to prevent AKI in children recovering from cardiac surgery performed with CPB. Future study of pre-operative aminophylline administration to prevent AKI may be warranted. PMID:26669642
Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study.

PubMed

Dellinger, Ryan W; Santos, Santiago Roel; Morris, Mark; Evans, Mal; Alminana, Dan; Guarente, Leonard; Marcotulli, Eric

2017-01-01

NRPT is a combination of nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD +) precursor vitamin found in milk, and pterostilbene (PT), a polyphenol found in blueberries. Here, we report this first-in-humans clinical trial designed to assess the safety and efficacy of a repeat dose of NRPT (commercially known as Basis). NRPT was evaluated in a randomized, double-blind, and placebo-controlled study in a population of 120 healthy adults between the ages of 60 and 80 years. The study consisted of three treatment arms: placebo, recommended dose of NRPT (NRPT 1X), and double dose of NRPT (NRPT 2X). All subjects took their blinded supplement daily for eight weeks. Analysis of NAD + in whole blood demonstrated that NRPT significantly increases the concentration of NAD + in a dose-dependent manner. NAD + levels increased by approximately 40% in the NRPT 1X group and approximately 90% in the NRPT 2X group after 4 weeks as compared to placebo and baseline. Furthermore, this significant increase in NAD + levels was sustained throughout the entire 8-week trial. NAD + levels did not increase for the placebo group during the trial. No serious adverse events were reported in this study. This study shows that a repeat dose of NRPT is a safe and effective way to increase NAD + levels sustainably.
Nifedipine vs Placebo for Treatment of Chronic Chilblains: A Randomized Controlled Trial

PubMed Central

Souwer, Ibo H.; Bor, Jacobus H. J.; Smits, Paul; Lagro-Janssen, Antoine L. M.

2016-01-01

PURPOSE Nifedipine is commonly prescribed for the treatment of chilblains (pernio, perniosis) on the basis of observational studies and a single small, older clinical trial. We aimed to confirm the proposed superiority of oral nifedipine 60 mg per day over placebo for treatment of chronic chilblains in primary care. METHODS We performed a randomized, placebo-controlled, double-blind, crossover trial, closely following the design of the older trial. A total of 32 patients with chronic chilblains were randomly assigned to nifedipine (30 mg controlled release twice a day) or placebo. The primary outcome was patient-reported complaints; the secondary outcome was patient-reported disability. Both were assessed from daily ratings on 100-mm visual analogue scales recorded in a diary. We took ambient temperatures into account and checked for a carry-over effect, and monitored for adverse effects. RESULTS After 6 weeks of treatment, mean scores on the visual analogue scale on complaints showed a nonsignificant difference of 1.84 mm (95% CI, −6.67 to 2.99 mm) in favor of nifedipine (P = .44). Mean scores on the visual analogue scale on disability showed a nonsignificant difference of 0.56 mm (95% CI, −2.97 to 4.09 mm) in favor of placebo (P = .75). There was no carry-over effect of prior study treatment. Nifedipine was associated with significantly lower systolic blood pressure and a significantly higher incidence of edema. CONCLUSIONS In our study, nifedipine was not superior to placebo for treating chronic chilblains. These findings contrast with those of the older study and do not support routine use of nifedipine for this condition. PMID:27621162
Ascending Single-Dose, Double-Blind, Placebo-Controlled Safety Study of Noribogaine in Opioid-Dependent Patients.

PubMed

Glue, Paul; Cape, Gavin; Tunnicliff, Donna; Lockhart, Michelle; Lam, Fred; Hung, Noelyn; Hung, C Tak; Harland, Sarah; Devane, Jane; Crockett, R S; Howes, John; Darpo, Borje; Zhou, Meijian; Weis, Holger; Friedhoff, Lawrence

2016-11-01

Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaine's active metabolite, in patients established on methadone opioid substitution therapy (OST). In this randomized, double-blind, placebo-controlled single ascending-dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST who had been switched to morphine during the previous week. Noribogaine doses were 60, 120, or 180 mg (n = 6/dose level) or matching placebo (n = 3/dose level). Noribogaine was well tolerated. The most frequent treatment-emergent adverse events were noneuphoric changes in light perception ∼1 hour postdose, headache, and nausea. Noribogaine had dose-linear increases for AUC and C max and was slowly eliminated (mean t 1/2 range, 24-30 hours). There was a concentration-dependent increase in QTcI (0.17 ms/ng/mL), with the largest observed mean effect of ∼16, 28, and 42 milliseconds in the 60-, 120-, and 180-mg groups, respectively. Noribogaine showed a nonstatistically significant trend toward decreased total score in opioid withdrawal ratings, most notably at the 120-mg dose; however, the study design may have confounded evaluations of time to resumption of OST. Future exposure-controlled multiple-dose noribogaine studies are planned that will address these safety and design issues. © 2016, The American College of Clinical Pharmacology.
Design of control-group conditions in clinical trials of behavioral interventions.

PubMed

Lindquist, Ruth; Wyman, Jean F; Talley, Kristine M C; Findorff, Mary J; Gross, Cynthia R

2007-01-01

To review considerations in the design of placebo (attention) control conditions for community-based clinical trials of health behavior change interventions and to provide practical strategies for the design of control conditions. A well-designed control condition is an essential component of a clinical trial to foster the unambiguous interpretation of study findings. Pitfalls in the design of control conditions in clinical trials of behavioral interventions are identified and strategies to address them are offered. Types of control conditions that have been used in fall prevention trials are described, along with their strengths and weaknesses. The control condition used in the recent fall evaluation and prevention program (FEPP) was designed to overcome limitations of previous trial designs; it is provided to illustrate how to apply specific design principles. Pitfalls in the design of behavioral intervention studies may be avoided with the application of sound design principles. The FEPP active control condition can be used as a model in the design of future studies.
Effects of lacosamide and carbamazepine on human motor cortex excitability: a double-blind, placebo-controlled transcranial magnetic stimulation study.

PubMed

Lang, Nicolas; Rothkegel, Holger; Peckolt, Hannes; Deuschl, Günther

2013-11-01

Lacosamide (LCM) and carbamazepine (CBZ) are antiepileptic drugs both acting on neuronal voltage-gated sodium channels. Patch-clamp studies demonstrated significant differences in how LCM and CBZ affect neuronal membrane excitability. Despite valuable information patch-clamp studies provide, they also comprise some constraints. For example, little is known about effects of LCM on intracortical synaptic excitability. In contrast, transcranial magnetic stimulation (TMS) can describe drug-induced changes at the system level of the human cerebral cortex. The present study was designed to explore dose-depended effects of LCM and effects of CBZ on motor cortex excitability with TMS in a randomized, double-blind, placebo-controlled crossover trial in healthy human subjects. Subjects received 600 mg CBZ, 200 mg LCM, 400 mg LCM or placebo preceding TMS measurements. Compared to placebo, TMS motor thresholds were significantly increased after carbamazepine and lacosamide, with a trend for a dose dependent effect of lacosamide. Both, carbamazepine and lacosamide did not affect TMS parameters of intracortical synaptic excitability. TMS measurements suggest that lacosamide and carbamazepine predominantly act on neuronal membrane excitability. Copyright © 2013 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Addition of atropine to submaximal exercise stress testing in patients evaluated for suspected ischaemia with SPECT imaging: a randomized, placebo-controlled trial.

PubMed

Manganelli, Fiore; Spadafora, Marco; Varrella, Paola; Peluso, Giuseppina; Sauro, Rosario; Di Lorenzo, Emilio; Rosato, Giuseppe; Daniele, Stefania; Cuocolo, Alberto

2011-02-01

To evaluate the effects of the addition of atropine to exercise testing in patients who failed to achieve their target heart rate (HR) during stress myocardial perfusion imaging with single-photon emission computed tomography (SPECT). The study was a prospective, randomized, placebo-controlled design. Patients with suspected or known coronary artery disease who failed to achieve a target HR (≥85% of maximal predicted HR) during exercise SPECT imaging were randomized to receive intravenous atropine (n=100) or placebo (n=101). The two groups of patients did not differ with respect to demographic or clinical characteristics. A higher proportion of patients in the atropine group achieved the target HR compared to the placebo group (60% versus 3%, p<0.0001). SPECT imaging was abnormal in a higher proportion of patients in the atropine group as compared to the placebo group (57% versus 42%, p<0.05). Stress-induced myocardial ischaemia was present in more patients in the atropine group as compared to placebo (47% versus 29%, p<0.01). In both groups of patients, no major side effects occurred. The addition of atropine at the end of exercise testing is more effective than placebo in raising HR to adequate levels, without additional risks of complications. The use of atropine in patients who initially failed to achieve their maximal predicted HR is associated with a higher probability of achieving a diagnostic myocardial perfusion study.
A Multi-Center, Randomized, Double-Blind Placebo-Controlled Trial of Intravenous-Ibuprofen (IV-Ibuprofen) for Treatment of Pain in Post-Operative Orthopedic Adult Patients

PubMed Central

Singla, Neil; Rock, Amy; Pavliv, Leo

2010-01-01

Objective To determine whether pre- and post-operative administration of intravenous ibuprofen (IV-ibuprofen) can significantly decrease pain and morphine use when compared with placebo in adult orthopedic surgical patients. Design This was a multi-center, randomized, double-blind placebo-controlled trial. Setting This study was completed at eight hospitals; six in the United States and two in South Africa. Patients A total of 185 adult patients undergoing elective orthopedic surgery. Interventions Patients were randomized to receive either 800 mg IV-ibuprofen or placebo every 6 hours, with the first dose administered pre-operatively. Additionally, all patients had access to intravenous morphine for rescue. Outcome Measures Efficacy of IV-ibuprofen was demonstrated by measuring the patient's self assessment of pain using a visual analog scale (VAS; assessed with movement and at rest) and a verbal response scale (VRS). Morphine consumption during the post-operative period was also assessed. Results In the immediate post-operative period, there was a 25.8% reduction in mean area under the curve-VAS assessed with movement (AUC-VASM) in patients receiving IV-ibuprofen (P < 0.001); a 31.8% reduction in mean AUC-VAS assessed at rest (AUC-VASR; P < 0.001) and a 20.2% reduction in mean VRS (P < 0.001) compared to those receiving placebo. Patients receiving IV-ibuprofen used 30.9% less morphine (P < 0.001) compared to those receiving placebo. Similar treatment emergent adverse events occurred in both study groups and there were no significant differences in the incidence of serious adverse events. Conclusion Pre- and post-operative administration of IV-ibuprofen significantly reduced both pain and morphine use in orthopedic surgery patients in this prospective randomized placebo-controlled trial. PMID:20609131
The effect of calcium and vitamin D supplementation on obesity in postmenopausal women: secondary analysis for a large-scale, placebo controlled, double-blind, 4-year longitudinal clinical trial.

PubMed

Zhou, Jiapeng; Zhao, Lan-Juan; Watson, Patrice; Zhang, Qin; Lappe, Joan M

2010-07-23

It is undetermined whether calcium supplementation has an effect on obesity or body composition in postmenopausal women. The purpose of the study is to detect the effect of calcium supplementation on indices of obesity and body composition. This is a secondary analysis of data from a population-based, double-blind, placebo-controlled, randomized trial designed to determine the effects of calcium and vitamin D on osteoporotic fractures. The cohort included 1179 postmenopausal women who were randomly assigned into one of three groups: 1) supplemental calcium (1400 mg/d or 1500 mg/d) plus vitamin D placebo (Ca-only group); 2) supplemental calcium (1400 mg/d or 1500 mg/d) plus supplemental vitamin D3 (1100 IU/d) (Ca + D group); or, 3) two placebos (placebo group). After applying the exclusion criteria for this analysis, 870 subjects were included in this study. The primary outcomes for the present study were changes in body mass index, trunk fat, trunk lean, and percentage of trunk fat after calcium supplementation. Changes in trunk fat, trunk lean, and percentage of trunk fat were significantly different between the calcium intervention groups (Ca-only group or Ca + D group) and the placebo group during the trial (P < 0.05). The calcium intervention groups gained less trunk fat and maintained more trunk lean when compared to the placebo group. No significant difference was observed for body mass index between groups. Calcium supplementation over four years has a beneficial effect on body composition in postmenopausal women.
Effects of a Lutein and Zeaxanthin Intervention on Cognitive Function: A Randomized, Double-Masked, Placebo-Controlled Trial of Younger Healthy Adults.

PubMed

Renzi-Hammond, Lisa M; Bovier, Emily R; Fletcher, Laura M; Miller, L Stephen; Mewborn, Catherine M; Lindbergh, Cutter A; Baxter, Jeffrey H; Hammond, Billy R

2017-11-14

Background: Past studies have suggested that higher lutein (L) and zeaxanthin (Z) levels in serum and in the central nervous system (as quantified by measuring macular pigment optical density, MPOD) are related to improved cognitive function in older adults. Very few studies have addressed the issue of xanthophylls and cognitive function in younger adults, and no controlled trials have been conducted to date to determine whether or not supplementation with L + Z can change cognitive function in this population. Objective: The purpose of this study was to determine whether or not supplementation with L + Z could improve cognitive function in young (age 18-30), healthy adults. Design: A randomized, double-masked, placebo-controlled trial design was used. Fifty-one young, healthy subjects were recruited as part of a larger study on xanthophylls and cognitive function. Subjects were randomized into active supplement ( n = 37) and placebo groups ( n = 14). MPOD was measured psychophysically using customized heterochromatic flicker photometry. Cognitive function was measured using the CNS Vital Signs testing platform. MPOD and cognitive function were measured every four months for a full year of supplementation. Results: Supplementation increased MPOD significantly over the course of the year, vs. placebo ( p < 0.001). Daily supplementation with L + Z and increases in MPOD resulted in significant improvements in spatial memory ( p < 0.04), reasoning ability ( p < 0.05) and complex attention ( p < 0.04), above and beyond improvements due to practice effects. Conclusions: Supplementation with L + Z improves CNS xanthophyll levels and cognitive function in young, healthy adults. Magnitudes of effects are similar to previous work reporting correlations between MPOD and cognition in other populations.
A preliminary investigation on the efficacy of N-acetyl cysteine for mania or hypomania.

PubMed

Magalhães, Pedro Vieira da Silva; Dean, Olivia M; Bush, Ashley I; Copolov, David L; Malhi, Gin S; Kohlmann, Kristy; Jeavons, Susan; Schapkaitz, Ian; Anderson-Hunt, Murray; Berk, Michael

2013-06-01

Oxidative imbalance has emerged as a treatment target in bipolar disorder. As very limited data are available on the clinical use of antioxidants for mania, we report here results from a post hoc and exploratory subgroup analysis of a randomized, placebo-controlled trial of N-acetyl cysteine (NAC). This was a placebo-controlled, randomized, clinical trial assessing the effect of NAC over 24 weeks in mania or hypomania. Symptomatic and functional outcomes were collected over the study period. Fifteen participants were available for this report; two participants in each group failed to complete all assessments. Within-group analyses pointed to an improvement in the NAC group on manic symptoms and worsening in the placebo group on depressive symptoms at endpoint. Although the sample size was small, these results indicated within-group efficacy for this glutathione precursor as compared to placebo. Future trials specifically designed to demonstrate the efficacy of NAC in mania are needed.
Randomized expectancy-enhanced placebo-controlled trial of the impact of Quantum BioEnergetic distant healing and paranormal belief on mood disturbance: a pilot study.

PubMed

Rock, Adam J; Permezel, Fiona E; Storm, Lance

2012-01-01

Previous research has demonstrated the effects of ostensible subtle energy on physical systems and subjective experience. However, one subtle energy technique that has been neglected, despite anecdotal support for its efficacy, is Quantum BioEnergetics (QBE). Furthermore, the influence of paranormal belief and experience (either real belief/experience or suggested belief/experience) on subtle energy effects remains unclear. The aim of the present study was to investigate experimentally the effects of distant QBE healing, and paranormal belief/experience, on mood. A randomized expectancy-enhanced placebo-controlled design was used. Data were collected at the QBE Centre, Melbourne. Participants were students from Deakin University and from the general public. Snowball sampling (ie, word-of-mouth) and convenience sampling using a ballot box placed in the university library. Profile of Mood States-Short Form was used to quantify positive and negative mood states. The QBE condition was associated with (1) significantly less Tension-Anxiety compared with the placebo and control condition; and (2) significantly less Anger-Hostility and Total Mood Disturbance compared with the control condition (but not the placebo condition). Furthermore, there was an interaction of condition and paranormal belief/experience with regard to Depression-Dejection, with believers assigned to the placebo condition scoring lowest on this Mood variable. Findings suggest that the use of QBE by an experienced practitioner reduces mood disturbance. In addition, the placebo condition may have evoked suggestibility effects in believers, which would mean that they may be more likely than nonbelievers to believe that they were receiving healing, thus resulting in lower Depression-Dejection scores. Copyright © 2012 Elsevier Inc. All rights reserved.
Placebo Use in Pain Management: A Mechanism-Based Educational Intervention Enhances Placebo Treatment Acceptability.

PubMed

Kisaalita, Nkaku R; Hurley, Robert W; Staud, Roland; Robinson, Michael E

2016-02-01

Health care providers use treatments whose effectiveness derives partially or completely from 'nonspecific' factors, frequently referred to as placebo effects. Although the ethics of interventional placebo use continues to be debated, evidence suggests that placebos can produce clinically meaningful analgesic effects. Burgeoning evidence suggest that patients with chronic pain might be open to placebo treatments in certain contexts despite limited knowledge of their well-established psychoneurobiological underpinnings. In this investigation we sought to examine the effects of a brief, mechanism-based placebo analgesia educational intervention on aspects placebo knowledge and acceptability. Participants with chronic musculoskeletal pain completed a web-based survey in which they rated their knowledge of placebo analgesia, assessed placebo acceptability across different medical contexts, and evaluated 6 unique patient-provider treatment scenarios to assess the role of treatment effectiveness and deception on patient-provider attributions. Using a pre-post design, participants were randomized to receive either a placebo educational intervention or an active control education. Results showed that the educational intervention greatly improved perceptions of placebo knowledge, effectiveness, and acceptability, even in deceptive treatment contexts. This was the first study of its kind to show the value of an educational intervention in increasing openness to and knowledge of placebo analgesic interventions among patients with chronic musculoskeletal pain. In this we article highlight how patients with chronic pain might be open to placebo interventions, particularly adjunct and/or complementary treatments, when provided education on the neurobiological and psychological mechanisms that underlie placebo effects. Study findings highlight ethically acceptable ways to potentially use placebo factors to enhance existing pain treatments and improve patient health outcomes. Published by Elsevier Inc.
Expectancies and memory for an emotional film fragment: a placebo study.

PubMed

Van Oorsouw, Kim; Merckelbach, Harald

2007-01-01

This study investigated whether positive ("memory-enhancing") and negative ("memory-impairing") placebos may enhance and undermine, respectively, memory of a film fragment. After watching an emotional film fragment, participants were assigned to a "memory-enhancing" placebo group (n = 30), control group (n = 30), or "memory-impairing" placebo group (n = 30). Only participants who believed in the placebo effect were included in the analyses. In the positive placebo group, memory for the film fragment was better than that of participants who received negative placebos or control participants. Participants in the negative placebo group made more distortion errors than participants in the positive placebo or control group. Our findings show that people's expectancies about their memory may affect their memory performance. These results may have implications for both clinical practice and the legal domain.
Probiotics for standard triple Helicobacter pylori eradication: a randomized, double-blind, placebo-controlled trial.

PubMed

Hauser, Goran; Salkic, Nermin; Vukelic, Karina; JajacKnez, Alenka; Stimac, Davor

2015-05-01

The primary objective in the study is determination of efficacy of probiotic preparation as a supportive therapy in eradication of Helicobacter pylori.The study was multicenter, prospective, randomized, placebo controlled, and double-blind. The subjects first filled out a specially designed questionnaire to assess the severity of the 10 symptoms, which can be related to eradication therapy to be monitored during the trial. Each subject then received 28 capsules of probiotic preparation or matching placebo capsules, which they were supposed to take over the following 14 days, twice a day, at least 2 hours prior to or after the antibiotic therapy administration.A total of 804 patients were enrolled in the trial, of which 650 (80.85%) were included in the analysis. The results show a significantly larger share of cured subjects in the probiotic arm versus the placebo arm (87.38% vs 72.55%; P < 0.001). Additionally, presence and intensity of epigastric pain, bloating, flatulence, taste disturbance, loss of appetite, nausea, vomiting, heartburn, rash, and diarrhea were monitored over the study period. At 15 days postinclusion, probiotic treatment was found superior to placebo in 7 of 10 mentioned symptoms. Average intensity for symptoms potentially related to antibiotic therapy was significantly higher in the placebo group, 0.76 vs 0.55 (P < 0.001).Adding probiotics to the standard triple therapy for H pylori eradication significantly contributes to treatment efficacy and distinctly decreases the adverse effects of therapy and the symptoms of the underlying disease.
The effects of repeated administration of camphor-crataegus berry extract combination on blood pressure and on attentional performance - a randomized, placebo-controlled, double-blind study.

PubMed

Erfurt, L; Schandry, R; Rubenbauer, S; Braun, U

2014-09-25

The present study investigated the effects of repeated administration of Korodin(®), a combination of camphor and crataegus berry extract, on blood pressure and attentional functioning. This study was conducted based on a randomized, placebo-controlled, double-blind design. 54 persons participated (33 female, 21 male) with a mean age of 24.3 years. Blood pressure and body mass index were in the normal range. Participants received 20 drops of either Korodin(®) or a placebo for four times with interjacent time intervals of about 10 min. Blood pressure was measured sphygmomanometrically before and after each administration. Attentional performance was quantified by using two paper-and-pencil tests, the d2 Test of Attention and Digit Symbol Test. Greater increases in blood pressure occurred after the four Korodin(®) administrations in comparison to the four placebo administrations. The performance in two parameters of d2 Test of Attention was consistently superior after the intake of Korodin(®). The excellent tolerability and safety of Korodin(®), even after a total consumption of 80 drops, was confirmed. Copyright © 2014 Elsevier GmbH. All rights reserved.
Impact of patient selection and study characteristics on signal detection in placebo-controlled trials with antidepressants.

PubMed

Mancini, Michele; Wade, Alan G; Perugi, Giulio; Lenox-Smith, Alan; Schacht, Alexander

2014-04-01

An increasing rate of antidepressant trials fail due to large placebo responses. This analysis aimed to identify variables influencing signal detection in clinical trials of major depressive disorder. Patient-level data of randomized patients with a duloxetine dose ≥ 60 mg/day were obtained from Lilly. Total scores of the Hamilton Depression Rating scale (HAM-D) were used as efficacy endpoints. In total, 4661 patients from 14 studies were included in the analysis. The overall effect size (ES), based on the HAM-D total score at endpoint, between duloxetine and placebo was -0.272. Although no statistically significant interactions were found, the following results for factors influencing ES were seen: a very low ES (-0.157) in patients in the lowest baseline HAM-D category and in patients recruited in the last category of the recruitment period (-0.122). A higher ES in patients recruited in centers with a site-size at but not more than 2.5 times the average site-size for the study (-0.345). Study characteristics that resulted in low signal detection in our database were: <80% study completers, a HAM-D placebo response >5 points, a high variability of placebo response (SD > 7 points HAM-D), >6 post baseline visits per study, and use of an active control drug. Simpler trial designs, more homogeneous and mid-sized study sites, a primary analysis based on a higher cutoff blinded to investigators to avoid the influence of score inflation in mild patients and, if possible, studies without an active control group could lead to a better signal detection of antidepressive efficacy. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.
Vortioxetine versus placebo in major depressive disorder comorbid with social anxiety disorder.

PubMed

Liebowitz, Michael R; Careri, Jason; Blatt, Kyra; Draine, Ann; Morita, Junko; Moran, Melissa; Hanover, Rita

2017-12-01

Major Depressive Disorder (MDD) and Social Anxiety Disorder (SAD) are highly comorbid, yet the combined condition has not been subject to any placebo-controlled treatment trials. This study reports a trial of vortioxetine, an antidepressant that has also shown benefit in Generalized Anxiety Disorder (GAD), in patients meeting DSM-5 criteria for both MDD and SAD. The study was a 12-week double-blind, placebo-controlled comparison of vortioxetine 10-20 mg/day or placebo administered on a 1:1 ratio. The study was designed to include 40 male or female outpatients aged 18-70 years. The primary endpoint was the "composite" Clinical Global Impression of Improvement (CGI-I) responder rate, factoring in improvement in both MDD and SAD features. Major secondary outcome measures were changes on the Montgomery Asberg Depression Rating Scale (MADRS) and Liebowitz Social Anxiety Scale (LSAS). On the composite CGI-I, 10 of 20 (50%) vortioxetine and six of 20 (30%) placebo-treated patients were rated as responders, a non-significant difference. However, vortioxetine-treated patients did show significantly greater improvement than those on placebo on both the MADRS (effect size 0.672) and LSAS (effect size 0.714). Efficacy in depression was seen before improvement in SAD. Adverse effects were similar to those previously reported. In this preliminary trial vortioxetine appears safe and effective for patients with MDD comorbid with SAD, with robust effect sizes on dimensional measures of both depression and social anxiety, but failure to separate from placebo on the primary outcome measure of composite responder rate. More studies of patients with comorbid conditions are needed, as this mirrors what is often seen in clinical practice. © 2017 Wiley Periodicals, Inc.
Long-Term Nightly Treatment with Indiplon in Adults with Primary Insomnia: Results of a Double-Blind, Placebo-Controlled, 3-Month Study

PubMed Central

Scharf, Martin B.; Black, Jed; Hull, Steven; Landin, Rick; Farber, Robert

2007-01-01

Objectives: To evaluate the efficacy and safety of indiplon in primary insomnia. Design: Randomized, double-blind, placebo-controlled, 3-month study. Setting: Multi-center outpatient setting. Patients: N=702 (61% female; mean age 46 years) who met DSM-IV criteria for primary insomnia of at least 3 months' duration. Interventions: Indiplon 10 mg (n=236), indiplon 20 mg (n=233), or placebo (n=233). Measurements: Subjective assessment of each of the following: latency to sleep onset (sLSO), total sleep time (sTST), number of awakenings after sleep onset (sNAASO), wake time after sleep onset (sWASO), sleep quality, Insomnia Severity Index (ISI), and global improvement. Results: Treatment with indiplon resulted in significant improvement relative to placebo at all time points for the primary endpoint, sLSO. Mean sLSO at Month 1 for each treatment group was: 10 mg (34.0 ± 1.3 mins), 20 mg (33.0 ± 1.3 mins), and placebo (48.7 ± 1.9 mins; P <0.0001 for both comparisons); efficacy was sustained through Month 3. Both doses of indiplon resulted in significant improvement in sleep maintenance and duration endpoints, sTST and sWASO, as well as sleep quality, ISI, and global improvement at all assessment time points. Conclusions: In patients with chronic insomnia, long-term nightly treatment with 10 mg and 20 mg doses of indiplon resulted in significant and sustained efficacy in sleep onset, maintenance, and duration, and significant associated improvement in both daytime functioning and quality of life. Citation: Scharf MB; Black J; Hull S et al. Long-term nightly treatment with indiplon in adults with primary insomnia: Results of a double-blind, placebo-controlled, 3-month study. SLEEP 2007;30(6):743-752. PMID:17580596
The Influence of the ‘Trier Social Stress Test’ on Free Throw Performance in Basketball: An Interdisciplinary Study

PubMed Central

Mascret, Nicolas; Ibáñez-Gijón, Jorge; Bréjard, Vincent; Buekers, Martinus; Casanova, Rémy; Marqueste, Tanguy; Montagne, Gilles; Rao, Guillaume; Roux, Yannick; Cury, François

2016-01-01

The aim of the present study was to explore the relationship between stress and sport performance in a controlled setting. The experimental protocol used to induce stress in a basketball free throw was the Trier Social Stress Test (TSST) and its control condition (Placebo-TSST). Participants (n = 19), novice basketball players but trained sportspersons, were exposed to two counterbalanced conditions in a crossover design. They were equipped with sensors to measure movement execution, while salivary cortisol and psychological state were also measured. The task consisted of two sequences of 40 free throws, one before either the TSST or Placebo-TSST and one after. Physiological and psychological measures evidenced that the TSST induced significant stress responses, whereas the Placebo-TSST did not. Shooting performance remained stable after the TSST but decreased after the Placebo-TSST. We found no effect of the TSST or Placebo-TSST on movement execution. A multivariate model of free throw performance demonstrated that timing, smoothness and explosiveness of the movements are more relevant to account for beginner’s behavior than stress-related physiological and psychological states. We conclude that the TSST is a suitable protocol to induce stress responses in sport context, even though the effects on beginners’ free throw performance and execution are small and complex. PMID:27309715

Do fatty acids help in overcoming reading difficulties? A double-blind, placebo-controlled study of the effects of eicosapentaenoic acid and carnosine supplementation on children with dyslexia.

PubMed

Kairaluoma, L; Närhi, V; Ahonen, T; Westerholm, J; Aro, M

2009-01-01

There are claims that dietary supplementation of unsaturated fatty acids could help children with dyslexia to overcome their reading problems. However, these claims have not yet been empirically tested. This study was designed to test whether dietary supplementation was superior to placebo in treating reading, spelling or other reading-related skills of children with dyslexia. The experimental group (eicosapentaenoic acid, EPA, n = 30) ate dietary supplements and the control group (placebo, n = 31) placebos during the 90-day treatment period. The supplements contained omega-3 fatty acid (ethyl-EPA, 500 mg/day) and carnosine (400 mg/day). The groups were matched for reading skills, grade, gender, attention problems, intelligence and amount of special education. The literacy-related skills of the two groups were assessed before and after the treatment period. No group differences were observed between EPA and placebo in measures of reading accuracy or speed, spelling, decoding fluency, arithmetical skills, reading-related language skills, attention or behavioural problems. The present findings do not support the hypothesis that omega-3 fatty acid (ethyl-EPA) or carnosine has a role in the treatment of reading and spelling problems in children with dyslexia.
The Influence of the 'Trier Social Stress Test' on Free Throw Performance in Basketball: An Interdisciplinary Study.

PubMed

Mascret, Nicolas; Ibáñez-Gijón, Jorge; Bréjard, Vincent; Buekers, Martinus; Casanova, Rémy; Marqueste, Tanguy; Montagne, Gilles; Rao, Guillaume; Roux, Yannick; Cury, François

2016-01-01

The aim of the present study was to explore the relationship between stress and sport performance in a controlled setting. The experimental protocol used to induce stress in a basketball free throw was the Trier Social Stress Test (TSST) and its control condition (Placebo-TSST). Participants (n = 19), novice basketball players but trained sportspersons, were exposed to two counterbalanced conditions in a crossover design. They were equipped with sensors to measure movement execution, while salivary cortisol and psychological state were also measured. The task consisted of two sequences of 40 free throws, one before either the TSST or Placebo-TSST and one after. Physiological and psychological measures evidenced that the TSST induced significant stress responses, whereas the Placebo-TSST did not. Shooting performance remained stable after the TSST but decreased after the Placebo-TSST. We found no effect of the TSST or Placebo-TSST on movement execution. A multivariate model of free throw performance demonstrated that timing, smoothness and explosiveness of the movements are more relevant to account for beginner's behavior than stress-related physiological and psychological states. We conclude that the TSST is a suitable protocol to induce stress responses in sport context, even though the effects on beginners' free throw performance and execution are small and complex.
The rationale and design of the Beta-blocker to LOwer CArdiovascular Dialysis Events (BLOCADE) Feasibility Study.

PubMed

Roberts, Matthew A; Pilmore, Helen L; Ierino, Francesco L; Badve, Sunil V; Cass, Alan; Garg, Amit X; Hawley, Carmel M; Isbel, Nicole M; Krum, Henry; Pascoe, Elaine M; Tonkin, Andrew M; Vergara, Liza A; Perkovic, Vlado

2015-03-01

The Beta-blocker to LOwer CArdiovascular Dialysis Events (BLOCADE) Feasibility Study aims to determine the feasibility of a large-scale randomized controlled trial with clinical endpoints comparing the beta-blocking agent carvedilol with placebo in patients receiving dialysis. The BLOCADE Feasibility Study is a randomized, double-blind, placebo-controlled, parallel group feasibility study comparing the beta-blocking agent carvedilol with placebo. Patients receiving dialysis for ≥3 months and who are aged ≥50 years, or who are ≥18 years and have diabetes or cardiovascular disease, were eligible. The primary outcome was the proportion of participants who complete a 6-week run-in phase in which all participants received carvedilol titrated from 3.125 mg twice daily to 6.25 mg twice daily. Other measures included how many patients are screened, the proportion recruited, the overall recruitment rate, the proportion of participants who remain on study drug for 12 months and the incidence of intra-dialytic hypotension while on randomized treatment. The BLOCADE Feasibility Study commenced recruiting in May 2011 and involves 11 sites in Australia and New Zealand. The BLOCADE Feasibility Study will inform the design of a larger clinical endpoint study to determine whether beta-blocking agents provide benefit to patients receiving dialysis, and define whether such a study is feasible. © 2014 Asian Pacific Society of Nephrology.
Lithium Treatment of Acute Mania in Adolescents: A Placebo-Controlled Discontinuation Study

ERIC Educational Resources Information Center

Kafantaris, Vivian; Coletti, Daniel J.; Dicker, Robert; Padula, Gina; Pleak, Richard R.; Alvir, Jose Ma. J.; Kane, John M.

2004-01-01

Objective: There are no published placebo-controlled studies of any agent in the treatment of acute mania in children or adolescents. This is the first placebo-controlled study of lithium's efficacy in the treatment of acute mania in adolescents. Method: In this discontinuation study, participants received open treatment with lithium at…
A studentized permutation test for three-arm trials in the 'gold standard' design.

PubMed

Mütze, Tobias; Konietschke, Frank; Munk, Axel; Friede, Tim

2017-03-15

The 'gold standard' design for three-arm trials refers to trials with an active control and a placebo control in addition to the experimental treatment group. This trial design is recommended when being ethically justifiable and it allows the simultaneous comparison of experimental treatment, active control, and placebo. Parametric testing methods have been studied plentifully over the past years. However, these methods often tend to be liberal or conservative when distributional assumptions are not met particularly with small sample sizes. In this article, we introduce a studentized permutation test for testing non-inferiority and superiority of the experimental treatment compared with the active control in three-arm trials in the 'gold standard' design. The performance of the studentized permutation test for finite sample sizes is assessed in a Monte Carlo simulation study under various parameter constellations. Emphasis is put on whether the studentized permutation test meets the target significance level. For comparison purposes, commonly used Wald-type tests, which do not make any distributional assumptions, are included in the simulation study. The simulation study shows that the presented studentized permutation test for assessing non-inferiority in three-arm trials in the 'gold standard' design outperforms its competitors, for instance the test based on a quasi-Poisson model, for count data. The methods discussed in this paper are implemented in the R package ThreeArmedTrials which is available on the comprehensive R archive network (CRAN). Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.
Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomised, placebo controlled study

PubMed Central

Schellenberg, R

2001-01-01

Objectives To compare the efficacy and tolerability of agnus castus fruit (Vitex agnus castus L extract Ze 440) with placebo for women with the premenstrual syndrome. Design Randomised, double blind, placebo controlled, parallel group comparison over three menstrual cycles. Setting General medicine community clinics. Participants 178 women were screened and 170 were evaluated (active 86; placebo 84). Mean age was 36 years, mean cycle length was 28 days, mean duration of menses was 4.5 days. Interventions Agnus castus (dry extract tablets) one tablet daily or matching placebo, given for three consecutive cycles. Main outcome measures Main efficacy variable: change from baseline to end point (end of third cycle) in women's self assessment of irritability, mood alteration, anger, headache, breast fullness, and other menstrual symptoms including bloating. Secondary efficacy variables: changes in clinical global impression (severity of condition, global improvement, and risk or benefit) and responder rate (50% reduction in symptoms). Results Improvement in the main variable was greater in the active group compared with placebo group (P<0.001). Analysis of the secondary variables showed significant (P<0.001) superiority of active treatment in each of the three global impression items. Responder rates were 52% and 24% for active and placebo, respectively. Seven women reported mild adverse events (four active; three placebo), none of which caused discontinuation of treatment. Conclusions Dry extract of agnus castus fruit is an effective and well tolerated treatment for the relief of symptoms of the premenstrual syndrome. PMID:11159568
Scotopic sensitivity/Irlen syndrome and the use of coloured filters: a long-term placebo-controlled study of reading strategies using analysis of miscue.

PubMed

Robinson, G L; Foreman, P J

1999-02-01

This study investigated the long-term effects of using coloured filters on the frequency and type of errors in oral reading. A double-masked, placebo-controlled crossover experimental design was used, with subjects being assessed over a period of 20 months. There were three experimental groups (Placebo tints, Blue tints, and Diagnosed tints) involving 113 subjects with reading difficulties, ranging in age from 9.2 yr. to 13.1 yr. The 35 controls (ranging in age from 9.4 yr. to 12.9 yr.) had reading difficulties but did not require coloured filters. There was a significant improvement for all groups in the accuracy of miscues over the period, although experimental groups over-all did not improve at a significantly different rate than the control group. The failure to find significantly greater improvement for the experimental groups over the control group for the total period, despite subjects' reports of improved print clarity, may be partly related to the lack of effective letter-sound analysis and synthesis skills and to the use of a word-identification strategy of guessing based on partial visual analysis.
Finnish Degenerative Meniscal Lesion Study (FIDELITY): a protocol for a randomised, placebo surgery controlled trial on the efficacy of arthroscopic partial meniscectomy for patients with degenerative meniscus injury with a novel ‘RCT within-a-cohort’ study design

PubMed Central

Sihvonen, Raine; Paavola, Mika; Malmivaara, Antti; Järvinen, Teppo L N

2013-01-01

Introduction Arthroscopic partial meniscectomy (APM) to treat degenerative meniscus injury is the most common orthopaedic procedure. However, valid evidence of the efficacy of APM is lacking. Controlling for the placebo effect of any medical intervention is important, but seems particularly pertinent for the assessment of APM, as the symptoms commonly attributed to a degenerative meniscal injury (medial joint line symptoms and perceived disability) are subjective and display considerable fluctuation, and accordingly difficult to gauge objectively. Methods and analysis A multicentre, parallel randomised, placebo surgery controlled trial is being carried out to assess the efficacy of APM for patients from 35 to 65 years of age with a degenerative meniscus injury. Patients with degenerative medial meniscus tear and medial joint line symptoms, without clinical or radiographic osteoarthritis of the index knee, were enrolled and then randomly assigned (1 : 1) to either APM or diagnostic arthroscopy (placebo surgery). Patients are followed up for 12 months. According to the prior power calculation, 140 patients were randomised. The two randomised patient groups will be compared at 12 months with intention-to-treat analysis. To safeguard against bias, patients, healthcare providers, data collectors, data analysts, outcome adjudicators and the researchers interpreting the findings will be blind to the patients’ interventions (APM/placebo). Primary outcomes are Lysholm knee score (a generic knee instrument), knee pain (using a numerical rating scale), and WOMET score (a disease-specific, health-related quality of life index). The secondary outcome is 15D (a generic quality of life instrument). Further, in one of the five centres recruiting patients for the randomised controlled trial (RCT), all patients scheduled for knee arthroscopy due to a degenerative meniscus injury are prospectively followed up using the same protocol as in the RCT to provide an external validation cohort. In this article, we present and discuss our study design, focusing particularly on the internal and external validity of our trial and the ethics of carrying out a placebo surgery controlled trial. Ethics and dissemination The protocol has been approved by the institutional review board of the Pirkanmaa Hospital District and the trial has been duly registered at ClinicalTrials.gov. The findings of this study will be disseminated widely through peer-reviewed publications and conference presentations. Trial registration ClinicalTrials.gov, number NCT00549172. PMID:23474796
The effectiveness of low-level diode laser therapy on orthodontic pain management: a systematic review and meta-analysis.

PubMed

Ren, Chong; McGrath, Colman; Yang, Yanqi

2015-09-01

To assess the effectiveness of diode low-level laser therapy (LLLT) for orthodontic pain control, a systematic and extensive electronic search for randomised controlled trials (RCTs) investigating the effects of diode LLLT on orthodontic pain prior to November 2014 was performed using the Cochrane Library (Issue 9, 2014), PubMed (1997), EMBASE (1947) and Web of Science (1956). The Cochrane tool for risk of bias evaluation was used to assess the bias risk in the chosen data. A meta-analysis was conducted using RevMan 5.3. Of the 186 results, 14 RCTs, with a total of 659 participants from 11 countries, were included. Except for three studies assessed as having a 'moderate risk of bias', the RCTs were rated as having a 'high risk of bias'. The methodological weaknesses were mainly due to 'blinding' and 'allocation concealment'. The meta-analysis showed that diode LLLT significantly reduced orthodontic pain by 39 % in comparison with placebo groups (P = 0.02). Diode LLLT was shown to significantly reduce the maximum pain intensity among parallel-design studies (P = 0.003 versus placebo groups; P = 0.000 versus control groups). However, no significant effects were shown for split-mouth-design studies (P = 0.38 versus placebo groups). It was concluded that the use of diode LLLT for orthodontic pain appears promising. However, due to methodological weaknesses, there was insufficient evidence to support or refute LLLT's effectiveness. RCTs with better designs and appropriate sample power are required to provide stronger evidence for diode LLLT's clinical applications.
Decline in placebo-controlled trial results suggests new directions for comparative effectiveness research.

PubMed

Olfson, Mark; Marcus, Steven C

2013-06-01

The Affordable Care Act offers strong support for comparative effectiveness research, which entails comparisons among active treatments, to provide the foundation for evidence-based practice. Traditionally, a key form of research into the effectiveness of therapeutic treatments has been placebo-controlled trials, in which a specified treatment is compared to placebo. These trials feature high-contrast comparisons between treatments. Historical trends in placebo-controlled trials have been evaluated to help guide the comparative effectiveness research agenda. We investigated placebo-controlled trials reported in four leading medical journals between 1966 and 2010. We found that there was a significant decline in average effect size or average difference in efficacy (the ability to produce a desired effect) between the active treatment and placebo. On average, recently studied treatments offered only small benefits in efficacy over placebo. A decline in effect sizes in conventional placebo-controlled trials supports an increased emphasis on other avenues of research, including comparative studies on the safety, tolerability, and cost of treatments with established efficacy.
Integrating nutrition and early child-development interventions among infants and preschoolers in rural India.

PubMed

Fernandez-Rao, Sylvia; Hurley, Kristen M; Nair, Krishnapillai Madhavan; Balakrishna, Nagalla; Radhakrishna, Kankipati V; Ravinder, Punjal; Tilton, Nicholas; Harding, Kimberly B; Reinhart, Greg A; Black, Maureen M

2014-01-01

This article describes the development, design, and implementation of an integrated randomized double-masked placebo-controlled trial (Project Grow Smart) that examines how home/preschool fortification with multiple micronutrient powder (MNP) combined with an early child-development intervention affects child development, growth, and micronutrient status among infants and preschoolers in rural India. The 1-year trial has an infant phase (enrollment age: 6-12 months) and a preschool phase (enrollment age: 36-48 months). Infants are individually randomized into one of four groups: placebo, placebo plus early learning, MNP alone, and MNP plus early learning (integrated intervention), conducted through home visits. The preschool phase is a cluster-randomized trial conducted in Anganwadi centers (AWCs), government-run preschools sponsored by the Integrated Child Development System of India. AWCs are randomized into MNP or placebo, with the MNP or placebo mixed into the children's food. The evaluation examines whether the effects of the MNP intervention vary by the quality of the early learning opportunities and communication within the AWCs. Study outcomes include child development, growth, and micronutrient status. Lessons learned during the development, design, and implementation of the integrated trial can be used to guide large-scale policy and programs designed to promote the developmental, educational, and economic potential of children in developing countries. © 2013 New York Academy of Sciences.
Should we reconsider the routine use of placebo controls in clinical research?

PubMed

Avins, Andrew L; Cherkin, Daniel C; Sherman, Karen J; Goldberg, Harley; Pressman, Alice

2012-04-27

Modern clinical-research practice favors placebo controls over usual-care controls whenever a credible placebo exists. An unrecognized consequence of this preference is that clinicians are more limited in their ability to provide the benefits of the non-specific healing effects of placebos in clinical practice. We examined the issues in choosing between placebo and usual-care controls. We considered why placebo controls place constraints on clinicians and the trade-offs involved in the choice of control groups. We find that, for certain studies, investigators should consider usual-care controls, even if an adequate placebo is available. Employing usual-care controls would be of greatest value for pragmatic trials evaluating treatments to improve clinical care and for which threats to internal validity can be adequately managed without a placebo-control condition. Intentionally choosing usual-care controls, even when a satisfactory placebo exists, would allow clinicians to capture the value of non-specific therapeutic benefits that are common to all interventions. The result could be more effective, patient-centered care that makes the best use of both specific and non-specific benefits of medical interventions.
Confusing placebo effect with natural history in epilepsy: A big data approach.

PubMed

Goldenholz, Daniel M; Moss, Robert; Scott, Jonathan; Auh, Sungyoung; Theodore, William H

2015-09-01

For unknown reasons, placebos reduce seizures in clinical trials in many patients. It is also unclear why some drugs showing statistical superiority to placebo in one trial may fail to do so in another. Using Seizuretracker.com, a patient-centered database of 684,825 seizures, we simulated "placebo" and "drug" trials. These simulations were employed to clarify the sources of placebo effects in epilepsy, and to identify methods of diminishing placebo effects. Simulation 1 included 9 trials with a 6-week baseline and 6-week test period, starting at time 0, 3, 6…24 months. Here, "placebo" reduced seizures regardless of study start time. Regression-to-the-mean persisted only for 3 to 6 months. Simulation 2 comprised a 6-week baseline and then 2 years of follow-up. Seizure frequencies continued to improve throughout follow-up. Although the group improved, individuals switched from improvement to worsening and back. Simulation 3 involved a placebo-controlled "drug" trial, to explore methods of placebo response reduction. An efficacious "drug" failed to demonstrate a significant effect compared with "placebo" (p = 0.12), although modifications either in study start time (p = 0.025) or baseline population reduction (p = 0.0028) allowed the drug to achieve a statistically significant effect compared with placebo. In epilepsy clinical trials, some seizure reduction traditionally attributed to placebo effect may reflect the natural course of the disease itself. Understanding these dynamics will allow future investigations into optimal clinical trial design and may lead to identification of more effective therapies. Ann Neurol 2015;78:329-336. © 2015 American Neurological Association.
Effects of garlic extract on platelet aggregation: a randomized placebo-controlled double-blind study.

PubMed

Morris, J; Burke, V; Mori, T A; Vandongen, R; Beilin, L J

1995-01-01

1. Studies of the effects of garlic on platelet aggregation have produced inconsistent results possibly related to variations in study design and in the garlic preparations used. 2. The present study examined the effects on platelet aggregation and serum thromboxane and lyso-platelet activating factor, of feeding garlic extract to healthy men using a placebo-controlled, double-blind design. The effects of the same garlic preparation on platelet aggregation in vitro were also investigated. 3. There were no significant differences in platelet aggregation with adenosine diphosphate, platelet activating factor (PAF) or collagen according to treatment group. Serum thromboxane and lysoPAF also showed no change related to garlic supplements. 4. In vitro aggregation with collagen decreased linearly with increasing amounts of garlic extract, but concentrations were higher than those attainable in vivo. Gastrointestinal side effects prevented the use of higher doses of garlic which must be considered to be pharmacological as they exceed changes achievable by dietary modification.
Patient Expectancy as a Mediator of Placebo Effects in Antidepressant Clinical Trials.

PubMed

Rutherford, Bret R; Wall, Melanie M; Brown, Patrick J; Choo, Tse-Hwei; Wager, Tor D; Peterson, Bradley S; Chung, Sarah; Kirsch, Irving; Roose, Steven P

2017-02-01

Causes of placebo effects in antidepressant trials have been inferred from observational studies and meta-analyses, but their mechanisms have not been directly established. The goal of this study was to examine in a prospective, randomized controlled trial whether patient expectancy mediates placebo effects in antidepressant studies. Adult outpatients with major depressive disorder were randomly assigned to open or placebo-controlled citalopram treatment. Following measurement of pre- and postrandomization expectancy, participants were treated with citalopram or placebo for 8 weeks. Independent samples t tests determined whether patient expectancy differed between the open and placebo-controlled groups, and mixed-effects models assessed group effects on Hamilton Depression Rating Scale (HAM-D) scores over time while controlling for treatment assignment. Finally, mediation analyses tested whether between-group differences in patient expectancy mediated the group effect on HAM-D scores. Postrandomization expectancy scores were significantly higher in the open group (mean=12.1 [SD=2.1]) compared with the placebo-controlled group (mean=11.0 [SD=2.0]). Mixed-effects modeling revealed a significant week-by-group interaction, indicating that HAM-D scores for citalopram-treated participants declined at a faster rate in the open group compared with the placebo-controlled group. Patient expectations postrandomization partially mediated group effects on week 8 HAM-D. Patient expectancy is a significant mediator of placebo effects in antidepressant trials. Expectancy-related interventions should be investigated as a means of controlling placebo responses in antidepressant clinical trials and improving patient outcome in clinical treatment.
WITHDRAWN: Transcutaneous electrical nerve stimulation and acupuncture-like transcutaneous electrical nerve stimulation for chronic low back pain.

PubMed

Gadsby, J G; Flowerdew, M W

2007-07-18

In view of the claims and counter-claims of the effectiveness of transcutaneous electrical nerve stimulation, it would seem appropriate to systematically review the literature. To determine the effectiveness of transcutaneous electrical nerve stimulation in reducing pain and improving range of movement in patients with chronic low back pain. Electronic searches of EMBASE, MEDLINE, CISCOM, AMED for all studies of TENS in the English language, identifying those treating chronic low back pain and hand searching their references. The inclusion criterion for studies included in this review, 6 of 68 identified, was comparisons of TENS/ALTENS versus placebo in patients with chronic low back pain. Outcome data on pain reduction, range of movement, functional status and work was extracted by two independent reviewers together with trial design qualities to construct a Quality Index. The ratio of odds of improvement in pain for each comparison was calculated: TENS vs. placebo at 1.62 (95% CI 0.90, 2.68); ALTENS vs. placebo at 7.22 (95% CI 2.60, 20.01) and TENS/ALTENS vs. placebo at 2.11 (95% CI 1.32, 3.38) times that of placebo. An improvement in pain reduction was seen in 45.80% (CI 37.00%, 55.00%) of TENS; 86.70% (CI 80.00%, 93.00%) of ALTENS; 54.00% (CI 46.20%, 61.80%) of TENS/ ALTENS and 36.40% (95%CI 28.40%, 44.40%) of placebo subjects. The odds of improvement in range of movement on ALTENS vs. placebo was 6.61 times (95% CI 2.36, 18.55) that of placebo. Transcutaneous electrical nerve stimulation appears to reduce pain and improve the range of movement in chronic low back pain subjects. A definitive randomised controlled study of ALTENS, TENS, placebo/no treatment controls, of sufficient power, is needed to confirm these findings.
Randomized controlled trial of zonisamide for the treatment of refractory partial-onset seizures.

PubMed

Faught, E; Ayala, R; Montouris, G G; Leppik, I E

2001-11-27

Zonisamide is a sulfonamide antiepilepsy drug with sodium and calcium channel-blocking actions. Experience in Japan and a previous European double-blind study have demonstrated its efficacy against partial-onset seizures. A randomized, double-blind, placebo-controlled trial enrolling 203 patients was conducted at 20 United States sites to assess zonisamide efficacy and dose response as adjunctive therapy for refractory partial-onset seizures. Zonisamide dosages were elevated by 100 mg/d each week. The study design allowed parallel comparisons with placebo for three dosages and a final crossover to 400 mg/d of zonisamide for all patients. The primary efficacy comparison was change in seizure frequency from a 4-week placebo baseline to weeks 8 through 12 on blinded therapy. At 400 mg/d, zonisamide reduced the median frequency of all seizures by 40.5% from baseline, compared with a 9% reduction (p = 0.0009) with placebo treatment, and produced a > or =50% seizure reduction (responder rate) in 42% of patients. A dosage of 100 mg/d produced a 20.5% reduction in median seizure frequency (p = 0.038 compared with placebo) and a dosage of 200 mg/d produced a 24.7% reduction in median seizure frequency (p = 0.004 compared with placebo). Dropouts from adverse events (10%) did not differ from placebo (8.2%, NS). The only adverse event differing significantly from placebo was weight loss, though somnolence, anorexia, and ataxia were slightly more common with zonisamide treatment. Serum zonisamide concentrations rose with increasing dose. Zonisamide is effective and well tolerated as an adjunctive agent for refractory partial-onset seizures. The minimal effective dosage was 100 mg/d, but 400 mg/d was the most effective dosage.
Randomised controlled trial of homoeopathy versus placebo in perennial allergic rhinitis with overview of four trial series

PubMed Central

Taylor, Morag A; Reilly, David; Llewellyn-Jones, Robert H; McSharry, Charles; Aitchison, Tom C

2000-01-01

Objective To test the hypothesis that homoeopathy is a placebo by examining its effect in patients with allergic rhinitis and so contest the evidence from three previous trials in this series. Design Randomised, double blind, placebo controlled, parallel group, multicentre study. Setting Four general practices and a hospital ear, nose, and throat outpatient department. Participants 51 patients with perennial allergic rhinitis. Intervention Random assignment to an oral 30c homoeopathic preparation of principal inhalant allergen or to placebo. Main outcome measures Changes from baseline in nasal inspiratory peak flow and symptom visual analogue scale score over third and fourth weeks after randomisation. Results Fifty patients completed the study. The homoeopathy group had a significant objective improvement in nasal airflow compared with the placebo group (mean difference 19.8 l/min, 95% confidence interval 10.4 to 29.1, P=0.0001). Both groups reported improvement in symptoms, with patients taking homoeopathy reporting more improvement in all but one of the centres, which had more patients with aggravations. On average no significant difference between the groups was seen on visual analogue scale scores. Initial aggravations of rhinitis symptoms were more common with homoeopathy than placebo (7 (30%) v 2 (7%), P=0.04). Addition of these results to those of three previous trials (n=253) showed a mean symptom reduction on visual analogue scores of 28% (10.9 mm) for homoeopathy compared with 3% (1.1 mm) for placebo (95% confidence interval 4.2 to 15.4, P=0.0007). Conclusion The objective results reinforce earlier evidence that homoeopathic dilutions differ from placebo. PMID:10948025
The effect of Camphor-Crataegus berry extract combination on blood pressure and mental functions in chronic hypotension--a randomized placebo controlled double blind design.

PubMed

Schandry, Rainer; Duschek, Stefan

2008-11-01

A number of studies have provided evidence for reduced cognitive performance due to chronically low blood pressure. The present studies explored whether these deficits can be reduced by pharmacological blood pressure elevation. Effects of the Camphor-Crataegus berry extract combination (Korodin(®)) were investigated in two studies with 40 and 48 hypotensive women based on a randomized, placebo controlled double blind design. The participants were presented with different tasks assessing performance in attention and cognition. Blood pressure was measured repeatedly during the experiment. The administration of the drug led to positive and differential effects on blood pressure and cognitive performance as compared to placebo. These effects were already visible within the time range of 2-5 min. A positive correlation between blood pressure increase and performance enhancement could be demonstrated for two of the four tasks. The results show that the application of Korodin(®) results in beneficial effects on resting blood pressure and cognitive performance. The positive association between the increase in blood pressure and cognitive enhancement suggests that blood pressure plays a causal role in the cognitive deficits in hypotension and underlines that they can be reduced through antihypotensive treatment.
Relative benefits of stimulant therapy with OROS methylphenidate versus mixed amphetamine salts extended release in improving the driving performance of adolescent drivers with attention-deficit/hyperactivity disorder.

PubMed

Cox, Daniel J; Merkel, R Lawrence; Moore, Melissa; Thorndike, Frances; Muller, Carrie; Kovatchev, Boris

2006-09-01

Automobile accidents are the leading cause of death among adolescents, and collisions are 2 to 4 times more likely to occur among adolescents with attention-deficit/hyperactivity disorder. Studies have demonstrated that stimulants improve driving performance. This study compared 2 long-acting stimulant medications during daytime and evening driving evaluations. Adolescent drivers with attention-deficit/hyperactivity disorder were compared on a driving simulator after taking 72 mg of OROS methylphenidate, 30 mg of mixed amphetamine salts extended release, or placebo in a randomized, double-blind, placebo-controlled, crossover study design. During laboratory testing, adolescents drove a driving simulator at 5:00 pm, 8:00 pm, and 11:00 pm. Driving performance was rated by adolescents and investigators. The study included 35 adolescent drivers with attention-deficit/hyperactivity disorder (19 boys/16 girls). The mean age was 17.8 years. The overall Impaired Driving Score demonstrated that OROS methylphenidate led to better driving performance compared with placebo and mixed amphetamine salts extended release, whereas mixed amphetamine salts extended release demonstrated no statistical improvement over placebo. Specifically, relative to placebo, OROS methylphenidate resulted in less time driving off the road, fewer instances of speeding, less erratic speed control, more time executing left turns, and less inappropriate use of brakes. OROS methylphenidate and mixed amphetamine salts extended release worked equally well for male and female adolescents and equally as well with teenagers who have combined and inattentive subtypes of attention-deficit/hyperactivity disorder. This study validates the use of stimulants to improve driving performance in adolescents with attention-deficit/hyperactivity disorder. In the study, OROS methylphenidate promoted significantly improved driving performance compared with placebo and mixed amphetamine salts extended release.

Comparison of Puff Topography, Toxicant Exposure, and Subjective Effects in Low- and High-Frequency Waterpipe Users: A Double-Blind, Placebo-Control Study

PubMed Central

Cobb, Caroline O.; Blank, Melissa D.; Morlett, Alejandra; Shihadeh, Alan; Jaroudi, Ezzat; Karaoghlanian, Nareg; Kilgalen, Barbara; Austin, Janet; Weaver, Michael F.

2015-01-01

Introduction: Clinical laboratory work among intermittent and daily waterpipe tobacco smokers has revealed significant risks for tobacco dependence and disease associated with waterpipe tobacco smoking (WTS). No studies have compared these groups directly. This study examined whether WTS frequency was associated with differential puff topography, toxicant exposure, and subjective response using a placebo-control design. Methods: Eighty participants reporting WTS of 2–5 episodes (LOW; n = 63) or ≥20 episodes (HIGH; n = 17) per month for ≥6 months completed 2 double-blind, counterbalanced 2-hr sessions that were preceded by ≥12hr of tobacco abstinence. Sessions differed by product smoked ad libitum for 45+ min: preferred brand/flavor of waterpipe tobacco (active) or a flavor-matched tobacco-free waterpipe product (placebo). Outcomes included puff topography, plasma nicotine, carboxyhemoglobin (COHb), and subjective response. Results: HIGH users had more puffs, shorter inter-puff-intervals, and a higher total puff volume for placebo relative to active, as well as relative to LOW users during placebo. Plasma nicotine concentrations increased when smoking active (but not placebo) with no significant differences between groups at 25min post-product administration. COHb increased significantly during all conditions; the largest increase was for HIGH users when smoking placebo. There was some evidence of higher baseline scores for nicotine/tobacco nicotine abstinence symptomology. Conclusions: Higher frequency waterpipe users may be more sensitive to the effects of waterpipe smoke nicotine content. Among HIGH users, higher baseline nicotine/tobacco abstinence symptoms may indicate greater nicotine dependence. These data support continued surveillance of WTS and development of dependence measures specific to this product. PMID:25257982
The Effect of Saffron on Depression among Recovered Consumers of Methamphetamine Living with HIV/AIDS.

PubMed

Jalali, Farzad; Hashemi, Seyedeh Fatemeh

2018-03-15

From one hand, depression is one of the symptoms that occur after abstinence from methamphetamine. On the other people living with HIV/AIDS are in isolation due to the nature of their illness and depression is one of the most common mental health problems they experience. This study was aimed at determining the effectiveness of saffron on reducing depression among recovered consumers of methamphetamine living with HIV/AIDS. The design of this study was semi-experimental with pre-test, post-test and control (placebo) groups. The statistical population consisted of all recovered consumers of methamphetamine living with HIV/AIDS who were referred to the Positive Club. Fifty-seven (57) recovered consumers of methamphetamine, living with HIV/AIDS, were selected by convenience sampling method. They were randomly assigned to an experimental (saffron) group and a control (placebo) group. The experimental group received 30 ml of saffron per day for 8 weeks, whereas the control (placebo) group received placebo the same way. BDI-II was used in this study as a measurement instrument. ANCOVA models were used for statistical inference. The findings showed that saffron and its ingredients had been effective in reducing depression among this group (P < 0.05). In fact, saffron with its active ingredients (Crusin and Saffranal) by serotonin and dopamine secretion in the brain, help in reducing depression among recovered consumers of methamphetamine living with HIV/AIDS.
Enzyme potentiated desensitisation in treatment of seasonal allergic rhinitis: double blind randomised controlled study

PubMed Central

Radcliffe, Michael J; Lewith, George T; Turner, Richard G; Prescott, Philip; Church, Martin K; Holgate, Stephen T

2003-01-01

Objective To assess the efficacy of enzyme potentiated desensitisation in the treatment of severe summer hay fever poorly controlled by pharmacotherapy. Design Double blind randomised placebo controlled parallel group study. Setting Hospital in Hampshire. Participants 183 participants aged between 18 and 64 with a history of severe summer hay fever for at least two years; all were skin prick test positive to timothy grass pollen. 90 randomised to active treatment; 93 randomised to placebo. Interventions Active treatment: two injections of enzyme potentiated desensitisation, given between eight and 11 weeks apart, each comprising 200 Fishman units of β glucuronidase, 50 pg 1,3-cyclohexanediol, 50 ng protamine sulphate, and a mixed inhaled allergen extract (pollen mixes for trees, grasses, and weeds; allergenic fungal spores; cat and dog danders; dust and storage mites) in a total volume of 0.05 ml of buffered saline. Placebo: two injections of 0.05 ml buffered saline solution. Main outcome measures Proportion of problem-free days; global rhinoconjunctivitis quality of life scores assessed weekly during pollen season. Results The active treatment group and the placebo group did not differ in the proportion of problem-free days, quality of life scores, symptom severity scores, change in quantitative skin prick provocation threshold, or change in conjunctival provocation threshold. No clinically significant adverse reactions occurred. Conclusions Enzyme potentiated desensitisation showed no treatment effect in this study. PMID:12896934
Randomized, Placebo-controlled Trial of Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis: The ACROSS Trial

PubMed Central

Janz, David R; Bastarache, Julie A; Rice, Todd W; Bernard, Gordon R; Warren, Melissa A; Wickersham, Nancy; Sills, Gillian; Oates, John A; Roberts, L Jackson; Ware, Lorraine B

2014-01-01

Objective This trial evaluated the efficacy of acetaminophen in reducing oxidative injury, as measured by plasma F2-Isoprostanes, in adult patients with severe sepsis and detectable plasma cell-free hemoglobin. Design Single center, randomized, double-blind, placebo controlled phase II trial. Setting Medical ICU in a tertiary, academic medical center. Patients Critically ill patients ≥18 years old with severe sepsis and detectable plasma cell-free hemoglobin. Interventions Patients were randomized 1:1 to enteral acetaminophen 1 gram every 6 hours for three days (n = 18) or placebo (n = 22) with the same dosing schedule and duration. Measurements and Main Results F2-Isoprostanes on study day 3, the primary outcome, did not differ between acetaminophen (30 pg/mL, IQR 24–41) and placebo (36 pg/mL, IQR 25–80, p = 0.35). However, F2-Isoprostanes were significantly reduced on study day 2 in the acetaminophen group (24 pg/mL, IQR 19 – 36) compared with placebo (36 pg/mL, IQR 23–55, p = 0.047). Creatinine on study day 3, a secondary outcome, was significantly lower in the acetaminophen group (1.0 mg/dL, IQR 0.6–1.4) compared with placebo (1.3 mg/dL, IQR 0.83 – 2.0, p = 0.039). There was no statistically significant difference in hospital mortality (acetaminophen 5.6% vs. placebo 18.2%, p = 0.355) or adverse events (AST or ALT >400)(acetaminophen 9.5% vs. placebo 4.3%, p = 0.599). Conclusions In adults with severe sepsis and detectable plasma cell-free hemoglobin, treatment with acetaminophen within 24 hours of ICU admission may reduce oxidative injury and improve renal function. Further study is needed to confirm these findings and determine the effect of acetaminophen on patient-centered outcomes. PMID:25474535
Network analysis of the genomic basis of the placebo effect

PubMed Central

Wang, Rui-Sheng; Hall, Kathryn T.; Giulianini, Franco; Passow, Dani; Kaptchuk, Ted J.

2017-01-01

The placebo effect is a phenomenon in which patients who are given an inactive treatment (e.g., inert pill) show a perceived or actual improvement in a medical condition. Placebo effects in clinical trials have been investigated for many years especially because placebo treatments often serve as the control arm of randomized clinical trial designs. Recent observations suggest that placebo effects may be modified by genetics. This observation has given rise to the term “placebome,” which refers to a group of genome-related mediators that affect an individual’s response to placebo treatments. In this study, we conduct a network analysis of the placebome and identify a placebome module in the comprehensive human interactome using a seed-connector algorithm. The placebome module is significantly enriched with neurotransmitter signaling pathways and brain-specific proteins. We validate the placebome module using a large cohort of the Women’s Genome Health Study (WGHS) trial and demonstrate that the placebome module is significantly enriched with genes whose SNPs modify the outcome in the placebo arm of the trial. To gain insights into placebo effects in different diseases and drug treatments, we use a network proximity measure to examine the closeness of the placebome module to different disease modules and drug target modules. The results demonstrate that the network proximity of the placebome module to disease modules in the interactome significantly correlates with the strength of the placebo effect in the corresponding diseases. The proximity of the placebome module to molecular pathways affected by certain drug classes indicates the existence of placebo-drug interactions. This study is helpful for understanding the molecular mechanisms mediating the placebo response, and sets the stage for minimizing its effects in clinical trials and for developing therapeutic strategies that intentionally engage it. PMID:28570268
Effects of oral administration of caffeine and D-ribose on mental fatigue.

PubMed

Ataka, Suzuka; Tanaka, Masaaki; Nozaki, Satoshi; Mizuma, Hiroshi; Mizuno, Kei; Tahara, Tsuyoshi; Sugino, Tomohiro; Shirai, Tomoko; Kajimoto, Yoshitaka; Kuratsune, Hirohiko; Kajimoto, Osami; Watanabe, Yasuyoshi

2008-03-01

We examined the effects of administering two different candidate antifatigue substances, caffeine and D-ribose, on mental fatigue. In a double-blinded, placebo-controlled, three-way crossover design, 17 healthy volunteers were randomized to oral caffeine (200 mg/d), D-ribose (2000 mg/d), or placebo for 8 d. As fatigue-inducing mental tasks, subjects performed a 30-min Uchida-Kraepelin psychodiagnostic test and a 30-min advanced trail-making test on four occasions. During the tasks, the task performance of the caffeine group was better than that of the placebo group. However, after the fatigue-inducing tasks, although subjective perception of fatigue, motivation, or sleepiness was not significantly different, plasma branched-chain amino acid levels in the caffeine group were lower than those of the placebo group. Administration of D-ribose had no effect. Because plasma branched-chain amino acid levels are decreased by mental fatigue, these results suggest that administration of caffeine improved task performance through the enhancement of central nervous system activity without increasing the sensation of fatigue. However, further decreases in branched-chain amino acid levels indicate that caffeine might promote deeper fatigue than placebo. Unfortunately, research subsequent to our study design has shown that D-ribose dosing higher than we used is needed to see a clinical effect and therefore no conclusions can be made from this study as to the efficacy of D-ribose.
Active placebo control groups of pharmacological interventions were rarely used but merited serious consideration: a methodological overview.

PubMed

Jensen, Jakob Solgaard; Bielefeldt, Andreas Ørsted; Hróbjartsson, Asbjørn

2017-07-01

Active placebos are control interventions that mimic the side effects of the experimental interventions in randomized trials and are sometimes used to reduce the risk of unblinding. We wanted to assess how often randomized clinical drug trials use active placebo control groups; to provide a catalog, and a characterization, of such trials; and to analyze methodological arguments for and against the use of active placebo. An overview consisting of three thematically linked substudies. In an observational substudy, we assessed the prevalence of active placebo groups based on a random sample of 200 PubMed indexed placebo-controlled randomized drug trials published in October 2013. In a systematic review, we identified and characterized trials with active placebo control groups irrespective of publication time. In a third substudy, we reviewed publications with substantial methodological comments on active placebo groups (searches in PubMed, The Cochrane Library, Google Scholar, and HighWirePress). The prevalence of trials with active placebo groups published in 2013 was 1 out of 200 (95% confidence interval: 0-2), 0.5% (0-1%). We identified and characterized 89 randomized trials (published 1961-2014) using active placebos, for example, antihistamines, anticholinergic drugs, and sedatives. Such trials typically involved a crossover design, the experimental intervention had noticeable side effects, and the outcomes were patient-reported. The use of active placebos was clustered in specific research settings and did not appear to reflect consistently the side effect profile of the experimental intervention, for example, selective serotonin reuptake inhibitors were compared with active placebos in pain trials but not in depression trials. We identified and analyzed 25 methods publications with substantial comments. The main argument for active placebo was to reduce risk of unblinding; the main argument against was the risk of unintended therapeutic effect. Pharmacological active placebo control interventions are rarely used in randomized clinical trials, but they constitute a methodological tool which merits serious consideration. We suggest that active placebos are used more often in trials of drugs with noticeable side effects, especially in situations where the expected therapeutic effects are modest and the risk of bias due to unblinding is high. Copyright © 2017 Elsevier Inc. All rights reserved.
Safety and efficacy of new glyceryl trinitrate suppository formula: first double blind placebo-controlled clinical trial.

PubMed

Emami, M H; Sayedyahossein, S; Aslani, A

2008-07-01

This study was designed to assess the safety and efficacy of 0.2 percent glyceryl trinitrate suppository form in the healing of chronic anal fissure. Thirty-four patients with symptomatic chronic anal fissures were assigned to 0.2 percent glyceryl trinitrate suppository (n = 21) or placebo (n = 13) in a double blind design. Patient's symptom scores were registered at first visit. A validated daily chart was given to assess their symptoms on a daily basis. Both groups received psyllium from the beginning of the study. They were assessed at two-week intervals for six weeks. Then, they started a washout period of one month and after that were crossed over for another six weeks. Chi-squared, t-tests, and analysis of variance were used for statistical analysis. Complete healing at six weeks was achieved in 12 of 21 patients (57 percent) in the glyceryl trinitrate group and 5 of 13 patients (38 percent) in the placebo (P < 0.05). The overall healing rates at the end of study were 15 of 21 (71 percent) vs. 11 of 13 (84 percent) in the glyceryl trinitrate and placebo groups, respectively (P > 0.05). Application of 0.2 percent glyceryl trinitrate suppository form represents a new, promising, and effective treatment for chronic anal fissure.
Rationale and design of ASTEROID 2, a randomized, placebo- and active comparator-controlled study to assess the efficacy and safety of vilaprisan in patients with uterine fibroids.

PubMed

Seitz, Christian; Bumbuliene, Žana; Costa, Ana Rosa; Heikinheimo, Oskari; Heweker, Andrea; Hudeček, Robert; Jacquemyn, Yves; Melis, Gian Benedetto; Parashar, Pooja; Rechberger, Tomasz; Sánchez, Antonio Cano; van Aken, Bart; Zatik, János; Gemzell-Danielsson, Kristina

2017-04-01

Uterine fibroids (UFs) may be treated with progesterone receptor modulators (PRMs), which have been shown to reduce heavy menstrual bleeding and the size of UFs. To date, one PRM (ulipristal acetate) has received regulatory approval for the treatment of UFs; therapy comprises intermittent treatment courses of up to 3months each, followed by a break to allow two menstruations to occur. We report the design of ASTEROID (Assess Safety and efficacy of vilaprisan in patients with uTERine fibrOIDs) 2, a phase 2 study examining the efficacy and safety of a novel PRM, vilaprisan, in women with UFs. In this randomized multi-arm study, vilaprisan (2mg daily) will be administered in different regimens: continuous treatment for 12 or 24weeks, or two 12-week treatment periods separated by a break to allow one menstruation to occur. Efficacy and safety will be compared with that of ulipristal acetate (5mg daily) and placebo. Patients randomized to receive placebo for 12weeks will also be given active treatment for 12weeks. The primary measure of efficacy will be amenorrhoea rate; secondary measures include time to normalized menstrual bleeding and percentage change in UF volume. Endometrial changes will be monitored throughout the study. The placebo- and active comparator-controlled trial ASTEROID 2 is the first study to evaluate systematically the efficacy and safety of different treatment regimens of PRMs in women with UFs. The findings of this study will direct the planning of future clinical trials of vilaprisan. Copyright © 2017 Bayer AG. Published by Elsevier Inc. All rights reserved.
Effects of Enteric-coated Lactoferrin Tablets Containing Lactobacillus brevis subsp. coagulans on Fecal Properties, Defecation Frequency and Intestinal Microbiota of Japanese Women with a Tendency for Constipation: a Randomized Placebo-controlled Crossover Study

PubMed Central

SUZUKI, Noriyuki; MURAKOSHI, Michiaki; ONO, Tomoji; MORISHITA, Satoru; KOIDE, Misao; BAE, Min Jung; TOTSUKA, Mamoru; SHIMIZU, Makoto; SUGIYAMA, Keikichi; NISHINO, Hoyoku; IIDA, Norio

2013-01-01

The effects of oral administration of enteric-coated tablets containing lactoferrin (LF; 100 mg/tablet) and heat-killed Lactobacillus brevis subsp. coagulans FREM BP-4693 (LB; 6×109 bacteria/tablet) on fecal properties were examined in 32 Japanese women (20–60 years of age) with a tendency for constipation (defecation frequency at equal to or less than 10 times/2 weeks) by a double-blind placebo-controlled crossover design. A significant increase in defecation days per week was obserbed in the subjects who ingested the tablets containing LF and LB compared with the placebo group. The number of bifidobacteria in feces also significantly increased compared with the placebo group. In an in vitro study, LF and tryptic hydrolysate of LF, but not peptic hydrolysate of LF, upregulated the growth of Bifidobacterium longum ATCC15707 when added to the culture. These results demonstrate the capability of the enteric-coated tablets containing LF and LB in improving intestinal function and suggest that they have a growth promoting function for bifidobacteria. PMID:24936358
The efficacy and safety of Baoji Tablets for treating common cold with summer-heat and dampness syndrome: study protocol for a randomized controlled trial

PubMed Central

2013-01-01

Background Despite the high incidence and the economic impact of the common cold, there are still no effective therapeutic options available. Although traditional Chinese medicine (TCM) is widely used in China to treat the common cold, there is still a lack of high-quality clinical trials. This article sets forth the protocol for a high-quality trial of a new TCM drug, Baoji Tablets, which is designed to treat the common cold with summer-heat and dampness syndrome (CCSDS). The trial is evaluating both the efficacy and safety of Baoji Tablets. Methods/design This study is designed as a multicenter, phase II, parallel-group, double-blind, double-dummy, randomized and placebo-controlled trial. A total of 288 patients will be recruited from four centers. The new tablets group are administered Baoji Tablets 0.9 g and dummy Baoji Pills 3.7 g. The old pills group are administered dummy Baoji Tablets 0.9 g and Baoji Pills 3.7 g. The placebo control group are administered dummy Baoji Tablets 0.9 g and dummy Baoji Pills 3.7 g. All drugs are taken three times daily for 3 days. The primary outcome is the duration of all symptoms. Secondary outcomes include the duration of primary and secondary symptoms, changes in primary and secondary symptom scores and cumulative symptom score at day 4, as well as an evaluation of treatment efficacy. Discussion This is the first multicenter, double-blind, double-dummy, randomized and placebo-controlled trial designated to treat CCSDS in an adult population from China. It will establish the basis for a scientific and objective assessment of the efficacy and safety of Baoji Tablets for treating CCSDS, and provide evidence for a phase III clinical trial. Trial registration This study is registered with the Chinese Clinical Trial Registry. The registration number is ChiCTR-TRC-13003197. PMID:24359521
The use of everolimus in the treatment of neurocognitive problems in tuberous sclerosis (TRON): study protocol for a randomised controlled trial.

PubMed

Randell, Elizabeth; McNamara, Rachel; Davies, D Mark; Owen-Jones, Eleri; Kirby, Nigel; Angel, Lianna; Drew, Cheney; Cannings-John, Rebecca; Smalley, Michelle; Saxena, Anurag; McDermott, Emer; Stockwell, Laura; de Vries, Petrus J; Hood, Kerry; Sampson, Julian R

2016-08-11

Tuberous sclerosis complex (TSC) is a genetic disorder affecting about 1 in 6000 people and is characterised by the development of tumours in many organs, including the skin and kidneys, and by a range of neurological and neuropsychiatric manifestations. TSC-associated neuropsychiatric disorders (TAND) occur in the majority of those with TSC, and they have a significant impact on patients and their families, given the everyday impact of TAND on education, employment, family and social life. The potential benefits of better treatment for TAND therefore include reduction in health care demands and wider benefits for patients and their carers. We have planned a single-centre, two-arm, individually randomised, phase II, double-blind, placebo-controlled trial of everolimus versus placebo in the treatment of neurocognitive problems in patients with tuberous sclerosis. Everolimus is a licensed medicine in this patient group, but for a different target of effect. The present trial is a proof-of-principle study developed to provide effect size estimates which may be used to inform the design of subsequent trials. Forty-eight patients aged 16-60 years with tuberous sclerosis who have an IQ >60 and a significant deficit (at least -2 SD) in one or more primary outcome measures will be randomly allocated in a ratio of 2:1 to receive everolimus or placebo, respectively. Participants will be assessed for eligibility and then be started on study medication 4 weeks later. They will then be randomised and receive placebo or everolimus for 24 weeks. Neurocognitive and safety assessments will be carried out at baseline and weeks 4, 12, 24 and 36. This study is designed to determine the effect sizes of treatment with everolimus or placebo for 6 months on specific neurocognitive functions-recall memory (verbal and non-verbal) and executive function-in people affected by TSC who have significant deficits in these functions. These data will provide new evidence to determine whether larger-scale trials are indicated and to explore suitable outcome measures and analytical methods for neurocognitive trial design. ISRCTN09739757 . Registered on 28 Dec 2011.
Does EEG-neurofeedback improve neurocognitive functioning in children with attention-deficit/hyperactivity disorder? A systematic review and a double-blind placebo-controlled study.

PubMed

Vollebregt, Madelon A; van Dongen-Boomsma, Martine; Buitelaar, Jan K; Slaats-Willemse, Dorine

2014-05-01

The number of placebo-controlled randomized studies relating to EEG-neurofeedback and its effect on neurocognition in attention-deficient/hyperactivity disorder (ADHD) is limited. For this reason, a double blind, randomized, placebo-controlled study was designed to assess the effects of EEG-neurofeedback on neurocognitive functioning in children with ADHD, and a systematic review on this topic was performed. Forty-one children (8-15 years) with a DSM-IV-TR diagnosis of ADHD were randomly allocated to EEG-neurofeedback or placebo-neurofeedback treatment for 30 sessions, twice a week. Children were stratified by age, electrophysiological state of arousal, and medication use. Neurocognitive tests of attention, executive functioning, working memory, and time processing were administered before and after treatment. Researchers, teachers, children and their parents, with the exception of the neurofeedback-therapist, were all blind to treatment assignment. Outcome measures were the changes in neurocognitive performance before and after treatment. www.clinicaltrials.gov: NCT00723684. No significant treatment effect on any of the neurocognitive variables was found. A systematic review of the current literature also did not find any systematic beneficial effect of EEG-neurofeedback on neurocognitive functioning. Overall, the existing literature and this study fail to support any benefit of neurofeedback on neurocognitive functioning in ADHD, possibly due to small sample sizes and other study limitations. © 2013 The Authors. Journal of Child Psychology and Psychiatry © 2013 Association for Child and Adolescent Mental Health.
Effect of L-methionine supplementation on plasma homocysteine and other free amino acids: a placebo-controlled double-blind cross-over study.

PubMed

Ditscheid, B; Fünfstück, R; Busch, M; Schubert, R; Gerth, J; Jahreis, G

2005-06-01

The essential amino acid L-methionine is a potential compound in the prophylaxis of recurrent or relapsing urinary tract infection due to acidification of urine. As an intermediate of L-methionine metabolism, homocysteine is formed. The objective was to study the metabolism of L-methionine and homocysteine, and to assess whether there are differences between patients with chronic urinary tract infection and healthy control subjects. A randomized placebo-controlled double-blind intervention study with cross-over design. Department of Nutritional Physiology, Institute of Nutrition in cooperation with the Department of Internal Medicine III, Friedrich Schiller University of Jena, Germany. Eight female patients with chronic urinary tract infection and 12 healthy women (controls). After a methionine-loading test, the volunteers received 500 mg L-methionine or a placebo three times daily for 4 weeks. Serum and urinary concentrations of methionine, homocysteine, cystathionine, cystine, serine, glycine and serum concentrations of vitamin B12, B6 and the state of folate. Homocysteine plasma concentrations increased from 9.4+/-2.7 micromol/l (patients) and 8.9+/-1.8 micromol/l (controls) in the placebo period to 11.2+/-4.1 micromol/l (P=0.031) and 11.0+/-2.3 micromol/l (P=0.000), respectively, during L-methionine supplementation. There were significant increases in serum methionine (53.6+/-22.0 micromol/l; P=0.003; n=20) and cystathionine (0.62+/-0.30 micromol/l; P=0.000; n=20) concentrations compared with the placebo period (33.0+/-12.0 and 0.30+/-0.10 micromol/l; n=20). Simultaneously, renal excretion of methionine and homocysteine was significantly higher during L-methionine intake. Despite an adequate vitamin status, the supplementation of 1500 mg of L-methionine daily significantly increases homocysteine plasma concentrations by an average of 2.0 micromol/l in patients and in control subjects. An optimal vitamin supplementation, especially with folate, might prevent such an increase.
Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels.

PubMed

Younger, Jarred; Noor, Noorulain; McCue, Rebecca; Mackey, Sean

2013-02-01

To determine whether low dosages (4.5 mg/day) of naltrexone reduce fibromyalgia severity as compared with the nonspecific effects of placebo. In this replication and extension study of a previous clinical trial, we tested the impact of low-dose naltrexone on daily self-reported pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality, and fatigue. Thirty-one women with fibromyalgia participated in the randomized, double-blind, placebo-controlled, counterbalanced, crossover study. During the active drug phase, participants received 4.5 mg of oral naltrexone daily. An intensive longitudinal design was used to measure daily levels of pain. When contrasting the condition end points, we observed a significantly greater reduction of baseline pain in those taking low-dose naltrexone than in those taking placebo (28.8% reduction versus 18.0% reduction; P = 0.016). Low-dose naltrexone was also associated with improved general satisfaction with life (P = 0.045) and with improved mood (P = 0.039), but not improved fatigue or sleep. Thirty-two percent of participants met the criteria for response (defined as a significant reduction in pain plus a significant reduction in either fatigue or sleep problems) during low-dose naltrexone therapy, as contrasted with an 11% response rate during placebo therapy (P = 0.05). Low-dose naltrexone was rated equally tolerable as placebo, and no serious side effects were reported. The preliminary evidence continues to show that low-dose naltrexone has a specific and clinically beneficial impact on fibromyalgia pain. The medication is widely available, inexpensive, safe, and well-tolerated. Parallel-group randomized controlled trials are needed to fully determine the efficacy of the medication. Copyright © 2013 by the American College of Rheumatology.
Psychiatric adverse events in randomized, double-blind, placebo-controlled clinical trials of varenicline: a pooled analysis.

PubMed

Tonstad, Serena; Davies, Simon; Flammer, Martina; Russ, Cristina; Hughes, John

2010-04-01

Varenicline (Chantix), Champix) has shown efficacy and tolerability as an aid to smoking cessation. In postmarketing surveillance, neuropsychiatric symptoms have appeared; however, their incidence and causal relationship to varenicline is not known. We assessed the incidence and relative risk (RR) of psychiatric disorders in ten randomized, double-blind, placebo-controlled trials of varenicline for smoking cessation. All smoking cessation phase II, III and IV randomized controlled clinical trials of varenicline versus placebo completed as of 31 December 2008, on file with the manufacturer (Pfizer, Inc.), were included. All studies have been published. All 3091 participants who received at least one dose of varenicline and all 2005 participants who received placebo were included in this analysis. These were men and women smoking > or =10 cigarettes/day, aged 18-75 years and without current psychiatric disease who received varenicline or placebo for 6 (one study), 12 (eight studies) or 52 (one study) weeks. Adverse events were recorded at each study visit and classified according to standard Medical Dictionary for Regulatory Activities (MedDRA) terms (version 11.0). The incidence of psychiatric disorders other than solely sleep disorders and disturbances was 10.7% in subjects treated with varenicline and 9.7% in subjects treated with placebo, with an RR of 1.02 (95% CI 0.86, 1.22). The RRs (95% CI) versus placebo of psychiatric adverse events with an incidence > or =1% in the varenicline group were 0.86 (0.67, 1.12) for anxiety disorders and symptoms, 0.76 (0.42, 1.39) for changes in physical activity, 1.42 (0.96, 2.08) for depressed mood disorders and disturbances, 1.21 (0.79, 1.83) for mood disorders and disturbances not elsewhere classified and 1.70 (1.50, 1.92) for sleep disorders and disturbances. There were no cases of suicidal ideation or behaviour in varenicline-treated subjects in the ten placebo-controlled studies analysed. However, among three trials that were excluded from the analysis because of their open-label design, two cases of suicidal ideation and one completed suicide were reported in patients who had been treated with varenicline. With the exception of sleep disorders and disturbances, there was no evidence of dose-responsivity. There was no significant increase in overall psychiatric disorders, other than sleep disorders and disturbances, in varenicline-treated subjects in this sample of smokers without current psychiatric disorders. Ongoing studies are testing the use of varenicline in psychiatric patients.
Do positive psychology exercises work? A replication of Seligman et al. (2005).

PubMed

Mongrain, Myriam; Anselmo-Matthews, Tracy

2012-04-01

The current work replicated a landmark study conducted by Seligman and colleagues (2005) that demonstrated the long-term benefits of positive psychology exercises (PPEs). In the original study, two exercises administered over 1 week ("Three Good Things" and "Using your Signature Strengths in a New Way") were found to have long-lasting effects on depression and happiness (Seligman, Steen, Park, & Peterson, 2005). These exercises were tested here using the same methodology except for improvements to the control condition, and the addition of a second "positive placebo" to isolate the common factor of accessing positive, self-relevant constructs. This component control design was meant to assess the effect of expectancies for success (expectancy control), as well the cognitive access of positive information about the self (positive placebo). Repeated measures analyses showed that the PPEs led to lasting increases in happiness, as did the positive placebo. The PPEs did not exceed the control condition in producing changes in depression over time. Brief, positive psychology interventions may boost happiness through a common factor involving the activation of positive, self-relevant information rather than through other specific mechanisms. Finally, the effects of PPEs on depression may be more modest than previously assumed. © 2012 Wiley Periodicals, Inc.
Safety of Flibanserin in Women Treated With Antidepressants: A Randomized, Placebo-Controlled Study.

PubMed

Clayton, Anita H; Croft, Harry A; Yuan, James; Brown, Louise; Kissling, Robert

2018-01-01

Depression is often associated with sexual dysfunction, and pharmacologic treatment for hypoactive sexual desire disorder can be considered in women receiving treatment for depression. To evaluate the safety of flibanserin in women treated for depression with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors. In this double-blinded, randomized, placebo-controlled trial, women with remitted or mild depression treated with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors who were not postmenopausal and were experiencing symptoms of hypoactive sexual desire disorder (ie, decreased sexual desire and related distress) received flibanserin 50 mg at bedtime (qhs) for 2 weeks and up-titrated to 100 mg qhs, flibanserin 100 mg qhs for the entire treatment period, or placebo for up to 12 weeks. Safety assessment included adverse events and symptoms of depression and anxiety. 73 patients were randomly assigned to flibanserin (both dose groups combined) and 38 to placebo. The sponsor terminated the study early at discontinuation of the development of flibanserin. Treatment duration was at least 8 weeks for 84.9% and 94.7% of patients in the flibanserin and placebo groups, respectively. The most common adverse events (incidence ≥ 2% in the flibanserin group and higher than that in the placebo group) included dry mouth (5.5% for flibanserin vs 2.6% for placebo), insomnia (5.5% vs 2.6%), back pain (4.1% vs 2.6%), and dizziness (4.1% vs 0.0%). There were no serious adverse events and no instances of suicidal ideation or behavior. The proportions of patients with symptom worsening in the flibanserin and placebo groups, respectively, were 6.9% and 21.6% for depression and 1.4% and 2.7% for anxiety. Remission of depression at study end point, as measured by the Quick Inventory of Depressive Symptomatology-Self Report, was experienced by 19.4% of flibanserin-treated patients and 10.8% of patients receiving placebo; remission of anxiety based on the Beck Anxiety Inventory was noted in 16.4% and 2.7% of patients, respectively. The results of this study support the safety of flibanserin in premenopausal women being treated with a serotonergic antidepressant. No increased risks were observed when adding flibanserin to a stable selective serotonin reuptake inhibitor or serotonin and norepinephrine reuptake inhibitor treatment regimen. This was a well-designed, randomized, placebo-controlled trial. The primary limitation was the early study discontinuation by the sponsor, which decreased the sample size and duration of treatment. In this small trial, flibanserin 100 mg qhs was generally safe and well tolerated in premenopausal women with mild or remitted depression taking a serotonergic antidepressant. Clayton AH, Croft HA, Yuan J, et al. Safety of Flibanserin in Women Treated With Antidepressants: A Randomized, Placebo-Controlled Study. J Sex Med 2018;15:43-51. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
Validating a human model for anxiety using startle potentiated by cue and context: the effects of alprazolam, pregabalin, and diphenhydramine

PubMed Central

Mol, N.; Kenemans, J. L.; Prinssen, E. P.; Niklson, I.; Xia-Chen, C.; Broeyer, F.; van Gerven, J.

2009-01-01

Background Fear-potentiated startle has been suggested as a translational model for evaluating efficacy of anxiolytic compounds in humans. Several known anxiolytic compounds have been tested as well as several putative anxiolytics. Because results of these studies have been equivocal, the aim of the present study was to examine another pharmacological permutation of the human potentiated startle model by comparing two anxiolytic agents to a non-anxiolytic sedative and placebo. Methods Twenty healthy volunteers participated in a double-blind, placebo-controlled, cross-over study with four sessions in which they received single doses of the anxiolytics alprazolam (1 mg) and pregabalin (200 mg), as well as diphenhydramine (50 mg) as a non-anxiolytic sedative control and placebo. The design included a cued shock condition that presumably evokes fear and an unpredictable shock context condition presumably evoking anxiety. Results None of the treatments reliably reduced either fear- or anxiety-potentiated startle. Alprazolam and diphenhydramine reduced overall baseline startle. Alprazolam was found to only affect contextual anxiety in a statistical significant way after two subjects who failed to show a contextual anxiety effect in the placebo condition were excluded from the analysis. Pregabalin did not significantly affect any of the physiological measures. Discussion The negative findings from this study are discussed in terms of methodological differences between designs and in variability of startle both between and within study participants. Conclusion Even though fear-potentiated startle may be used to translate preclinical evidence to human populations, methodological issues still hamper the application of this model to early screening of putative anxiolytic drugs. PMID:19415242
Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy.

PubMed

Adams, David; Suhr, Ole B; Dyck, Peter J; Litchy, William J; Leahy, Raina G; Chen, Jihong; Gollob, Jared; Coelho, Teresa

2017-09-11

Patisiran is an investigational RNA interference (RNAi) therapeutic in development for the treatment of hereditary ATTR (hATTR) amyloidosis, a progressive disease associated with significant disability, morbidity, and mortality. Here we describe the rationale and design of the Phase 3 APOLLO study, a randomized, double-blind, placebo-controlled, global study to evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy. Eligible patients are 18-85 years old with hATTR amyloidosis, investigator-estimated survival of ≥2 years, Neuropathy Impairment Score (NIS) of 5-130, and polyneuropathy disability score ≤IIIb. Patients are randomized 2:1 to receive either intravenous patisiran 0.3 mg/kg or placebo once every 3 weeks. The primary objective is to determine the efficacy of patisiran at 18 months based on the difference in the change in modified NIS+7 (a composite measure of motor strength, sensation, reflexes, nerve conduction, and autonomic function) between the patisiran and placebo groups. Secondary objectives are to evaluate the effect of patisiran on Norfolk-Diabetic Neuropathy quality of life questionnaire score, nutritional status (as evaluated by modified body mass index), motor function (as measured by NIS-weakness and timed 10-m walk test), and autonomic symptoms (as measured by the Composite Autonomic Symptom Score-31 questionnaire). Exploratory objectives include assessment of cardiac function and pathologic evaluation to assess nerve fiber innervation and amyloid burden. Safety of patisiran will be assessed throughout the study. APOLLO represents the largest randomized, Phase 3 study to date in patients with hATTR amyloidosis, with endpoints that capture the multisystemic nature of this disease. This trial is registered at clinicaltrials.gov ( NCT01960348 ); October 9, 2013.

Z-drug for schizophrenia: A systematic review and meta-analysis.

PubMed

Kishi, Taro; Inada, Ken; Matsui, Yuki; Iwata, Nakao

2017-10-01

No systematic reviews and meta-analyses on the use of Z-drug for schizophrenia are available. Randomized, placebo-controlled, or non-pharmacological intervention-controlled trials published before 03/20/2017 were retrieved from major healthcare databases and clinical trial registries. A meta-analysis including only randomized, placebo-controlled trials was performed. Efficacy outcomes were measured as improvement in overall schizophrenia symptoms, total sleep time, and wake after sleep onset. Safety/acceptability outcomes were discontinuation rate and individual adverse events. Four trials [1 alpidem placebo-controlled study (n=66), 2 eszopiclone placebo-controlled studies (n=60), and 1 eszopiclone, shallow needling-controlled study (n=96)] were identified. The meta-analysis showed no significant differences in any outcome between pooled Z-drug and placebo treatment groups. For individual studies, alpidem was superior to placebo in improving the overall schizophrenia symptoms. One of the eszopiclone studies showed that eszopiclone was superior to placebo in improving the Insomnia Severity Index scores. Another eszopiclone study showed that eszopiclone did not differ from shallow needling therapy in improving both schizophrenia- and insomnia-related symptoms. Although this study failed to show significant benefits for the use of Z-drug in the treatment of schizophrenia, it showed that short-term use of eszopiclone is an acceptable method for treating persistent insomnia among these patients. Copyright © 2017 Elsevier B.V. All rights reserved.
Placebo-Controlled Study of Pimozide Augmentation of Fluoxetine in Body Dysmorphic Disorder

PubMed Central

Phillips, Katharine A.

2006-01-01

Objective Although body dysmorphic disorder often responds to serotonin reuptake inhibitors (SRIs), most patients do not respond or respond only partially. However, placebo-controlled studies of augmentation of SRIs have not been done. Furthermore, although 40%–50% of patients are delusional, studies of antipsychotic medications have not been done. Method Twenty-eight patients with body dysmorphic disorder or its delusional variant participated in an 8-week, placebo-controlled, double-blind, parallel-group study of pimozide augmentation of fluoxetine. Results Pimozide was not more effective than placebo: two (18.2%) of 11 subjects responded to pimozide and three (17.6%) of 17 subjects responded to placebo. There was no significant effect of baseline delusionality on endpoint severity of body dysmorphic disorder. Delusionality did not decrease significantly more with pimozide than placebo. Conclusions Pimozide augmentation of fluoxetine treatment for body dysmorphic disorder was not more effective than placebo, even in more delusional patients. Further studies of augmentation for SRIs are needed. PMID:15677604
The impact of intranasal oxytocin on attention to social emotional stimuli in patients with anorexia nervosa: a double blind within-subject cross-over experiment.

PubMed

Kim, Youl-Ri; Kim, Chan-Hyung; Park, Jin Hong; Pyo, Jimin; Treasure, Janet

2014-01-01

Social factors may be of importance causally and act as maintenance factors in patients with anorexia nervosa. Oxytocin is a neuromodulatory hormone involved in social emotional processing associated with attentional processes. This study aimed to examine the impact of oxytocin on attentional processes to social faces representing anger, disgust, and happiness in patients with anorexia nervosa. A double-blind, placebo-controlled within-subject crossover design was used. Intranasal oxytocin or placebo followed by a visual probe detection task with faces depicting anger, disgust, and happiness was administered to 64 female subjects: 31 patients with anorexia nervosa and 33 control students. Attentional bias to the disgust stimuli was observed in both groups under the placebo condition. The attentional bias to disgust was reduced under the oxytocin condition (a moderate effect in the patient group). Avoidance of angry faces was observed in the patient group under the placebo condition and vigilance was observed in the healthy comparison group; both of these information processing responses were moderated by oxytocin producing an increase in vigilance in the patients. Happy/smiling faces did not elicit an attentional response in controls or the patients under either the placebo or oxytocin conditions. Oxytocin attenuated attentional vigilance to disgust in patients with anorexia nervosa and healthy controls. On the other hand, oxytocin changed the response to angry faces from avoidance to vigilance in patients but reduced vigilance to anger in healthy controls. We conclude that patients with anorexia nervosa appear to use different strategies/circuits to emotionally process anger from their healthy counterparts.
Intelligence and Persisting with Medication for Two Years: Analysis in a Randomised Controlled Trial

ERIC Educational Resources Information Center

Deary, Ian J.; Gale, Catharine R.; Stewart, Marlene C. W.; Fowkes, F. Gerald R.; Murray, Gordon D.; Batty, G. David; Price, Jacqueline F.

2009-01-01

The study examined whether verbal intelligence is associated with persisting to take medication for up to two years. The design is a prospective follow-up of compliance with taking medication in high-risk individuals participating in a randomised, placebo-controlled trial set in Central Scotland. Participants were 1993 people aged between 50 and…
Methods for the design of vasomotor symptom trials: the menopausal strategies: finding lasting answers to symptoms and health network.

PubMed

Newton, Katherine M; Carpenter, Janet S; Guthrie, Katherine A; Anderson, Garnet L; Caan, Bette; Cohen, Lee S; Ensrud, Kristine E; Freeman, Ellen W; Joffe, Hadine; Sternfeld, Barbara; Reed, Susan D; Sherman, Sheryl; Sammel, Mary D; Kroenke, Kurt; Larson, Joseph C; Lacroix, Andrea Z

2014-01-01

This report describes the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health network and methodological issues addressed in designing and implementing vasomotor symptom trials. Established in response to a National Institutes of Health request for applications, the network was charged with conducting rapid throughput randomized trials of novel and understudied available interventions postulated to alleviate vasomotor and other menopausal symptoms. Included are descriptions of and rationale for criteria used for interventions and study selection, common eligibility and exclusion criteria, common primary and secondary outcome measures, consideration of placebo response, establishment of a biorepository, trial duration, screening and recruitment, statistical methods, and quality control. All trial designs are presented, including the following: (1) a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the effectiveness of the selective serotonin reuptake inhibitor escitalopram in reducing vasomotor symptom frequency and severity; (2) a two-by-three factorial design trial to test three different interventions (yoga, exercise, and ω-3 supplementation) for the improvement of vasomotor symptom frequency and bother; and (3) a three-arm comparative efficacy trial of the serotonin-norepinephrine reuptake inhibitor venlafaxine and low-dose oral estradiol versus placebo for reducing vasomotor symptom frequency. The network's structure and governance are also discussed. The methods used in and the lessons learned from the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health trials are shared to encourage and support the conduct of similar trials and to encourage collaborations with other researchers.
Appetite and Gut Hormones Response to a Putative α-Glucosidase Inhibitor, Salacia Chinensis, in Overweight/Obese Adults: A Double Blind Randomized Controlled Trial.

PubMed

Hao, Lihong; Schlussel, Yvette; Fieselmann, Krista; Schneider, Stephen H; Shapses, Sue A

2017-08-12

Animal studies indicate Salacia reduces body weight, possibly due to its α-glucosidase inhibitor (α-GI) properties, but this has not been examined previously. In this study, a randomized, placebo-controlled, three-way cross-over design was used to evaluate whether Salacia Chinensis (SC) reduces appetite in healthy overweight/obese individuals (body mass index 28.8 ±3.6 kg/m²; 32 ± 12 years). Forty-eight participants were fasted overnight and consumed a dose of SC (300 or 500 mg) or placebo with a fixed breakfast meal at each visit. Appetite sensations, glycemic indices and gastrointestinal peptides were measured. Results indicated that SC had no effect on postprandial appetite. However, in women, hunger was reduced by SC compared to placebo at multiple time points (300 mg; p < 0.05), but not in men. Area under the curve (AUC) for serum glucose, insulin and amylin was attenuated with SC compared to placebo ( p < 0.05). Glucagon like peptide-1 had two peaks after the meal, but the AUC did not differ between groups. The AUC of peak areas for peptide YY and ghrelin were greater for SC than placebo ( p < 0.05). These findings indicate that Salacia decreases glycemic indices supporting its role as an α-GI, and affects certain gastrointestinal peptides suggesting it may be an appetite modulator.
Effects of Ginger on Serum Lipids and Lipoproteins in Peritoneal Dialysis Patients: A Randomized Controlled Trial.

PubMed

Tabibi, Hadi; Imani, Hossein; Atabak, Shahnaz; Najafi, Iraj; Hedayati, Mehdi; Rahmani, Leila

2016-01-01

♦ In peritoneal dialysis (PD) patients, one of the major risk factors for cardiovascular disease is lipid abnormalities. This study was designed to investigate the effects of ginger supplementation on serum lipids and lipoproteins in PD patients. ♦ In this randomized, double-blind, placebo-controlled trial, 36 PD patients were randomly assigned to either the ginger or the placebo group. The patients in the ginger group received 1,000 mg ginger daily for 10 weeks, while the placebo group received corresponding placebos. At baseline and at the end of week 10, 7 mL of blood were obtained from each patient after a 12- to 14-hour fast, and serum concentrations of triglyceride, total cholesterol, low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), and lipoprotein (a) [Lp (a)] were measured. ♦ Serum triglyceride concentration decreased significantly up to 15% in the ginger group at the end of week 10 compared with baseline (p < 0.01), and the reduction was significant in comparison with the placebo group (p < 0.05). There were no significant differences between the 2 groups in mean changes of serum total cholesterol, LDL-C, HDL-C, and Lp (a). ♦ This study indicates that daily administration of 1,000 mg ginger reduces serum triglyceride concentration, which is a risk factor for cardiovascular disease, in PD patients. Copyright © 2016 International Society for Peritoneal Dialysis.
Erlotinib, erlotinib-sulindac vs. placebo: a randomized, double-blind, placebo-controlled window trial in operable head and neck cancer

PubMed Central

Gross, Neil D.; Bauman, Julie E.; Gooding, William E.; Denq, William; Thomas, Sufi M.; Wang, Lin; Chiosea, Simion; Hood, Brian L.; Flint, Melanie S.; Sun, Mai; Conrads, Thomas P.; Ferris, Robert L.; Johnson, Jonas T.; Kim, Seungwon; Argiris, Athanassios; Wirth, Lori; Nikiforova, Marina N.; Siegfried, Jill M.; Grandis, Jennifer R.

2014-01-01

Purpose The epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) pathways are upregulated in head and neck squamous cell carcinoma (HNSCC). Preclinical models indicate synergistic anti-tumor activity from dual blockade. We conducted a randomized, double-blind, placebo-controlled window trial of erlotinib, an EGFR inhibitor; erlotinib plus sulindac, a non-selective COX inhibitor, vs. placebo. Experimental Design Patients with untreated, operable Stage II-IVb HNSCC were randomized 5:5:3 to erlotinib, erlotinib-sulindac, or placebo. Tumor specimens were collected before and after 7-14 days of treatment. The primary endpoint was change in Ki-67 proliferation index. We hypothesized an ordering effect in Ki-67 reduction: erlotinib-sulindac > erlotinib > placebo. We evaluated tissue microarrays by immunohistochemistry for pharmacodynamic modulation of EGFR and COX-2 signaling intermediates. Results From 2005-2009, 47 patients were randomized for the target 39 evaluable patients. Thirty-four tumor pairs were of sufficient quality to assess biomarker modulation. Ki-67 was significantly decreased by erlotinib or erlotinib-sulindac (omnibus comparison, two-sided Kruskal-Wallis, p=0.04). Wilcoxon pairwise contrasts confirmed greater Ki-67 effect in both erlotinib groups (erlotinib-sulindac vs. placebo p=0.043; erlobinib vs. placebo, p=0.027). There was a significant trend in ordering of Ki-67 reduction: erlotinib-sulindac > erlotinib > placebo (two-sided exact Jonckheere-Terpstra, p =0.0185). Low baseline pSrc correlated with greater Ki-67 reduction (R2 = .312, p = 0.024). Conclusions Brief treatment with erlotinib significantly decreased proliferation in HNSCC, with additive effect from sulindac. Efficacy studies of dual EGFR-COX inhibition are justified. pSrc is a potential resistance biomarker for anti-EGFR therapy, and warrants investigation as a molecular target. PMID:24727329
Effect of Tribulus terrestris, ginger, saffron, and Cinnamomum on menopausal symptoms: a randomised, placebo-controlled clinical trial.

PubMed

Taavoni, Simin; Ekbatani, Neda Nazem; Haghani, Hamid

2017-03-01

Menopausal symptoms experienced by women vary widely, and while many women transition through menopause with manageable symptoms, others experience severe symptoms, which may impair their quality of life. The purpose of this study was to determine the effect of Tribulus terrestris , ginger, saffron, and Cinnamomum on menopausal symptoms. A randomised, triple-blind, controlled trial design was used for this study. The participants were 80 postmenopausal women aged 50-60 years. A demographic data form and the Menopause Rating Scale were used to collect data. The women were randomly divided into two groups, each of which received either an Aphrodit capsule or a placebo twice a day for four weeks. The two bottles looked exactly the same, so that the investigator and the participants were not aware of the contents of the bottles. Each Aphrodit capsule contained 40 mg of Tribulus terrestris , 12.27 mg of Zingiber officinale , 3 mg of Crocus sativus extract, and 11 mg of Cinnamomum zeylanicum , while the placebo capsules contained 50 mg of starch. Descriptive and inferential statistics were used to analyse the data. A statistically significant change was reported in the menopausal symptoms of the intervention group compared with the placebo group. The results of the study demonstrate that the Aphrodit capsule was effective in reducing menopausal symptoms.
Efficacy and safety of rasagiline as an adjunct to levodopa treatment in Chinese patients with Parkinson's disease: a randomized, double-blind, parallel-controlled, multi-centre trial.

PubMed

Zhang, Lina; Zhang, Zhiqin; Chen, Yangmei; Qin, Xinyue; Zhou, Huadong; Zhang, Chaodong; Sun, Hongbin; Tang, Ronghua; Zheng, Jinou; Yi, Lin; Deng, Liying; Li, Jinfang

2013-08-01

Rasagiline mesylate is a highly potent, selective and irreversible monoamine oxidase type B (MAOB) inhibitor and is effective as monotherapy or adjunct to levodopa for patients with Parkinson's disease (PD). However, few studies have evaluated the efficacy and safety of rasagiline in the Chinese population. This study was designed to investigate the safety and efficacy of rasagiline as adjunctive therapy to levodopa treatment in Chinese PD patients. This was a randomized, double-blind, placebo-controlled, parallel-group, multi-centre trial conducted over a 12-wk period that enrolled 244 PD patients with motor fluctuations. Participants were randomly assigned to oral rasagiline mesylate (1 mg) or placebo, once daily. Altogether, 219 patients completed the trial. Rasagiline showed significantly greater efficacy compared with placebo. During the treatment period, the primary efficacy variable--mean adjusted total daily off time--decreased from baseline by 1.7 h in patients treated with 1.0 mg/d rasagiline compared to placebo (p < 0.05). Scores using the Unified Parkinson's Disease Rating Scale also improved during rasagiline treatment. Rasagiline was well tolerated. This study demonstrated that rasagiline mesylate is effective and well tolerated as an adjunct to levodopa treatment in Chinese PD patients with fluctuations.
Therapeutic efficacy of traditional Chinese medicine, Shen-Mai San, in cancer patients undergoing chemotherapy or radiotherapy: study protocol for a randomized, double-blind, placebo-controlled trial

PubMed Central

2012-01-01

Background Cancer is one of the major health issues worldwide. An increasing number of cancer patients are offered treatment with surgery, chemotherapy and radiotherapy. Traditional Chinese medicine (TCM) is one of the most common complementary therapies offered to cancer patients in Taiwan. We designed a randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy of TCM in patients with cancer. Methods/design In this study, inclusion criteria are postoperative patients with histologically confirmed cancer within 3 years who are undergoing chemotherapy or radiotherapy, more than 18 years old, have given signed informed consent, have the ability to read Chinese, and the ability for oral intake. Exclusion criteria include being pregnant, breast feeding, having completed chemotherapy or radiotherapy, brain metastasis with Eastern Cooperative Oncology Group (ECOG) performance status of two to four, delusion or hallucinations, acute infection, and have received medications under other clinical trials. The patients were separated into an intervention group (Shen-Mai-San, SMS) and a placebo group for four weeks using a randomized, double-blind procedure. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire (QOL-C30) was used to evaluate the quality of life. General data, hemoglobin (Hb), hematocrit (Hct), glutamic-oxalacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), blood urea nitrogen (BUN), creatinine, carcinoembryonic antigen (CEA), TCM diagnosis data and heart rate variability (HRV) were also recorded. These data were collected at baseline, two weeks and four weeks after receiving medication. The patients were prescribed granules which contained therapeutic medicines or placebo. Paired-T test was used for statistical analysis. Discussion Shen-Mai-San is composed of processed Ginseng radis, Liriope spicata, and Schizandrae fructus. It was found to be effective for treating cancer-related fatigue and had anti-fatigue activity. In TCM theory, SMS has a synergistic effect for qi and yin deficiency and has the ability to prevent fatigue. The symptoms of qi and yin deficiency are similar to chemotherapy- or radiotherapy-induced side effects. In order to evaluate the efficacy of SMS on cancer treatment, we designed a randomized, double-blind, placebo-controlled trial. Trial registration This study is registered to Clinical Trails.gov NCT01580358 PMID:23206440
Using comparative effectiveness design to improve the generalizability of bipolar treatment trials data: contrasting LiTMUS baseline data with pre-existing placebo controlled trials.

PubMed

Friedman, E S; Calabrese, J R; Ketter, T A; Leon, A C; Thase, M E; Bowden, C L; Sylvia, L G; Ostracher, M J; Severe, J; Iosifescu, D V; Nierenberg, A A; Reilly-Harrington, N A

2014-01-01

Efficacy-based double-blind placebo controlled trials were conducted to establish efficacy and safety for FDA approval. Such designs allowed and encouraged the use of exclusion criteria to improve assay sensitivity and internal validity. The LiTMUS trial increased the representation of real-world individuals with bipolar disorder despite the acknowledgment that this compromises assay sensitivity. To maximize generalizability, LiTMUS used broad inclusion and narrow exclusion criteria: participants experiencing mood symptoms of sufficient intensity (at least with a CGI-BP ≥ 3) that would warrant a change in treatment, and that lithium treatment would be a reasonable therapeutic option if they were randomized to it. At baseline demographic, illness, clinical, and treatment characteristics were collected. The LiTMUS study design and baseline sociodemographic data were compared to previous efficacy studies. As compared to the previous bipolar disorder efficacy studies, LiTMUS participants were of similar age, gender, weight and illness severity; however LiTMUS participants were more racially and ethnically representative of the general population, had a greater number of mood episodes in the past 12 months, more Axis I/II comorbidity, a greater number of prior suicide attempts, and higher functional capacity. LiTMUS was a comparative effectiveness trial that had broad inclusion and minimal exclusion criteria that produced a more representative sample comprised of real-world participants. This design enables the results of the LiTMUS study to be a more representative of real world pharmacotherapuetic outcomes. Limitations include possible selection bias, paucity of sociodemographic data in efficacy trials, and lack of a placebo. Copyright © 2013. Published by Elsevier B.V.
Antipyretic effect of ibuprofen in Gabonese children with uncomplicated falciparum malaria: a randomized, double-blind, placebo-controlled trial

PubMed Central

Matsiégui, Pierre-Blaise; Missinou, Michel A; Necek, Magdalena; Mavoungou, Elie; Issifou, Saadou; Lell, Bertrand; Kremsner, Peter G

2008-01-01

Background Antipyretic drugs are widely used in children with fever, though there is a controversy about the benefit of reducing fever in children with malaria. In order to assess the effect of ibuprofen on fever compared to placebo in children with uncomplicated Plasmodium falciparum malaria in Gabon, a randomized double blind placebo controlled trial, was designed. Methods Fifty children between two and seven years of age with uncomplicated malaria were included in the study. For the treatment of fever, all patients "received" mechanical treatment when the temperature rose above 37.5°C. In addition to the mechanical treatment, continuous fanning and cooling blanket, patients were assigned randomly to receive ibuprofen (7 mg/kg body weight, every eight hours) or placebo. Results The fever clearance time using a fever threshold of 37.5°C was similar in children receiving ibuprofen compared to those receiving placebo. The difference was also not statistically significant using a fever threshold of 37.8°C or 38.0°C. However, the fever time and the area under the fever curve were significantly smaller in the ibuprofen group compared to the placebo group. Conclusion Ibuprofen is effective in reducing the time with fever. The effect on fever clearance is less obvious and depends on definition of the fever threshold. Trial registration The trial registration number is: NCT00167713 PMID:18503714
Individualized Homeopathic Treatment and Fluoxetine for Moderate to Severe Depression in Peri- and Postmenopausal Women (HOMDEP-MENOP Study): A Randomized, Double-Dummy, Double-Blind, Placebo-Controlled Trial

PubMed Central

Macías-Cortés, Emma del Carmen; Llanes-González, Lidia; Aguilar-Faisal, Leopoldo; Asbun-Bojalil, Juan

2015-01-01

Background Perimenopausal period refers to the interval when women's menstrual cycles become irregular and is characterized by an increased risk of depression. Use of homeopathy to treat depression is widespread but there is a lack of clinical trials about its efficacy in depression in peri- and postmenopausal women. The aim of this study was to assess efficacy and safety of individualized homeopathic treatment versus placebo and fluoxetine versus placebo in peri- and postmenopausal women with moderate to severe depression. Methods/Design A randomized, placebo-controlled, double-blind, double-dummy, superiority, three-arm trial with a 6 week follow-up study was conducted. The study was performed in a public research hospital in Mexico City in the outpatient service of homeopathy. One hundred thirty-three peri- and postmenopausal women diagnosed with major depression according to DSM-IV (moderate to severe intensity) were included. The outcomes were: change in the mean total score among groups on the 17-item Hamilton Rating Scale for Depression, Beck Depression Inventory and Greene Scale, after 6 weeks of treatment, response and remission rates, and safety. Efficacy data were analyzed in the intention-to-treat population (ANOVA with Bonferroni post-hoc test). Results After a 6-week treatment, homeopathic group was more effective than placebo by 5 points in Hamilton Scale. Response rate was 54.5% and remission rate, 15.9%. There was a significant difference among groups in response rate definition only, but not in remission rate. Fluoxetine-placebo difference was 3.2 points. No differences were observed among groups in the Beck Depression Inventory. Homeopathic group was superior to placebo in Greene Climacteric Scale (8.6 points). Fluoxetine was not different from placebo in Greene Climacteric Scale. Conclusion Homeopathy and fluoxetine are effective and safe antidepressants for climacteric women. Homeopathy and fluoxetine were significantly different from placebo in response definition only. Homeopathy, but not fluoxetine, improves menopausal symptoms scored by Greene Climacteric Scale. Trial Registration ClinicalTrials.gov NCT01635218 Protocol Publication http://www.trialsjournal.com/content/14/1/105. PMID:25768800
Effects of Low Dose Metformin in Adolescents with Type I Diabetes Mellitus: A Randomized, Double-Blinded Placebo-Controlled Study

PubMed Central

Nadeau, Kristen; Chow, Kelsey; Alam, Lyla; Lindquist, Kara; Cambell, Sarah; McFann, Kim; Klingensmith, Georgeanna; Walravens, Phillipe

2014-01-01

Background Insulin resistance increases during adolescence in those with type 1 diabetes (T1DM), complicating glycemic control and potentially increasing cardiovascular disease (CVD) risk. Metformin, typically used in type 2 diabetes (T2DM), is a possible adjunct therapy in T1DM to help improve glycemic control and insulin sensitivity. Objective We hypothesized that metformin would improve metabolic parameters in adolescents with T1DM. Design, Setting, and Participants This randomized, double-blinded, placebo-controlled trial included 74 pubertal adolescents (ages 13–20 years) with T1DM. Participants were randomized to receive either metformin or placebo for six months. HbA1c, insulin dose, waist circumference, BMI, and blood pressure were measured at baseline, 3 and 6 months, with fasting lipids measured at baseline and 6 months. Results Total daily insulin dose, BMI Z-score and waist circumference significantly decreased at 3 and 6 months compared to baseline within the metformin group, even among normal-weight participants. In placebo group, total insulin dose and systolic blood pressure increased significantly at 3 months and total insulin dose increased significantly at 6 months. No significant change was observed in HbA1c at any time point between metformin and placebo groups or within either group. Conclusions Low-dose metformin likely improves BMI as well as insulin sensitivity in T1DM adolescents, as indicated by a decrease in total daily insulin dose. The decrease in waist circumference indicates that fat distribution is also likely impacted by metformin in T1DM. Further studies with higher metformin doses and more detailed measurements are needed to confirm these results, their underlying mechanisms, and potential impact on CVD in T1DM youth. PMID:24698216
Specific music therapy techniques in the treatment of primary headache disorders in adolescents: a randomized attention-placebo-controlled trial.

PubMed

Koenig, Julian; Oelkers-Ax, Rieke; Kaess, Michael; Parzer, Peter; Lenzen, Christoph; Hillecke, Thomas Karl; Resch, Franz

2013-10-01

Migraine and tension-type headache have a high prevalence in children and adolescents. In addition to common pharmacologic and nonpharmacologic interventions, music therapy has been shown to be efficient in the prophylaxis of pediatric migraine. This study aimed to assess the efficacy of specific music therapy techniques in the treatment of adolescents with primary headache (tension-type headache and migraine). A prospective, randomized, attention-placebo-controlled parallel group trial was conducted. Following an 8-week baseline, patients were randomized to either music therapy (n = 40) or a rhythm pedagogic program (n = 38) designed as an "attention placebo" over 6 sessions within 8 weeks. Reduction of both headache frequency and intensity after treatment (8-week postline) as well as 6 months after treatment were taken as the efficacy variables. Treatments were delivered in equal dose and frequency by the same group of therapists. Data analysis of subjects completing the protocol showed that neither treatment was superior to the other at any point of measurement (posttreatment and follow-up). Intention-to-treat analysis revealed no impact of drop-out on these results. Both groups showed a moderate mean reduction of headache frequency posttreatment of about 20%, but only small numbers of responders (50% frequency reduction). Follow-up data showed no significant deteriorations or improvements. This article presents a randomized placebo-controlled trial on music therapy in the treatment of adolescents with frequent primary headache. Music therapy is not superior to an attention placebo within this study. These results draw attention to the need of providing adequate controls within therapeutic trials in the treatment of pain. Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.
HT1001, a proprietary North American ginseng extract, improves working memory in schizophrenia: a double-blind, placebo-controlled study.

PubMed

Chen, Eric Y H; Hui, Christy L M

2012-08-01

Evidence suggests that HT1001™, a proprietary North American ginseng extract containing known levels of active ginsenosides, may improve cognitive function. Importantly, individuals with schizophrenia show marked deficits in working memory, which are believed to be predictive of functional outcome in this population. The present study aimed to characterize the effect of HT1001 on working memory in a group of stable individuals with schizophrenia. In a double-blind, placebo-controlled study design, a total of 64 individuals satisfying DSM-IV criteria for schizophrenia were randomly assigned to receive either HT100 or placebo for 4 weeks. Verbal working memory and visual working memory were assessed at baseline and again at the end of the treatment phase using the Letter-Number Span Test and Visual Pattern Test, respectively. Symptoms and medication side effects were also measured at baseline and post-treatment. Visual working memory was significantly improved in the HT1001 group, but not in the placebo group. Furthermore, extrapyramidal symptoms were significantly reduced after 4 weeks treatment with HT1001, whereas no difference in extrapyramidal effects was observed in the placebo group. These results provide a solid foundation for the further investigation of HT1001 as an adjunct therapy in schizophrenia, as an improvement in working memory and a reduction in medication-related side effects has considerable potential to improve functional outcome in this population. Copyright © 2011 John Wiley & Sons, Ltd.
N08C9 (Alliance): A Phase 3 Randomized Study of Sulfasalazine Versus Placebo in the Prevention of Acute Diarrhea in Patients Receiving Pelvic Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miller, Robert C., E-mail: miller.robert@mayo.edu; Petereit, Daniel G.; Sloan, Jeff A.

Purpose: To provide confirmatory evidence on the use of sulfasalazine to reduce enteritis during pelvic radiation therapy (RT), following 2 prior single-institution trials suggestive that benefit existed. Methods and Materials: A multi-institution, randomized, double-blind, placebo-controlled phase 3 trial was designed to assess the efficacy of sulfasalazine versus placebo in the treatment of RT-related enteritis during RT including the posterior pelvis (45.0-53.5 Gy) and conducted through a multicenter national cooperative research alliance. Patients received 1000 mg of sulfasalazine or placebo orally twice daily during and for 4 weeks after RT. The primary endpoint was maximum severity of diarrhea (Common Terminology Criteria for Adverse Events versionmore » 4.0). Toxicity and bowel function were assessed by providers through a self-administered bowel function questionnaire taken weekly during RT and for 6 weeks afterward. Results: Eighty-seven patients were enrolled in the trial between April 29, 2011, and May 13, 2013, with evenly distributed baseline factors. At the time of a planned interim toxicity analysis, more patients with grade ≥3 diarrhea received sulfasalazine than received placebo (29% vs 11%, P=.04). A futility analysis showed that trial continuation would be unlikely to yield a positive result, and a research board recommended halting study treatment. Final analysis of the primary endpoint showed no significant difference in maximum diarrhea severity between the sulfasalazine and placebo arms (P=.41). Conclusions: Sulfasalazine does not reduce enteritis during pelvic RT and may be associated with a higher risk of adverse events than placebo. This trial illustrates the importance of confirmatory phase 3 trials in the evaluation of symptom-control agents.« less
Treatment for premenstrual syndrome with Vitex agnus castus: A prospective, randomized, multi-center placebo controlled study in China.

PubMed

He, Zhong; Chen, Rong; Zhou, Yingfang; Geng, Li; Zhang, Zhenyu; Chen, Shuling; Yao, Yanjun; Lu, Junli; Lin, Shouqing

2009-05-20

To investigate the efficacy and safety of VAC BNO 1095 extract in Chinese women suffering from moderate to severe premenstrual syndrome (PMS). Prospective, double-blind, placebo controlled, parallel-group, multi-center clinical trial design was employed. After screening and preparation phase lasting three cycles, Eligible patients were randomly assigned into treatment or placebo groups and had treatment with VAC extract or placebo for up to three cycles. Efficacy was assessed using the Chinese version PMS-diary (PMSD) and PMTS. Two hundred and seventeen women were eligible to enter the treatment phase (TP) and were randomly assigned into the treatment group (108) or the placebo group (109), 208 provided the efficacy data (treatment 104, placebo 104), and 202 completed the treatment phase (treatment 101, placebo 101). The mean total PMSD score decreased from 29.23 at baseline (0 cycle) to 6.41 at the termination (3rd cycle) for the treatment group and from 28.14 at baseline (0 cycle) to 12.64 at the termination (3rd cycle) for the placebo group. The total PMSD score of 3rd cycle was significantly lower than the baseline in both groups (p<0.0001). The difference in the mean scores from the baseline to the 3rd cycle in the treatment group (22.71+/-10.33) was significantly lower than the difference in the placebo group (15.50+/-12.94, p<0.0001). Results of PMTS were similar, the total scores for PMTS were significantly lower between the two groups (p<0.01) and within each group (p<0.01). The score was decreased from 26.17+/-4.79 to 9.92+/-9.01 for the treatment group, and from 27.10+/-4.76 to 14.59+/-10.69 for the placebo group. A placebo effect of 50% was found in the present study. No serious adverse event (SAE) occurred in both groups. Vitex agnus castus (VAC BNO 1095 corresponding to 40mg herbal drug) is a safe, well tolerated and effective drug of the treatment for Chinese women with the moderate to severe PMS.
Prebiotic supplementation improves appetite control in children with overweight and obesity: a randomized controlled trial.

PubMed

Hume, Megan P; Nicolucci, Alissa C; Reimer, Raylene A

2017-04-01

Background: Prebiotics have been shown to improve satiety in adults with overweight and obesity; however, studies in children are limited. Objective: We examined the effects of prebiotic supplementation on appetite control and energy intake in children with overweight and obesity. Design: This study was a randomized, double-blind, placebo-controlled trial. Forty-two boys and girls, ages 7-12 y, with a body mass index (BMI) of ≥85th percentile were randomly assigned to 8 g oligofructose-enriched inulin/d or placebo (maltodextrin) for 16 wk. Objective measures of appetite included energy intake at an ad libitum breakfast buffet, 3-d food records, and fasting satiety hormone concentrations. Subjective appetite ratings were obtained from visual analog scales before and after the breakfast. Children's Eating Behavior Questionnaires were also completed by caregivers. Results: Compared with placebo, prebiotic intake resulted in significantly higher feelings of fullness ( P = 0.04) and lower prospective food consumption ( P = 0.03) at the breakfast buffet at 16 wk compared with baseline. Compared with placebo, prebiotic supplementation significantly reduced energy intake at the week 16 breakfast buffet in 11- and 12-y-olds ( P = 0.04) but not in 7- to 10-y-olds. Fasting adiponectin ( P = 0.04) and ghrelin ( P = 0.03) increased at 16 wk with the prebiotic compared with placebo. In intent-to-treat analysis, there was a trend for prebiotic supplementation to reduce BMI z score to a greater extent than placebo (-3.4%; P = 0.09) and a significant -3.8% reduction in per-protocol analysis ( P = 0.043). Conclusions: Independent of other lifestyle changes, prebiotic supplementation in children with overweight and obesity improved subjective appetite ratings. This translated into reduced energy intake in a breakfast buffet in older but not in younger children. This simple dietary change has the potential to help with appetite regulation in children with obesity. This trial was registered at clinicaltrials.gov as NCT02125955. © 2017 American Society for Nutrition.

Systemic hydrocortisone to prevent bronchopulmonary dysplasia in preterm infants (the SToP-BPD study); a multicenter randomized placebo controlled trial

PubMed Central

2011-01-01

Background Randomized controlled trials have shown that treatment of chronically ventilated preterm infants after the first week of life with dexamethasone reduces the incidence of the combined outcome death or bronchopulmonary dysplasia (BPD). However, there are concerns that dexamethasone may increase the risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. So far no randomized controlled trial has investigated its efficacy when administered after the first week of life to ventilated preterm infants. Methods/Design The SToP-BPD trial is a randomized double blind placebo controlled multicenter study including 400 very low birth weight infants (gestational age < 30 weeks and/or birth weight < 1250 grams), who are ventilator dependent at a postnatal age of 7 - 14 days. Hydrocortisone (cumulative dose 72.5 mg/kg) or placebo is administered during a 22 day tapering schedule. Primary outcome measure is the combined outcome mortality or BPD at 36 weeks postmenstrual age. Secondary outcomes are short term effects on the pulmonary condition, adverse effects during hospitalization, and long-term neurodevelopmental sequelae assessed at 2 years corrected gestational age. Analysis will be on an intention to treat basis. Discussion This trial will determine the efficacy and safety of postnatal hydrocortisone administration at a moderately early postnatal onset compared to placebo for the reduction of the combined outcome mortality and BPD at 36 weeks postmenstrual age in ventilator dependent preterm infants. Trial registration number Netherlands Trial Register (NTR): NTR2768 PMID:22070744
Manual-guided psychosocial treatment. A new virtual requirement for pharmacotherapy trials?

PubMed

Carroll, K M

1997-10-01

The conduct of randomized clinical trials to evaluate the efficacy of pharmacotherapies for mental disorders is guided by research standards (at a high level of rigor) that govern most design elements, including randomization of subjects, use of placebo controls, formulation and dosage of the therapeutic agent, and monitoring of serum levels. In contrast, no such widely accepted guidelines are recognized for standardization of an essential, if unacknowledged, element of all such studies: the concomitant provision of at least a minimal form of psychosocial treatment. Standardized provision of psychosocial treatments in pharmacotherapy trials will foster replicability of findings and address several common problems (e.g., attrition, medication noncompliance, reduction of error variance, and ethical issues associated with placebo controls). Careful selection and standardization of the psychosocial context in which medications are delivered will improve the validity, precision, and power of pharmacotherapy efficacy research, and should be considered a virtual requirement in research design.
HIV prevention trial design in an era of effective pre-exposure prophylaxis.

PubMed

Cutrell, Amy; Donnell, Deborah; Dunn, David T; Glidden, David V; Grobler, Anneke; Hanscom, Brett; Stancil, Britt S; Meyer, R Daniel; Wang, Ronnie; Cuffe, Robert L

2017-01-01

Pre-exposure prophylaxis (PrEP) has demonstrated remarkable effectiveness protecting at-risk individuals from HIV-1 infection. Despite this record of effectiveness, concerns persist about the diminished protective effect observed in women compared with men and the influence of adherence and risk behaviors on effectiveness in targeted subpopulations. Furthermore, the high prophylactic efficacy of the first PrEP agent, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), presents challenges for demonstrating the efficacy of new candidates. Trials of new agents would typically require use of non-inferiority (NI) designs in which acceptable efficacy for an experimental agent is determined using pre-defined margins based on the efficacy of the proven active comparator (i.e. TDF/FTC) in placebo-controlled trials. Setting NI margins is a critical step in designing registrational studies. Under- or over-estimation of the margin can call into question the utility of the study in the registration package. The dependence on previous placebo-controlled trials introduces the same issues as external/historical controls. These issues will need to be addressed using trial design features such as re-estimated NI margins, enrichment strategies, run-in periods, crossover between study arms, and adaptive re-estimation of sample sizes. These measures and other innovations can help to ensure that new PrEP agents are made available to the public using stringent standards of evidence.
Improvement in health-related quality of life after therapy with omeprazole in patients with coronary artery disease and recurrent angina-like chest pain. A double-blind, placebo-controlled trial of the SF-36 survey

PubMed Central

2011-01-01

Background Many patients with coronary artery disease (CAD) have overlapping gastroenterological causes of recurrent chest pain, mainly due to gastroesophageal reflux (GER) and aspirin-induced gastrointestinal tract damage. These symptoms can be alleviated by proton pump inhibitors (PPIs). The study addressed whether omeprazole treatment also affects general health-related quality of life (HRQL) in patients with CAD. Study 48 patients with more than 50% narrowing of the coronary arteries on angiography without clinically overt gastrointestinal symptoms were studied. In a double-blind, placebo-controlled, cross-over study design, patients were randomized to take omeprazole 20 mg bid or a placebo for two weeks, and then crossed over to the other study arm. The SF-36 questionnaire was completed before treatment and again after two weeks of therapy. Results Patients treated with omeprazole in comparison to the subjects taking the placebo had significantly greater values for the SF-36 survey (which relates to both physical and mental health), as well as for bodily pain, general health perception, and physical health. In comparison to the baseline values, therapy with omeprazole led to a significant increase in the three summarized health components: total SF-36; physical and mental health; and in the following detailed health concept scores: physical functioning, limitations due to physical health problems, bodily pain and emotional well-being. Conclusions A double dose of omeprazole improved the general HRQL in patients with CAD without severe gastrointestinal symptoms more effectively than the placebo. PMID:21939510
Effect of a 2% topical chamomile application for treating burning mouth syndrome: a controlled clinical trial.

PubMed

Valenzuela, Sara; Pons-Fuster, Alvaro; López-Jornet, Pia

2016-08-01

The treatments for burning mouth syndrome (BMS) proposed to date have been varied but have only achieved limited efficacy. Chamomile has analgesic and anti-inflammatory properties. The aim of this study was to evaluate the efficacy of topical applications of 2% chamomile gel in comparison with a placebo for the treatment of BMS. The study was designed as a prospective randomized placebo-controlled double-blind monocentric study. A total of 62 patients with idiopathic BMS were divided into two groups: Group A received applications of a 2% chamomile gel, and Group B (placebo) were administered a placebo; both treatments were applied twice daily for 1 month. Three variables were evaluated at base line, 15 and 30 days: pain (assessed using a visual analogue scale [VAS]), xerostomia severity (Xerostomia Inventory), and oral quality of life (assessed by means of the Oral Health Impact Profile-14). A total of 57 patients completed the study. Pain, xerostomia, and quality of life underwent improvements with statistical significance at 15 and 30 days in both groups (P < 0.001). But when the two groups were compared, differences in VAS pain were not significant (P = 0.847), nor were xerostomia severity (P = 0.536), or oral quality of life (P = 0.076). The chamomile gel product was well tolerated. As treatment with chamomile and the placebo produced similar outcomes, the efficacy of 2% chamomile gel for treating BMS appears questionable. However, further studies with larger patient samples are needed to confirm this. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
The influence of ginger (Zingiber officinale) on human sperm quality and DNA fragmentation: A double-blind randomized clinical trial

PubMed Central

Hosseini, Jalil; Mardi Mamaghani, Azar; Hosseinifar, Hani; Sadighi Gilani, Mohammad Ali; Dadkhah, Farid; Sepidarkish, Mahdi

2016-01-01

Background: Although the effectiveness of ginger as an antioxidant agent has been exploited, little human research has been conducted on its activity on male reproductive functions. Objective: This study was designed to investigate the effects of ginger (Zingiber officinale) on sperm DNA fragmentation (SDF) in infertile men. Materials and Methods: This randomized double-blind, placebo-controlled trial with a 1:1 allocation was performed on 100 infertility treatment candidates who were admitted to Royan Institute for Reproductive Biomedicine, Tehran, Iran. Patients were randomly assigned to receive one of two treatments: ginger and placebo. Patients were given a 3-month oral treatment (members received capsules containing 250 mg of ginger powder twice a day in ginger and a placebo in other group). Before and after treatment, standardized semen samples were obtained to determine sperm concentration, motility, and SDF according to World Health Organization. Results: There was no significant difference between two groups regarding SDF at baseline (53.48. 95%CI: 37.95-69.02) in cases and (56.75, 95%CI: 40.01-73.5) in controls. The average positive percentage of SDF in patients receiving ginger (17.77, 95%CI: 6.16-29.39) was lower compared with placebo (40.54, 95%CI: 23.94-57.13) after three month of treatment (p=0.02). In multivariate analysis, SDF was significantly lower in patients receiving ginger compared with placebo (mean difference: 3.21, 95%CI: 0.78-5.63, p=0.009). There were no significant differences between two groups regarding to semen parameters. Conclusion: The present study has demonstrated that ginger in a controlled study of efficacy was effective in decreasing SDF in infertile men. PMID:27679829
Concordance of Results from Randomized and Observational Analyses within the Same Study: A Re-Analysis of the Women's Health Initiative Limited-Access Dataset.

PubMed

Bolland, Mark J; Grey, Andrew; Gamble, Greg D; Reid, Ian R

2015-01-01

Observational studies (OS) and randomized controlled trials (RCTs) often report discordant results. In the Women's Health Initiative Calcium and Vitamin D (WHI CaD) RCT, women were randomly assigned to CaD or placebo, but were permitted to use personal calcium and vitamin D supplements, creating a unique opportunity to compare results from randomized and observational analyses within the same study. WHI CaD was a 7-year RCT of 1g calcium/400IU vitamin D daily in 36,282 post-menopausal women. We assessed the effects of CaD on cardiovascular events, death, cancer and fracture in a randomized design- comparing CaD with placebo in 43% of women not using personal calcium or vitamin D supplements- and in a observational design- comparing women in the placebo group (44%) using personal calcium and vitamin D supplements with non-users. Incidence was assessed using Cox proportional hazards models, and results from the two study designs deemed concordant if the absolute difference in hazard ratios was ≤0.15. We also compared results from WHI CaD to those from the WHI Observational Study(WHI OS), which used similar methodology for analyses and recruited from the same population. In WHI CaD, for myocardial infarction and stroke, results of unadjusted and 6/8 covariate-controlled observational analyses (age-adjusted, multivariate-adjusted, propensity-adjusted, propensity-matched) were not concordant with the randomized design results. For death, hip and total fracture, colorectal and total cancer, unadjusted and covariate-controlled observational results were concordant with randomized results. For breast cancer, unadjusted and age-adjusted observational results were concordant with randomized results, but only 1/3 other covariate-controlled observational results were concordant with randomized results. Multivariate-adjusted results from WHI OS were concordant with randomized WHI CaD results for only 4/8 endpoints. Results of randomized analyses in WHI CaD were concordant with observational analyses for 5/8 endpoints in WHI CaD and 4/8 endpoints in WHI OS.
Concordance of Results from Randomized and Observational Analyses within the Same Study: A Re-Analysis of the Women’s Health Initiative Limited-Access Dataset

PubMed Central

Bolland, Mark J.; Grey, Andrew; Gamble, Greg D.; Reid, Ian R.

2015-01-01

Background Observational studies (OS) and randomized controlled trials (RCTs) often report discordant results. In the Women’s Health Initiative Calcium and Vitamin D (WHI CaD) RCT, women were randomly assigned to CaD or placebo, but were permitted to use personal calcium and vitamin D supplements, creating a unique opportunity to compare results from randomized and observational analyses within the same study. Methods WHI CaD was a 7-year RCT of 1g calcium/400IU vitamin D daily in 36,282 post-menopausal women. We assessed the effects of CaD on cardiovascular events, death, cancer and fracture in a randomized design- comparing CaD with placebo in 43% of women not using personal calcium or vitamin D supplements- and in a observational design- comparing women in the placebo group (44%) using personal calcium and vitamin D supplements with non-users. Incidence was assessed using Cox proportional hazards models, and results from the two study designs deemed concordant if the absolute difference in hazard ratios was ≤0.15. We also compared results from WHI CaD to those from the WHI Observational Study(WHI OS), which used similar methodology for analyses and recruited from the same population. Results In WHI CaD, for myocardial infarction and stroke, results of unadjusted and 6/8 covariate-controlled observational analyses (age-adjusted, multivariate-adjusted, propensity-adjusted, propensity-matched) were not concordant with the randomized design results. For death, hip and total fracture, colorectal and total cancer, unadjusted and covariate-controlled observational results were concordant with randomized results. For breast cancer, unadjusted and age-adjusted observational results were concordant with randomized results, but only 1/3 other covariate-controlled observational results were concordant with randomized results. Multivariate-adjusted results from WHI OS were concordant with randomized WHI CaD results for only 4/8 endpoints. Conclusions Results of randomized analyses in WHI CaD were concordant with observational analyses for 5/8 endpoints in WHI CaD and 4/8 endpoints in WHI OS. PMID:26440516
Antibiotics in third molar extraction; are they really necessary: A non-inferiority randomized controlled trial

PubMed Central

Arora, Ankit; Roychoudhury, Ajoy; Bhutia, Ongkila; Pandey, Sandeep; Singh, Surender; Das, Bimal K.

2014-01-01

Introduction: Antibiotic resistance is now a serious problem, although it was not so only a few years ago. The need of the hour is to give clear evidence of the efficacy of antibiotic use, or lack thereof, to the surgeon for a procedure as common as mandibular third molar surgery. Aim: This study aimed to evaluate whether postoperative combined amoxicillin and clavulanic acid in mandibular third molar extraction is effective in preventing inflammatory complications. Study and Design: The study was structured as a prospective randomized double-blind placebo-controlled clinical trial. Materials and Methods: A study was designed wherein the 96 units (two bilaterally similar impacted mandibular third molars per head in 48 patients) were randomly assigned to two treatment groups (Group I and Group II). Each patient served as his/her own control. Each patient received 625 mg of combined amoxicillin and clavulanic acid 1 h before surgery. In the case of third molars belonging to Group I, 625 mg of combined amoxicillin and clavulanic acid TDS was continued for 3 days; in Group II, placebo in similar-looking packs was continued for 3 days. The patients were evaluated on the third and seventh postoperative days for signs of clinical infection and for microbial load evaluation. Statistical Analysis: The data between the two groups were statistically analyzed by the two-tailed Fisher's exact test, with a 95% confidence interval. Results: The difference was not statistically significant between the test group and the control group with regard to erythema, dehiscence, swelling, pain, trismus, and infection based on microbial load. The data were statistically significant for alveolar osteitis, with the occurrence of alveolar osteitis (14.58%) in the placebo group. Conclusion: Postoperative antibiotics are recommended only for patients undergoing contaminated, long-duration surgery. PMID:25937728
Is hydroxychloroquine effective in treating primary Sjogren's syndrome: a systematic review and meta-analysis.

PubMed

Wang, Shi-Qin; Zhang, Li-Wei; Wei, Pan; Hua, Hong

2017-05-12

To systematically review and assess the efficacy and safety of hydroxychloroquine (HCQ) for treating primary Sjogren's syndrome (pSS). Five electronic databases (Pubmed, EMBASE, Web of science, Ovid, Cochrane Library) were searched for randomized controlled trials and retrospective or prospective studies published in English that reported the effect of HCQ on pSS. The subjective symptoms (sicca symptoms, fatigue and pain) and the objective indexes (erythrocyte sedimentation rate and Schirmer test) were assessed as main outcome measures. A meta-analysis and descriptive study on the efficacy and safety of HCQ were conducted. The estimate of the effect of HCQ treatment was expressed as a proportion together with 95% confidence interval, and plotted on a forest plot. Four trials with totals of 215 SS patients, including two randomized controlled trials, one double blind crossover trial and one retrospective open-label study, were analyzed in this review. For dry mouth and dry eyes, the effectiveness of HCQ treatment was essentially the same as placebo treatment. For fatigue, the effectiveness of HCQ was lower than placebo. The efficacy of HCQ in treating pain associated with pSS was superior to that of the placebo. There was no significant difference between HCQ-treated groups and controls in terms of Schirmer test results, but HCQ could reduce the erythrocyte sedimentation rate compare with placebo. A descriptive safety assessment showed that gastrointestinal adverse effects were the most common adverse effects associated with HCQ. This systematic review showed that there is no significant difference between HCQ and placebo in the treatment of dry mouth and dry eye in pSS. Well-designed, randomized, controlled trials are needed to provide higher-quality evidence to confirm our findings, and future studies should focus on some other index or extraglandular measures, such as cutaneous manifestations, to further explore the therapeutic effect of HCQ in pSS.
Demographic variables, design characteristics, and effect sizes of randomized, placebo-controlled, monotherapy trials of major depressive disorder and bipolar depression.

PubMed

Papakostas, George I; Martinson, Max A; Fava, Maurizio; Iovieno, Nadia

2016-05-01

The aim of this work is to compare the efficacy of pharmacologic agents for the treatment of major depressive disorder (MDD) and bipolar depression. MEDLINE/PubMed databases were searched for studies published in English between January 1980 and September 2014 by cross-referencing the search term placebo with each of the antidepressant agents identified and with bipolar. The search was supplemented by manual bibliography review. We selected double-blind, randomized, placebo-controlled trials of antidepressant monotherapies for the treatment of MDD and of oral drug monotherapies for the treatment of bipolar depression. 196 trials in MDD and 19 trials in bipolar depression were found eligible for inclusion in our analysis. Data were extracted by one of the authors and checked for accuracy by a second one. Data extracted included year of publication, number of patients randomized, probability of receiving placebo, duration of the trial, baseline symptom severity, dosing schedule, study completion rates, and clinical response rates. Response rates for drug versus placebo in trials of MDD and bipolar depression were 52.7% versus 37.5% and 54.7% versus 40.5%, respectively. The random-effects meta-analysis indicated that drug therapy was more effective than placebo in both MDD (risk ratio for response = 1.373; P < .001) and bipolar depression (risk ratio = 1.257; P < .001) trials. The meta-regression analysis suggested a statistically significant difference in the risk ratio of responding to drug versus placebo between MDD and bipolar depression trials in favor of MDD (P = .008). Although a statistically significantly greater treatment effect size was noted in MDD relative to bipolar depression studies, the absolute magnitude of the difference was numerically small. Therefore, the present study suggests no clinically significant differences in the overall short-term efficacy of pharmacologic monotherapies for MDD and bipolar depression. © Copyright 2016 Physicians Postgraduate Press, Inc.
A Randomized, Placebo-Controlled Trial of Latrepirdine in Huntington Disease

PubMed Central

Kieburtz, Karl; McDermott, Michael P.; Voss, Tiffini S.; Corey-Bloom, Jody; Deuel, Lisa M.; Dorsey, E. Ray; Factor, Stewart; Geschwind, Michael D.; Hodgeman, Karen; Kayson, Elise; Noonberg, Sarah; Pourfar, Michael; Rabinowitz, Karen; Ravina, Bernard; Sanchez-Ramos, Juan; Seely, Lynn; Walker, Francis; Feigin, Andrew

2014-01-01

Objectives To evaluate the safety and tolerability of latrepirdine in Huntington disease (HD) and explore its effects on cognition, behavior, and motor symptoms. Design Double-blind, randomized, placebo-controlled trial. Setting Multicenter outpatient trial. Participants Ninety-one participants with mild to moderate HD enrolled at 17 US and UK centers from July 18, 2007, through July 16, 2008. Intervention Latrepirdine, 20 mg 3 times daily (n=46), or matching placebo (n=45) for a 90-day treatment period. Main Outcome Measures The primary outcome variable was tolerability, defined as the ability to complete the study at the assigned drug dosage. Secondary outcome variables included score changes from baseline to day 90 on the Unified Huntington's Disease Rating Scale (UHDRS), the Mini-Mental State Examination (MMSE), and the Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-cog). Results Latrepirdine was well tolerated (87% of the patients given latrepirdine completed the study vs 82% in the placebo group), and adverse event rates were comparable in the 2 groups (70% in the latrepirdine group and 80% in the placebo group). Treatment with latrepirdine resulted in improved mean MMSE scores compared with stable performance in the placebo group (treatment effect, 0.97 points; 95% confidence interval, 0.10-1.85; P=.03). No significant treatment effects were seen on the UHDRS or the ADAS-cog. Conclusions Short-term administration of latrepirdine is well tolerated in patients with HD and may have a beneficial effect on cognition. Further investigation of latrepirdine is warranted in this population with HD. PMID:20142523
Safety and Efficacy of Black Cohosh and Red Clover for the Management of Vasomotor Symptoms: A Randomized Controlled Trial

PubMed Central

Geller, Stacie E.; Shulman, Lee P.; van Breemen, Richard B.; Banuvar, Suzanne; Zhou, Ying; Epstein, Geena; Hedayat, Samad; Nikolic, Dejan; Krause, Elizabeth C.; Piersen, Colleen E.; Bolton, Judy L.; Pauli, Guido F.; Farnsworth, Norman R.

2009-01-01

Objective The aim of this study was to evaluate the safety and efficacy of black cohosh and red clover compared with placebo for the relief of menopausal vasomotor symptoms. Design This study was a randomized, four-arm, double-blind clinical trial of standardized black cohosh, red clover, placebo and 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (CEE/MPA; n = 89). Primary outcome measures were reduction in vasomotor symptoms (hot flashes and night sweats) by black cohosh and red clover compared with placebo; secondary outcomes included safety evaluation, reduction of somatic symptoms, relief of sexual dysfunction, and overall improvement in quality of life. Results Reductions in number of vasomotor symptoms after 12-month intervention were as follows: black cohosh (34%), red clover (57%), placebo (63%), and CEE/MPA (94%), with only CEE/MPA differing significantly from placebo. Black cohosh and red clover did not significantly reduce the frequency of vasomotor symptoms as compared with placebo. Secondary measures indicated that both botanicals were safe as administered. In general, there were no improvements in other menopausal symptoms. Conclusions Compared with placebo, black cohosh and red clover did not reduce the number of vasomotor symptoms. Safety monitoring indicated that chemically and biologically standardized extracts of black cohosh and red clover were safe during daily administration for 12 months. PMID:19609225
Budesonide foam induces remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis.

PubMed

Sandborn, William J; Bosworth, Brian; Zakko, Salam; Gordon, Glenn L; Clemmons, David R; Golden, Pamela L; Rolleri, Robert L; Yu, Jing; Barrett, Andrew C; Bortey, Enoch; Paterson, Craig; Forbes, William P

2015-04-01

Budesonide is a high-potency, second-generation corticosteroid designed to minimize systemic adverse consequences of conventional corticosteroids. We performed 2 randomized, phase 3 trials to evaluate the ability of budesonide rectal foam, formulated to optimize retention and provide uniform delivery of budesonide to the rectum and distal colon, to induce remission in patients with ulcerative proctitis or ulcerative proctosigmoiditis. Two identically designed, randomized, double-blind, placebo-controlled trials evaluated the efficacy of budesonide foam for induction of remission in 546 patients with mild to moderate ulcerative proctitis or ulcerative proctosigmoiditis who received budesonide foam 2 mg/25 mL twice daily for 2 weeks, then once daily for 4 weeks, or placebo. Remission at week 6 occurred significantly more frequently among patients receiving budesonide foam than placebo (Study 1: 38.3% vs 25.8%; P = .0324; Study 2: 44.0% vs 22.4%; P < .0001). A significantly greater percentage of patients receiving budesonide foam vs placebo achieved rectal bleeding resolution (Study 1: 46.6% vs 28.0%; P = .0022; Study 2: 50.0% vs 28.6%; P = .0002) and endoscopic improvement (Study 1: 55.6% vs 43.2%; P = .0486; Study 2: 56.0% vs 36.7%; P = .0013) at week 6. Most adverse events occurred at similar frequencies between groups, although events related to changes in cortisol values were reported more frequently with budesonide foam. There were no cases of clinically symptomatic adrenal insufficiency. Budesonide rectal foam was well tolerated and more efficacious than placebo in inducing remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis. ClinicalTrials.gov ID: NCT01008410 and NCT01008423. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
Ondansetron, granisetron, and dexamethasone compared for the prevention of postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy : A randomized placebo-controlled study.

PubMed

Erhan, Yamac; Erhan, Elvan; Aydede, Hasan; Yumus, Okan; Yentur, Alp

2008-06-01

Laparoscopic cholecystectomies are associated with an appreciably high rate of postoperative nausea and vomiting (PONV). This study was designed to compare the effectiveness of ondansetron, granisetron, and dexamethasone for the prevention of PONV in patients after laparoscopic cholecystectomy. A total of 80 American Society of Anesthesiologists (ASA) physical class I-II patients scheduled for laparoscopic cholecystectomy were included in this randomized, double blind, placebo-controlled study. All patients received a similar standardized anesthesia and operative treatment. Patients were randomly divided into four groups (n = 20 each). Group 1, consisting of control patients, received 0.9% NaCl; group 2 patients received ondansetron 4 mg i.v.; group 3 patients received granisetron 3 mg i.v.; and group 4 patients received dexamethasone 8 mg i.v., all before the induction of anesthesia. Both nausea and vomiting were assessed during the first 24 h after the procedure. The total incidence of PONV was 75% with placebo, 35% with ondansetron, 30% with granisetron, and 25% with dexamethasone. The incidence of PONV was significantly less frequent in groups receiving antiemetics (p < 0.05). The differences between dexamethasone, granisetron, and ondansetron were not significant. Prophylactic dexamethasone 8 mg i.v. significantly reduced the incidence of PONV in patients undergoing laparoscopic cholecystectomy. Dexamethasone 8 mg was as effective as ondansetron 4 mg and granisetron 3 mg, and it was more effective than placebo.
Evidence for Neuroplastic Compensation in the Cerebral Cortex of Persons with Depressive Illness

PubMed Central

Bansal, Ravi; Hellerstein, David J.; Peterson, Bradley S.

2017-01-01

We yoked anatomical brain Magnetic Resonance Imaging to a randomized, double-blind, placebo-controlled trial (RCT) of antidepressant medication for 10-week’s duration in patients with dysthymia. The RCT study design mitigated ascertainment bias by randomizing patients to receive either duloxetine or placebo, and it supported true causal inferences about treatment effects on the brain by controlling treatment assignment experimentally. We acquired 121 anatomical scans: at baseline and endpoint in 41 patients, and once in 39 healthy controls. At baseline, patients had diffusely thicker cortices than did healthy participants, and patients who had thicker cortices had proportionately less severe symptoms. During the trial, symptoms improved significantly more in medication- compared with placebo-treated patients; concurrently, thicknesses in medication-treated patients declined toward values in healthy controls, but they increased slightly, away from control values, in placebo-treated patients. Changes in symptom severity during the trial mediated the association of treatment assignment with the change in thickness, suggesting that the beneficial effects of medication on symptom severity were at least partially responsible for normalizing cortical thickness. Together our findings suggest that baseline cortical hypertrophy in medication-free patients likely represented a compensatory, neuroplastic response that attenuated symptom severity. Medication then reduced symptoms and lessened the need for compensation, thereby normalizing thickness. This is to the best of our knowledge the first study to report within an RCT a differential change in cortical morphology during medication treatment for depressive illness and the first to provide within an RCT in vivo evidence for the presence of neuroanatomical plasticity in humans. PMID:28265119
The effect of conscious control on handwriting in children with attention deficit hyperactivity disorder.

PubMed

Tucha, Oliver; Lange, Klaus W

2005-08-01

Two experiments were performed regarding the effect of conscious control on handwriting fluency in healthy adults and ADHD children. First, 26 healthy students were asked to write a sentence under different conditions. The results indicate that automated handwriting movements are independent from visual feedback. Second, the writing performance of 12 children with ADHD was examined on their usual medication with methylphenidate and under placebo. In comparison to placebo, medication with methylphenidate resulted in a reduced fluency of handwriting. Automated handwriting movements could be elicited in children with ADHD on medication. The results suggest that both visual and mental control of handwriting movements affect the automation of handwriting movements. Furthermore, a simple training procedure was designed and performed in a case study of a boy with ADHD.
The role of the dopaminergic system in mood, motivation and cognition in Parkinson's disease: a double blind randomized placebo-controlled experimental challenge with pramipexole and methylphenidate.

PubMed

Drijgers, Rosa L; Verhey, Frans R J; Tissingh, Gerrit; van Domburg, Peter H M F; Aalten, Pauline; Leentjens, Albert F G

2012-09-15

In Parkinson's disease (PD) reduced dopaminergic activity in the mesocorticolimbic pathway is implied in the pathophysiology of several non-motor symptoms related to mood, motivation and cognition. Insight in the pathophysiology of these syndromes may pave the way for more rational treatments. In a double-blind, randomized, placebo controlled, crossover design with three arms, we studied the effects of a direct dopaminergic challenge with the dopamine 2 receptor agonist pramipexole, an indirect challenge with the dopamine reuptake inhibitor methylphenidate, and placebo on measures of mood, motivation and cognition in 23 agonist-naïve PD patients and 23 healthy controls. Acute challenge with pramipexole had a negative effect on mood and fatigue in both patients and controls. In addition, challenge with pramipexole led to increased anger, fatigue, vigor and tension in healthy control subjects, but not in PD patients. Challenge with methylphenidate had a positive effect on anhedonia and vigor in PD patients. Due to its side effects after a single administration, pramipexole is probably less suitable for acute challenge studies. The acute effects of a methylphenidate challenge on anhedonia and vigor in PD patients make this drug an interesting choice for further studies of the treatment of mood and motivational disorders in this population. Copyright © 2012 Elsevier B.V. All rights reserved.
Therapeutic touch and postoperative pain: a Rogerian research study.

PubMed

Meehan, T C

1993-01-01

This article details Meehan's research study concerning the conceptualization of therapeutic touch within Rogers' science of unitary human beings and an investigation of the effects of therapeutic touch on pain experience in postoperative patients. Using a single trial, single-blind, three-group design, 108 postoperative patients were randomly assigned to receive one of the following: therapeutic touch, a placebo control intervention which mimicked therapeutic touch, or the standard intervention of a narcotic analgesic. Using a visual analogue scale, pain was measured before and one hour following intervention. The hypothesis, that therapeutic touch would significantly decrease postoperative pain compared to the placebo control intervention, was not supported. Secondary analyses suggest that therapeutic touch may decrease patients' need for analgesic medication. Implications for further research and practice are suggested.
Residual effects of zopiclone 7.5 mg on highway driving performance in insomnia patients and healthy controls: a placebo controlled crossover study.

PubMed

Leufkens, T R M; Ramaekers, J G; de Weerd, A W; Riedel, W J; Vermeeren, A

2014-07-01

Residual effects of hypnotics on driving performance have been mainly determined in studies using a standardized driving test with healthy good sleepers. Responses to effects may differ, however, between insomniacs and healthy volunteers due to the underlying sleep disorder. In addition, a majority of insomniacs uses hypnotics chronically resulting in the development of tolerance to impairing effects. Impaired driving performance in healthy volunteers may then be an overestimation of the actual effects in insomniacs. The present study aims to compare the residual effects of zopiclone 7.5 mg on on-the-road driving performance of 16 middle-aged insomniacs chronically using hypnotics (chronic users), 16 middle-aged insomniacs not or infrequently using hypnotics (infrequent users), and 16 healthy, age matched, good sleepers (controls). The study was conducted according to a 3 × 2 double-blind, placebo controlled crossover design, with three groups and two treatment conditions. Treatments were single oral doses of zopiclone 7.5 mg and placebo administered at bedtime (2330 hours). Between 10 and 11 h after administration subjects performed a standardized highway driving test. Zopiclone 7.5 mg significantly impaired on-the-road driving performance in both insomnia groups and healthy controls. The magnitude of impairment was significantly less in the chronic users group as compared with the controls. The smaller magnitude of effects suggests that investigating residual effects of hypnotics in healthy volunteers may yield a minor overestimation of the actual effects in insomnia patients.

Does Dapagliflozin Affect Energy Intake and Appetite? A Randomized, Controlled Exploratory Study in Healthy Subjects.

PubMed

Bertran, Elizabeth; Berlie, Helen D; Nixon, Aaron; Jaber, Linda

2018-05-03

The primary aims of this study were to assess the effects of dapagliflozin versus placebo on energy intake and appetite ratings in healthy individuals. This was a randomized, single-blind, placebo-controlled, 2-period crossover study. In each period, healthy individuals received either dapagliflozin or placebo for 2 weeks. On assessment days, participants were asked to consume a standard preload breakfast. Appetite ratings were measured with 100-mm visual analog scales immediately before and during the 4.25-hour period after breakfast. Energy intake was measured at an ad libitum lunch. Energy intake and appetite responses were assessed at the end of each 2-week treatment period by mixed-design analysis of variance. Eighteen individuals completed all assessments (44% female; mean age, 22.8 years; 44% Caucasian; mean BMI, 25.2 kg/m 2 ). There was no difference in energy intake on dapagliflozin compared to placebo (mean difference, -19.8 kcal; P = .516). Mean differences in prebreakfast desire for salty foods (11.3 mm, P = .094) and postbreakfast desire for sweet foods (8.1 mm, P = .054) trended higher with dapagliflozin relative to placebo. Our data do not support an effect of dapagliflozin on energy intake or appetite measures in young, healthy subjects. Although not statistically significant, the size of the mean differences in prebreakfast desire for salty foods and postbreakfast desire for sweet foods on dapagliflozin were larger than placebo and reflect the drug's natriuretic and glucuretic effects. These findings should be further evaluated in patients with type 2 diabetes. © 2018, The American College of Clinical Pharmacology.
Exposure to candesartan during the first trimester of pregnancy in type 1 diabetes: experience from the placebo-controlled DIabetic REtinopathy Candesartan Trials.

PubMed

Porta, M; Hainer, J W; Jansson, S-O; Malm, A; Bilous, R; Chaturvedi, N; Fuller, J H; Klein, R; Orchard, T; Parving, H-H; Sjølie, A-K

2011-06-01

The teratogenic consequences of angiotensin-converting enzyme inhibitors angiotensin receptor blockers (ARBs) during the second and third trimesters of pregnancy are well described. However, the consequences of exposure during the first trimester are unclear, especially in diabetes. We report the experience from DIRECT (DIabetic REtinopathy and Candesartan Trials), three placebo-controlled studies designed to examine the effects of an ARB, candesartan, on diabetic retinopathy. Over 4 years or longer, 178 normotensive women with type 1 diabetes (86 randomised to candesartan, 32 mg once daily, and 92 assigned to placebo) became pregnant (total of 208 pregnancies). More than half of patients were exposed to candesartan or placebo prior to or in early pregnancy, but all discontinued it at an estimated 8 weeks from the last menstrual period. Full-term pregnancies (51 vs 50), premature deliveries (21 vs 27), spontaneous miscarriages (12 vs 15), elective terminations (15 vs 14) and other outcomes (1 vs 2) were similar in the candesartan and placebo groups. There were two stillbirths and two 'sick babies' in the candesartan group, and one stillbirth, eight 'sick babies' and one cardiac malformation in the placebo group. The risk for fetal consequences of ARBs in type 1 diabetes may not be high if exposure is clearly limited to the first trimester. Long-term studies in fertile women can be conducted with ARBs during pregnancy, provided investigators diligently stop their administration upon planning or detection of pregnancy. ClinicalTrials.gov DIRECT-Prevent 1 NCT00252733; DIRECT-Protect 1 NCT00252720; DIRECT-Protect 2 NCT00252694. The study was funded jointly by AstraZeneca and Takeda.
An Herbal Drug, Gongjin-dan, Ameliorates Acute Fatigue Caused by Short-Term Sleep-Deprivation: A Randomized, Double-Blinded, Placebo-Controlled, Crossover Clinical Trial.

PubMed

Son, Mi Ju; Im, Hwi-Jin; Ku, Boncho; Lee, Jun-Hwan; Jung, So Young; Kim, Young-Eun; Lee, Sung Bae; Kim, Jun Young; Son, Chang-Gue

2018-01-01

Introduction: Gongjin-dan (GJD) is an herbal drug commonly used in Korea and China to combat fatigue, but there are only few clinical studies on its effectiveness and experimental studies on its mechanism of action, and no randomized controlled trial of GJD on the efficacy and mechanism of action has been reported. Here, we performed an exploratory study to evaluate both questions regarding GJD use in humans. Methods: A randomized, double-blinded, placebo-controlled, crossover clinical trial was conducted in the Republic of Korea. Healthy male participants were recruited and randomly allocated to groups receiving GJD-placebo or placebo-GJD in sequence. Fatigue was artificially induced by sleep deprivation for 2 nights. The primary outcome was a change in serum cortisol level; levels of biomarkers for stress hormones as well as oxidative stress and immunologic factors were also assessed, and questionnaires on fatigue and sleep quality were conducted. Results: Twelve and 11 participants were assigned to the GJD-placebo and placebo-GJD groups, respectively. Of all 23 participants, depending on crossover design, we analyzed a total of 20 participants for GJD, and 21 for placebo. An increase in serum cortisol appeared to be attenuated by GJD administration ( p = 0.25), but the effect was not statistically significant; a similar pattern was observed in salivary cortisol levels ( p = 0.14). Overall, GJD showed a tendency to reduce fatigue according to the Brief Fatigue Inventory (BFI, p = 0.07) and the Fatigue Severity Scale (FSS, p = 0.13) questionnaires. BFI and FSS scores in the first stage (before the crossover), however, were significantly improved (BFI, p = 0.02; FSS, p = 0.05) after GJD treatment (relative to placebo). GJD also seemed to improve sleep quality as assessed by the Leeds Sleep Evaluation Questionnaire ( p = 0.06), with a significant improvement specifically in the condition "Getting To Sleep" ( p = 0.02). Five participants experienced minor adverse events, but no adverse events were specific to the GJD administration period. Conclusions: This trial produced the first clinical evidence that GJD might have anti-fatigue properties, especially under sleep deprivation; however, the investigation of cortisol-mediated mechanisms requires further larger-scale studies in the future. World Health Organization International Clinical Trials Registry Platform KCT0001681 (http://apps.who.int/trialsearch/Trial2.aspx?TrialID=KCT0001681).
Active Albuterol or Placebo, Sham Acupuncture, or No Intervention in Asthma

PubMed Central

Wechsler, Michael E.; Kelley, John M.; Boyd, Ingrid O.E.; Dutile, Stefanie; Marigowda, Gautham; Kirsch, Irving; Israel, Elliot; Kaptchuk, Ted J.

2011-01-01

BACKGROUND In prospective experimental studies in patients with asthma, it is difficult to determine whether responses to placebo differ from the natural course of physiological changes that occur without any intervention. We compared the effects of a bronchodilator, two placebo interventions, and no intervention on outcomes in patients with asthma. METHODS In a double-blind, crossover pilot study, we randomly assigned 46 patients with asthma to active treatment with an albuterol inhaler, a placebo inhaler, sham acupuncture, or no intervention. Using a block design, we administered one each of these four interventions in random order during four sequential visits (3 to 7 days apart); this procedure was repeated in two more blocks of visits (for a total of 12 visits by each patient). At each visit, spirometry was performed repeatedly over a period of 2 hours. Maximum forced expiratory volume in 1 second (FEV1) was measured, and patients’ self-reported improvement ratings were recorded. RESULTS Among the 39 patients who completed the study, albuterol resulted in a 20% increase in FEV1, as compared with approximately 7% with each of the other three interventions (P<0.001). However, patients’ reports of improvement after the intervention did not differ significantly for the albuterol inhaler (50% improvement), placebo inhaler (45%), or sham acupuncture (46%), but the subjective improvement with all three of these interventions was significantly greater than that with the no-intervention control (21%) (P<0.001). CONCLUSIONS Although albuterol, but not the two placebo interventions, improved FEV1 in these patients with asthma, albuterol provided no incremental benefit with respect to the self-reported outcomes. Placebo effects can be clinically meaningful and can rival the effects of active medication in patients with asthma. However, from a clinical-management and research-design perspective, patient self-reports can be unreliable. An assessment of untreated responses in asthma may be essential in evaluating patient-reported outcomes. (Funded by the National Center for Complementary and Alternative Medicine; ClinicalTrials.gov number, NCT01143688.) PMID:21751905
Active albuterol or placebo, sham acupuncture, or no intervention in asthma.

PubMed

Wechsler, Michael E; Kelley, John M; Boyd, Ingrid O E; Dutile, Stefanie; Marigowda, Gautham; Kirsch, Irving; Israel, Elliot; Kaptchuk, Ted J

2011-07-14

In prospective experimental studies in patients with asthma, it is difficult to determine whether responses to placebo differ from the natural course of physiological changes that occur without any intervention. We compared the effects of a bronchodilator, two placebo interventions, and no intervention on outcomes in patients with asthma. In a double-blind, crossover pilot study, we randomly assigned 46 patients with asthma to active treatment with an albuterol inhaler, a placebo inhaler, sham acupuncture, or no intervention. Using a block design, we administered one each of these four interventions in random order during four sequential visits (3 to 7 days apart); this procedure was repeated in two more blocks of visits (for a total of 12 visits by each patient). At each visit, spirometry was performed repeatedly over a period of 2 hours. Maximum forced expiratory volume in 1 second (FEV(1)) was measured, and patients' self-reported improvement ratings were recorded. Among the 39 patients who completed the study, albuterol resulted in a 20% increase in FEV(1), as compared with approximately 7% with each of the other three interventions (P<0.001). However, patients' reports of improvement after the intervention did not differ significantly for the albuterol inhaler (50% improvement), placebo inhaler (45%), or sham acupuncture (46%), but the subjective improvement with all three of these interventions was significantly greater than that with the no-intervention control (21%) (P<0.001). Although albuterol, but not the two placebo interventions, improved FEV(1) in these patients with asthma, albuterol provided no incremental benefit with respect to the self-reported outcomes. Placebo effects can be clinically meaningful and can rival the effects of active medication in patients with asthma. However, from a clinical-management and research-design perspective, patient self-reports can be unreliable. An assessment of untreated responses in asthma may be essential in evaluating patient-reported outcomes. (Funded by the National Center for Complementary and Alternative Medicine.).
The role of BDNF, leptin, and catecholamines in reward learning in bulimia nervosa.

PubMed

Homan, Philipp; Grob, Simona; Milos, Gabriella; Schnyder, Ulrich; Eckert, Anne; Lang, Undine; Hasler, Gregor

2014-12-07

A relationship between bulimia nervosa and reward-related behavior is supported by several lines of evidence. The dopaminergic dysfunctions in the processing of reward-related stimuli have been shown to be modulated by the neurotrophin brain derived neurotrophic factor (BDNF) and the hormone leptin. Using a randomized, double-blind, placebo-controlled, crossover design, a reward learning task was applied to study the behavior of 20 female subjects with remitted bulimia nervosa and 27 female healthy controls under placebo and catecholamine depletion with alpha-methyl-para-tyrosine (AMPT). The plasma levels of BDNF and leptin were measured twice during the placebo and the AMPT condition, immediately before and 1 hour after a standardized breakfast. AMPT-induced differences in plasma BDNF levels were positively correlated with the AMPT-induced differences in reward learning in the whole sample (P=.05). Across conditions, plasma brain derived neurotrophic factor levels were higher in remitted bulimia nervosa subjects compared with controls (diagnosis effect; P=.001). Plasma BDNF and leptin levels were higher in the morning before compared with after a standardized breakfast across groups and conditions (time effect; P<.0001). The plasma leptin levels were higher under catecholamine depletion compared with placebo in the whole sample (treatment effect; P=.0004). This study reports on preliminary findings that suggest a catecholamine-dependent association of plasma BDNF and reward learning in subjects with remitted bulimia nervosa and controls. A role of leptin in reward learning is not supported by this study. However, leptin levels were sensitive to a depletion of catecholamine stores in both remitted bulimia nervosa and controls. © The Author 2015. Published by Oxford University Press on behalf of CINP.
Are we drawing the right conclusions from randomised placebo-controlled trials? A post-hoc analysis of data from a randomised controlled trial

PubMed Central

2009-01-01

Background Assumptions underlying placebo controlled trials include that the placebo effect impacts on all study arms equally, and that treatment effects are additional to the placebo effect. However, these assumptions have recently been challenged, and different mechanisms may potentially be operating in the placebo and treatment arms. The objective of the current study was to explore the nature of placebo versus pharmacological effects by comparing predictors of the placebo response with predictors of the treatment response in a randomised, placebo-controlled trial of a phytotherapeutic combination for the treatment of menopausal symptoms. A substantial placebo response was observed but no significant difference in efficacy between the two arms. Methods A post hoc analysis was conducted on data from 93 participants who completed this previously published study. Variables at baseline were investigated as potential predictors of the response on any of the endpoints of flushing, overall menopausal symptoms and depression. Focused tests were conducted using hierarchical linear regression analyses. Based on these findings, analyses were conducted for both groups separately. These findings are discussed in relation to existing literature on placebo effects. Results Distinct differences in predictors were observed between the placebo and active groups. A significant difference was found for study entry anxiety, and Greene Climacteric Scale (GCS) scores, on all three endpoints. Attitude to menopause was found to differ significantly between the two groups for GCS scores. Examination of the individual arms found anxiety at study entry to predict placebo response on all three outcome measures individually. In contrast, low anxiety was significantly associated with improvement in the active treatment group. None of the variables found to predict the placebo response was relevant to the treatment arm. Conclusion This study was a post hoc analysis of predictors of the placebo versus treatment response. Whilst this study does not explore neurobiological mechanisms, these observations are consistent with the hypotheses that 'drug' effects and placebo effects are not necessarily additive, and that mutually exclusive mechanisms may be operating in the two arms. The need for more research in the area of mechanisms and mediators of placebo versus active responses is supported. Trial Registration International Clinical Trials Registry ISRCTN98972974. PMID:19549306
Modafinil improves information processing speed and increases energetic resources for orientation of attention in narcoleptics: double-blind, placebo-controlled ERP studies with low-resolution brain electromagnetic tomography (LORETA).

PubMed

Saletu, Michael; Anderer, Peter; Saletu-Zyhlarz, Gerda Maria; Mandl, Magdalena; Saletu, Bernd; Zeitlhofer, Josef

2009-09-01

Recent neuroimaging studies in narcolepsy discovered significant gray matter loss in the right prefrontal and frontomesial cortex, a critical region for executive processing. In the present study, event-related potential (ERP) low-resolution brain electromagnetic tomography (LORETA) was used to investigate cognition before and after modafinil as compared with placebo. In a double-blind, placebo-controlled cross-over design, 15 patients were treated with a 3-week fixed titration scheme of modafinil and placebo. The Epworth Sleepiness Scale (ESS), Maintenance of Wakefulness Test (MWT) and auditory ERPs (odd-ball paradigm) were obtained before and after the 3 weeks of therapy. Latencies, amplitudes and LORETA sources were determined for standard (N1 and P2) and target (N2 and P300) ERP components. The ESS score improved significantly from 15.4 (+/- 4.0) under placebo to 10.2 (+/- 4.1) under 400mg modafinil (p=0.004). In the MWT, latency to sleep increased nonsignificantly after modafinil treatment (11.9+/-6.9 versus 13.3+/-7.1 min). In the ERP, N2 and P300 latencies were shortened significantly. While ERP amplitudes showed only minor changes, LORETA revealed increased source strengths: for N1 in the left auditory cortex and for P300 in the medial and right dorsolateral prefrontal cortex. LORETA revealed that modafinil improved information processing speed and increased energetic resources in prefrontal cortical regions, which is in agreement with other neuroimaging studies.
Progressive augmentation and ventilatory long-term facilitation are enhanced in sleep apnoea patients and are mitigated by antioxidant administration

PubMed Central

Lee, Dorothy S; Badr, M Safwan; Mateika, Jason H

2009-01-01

Progressive augmentation (PA) and ventilatory long-term facilitation (vLTF) of respiratory motor output are forms of respiratory plasticity that are initiated during exposure to intermittent hypoxia. The present study was designed to determine whether PA and vLTF are enhanced in obstructive sleep apnoea (OSA) participants compared to matched healthy controls. The study was also designed to determine whether administration of an antioxidant cocktail mitigates PA and vLTF. Thirteen participants with sleep apnoea and 13 controls completed two trials. During both trials participants were exposed to intermittent hypoxia which included twelve 4-min episodes of hypoxia (, 50 mmHg; , 4 mmHg above baseline) followed by 30 min of recovery. Prior to exposure to intermittent hypoxia, participants were administered, in a randomized fashion, either an antioxidant or a placebo cocktail. Baseline measures of minute ventilation during the placebo and antioxidant trials were not different between or within groups. During the placebo trial, PA was evident in both groups; however it was enhanced in the OSA group compared to control (last hypoxic episode 36.9 ± 2.8 vs. 27.7 ± 2.2 l min−1; P≤ 0.01). Likewise, vLTF was evident during the recovery period in both groups; on the other hand vLTF was greater in the OSA group compared to control (29.3 ± 2.8 vs. 20.4 ± 1.3 l min−1; P≤ 0.01). PA and vLTF were reduced in the OSA group following antioxidant administration compared to the placebo (PA 30.6 ± 2.0 vs. 36.9 ± 2.8 l min−1, P≤ 0.01; vLTF 23.3 ± 1.4 vs. 29.3 ± 2.8 l min−1, P≤ 0.05). We conclude that PA and vLTF are enhanced in participants with OSA and that these forms of respiratory plasticity are mitigated after treatment with an antioxidant cocktail. PMID:19805747
No Evidence of Intelligence Improvement after Working Memory Training: A Randomized, Placebo-Controlled Study

ERIC Educational Resources Information Center

Redick, Thomas S.; Shipstead, Zach; Harrison, Tyler L.; Hicks, Kenny L.; Fried, David E.; Hambrick, David Z.; Kane, Michael J.; Engle, Randall W.

2013-01-01

Numerous recent studies seem to provide evidence for the general intellectual benefits of working memory training. In reviews of the training literature, Shipstead, Redick, and Engle (2010, 2012) argued that the field should treat recent results with a critical eye. Many published working memory training studies suffer from design limitations…
Systematic review of quality of life and functional outcomes in randomized placebo-controlled studies of medications for attention-deficit/hyperactivity disorder.

PubMed

Coghill, David R; Banaschewski, Tobias; Soutullo, César; Cottingham, Matthew G; Zuddas, Alessandro

2017-11-01

Children, adolescents and adults with attention-deficit/hyperactivity disorder (ADHD) experience functional impairment and poor health-related quality of life (HRQoL) in addition to symptoms of inattention/hyperactivity-impulsivity. To synthesize qualitatively the published evidence from randomized, double-blind, placebo-controlled trials of the effectiveness of pharmacotherapy on functional impairment or HRQoL in patients with ADHD, a systematic PubMed searching and screening strategy was designed to identify journal articles meeting pre-specified criteria. Post hoc analyses and meta-analyses were excluded. HRQoL outcomes, functional outcomes and the principal ADHD symptom-based outcome were extracted from included studies. An effect size of 0.5 versus placebo was used as a threshold for potential clinical relevance (unreported effect sizes were calculated when possible). Of 291 records screened, 35 articles describing 34 studies were included. HRQoL/functioning was usually self-rated in adults and proxy-rated in children/adolescents. Baseline data indicated substantial HRQoL deficits in children/adolescents. Placebo-adjusted effects of medication on ADHD symptoms, HRQoL and functioning, respectively, were statistically or nominally significant in 18/18, 10/12 and 7/9 studies in children/adolescents and 14/16, 9/11 and 9/10 studies in adults. Effect sizes were ≥0.5 versus placebo for symptoms, HRQoL and functioning, respectively, in 14/16, 7/9 and 4/8 studies in children/adolescents; and 6/12, 1/6 and 1/8 studies in adults. Effect sizes were typically larger for stimulants than for non-stimulants, for symptoms than for HRQoL/functioning, and for children/adolescents than for adults. The efficacy of ADHD medication extends beyond symptom control and may help reduce the related but distinct functional impairments and HRQoL deficits in patients with ADHD.
REACTIVATION OF LATENT VIRUSES IN INDIVIDUALS RECEIVING RITUXIMAB FOR NEW ONSET TYPE 1 DIABETES

PubMed Central

Kroll, Jing Lu; Beam, Craig; Li, Shaobing; Viscidi, Raphael; Dighero, Bonnie; Cho, Alice; Boulware, David; Pescovitz, Mark; Weinberg, Adriana

2013-01-01

Background Rituximab has been successfully used as an experimental therapy in different autoimmune diseases. Recently, a double-blind placebo-controlled phase-2 study in early onset type 1 diabetes showed that rituximab delayed progression of the disease. However, like with any immunosuppressive therapy, there is a concern of opportunistic viral reactivations with the use of rituximab, including herpes and polyomaviruses. Objectives To study the incidence of new infections and reactivations with BK, JC, Epstein-Barr and cytomegalovirus (BKV, JCV, EBV and CMV) in T1D participants in the phase-2 rituximab study. Study Design Subjects received 4 weekly doses of rituximab (N=57) or placebo (N=30) during the first month of study. Blood samples obtained at weeks 0, 12, 26, 56 and 78 were assayed for CMV, EBV, BKV and JCV by real-time DNA PCR and serology. Results EBV reactivations were diagnosed by PCR in 25% of placebo, but none of rituximab recipients (p<0.01). There were no episodes of CMV viremia in either treatment group. BKV viremias were significantly more common in the rituximab recipients (9%) compared with placebo controls (0, p<0.01). No JCV reactivations were detected in this study, but among 6 rituximab and 2 placebo recipients who seroconverted for JCV during the study, only one rituximab recipient had detectable viremia. All infections were asymptomatic. Conclusions Four doses of rituximab administered to individuals with early onset T1D decreased the incidence of asymptomatic EBV reactivations, as predicted by the rituximab-mediated elimination of memory B-cells, but increased the frequency of asymptomatic viremias caused by polyomaviruses. PMID:23422292
Early interventional treatment with intranasal corticosteroids compared with postonset treatment in pollinosis.

PubMed

Higaki, Takaya; Okano, Mitsuhiro; Makihara, Seiichiro; Fujiwara, Tazuko; Haruna, Takenori; Noda, Yohei; Kariya, Shin; Nishizaki, Kazunori

2012-12-01

The usefulness of early interventional treatment (EIT) with intranasal corticosteroids (INSs) compared with postonset treatment (POT) has not been clarified. To study the efficacy and safety of EIT with INSs compared with POT and placebo in Japanese cedar/cypress pollinosis. We designed a 3-armed, double-blinded, randomized, placebo-controlled trial. Patients received mometasone furoate nasal spray (EIT group: n = 25), placebo (n = 25), or 4 weeks of placebo followed by 8 weeks of mometasone (POT group: n = 25) for a 12-week period starting on February 1, 2011. The primary end point was the comparison of the total nasal symptom score (TNSS) among the 3 groups. Total ocular symptom score (TOSS), total naso-ocular symptom score (TSS), Allergic Rhinitis and Its Impact (ARIA) on Asthma classification, and safety were the main secondary end points. The placebo and POT groups, but not the EIT group, had a significant exacerbation of TNSS and TOSS soon after the start of pollen counts being high on consecutive days. The 12-week mean TSS in the EIT group (score, 2.3) was significantly lower than in the placebo (5.0; P < .01) and POT (3.9; P = .03) groups. All patients in the placebo and POT groups were classified as having persistent rhinitis, whereas 80% of the EIT group met the ARIA classification criteria (P = .03). The quality-of-life score and nasal eosinophil cationic protein levels were lower in the EIT and POT groups compared with the placebo group. Daytime sleepiness, smell disturbance, and the mean dose of loratadine taken as the rescue medication were similar. Treatment with mometasone was well tolerated. EIT with INSs is superior to POT in controlling pollinosis. Copyright © 2012 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Placebo effects in psychiatry: mediators and moderators

PubMed Central

Weimer, Katja; Colloca, Luana; Enck, Paul

2015-01-01

A strong placebo response in psychiatric disorders has been noted for the past 50 years and various attempts have been made to identify predictors of it, by use of meta-analyses of randomised controlled trials and laboratory studies. We reviewed 31 meta-analyses and systematic reviews of more than 500 randomised placebo-controlled trials across psychiatry (depression, schizophrenia, mania, attention-deficit hyperactivity disorder, autism, psychosis, binge-eating disorder, and addiction) for factors identified to be associated with increased placebo response. Of 20 factors discussed, only three were often linked to high placebo responses: low baseline severity of symptoms, more recent trials, and unbalanced randomisation (more patients randomly assigned to drug than placebo). Randomised controlled trials in non-drug therapy have not added further predictors, and laboratory studies with psychological, brain, and genetic approaches have not been successful in identifying predictors of placebo responses. This comprehensive Review suggests that predictors of the placebo response are still to be discovered, the response probably has more than one mediator, and that different and distinct moderators are probably what cause the placebo response within psychiatry and beyond. PMID:25815249
Does cannabis use moderate smoking cessation outcomes in treatment-seeking tobacco smokers? Analysis from a large multi-center trial.

PubMed

Rabin, Rachel A; Ashare, Rebecca L; Schnoll, Robert A; Cinciripini, Paul M; Hawk, Larry W; Lerman, Caryn; Tyndale, Rachel F; George, Tony P

2016-06-01

Tobacco and cannabis are frequently used in combination and cannabis co-use may lead to poor tobacco cessation outcomes. Therefore, it is important to explore if cannabis co-use is associated with a reduced likelihood of achieving successful tobacco abstinence among treatment-seeking tobacco smokers. The present study examined whether current cannabis use moderated tobacco cessation outcomes after 12 weeks of pharmacological treatment (varenicline vs. nicotine patch vs. placebo) with adjunctive behavioral counseling. Treatment-seeking tobacco smokers (N = 1,246) were enrolled in an intent-to-treat study, of which 220 were current cannabis users. Individuals were randomly assigned to 12 weeks of placebo (placebo pill plus placebo patch), nicotine patch (active patch plus placebo pill), or varenicline (active pill plus placebo patch), plus behavioral counseling. The primary endpoint was biochemically verified 7-day point prevalence abstinence at the end of treatment. Controlling for rate of nicotine metabolism, treatment arm, age, sex, alcohol, and level of nicotine dependence, cannabis users were as successful at achieving biochemically verified 7-day point prevalence abstinence compared to tobacco-only smokers. Findings suggest that cannabis use does not hinder the ability to quit tobacco smoking. Future tobacco cessation studies should employ prospective, longitudinal designs investigating cannabis co-use over time and at different severity levels. (Am J Addict 2016;25:291-296). © 2016 American Academy of Addiction Psychiatry.
Placebo influences on dyskinesia in Parkinson's disease.

PubMed

Goetz, Christopher G; Laska, Eugene; Hicking, Christine; Damier, Philippe; Müller, Thomas; Nutt, John; Warren Olanow, C; Rascol, Olivier; Russ, Hermann

2008-04-15

Clinical features that are prognostic indicators of placebo response among dyskinetic Parkinson's disease patients were determined. Placebo-associated improvements occur in Parkinsonism, but responses in dyskinesia have not been studied. Placebo data from two multicenter studies with identical design comparing sarizotan to placebo for treating dyskinesia were accessed. Sarizotan (2 mg/day) failed to improve dyskinesia compared with placebo, but both treatments improved dyskinesia compared with baseline. Stepwise regression identified baseline characteristics that influenced dyskinesia response to placebo, and these factors were entered into a logistic regression model to quantify their influence on placebo-related dyskinesia improvements and worsening. Because placebo-associated improvements in Parkinsonism have been attributed to heightened dopaminergic activity, we also examined the association between changes in Parkinsonism and dyskinesia. Four hundred eighty-four subjects received placebo treatment; 178 met criteria for placebo-associated dyskinesia improvement and 37 for dyskinesia worsening. Older age, lower baseline Parkinsonism score, and lower total daily levodopa doses were associated with placebo-associated improvement, whereas lower baseline dyskinesia score was associated with placebo-associated worsening. Placebo-associated dyskinesia changes were not correlated with Parkinsonism changes, and all effects in the sarizotan group were statistically explained by the placebo-effect regression model. Dyskinesias are affected by placebo treatment. The absence of correlation between placebo-induced changes in dyskinesia and Parkinsonism argues against a dopaminergic activation mechanism to explain placebo-associated improvements in dyskinesia. The magnitude and variance of placebo-related changes and the factors that influence them can be helpful in the design of future clinical trials of antidyskinetic agents. 2007 Movement Disorder Society
Placebo Influences on Dyskinesia in Parkinson's Disease

PubMed Central

Goetz, Christopher G.; Laska, Eugene; Hicking, Christine; Damier, Philippe; Müller, Thomas; Nutt, John; Olanow, C. Warren; Rascol, Olivier; Russ, Hermann

2009-01-01

Clinical features that are prognostic indicators of placebo response among dyskinetic Parkinson's disease patients were determined. Placebo-associated improvements occur in Parkinsonism, but responses in dyskinesia have not been studied. Placebo data from two multicenter studies with identical design comparing sarizotan to placebo for treating dyskinesia were accessed. Sarizotan (2 mg/day) failed to improve dyskinesia compared with placebo, but both treatments improved dyskinesia compared with baseline. Stepwise regression identified baseline characteristics that influenced dyskinesia response to placebo, and these factors were entered into a logistic regression model to quantify their influence on placebo-related dyskinesia improvements and worsening. Because placebo-associated improvements in Parkinsonism have been attributed to heightened dopaminergic activity, we also examined the association between changes in Parkinsonism and dyskinesia. Four hundred eighty-four subjects received placebo treatment; 178 met criteria for placebo-associated dyskinesia improvement and 37 for dyskinesia worsening. Older age, lower baseline Parkinsonism score, and lower total daily levodopa doses were associated with placebo-associated improvement, whereas lower baseline dyskinesia score was associated with placebo-associated worsening. Placebo-associated dyskinesia changes were not correlated with Parkinsonism changes, and all effects in the sarizotan group were statistically explained by the placebo-effect regression model. Dyskinesias are affected by placebo treatment. The absence of correlation between placebo-induced changes in dyskinesia and Parkinsonism argues against a dopaminergic activation mechanism to explain placebo-associated improvements in dyskinesia. The magnitude and variance of placebo-related changes and the factors that influence them can be helpful in the design of future clinical trials of antidyskinetic agents. PMID:18175337
Efficacy and Safety of Postoperative Pain Relief by Parecoxib Injection after Laparoscopic Surgeries: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

PubMed

Huang, Jun-Ming; Lv, Zheng-Tao; Zhang, Ya-Nan; Jiang, Wen-Xiu; Li, Han-Ning; Nie, Ming-Bo

2017-10-17

This study aims to evaluate the efficacy and safety of parecoxib injection in pain relief after laparoscopic surgeries. A comprehensive literature search based on 4 online databases (PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science) was applied to retrieve all related randomized controlled trials (RCTs). Two independent reviewers screened each article for eligibility according to the predetermined inclusion criteria. The Cochrane Collaboration's tool was applied to evaluate the methodological quality of included studies. A standardized data collection sheet was designed to extract data from included studies. RevMan version 5.3 (The Cochrane Collaboration, Copenhagen, Denmark) was selected to perform meta-analysis. A total of 1,060 participants who were scheduled for gynecological laparoscopic surgery or laparoscopic cholecystectomy (LC) were enrolled in 12 selected RCTs. The methodological qualities of the studies were evaluated as moderate to high. The combined data showed that perioperative parecoxib injection could significantly reduce the proportion of patients who required adjuvant pain relieve after laparoscopic surgeries. Significantly lower pain scores in the parecoxib groups were observed, which proved that preoperative or intraoperative injection of 40 mg parecoxib was more effective than placebo for immediate pain relief after LC. But preoperative injection of 40 mg parecoxib showed no improvement compared with placebo in the management of immediate pain following gynecological laparoscopic surgery. The occurrence of adverse events showed no differences between perioperative parecoxib administration and placebo control. Perioperative parecoxib administration was effective in reducing the proportion of patients who required adjuvant pain relief after laparoscopic surgeries without significant adverse events compared with placebo. The effect of parecoxib injection on immediate pain relief remains in question. Future RCTs with larger sample sizes are encouraged. © 2017 World Institute of Pain.
Randomised controlled study in the primary healthcare sector to investigate the effectiveness and safety of auriculotherapy for the treatment of uncomplicated chronic rachialgia: a study protocol

PubMed Central

Vas, Jorge; Aguilar, Inmaculada; Campos, M Ángeles; Méndez, Camila; Perea-Milla, Emilio; Modesto, Manuela; Caro, Paloma; Martos, Francisco; García-Ruiz, Antonio J

2008-01-01

Background Uncomplicated chronic rachialgia is a highly prevalent complaint, and one for which therapeutic results are contradictory. The aim of the present study is to evaluate the effectiveness and safety of treatment with auriculopressure, in the primary healthcare sector, carried out by trained healthcare professionals via a 30-hour course. Methods/Design The design consists of a multi-centre randomized controlled trial, with placebo, with two parallel groups, and including an economic evaluation. Patients with chronic uncomplicated rachialgia, whose GP is considering referral for auriculopressure sensory stimulation, are eligible for inclusion. Sampling will be by consecutive selection, and randomised allocation to one of the two study arms will be determined using a centralised method, following a 1:1 plan (true auriculopressure; placebo auriculopressure). The implants (true and placebo) will be replaced once weekly, and the treatment will have a duration of 8 weeks. The primary outcome measure will be the change in pain intensity, measured on a visual analogue scale (VAS) of 100 mm, at 9 weeks after beginning the treatment. A follow up study will be performed at 6 months after beginning treatment. An assessment will also be made of the changes measured in the Spanish version of the McGill Pain Questionnaire, of the changes in the Lattinen test, and of the changes in quality of life (SF-12). Also planned is an analysis of cost-effectiveness and also, if necessary, a cost-benefit analysis. Discussion This study will contribute to developing evidence on the use of auriculotherapy using Semen vaccariae [wang bu liu xing] for the treatment of uncomplicated chronic rachialgia. Trial registration Current Controlled Trials ISRCTN01897462. PMID:18601750
Sodium valproate in the treatment of aggressive behavior in patients with dementia--a randomized placebo controlled clinical trial.

PubMed

Sival, Rob C; Haffmans, P M Judith; Jansen, Paul A F; Duursma, Sijmen A; Eikelenboom, Piet

2002-06-01

The efficacy and tolerability of sodium valproate 2 x 240 mg compared to placebo were investigated in aggressive behavior in dementia. A randomized, placebo controlled, double-blind cross-over design. The trial included a baseline period (one week); a placebo period (three weeks); a wash-out period with placebo (one week); and a treatment period with sodium valproate (three weeks). A psychogeriatric short-stay ward at a psychiatric teaching hospital. Demented patients who met Patel's criteria for aggressive behavior and had a score of > or =3 on at least one of the items of the Social Dysfunction and Aggression scale-9 (SDAS-9). A fixed dose of sodium valproate 2 x 6 ml of a 40 mg/ml suspension (daily defined dose of 480 mg) was compared to placebo. Primary outcome variables were changes of the score of SDAS-9 and Clinical Global Impression scale (CGI) performed at the last week of each treatment period. Data of 42 patients (F=25 and M=17; age 80.4+/-6.8 years) were analyzed. Treatment with sodium valproate showed no differences compared to placebo on aggressive behavior. The mean plasma level of sodium valproate was 40.9+/-10.8 microg/ml. Regression analysis showed a trend for improvement between the plasma levels of sodium valproate and the SDAS-9 and the CGI scores. Adverse events were not related to the plasma levels of sodium valproate. Secondary outcome measurements showed significant improvement on restless, melancholic and anxious behavior; a trend for improvement was found on suspicious and dependent behavior. Possible limitations of this study are the low dose of sodium valproate, the relatively short treatment period (three weeks), and the absence of statistical corrections for multiple comparisons. This study showed no effect of sodium valproate 2 x 240 mg over placebo on aggressive behavior in dementia. Copyright 2002 John Wiley & Sons, Ltd.

Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine

NASA Technical Reports Server (NTRS)

Jankovic, J.; Gilden, J. L.; Hiner, B. C.; Kaufmann, H.; Brown, D. C.; Coghlan, C. H.; Rubin, M.; Fouad-Tarazi, F. M.

1993-01-01

PURPOSE: To investigate the efficacy and safety of midodrine for treatment of patients with orthostatic hypotension due to autonomic failure. PATIENTS: Ninety-seven patients with orthostatic hypotension were randomized in a 4-week, double-blinded, placebo-controlled study with a 1-week placebo run-in period. Patients ranged in age from 22 to 86 years (mean: 61 years). METHODS: After a 1-week run-in phase, either placebo or midodrine at a dose of 2.5 mg, 5 mg, or 10 mg was administered three times a day for 4 weeks. Both the placebo group and the 2.5-mg midodrine group received constant doses throughout the double-blind phase. The patients receiving 5 mg or 10 mg of midodrine were given doses that were increased at weekly intervals by 2.5-mg increments until the designated dose was reached. Efficacy evaluations were based on an improvement at 1-hour postdose in standing systolic blood pressure and in symptoms of orthostatic hypotension (syncope, dizziness/lightheadedness, weakness/fatigue, and low energy level). RESULTS: Midodrine (10 mg) increased standing systolic blood pressure by 22 mm Hg (28%, p < 0.001 versus placebo). Midodrine improved (p < 0.05) the following symptoms of orthostatic hypotension compared to placebo: dizziness/lightheadedness, weakness/fatigue, syncope, low energy level, impaired ability to stand, and feelings of depression. The overall side effects were mainly mild to moderate. One or more side effects were reported by 22% of the placebo group compared with 27% of the midodrine-treated group. Scalp pruritus/tingling, which was reported by 10 of 74 (13.5%) of the midodrine-treated patients, was most frequent. Other reported side effects included supine hypertension (8%) and feelings of urinary urgency (4%). CONCLUSION: We conclude that midodrine is an effective and well-tolerated treatment for moderate-to-severe orthostatic hypotension associated with autonomic failure.
Placebo effects in competitive sport: qualitative data.

PubMed

Beedie, Christopher J

2007-01-01

The paper examines the placebo effect in sports performance. The possibility that the placebo effect is a more common phenomenon than the quantity of published research would suggest is briefly addressed. It is suggested that the placebo control design often used in sports performance research masks any placebo effects and thus presents a false picture of the mechanisms underlying performance-enhancing interventions in the real world. An electronic survey was sent to 48 competitive, international and professional athletes. Questions related to the placebo effect in competitive sport. Thirty responses were received. Data indicate that the majority (97%) of respondents believe that the placebo effect can exert an influence on sports performance, and that a significant number (73%) have experienced what they defined as a placebo effect. Inductive content analysis reveals that these experiences fall into several categories such as explicit placebo effects, inadvertent false beliefs, ritual and reverse placebo effects. Furthermore, 10 respondents (33%) offer explanations as to the nature of the placebo effect. Again, inductive content analysis reveals that these explanations fall into several categories including deliberate changes in competitive strategy, belief/expectancy, faith in a third party, and marketing. Overall, responses support previous experimental research and anecdotal reports that have found a relationship between belief and sports performance. It is suggested that further research be structured to not simply control for the placebo effect, but to elucidate it. Key pointsA survey of 30 athletes revealed that 73% have experienced a placebo effect in sport.Athletes suggest several potential explanations for these effects.Findings support the idea that placebo effects might be common in sport.Researchers and practitioners should be aware of the possible impact of these effects on research findings and competitive performance.
Aged Garlic Extract Improves Adiponectin Levels in Subjects with Metabolic Syndrome: A Double-Blind, Placebo-Controlled, Randomized, Crossover Study

PubMed Central

Gómez-Arbeláez, Diego; Lahera, Vicente; Oubiña, Pilar; Valero-Muñoz, Maria; de las Heras, Natalia; Rodríguez, Yudy; García, Ronald Gerardo; Camacho, Paul Anthony; López-Jaramillo, Patricio

2013-01-01

Background. Garlic (Allium sativum) has been shown to have important benefits in individuals at high cardiovascular risk. The aim of the present study was to evaluate the effects of the administration of aged garlic extract (AGE) on the risk factors that constitute the cluster of metabolic syndrome (MS). Methods and Design. Double-blind, crossover, randomized, placebo-controlled clinical trial to assess the effect of 1.2 g/day of AGE (Kyolic), for 24 weeks of treatment (12 weeks of AGE and 12 weeks of placebo), on subjects with MS. Results. The administration of AGE increased the plasma levels of adiponectin (P = 0.027). No serious side effects associated with the intervention were reported. Conclusion. The present results have shown for the first time that the administration of AGE for 12 weeks increased plasma adiponectin levels in patients with MS. This suggests that AGE might be a useful, novel, nonpharmacological therapeutic intervention to increase adiponectin and to prevent cardiovascular (CV) complications in individuals with MS. PMID:23533302
A Rosa canina - Urtica dioica - Harpagophytum procumbens/zeyheri Combination Significantly Reduces Gonarthritis Symptoms in a Randomized, Placebo-Controlled Double-Blind Study.

PubMed

Moré, Margret; Gruenwald, Joerg; Pohl, Ute; Uebelhack, Ralf

2017-12-01

The special formulation MA212 (Rosaxan) is composed of rosehip ( Rosa canina L.) puree/juice concentrate, nettle ( Urtica dioica L.) leaf extract, and devil's claw ( Harpagophytum procumbens DC. ex Meisn. or Harpagophytum zeyheri Decne.) root extract and also supplies vitamin D. It is a food for special medical purposes ([EU] No 609/2013) for the dietary management of pain in patients with gonarthritis.This 12-week randomized, placebo-controlled double-blind parallel-design study aimed to investigate the efficacy and safety of MA212 versus placebo in patients with gonarthritis.A 3D-HPLC-fingerprint (3-dimensional high pressure liquid chromatography fingerprint) of MA212 demonstrated the presence of its herbal ingredients. Ninety-two randomized patients consumed 40 mL of MA212 (n = 46) or placebo (n = 44) daily. The Western Ontario and McMaster Universities Arthritis Index (WOMAC), quality-of-life scores at 0, 6, and 12 weeks, and analgesic consumption were documented. Statistically, the initial WOMAC subscores/scores did not differ between groups. During the study, their means significantly improved in both groups. The mean pre-post change of the WOMAC pain score (primary endpoint) was 29.87 in the MA212 group and 10.23 in the placebo group. The group difference demonstrated a significant superiority in favor of MA212 (p U < 0.001; p t < 0.001). Group comparisons of all WOMAC subscores/scores at 6 and 12 weeks reached same significances. Compared to placebo, both physical and mental quality of life significantly improved with MA212. There was a trend towards reduced analgesics consumption with MA212, compared to placebo. In the final efficacy evaluation, physicians (p Chi < 0.001) and patients (p Chi < 0.001) rated MA212 superior to placebo. MA212 was well tolerated.This study demonstrates excellent efficacy for MA212 in gonarthritis patients. Georg Thieme Verlag KG Stuttgart · New York.
Efficacy and safety of topical diclofenac/menthol gel for ankle sprain: A randomized, double-blind, placebo- and active-controlled trial

PubMed Central

Collaku, Agron; Reed, Kenneth

2017-01-01

Purpose This study was performed to evaluate topical 1% diclofenac/3% menthol gel in treating ankle sprain. Design In this randomized, double-blind, placebo-controlled trial, adolescents and adults with acute ankle sprain (N = 385) applied 4 g of gel containing 1% diclofenac/3% menthol (n = 117), 1% diclofenac (n = 112), 3% menthol (n = 77), or placebo (n = 75) four times daily. The primary outcome was the area under the curve of pain intensity (PI) on movement [0 (no pain) to 10 (extreme pain)] from 24 to 72 hours post-application (AUC1–3 days). Secondary outcomes included pain relief (PR); PI; time to onset of PR, meaningful PR, cooling, and complete recovery; PI difference; sum of PI difference; total PR; reduction in ankle swelling; and the patient’s global assessment of response to treatment. Results There were no statistically significant differences in AUC1–3 between 1% diclofenac/3% menthol and placebo, diclofenac, or menthol gels and no meaningful advantages of 1% diclofenac/3% menthol for any secondary outcome. There was a higher incidence of skin and application-site events with 1% diclofenac/3% menthol than with placebo or 1% diclofenac. Conclusion No significant improvement was observed with topical 1% diclofenac/3% menthol gel compared with placebo, 1% diclofenac, or 3% menthol gel in treating pain from ankle sprain. ClinicalTrials.Gov Identifier: NCT02100670 PMID:28345425
Lower Placebo Responses After Long-Term Exposure to Fibromyalgia Pain.

PubMed

Kosek, Eva; Rosen, Annelie; Carville, Serena; Choy, Ernest; Gracely, Richard H; Marcus, Hanke; Petzke, Frank; Ingvar, Martin; Jensen, Karin B

2017-07-01

Knowledge about placebo mechanisms in patients with chronic pain is scarce. Fibromyalgia syndrome (FM) is associated with dysfunctions of central pain inhibition, and because placebo analgesia entails activation of endogenous pain inhibition, we hypothesized that long-term exposure to FM pain would negatively affect placebo responses. In our study we examined the placebo group (n = 37, mean age 45 years) from a 12-week, randomized, double-blind, placebo-controlled trial investigating the effects of milnacipran or placebo. Twenty-two patients were classified as placebo nonresponders and 15 as responders, according to the Patient Global Impression of Change scale. Primary outcome was the change in pressure pain sensitivity from baseline to post-treatment. Secondary outcomes included ratings of clinical pain (visual analog scale), FM effect (Fibromyalgia Impact Questionnaire), and pain drawing. Among placebo responders, longer FM duration was associated with smaller reductions in pressure pain sensitivity (r = .689, P = .004), but not among nonresponders (r = -.348, P = .112). In our study we showed that FM duration influences endogenous pain regulation, because pain levels and placebo-induced analgesia were negatively affected. Our results point to the importance of early FM interventions, because endogenous pain regulation may still be harnessed at that early time. Also, placebo-controlled trials should take FM duration into consideration when interpreting results. This study presents a novel perspective on placebo analgesia, because placebo responses among patients with chronic pain were analyzed. Long-term exposure to fibromyalgia pain was associated with lower placebo analgesia, and the results show the importance of taking pain duration into account when interpreting the results from placebo-controlled trials. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
Vasopressin, but not oxytocin, increases empathic concern among individuals who received higher levels of paternal warmth: A randomized controlled trial.

PubMed

Tabak, Benjamin A; Meyer, Meghan L; Castle, Elizabeth; Dutcher, Janine M; Irwin, Michael R; Han, Jung H; Lieberman, Matthew D; Eisenberger, Naomi I

2015-01-01

Empathy improves our ability to communicate in social interactions and motivates prosocial behavior. The neuropeptides arginine vasopressin and oxytocin play key roles in socioemotional processes such as pair bonding and parental care, which suggests that they may be involved in empathic processing. We investigated how vasopressin and oxytocin affect empathic responding in a randomized, double-blind, placebo controlled, between-subjects study design. We also examined the moderating role of parental warmth, as reported in the early family environment, on empathic responding following vasopressin, oxytocin, or placebo administration. Among participants who reported higher levels of paternal warmth (but not maternal warmth), vasopressin (vs. placebo and oxytocin) increased ratings of empathic concern after viewing distressing and uplifting videos. No main or interaction effects were found for individuals who received oxytocin. Vasopressin has a role in enhancing empathy among individuals who received higher levels of paternal warmth. NCT01680718. Copyright © 2014 Elsevier Ltd. All rights reserved.
Ethical considerations in placebo-controlled randomised clinical trials.

PubMed

Kaufman, Kenneth R

2015-06-01

Ethical considerations in standard medical care and clinical research are underpinnings to quality medicine. Similarly, the placebo-controlled double-blind randomised clinical trial is the gold standard for medical research and fundamental to the development of evidence-based medicine. Researchers and clinicians are challenged by ethical concerns in the informed consent with a need to maximise understanding and minimise therapeutic misconception. This editorial expands on themes raised by Chen et al 's article 'Disclosing the Potential Impact of Placebo Controls in Antidepressant Trials' and serves as an invitation for further submissions to BJPsych Open on ethics, research design and informed consent. None. © The Royal College of Psychiatrists 2015. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.
Effect of aromatherapy massage on dysmenorrhea in Turkish students.

PubMed

Apay, Serap Ejder; Arslan, Sevban; Akpinar, Reva Balci; Celebioglu, Ayda

2012-12-01

The purpose of this study was to investigate the effect of aromatherapy massage on dysmenorrhea. The study used a quasiexperimental design with the subjects as their own control. Every participant applied both aromatherapy massage with lavender oil and placebo massage with odorless liquid petrolatum [soft paraffin]. The population comprised 438 midwifery and nursing students. The 150 students who had declared that they had suffered from dysmenorrhea used a visual analog scale to indicate their level of pain. Higher scores reflected a greater severity of dysmenorrhea. Forty-four students volunteered to participate in the study. When the lavender massage and the placebo massage were compared, the visual analog scale score of the lavender massage was found to decrease at a statistically significant rate. This study showed that massage was effective in reducing dysmenorrhea. In addition, this study showed that the effect of aromatherapy massage on pain was higher than that of placebo massage. Copyright © 2012 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.
Studying cerebral hemodynamics and metabolism using simultaneous near-infrared spectroscopy and transcranial Doppler ultrasound: a hyperventilation and caffeine study

PubMed Central

Yang, Runze; Brugniaux, Julien; Dhaliwal, Harinder; Beaudin, Andrew E; Eliasziw, Misha; Poulin, Marc J; Dunn, Jeff F

2015-01-01

Caffeine is one of the most widely consumed psycho-stimulants in the world, yet little is known about its effects on brain oxygenation and metabolism. Using a double-blind, placebo-controlled, randomized cross-over study design, we combined transcranial Doppler ultrasound (TCD) and near-infrared spectroscopy (NIRS) to study caffeine's effect on middle cerebral artery peak blood flow velocity (Vp), brain tissue oxygenation (StO2), total hemoglobin (tHb), and cerebral oxygen metabolism (CMRO2) in five subjects. Hyperventilation-induced hypocapnia served as a control to verify the sensitivity of our measurements. During hypocapnia (∼16 mmHg below resting values), Vp decreased by 40.0 ± 2.4% (95% CI, P < 0.001), while StO2 and tHb decreased by 2.9 ± 0.3% and 2.6 ± 0.4%, respectively (P = 0.003 and P = 0.002, respectively). CMRO2, calculated using the Fick equation, was reduced by 29.3 ± 9% compared to the isocapnic-euoxia baseline (P < 0.001). In the pharmacological experiments, there was a significant decrease in Vp, StO2, and tHb after ingestion of 200 mg of caffeine compared with placebo. There was no significant difference in CMRO2 between caffeine and placebo. Both showed a CMRO2 decline compared to baseline showing the importance of a placebo control. In conclusion, this study showed that profound hypocapnia impairs cerebral oxidative metabolism. We provide new insight into the effects of caffeine on cerebral hemodynamics. Moreover, this study showed that multimodal NIRS/TCD is an excellent tool for studying brain hemodynamic responses to pharmacological interventions and physiological challenges. PMID:25907789
Text Messages Promoting Mental Imagery Increase Self-Reported Physical Activity in Older Adults: A Randomized Controlled Study.

PubMed

Robin, Nicolas; Toussaint, Lucette; Coudevylle, Guillaume R; Ruart, Shelly; Hue, Olivier; Sinnapah, Stephane

2018-06-22

This study tested whether text messages prompting adults 50 years of age and older to perform mental imagery would increase aerobic physical activity (APA) duration using a randomized parallel trial design. Participants were assigned to an Imagery 1, Imagery 2, or placebo group. For 4 weeks, each group was exposed to two conditions (morning text message vs. no morning text message). In the morning message condition, the imagery groups received a text message with the instruction to mentally imagine performing an APA, and the placebo group received a placebo message. All participants received an evening text message of "Did you do your cardio today? If yes, what did you do?" for 3 days per week. Participants of the imagery groups reported significantly more weekly minutes of APA in the morning text message condition compared with the no morning message condition. Electronic messages were effective at increasing minutes of APA.
Effect of Tribulus terrestris, ginger, saffron, and Cinnamomum on menopausal symptoms: a randomised, placebo-controlled clinical trial

PubMed Central

Taavoni, Simin; Haghani, Hamid

2017-01-01

Menopausal symptoms experienced by women vary widely, and while many women transition through menopause with manageable symptoms, others experience severe symptoms, which may impair their quality of life. The purpose of this study was to determine the effect of Tribulus terrestris, ginger, saffron, and Cinnamomum on menopausal symptoms. A randomised, triple-blind, controlled trial design was used for this study. The participants were 80 postmenopausal women aged 50–60 years. A demographic data form and the Menopause Rating Scale were used to collect data. The women were randomly divided into two groups, each of which received either an Aphrodit capsule or a placebo twice a day for four weeks. The two bottles looked exactly the same, so that the investigator and the participants were not aware of the contents of the bottles. Each Aphrodit capsule contained 40 mg of Tribulus terrestris, 12.27 mg of Zingiber officinale, 3 mg of Crocus sativus extract, and 11 mg of Cinnamomum zeylanicum, while the placebo capsules contained 50 mg of starch. Descriptive and inferential statistics were used to analyse the data. A statistically significant change was reported in the menopausal symptoms of the intervention group compared with the placebo group. The results of the study demonstrate that the Aphrodit capsule was effective in reducing menopausal symptoms. PMID:28546803
Tribulus terrestris for treatment of sexual dysfunction in women: randomized double-blind placebo - controlled study.

PubMed

Akhtari, Elham; Raisi, Firoozeh; Keshavarz, Mansoor; Hosseini, Hamed; Sohrabvand, Farnaz; Bioos, Soodabeh; Kamalinejad, Mohammad; Ghobadi, Ali

2014-04-28

Tribulus terrestris as a herbal remedy has shown beneficial aphrodisiac effects in a number of animal and human experiments. This study was designed as a randomized double-blind placebo-controlled trial to assess the safety and efficacy of Tribulus terrestris in women with hypoactive sexual desire disorder during their fertile years. Sixty seven women with hypoactive sexual desire disorder were randomly assigned to Tribulus terrestris extract (7.5 mg/day) or placebo for 4 weeks. Desire, arousal, lubrication, orgasm, satisfaction, and pain were measured at baseline and after 4 weeks after the end of the treatment by using the Female Sexual Function Index (FSFI). Two groups were compared by repeated measurement ANOVA test. Thirty women in placebo group and thirty women in drug group completed the study. At the end of the fourth week, patients in the Tribulus terrestris group had experienced significant improvement in their total FSFI (p < 0.001), desire (p < 0.001), arousal (p = 0.037), lubrication (p < 0.001), satisfaction (p < 0.001) and pain (p = 0.041) domains of FSFI. Frequency of side effects was similar between the two groups. Tribulus terrestris may safely and effectively improve desire in women with hypoactive sexual desire disorder. Further investigation of Tribulus terrestris in women is warranted.
Tribulus terrestris for treatment of sexual dysfunction in women: randomized double-blind placebo - controlled study

PubMed Central

2014-01-01

Background Tribulus terrestris as a herbal remedy has shown beneficial aphrodisiac effects in a number of animal and human experiments. This study was designed as a randomized double-blind placebo-controlled trial to assess the safety and efficacy of Tribulus terrestris in women with hypoactive sexual desire disorder during their fertile years. Sixty seven women with hypoactive sexual desire disorder were randomly assigned to Tribulus terrestris extract (7.5 mg/day) or placebo for 4 weeks. Desire, arousal, lubrication, orgasm, satisfaction, and pain were measured at baseline and after 4 weeks after the end of the treatment by using the Female Sexual Function Index (FSFI). Two groups were compared by repeated measurement ANOVA test. Results Thirty women in placebo group and thirty women in drug group completed the study. At the end of the fourth week, patients in the Tribulus terrestris group had experienced significant improvement in their total FSFI (p < 0.001), desire (p < 0.001), arousal (p = 0.037), lubrication (p < 0.001), satisfaction (p < 0.001) and pain (p = 0.041) domains of FSFI. Frequency of side effects was similar between the two groups. Conclusions Tribulus terrestris may safely and effectively improve desire in women with hypoactive sexual desire disorder. Further investigation of Tribulus terrestris in women is warranted. PMID:24773615
Erotic Stimulus Processing under Amisulpride and Reboxetine: A Placebo-Controlled fMRI Study in Healthy Subjects

PubMed Central

Wiegers, Maike; Metzger, Coraline D.; Walter, Martin; Grön, Georg; Abler, Birgit

2015-01-01

Background: Impaired sexual function is increasingly recognized as a side effect of psychopharmacological treatment. However, underlying mechanisms of action of the different drugs on sexual processing are still to be explored. Using functional magnetic resonance imaging, we previously investigated effects of serotonergic (paroxetine) and dopaminergic (bupropion) antidepressants on sexual functioning (Abler et al., 2011). Here, we studied the impact of noradrenergic and antidopaminergic medication on neural correlates of visual sexual stimulation in a new sample of subjects. Methods: Nineteen healthy heterosexual males (mean age 24 years, SD 3.1) under subchronic intake (7 days) of the noradrenergic agent reboxetine (4mg/d), the antidopaminergic agent amisulpride (200mg/d), and placebo were included and studied with functional magnetic resonance imaging within a randomized, double-blind, placebo-controlled, within-subjects design during an established erotic video-clip task. Subjective sexual functioning was assessed using the Massachusetts General Hospital-Sexual Functioning Questionnaire. Results: Relative to placebo, subjective sexual functioning was attenuated under reboxetine along with diminished neural activations within the caudate nucleus. Altered neural activations correlated with decreased sexual interest. Under amisulpride, neural activations and subjective sexual functioning remained unchanged. Conclusions: In line with previous interpretations of the role of the caudate nucleus in the context of primary reward processing, attenuated caudate activation may reflect detrimental effects on motivational aspects of erotic stimulus processing under noradrenergic agents. PMID:25612894
Effects of the combination of metyrapone and oxazepam on cocaine craving and cocaine taking: a double-blind, randomized, placebo-controlled pilot study.

PubMed

Kablinger, Anita S; Lindner, Marie A; Casso, Stephanie; Hefti, Franz; DeMuth, George; Fox, Barbara S; McNair, Lindsay A; McCarthy, Bruce G; Goeders, Nicholas E

2012-07-01

Although cocaine dependence affects an estimated 1.6 million people in the USA, there are currently no medications approved for the treatment of this disorder. Experiments performed in animal models have demonstrated that inhibitors of the stress response effectively reduce intravenous cocaine self-administration. This exploratory, double-blind, placebo-controlled study was designed to assess the safety and efficacy of combinations of the cortisol synthesis inhibitor metyrapone, and the benzodiazepine oxazepam, in 45 cocaine-dependent individuals. The subjects were randomized to a total daily dose of 500 mg metyrapone/20 mg oxazepam (low dose), a total daily dose of 1500 mg metyrapone/20 mg oxazepam (high dose), or placebo for 6 weeks of treatment. The outcome measures were a reduction in cocaine craving and associated cocaine use as determined by quantitative measurements of the cocaine metabolite benzoylecgonine (BE) in urine at all visits. Of the randomized subjects, 49% completed the study. The combination of metyrapone and oxazepam was well tolerated and tended to reduce cocaine craving and cocaine use, with significant reductions at several time points when controlling for baseline scores. These data suggest that further assessments of the ability of the metyrapone and oxazepam combination to support cocaine abstinence in cocaine-dependent subjects are warranted.
Effects of acute MDMA intoxication on mood and impulsivity: role of the 5-HT2 and 5-HT1 receptors.

PubMed

van Wel, Janelle H P; Kuypers, Kim P C; Theunissen, Eef L; Bosker, Wendy M; Bakker, Katja; Ramaekers, Johannes G

2012-01-01

MDMA induces positive mood and increases impulse control during intoxication, but only a few studies on the neuropharmacological mechanisms underlying these processes have been conducted. It was hypothesized that pretreatment with 5-HT(1) and 5-HT(2) receptor blockers would prevent MDMA effects on mood and impulsivity. Subjects (N = 17) participated in a double-blind, placebo controlled, within-subject design involving 6 experimental conditions consisting of pretreatment (T1) and treatment (T2). T1 preceded T2 by 30 minutes. T1-T2 combinations were: placebo-placebo, 20 mg pindolol-placebo, 50 mg ketanserin-placebo, placebo-75 mg MDMA, 20 mg pindolol-75 mg MDMA and 50 mg ketanserin-75 g MDMA. Subjects completed a Profile of Mood States (POMS) questionnaire and several impulsivity tasks (Stop signal task, Matching familiar figures task, Cue dependent reversal learning task) at 1.5 hrs post-treatment. MDMA alone increased both positive (vigor, arousal, friendliness, elation, positive mood) and negative affect (anxiety, confusion) as assessed by the POMS questionnaire. MDMA also increased stop reaction time in the Stop signal task and reaction time in the Matching familiar figures task. Pretreatment with ketanserin blocked MDMA effects on positive affect, but not negative affect. Ketanserin did not influence the effects of MDMA on impulsivity. Pindolol did not interact with MDMA on any of the measures. In conclusion, 5-HT(2) receptors mediate positive moods induced by MDMA but not negative moods or impulsivity. 5-HT(1) receptors do not appear to be involved in MDMA effects on mood and impulse control. Nederlands Trial Register NTR2352.
Effects of Acute MDMA Intoxication on Mood and Impulsivity: Role of the 5-HT2 and 5-HT1 Receptors

PubMed Central

van Wel, Janelle H. P.; Kuypers, Kim P. C.; Theunissen, Eef L.; Bosker, Wendy M.; Bakker, Katja; Ramaekers, Johannes G.

2012-01-01

MDMA induces positive mood and increases impulse control during intoxication, but only a few studies on the neuropharmacological mechanisms underlying these processes have been conducted. It was hypothesized that pretreatment with 5-HT1 and 5-HT2 receptor blockers would prevent MDMA effects on mood and impulsivity. Subjects (N = 17) participated in a double-blind, placebo controlled, within-subject design involving 6 experimental conditions consisting of pretreatment (T1) and treatment (T2). T1 preceded T2 by 30 minutes. T1–T2 combinations were: placebo-placebo, 20 mg pindolol-placebo, 50 mg ketanserin-placebo, placebo-75 mg MDMA, 20 mg pindolol-75 mg MDMA and 50 mg ketanserin-75 g MDMA. Subjects completed a Profile of Mood States (POMS) questionnaire and several impulsivity tasks (Stop signal task, Matching familiar figures task, Cue dependent reversal learning task) at 1.5 hrs post-treatment. MDMA alone increased both positive (vigor, arousal, friendliness, elation, positive mood) and negative affect (anxiety, confusion) as assessed by the POMS questionnaire. MDMA also increased stop reaction time in the Stop signal task and reaction time in the Matching familiar figures task. Pretreatment with ketanserin blocked MDMA effects on positive affect, but not negative affect. Ketanserin did not influence the effects of MDMA on impulsivity. Pindolol did not interact with MDMA on any of the measures. In conclusion, 5-HT2 receptors mediate positive moods induced by MDMA but not negative moods or impulsivity. 5-HT1 receptors do not appear to be involved in MDMA effects on mood and impulse control. Trial Registration Nederlands Trial Register NTR2352 PMID:22808116
A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease.

PubMed

Turner, R Scott; Thomas, Ronald G; Craft, Suzanne; van Dyck, Christopher H; Mintzer, Jacobo; Reynolds, Brigid A; Brewer, James B; Rissman, Robert A; Raman, Rema; Aisen, Paul S

2015-10-20

A randomized, placebo-controlled, double-blind, multicenter 52-week phase 2 trial of resveratrol in individuals with mild to moderate Alzheimer disease (AD) examined its safety and tolerability and effects on biomarker (plasma Aβ40 and Aβ42, CSF Aβ40, Aβ42, tau, and phospho-tau 181) and volumetric MRI outcomes (primary outcomes) and clinical outcomes (secondary outcomes). Participants (n = 119) were randomized to placebo or resveratrol 500 mg orally once daily (with dose escalation by 500-mg increments every 13 weeks, ending with 1,000 mg twice daily). Brain MRI and CSF collection were performed at baseline and after completion of treatment. Detailed pharmacokinetics were performed on a subset (n = 15) at baseline and weeks 13, 26, 39, and 52. Resveratrol and its major metabolites were measurable in plasma and CSF. The most common adverse events were nausea, diarrhea, and weight loss. CSF Aβ40 and plasma Aβ40 levels declined more in the placebo group than the resveratrol-treated group, resulting in a significant difference at week 52. Brain volume loss was increased by resveratrol treatment compared to placebo. Resveratrol was safe and well-tolerated. Resveratrol and its major metabolites penetrated the blood-brain barrier to have CNS effects. Further studies are required to interpret the biomarker changes associated with resveratrol treatment. This study provides Class II evidence that for patients with AD resveratrol is safe, well-tolerated, and alters some AD biomarker trajectories. The study is rated Class II because more than 2 primary outcomes were designated. © 2015 American Academy of Neurology.
A systematic review and meta-analysis assessing adverse event profile and tolerability of nicergoline

PubMed Central

Fioravanti, Mario; Nakashima, Taku; Xu, Jun; Garg, Amit

2014-01-01

Objective To evaluate the safety profile of nicergoline compared with placebo and other active agents from published randomised controlled trials. Design Systematic review and meta-analysis of nicergoline compared with placebo and other active agents across various indications. Data sources MEDLINE, Medline-in-process, Cochrane, EMBASE, EMBASE alerts, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR) and Cochrane Methodology Register (CMR) for all the randomised controlled trials, open-label or blinded, in adults treated with nicergoline. Studies published until August 2013 were included. Review method 29 studies were included for data extraction. The studies included in this review were majorly from European countries and mostly in cerebrovascular disease (n=15) and dementia (n=8). Results The treatment withdrawals were comparatively lower in the nicergoline group as compared with the placebo group (RR=0.92; 95% CI 0.7 to 1.21) and other active comparators (RR=0.45; 95% CI 0.10 to 1.95), but the difference was non-significant. Incidence of any adverse events (AEs) was slightly higher (RR=1.05; 95% CI 0.93 to 1.2) while incidence of serious AEs was lower (RR=0.85; 95% CI 0.50 to 1.45) in the nicergoline compared with placebo group. Frequency of anxiety was significantly lower in nicergoline as compared with placebo (p=0.01). Other AEs including diarrhoea, gastric upset, dizziness and drowsiness were less frequent in the nicergoline group when compared with placebo/active drugs, but the difference was non-significant. Frequency of hypotension and hot flushes was slightly higher in the nicergoline group but the difference was non-significant. None of the studies reported any incidence of fibrosis or ergotism with nicergoline treatment. Conclusions Nicergoline is an ergot derivative, but its safety profile is better than other ergot derivatives like ergotamine and ergotoxine. This systematic review and meta-analysis suggests that nicergoline has a good safety profile. None of the studies included in this systematic review reported any incidence of fibrosis or ergotism with nicergoline. PMID:25079927

Effect of N-Methyl-D-Aspartate Receptor Antagonist Dextromethorphan on Opioid Analgesia in Pediatric Intensive Care Unit

PubMed Central

Al Alem, Hala; Al Shehri, Ali; Al-Jeraisy, Majed

2016-01-01

Objective. Pain control is an essential goal in the management of critical children. Narcotics are the mainstay for pain control. Patients frequently need escalating doses of narcotics. In such cases an adjunctive therapy may be beneficial. Dextromethorphan (DM) is NMDA receptor antagonist and may prevent tolerance to narcotics; however, its definitive role is still unclear. We sought whether dextromethorphan addition could decrease the requirements of fentanyl to control pain in critical children. Design. Double-blind, randomized control trial (RCT). Setting. Pediatric multidisciplinary ICU in tertiary care center. Patients. Thirty-six pediatric patients 2–14 years of age in a multidisciplinary PICU requiring analgesia were randomized into dextromethorphan and placebo. The subjects in both groups showed similarity in most of the characteristics. Interventions. Subjects while receiving fentanyl for pain control received dextromethorphan or placebo through nasogastric/orogastric tubes for 96 hours. Pain was assessed using FLACC and faces scales. Measurements and Main Results. This study found no statistical significant difference in fentanyl requirements between subjects receiving dextromethorphan and those receiving placebo (p = 0.127). Conclusions. Dextromethorphan has no effect on opioid requirement for control of acute pain in children admitted with acute critical care illness in PICU. The registration number for this trial is NCT01553435. PMID:27867308
Effect of N-Methyl-D-Aspartate Receptor Antagonist Dextromethorphan on Opioid Analgesia in Pediatric Intensive Care Unit.

PubMed

Naeem, Mohammed; Al Alem, Hala; Al Shehri, Ali; Al-Jeraisy, Majed

2016-01-01

Objective . Pain control is an essential goal in the management of critical children. Narcotics are the mainstay for pain control. Patients frequently need escalating doses of narcotics. In such cases an adjunctive therapy may be beneficial. Dextromethorphan (DM) is NMDA receptor antagonist and may prevent tolerance to narcotics; however, its definitive role is still unclear. We sought whether dextromethorphan addition could decrease the requirements of fentanyl to control pain in critical children. Design . Double-blind, randomized control trial (RCT). Setting . Pediatric multidisciplinary ICU in tertiary care center. Patients . Thirty-six pediatric patients 2-14 years of age in a multidisciplinary PICU requiring analgesia were randomized into dextromethorphan and placebo. The subjects in both groups showed similarity in most of the characteristics. Interventions . Subjects while receiving fentanyl for pain control received dextromethorphan or placebo through nasogastric/orogastric tubes for 96 hours. Pain was assessed using FLACC and faces scales. Measurements and Main Results . This study found no statistical significant difference in fentanyl requirements between subjects receiving dextromethorphan and those receiving placebo ( p = 0.127). Conclusions . Dextromethorphan has no effect on opioid requirement for control of acute pain in children admitted with acute critical care illness in PICU. The registration number for this trial is NCT01553435.
Randomized, double-blinded, placebo-controlled trial comparing two multimodal opioid-minimizing pain management regimens following transsphenoidal surgery.

PubMed

Shepherd, Deborah M; Jahnke, Heidi; White, William L; Little, Andrew S

2018-02-01

OBJECTIVE Pain control is an important clinical consideration and quality-of-care metric. No studies have examined postoperative pain control following transsphenoidal surgery for pituitary lesions. The study goals were to 1) report postoperative pain scores following transsphenoidal surgery, 2) determine if multimodal opioid-minimizing pain regimens yielded satisfactory postoperative pain control, and 3) determine if intravenous (IV) ibuprofen improved postoperative pain scores and reduced opioid use compared with placebo. METHODS This study was a single-center, randomized, double-blinded, placebo-controlled intervention trial involving adult patients with planned transsphenoidal surgery for pituitary tumors randomized into 2 groups. Group 1 patients were treated with scheduled IV ibuprofen, scheduled oral acetaminophen, and rescue opioids. Group 2 patients were treated with IV placebo, scheduled oral acetaminophen, and rescue opioids. The primary end point was patient pain scores (visual analog scale [VAS], rated 0-10) for 48 hours after surgery. The secondary end point was opioid use as estimated by oral morphine equivalents (OMEs). RESULTS Of 136 patients screened, 62 were enrolled (28 in Group 1, 34 in Group 2). The study was terminated early because the primary and secondary end points were reached. Baseline characteristics between groups were well matched except for age (Group 1, 59.3 ± 14.4 years; Group 2, 49.8 ± 16.2 years; p = 0.02). Mean VAS pain scores were significantly different, with a 43% reduction in Group 1 (1.7 ± 2.2) compared with Group 2 (3.0 ± 2.8; p < 0.0001). Opioid use was significantly different, with a 58% reduction in Group 1 (26.3 ± 28.7 mg OME) compared with Group 2 (62.5 ± 63.8 mg OME; p < 0.0001). CONCLUSIONS Multimodal opioid-minimizing pain-management protocols resulted in acceptable pain control following transsphenoidal surgery. IV ibuprofen resulted in significantly improved pain scores and significantly decreased opioid use compared with placebo. Postoperative multimodal pain management, including a nonsteroidal antiinflammatory medication, should be considered after surgery to improve patient comfort and to limit opioid use. Clinical trial registration no.: NCT02351700 (clinicaltrials.gov) ■ CLASSIFICATION OF EVIDENCE Type of question: therapeutic; study design: randomized, controlled trial; evidence: Class III.
Single-dose intra-articular bupivacaine plus morphine after knee arthroscopic surgery: a meta-analysis of randomised placebo-controlled studies

PubMed Central

Wang, Yi-lun; Zeng, Chao; Xie, Dong-xing; Yang, Ye; Wei, Jie; Yang, Tuo; Li, Hui; Lei, Guang-hua

2015-01-01

Objectives To evaluate the efficacy and safety of single-dose intra-articular bupivacaine plus morphine after knee arthroscopic surgery. Design Meta-analysis. Data sources and study eligibility criteria A comprehensive literature search, using Medline (1966–2014), the Cochrane Central Register of Controlled Trials and Embase databases, was conducted to identify randomised placebo-controlled trials that used a combination of single-dose intra-articular bupivacaine and morphine for postoperative pain relief. Results 12 articles were included in this meta-analysis. The mean visual analogue scale (VAS) scores of the bupivacaine plus morphine group were significantly lower than those of the placebo group (weighted mean difference (WMD) −1.75; 95% CI −2.16 to −1.33; p<0.001). The VAS scores at the last follow-up time point (last VAS scores) of the bupivacaine plus morphine group were also significantly lower than those of the placebo group (WMD −1.46; 95% CI −1.63 to −1.29; p<0.001). The number of patients requiring supplementary analgesia was also significantly reduced (RR 0.60; 95% CI 0.39 to 0.93; p=0.02), while there was no significant difference in the time to first analgesic request (WMD 3.46; 95% CI −1.81 to 8.72; p=0.20) or short-term side effects (RR 1.67; 95% CI 0.65 to 4.26; p=0.29). Conclusions The administration of single-dose intra-articular bupivacaine plus morphine after knee arthroscopic surgery is effective for pain relief, and its short-term side effects remain similar to saline placebo. PMID:26078306
Effect of a lateral glide mobilisation with movement of the hip on vibration threshold in healthy volunteers.

PubMed

Smith, Darren A; Saranga, Jacob; Pritchard, Andrew; Kommatas, Nikolaos A; Punnoose, Shinu Kovelal; Kale, Supriya Tukaram

2018-01-01

Mulligan's mobilisation-with-movement (MWM) techniques are proposed to achieve their clinical benefit via neurophysiological mechanisms. However, previous research has focussed on responses in the sympathetic nervous system only, and is not conclusive. An alternative measure of neurophysiological response to MWM is required to support or refute this mechanism of action. Recently, vibration threshold (VT) has been used to quantify changes in the sensory nervous system in patients experiencing musculoskeletal pain. To investigate the effect of a lateral glide MWM of the hip joint on vibration threshold compared to a placebo and control condition in asymptomatic volunteers. Fifteen asymptomatic volunteers participated in this single-blinded, randomised, within-subject, placebo, control design. Participants received each of three interventions in a randomised order; a lateral glide MWM of the hip joint into flexion, a placebo MWM, and a control intervention. Vibration threshold (VT) measures were taken at baseline and immediately after each intervention. Mean change in VT from baseline was calculated for each intervention and then analysed for between group differences using a one-way analysis of variance (ANOVA). A one-way ANOVA revealed no statistically significant differences between the three experimental conditions (P = 0.812). This small study found that a lateral glide MWM of the hip did not significantly change vibration threshold compared to a placebo and control intervention in an asymptomatic population. This study provides a method of using vibration threshold to investigate the potential neurophysiological effects of a manual therapy intervention that should be repeated in a larger, symptomatic population. Copyright © 2016 Elsevier Ltd. All rights reserved.
The ethics of placebo-controlled trials: methodological justifications.

PubMed

Millum, Joseph; Grady, Christine

2013-11-01

The use of placebo controls in clinical trials remains controversial. Ethical analysis and international ethical guidance permit the use of placebo controls in randomized trials when scientifically indicated in four cases: (1) when there is no proven effective treatment for the condition under study; (2) when withholding treatment poses negligible risks to participants; (3) when there are compelling methodological reasons for using placebo, and withholding treatment does not pose a risk of serious harm to participants; and, more controversially, (4) when there are compelling methodological reasons for using placebo, and the research is intended to develop interventions that can be implemented in the population from which trial participants are drawn, and the trial does not require participants to forgo treatment they would otherwise receive. The concept of methodological reasons is essential to assessing the ethics of placebo controls in these controversial last two cases. This article sets out key considerations relevant to considering whether methodological reasons for a placebo control are compelling. © 2013.
The Minnesota Green Tea Trial (MGTT), a randomized controlled trial of the efficacy of green tea extract on biomarkers of breast cancer risk: Study rationale, design, methods, and participant characteristics

PubMed Central

Samavat, Hamed; Dostal, Allison M.; Wang, Renwei; Bedell, Sarah; Emory, Tim H.; Ursin, Giske; Torkelson, Carolyn J.; Gross, Myron D.; Le, Chap T.; Yu, Mimi C.; Yang, Chung S.; Yee, Douglas; Wu, Anna H.; Yuan, Jian-Min; Kurzer, Mindy S.

2015-01-01

Purpose The Minnesota Green Tea Trial (MGTT) was a randomized, placebo-controlled, double-blinded trial investigating the effect of daily green tea extract consumption for 12 months on biomarkers of breast cancer risk. Methods Participants were healthy postmenopausal women at high risk of breast cancer due to dense breast tissue with differing catechol-O-methyltransferase (COMT) genotypes. The intervention was a green tea catechin extract containing 843.0 ± 44.0 mg/day epigallocatechin gallate or placebo capsules for one year. Annual digital screening mammograms were obtained at baseline and month 12, and fasting blood and 24-hour urine samples were provided at baseline, months 6, and 12. Primary endpoints included changes in percent mammographic density, circulating endogenous sex hormones and insulin-like growth factor axis proteins; secondary endpoints were changes in urinary estrogens and estrogen metabolites and circulating F2-isoprostanes, a biomarker of oxidative stress. Results The MGTT screened more than 100,000 mammograms and randomized 1075 participants based on treatment (green tea extract vs. placebo), stratified by COMT genotype activity (high COMT vs. low/intermediate COMT genotype activity). 937 women successfully completed the study and 138 dropped out (overall dropout rate= 12.8%). Conclusions In this paper we report the rationale, design, recruitment, participant characteristics, and methods for biomarker and statistical analyses. PMID:26206423
3D technology of Sony Bloggie has no advantage in decision-making of tennis serve direction: A randomized placebo-controlled study.

PubMed

Liu, Sicong; Ritchie, Jason; Sáenz-Moncaleano, Camilo; Ward, Savanna K; Paulsen, Cody; Klein, Tyler; Gutierrez, Oscar; Tenenbaum, Gershon

2017-06-01

This study aimed at exploring whether 3D technology enhances tennis decision-making under the conceptual framework of human performance model. A 3 (skill-level: varsity, club, recreational) × 3 (experimental condition: placebo, weak 3D [W3D], strong 3D [S3D]) between-participant design was used. Allocated to experimental conditions by a skill-level stratified randomization, 105 tennis players judged tennis serve direction from video scenarios and rated their perceptions of enjoyment, flow, and presence during task performance. Results showed that varsity players made more accurate decisions than less skilled ones. Additionally, applying 3D technology to typical video displays reduced tennis players' decision-making accuracy, although wearing the 3D glasses led to a placebo effect that shortened the decision-making reaction time. The unexpected negative effect of 3D technology on decision-making was possibly due to participants being more familiar to W3D than to S3D, and relatedly, a suboptimal task-technology match. Future directions for advancing this area of research are offered. Highlights 3D technology augments binocular depth cues to tradition video displays, and thus results in the attainment of more authentic visual representation. This process enhances task fidelity in researching perceptual-cognitive skills in sports. The paper clarified both conceptual and methodological difficulties in testing 3D technology in sports settings. Namely, the nomenclature of video footage (with/without 3D technology) and the possible placebo effect (arising from wearing glasses of 3D technology) merit researchers' attention. Participants varying in level of domain-specific expertise were randomized into viewing conditions using a placebo-controlled design. Measurement consisted of both participants' subjective experience (i.e., presence, flow, and enjoyment) and objective performance (i.e., accuracy and reaction time) in a decision-making task. Findings revealed that wearing glasses of 3D technology resulted in a placebo effect that shortened participants' reaction times in decision-making. Moreover, participants' decision-making accuracy decreased when viewing video scenarios using 3D technology. The findings generated meaningful implications regarding applying 3D technology to sports research.
The effect of probiotics as a treatment for constipation in elderly people: A systematic review.

PubMed

Martínez-Martínez, Maria Isabel; Calabuig-Tolsá, Raquel; Cauli, Omar

2017-07-01

Treating constipation in elderly people remains a challenge; the administration of probiotics may be a valid therapy for this problem as an alternative to traditional drug-based treatments. The objective of this systematic review was to evaluate the efficiency of probiotics in treating constipation in elderly people. Articles related to this topic and published, without any time limitations, in the Medline, Embase, Scopus, Lilacs, or Cochrane databases were systematically reviewed according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The primary search terms were 'constipation' and 'probiotics'. The main inclusion criteria were: 1) the article was original and the whole text was published in English or Spanish and 2) included the primary search terms in the title, summary, or body text; 3) the studies had to have included 60 or more participants defined as 'elderly' and 4) have specifically evaluated the effect of the administration of probiotics. Of the 475 articles consulted, 9 met the inclusion criteria. Among the selected studies, there were four randomised and placebo-controlled trials and the remaining five reports were observational. Overall, our analysis of the randomised and placebo-controlled trials suggests that administration of probiotics significantly improved constipation in elderly individuals by 10-40% compared to placebo controls in which no probiotic was administered. The strain of bacteria most commonly tested was Bifidobacterium longum. However, caution is needed when interpreting these reports because of the heterogeneity of the original study designs, populations, and the risk of bias. Therefore, further placebo-controlled trials are necessary to determine the most efficient strains, doses, and the optimal treatment duration. Copyright © 2017 Elsevier B.V. All rights reserved.
The placebo effect and its determinants in fibromyalgia: meta-analysis of randomised controlled trials.

PubMed

Chen, Xi; Zou, Kun; Abdullah, Natasya; Whiteside, Nicola; Sarmanova, Aliya; Doherty, Michael; Zhang, Weiya

2017-07-01

The aims of this study were to determine whether placebo treatment in randomised controlled trials (RCTs) is effective for fibromyalgia and to identify possible determinants of the magnitude of any such placebo effect. A systematic literature search was undertaken for RCTs in people with fibromyalgia that included a placebo and/or a no-treatment (observation only or waiting list) control group. Placebo effect size (ES) for pain and other outcomes was measured as the improvement of each outcome from baseline divided by the standard deviation of the change from baseline. This effect was compared with changes in the no-treatment control groups. Meta-analysis was undertaken to combine data from different studies. Subgroup analysis was conducted to identify possible determinants of the placebo ES. A total of 3912 studies were identified from the literature search. After scrutiny, 229 trials met the inclusion criteria. Participants who received placebo in the RCTs experienced significantly better improvements in pain, fatigue, sleep quality, physical function, and other main outcomes than those receiving no treatment. The ES of placebo for pain relief was clinically moderate (0.53, 95%CI 0.48 to 0.57). The ES increased with increasing strength of the active treatment, increasing participant age and higher baseline pain severity, but decreased in RCTS with more women and with longer duration of fibromyalgia. In addition, placebo treatment in RCTs is effective in fibromyalgia. A number of factors (expected strength of treatment, age, gender, disease duration) appear to influence the magnitude of the placebo effect in this condition.
Combining rigour with relevance: a novel methodology for testing Chinese herbal medicine.

PubMed

Flower, Andrew; Lewith, George; Little, Paul

2011-03-24

There is a need to develop an evidence base for Chinese herbal medicine (CHM) that is both rigorous and reflective of good practice. This paper proposes a novel methodology to test individualised herbal decoctions using a randomised, double blinded, placebo controlled clinical trial. A feasibility study was conducted to explore the role of CHM in the treatment of endometriosis. Herbal formulae were pre-cooked and dispensed as individual doses in sealed plastic sachets. This permitted the development and testing of a plausible placebo decoction. Participants were randomised at a distant pharmacy to receive either an individualised herbal prescription or a placebo. The trial met the predetermined criteria for good practice. Neither the participants nor the practitioner-researcher could reliably identify group allocation. Of the 28 women who completed the trial, in the placebo group (n=15) 3 women (20%) correctly guessed they were on placebo, 8 (53%) thought they were on herbs and 4 (27%) did not know which group they had been allocated to. In the active group (n=13) 2 (15%) though they were on placebo, 8 (62%) thought they were on herbs and 3 (23%) did not know. Randomisation, double blinding and allocation concealment were successful and the study model appeared to be feasible and effective. It is now possible to subject CHM to rigorous scientific scrutiny without compromising model validity. Improvement in the design of the placebo using food colourings and flavourings instead of dried food will help guarantee the therapeutic inertia of the placebo decoction. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
The 11-β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor INCB13739 Improves Hyperglycemia in Patients With Type 2 Diabetes Inadequately Controlled by Metformin Monotherapy

PubMed Central

Rosenstock, Julio; Banarer, Salomon; Fonseca, Vivian A.; Inzucchi, Silvio E.; Sun, William; Yao, Wenqing; Hollis, Gregory; Flores, Robert; Levy, Richard; Williams, William V.; Seckl, Jonathan R.; Huber, Reid

2010-01-01

OBJECTIVE 11-β-hydroxysteroid dehydrogenase type 1 (11βHSD1) converts inactive cortisone into active cortisol, thereby amplifying intracellular glucocorticoid action. The efficacy and safety of the 11βHSD1 inhibitor INCB13739 were assessed when added to ongoing metformin monotherapy in patients with type 2 diabetes exhibiting inadequate glycemic control (A1C 7–11%). RESEARCH DESIGN AND METHODS This double-blind placebo-controlled paralleled study randomized 302 patients with type 2 diabetes (mean A1C 8.3%) on metformin monotherapy (mean 1.5 g/day) to receive one of five INCB13739 doses or placebo once daily for 12 weeks. The primary end point was the change in A1C at study end. Other end points included changes in fasting glucose, lipids, weight, adverse events, and safety. RESULTS After 12 weeks, 200 mg of INCB13739 resulted in significant reductions in A1C (−0.6%), fasting plasma glucose (−24 mg/dl), and homeostasis model assessment–insulin resistance (HOMA-IR) (−24%) compared with placebo. Total cholesterol, LDL cholesterol, and triglycerides were all significantly decreased in hyperlipidemic patients. Body weight decreased relative to placebo after INCB13739 therapy. A reversible dose-dependent elevation in adrenocorticotrophic hormone, generally within the normal reference range, was observed. Basal cortisol homeostasis, testosterone in men, and free androgen index in women were unchanged by INCB13739. Adverse events were similar across all treatment groups. CONCLUSIONS INCB13739 added to ongoing metformin therapy was efficacious and well tolerated in patients with type 2 diabetes who had inadequate glycemic control with metformin alone. 11βHSD1 inhibition offers a new potential approach to control glucose and cardiovascular risk factors in type 2 diabetes. PMID:20413513
The RAndomized Placebo Phase Study Of Rilonacept in the Treatment of Systemic Juvenile Idiopathic Arthritis (RAPPORT)

PubMed Central

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
Experience and challenges presented by a multicenter crossover study of combination analgesic therapy for the treatment of painful HIV-associated polyneuropathies

PubMed Central

Harrison, Taylor; Miyahara, Sachiko; Lee, Anthony; Evans, Scott; Bastow, Barbara; Simpson, David; Gilron, Ian; Dworkin, Robert; Daar, Eric S.; Wieclaw, Linda; Clifford, David B.

2014-01-01

Objective There is limited evidence for efficacy of analgesics as monotherapy for neuropathic pain associated with HIV-associated polyneuropathies, in spite of demonstrated efficacy in other neuropathic pain conditions. We evaluated the tolerability and analgesic efficacy of duloxetine, methadone, and the combination of duloxetine-methadone compared to placebo. Design This study was a phase II, randomized, double blind, placebo-controlled, four-period crossover multi-center study of analgesic therapy for patients with at least moderate neuropathic pain due to HIV-associated polyneuropathy. Duloxetine, methadone, combination duloxetine-methadone, and placebo were administered in four different possible sequences. The primary outcome measure was mean pain intensity (MPI) measured daily in a study-supplied pain diary. Results A total of 15 patients were enrolled from 8 study sites and 8 patients completed the entire trial. Study treatments failed to show statistically significant change in MPI compared to placebo. Adverse events were frequent and associated with high rates of drug discontinuation and study drop-out. Conclusions Challenges with participant recruitment and poor retention precluded trial completion to its planned targets, limiting our evaluation of the analgesic efficacy of the study treatments. Challenges to successful completion of this study and lessons learned are discussed. PMID:23565581
Headache: the placebo effects in the control groups in randomized clinical trials; an analysis of systematic reviews.

PubMed

de Groot, Femke M; Voogt-Bode, Annieke; Passchier, Jan; Berger, Marjolein Y; Koes, Bart W; Verhagen, Arianne P

2011-06-01

The purpose of this study is to describe the effects in the placebo and "no treatment" arms in trials with headache patients. This is a secondary analysis of randomized controlled trials from 8 systematic reviews and selected trials with a "no treatment" or placebo control group. The different types of "no treatment" and placebo interventions were assessed and classified into 6 subgroups. The analyses were carried out according to type of outcome variable. In total, 119 studies were included (7119 participants). The mean recovery rate in all control groups was 35.7%. Significantly more participants recovered in control groups of pharmacological studies than in nonpharmacological studies: 38.5% vs 15.0%, respectively. Adults were more likely to recover in nonpharmacological studies and children in pharmacological studies. The mean recovery rate in the control groups was 36%. The recovery rate varied substantially between type of intervention and patients. Copyright © 2011 National University of Health Sciences. Published by Mosby, Inc. All rights reserved.
The Effect of the Type and Colour of Placebo Stimuli on Placebo Effects Induced by Observational Learning.

PubMed

Świder, Karolina; Bąbel, Przemysław

2016-01-01

Research shows that placebo analgesia and nocebo hyperalgesia can be induced through observational learning. Our aim was to replicate and extend these results by studying the influence of the type and colour of stimuli used as placebos on the placebo effects induced by observational learning. Three experimental and two control groups were tested. All participants received pain stimuli of the same intensity preceded by colour lights (green and red) or geometric shapes (circles and squares). Before receiving pain stimuli, participants in the experimental groups, but not in the control groups, observed a model who rated pain stimuli that were preceded by either green lights (green placebo group), red lights (red placebo group), or circles (circle placebo group) as being less painful than those preceded by either red lights (green placebo group), green lights (red placebo group), or squares (circle placebo group). As a result participants in the experimental groups rated pain stimuli preceded by either green lights (green placebo group), red lights (red placebo group), or circles (circle placebo group) as being less painful than the participants in the control groups did, indicating that placebo effect was induced. No statistically significant differences were found in the magnitudes of the placebo effects between the three experimental groups (green placebo, red placebo, and circle placebo groups), indicating that neither the type nor the colour of placebo stimuli affected the placebo effects induced by observational learning. The placebo effects induced by observational learning were found to be unrelated to the individual differences in pain anxiety, fear of pain, and empathy.
The Effect of the Type and Colour of Placebo Stimuli on Placebo Effects Induced by Observational Learning

PubMed Central

Świder, Karolina; Bąbel, Przemysław

2016-01-01

Research shows that placebo analgesia and nocebo hyperalgesia can be induced through observational learning. Our aim was to replicate and extend these results by studying the influence of the type and colour of stimuli used as placebos on the placebo effects induced by observational learning. Three experimental and two control groups were tested. All participants received pain stimuli of the same intensity preceded by colour lights (green and red) or geometric shapes (circles and squares). Before receiving pain stimuli, participants in the experimental groups, but not in the control groups, observed a model who rated pain stimuli that were preceded by either green lights (green placebo group), red lights (red placebo group), or circles (circle placebo group) as being less painful than those preceded by either red lights (green placebo group), green lights (red placebo group), or squares (circle placebo group). As a result participants in the experimental groups rated pain stimuli preceded by either green lights (green placebo group), red lights (red placebo group), or circles (circle placebo group) as being less painful than the participants in the control groups did, indicating that placebo effect was induced. No statistically significant differences were found in the magnitudes of the placebo effects between the three experimental groups (green placebo, red placebo, and circle placebo groups), indicating that neither the type nor the colour of placebo stimuli affected the placebo effects induced by observational learning. The placebo effects induced by observational learning were found to be unrelated to the individual differences in pain anxiety, fear of pain, and empathy. PMID:27362552
A randomized trial of controlled-release oxycodone during inpatient rehabilitation following unilateral total knee arthroplasty.

PubMed

Cheville, A; Chen, A; Oster, G; McGarry, L; Narcessian, E

2001-04-01

Reliance on "as-needed" analgesia following total knee arthroplasty may lead to inadequate control of pain and delayed recovery of function. Preemptive use of controlled-release opioids may improve pain control, accelerate recovery, and reduce the need for inpatient rehabilitative services. This study was designed to determine whether controlled-release opioids enhance post-arthroplasty pain control and facilitate functional recovery during rehabilitation. Fifty-nine patients admitted for inpatient rehabilitation following unilateral total knee arthroplasty were randomized to receive OxyContin (controlled-release oxycodone) (twenty-nine patients) or a placebo (thirty patients) every twelve hours. Both groups could receive on-request, immediate-release oxycodone (5 mg every four hours). The dose of study medication was increased on the basis of the frequency of requests for immediate-release oxycodone. Measures of interest included pain ratings as determined with a visual-analog scale, changes in the range of motion of the knee and quadriceps strength, and improvements in selected Functional Independence Measure scores during the first eight physical therapy sessions. The duration of the hospital stay for rehabilitation also was compared between the two groups. Baseline demographic, clinical, and functional characteristics were similar between the OxyContin and placebo groups. Compared with the placebo group, the patients who received OxyContin reported significantly less pain as well as significantly greater range of motion of the knee (passive motion, p = 0.036; active motion, p< 0.001) and quadriceps strength (p = 0.001) by the eighth physical therapy session. The patients who received OxyContin also were discharged from the rehabilitation hospital at an average of 2.3 days earlier than the patients in the placebo group (p = 0.013). Preemptive use of controlled-release oxycodone during rehabilitation following total knee arthroplasty leads to improved pain control, more rapid functional recovery, and a reduced need for inpatient rehabilitative services.
Oral Aripiprazole as Maintenance Treatment in Adolescent Schizophrenia: Results From a 52-Week, Randomized, Placebo-Controlled Withdrawal Study.

PubMed

Correll, Christoph U; Kohegyi, Eva; Zhao, Cathy; Baker, Ross A; McQuade, Robert; Salzman, Phyllis M; Sanchez, Raymond; Nyilas, Margaretta; Carson, William

2017-09-01

To evaluate the efficacy, safety, and tolerability of aripiprazole, a dopamine D 2 receptor partial agonist, as maintenance treatment in adolescent outpatients with schizophrenia. This was a multicenter, double-blind, placebo-controlled, randomized withdrawal design trial. Participants 13 to 17 years of age with a diagnosis of schizophrenia (DSM-IV-TR) were first cross-titrated from their other oral antipsychotic(s) (4-6 weeks), then stabilized (7-21 weeks) on oral aripiprazole 10 to 30 mg/d, and finally randomized 2:1 to continuation of oral aripiprazole or to placebo in a double-blind maintenance phase (≤52 weeks). The primary endpoint was time from randomization to exacerbation of psychotic symptoms/impending relapse. Safety and tolerability were assessed. Of 201 enrolled participants, 146 were randomized to aripiprazole (n = 98) or placebo (n = 48) in the double-blind maintenance phase. Treatment with aripiprazole was associated with a significantly longer time to exacerbation of psychotic symptoms/impending relapse compared with placebo (hazard ratio, 0.46 [95% CI = 0.24-0.88]; p = .016). Aripiprazole was associated with lower rates of serious treatment-emergent adverse events (TEAEs) versus placebo (3.1% versus 12.5%; p = .059) and severe TEAEs (2.0% versus 10.4%; p = .039). The rate of discontinuation due to TEAEs was lower with aripiprazole versus placebo (20.4% versus 39.6%, p = .014; number-needed-to-harm = 5.1). The incidences of extrapyramidal symptoms, weight gain, and somnolence were similar or lower with aripiprazole than with placebo, and no TEAEs related to elevated serum prolactin were reported. Based on Tanner staging, 27.6% of participants treated with aripiprazole and 16.7% of those who received placebo progressed one or two stages from baseline. Aripiprazole was observed to be safe and effective for the maintenance treatment of adolescents with schizophrenia. Efficacy and Safety Study of Oral Aripiprazole in Adolescents With Schizophrenia; http://clinicaltrials.gov/; NCT01149655. Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
The CREST-E study of creatine for Huntington disease: A randomized controlled trial.

PubMed

Hersch, Steven M; Schifitto, Giovanni; Oakes, David; Bredlau, Amy-Lee; Meyers, Catherine M; Nahin, Richard; Rosas, Herminia Diana

2017-08-08

To investigate whether creatine administration could slow progressive functional decline in adults with early symptoms of Huntington disease. We conducted a multicenter, randomized, double-blind, placebo-controlled study of up to 40 g daily of creatine monohydrate in participants with stage I and II HD treated for up to 48 months. The primary outcome measure was the rate of change in total functional capacity (TFC) between baseline and end of follow-up. Secondary outcome measures included changes in additional clinical scores, tolerability, and quality of life. Safety was assessed by adverse events and laboratory studies. At 46 sites in North America, Australia, and New Zealand, 553 participants were randomized to creatine (275) or placebo (278). The trial was designed to enroll 650 patients, but was halted for futility after the first interim analysis. The estimated rates of decline in the primary outcome measure (TFC) were 0.82 points per year for participants on creatine, 0.70 points per year for participants on placebo, favoring placebo (nominal 95% confidence limits -0.11 to 0.35). Adverse events, mainly gastrointestinal, were significantly more common in participants on creatine. Serious adverse events, including deaths, were more frequent in the placebo group. Subgroup analysis suggested that men and women may respond differently to creatine treatment. Our data do not support the use of creatine treatment for delaying functional decline in early manifest HD. NCT00712426. This study provides Class II evidence that for patients with early symptomatic HD, creatine monohydrate is not beneficial for slowing functional decline. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Prospective, randomized, controlled, proof-of-concept study of the Ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients.

PubMed

Beck, David E; Sweeney, W Brian; McCarter, Martin D

2014-12-01

Postoperative ileus is a significant clinical challenge lacking effective management strategies. Ghrelin-receptor stimulation has promotility effects in the upper and lower gastrointestinal tract. This proof-of-concept, phase 2, randomized study evaluated the safety and efficacy of the ghrelin-receptor agonist ipamorelin in the treatment of postoperative ileus following abdominal surgery (ClinicalTrials.gov NCT00672074). The design was a multicenter, double-blind, placebo-controlled, clinical trial. The settings include hospital inpatients. The patients were adults undergoing small and large bowel resection by open or laparoscopic surgery. The intervention was intravenous infusions of 0.03-mg/kg ipamorelin vs placebo twice daily, on postoperative day 1 to 7 or hospital discharge. Safety was assessed by monitoring adverse events and laboratory tests. The key efficacy endpoint was time from first dose of study drug to tolerance of a standardized solid meal. One hundred seventeen patients were enrolled, of whom 114 patients composed the safety and modified intent-to-treat populations. Demographic and disease characteristics were balanced between groups. Overall incidence of any treatment-emergent adverse events was 87.5 % in the ipamorelin group and 94.8 % in placebo group. Median time to first tolerated meal was 25.3 and 32.6 h in the ipamorelin and placebo groups, respectively (p = 0.15). This proof of concept study was small and enrolled patients with a broad range of underlying conditions. Ipamorelin 0.03-mg/kg twice daily for up to 7 days was well tolerated. There were no significant differences between ipamorelin and placebo in the key and secondary efficacy analyses.
Effect of Salsalate on Insulin Action, Secretion, and Clearance in Nondiabetic, Insulin-Resistant Individuals: A Randomized, Placebo-Controlled Study

PubMed Central

Liu, Alice; Ariel, Danit; Abbasi, Fahim; Lamendola, Cindy; Grove, Kaylene; Tomasso, Vanessa; Ochoa, Hector; Reaven, Gerald

2014-01-01

OBJECTIVE Salsalate treatment has been shown to improve glucose homeostasis, but the mechanism remains unclear. The aim of this study was to evaluate the effect of salsalate treatment on insulin action, secretion, and clearance rate in nondiabetic individuals with insulin resistance. RESEARCH DESIGN AND METHODS This was a randomized (2:1), single-blind, placebo-controlled study of salsalate (3.5 g daily for 4 weeks) in nondiabetic individuals with insulin resistance. All individuals had measurement of glucose tolerance (75-g oral glucose tolerance test), steady-state plasma glucose (SSPG; insulin suppression test), and insulin secretion and clearance rate (graded-glucose infusion test) before and after treatment. RESULTS Forty-one individuals were randomized to salsalate (n = 27) and placebo (n = 14). One individual from each group discontinued the study. Salsalate improved fasting (% mean change −7% [95% CI −10 to −14] vs. 1% [−3 to 5], P = 0.005) but not postprandial glucose concentration compared with placebo. Salsalate also lowered fasting triglyceride concentration (−25% [−34 to −15] vs. −6% [−26 to 14], P = 0.04). Salsalate had no effect on SSPG concentration or insulin secretion rate but significantly decreased insulin clearance rate compared with placebo (−23% [−30 to −16] vs. 3% [−10 to 15], P < 0.001). Salsalate was well tolerated, but four individuals needed a dose reduction due to symptoms. CONCLUSIONS Salsalate treatment in nondiabetic, insulin-resistant individuals improved fasting, but not postprandial, glucose and triglyceride concentration. These improvements were associated with a decrease in insulin clearance rate without change in insulin action or insulin secretion. PMID:24963111
Two Double-Blind, Multicenter, Randomized, Placebo-Controlled, Single-Dose Studies of Sumatriptan/Naproxen Sodium in the Acute Treatment of Migraine: Function, Productivity, and Satisfaction Outcomes

PubMed Central

Landy, Stephen; DeRossett, Sarah E.; Rapoport, Alan; Rothrock, John; Ames, Michael H.; McDonald, Susan A.; Burch, Steven P.

2007-01-01

Objective To describe return to normal function, productivity, and satisfaction of patients with moderate or severe migraine attacks treated with combined sumatriptan/naproxen sodium, sumatriptan alone, naproxen sodium alone, or placebo. Patients, design, and setting Patients in 2 identical, US, phase 3, randomized, double-blind, parallel-group, placebo-controlled, single-dose, multicenter studies treated a single moderate or severe migraine attack with sumatriptan/naproxen sodium (85 mg sumatriptan formulated with RT Technology and 500 mg naproxen sodium in a single-tablet formulation), sumatriptan, naproxen sodium, or placebo. Main outcome measures Ability to function (not impaired, mildly impaired, severely impaired, or required bed rest) was collected in diary cards completed immediately prior to treatment, every 30 minutes for the first 2 hours, and hourly from 2 to 24 hours while awake. Patients completed the Productivity Assessment Questionnaire (PAQ) 24 hours after study drug administration. The Patient Perception of Migraine Questionnaire (PPMQ) was administered at screening and 24 hours post treatment to capture patient satisfaction. Results Compared with the other groups, the sumatriptan/naproxen sodium group reported significantly higher levels of normal or mildly impaired functioning as early as 2 and 4 hours after dosing. They also demonstrated greater reductions in workplace productivity loss compared with placebo in both studies, and were consistently more satisfied with their treatment compared with patients in other treatment groups and compared with their usual medications. Conclusions Treatment with sumatriptan/naproxen sodium allowed significantly more subjects to return to normal or mildly impaired functioning more quickly, and sumatriptan/naproxen sodium patients were significantly more satisfied with their treatment compared with other treatment groups. Overall productivity loss was significantly reduced following use of sumatriptan/naproxen sodium. PMID:17955107
Long-Term Teduglutide for the Treatment of Patients With Intestinal Failure Associated With Short Bowel Syndrome.

PubMed

Schwartz, Lauren K; O'Keefe, Stephen J D; Fujioka, Ken; Gabe, Simon M; Lamprecht, Georg; Pape, Ulrich-Frank; Li, Benjamin; Youssef, Nader N; Jeppesen, Palle B

2016-02-04

In the pivotal 24-week, phase III, placebo-controlled trial, teduglutide significantly reduced parenteral support (PS) requirements in patients with short bowel syndrome (SBS). STEPS-2 was a 2-year, open-label extension of that study designed to evaluate long-term safety and efficacy of teduglutide. Enrolled patients had completed 24 weeks of either teduglutide (TED/TED) or placebo (PBO/TED) in the initial placebo-controlled study or qualified for that study, but were not treated (NT/TED) because of full enrollment. Patients received subcutaneous teduglutide 0.05 mg/kg/day for up to 24 months (NT/TED and PBO/TED) or up to 30 months (TED/TED). Clinical response was defined as 20-100% reduction from baseline in weekly PS volume; baseline was considered the beginning of teduglutide treatment in the initial placebo-controlled study (TED/TED) or STEPS-2 (NT/TED and PBO/TED). Descriptive statistics summarized changes in efficacy and safety variables. Of 88 enrolled patients, 65 (74%) completed STEPS-2. The most common treatment-emergent adverse events were abdominal pain (34%), catheter sepsis (28%), and decreased weight (25%). Mean weight, body mass index, and serum albumin remained stable. In patients who completed the study, clinical response was achieved in 28/30 (93%) TED/TED, 16/29 (55%) PBO/TED, and 4/6 (67%) NT/TED patients. Mean PS volume reductions from baseline were 7.6 (66%), 3.1 (28%), and 4.0 (39%) l/week in the TED/TED, PBO/TED, and NT/TED groups, respectively. Thirteen patients achieved full enteral autonomy. In patients with SBS, long-term teduglutide treatment resulted in sustained, continued reductions in PS requirements. Overall health and nutritional status was maintained despite PS reductions.
Long-Term Teduglutide for the Treatment of Patients With Intestinal Failure Associated With Short Bowel Syndrome

PubMed Central

Schwartz, Lauren K; O'Keefe, Stephen J D; Fujioka, Ken; Gabe, Simon M; Lamprecht, Georg; Pape, Ulrich-Frank; Li, Benjamin; Youssef, Nader N; Jeppesen, Palle B

2016-01-01

OBJECTIVES: In the pivotal 24-week, phase III, placebo-controlled trial, teduglutide significantly reduced parenteral support (PS) requirements in patients with short bowel syndrome (SBS). STEPS-2 was a 2-year, open-label extension of that study designed to evaluate long-term safety and efficacy of teduglutide. METHODS: Enrolled patients had completed 24 weeks of either teduglutide (TED/TED) or placebo (PBO/TED) in the initial placebo-controlled study or qualified for that study, but were not treated (NT/TED) because of full enrollment. Patients received subcutaneous teduglutide 0.05 mg/kg/day for up to 24 months (NT/TED and PBO/TED) or up to 30 months (TED/TED). Clinical response was defined as 20–100% reduction from baseline in weekly PS volume; baseline was considered the beginning of teduglutide treatment in the initial placebo-controlled study (TED/TED) or STEPS-2 (NT/TED and PBO/TED). Descriptive statistics summarized changes in efficacy and safety variables. RESULTS: Of 88 enrolled patients, 65 (74%) completed STEPS-2. The most common treatment-emergent adverse events were abdominal pain (34%), catheter sepsis (28%), and decreased weight (25%). Mean weight, body mass index, and serum albumin remained stable. In patients who completed the study, clinical response was achieved in 28/30 (93%) TED/TED, 16/29 (55%) PBO/TED, and 4/6 (67%) NT/TED patients. Mean PS volume reductions from baseline were 7.6 (66%), 3.1 (28%), and 4.0 (39%) l/week in the TED/TED, PBO/TED, and NT/TED groups, respectively. Thirteen patients achieved full enteral autonomy. CONCLUSIONS: In patients with SBS, long-term teduglutide treatment resulted in sustained, continued reductions in PS requirements. Overall health and nutritional status was maintained despite PS reductions. PMID:26844839
Long-term effects of vitamin D supplementation in vitamin D deficient obese children participating in an integrated weight-loss programme (a double-blind placebo-controlled study) - rationale for the study design.

PubMed

Szlagatys-Sidorkiewicz, Agnieszka; Brzeziński, Michał; Jankowska, Agnieszka; Metelska, Paulina; Słomińska-Frączek, Magdalena; Socha, Piotr

2017-04-04

Obesity is associated not only with an array of metabolic disorders (e.g. insulin resistance, hiperinsulinemia, impaired tolerance of glucose, lipid disorders) but also skeletal and joint abnormalities. Recently, a pleiotropic role of vitamin D has been emphasized. Obese children frequently present with vitamin D deficiency, and greater fat mass is associated with lower serum concentration of this vitamin. Although some evidence suggests that weight loss may affect vitamin D status, this issue has not been studied extensively thus far. The aim of a double-blind placebo-controlled study is to assess long-term health effects of vitamin D supplementation in vitamin D deficient obese children participating in an integrated weight-loss programme. A randomized double-blind, placebo-controlled trial analysing the effects of vitamin D3 supplementation in overweight or obese vitamin D deficient (<30 ng/ml) children participating in an integrated weight-loss programme. Children are randomized to receive either vitamin D (1200 IU) or placebo for 26 weeks. Primary endpoints include changes in BMI (body mass index), body composition and bone mineral density at the end of the study period, and secondary endpoints - the changes in laboratory parameter reflecting liver and kidney function (transaminases, creatinine) and glucose homeostasis (glucose and insulin levels during oral glucose tolerance test). The effects of vitamin D supplementation in obese individuals, especially children, subjected to a weight-loss program are still poorly understood. Considering physiological processes associated with puberty and adolescent growth, we speculate that supplementation may enhance weight reduction and prevent bone loss in obese children deficient in this vitamin. NCT 02828228 ; Trial registration date: 8 Jun 2016; Registered in: ClinicalTrials.gov. The trial was registered retrospectively.
Ethical considerations in design of a study to evaluate a US Food and Drug Administration-approved indication: antivenom versus placebo for copperhead envenomation.

PubMed

Gerardo, Charles J; Lavonas, Eric J; McKinney, Ross E

2014-10-01

In 2000, the US Food and Drug Administration approved CroFab(®) Crotalidae Polyvalent Immune Fab, ovine (FabAV), which had received orphan drug designation, for use in patients with minimal to moderate North American crotaline envenomations including copperhead snakes. As existing evidence on the effectiveness of FabAV for this indication is limited, wide practice variation in its use exists. In order to provide more definitive clinical evidence as to the role of this treatment, a new randomized, placebo-controlled trial of FabAV specifically for copperhead bites was initiated. In light of the existing US Food and Drug Administration approval, ethical considerations of participation in this trial have been raised. We discuss the ethical principles pertinent to this randomized, placebo-controlled trial with placebo arm. We apply an accepted framework for ethical research to this trial. Due to the evidence gap in the literature, wide-ranging treatment recommendations by medical experts, and broad practice variation, clinical equipoise exists in the treatment of copperhead envenomation with FabAV. The impact of this clinical equipoise on the value and scientific validity of the trial is discussed. The trial's risk-benefit ratio is also considered. Potential risks to the patients are minimized as the protocol includes a plan for rescue therapy in the event that patients progress to severe envenomation symptoms. Overall, risks are further minimized by the inclusion of an interim analysis with stopping rules based on demonstrated efficacy should the therapy clearly prove to be beneficial. Although a post-marketing clinical study of this nature is unusual for an approved indication, this trial adheres to all ethical preconditions found in existing guidelines for clinical research involving human subjects. © The Author(s) 2014.
[Design of a multicenter study for assessing the effectiveness of extracorporeal shockwave therapy in epicondylitis humeri radialis].

PubMed

Haake, M; Jensen, K; Prinz, H; Willenberg, T

2000-01-01

Previously published studies concerning, extracorporeal shock-wave therapy (ESWT) in the treatment of lateral epicondylitis do not fulfil the biometric standards of modern clinical research. The objective of the trial is to show that ESWT is effective in the treatment of chronic LE. A prospective, randomized, placebo-controlled, single-blinded, multicenter trial with an independent blinded observer was designed. The effectiveness of ESWT is evaluated by comparison with a control group in which sham-ESWT is performed, both under local anaesthesia. Outcome is determined on the basis of the Roles/Maudsley-Score. Inclusion criteria are a history of at least 6 months of LE and failure of conventional treatment. The therapy includes 3 sessions of low energy ESWT with 2000 impulses (energy flux density 0.07-0.09 mJ/mm2). Sample size is 272 patients. Randomisation started in October 1998 and is planned over a period of two and a half years. Only a randomised clinical trial with adequate control of placebo effects and observer bias can provide the required evidence for the efficiency of ESWT in the treatment of lateral epicondylitis of the elbow.
A randomized placebo-controlled clinical trial of five smoking cessation pharmacotherapies

PubMed Central

Piper, Megan E.; Smith, Stevens S.; Schlam, Tanya R.; Fiore, Michael C.; Jorenby, Douglas E.; Fraser, David; Baker, Timothy B.

2010-01-01

Context Little direct evidence exists on the relative efficacies of different smoking cessation pharmacotherapies, yet such evidence is needed to make informed decisions about their clinical use. Objective The primary objective of this research was to assess the relative efficacies of five smoking cessation pharmacotherapy interventions using placebo-controlled, head-to-head comparisons. Design This was a randomized double-blind, placebo-controlled clinical trial. Setting Smokers were recruited from the community at two urban research sites. Patients Participants were 1504 adult smokers who smoked at least 10 cigarettes per day during the past 6 months and reported being motivated to quit smoking. Participants were excluded if they reported: using any form of tobacco other than cigarettes; current use of bupropion; having a current psychosis or schizophrenia diagnosis; or having medical contraindications for any of the study medications. Interventions Participants were randomized to one of six treatment conditions: nicotine lozenge, nicotine patch, bupropion SR, nicotine patch + nicotine lozenge, bupropion + nicotine lozenge or placebo. In addition, all participants received six individual counseling sessions. Main Outcome Measures The main outcome measures were biochemically-confirmed 7-day point-prevalence abstinence assessed at 1 week post-quit, end of treatment (8 weeks post-quit) and 6 months post-quit. Other outcomes were initial cessation, number of days to lapse, number of days to relapse, and latency to relapse after the first lapse. Results All pharmacotherapies differed from placebo when examined without protection for multiple comparisons (OR’s = 1.63–2.34). With such protection, only the nicotine patch + nicotine lozenge (OR = 2.34, p < .001) produced significantly higher abstinence rates at 6-months post-quit than did placebo. Conclusions While the nicotine lozenge, bupropion, and bupropion + lozenge produced effects that were comparable to those reported in previous research, the nicotine patch + lozenge produced the greatest benefit relative to placebo for smoking cessation. PMID:19884613
Is Skin-Touch Sham Needle Not Placebo? A Double-Blind Crossover Study on Pain Alleviation

PubMed Central

Homma, Ikuo; Izumizaki, Masahiko

2015-01-01

It remains an open question whether placebo/sham acupuncture, in which the needle tip presses the skin, can be used as a placebo device for research on pain. We compare the analgesic effect of the skin-touch placebo needle with that of the no-touch placebo needle, in which the needle tip does not touch the skin, in a double-blind crossover manner including no-treatment control in 23 healthy volunteers. The subjects received painful electrical stimulation in the forearm before and during needle retention to the LI 4 acupoint and after the removal of the needle and rated pain intensity using a visual analogue scale. We found no significant difference in analgesic effects among the skin-touch placebo needle, no-touch placebo needle, and no-treatment control at every point before, during, and after the treatments (p > 0.05). The results indicate that the skin-touch placebo needle can be used as a placebo device in clinical studies on pain. PMID:26064153
Dexamethasone facilitates fear extinction and safety discrimination in PTSD: A placebo-controlled, double-blind study.

PubMed

Michopoulos, Vasiliki; Norrholm, Seth D; Stevens, Jennifer S; Glover, Ebony M; Rothbaum, Barbara O; Gillespie, Charles F; Schwartz, Ann C; Ressler, Kerry J; Jovanovic, Tanja

2017-09-01

Psychophysiological hallmarks of posttraumatic stress disorder (PTSD) include exaggerated fear responses, impaired inhibition and extinction of conditioned fear, and decreased discrimination between safety and fear cues. This increased fear load associated with PTSD can be a barrier to effective therapy thus indicating the need for new treatments to reduce fear expression in people with PTSD. One potential biological target for reducing fear expression in PTSD is the hypothalamic-pituitary-adrenal (HPA) axis, which is dysregulated in PTSD. Recent translational rodent studies and cross-sectional clinical studies have shown that dexamethasone administration and the resulting suppression of cortisol in individuals with PTSD leads to a decrease in the fear responses characteristic of PTSD. These data, taken together, suggest that dexamethasone may serve as a novel pharmacologic intervention for heightened fear responses in PTSD. We conducted a double-blind, placebo-controlled trial to test our hypothesis that dexamethasone administration and the concomitant suppression of HPA axis hyperactivity would attenuate fear expression and enhance fear extinction in individuals with PTSD. Study participants (n=62) were recruited from Grady Memorial Hospital in Atlanta, GA. Participants were randomized to receive dexamethasone or placebo prior to fear conditioning and extinction, in a counterbalanced design (treatments separated by a week). Both PTSD- (n=37) and PTSD+ (n=25) participants showed significant startle increases in the presence of the danger signal during placebo and dexamethasone treatments (all p<0.05). However, only PTSD- control participants showed decreases in fear-potentiated startle across extinction blocks during both conditions (p's≤0.001), with PTSD+ participants showing deficits in fear extinction and safety discrimination in the placebo condition. Notably, extinction and discrimination deficits in PTSD+ subjects were markedly reversed with dexamethasone (p<0.001). These data suggest that dexamethasone may serve as a pharmacological agent with which to facilitate fear extinction and discrimination in individuals with PTSD. Copyright © 2017 Elsevier Ltd. All rights reserved.
The Effects of Oscillatory Biofield Therapy on Pain and Functional Limitations Associated with Carpal Tunnel Syndrome: Randomized, Placebo-Controlled, Double-Blind Study

PubMed Central

Bell, Thomas J.; Martin, Jason Benson; Arab, Amir Massoud

2016-01-01

Abstract Objectives: Biofield treatments have been used for pain control in patients with cancer and chronic pain. However, research on the effect of biofield treatment on specific somatic disorders is lacking. This study intends to investigate the effect of oscillating biofield therapy (OBFT) on symptoms of carpal tunnel syndrome. Design: Randomized, placebo-controlled, double-blind study. Participants: Thirty patients with chronic carpal tunnel syndrome participated in the study. Intervention: Patients were randomly assigned to active or placebo treatment groups. Those in the treatment group received six sessions of OBFT with intention to treat during a period of 2 weeks. Patients in the placebo group had the same number of treatment sessions with mock OBFT treatment. Outcome measure: The Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire; Symptom Severity Scale (SSS); and Functional Status Scale (FSS) were used for outcome assessment. Results: Both clinically and statistically significant changes in intensity of pain with activity (95% confidence interval [CI], 2.5–4.2; p = 0.000), night pain (p = 0.000, 95% CI, 3.2–5.7), DASH questionnaire (95% CI, 12.0–21.9; p = 0.000), SSS (95% CI, 0.64–1.15; p = 0.003), and FSS (95% CI, 0.41–0.97; p = 0.029) were found between the treatment and placebo groups. Statistically significant reduction in number of patients with positive results on the Phalen test (87%; p = 0.000), Tinel sign (73%; p = 0.000), and hand paresthesia (80%; p = 0.000) was noted in the treatment group. During 6-month follow-up, 86% of patients in the treatment group remained pain free and had no functional limitations. Conclusion: OBFT can be a viable and effective treatment for improving symptoms and functional limitations associated with chronic carpal tunnel syndrome. PMID:27487406
Budesonide Multi-matrix for the Treatment of Patients with Ulcerative Colitis.

PubMed

Lichtenstein, Gary R

2016-02-01

Ulcerative colitis (UC) is a chronic idiopathic inflammatory disorder in which patients cycle between active disease and remission. Budesonide multi-matrix (MMX) is an oral second-generation corticosteroid designed to deliver active drug throughout the colon. In pharmacokinetic studies, the mean relative absorption of budesonide in the region between the ascending colon and the descending/sigmoid colon was 95.9 %. In 2 identically designed, phase 3 studies (CORE I and II), budesonide MMX 9 mg once daily was efficacious and well tolerated for induction of remission of mild to moderate UC. Clinical and endoscopic remission rates were 17.9 % (CORE I) and 17.4 % (CORE II) for budesonide MMX 9 mg compared with 7.4 and 4.5 %, respectively, with placebo (p < 0.05, budesonide MMX 9 mg vs. placebo in both studies), 12.1 % with mesalamine 2.4 g, and 12.6 % with budesonide controlled ileal release capsules 9 mg. A 12-month maintenance therapy study suggested that budesonide MMX 6 mg may prolong time to clinical relapse: Median time was >1 year with budesonide MMX 6 mg versus 181 days (p = 0.02) with placebo; however, further studies are needed. In the CORE studies, budesonide MMX exhibited a favorable safety profile; the majority of adverse events were mild or moderate in intensity, and serious adverse events were uncommon. Furthermore, rates of potential glucocorticoid-related adverse events were comparable across treatment groups. The long-term (12-month) safety of budesonide MMX appears to be comparable with placebo. Data support budesonide MMX in the management algorithm of UC.
A group sequential adaptive treatment assignment design for proof of concept and dose selection in headache trials.

PubMed

Hall, David B; Meier, Ulrich; Diener, Hans-Cristoph

2005-06-01

The trial objective was to test whether a new mechanism of action would effectively treat migraine headaches and to select a dose range for further investigation. The motivation for a group sequential, adaptive, placebo-controlled trial design was (1) limited information about where across the range of seven doses to focus attention, (2) a need to limit sample size for a complicated inpatient treatment and (3) a desire to reduce exposure of patients to ineffective treatment. A design based on group sequential and up and down designs was developed and operational characteristics were explored by trial simulation. The primary outcome was headache response at 2 h after treatment. Groups of four treated and two placebo patients were assigned to one dose. Adaptive dose selection was based on response rates of 60% seen with other migraine treatments. If more than 60% of treated patients responded, then the next dose was the next lower dose; otherwise, the dose was increased. A stopping rule of at least five groups at the target dose and at least four groups at that dose with more than 60% response was developed to ensure that a selected dose would be statistically significantly (p=0.05) superior to placebo. Simulations indicated good characteristics in terms of control of type 1 error, sufficient power, modest expected sample size and modest bias in estimation. The trial design is attractive for phase 2 clinical trials when response is acute and simple, ideally binary, placebo comparator is required, and patient accrual is relatively slow allowing for the collection and processing of results as a basis for the adaptive assignment of patients to dose groups. The acute migraine trial based on this design was successful in both proof of concept and dose range selection.
Short-term effects of a green coffee extract-, Garcinia c ambogia- and L-carnitine-containing chewing gum on snack intake and appetite regulation.

PubMed

Bobillo, Cecilia; Finlayson, Graham; Martínez, Ana; Fischman, Daniela; Beneitez, Analisa; Ferrero, Alejandro J; Fernández, Belisario E; Mayer, Marcos A

2018-03-01

Different studies have assessed the influence of chewing gum to aid control of appetite and reduce food intake. The aims of the present study were to evaluate the effects of chewing gum on satiety, food hedonics and snack intake and to explore the potential effects of the combination of Garcinia c ambogia, green coffee extract and L-carnitine on satiety, when administered in a gum format. This was a prospective study in which 57 subjects randomly received three kinds of treatments, in a crossover design: (1) active gum; (2) placebo gum; and (3) no gum. Food preferences and appetite sensations were evaluated by means of the Leeds Food Preference Questionnaire and visual analog scales. There was a significant reduction in low-fat sweet snack intake with placebo gum and the active gum compared to no gum and a reduction in high-fat sweet snack intake with the active gum compared to placebo gum and no gum. Total caloric intake was only reduced in the active gum condition. Both the active and placebo gum conditions significantly reduced hunger and prospective food consumption and increased fullness compared to no gum and were associated with a reduced wanting for sweet food in the LFPQ, consistent in a reduction in the relative preference for sweet snacks versus savoury snacks. This study supports the notion that chewing gum containing nutraceutical products might aid in the control over snack intake and reduce hunger sensations.
Cranberry Juice Fails to Prevent Recurrent Urinary Tract Infection: Results From a Randomized Placebo-Controlled Trial

PubMed Central

Barbosa-Cesnik, Cibele; Brown, Morton B.; Buxton, Miatta; Zhang, Lixin; DeBusscher, Joan

2011-01-01

Background. A number of observational studies and a few small or open randomized clinical trials suggest that the American cranberry may decrease incidence of recurring urinary tract infection (UTI). Methods. We conducted a double-blind, placebo-controlled trial of the effects of cranberry on risk of recurring UTI among 319 college women presenting with an acute UTI. Participants were followed up until a second UTI or for 6 months, whichever came first. A UTI was defined on the basis of the combination of symptoms and a urine culture positive for a known uropathogen. The study was designed to detect a 2-fold difference between treated and placebo groups, as was detected in unblinded trials. We assumed 30% of participants would experience a UTI during the follow-up period. Results. Overall, the recurrence rate was 16.9% (95% confidence interval, 12.8%–21.0%), and the distribution of the recurrences was similar between study groups, with the active cranberry group presenting a slightly higher recurrence rate (20.0% vs 14.0%). The presence of urinary symptoms at 3 days, 1–2 weeks, and at ≥1 month was similar between study groups, with overall no marked differences. Conclusions. Among otherwise healthy college women with an acute UTI, those drinking 8 oz of 27% cranberry juice twice daily did not experience a decrease in the 6-month incidence of a second UTI, compared with those drinking a placebo. PMID:21148516
Anti-Nociceptive Effects of Elcatonin Injection for Postmenopausal Women with Back Pain: A Randomized Controlled Trial

PubMed Central

Ikegami, Shota; Kamimura, Mikio; Uchiyama, Shigeharu; Nakagawa, Hiroyuki; Hashidate, Hiroyuki; Takahara, Kenji; Takahashi, Jun; Kato, Hiroyuki

2010-01-01

Background: Eel calcitonin (elcatonin) injection is widely used for elderly patients suffering from somatic pain in Japan. However, there have been few reports on the analgesic effects of elcatonin injection. The purpose of this study was to examine the analgesic effects of elcatonin injection in postmenopausal women with lower back pain. Methods: This study was designed as a double-blind, randomized, placebo-controlled study. Thirty-six women aged ≥50 years with acute lower back pain participated in this study. They were randomly divided into two treatment groups according to whether they received a placebo or a weekly trigger point injection of elcatonin (20 units). They were observed for 5 weeks and the extent of pain at motion and at rest according to the visual analog scale (VAS) was evaluated. The mean VAS scores for the elcatonin group were then compared with those of the placebo group. Results: There were no statistically significant differences in the mean VAS scores for pain at rest between the two groups during the 5-week treatment course. However, the mean VAS scores for motion pain in the elcatonin group were significantly lower than those in the placebo group at the third, fifth and sixth weeks. Conclusions: Elcatonin injection (20 units) significantly relieved motion pain in the lower back in postmenopausal women after three weeks of treatment. This analgesic effect continued for the subsequent 3 weeks. PMID:20448810
Safety and Tolerability of Panax ginseng Root Extract: A Randomized, Placebo-Controlled, Clinical Trial in Healthy Korean Volunteers

PubMed Central

Lee, Nam-Hun; Yoo, Sa-Ra; Kim, Hyeong-Geug; Cho, Jung-Hyo

2012-01-01

Abstract Objectives Panax ginseng has been extensively used as an adaptogen and is among the top 10 selling herbal supplements in the United States over the past decade. However, there have been few reports about the toxicity of P. ginseng in human studies. Given the lack of toxicological studies in human, this study investigated whether P. ginseng administration causes any noticeable toxic effects in healthy volunteers. Methods This study was designed as a randomized, double-blind, placebo-controlled, and parallel group trial in healthy volunteers. The subjects were required to be healthy, free from any significant disease, as assessed at screening by physical examination, medical history, and laboratory (hematological and biochemical) tests. Eligible subjects received P. ginseng extract (1 g/day or 2 g/day) or placebo over a 4-week period. Results Although mild adverse events, such as dyspepsia, hot flash, insomnia, and constipation, were reported in both P. ginseng and placebo group, no serious untoward reactions were reported following P. ginseng administration. Nonsignificant changes were observed in hematological and biochemical tests. Conclusions P. ginseng administration for 4 weeks was shown to be safe, tolerable, and free of any untoward toxic effect in healthy male and female volunteers. Future results from ongoing multicenter collaborative efforts to evaluate short- and long-term effects of P. ginseng may contribute to our current understanding of safety and tolerability of this herbal product. PMID:22909282
No effect on QT intervals of mipomersen, a 2'-O-methoxyethyl modified antisense oligonucleotide targeting ApoB-100 mRNA, in a phase I dose escalation placebo-controlled study, and confirmed by a thorough QT (tQT) study, in healthy subjects.

PubMed

Yu, Rosie Z; Gunawan, Rudy; Li, Zhaoyang; Mittleman, Robert S; Mahmood, Asif; Grundy, John S; Singleton, Walter; Geary, Richard; Wang, Yanfeng

2016-03-01

The aim of this study to evaluate the effect of mipomersen on QT intervals in a phase I dose escalation, placebo-controlled study, and a thorough QT (tQT) study in healthy subjects. In the initial phase I study, 29 healthy subjects received either single or multiple (for 4 weeks) ascending doses of mipomersen (50-400 mg) administered subcutaneously (SC) or via a 2-h intravenous (IV) infusion, and 7 subjects received placebo. In the confirmative tQT study, 58 healthy subjects received placebo, 400 mg IV moxifloxacin, 200 mg SC, or 200 mg IV of mipomersen in a double-blind, 4-way crossover design with a minimum 5-day washout between treatments. ECG measurements were performed at baseline and selected time points (including Tmax). The correlation between QTcF intervals corrected for baseline and time-matched placebo when available with PK plasma exposure was evaluated by linear regression analysis. In the phase I study, no positive correlation between the PK exposure and ∆QTcF or ∆∆QTcF was observed within the wide dose or exposure range tested. Similar results were observed in the tQT study, where the predicted ΔΔQTcF and its upper bound of the 90% CI at Cmax of therapeutic and supratherapeutic dose were approximately -1.7 and 2.9 ms, respectively. Mipomersen showed no effect on QT intervals in both the phase I dose escalation study and the tQT study. These results support the proposal that QT assessment can be made in a phase I dose escalation study, and no tQT study may be necessary if the phase I dose escalation study showed a negative QT effect.
The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone

PubMed Central

DeFronzo, Ralph A.; Hissa, Miguel N.; Garber, Alan J.; Luiz Gross, Jorge; Yuyan Duan, Raina; Ravichandran, Shoba; Chen, Roland S.

2009-01-01

OBJECTIVE This 24-week trial assessed the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes with inadequate glycemic control with metformin alone. RESEARCH DESIGN AND METHODS This was a randomized, double-blind, placebo-controlled study of saxagliptin (2.5, 5, or 10 mg once daily) or placebo plus a stable dose of metformin (1,500–2,500 mg) in 743 patients (A1C ≥7.0 and ≤10.0%). Efficacy analyses were performed using an ANCOVA model using last observation carried forward methodology on primary (A1C) and secondary (fasting plasma glucose [FPG] and postprandial glucose [PPG] area under the curve [AUC]) end points. RESULTS Saxagliptin (2.5, 5, and 10 mg) plus metformin demonstrated statistically significant adjusted mean decreases from baseline to week 24 versus placebo in A1C (−0.59, −0.69, and −0.58 vs. +0.13%; all P < 0.0001), FPG (−14.31, −22.03, and −20.50 vs. +1.24 mg/dl; all P < 0.0001), and PPG AUC (−8,891, −9,586, and −8,137 vs. −3,291 mg · min/dl; all P < 0.0001). More than twice as many patients achieved A1C <7.0% with 2.5, 5, and 10 mg saxagliptin versus placebo (37, 44, and 44 vs. 17%; all P < 0.0001). β-Cell function and postprandial C-peptide, insulin, and glucagon AUCs improved in all saxagliptin treatment groups at week 24. Incidence of hypoglycemic adverse events and weight reductions were similar to those with placebo. CONCLUSIONS Saxagliptin once daily added to metformin therapy was generally well tolerated and led to statistically significant improvements in glycemic indexes versus placebo added to metformin in patients with type 2 diabetes inadequately controlled with metformin alone. PMID:19478198

Imaging the neuroplastic effects of ketamine with VBM and the necessity of placebo control.

PubMed

Höflich, A; Ganger, S; Tik, M; Hahn, A; Kranz, G S; Vanicek, T; Spies, M; Kraus, C; Windischberger, C; Kasper, S; Winkler, D; Lanzenberger, R

2017-02-15

In the last years a plethora of studies have investigated morphological changes induced by behavioural or pharmacological interventions using structural T1-weighted MRI and voxel-based morphometry (VBM). Ketamine is thought to exert its antidepressant action by restoring neuroplasticity. In order to test for acute impact of a single ketamine infusion on grey matter volume we performed a placebo-controlled, double-blind investigation in healthy volunteers using VBM. 28 healthy individuals underwent two MRI sessions within a timeframe of 2 weeks, each consisting of two structural T1-weighted MRIs within a single session, one before and one 45min after infusion of S-ketamine (bolus of 0.11mg/kg, followed by an maintenance infusion of 0.12mg/kg) or placebo (0.9% NaCl infusion) using a crossover design. In the repeated-measures ANOVA with time (post-infusion/pre-infusion) and medication (placebo/ketamine) as factors, no significant effect of interaction and no effect of medication was found (FWE-corrected). Importantly, further post-hoc t-tests revealed a strong "decrease" of grey matter both in the placebo and the ketamine condition over time. This effect was evident mainly in frontal and temporal regions bilaterally with t-values ranging from 4.95 to 5.31 (FWE-corrected at p<0.05 voxel level). The vulnerabilities of VBM have been repeatedly demonstrated, with reports of influence of blood flow, tissue water and direct effects of pharmacological compounds on the MRI signal. Here again, we highlight that the relationship between intervention and VBM results is apparently subject to a number of physiological influences, which are partly unknown. Future studies focusing on the effects of ketamine on grey matter should try to integrate known influential factors such as blood flow into analysis. Furthermore, the results of this study highlight the importance of a carefully performed placebo condition in pharmacological fMRI studies. Copyright © 2016 Elsevier Inc. All rights reserved.
Efficacy of montelukast for treating perennial allergic rhinitis.

PubMed

Philip, George; Williams-Herman, Debora; Patel, Piyush; Weinstein, Steven F; Alon, Achilles; Gilles, Leen; Tozzi, Carol A; Dass, S Balachandra; Reiss, Theodore F

2007-01-01

Perennial allergic rhinitis (PAR) is a chronic inflammatory nasal condition in individuals exposed year-round to allergens. This was a double-blind study of 15- to 85-year-old patients randomly allocated to montelukast, 10 mg (n=630), placebo (n=613), or the positive control cetirizine, 10 mg (n=122) for 6 weeks. The primary efficacy end point was change from baseline in Daytime Nasal Symptoms Score (DNSS; mean of congestion, rhinorrhea, sneezing, and itching scores, rated daily by patients [scale: 0=none to 3=severe]) averaged during the initial 4 weeks (primary analysis) or entire 6 weeks of treatment. Also assessed were combined post hoc results of primary end point data from this study and another similarly designed study (Patel P, et al. Randomized, double-blind, placebo-controlled study of montelukast for treating perennial allergic rhinitis, Ann Allergy Asthma Immunol 95:551, 2005). Over 4 weeks, montelukast showed numerical improvement over placebo in DNSS (least-squares mean difference of -0.04 [95% confidence interval (CI}, -0.09, 0.01]); the difference between cetirizine and placebo was significant: -0.10 (95% CI, -0.19, -0.01). However, when averaged over 6 weeks, neither active treatment was significantly different from placebo. The Rhinoconjunctivitis Quality-of-Life score was significantly improved by montelukast (p < 0.05), but not by cetirizine, during 4 and 6 weeks. The treatment effect of montelukast, but not cetirizine, generally remained consistent through the 6 weeks of treatment. In pooled data, montelukast consistently improved DNSS versus placebo during all 6 weeks of treatment (-0.07 [95% CI, -0.10, -0.041). In conclusion, montelukast produced numerical improvement in daytime nasal symptoms and significant improvement in quality of life. In a pooled post hoc analysis, montelukast provided consistent improvement in daytime nasal symptoms over 6 weeks, supportive of an overall benefit in PAR.
Placebo controlled, prospectively randomized, double-blinded study for the investigation of the effectiveness and safety of the acoustic wave therapy (AWT(®)) for cellulite treatment.

PubMed

Russe-Wilflingseder, Katharina; Russe-Wilfingsleder, Katharina; Russe, Elisabeth; Vester, Johannes C; Haller, Gerd; Novak, Pavel; Krotz, Alexander

2013-06-01

Placebo controlled double-blinded, prospectively randomized clinical trial with 17 patients (11 verum, 5 placebo) for evaluation of cellulite treatment with Acoustic Wave Therapy, (AWT(®)) was performed. The patients were treated once a week for 7 weeks, a total of 8 treatments with the D-ACTOR(®) 200 by Storz Medical AG. Data were collected at baseline, before 8th treatment, at 1 month (follow-up 1) and at 3 months (follow-up 2) after the last treatment with a patients' questionnaire, weight control, measurement of circumference and standardized photography. Treatment progress was further documented using a specially designed 3D imaging system (SkinSCAN(3D), 3D-Shape GmbH) providing an objective measure of cellulite (primary efficacy criteria). Patient's questionnaire in the verum group revealed an improvement in number and depth of dimples, skin firmness and texture, in shape and in reduction of circumference. The overall result (of skin waviness, Sq and Sz, surface and volume of depressions and elevations, Vvv and Vmp) at two follow-up visits indicates a more than medium sized superiority (MW = 0.6706) and is statistically significant (pWei-Lachin = 0.0106). The placebo group revealed no statistical significance. No side effects were seen. This indicates the efficacy and safety of AWT(®) for patients with cellulite.
Effect of Pregabalin on Cardiovascular Responses to Exercise and Postexercise Pain and Fatigue in Fibromyalgia: A Randomized, Double-Blind, Crossover Pilot Study

PubMed Central

White, Andrea T.; Light, Kathleen C.; Bateman, Lucinda; Hughen, Ronald W.; Vanhaitsma, Timothy A.; Light, Alan R.

2015-01-01

Pregabalin, an approved treatment for fibromyalgia (FM), has been shown to decrease sympathetic nervous system (SNS) activity and inhibit sympathetically maintained pain, but its effects on exercise responses have not been reported. Methods. Using a randomized double-blind crossover design, we assessed the effect of 5 weeks of pregabalin (versus placebo) on acute cardiovascular and subjective responses to moderate exercise in 19 FM patients. Blood pressure (BP), heart rate (HR), and ratings of perceived exertion (RPE) during exercise and ratings of pain, physical fatigue, and mental fatigue before, during, and for 48 hours after exercise were compared in patients on pregabalin versus placebo and also versus 18 healthy controls. Results. On placebo, exercise RPE and BP were significantly higher in FM patients than controls (p < 0.04). Pregabalin responders (n = 12, defined by patient satisfaction and symptom changes) had significantly lower exercise BP, HR, and RPE on pregabalin versus placebo (p < 0.03) and no longer differed from controls (p > 0.26). Cardiovascular responses of nonresponders (n = 7) were not altered by pregabalin. In responders, pregabalin improved ratings of fatigue and pain (p < 0.04), but negative effects on pain and fatigue were seen in nonresponders. Conclusions. These preliminary findings suggest that pregabalin may normalize cardiovascular and subjective responses to exercise in many FM patients. PMID:27026828
Efficacy of electroacupuncture for symptoms of menopausal transition: study protocol for a randomized controlled trial.

PubMed

Liu, Zhishun; Wang, Yang; Xu, Huanfang; Wu, Jiani; He, Liyun; Jiang, John Yi; Yan, Shiyan; Du, Ruosang; Liu, Baoyan

2014-06-21

Previous studies have shown that acupuncture can alleviate postmenopausal symptoms, such as hot flashes, but few studies have assessed symptoms during the menopausal transition (MT) period. Thus, the effect of acupuncture upon MT symptoms is unclear. We designed a large-scale trial aimed at evaluating the efficacy of electroacupuncture for MT symptoms compared with sham electroacupuncture and at observing the safety of electroacupuncture. In this multicenter randomized controlled trial, 360 women will be randomized to either an electroacupuncture group or a sham electroacupuncture group. During the 8-week-long treatment, a menopause rating scale, average 24-hour hot flash score, Menopause-Specific Quality of Life Questionnaire score, and level of female hormones will be observed. Follow-ups at the 20th and 32nd week will be made. Though there is no completely inert placebo acupuncture and blinding is difficult in acupuncture trials, the placebo effect of EA can still be partially excluded in this study. For the placebo control, we use non-points and a tailor-made sham needle. This needle is different from a retractable needle, which is usually used for sham acupuncture. The needle in this trial is more simply constructed and more acceptable to Chinese people. We expect to evaluate the efficacy of electroacupuncture for MT symptoms and clarify its effect on these symptoms. ClinicalTrials.gov Identifier: NCT01849172 (Date of registration: 05/05/2013).
Meta-Analysis: Risk of Tics Associated With Psychostimulant Use in Randomized, Placebo-Controlled Trials.

PubMed

Cohen, Stephanie C; Mulqueen, Jilian M; Ferracioli-Oda, Eduardo; Stuckelman, Zachary D; Coughlin, Catherine G; Leckman, James F; Bloch, Michael H

2015-09-01

Clinical practice currently restricts the use of psychostimulant medications in children with tics or a family history of tics for fear that tics will develop or worsen as a side effect of treatment. Our goal was to conduct a meta-analysis to examine the risk of new onset or worsening of tics as an adverse event of psychostimulants in randomized, placebo-controlled trials. We conducted a PubMed search to identify all double-blind, randomized, placebo-controlled trials examining the efficacy of psychostimulant medications in the treatment of children with attention-deficit/hyperactivity disorder (ADHD). We used a fixed effects meta-analysis with risk ratio of new onset or worsening tics in children treated with psychostimulants compared to placebo. We used stratified subgroup analysis and meta-regression to examine the effects of stimulant type, dose, duration of treatment, recorder of side effect data, trial design, and mean age of participants on the measured risk of tics. We identified 22 studies involving 2,385 children with ADHD for inclusion in our meta-analysis. New onset tics or worsening of tic symptoms were commonly reported in the psychostimulant (event rate = 5.7%, 95% CI = 3.7%-8.6%) and placebo groups (event rate = 6.5%, 95% CI = 4.4%-9.5%). The risk of new onset or worsening of tics associated with psychostimulant treatment was similar to that observed with placebo (risk ratio = 0.99, 95% CI = 0.78-1.27, z = -0.05, p = .962). Type of psychostimulant, dose, duration of treatment, recorder, and participant age did not affect risk of new onset or worsening of tics. Crossover studies were associated with a significantly greater measured risk of tics with psychostimulant use compared to parallel group trials. Meta-analysis of controlled trials does not support an association between new onset or worsening of tics and psychostimulant use. Clinicians may want to consider rechallenging children who report new onset or worsening of tics with psychostimulant use, as these symptoms are much more likely to be coincidental rather than caused by psychostimulants. Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
The antidepressant debate and the balanced placebo trial design: an ethical analysis.

PubMed

Waring, Duff R

2008-12-01

There is ongoing debate about whether randomized, placebo-controlled trials under a double-blind have reliably established the pharmacological efficacy of antidepressants. Numerous meta-analyses of antidepressant efficacy trials, e.g., Kirsch et al. [Kirsch, I., Moore, T. J., Scoboria, A., & Nicholls, S. (2002). The emperor's new drugs: An analysis of antidepressant medication data submitted to the U.S. food and drug administration. Prevention and Treatment, 5, Article 23. (Retrieved July 19, 2007 from http://journals.apa.org/prevention/volume5)], have shown a modest drug-placebo difference but methodological problems with standard trial design preclude a definitive conclusion that this difference results from specific biological effects of antidepressants or the nonspecific factors that have not been adequately excluded. Standard trial design assumes the additivity thesis of pharmacological efficacy, being the assumption that the specific or "true" magnitude of the pharmacological effect is limited to the difference between the drug and placebo responses in a standard trial. If the drug effects are as small as these meta-analyses suggest, then their clinical effectiveness is questionable. If the drug effects are actually larger but masked by placebo effects, then the additivity thesis is not valid and we risk false negative results with standard trial design. Kirsch et al. propose an alternative, four arm balanced placebo trial design (BPTD) that can accurately test the additivity thesis. The BPTD uses antidepressants, active placebos and the intentional deception of research subjects. My focal question is whether the BPTD is ethically defensible. I will explore two objections that can be raised against it: 1) lying to BPTD research subjects violates their autonomy and exploits their illness and 2) the BPTD may not enable us to test the additivity thesis with accuracy, i.e., it may contribute to the masking of drug effects that it aims to avoid. I argue that these objections support the conclusion that the BPTD is ethically indefensible.
Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials.

PubMed

Chaturvedi, Nish; Porta, Massimo; Klein, Ronald; Orchard, Trevor; Fuller, John; Parving, Hans Henrik; Bilous, Rudy; Sjølie, Anne Katrin

2008-10-18

Results of previous studies suggest that renin-angiotensin system blockers might reduce the burden of diabetic retinopathy. We therefore designed the DIabetic REtinopathy Candesartan Trials (DIRECT) Programme to assess whether candesartan could reduce the incidence and progression of retinopathy in type 1 diabetes. Two randomised, double-blind, parallel-design, placebo-controlled trials were done in 309 centres worldwide. Participants with normotensive, normoalbuminuric type 1 diabetes without retinopathy were recruited to the DIRECT-Prevent 1 trial and those with existing retinopathy were recruited to DIRECT-Protect 1, and were assigned to candesartan 16 mg once a day or matching placebo. After 1 month, the dose was doubled to 32 mg. Investigators and participants were unaware of the treatment allocation status. The primary endpoints were incidence and progression of retinopathy and were defined as at least a two-step and at least a three-step increase on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, respectively. These trials are registered with ClinicalTrials.gov, numbers NCT00252733 for DIRECT-Prevent 1 and NCT00252720 for DIRECT-Protect 1. 1421 participants (aged 18-50 years) were randomly assigned to candesartan (n=711) or to placebo (n=710) in DIRECT-Prevent 1, and 1905 (aged 18-55 years) to candesartan (n=951) or to placebo (n=954) in DIRECT-Protect 1. Incidence of retinopathy was seen in 178 (25%) participants in the candesartan group versus 217 (31%) in the placebo group. Progression of retinopathy occurred in 127 (13%) participants in the candesartan group versus 124 (13%) in the placebo group. Hazard ratio (HR for candesartan vs placebo) was 0.82 (95% CI 0.67-1.00, p=0.0508) for incidence of retinopathy and 1.02 (0.80-1.31, p=0.85) for progression of retinopathy. The post-hoc outcome of at least a three-step increase for incidence yielded an HR of 0.65 (0.48-0.87, p=0.0034), which was attenuated but still significant after adjustment for baseline characteristics (0.71, 0.53-0.95, p=0.046). Final ETDRS level was more likely to have improved with candesartan treatment in both DIRECT-Prevent 1 (odds 1.16, 95% CI 1.05-1.30, p=0.0048) and DIRECT-Protect 1 (1.12, 95% CI 1.01-1.25, p=0.0264). Adverse events did not differ between the treatment groups. Although candesartan reduces the incidence of retinopathy, we did not see a beneficial effect on retinopathy progression.
Acute EGCG Supplementation Reverses Endothelial Dysfunction in Patients with Coronary Artery Disease

PubMed Central

Widlansky, Michael E.; Hamburg, Naomi M.; Anter, Elad; Holbrook, Monika; Kahn, David F.; Elliott, James G.; Keaney, John F.; Vita, Joseph A.

2013-01-01

Background Epidemiological studies demonstrate an inverse relation between dietary flavonoid intake and cardiovascular risk. Recent studies with flavonoid-containing beverages suggest that the benefits of these nutrients may relate, in part, to improved endothelial function. Objective We hypothesized that dietary supplementation with epigallocatechin gallate (EGCG), a major catechin in tea, would improve endothelial function in humans. Design We examined the effects of EGCG on endothelial function in a double blind, placebo-controlled, crossover design study. We measured brachial artery flow-mediated dilation by vascular ultrasound at six time points: prior to treatment with EGCG or placebo, two hours after an initial dose of EGCG (300 mg) or placebo, and after two weeks of treatment with EGCG (150 mg twice daily) or placebo. The order of treatments (EGCG or placebo) was randomized and there was a one-week washout period between treatments. Results A total of 42 subjects were enrolled, and brachial artery flow-mediated dilation improved from 7.1±4.1 to 8.6±4.7% two hours after the first dose of 300mg of EGCG (P=0.01), but was similar to baseline (7.8±4.2%, P=0.12) after two weeks of treatment with the final measurements made approximately 14 hours after the last dose. Placebo treatment had no significant effect, and there were no changes in reactive hyperemia or the response to sublingual nitroglycerin. The changes in vascular function paralleled plasma EGCG concentrations, which increased from 2.6±10.9 to 92.8±78.7 ng/ml after acute EGCG (P<0.001), but were unchanged from baseline after two weeks of treatment (3.4±13.1 ng/ml). Conclusion EGCG acutely improves endothelial function in humans with coronary artery disease, and may account for a portion of the beneficial effects of flavonoid-rich food on endothelial function. PMID:17536120
Utility of intranasal Ketamine and Midazolam to perform gastric aspirates in children: a double-blind, placebo controlled, randomized study

PubMed Central

2014-01-01

Background We performed a prospective, randomized, placebo-controlled study aimed to evaluate the efficacy and safety of a sedation protocol based on intranasal Ketamine and Midazolam (INKM) administered by a mucosal atomizer device in uncooperative children undergoing gastric aspirates for suspected tuberculosis. Primary outcome: evaluation of Modified Objective Pain Score (MOPS) reduction in children undergoing INKM compared to the placebo group. Secondary outcomes: evaluation of safety of INKM protocol, start time sedation effect, duration of sedation and evaluation of parents and doctors’ satisfaction about the procedure. Methods In the sedation group, 19 children, mean age 41.5 months, received intranasal Midazolam (0.5 mg/kg) and Ketamine (2 mg/kg). In the placebo group, 17 children received normal saline solution twice in each nostril. The child’s degree of sedation was scored using the MOPS. A questionnaire was designed to evaluate the parents’ and doctors’ opinions on the procedures of both groups. Results Fifty-seven gastric washings were performed in the sedation-group, while in the placebo-group we performed 51 gastric aspirates. The degree of sedation achieved by INMK enabled all procedures to be completed without additional drugs. The mean duration of sedation was 71.5 min. Mean MOPS was 3.5 (range 1-8) in the sedation-group, 7.2 (range 4-9) in the placebo-group (p <0.0001). The questionnaire revealed high levels of satisfaction by both doctors and parents in the sedation-group compared to the placebo-group. The only side effect registered was post-sedation agitation in 6 procedures in the sedation group (10.5%). Conclusions Our experience suggests that atomized INKM makes gastric aspirates more acceptable and easy to perform in children. Trial registration Unique trial Number: UMIN000010623; Receipt Number: R000012422. PMID:24598046
A randomized, double-blind, placebo-controlled trial of a traditional herbal formula, Yukmijihwang-tang in elderly subjects with xerostomia.

PubMed

Han, Gajin; Ko, Seok-Jae; Kim, Juyeon; Oh, Ja-Young; Park, Jae-Woo; Kim, Jinsung

2016-04-22

Yukmijihwang-tang (YMJ) is a typical herbal formula to treat Yin-deficiency (YD) syndrome by enriching the fluid-humor of the body. YMJ has been used to treat dry mouth symptoms for hundreds of years in traditional East Asian medicine. Xerostomia, a subjective oral dryness, is common in the elderly and results in impaired quality of life. Many conventional treatments for xerostomia provide only temporary symptom relief, and have side effects. The aim of this study is to investigate the efficacy and safety of YMJ for the treatment of xerostomia in the elderly. This study was designed as a randomized, placebo-controlled, double-blinded, two center trial. Ninety-six subjects aged 60-80 years who had experienced xerostomia for at least 3 months and presented with score>40 on the visual analog scale (VAS) for subjective oral dryness were recruited and randomly allocated to YMJ and placebo groups. YMJ or placebo was administered to each group for 8 weeks (3g of YMJ or placebo, three times per day). The primary outcome was change of VAS for xerostomia from 0 to 8 weeks. VAS for xerostomia was decreased by 22.04±22.76 in the YMJ group and 23.58±23.04 in the placebo group. YMJ had no effect on xerostomia. However, participants with BMIs lower than 29.37kg/m(2) showed improvement of xerostomia after 8 weeks of treatment with YMJ compared to placebo. In addition, YMJ improved oral moisture, which is associated with subjective oral dryness in the YMJ group, and the relationship between VAS for xerostomia and YD was significant. A trend was observed in which YMJ improved oral moisture status and subjective oral dryness in elderly subjects with lower BMI and greater tendency toward YD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Effect of Stress-Response Psycho-Training on the Stress Levels of Mothers with Autistic Children

ERIC Educational Resources Information Center

Karaman, Ömer

2018-01-01

The aim of the study was to assess the effect of stress-response psycho-training on the stress levels of mothers with autistic children. The research was experimental in design encompassing a pretest-posttest model with control and placebo groups. Participation in the study was voluntary with a total of 28 mothers of autistic children included…
Nocturnal temperature controlled laminar airflow for treating atopic asthma: a randomised controlled trial

PubMed Central

Boyle, Robert J; Pedroletti, Christophe; Wickman, Magnus; Bjermer, Leif; Valovirta, Erkka; Dahl, Ronald; Von Berg, Andrea; Zetterström, Olof

2011-01-01

Objective To determine whether environmental control using nocturnal temperature controlled laminar airflow (TLA) treatment could improve the quality of life of patients with persistent atopic asthma. Design Randomised, double-blind, placebo-controlled, parallel-group trial. Setting Nineteen European asthma clinics. Participants 312 patients aged 7–70 with inadequately controlled persistent atopic asthma. Main outcome measure Proportion of patients with an increase of ≥0.5 points in asthma quality of life score after 1 year of treatment. Results TLA devices were successfully installed in the bedrooms of 282 (90%) patients included in the primary efficacy analysis. There was a difference in treatment response rate between active (143 of 189, 76%) and placebo (56 of 92, 61%) groups, difference 14.8% (95% CI 3.1 to 26.5, p=0.02).3 In patients aged ≥12, on whom the study was powered, the difference in response rate was similar-active 106 of 143 (74%), placebo 42 of 70 (60%), difference 14.1% (0.6 to 27.7, p=0.059). There was a difference between groups in fractional exhaled nitric oxide change of −7.1 ppb (−13.6 to −0.7, p=0.03). Active treatment was associated with less increase in cat-specific IgE than placebo. There was no difference in adverse event rates between treatment groups. Conclusion Inhalant exposure reduction with TLA improves quality of life, airway inflammation and systemic allergy in patients with persistent atopic asthma. TLA may be a treatment option for patients with inadequately controlled persistent atopic asthma. Trial registration number Clinical Trials NCT00986323. PMID:22131290
Does des-acyl ghrelin improve glycemic control in obese diabetic subjects by decreasing acylated ghrelin levels?

PubMed

Özcan, Behiye; Neggers, Sebastian J C M M; Miller, Anne Reifel; Yang, Hsiu-Chiung; Lucaites, Virginia; Abribat, Thierry; Allas, Soraya; Huisman, Martin; Visser, Jenny A; Themmen, Axel P N; Sijbrands, Eric J G; Delhanty, Patric J D; van der Lely, Aart Jan

2014-06-01

The objective of this study was to assess the effects of a continuous overnight infusion of des-acyl ghrelin (DAG) on acylated ghrelin (AG) levels and glucose and insulin responses to a standard breakfast meal (SBM) in eight overweight patients with type 2 diabetes. Furthermore, in the same patients and two additional subjects, the effects of DAG infusion on AG concentrations and insulin sensitivity during a hyperinsulinemic-euglycemic clamp (HEC) were assessed. A double-blind, placebo-controlled cross-over study design was implemented, using overnight continuous infusions of 3 and 10 μg DAG/kg per h and placebo to study the effects on a SBM. During a HEC, we studied the insulin sensitivity. We observed that, compared with placebo, overnight DAG administration significantly decreased postprandial glucose levels, both during continuous glucose monitoring and at peak serum glucose levels. The degree of improvement in glycemia was correlated with baseline plasma AG concentrations. Concurrently, DAG infusion significantly decreased fasting and postprandial AG levels. During the HEC, 2.5 h of DAG infusion markedly decreased AG levels, and the M-index, a measure of insulin sensitivity, was significantly improved in the six subjects in whom we were able to attain steady-state euglycemia. DAG administration was not accompanied by many side effects when compared with placebo. DAG administration improves glycemic control in obese subjects with type 2 diabetes through the suppression of AG levels. DAG is a good candidate for the development of compounds in the treatment of metabolic disorders or other conditions with a disturbed AG:DAG ratio, such as type 2 diabetes mellitus or Prader-Willi syndrome. © 2014 European Society of Endocrinology.
Oral administration of Lactobacillus paracasei NCC 2461 for the modulation of grass pollen allergic rhinitis: a randomized, placebo-controlled study during the pollen season.

PubMed

Nembrini, Chiara; Singh, Anurag; De Castro, Carlos Antonio; Mercenier, Annick; Nutten, Sophie

2015-01-01

The efficacy of Lactobacillus paracasei NCC 2461 in modulating allergic rhinitis was previously evaluated in two exploratory clinical studies. Oral administration with NCC 2461 reduced specific subjective symptoms following nasal provocation tests with controlled grass pollen allergen concentrations. Our aim was to confirm the anti-allergic effect of NCC 2461 in grass pollen allergic subjects exposed to natural doses of allergens during the pollen season. A double-blind, randomized, placebo-controlled, parallel study was conducted with 131 grass pollen allergic subjects from May to July 2012 in concomitance with the pollen season in Berlin. NCC 2461 or placebo was administered daily for an 8-week period to adult subjects with clinical history of allergic rhinitis to grass pollen, positive skin prick test and IgE to grass pollen. During the 8 weeks, symptoms and quality of life questionnaires were filled out, and plasma was collected for IgE analysis at screening and at the end of the intervention. All subjects were included within a 5-day interval, ensuring exposure to similar air pollen counts for each individual during the trial period. The results obtained show that symptoms increased with pollen loads, confirming a natural exposure to the allergen and presence of pollen-induced allergic rhinitis in the subjects. However, no significant differences were observed in allergic rhinitis symptoms scores, quality of life, or specific IgE levels between subjects receiving NCC 2461 as compared to placebo administration. In contrast to previous findings, oral administration of NCC 2461 did not show a beneficial effect on allergic rhinitis in a field trial. The influence of study design, allergen exposure and intervention window on the efficacy of NCC 2461 in modulating respiratory allergy should be further evaluated.
Rupatadine does not potentiate the CNS depressant effects of lorazepam: randomized, double-blind, crossover, repeated dose, placebo-controlled study

PubMed Central

García-Gea, Consuelo; Ballester, Maria Rosa; Martínez, Juan; Antonijoan, Rosa Maria; Donado, Esther; Izquierdo, Iñaki; Barbanoj, Manuel-José

2010-01-01

AIM The main objective was to assess whether benzodiazepine intake when rupatadine plasma concentrations were at steady-state would increase the CNS depressant effects. Rupatadine is a new H1-antihistamine which also inhibits platelet activating factor (PAF) release and has been shown to be clinically effective at doses of 10 mg. METHODS Sixteen healthy young volunteers took part in a crossover, randomized, double-blind, placebo controlled trial comprising two experimental periods (repeated administration for 7 days of rupatadine 10 mg or placebo as single oral daily doses, separated by a washout of 14 days). On days 5 and 7, according to a fully balanced design, a single oral dose of lorazepam 2 mg or placebo was added. CNS effects were evaluated on these days by seven objective tests of psychomotor performance and eight subjective visual analogue scales (VAS) at pre-dose and several times after drug intake. Four treatment conditions were evaluated: placebo, rupatadine 10 mg, lorazepam 2 mg and rupatadine 10 mg + lorazepam 2 mg. RESULTS Significant CNS effects, either impairment of psychomotor performance or subjective sedation, were observed when lorazepam was administered, either alone or in combination with steady state concentrations of rupatadine. No significant differences were found between these two conditions. In addition, rupatadine was not different from placebo. All treatments were well tolerated. CONCLUSION Repeated doses of rupatadine (10 mg orally) did not enhance the CNS depressant effects of lorazepam (2 mg orally, single dose) either in objective psychomotor tasks or in subjective evaluations. PMID:20565458
Antiherpes virus-specific treatment and cognition in schizophrenia: a test-of-concept randomized double-blind placebo-controlled trial.

PubMed

Prasad, Konasale M; Eack, Shaun M; Keshavan, Matcheri S; Yolken, Robert H; Iyengar, Satish; Nimgaonkar, Vishwajit L

2013-07-01

To test our hypothesis that valacyclovir, an antiherpes virus-specific medication, added to antipsychotics (APs) would improve cognitive performance and psychopathology among schizophrenia subjects exposed to neurotropic herpes simplex virus, type 1 (HSV1). Using a double-blind placebo-controlled design, we randomized 24 HSV1-seropositive schizophrenia subjects to receive either valacyclovir (n = 12) or placebo (n = 12) for 18 weeks in addition to stable doses of APs. Valacyclovir dose was stabilized at 1.5 g twice daily orally. At each visit, subjects were evaluated for severity of psychopathology and side effects using standardized scales and a study-specific semistructured checklist. A computerized neurocognitive battery validated on both schizophrenia and healthy subjects was administered at baseline and follow-up. Intent-to-treat analysis, using linear regression models that included all randomized subjects, were used to examine differential changes in cognition and psychopathology scores over 18 weeks between valacyclovir and placebo, accounting for placebo response. Valacyclovir group improved in verbal memory, working memory, and visual object learning compared with placebo group. The effect sizes (Cohen's d) were 0.79 for working memory, 1.14 for immediate verbal memory, and 0.97 for the visual object learning. Psychotic symptom severity did not improve. Supplemental valacyclovir may alleviate impairments in cognitive domains that are often observed in schizophrenia but not psychotic symptoms in those exposed to HSV1. If replicated, this approach could provide a novel strategy to treat cognitive impairments in a subgroup of schizophrenia subjects who can be reliably identified using a blood test.
Effect of genistein on endothelial function in postmenopausal women: a randomized, double-blind, controlled study.

PubMed

Squadrito, Francesco; Altavilla, Domenica; Crisafulli, Alessandra; Saitta, Antonino; Cucinotta, Domenico; Morabito, Nunziata; D'Anna, Rosario; Corrado, Francesco; Ruggeri, Pietro; Frisina, Nicola; Squadrito, Giovanni

2003-04-15

Genistein, a phytoestrogen found in soybeans, corrects endothelial dysfunction induced by oophorectomy in animals. Using a double-blind, controlled, randomized design, we evaluated its effects on endothelial function in women. We enrolled 79 healthy postmenopausal women (mean [+/- SD] age, 56 +/- 4 years) and randomly assigned them to receive continuous estrogen/progestin therapy (n = 26; 17beta-estradiol [1 mg/d] combined with norethisterone acetate [0.5 mg/d]), genistein (n = 27; 54 mg/d), or placebo (n = 26). Brachial artery flow-mediated, endothelium-dependent vasodilation and plasma levels of nitrites/nitrates (a marker of nitric oxide metabolism) and endothelin-1 were measured at baseline and after 1 year of therapy. Treatment with genistein increased levels of nitrites/nitrates (mean increase, 21 micromol/L; 95% confidence interval [CI]: 15 to 26 micromol/L; P <0.001 vs. placebo); estrogen/progestin therapy caused similar changes (P <0.001 vs. placebo). Plasma endothelin-1 levels decreased following 12 months of genistein (mean decrease, 7 pg/mL; 95% CI: 3 to 10 pg/mL; P <0.001 vs. placebo) and after 12 months of estrogen/progestin (P <0.001 vs. placebo). When compared with placebo, brachial artery flow-mediated dilation was improved by genistein (mean increase, 5.5%; 95% CI: 3.9% to 7.0%; P <0.001) and by estrogen/progestin (P <0.001). There were no significant differences between estrogen and genistein for any of these parameters (all P >0.4). One year of genistein therapy improves endothelium function in postmenopausal women to a similar extent as does an estrogen/progestin regimen.
Achieving cannabis cessation -- evaluating N-acetylcysteine treatment (ACCENT): design and implementation of a multi-site, randomized controlled study in the National Institute on Drug Abuse Clinical Trials Network.

PubMed

McClure, Erin A; Sonne, Susan C; Winhusen, Theresa; Carroll, Kathleen M; Ghitza, Udi E; McRae-Clark, Aimee L; Matthews, Abigail G; Sharma, Gaurav; Van Veldhuisen, Paul; Vandrey, Ryan G; Levin, Frances R; Weiss, Roger D; Lindblad, Robert; Allen, Colleen; Mooney, Larissa J; Haynes, Louise; Brigham, Gregory S; Sparenborg, Steve; Hasson, Albert L; Gray, Kevin M

2014-11-01

Despite recent advances in behavioral interventions for cannabis use disorders, effect sizes remain modest, and few individuals achieve long-term abstinence. One strategy to enhance outcomes is the addition of pharmacotherapy to complement behavioral treatment, but to date no efficacious medications targeting cannabis use disorders in adults through large, randomized controlled trials have been identified. The National Institute on Drug Abuse Clinical Trials Network (NIDA CTN) is currently conducting a study to test the efficacy of N-acetylcysteine (NAC) versus placebo (PBO), added to contingency management, for cannabis cessation in adults (ages 18-50). This study was designed to replicate positive findings from a study in cannabis-dependent adolescents that found greater odds of abstinence with NAC compared to PBO. This paper describes the design and implementation of an ongoing 12-week, intent-to-treat, double-blind, randomized, placebo-controlled study with one follow-up visit four weeks post-treatment. Approximately 300 treatment-seeking cannabis-dependent adults will be randomized to NAC or PBO across six study sites in the United States. The primary objective of this 12-week study is to evaluate the efficacy of twice-daily orally-administered NAC (1200 mg) versus matched PBO, added to contingency management, on cannabis abstinence. NAC is among the first medications to demonstrate increased odds of abstinence in a randomized controlled study among cannabis users in any age group. The current study will assess the cannabis cessation efficacy of NAC combined with a behavioral intervention in adults, providing a novel and timely contribution to the evidence base for the treatment of cannabis use disorders. Copyright © 2014 Elsevier Inc. All rights reserved.
Achieving Cannabis Cessation - Evaluating N-acetylcysteine Treatment (ACCENT): Design and implementation of a multi-site, randomized controlled study in the National Institute on Drug Abuse Clinical Trials Network

PubMed Central

McClure, Erin A.; Sonne, Susan C.; Winhusen, Theresa; Carroll, Kathleen M.; Ghitza, Udi E.; McRae-Clark, Aimee L.; Matthews, Abigail G.; Sharma, Gaurav; Van Veldhuisen, Paul; Vandrey, Ryan G.; Levin, Frances R.; Weiss, Roger D.; Lindblad, Robert; Allen, Colleen; Mooney, Larissa J.; Haynes, Louise; Brigham, Gregory S.; Sparenborg, Steve; Hasson, Albert L.; Gray, Kevin M.

2014-01-01

Despite recent advances in behavioral interventions for cannabis use disorders, effect sizes remain modest, and few individuals achieve long-term abstinence. One strategy to enhance outcomes is the addition of pharmacotherapy to complement behavioral treatment, but to date no efficacious medications targeting cannabis use disorders in adults through large, randomized controlled trials have been identified. The National Institute on Drug Abuse Clinical Trials Network (NIDA CTN) is currently conducting a study to test the efficacy of N-acetylcysteine (NAC) versus placebo (PBO), added to contingency management, for cannabis cessation in adults (ages 18–50). This study was designed to replicate positive findings from a study in cannabis-dependent adolescents that found greater odds of abstinence with NAC compared to PBO. This paper describes the design and implementation of an ongoing 12-week, intent-to-treat, double-blind, randomized, placebo-controlled study with one follow-up visit four weeks post-treatment. Approximately 300 treatment-seeking cannabis-dependent adults will be randomized to NAC or PBO across six study sites in the United States. The primary objective of this 12-week study is to evaluate the efficacy of twice-daily orally-administered NAC (1200 mg) versus matched PBO, added to contingency management, on cannabis abstinence. NAC is among the first medications to demonstrate increased odds of abstinence in a randomized controlled study among cannabis users in any age group. The current study will assess the cannabis cessation efficacy of NAC combined with a behavioral intervention in adults, providing a novel and timely contribution to the evidence base for the treatment of cannabis use disorders. PMID:25179587

Garlic for hypertension: A systematic review and meta-analysis of randomized controlled trials.

PubMed

Xiong, X J; Wang, P Q; Li, S J; Li, X K; Zhang, Y Q; Wang, J

2015-03-15

In the past decade, garlic has become one of the most popular complementary therapies for blood pressure (BP) control used by hypertensive patients. Numerous clinical studies have focused on the BP-lowering effect of garlic, but results have been inconsistent. Overall, there is a dearth of information available to guide the clinical community on the efficacy of garlic in hypertensive patients. To systematically review the medical literature to investigate the current evidence of garlic for the treatment of hypertension. PubMed, the Cochrane Library and EMBASE were searched for appropriate articles from their respective inceptions until August 2014. Randomized, placebo-controlled trials comparing garlic vs. a placebo in patients with hypertension were considered. Papers were independently reviewed by two reviewers and were analyzed using Cochrane software Revman 5.2. A total of seven randomized, placebo-controlled trials were identified. Compared with the placebo, this meta-analysis revealed a significant lowering effect of garlic on both systolic BP (WMD: -6.71 mmHg; 95% CI: -12.44 to -0.99; P = 0.02) and diastolic BP (WMD: -4.79 mmHg; 95% CI: -6.60 to -2.99; P < 0.00001). No serious adverse events were reported in any of the trials. The present review suggests that garlic is an effective and safe approach for hypertension. However, more rigorously designed randomized controlled trials focusing on primary endpoints with long-term follow-up are still warranted before garlic can be recommended to treat hypertensive patients. Copyright © 2015 Elsevier GmbH. All rights reserved.
Discontinuation, Efficacy, and Safety of Cholinesterase Inhibitors for Alzheimer’s Disease: a Meta-Analysis and Meta-Regression of 43 Randomized Clinical Trials Enrolling 16 106 Patients

PubMed Central

Blanco-Silvente, Lídia; Saez, Marc; Barceló, Maria Antònia; Garre-Olmo, Josep; Vilalta-Franch, Joan; Capellà, Dolors

2017-01-01

Abstract Background: We investigated the effect of cholinesterase inhibitors on all-cause discontinuation, efficacy and safety, and the effects of study design-, intervention-, and patient-related covariates on the risk-benefit of cholinesterase inhibitors for Alzheimer’s disease. Methods: A systematic review and meta-analysis of randomized placebo-controlled clinical trials comparing cholinesterase inhibitors and placebo was performed. The effect of covariates on study outcomes was analysed by means of meta-regression using a Bayesian framework. Results: Forty-three randomized placebo-controlled clinical trials involving 16106 patients were included. All-cause discontinuation was higher with cholinesterase inhibitors (OR = 1.66), as was discontinuation due to adverse events (OR=1.75). Cholinesterase inhibitors improved cognitive function (standardized mean difference = 0.38), global symptomatology (standardized mean difference=0.28) and functional capacity (standardized mean difference=0.16) but not neuropsychiatric symptoms. Rivastigmine was associated with a poorer outcome on all-cause discontinuation (Diff OR = 1.66) and donepezil with a higher efficacy on global change (Diff standardized mean difference = 0.41). The proportion of patients with serious adverse events decreased with age (Diff OR = -0.09). Mortality was lower with cholinesterase inhibitors than with placebo (OR = 0.65). Conclusion: While cholinesterase inhibitors show a poor risk-benefit relationship as indicated by mild symptom improvement and a higher than placebo all-cause discontinuation, a reduction of mortality was suggested. Intervention- and patient-related factors modify the effect of cholinesterase inhibitors in patients with Alzheimer’s disease. PMID:28201726
Discontinuation, Efficacy, and Safety of Cholinesterase Inhibitors for Alzheimer's Disease: a Meta-Analysis and Meta-Regression of 43 Randomized Clinical Trials Enrolling 16 106 Patients.

PubMed

Blanco-Silvente, Lídia; Castells, Xavier; Saez, Marc; Barceló, Maria Antònia; Garre-Olmo, Josep; Vilalta-Franch, Joan; Capellà, Dolors

2017-07-01

We investigated the effect of cholinesterase inhibitors on all-cause discontinuation, efficacy and safety, and the effects of study design-, intervention-, and patient-related covariates on the risk-benefit of cholinesterase inhibitors for Alzheimer's disease. A systematic review and meta-analysis of randomized placebo-controlled clinical trials comparing cholinesterase inhibitors and placebo was performed. The effect of covariates on study outcomes was analysed by means of meta-regression using a Bayesian framework. Forty-three randomized placebo-controlled clinical trials involving 16106 patients were included. All-cause discontinuation was higher with cholinesterase inhibitors (OR = 1.66), as was discontinuation due to adverse events (OR=1.75). Cholinesterase inhibitors improved cognitive function (standardized mean difference = 0.38), global symptomatology (standardized mean difference=0.28) and functional capacity (standardized mean difference=0.16) but not neuropsychiatric symptoms. Rivastigmine was associated with a poorer outcome on all-cause discontinuation (Diff OR = 1.66) and donepezil with a higher efficacy on global change (Diff standardized mean difference = 0.41). The proportion of patients with serious adverse events decreased with age (Diff OR = -0.09). Mortality was lower with cholinesterase inhibitors than with placebo (OR = 0.65). While cholinesterase inhibitors show a poor risk-benefit relationship as indicated by mild symptom improvement and a higher than placebo all-cause discontinuation, a reduction of mortality was suggested. Intervention- and patient-related factors modify the effect of cholinesterase inhibitors in patients with Alzheimer's disease. © The Author 2017. Published by Oxford University Press on behalf of CINP.
Effect of an herbal/botanical supplement on strength, balance, and muscle function following 12-weeks of resistance training: a placebo controlled study.

PubMed

Furlong, Jonathan; Rynders, Corey A; Sutherlin, Mark; Patrie, James; Katch, Frank I; Hertel, Jay; Weltman, Arthur

2014-01-01

StemSport (SS; StemTech International, Inc. San Clemente, CA) contains a proprietary blend of the botanical Aphanizomenon flos-aquae and several herbal antioxidant and anti-inflammatory substances. SS has been purported to accelerate tissue repair and restore muscle function following resistance exercise. Here, we examine the effects of SS supplementation on strength adaptations resulting from a 12-week resistance training program in healthy young adults. Twenty-four young adults (16 males, 8 females, mean age = 20.5 ± 1.9 years, mass = 70.9 ± 11.9 kg, stature = 176.6 ± 9.9 cm) completed the twelve week training program. The study design was a double-blind, placebo controlled parallel group trial. Subjects either received placebo or StemSport supplement (SS; mg/day) during the training. 1-RM bench press, 1-RM leg press, vertical jump height, balance (star excursion and center of mass excursion), isokinetic strength (elbow and knee flexion/extension) and perception of recovery were measured at baseline and following the 12-week training intervention. Resistance training increased 1-RM strength (p < 0.008), vertical jump height (p < 0.03), and isokinetic strength (p < 0.05) in both SS and placebo groups. No significant group-by-time interactions were observed (all p-values >0.10). These data suggest that compared to placebo, the SS herbal/botanical supplement did not enhance training induced adaptations to strength, balance, and muscle function above strength training alone.
Summary of anti-malarial prophylactic efficacy of tafenoquine from three placebo-controlled studies of residents of malaria-endemic countries.

PubMed

Dow, Geoffrey S; Liu, Jun; Lin, Gina; Hetzell, Brian; Thieling, Sarah; McCarthy, William F; Tang, Douglas; Smith, Bryan

2015-11-26

Tafenoquine is a long half-life primaquine analog being developed for malaria prophylaxis. The US Army recently performed a unified analysis of efficacy in preparation for a regulatory submission, utilizing legacy data from three placebo-controlled studies conducted in the late 1990s and early 2000s. The subjects were residents of Africa who were naturally exposed to Plasmodium falciparum for 12-26 weeks. The prophylactic efficacy of tafenoquine and mefloquine (included in some studies as a comparator) was calculated using incidence density among subjects who had completed the three-day loading doses of study drug, had at least one maintenance dose and had at least one blood smear assessed during the prophylactic period. The three placebo-controlled studies were analysed separately and then in two pooled analyses: one for tafenoquine versus placebo (three studies) and one for tafenoquine and mefloquine versus placebo (two studies). The pooled protective efficacy (PE) of a tafenoquine regimen with three daily loading doses plus weekly maintenance at 200-mg for 10 weeks or longer (referred to as 200-mg weekly hereafter) relative to placebo in three placebo-controlled studies was 93.1 % [95 % confidence interval (CI) 89.1-95.6 %; total N = 492]. The pooled PEs of regimens of tafenoquine 200-mg weekly and mefloquine 250-mg weekly relative to placebo in two placebo-controlled studies (total N = 519) were 93.5 % (95 % CI 88.6-96.2 %) and 94.5 % (95 % CI 88.7-97.3 %), respectively. Three daily loading plus weekly maintenance doses of 50- and 100-mg, but not 25-mg, exhibited similar PEs. The PEs of tafenoquine regimens of a three-day loading dose at 400-mg with and without follow-up weekly maintenance doses at 400-mg were 93.7 % (95 % CI 85.4-97.3 %) and 81.0 % (95 % CI 66.8-89.1 %), respectively. Tafenoquine provided the same level of prophylactic efficacy as mefloquine in residents of Africa. These data support the prophylactic efficacy of tafenoquine and mefloquine that has already been demonstrated in the intended malaria naive population.
Study protocol for the G-SPIRIT trial: a randomised, placebo-controlled, double-blinded phase III trial of granulocyte colony-stimulating factor-mediated neuroprotection for acute spinal cord injury

PubMed Central

Koda, Masao; Hanaoka, Hideki; Sato, Takatoshi; Fujii, Yasuhisa; Hanawa, Michiko; Takahashi, Sho; Furuya, Takeo; Ijima, Yasushi; Saito, Junya; Kitamura, Mitsuhiro; Ohtori, Seiji; Matsumoto, Yukei; Abe, Tetsuya; Watanabe, Kei; Hirano, Toru; Ohashi, Masayuki; Shoji, Hirokazu; Mizouchi, Tatsuki; Takahashi, Ikuko; Kawahara, Norio; Kawaguchi, Masahito; Orita, Yugo; Sasamoto, Takeshi; Yoshioka, Masahito; Fujii, Masafumi; Yonezawa, Katsutaka; Soma, Daisuke; Taneichi, Hiroshi; Takeuchi, Daisaku; Inami, Satoshi; Moridaira, Hiroshi; Ueda, Haruki; Asano, Futoshi; Shibao, Yosuke; Aita, Ikuo; Takeuchi, Yosuke; Mimura, Masaya; Shimbo, Jun; Someya, Yukio; Ikenoue, Sumio; Sameda, Hiroaki; Takase, Kan; Ikeda, Yoshikazu; Nakajima, Fumitake; Hashimoto, Mitsuhiro; Ozawa, Tomoyuki; Hasue, Fumio; Fujiyoshi, Takayuki; Kamiya, Koshiro; Watanabe, Masahiko; Katoh, Hiroyuki; Matsuyama, Yukihiro; Yamamoto, Yu; Togawa, Daisuke; Hasegawa, Tomohiko; Kobayashi, Sho; Yoshida, Go; Oe, Shin; Banno, Tomohiro; Arima, Hideyuki; Akeda, Koji; Kawamoto, Eiji; Imai, Hiroshi; Sakakibara, Toshihiko; Sudo, Akihiro; Ito, Yasuo; Kikuchi, Tsuyoshi; Osaki, Shuhei; Tanaka, Nobuhiro; Nakanishi, Kazuyoshi; Kamei, Naosuke; Kotaka, Shinji; Baba, Hideo; Okudaira, Tsuyoshi; Konishi, Hiroaki; Yamaguchi, Takayuki; Ito, Keigo; Katayama, Yoshito; Matsumoto, Taro; Matsumoto, Tomohiro; Idota, Masaru; Kanno, Haruo; Aizawa, Toshimi; Hashimoto, Ko; Eto, Toshimitsu; Sugaya, Takehiro; Matsuda, Michiharu; Fushimi, Kazunari; Nozawa, Satoshi; Iwai, Chizuo; Taguchi, Toshihiko; Kanchiku, Tsukasa; Suzuki, Hidenori; Nishida, Norihiro; Funaba, Masahiro; Yamazaki, Masashi

2018-01-01

Introduction Granulocyte colony-stimulating factor (G-CSF) is generally used for neutropaenia. Previous experimental studies revealed that G-CSF promoted neurological recovery after spinal cord injury (SCI). Next, we moved to early phase of clinical trials. In a phase I/IIa trial, no adverse events were observed. Next, we conducted a non-randomised, non-blinded, comparative trial, which suggested the efficacy of G-CSF for promoting neurological recovery. Based on those results, we are now performing a phase III trial. Methods and analysis The objective of this study is to evaluate the efficacy of G-CSF for acute SCI. The study design is a prospective, multicentre, randomised, double-blinded, placebo-controlled comparative study. The current trial includes cervical SCI (severity of American Spinal Injury Association (ASIA) Impairment Scale B/C) within 48 hours after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group is administered 400 µg/m2/day×5 days of G-CSF in normal saline via intravenous infusion for 5 consecutive days. The placebo group is similarly administered a placebo. Our primary endpoint is changes in ASIA motor scores from baseline to 3 months. Each group includes 44 patients (88 total patients). Ethics and dissemination The study will be conducted according to the principles of the World Medical Association Declaration of Helsinki and in accordance with the Japanese Medical Research Involving Human Subjects Act and other guidelines, regulations and Acts. Results of the clinical study will be submitted to the head of the respective clinical study site as a report after conclusion of the clinical study by the sponsor-investigator. Even if the results are not favourable despite conducting the clinical study properly, the data will be published as a paper. Trial registration number UMIN000018752. PMID:29730616
Are Children the Better Placebo Analgesia Responders? An Experimental Approach.

PubMed

Wrobel, Nathalie; Fadai, Tahmine; Sprenger, Christian; Hebebrand, Johannes; Wiech, Katja; Bingel, Ulrike

2015-10-01

There is little information regarding changes in placebo responsiveness with age, although first predictors of placebo responders such as psychological and physiological processes have been identified. Reviews and meta-analyses indicate that placebo response rates in randomized controlled trials (RCTs) are higher in children and adolescents compared with adults. As these studies cannot control for age-dependent differences in the natural course of the disease, biases might contribute to different placebo rates in RCTs. To avoid these biases, this study investigated age-related differences in placebo responsiveness between children and adults in a well-established experimental model of placebo analgesia combining classic conditioning and expectation. Our data confirm placebo analgesic responses in children, which did not differ in magnitude from those of adults. The influence of previous experience on subsequent treatment outcome was stronger in children than in adults, indicating an increased relevance of learning processes for treatment outcomes in children. Further studies are needed to understand the influence of treatment-related learning processes in children and adolescents, which might critically determine treatment responsiveness during adulthood. This study is the first to experimentally explore placebo analgesia and influences of previous experience on placebo responses in children compared with adults. We found comparable placebo responses in both groups and an increased relevance of learning processes for treatment outcomes in children. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.
Homeopathy for Depression: A Randomized, Partially Double-Blind, Placebo-Controlled, Four-Armed Study (DEP-HOM)

PubMed Central

Adler, Ubiratan C.; Krüger, Stephanie; Teut, Michael; Lüdtke, Rainer; Schützler, Lena; Martins, Friederike; Willich, Stefan N.; Linde, Klaus; Witt, Claudia M.

2013-01-01

Background The specific clinical benefit of the homeopathic consultation and of homeopathic remedies in patients with depression has not yet been investigated. Aims To investigate the 1) specific effect of individualized homeopathic Q-potencies compared to placebo and 2) the effect of an extensive homeopathic case taking (case history I) compared to a shorter, rather conventional one (case history II) in the treatment of acute major depression (moderate episode) after six weeks. Methods A randomized, partially double-blind, placebo-controlled, four-armed trial using a 2×2 factorial design with a six-week study duration per patient was performed. Results A total of 44 from 228 planned patients were randomized (2∶1∶2∶1 randomization: 16 homeopathic Q-potencies/case history I, 7 placebo/case history I, 14 homeopathic Q-potencies/case history II, 7 placebo/case history II). Because of recruitment problems, the study was terminated prior to full recruitment, and was underpowered for the preplanned confirmatory hypothesis testing. Exploratory data analyses showed heterogeneous and inconclusive results with large variance in the sample. The mean difference for the Hamilton-D after 6 weeks was 2.0 (95%CI −1.2;5.2) for Q-potencies vs. placebo and −3.1 (−5.9;−0.2) for case history I vs. case history II. Overall, no consistent or clinically relevant results across all outcomes between homeopathic Q-potencies versus placebo and homeopathic versus conventional case taking were observed. The frequency of adverse events was comparable for all groups. Conclusions Although our results are inconclusive, given that recruitment into this trial was very difficult and we had to terminate early, we cannot recommend undertaking a further trial addressing this question in a similar setting. Prof. Dr. Claudia Witt had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Trial registration clinicaltrials.gov identifier NCT01178255. Protocol publication: http://www.trialsjournal.com/content/12/1/43 PMID:24086352
Comparison between the combination of gabapentin, ketamine, lornoxicam, and local ropivacaine and each of these drugs alone for pain after laparoscopic cholecystectomy: a randomized trial.

PubMed

Kotsovolis, Georgios; Karakoulas, Konstantinos; Grosomanidis, Vasileios; Tziris, Nikolaos

2015-04-01

The main purpose of the study was to test whether the combination of gabapentin (600 mg 4 hours before surgery, 600 mg after 24 hours), ketamine (0.3 mg/kg before anesthesia), lornoxicam (8 mg before anesthesia and 8 mg/12 hours), and local ropivacaine (5 mL 7.5% at insertion sites) provides superior analgesia to each of these drugs alone in the first 24 hours after laparoscopic cholecystectomy. The secondary purpose was to examine whether this combination has less opioid-related side effects. This was a 2-center randomized placebo-controlled trial. One hundred forty-eight patients, between 18 and 70 years of age, were randomly assigned to 6 groups (28 in each group) with the use of computer software: A(gabapentin/ketamine/lornoxicam/ropivacaine); B(gabapentin/placebo/placebo/placebo); C (placebo/ketamine/placebo/placebo); D (placebo/placebo/lornoxicam/placebo); E (placebo/placebo/placebo/ropivacaine); and F (placebo/placebo/placebo/placebo). Only the principal investigator was aware of patients' allocation and provided drugs and placebo in covered prefilled syringes. The primary outcome of the study was the 24-hour morphine consumption. Secondary outcomes were frequency of opioid-related side effects (nausea, vomiting, sedation, pruritus, and dysuria). Only groups A (6.4 mg), B (9.46 mg), and D (9.36 mg) had lower morphine consumption than control group (20.29 mg) (P < 0.001, P = 0.01, and P = 0.008, respectively). Group A was not different from B and D (P = 0.92, P = 0.93). The only difference was in episodes of nausea between groups A (n = 5) and the control group (n = 12) (P = 0.018). The combination of gabapentin, ketamine, lornoxicam, and local ropivacaine does not provide superior analgesia than gabapentin alone or lornoxicam alone after laparoscopic cholecystectomy. The combination reduces only the frequency of postoperative nausea, but larger studies are needed for safer results. © 2014 World Institute of Pain.
Effects of guar gum ingestion on postprandial blood pressure in older adults.

PubMed

Jang, A L; Hwang, S K; Kim, D U

2015-03-01

The aim of this study was to investigate the effects of guar gum on postprandial blood pressure in older people. A randomized, double-blind, placebo-controlled, cross-over design. Community senior centers in B city, South Korea. Twenty-two older female adults aged 67 to 88 with postprandial hypotension. The participants were randomly assigned to guar gum (semi-fluid food with 9 gram) or placebo intervention during the first treatment phase. After a washout period of 1 week, the two interventions were switched to the other in the second treatment phase. Blood pressure was measured during both phases before having a meal and every 15 minutes during 120 minutes after a meal with automated sphygmomanometer. Change in systolic blood pressure (SBP) over time was significantly different between guar gum and placebo groups (F=4.07, p=0.001). Compared with placebo group, guar gum group had significantly low prevalence of postprandial hypotension (PPH) (guar gum group=18.2% vs. placebo group=72.7%; χ² =13.20, p<0.001). It also had significant difference in change of diastolic blood pressure (DBP) over time between guar gum and placebo groups (F=2.49, p=0.027). This findings show that guar gum could be effective on postprandial drops in blood pressure in older female adults.
Placebo Devices as Effective Control Methods in Acupuncture Clinical Trials: A Systematic Review

PubMed Central

Zhang, Claire Shuiqing; Tan, Hsiewe Ying; Zhang, George Shengxi; Zhang, Anthony Lin; Xue, Charlie Changli; Xie, Yi Min

2015-01-01

While the use of acupuncture has been recognised by the World Health Organisation, its efficacy for many of the common clinical conditions is still undergoing validation through randomised controlled trials (RCTs). A credible placebo control for such RCTs to enable meaningful evaluation of its efficacy is to be established. While several non-penetrating acupuncture placebo devices, namely the Streitberger, the Park and the Takakura Devices, have been developed and used in RCTs, their suitability as inert placebo controls needs to be rigorously determined. This article systematically reviews these devices as placebo interventions. Electronic searches were conducted on four English and two Chinese databases from their inceptions to July 2014; hand searches of relevant references were also conducted. RCTs, in English or Chinese language, comparing acupuncture with one of the aforementioned devices as the control intervention on human participants with any clinical condition and evaluating clinically related outcomes were included. Thirty-six studies were included for qualitative analysis while 14 were in the meta-analysis. The meta-analysis does not support the notion of either the Streitberger or the Park Device being inert control interventions while none of the studies involving the Takakura Device was included in the meta-analysis. Sixteen studies reported the occurrence of adverse events, with no significant difference between verum and placebo acupuncture. Author-reported blinding credibility showed that participant blinding was successful in most cases; however, when blinding index was calculated, only one study, which utilised the Park Device, seemed to have an ideal blinding scenario. Although the blinding index could not be calculated for the Takakura Device, it was the only device reported to enable practitioner blinding. There are limitations with each of the placebo devices and more rigorous studies are needed to further evaluate their effects and blinding credibility. PMID:26536619
Probiotic Supplementation in Morbid Obese Patients Undergoing One Anastomosis Gastric Bypass-Mini Gastric Bypass (OAGB-MGB) Surgery: a Randomized, Double-Blind, Placebo-Controlled, Clinical Trial.

PubMed

Karbaschian, Zohreh; Mokhtari, Zeinab; Pazouki, Abdolreza; Kabir, Ali; Hedayati, Mahdi; Moghadam, Somayeh Soleymanzadeh; Mirmiran, Parvin; Hekmatdoost, Azita

2018-05-03

Bariatric surgery is known as one of the most effective treatments for sustainable weight loss; however, it may be associated with some complications. This study was designed to examine the effects of probiotic supplementation on some morbidities related to this surgery. This was a placebo-controlled, double-blind, randomized clinical trial on morbid obese patients referred for One Anastomosis Gastric Bypass- Mini Gastric Bypass (OAGB-MGB) surgery to a tertiary referral center. Patients were assigned to receive a probiotic supplement (Familact®) or placebo from 4 weeks prior to surgery to 12 weeks after surgery. Anthropometric, biochemical, and inflammatory indices were evaluated at the beginning and the end of the study. At the end of study, significant improvements in some serum inflammatory markers, vitamin D status, and anthropometric measurements were observed (p < 0.05), which were significantly more in probiotic group rather than placebo group (p < 0.05). Moreover, significant improvements in glycemic indices and lipid profile were observed in both groups; however, these changes were not significantly different between the groups. There was no significant difference in serum levels of vitamin B 12 , folate, and homocysteine between groups at week 16 of the study. Our results indicate that probiotic supplementation promotes inflammatory markers, body weight loss, and status of vitamin D in patients undergoing OAGB-MGB bypass. Whether these findings will sustain in longer treatment duration remained to be elucidated in future studies. This study has been registered at Clinicaltrial.gov with registration number NCT02708589.
Bleeding and pneumonia in intensive care patients given ranitidine and sucralfate for prevention of stress ulcer: meta-analysis of randomised controlled trials

PubMed Central

Messori, A; Trippoli, S; Vaiani, M; Gorini, M; Corrado, A

2000-01-01

Objectives To determine the effectiveness of ranitidine and sucralfate in the prevention of stress ulcer in critical patients and to assess if these treatments affect the risk of nosocomial pneumonia. Design Published studies retrieved through Medline and other databases. Five meta-analyses evaluated effectiveness in terms of bleeding rates (A: ranitidine v placebo; B: sucralfate v placebo) and infectious complications in terms of incidence of nosocomial pneumonia (C: ranitidine v placebo; D: sucralfate v placebo; E: ranitidine v sucralfate). Trial quality was determined with an empirical ad hoc procedure. Main outcome measures Rates of clinically important gastrointestinal bleeding and nosocomial pneumonia (compared between the two study arms and expressed with odds ratios specific for individual studies and meta-analytic summary odds ratios). Results Meta-analysis A (five studies) comprised 398 patients; meta-analysis C (three studies) comprised 311 patients; meta-analysis D (two studies) comprised 226 patients: and meta-analysis E (eight studies) comprised 1825 patients. Meta-analysis B was not carried out as the literature search selected only one clinical trial. In meta-analysis A ranitidine was found to have the same effectiveness as placebo (odds ratio of bleeding 0.72, 95% confidence interval 0.30 to 1.70, P=0.46). In placebo controlled studies (meta-analyses C and D) ranitidine and sucralfate had no influence on the incidence of nosocomial pneumonia. In comparison with sucralfate, ranitidine significantly increased the incidence of nosocomial pneumonia (meta-analysis E: 1.35, 1.07 to 1.70, P=0.012). The mean quality score in the four analyses (on a 0 to 10 scale) ranged from 5.6 in meta-analysis E to 6.6 in meta-analysis A. Conclusions Ranitidine is ineffective in the prevention of gastrointestinal bleeding in patients in intensive care and might increase the risk of pneumonia. Studies on sucralfate do not provide conclusive results. These findings are based on small numbers of patients, and firm conclusions cannot presently be proposed. PMID:11061729
Effect of blue-blocking glasses in major depressive disorder with sleep onset insomnia: A randomized, double-blind, placebo-controlled study.

PubMed

Esaki, Yuichi; Kitajima, Tsuyoshi; Takeuchi, Ippei; Tsuboi, Soji; Furukawa, Osamu; Moriwaki, Masatsugu; Fujita, Kiyoshi; Iwata, Nakao

2017-01-01

Blue wavelengths form the portion of the visible electromagnetic spectrum that most potently regulates circadian rhythm. We hypothesized that wearing blue-blocking (BB) glasses in the evening may influence circadian rhythm disturbances in patients with major depressive disorder (MDD), resulting in improved sleep and mood. We used a randomized placebo-controlled double-blinded design. Patients with MDD with sleep onset insomnia were randomly assigned to wearing either BB glasses or clear glasses (placebo). Patients were instructed to wear the glasses from 20:00 hours until bedtime for 2 weeks. We assessed sleep state (sleep quality on a visual analog scale, the Morningness-Eveningness Questionnaire [MEQ], and a sleep diary) and depressive symptoms at baseline and after 2 weeks. Data were analyzed with a full analysis set. In total, 20 patients were randomly assigned to the BB and placebo groups (BB group, n = 10; placebo group, n = 10). There were three dropouts (BB group, n = 1; placebo group, n = 2). At baseline, sleep quality, sleep latency (assessed via a sleep diary), and antipsychotics use differed between the groups. To take account of these differences, the baseline sleep state or depressive symptoms and antipsychotics use were used as covariates in the later analysis. The change scores for sleep quality did not show a significant improvement in the BB group compared with the placebo group (mean [standard deviation, SD] scores for BB versus placebo: 36.1 [31.7] versus 16.2 [15.1], p = 0.43), although half of the BB group showed a clear improvement in sleep quality. The change in MEQ scores did not significantly differ between the groups (p = 0.14), although there was a trend of a shift to morning type in the BB group (3.10 [4.95] points) and to evening type in the placebo group (0.50 [3.89] points). There were no statistically significant changes in depressive symptoms in either group. Across both groups, 40% of the participants reported pain or discomfort from wearing the glasses, which were available in only one size. Thus, the failure to find significant differences may have resulted from the glasses used in this study. Glasses fitted to individual patients may improve efficacy and safety. Replication of the study with a larger sample size and size-adjustable glasses is needed.
Development of a Novel Six-Month Nutrition Intervention for a Randomized Trial in Older Men with Mobility Limitations.

PubMed

Apovian, C M; Singer, M R; Campbell, W W; Bhasin, S; McCarthy, A C; Shah, M; Basaria, S; Moore, L L

2017-01-01

Nutrition impacts the development of sarcopenia and protein intake is an important modulator of skeletal muscle mass loss in older people. The Optimizing Protein Intake in Older Men with Mobility Limitation (OPTIMEN) Trial was designed to assess the independent and combined effects of higher protein intake and a promyogenic agent, testosterone, on lean body mass, muscle strength and physical function in older men with mobility disability. The purpose of this paper is to describe the experimental design and nutrition intervention, including techniques used by research dietitians to develop and deliver energy and protein-specific meals to the homes of community-dwelling participants. Strategies to enhance long-term dietary compliance are detailed. Randomized, double-blind, placebo-controlled six-month intervention trial. Participants were recruited from Boston MA USA and surrounding communities. Older men who were mobility-limited (Short Physical Performance Battery (SPPB) 3-10) and consuming less protein (<0.83 g/kg/day) were recruited for this study. Here we report the successful implementation of a double-blind, placebo-controlled, parallel group, randomized controlled trial with a 6-month intervention period among community-living men, age 65 years and older with a mobility limitation. A controlled feeding plan was used to deliver required energy intakes and prescribed protein quantities of 0.8 or 1.3 grams/kilogram/day (g/kg/d) in three meals plus snacks and supplements. A 2x2 factorial design was used to assess the effects of protein level alone and in combination with testosterone (vs. placebo) on changes in lean body mass (primary outcome), muscle strength, and physical function. A total of 154 men met the eligibility criteria; 112 completed a 2-week run-in period designed to evaluate compliance with the nutrition intervention. Of these, 92 subjects met compliance eligibility criteria and agreed to be randomized; 85% completed the full trial. The study successfully delivered three meals per day to subjects, with a high degree of compliance and subject satisfaction. Overall self-reported compliance rates were 80% and 93% for the meals and supplements, respectively. Details of compliance strategies are discussed. This community-based study design may serve as a model for longer-term nutritional interventions requiring monitoring of dietary compliance in a home-based feeding and supplementation trial.
Optimality, sample size, and power calculations for the sequential parallel comparison design.

PubMed

Ivanova, Anastasia; Qaqish, Bahjat; Schoenfeld, David A

2011-10-15

The sequential parallel comparison design (SPCD) has been proposed to increase the likelihood of success of clinical trials in therapeutic areas where high-placebo response is a concern. The trial is run in two stages, and subjects are randomized into three groups: (i) placebo in both stages; (ii) placebo in the first stage and drug in the second stage; and (iii) drug in both stages. We consider the case of binary response data (response/no response). In the SPCD, all first-stage and second-stage data from placebo subjects who failed to respond in the first stage of the trial are utilized in the efficacy analysis. We develop 1 and 2 degree of freedom score tests for treatment effect in the SPCD. We give formulae for asymptotic power and for sample size computations and evaluate their accuracy via simulation studies. We compute the optimal allocation ratio between drug and placebo in stage 1 for the SPCD to determine from a theoretical viewpoint whether a single-stage design, a two-stage design with placebo only in the first stage, or a two-stage design is the best design for a given set of response rates. As response rates are not known before the trial, a two-stage approach with allocation to active drug in both stages is a robust design choice. Copyright © 2011 John Wiley & Sons, Ltd.
A Randomized, Double-Blind, Placebo-Controlled Trial of Eszopiclone for the Treatment of Insomnia in Patients with Chronic Low Back Pain

PubMed Central

Goforth, Harold W.; Preud'homme, Xavier A.; Krystal, Andrew D.

2014-01-01

Study Objectives: Insomnia, which is very common in patients with chronic low back pain (LBP), has long been viewed as a pain symptom that did not merit specific treatment. Recent data suggest that adding insomnia therapy to pain-targeted treatment should improve outcome; however, this has not been empirically tested in LBP or in any pain condition treated with a standardized pain medication regimen. We sought to test the hypothesis that adding insomnia therapy to pain-targeted treatment might improve sleep and pain in LBP. Design: Double-blind, placebo-controlled, parallel-group, 1-mo trial. Setting: Duke University Medical Center Outpatient Sleep Clinic. Patients: Fifty-two adult volunteers with LBP of at least 3 mo duration who met diagnostic criteria for insomnia (mean age: 42.5 y; 63% females). Interventions: Subjects were randomized to eszopiclone (ESZ) 3 mg plus naproxen 500 mg BID or matching placebo plus naproxen 500 mg twice a day. Measurements and Results: ESZ significantly improved total sleep time (mean increase: ESZ, 95 min; placebo, 9 min) (primary outcome) and nearly all sleep measures as well as visual analog scale pain (mean decrease: ESZ, 17 mm; placebo, 2 mm) (primary pain outcome), and depression (mean Hamilton Depression Rating Scale improvement ESZ, 3.8; placebo, 0.4) compared with placebo. Changes in pain ratings were significantly correlated with changes in sleep. Conclusions: The addition of insomnia-specific therapy to a standardized naproxen pain regimen significantly improves sleep, pain, and depression in patients with chronic low back pain (LBP). The findings indicate the importance of administering both sleep and pain-directed therapies to patients with LBP in clinical practice and provide strong evidence that improving sleep disturbance may improve pain. Trial Registration: clinicaltrials.gov identifier: NCT00365976 Citation: Goforth HW, Preud'homme XA, Krystal AD. A randomized, double-blind, placebo-controlled trial of eszopiclone for the treatment of insomnia in patients with chronic low back pain. SLEEP 2014;37(6):1053-1060. PMID:24882900
A randomized study of the efficacy and safety of parecoxib for the treatment of pain following total knee arthroplasty in Korean patients.

PubMed

Essex, Margaret Noyes; Choi, Hee-Youn; Bhadra Brown, Pritha; Cheung, Raymond

2018-01-01

Parecoxib is an injectable cyclooxygenase-2 inhibitor with proven postoperative analgesic efficacy in a variety of settings, including total knee arthroplasty (TKA). The effect of ethnicity on the efficacy of parecoxib for post-TKA pain has not been studied. This was a parallel-group, double-blind, randomized, placebo- controlled study of ethnically Korean patients aged ≥18 years who had unilateral TKA. Patients who reported moderate or severe pain 6 hours after the end of postoperative opioid analgesia were randomized to receive a single intravenous dose of parecoxib sodium 40 mg or placebo. Patients were evaluated for 24 hours postdose. The primary efficacy endpoints included time-specific pain intensity difference (PID), time-specific pain relief (PR), and time to rescue medication. The incidence and nature of adverse events (AEs) assessed safety. Of the 116 patients randomized, 58 received parecoxib and 58 placebo. Mean (SD) PID was significantly greater for parecoxib vs placebo 1 hour postdose (0.69 [0.67] vs 0.40 [0.59], respectively; p <0.05), and for each time point up to 24 hours. Similarly, mean (SD) PR was significantly greater for parecoxib vs placebo 1.5 hours postdose (1.63 [0.85] vs 1.07 [0.90], respectively; p =0.001), and for each time point up to 24 hours. The median time (hours:minutes) to rescue medication was significantly longer for parecoxib vs placebo (21:30 vs 4:08, respectively; p <0.001). Generally, fewer AEs were reported with parecoxib than placebo, and the AE profile was consistent with previous studies. These results are comparable to the findings from a similarly designed study in a Caucasian patient population. Parecoxib 40 mg significantly improved postoperative pain vs placebo in Korean patients after TKA. The efficacy and safety of parecoxib in Korean patients is similar to that seen in Caucasian patients.
A randomized study of the efficacy and safety of parecoxib for the treatment of pain following total knee arthroplasty in Korean patients

PubMed Central

Essex, Margaret Noyes; Choi, Hee-Youn; Bhadra Brown, Pritha; Cheung, Raymond

2018-01-01

Purpose Parecoxib is an injectable cyclooxygenase-2 inhibitor with proven postoperative analgesic efficacy in a variety of settings, including total knee arthroplasty (TKA). The effect of ethnicity on the efficacy of parecoxib for post-TKA pain has not been studied. Patients and methods This was a parallel-group, double-blind, randomized, placebo- controlled study of ethnically Korean patients aged ≥18 years who had unilateral TKA. Patients who reported moderate or severe pain 6 hours after the end of postoperative opioid analgesia were randomized to receive a single intravenous dose of parecoxib sodium 40 mg or placebo. Patients were evaluated for 24 hours postdose. The primary efficacy endpoints included time-specific pain intensity difference (PID), time-specific pain relief (PR), and time to rescue medication. The incidence and nature of adverse events (AEs) assessed safety. Results Of the 116 patients randomized, 58 received parecoxib and 58 placebo. Mean (SD) PID was significantly greater for parecoxib vs placebo 1 hour postdose (0.69 [0.67] vs 0.40 [0.59], respectively; p<0.05), and for each time point up to 24 hours. Similarly, mean (SD) PR was significantly greater for parecoxib vs placebo 1.5 hours postdose (1.63 [0.85] vs 1.07 [0.90], respectively; p=0.001), and for each time point up to 24 hours. The median time (hours:minutes) to rescue medication was significantly longer for parecoxib vs placebo (21:30 vs 4:08, respectively; p<0.001). Generally, fewer AEs were reported with parecoxib than placebo, and the AE profile was consistent with previous studies. These results are comparable to the findings from a similarly designed study in a Caucasian patient population. Conclusion Parecoxib 40 mg significantly improved postoperative pain vs placebo in Korean patients after TKA. The efficacy and safety of parecoxib in Korean patients is similar to that seen in Caucasian patients. PMID:29503579
Treatment of erectile dysfunction with sildenafil citrate in renal allograft recipients: a randomized, double-blind, placebo-controlled, crossover trial.

PubMed

Sharma, Raj K; Prasad, Narayan; Gupta, Amit; Kapoor, Rakesh

2006-07-01

Erectile dysfunction (ED) is observed frequently in patients with end-stage renal disease, hemodialysis patients, and renal allograft recipients. There are few studies of sildenafil use in renal allograft recipients. The study is designed as a randomized, double-blind, placebo-controlled, crossover trial. Efficacy was assessed by using the self-administered International Index of Erectile Function (IIEF), a 15-question validated measure of ED, and a global efficacy question (Did the treatment improve your erection?). Thirty-two eligible renal transplant recipients were included in this study. After treatment with sildenafil citrate, patients had significantly better scores in 13 of 15 questions, except for questions 11 (desire frequency; P = 0.39) and 12 (desire level; P = 0.61). Treatment efficacy assessed through questions 3 (penetration ability; P < 0.001) and 4 (maintenance frequency; P < 0.001) was significantly better after sildenafil therapy. There were no significant differences between baseline and post-placebo treatment scores, except for question 13 (relationship satisfaction). Patients treated with sildenafil had significantly better scores in 4 domains compared with baseline, but a difference was not observed in the sexual desire domain (P = 0.32). There were no significant differences in scores between placebo and baseline in any domain. On the global efficacy question, 81.3% of patients showed improvement compared with 18.7% with placebo. There were no differences in areas under the curve and maximum cyclosporine concentrations before and after sildenafil therapy. No patient discontinued the drug because of side effects except for 1 patient with visual hallucination. Treatment with sildenafil in renal transplant recipients is a valid option with an effective response.

Effects of lemon verbena extract (Recoverben®) supplementation on muscle strength and recovery after exhaustive exercise: a randomized, placebo-controlled trial.

PubMed

Buchwald-Werner, Sybille; Naka, Ioanna; Wilhelm, Manfred; Schütz, Elivra; Schoen, Christiane; Reule, Claudia

2018-01-01

Exhaustive exercise causes muscle damage accompanied by oxidative stress and inflammation leading to muscle fatigue and muscle soreness. Lemon verbena leaves, commonly used as tea and refreshing beverage, demonstrated antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effects of a proprietary lemon verbena extract (Recoverben®) on muscle strength and recovery after exhaustive exercise in comparison to a placebo product. The study was performed as a randomized, placebo-controlled, double-blind study with parallel design. Forty-four healthy males and females, which were 22-50 years old and active in sports, were randomized to 400 mg lemon verbena extract once daily or placebo. The 15 days intervention was divided into 10 days supplementation prior to the exhaustive exercise day (intensive jump-protocol), one day during the test and four days after. Muscle strength (MVC), muscle damage (CK), oxidative stress (GPx), inflammation (IL6) and volunteer-reported muscle soreness intensity were assessed pre and post exercise. Participants in the lemon verbena group benefited from less muscle damage as well as faster and full recovery. Compared to placebo, lemon verbena extract receiving participants had significantly less exercise-related loss of muscle strength ( p = 0.0311) over all timepoints, improved glutathione peroxidase activity by trend ( p = 0.0681) and less movement induced pain ( p = 0.0788) by trend. Creatine kinase and IL-6 didn't show significant discrimmination between groups. Lemon verbena extract (Recoverben®) has been shown to be a safe and well-tolerated natural sports ingredient, by reducing muscle damage after exhaustive exercise. The trial was registered in the clinical trials registry (clinical trial.gov NCT02923102). Registered 28 September 2016.
The hemodynamic effects of intravenous paracetamol (acetaminophen) vs normal saline in cardiac surgery patients: A single center placebo controlled randomized study

PubMed Central

Churilov, Leonid

2018-01-01

The hemodynamic effects of intravenous (IV) paracetamol in patients undergoing cardiac surgery are unknown. We performed a prospective single center placebo controlled randomized study with parallel group design in adult patients undergoing elective cardiac surgery. Participants received paracetamol (1 gram) IV or placebo (an equal volume of 0.9% saline) preoperatively followed by two postoperative doses 6 hours apart. The primary endpoint was the absolute change in systolic (SBP) 30 minutes after the preoperative infusion, analysed using an ANCOVA model. Secondary endpoints included absolute changes in mean arterial pressure (MAP) and diastolic blood pressure (DPB), and other key hemodynamic variables after each infusion. All other endpoints were analysed using random-effect generalized least squares regression modelling with individual patients treated as random effects. Fifty participants were randomly assigned to receive paracetamol (n = 25) or placebo (n = 25). Post preoperative infusion, paracetamol decreased SBP by a mean (SD) of 13 (18) mmHg, p = 0.02, compared to a mean (SD) of 1 (11) mmHg with saline. Paracetamol decreased MAP and DBP by a mean (SD) of 9 (12) mmHg and 8 (9) mmHg (p = 0.01 and 0.02), respectively, compared to a mean (SD) of 1 (8) mmHg and 0 (6) mmHg with placebo. Postoperatively, there were no significant differences in pressure or flow based hemodynamic parameters in both groups. This study provides high quality evidence that the administration of IV paracetamol in patients undergoing cardiac surgery causes a transient decrease in preoperative blood pressure when administered before surgery but no adverse hemodynamic effects when administered in the postoperative setting. PMID:29659631
The hemodynamic effects of intravenous paracetamol (acetaminophen) vs normal saline in cardiac surgery patients: A single center placebo controlled randomized study.

PubMed

Chiam, Elizabeth; Bellomo, Rinaldo; Churilov, Leonid; Weinberg, Laurence

2018-01-01

The hemodynamic effects of intravenous (IV) paracetamol in patients undergoing cardiac surgery are unknown. We performed a prospective single center placebo controlled randomized study with parallel group design in adult patients undergoing elective cardiac surgery. Participants received paracetamol (1 gram) IV or placebo (an equal volume of 0.9% saline) preoperatively followed by two postoperative doses 6 hours apart. The primary endpoint was the absolute change in systolic (SBP) 30 minutes after the preoperative infusion, analysed using an ANCOVA model. Secondary endpoints included absolute changes in mean arterial pressure (MAP) and diastolic blood pressure (DPB), and other key hemodynamic variables after each infusion. All other endpoints were analysed using random-effect generalized least squares regression modelling with individual patients treated as random effects. Fifty participants were randomly assigned to receive paracetamol (n = 25) or placebo (n = 25). Post preoperative infusion, paracetamol decreased SBP by a mean (SD) of 13 (18) mmHg, p = 0.02, compared to a mean (SD) of 1 (11) mmHg with saline. Paracetamol decreased MAP and DBP by a mean (SD) of 9 (12) mmHg and 8 (9) mmHg (p = 0.01 and 0.02), respectively, compared to a mean (SD) of 1 (8) mmHg and 0 (6) mmHg with placebo. Postoperatively, there were no significant differences in pressure or flow based hemodynamic parameters in both groups. This study provides high quality evidence that the administration of IV paracetamol in patients undergoing cardiac surgery causes a transient decrease in preoperative blood pressure when administered before surgery but no adverse hemodynamic effects when administered in the postoperative setting.
Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: a randomised, double-blind, placebo-controlled study in cannabis users.

PubMed

Hindocha, Chandni; Freeman, Tom P; Schafer, Grainne; Gardener, Chelsea; Das, Ravi K; Morgan, Celia J A; Curran, H Valerie

2015-03-01

Acute administration of the primary psychoactive constituent of cannabis, Δ-9-tetrahydrocannabinol (THC), impairs human facial affect recognition, implicating the endocannabinoid system in emotional processing. Another main constituent of cannabis, cannabidiol (CBD), has seemingly opposite functional effects on the brain. This study aimed to determine the effects of THC and CBD, both alone and in combination on emotional facial affect recognition. 48 volunteers, selected for high and low frequency of cannabis use and schizotypy, were administered, THC (8mg), CBD (16mg), THC+CBD (8mg+16mg) and placebo, by inhalation, in a 4-way, double-blind, placebo-controlled crossover design. They completed an emotional facial affect recognition task including fearful, angry, happy, sad, surprise and disgust faces varying in intensity from 20% to 100%. A visual analogue scale (VAS) of feeling 'stoned' was also completed. In comparison to placebo, CBD improved emotional facial affect recognition at 60% emotional intensity; THC was detrimental to the recognition of ambiguous faces of 40% intensity. The combination of THC+CBD produced no impairment. Relative to placebo, both THC alone and combined THC+CBD equally increased feelings of being 'stoned'. CBD did not influence feelings of 'stoned'. No effects of frequency of use or schizotypy were found. In conclusion, CBD improves recognition of emotional facial affect and attenuates the impairment induced by THC. This is the first human study examining the effects of different cannabinoids on emotional processing. It provides preliminary evidence that different pharmacological agents acting upon the endocannabinoid system can both improve and impair recognition of emotional faces. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.
Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: A randomised, double-blind, placebo-controlled study in cannabis users

PubMed Central

Hindocha, Chandni; Freeman, Tom P.; Schafer, Grainne; Gardener, Chelsea; Das, Ravi K.; Morgan, Celia J.A.; Curran, H. Valerie

2015-01-01

Acute administration of the primary psychoactive constituent of cannabis, Δ-9-tetrahydrocannabinol (THC), impairs human facial affect recognition, implicating the endocannabinoid system in emotional processing. Another main constituent of cannabis, cannabidiol (CBD), has seemingly opposite functional effects on the brain. This study aimed to determine the effects of THC and CBD, both alone and in combination on emotional facial affect recognition. 48 volunteers, selected for high and low frequency of cannabis use and schizotypy, were administered, THC (8 mg), CBD (16 mg), THC+CBD (8 mg+16 mg) and placebo, by inhalation, in a 4-way, double-blind, placebo-controlled crossover design. They completed an emotional facial affect recognition task including fearful, angry, happy, sad, surprise and disgust faces varying in intensity from 20% to 100%. A visual analogue scale (VAS) of feeling ‘stoned’ was also completed. In comparison to placebo, CBD improved emotional facial affect recognition at 60% emotional intensity; THC was detrimental to the recognition of ambiguous faces of 40% intensity. The combination of THC+CBD produced no impairment. Relative to placebo, both THC alone and combined THC+CBD equally increased feelings of being ‘stoned’. CBD did not influence feelings of ‘stoned’. No effects of frequency of use or schizotypy were found. In conclusion, CBD improves recognition of emotional facial affect and attenuates the impairment induced by THC. This is the first human study examining the effects of different cannabinoids on emotional processing. It provides preliminary evidence that different pharmacological agents acting upon the endocannabinoid system can both improve and impair recognition of emotional faces. PMID:25534187
The effects of energy drink in combination with alcohol on performance and subjective awareness.

PubMed

Alford, Chris; Hamilton-Morris, Jennifer; Verster, Joris C

2012-08-01

This study investigated the coadministration of an energy drink with alcohol to study the effects on subjective intoxication and objective performance. This study aims to evaluate the objective and subjective effects of alcohol versus placebo at two alcohol doses, alone and in combination with an energy drink, in a balanced order, placebo-controlled, double-blind design. Two groups of ten healthy volunteers, mean (SD) age of 24 (6.5), participated in the study. One group consumed energy drink containing 80 mg of caffeine and the other consumed a placebo drink, with both receiving two alcohol doses (0.046 and 0.087% breathalyser alcohol concentration). Tests included breath alcohol assessment, objective measures of performance (reaction time, word memory and Stroop task) and subjective visual analogue mood scales. Participants showed significantly impaired reaction time and memory after alcohol compared to the no alcohol condition and had poorer memory after the higher alcohol dose. Stroop performance was improved with the energy drink plus alcohol combination compared to the placebo drink plus alcohol combination. Participants felt significant subjective dose-related impairment after alcohol compared to no alcohol. Neither breath alcohol concentration nor the subjective measures showed a significant difference between the energy drink and the placebo energy drink when combined with alcohol. Subjective effects reflected awareness of alcohol intoxication and sensitivity to increasing alcohol dose. There were no overall significant group differences for subjective measures between energy drink and placebo groups in the presence of alcohol and no evidence that the energy drink masked the subjective effects of alcohol at either dose.
Double-blind, placebo-controlled, multiple-ascending-dose study on the pharmacodynamics of ABIO-08/01, a new CNS drug with potential anxiolytic activity. 2. EEG-tomography findings based on LORETA (low-resolution brain electromagnetic tomography).

PubMed

Saletu, Bernd; Anderer, Peter; Wolzt, Michael; Nosiska, Dorothea; Assandri, Alessandro; Noseda, Emanuele; Nannipieri, Fabrizio; Saletu-Zyhlarz, Gerda M

2009-01-01

Effects of ABIO-08/01, a new potentially anxiolytic isoxazoline, on regional electrical brain generators were investigated by 3-dimensional EEG tomography. In a double- blind, placebo-controlled, multiple-ascending-dose study, 16 healthy males (30.2 +/- 5.7 years) received 3 oral drug doses (10, 20, 40 mg) and placebo for 7 days (8-day wash-out) in a randomized non-balanced design for phase-1 studies. A 3-min vigilance-controlled (V) EEG, a 4-min resting (R) EEG with eyes closed, a 1-min eyes-open (EO) EEG and psychometric tests were performed 0, 1 and 6 h after taking the drug on days 1 and 5. Low-resolution brain electromagnetic tomography (LORETA) was computed from the spectrally analyzed EEG data, and differences between drug and placebo were displayed as statistical parametric maps. Data were registered to the Talairach-Tournoux Human Brain Atlas available as a digitized MRI. An overall omnibus significance test followed by a voxel-by-voxel t test demonstrated significant regional EEG changes after ABIO-08/01 versus placebo, dependent on recording condition, dose and time. While in the EO-EEG specifically the lowest dose of ABIO-08/01 induced pronounced sedative effects (delta/theta and beta increase) 1 h after acute and slightly less so after superimposed administration, in the 6th hour a decrease in alpha and beta activity signaled less sedative and more relaxant action. In the V-EEG these changes were less pronounced, in the R-EEG partly opposite. Hemisphere-specific changes were observed, suggesting increases in LORETA power over the left temporal, parietal, superior frontal regions and decreases over the right prefrontal, temporal pole and occipital regions. These LORETA changes are discussed in the light of neuroimaging findings on anxiety and anxiolytics. 2009 S. Karger AG, Basel.
Field assessment of a novel household-based water filtration device: a randomised, placebo-controlled trial in the Democratic Republic of Congo.

PubMed

Boisson, Sophie; Kiyombo, Mbela; Sthreshley, Larry; Tumba, Saturnin; Makambo, Jacques; Clasen, Thomas

2010-09-10

Household water treatment can improve the microbiological quality of drinking water and may prevent diarrheal diseases. However, current methods of treating water at home have certain shortcomings, and there is evidence of bias in the reported health impact of the intervention in open trial designs. We undertook a randomised, double-blinded, placebo-controlled trial among 240 households (1,144 persons) in rural Democratic Republic of Congo to assess the field performance, use and effectiveness of a novel filtration device in preventing diarrhea. Households were followed up monthly for 12 months. Filters and placebos were monitored for longevity and for microbiological performance by comparing thermotolerant coliform (TTC) levels in influent and effluent water samples. Mean longitudinal prevalence of diarrhea was estimated among participants of all ages. Compliance was assessed through self-reported use and presence of water in the top vessel of the device at the time of visit. Over the 12-month follow-up period, data were collected for 11,236 person-weeks of observation (81.8% total possible). After adjusting for clustering within the household, the longitudinal prevalence ratio of diarrhoea was 0.85 (95% confidence interval: 0.61-1.20). The filters achieved a 2.98 log reduction in TTC levels while, for reasons that are unclear, the placebos achieved a 1.05 log reduction (p<0.0001). After 8 months, 68% of intervention households met the study's definition of current users, though most (73% of adults and 95% of children) also reported drinking untreated water the previous day. The filter maintained a constant flow rate over time, though 12.4% of filters were damaged during the course of the study. While the filter was effective in improving water quality, our results provide little evidence that it was protective against diarrhea. The moderate reduction observed nevertheless supports the need for larger studies that measure impact against a neutral placebo. Current Controlled Trials ISRCTN03844341.
Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials.

PubMed

Berry-Kravis, Elizabeth; Des Portes, Vincent; Hagerman, Randi; Jacquemont, Sébastien; Charles, Perrine; Visootsak, Jeannie; Brinkman, Marc; Rerat, Karin; Koumaras, Barbara; Zhu, Liansheng; Barth, Gottfried Maria; Jaecklin, Thomas; Apostol, George; von Raison, Florian

2016-01-13

Fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autistic spectrum disorder, is typically caused by transcriptional silencing of the X-linked FMR1 gene. Work in animal models has described altered synaptic plasticity, a result of the up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling, as a putative downstream effect. Post hoc analysis of a randomized, placebo-controlled, crossover phase 2 trial suggested that the selective mGluR5 antagonist mavoglurant improved behavioral symptoms in FXS patients with completely methylated FMR1 genes. We present the results of two phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of mavoglurant in FXS, designed to confirm this result in adults (n = 175, aged 18 to 45 years) and adolescents (n = 139, aged 12 to 17 years). In both trials, participants were stratified by methylation status and randomized to receive mavoglurant (25, 50, or 100 mg twice daily) or placebo over 12 weeks. Neither of the studies achieved the primary efficacy end point of improvement on behavioral symptoms measured by the Aberrant Behavior Checklist-Community Edition using the FXS-specific algorithm (ABC-C(FX)) after 12 weeks of treatment with mavoglurant. The safety and tolerability profile of mavoglurant was as previously described, with few adverse events. Therefore, under the conditions of our study, we could not confirm the mGluR theory of FXS nor the ability of the methylation state of the FMR1 promoter to predict mavoglurant efficacy. Preclinical results suggest that future clinical trials might profitably explore initiating treatment in a younger population with longer treatment duration and longer placebo run-ins and identifying new markers to better assess behavioral and cognitive benefits. Copyright © 2016, American Association for the Advancement of Science.
Oral Administration of Lactobacillus plantarum 299v Reduces Cortisol Levels in Human Saliva during Examination Induced Stress: A Randomized, Double-Blind Controlled Trial.

PubMed

Andersson, Hannah; Tullberg, Cecilia; Ahrné, Siv; Hamberg, Kristina; Lazou Ahrén, Irini; Molin, Göran; Sonesson, Mikael; Håkansson, Åsa

2016-01-01

Objective . To clarify the effect of Lactobacillus plantarum 299v on the salivary cortisol and salivary IgA levels in young adults under examination stress. Design . Forty-one students with an upcoming academic exam were included in a randomized double-blind, placebo-controlled study. The probiotic bacteria or the placebo product was administered in capsules once a day during 14 days. Saliva was collected and a perceived stress test was filled out at each sampling occasion. Saliva was collected for cortisol analysis by Electrochemiluminescence Immunoassay (ECLI) and salivary IgA was analysed by Enzyme-Linked Immunosorbent Assay (ELISA). Abundance of lactobacilli was evaluated by cultivation of saliva on selective medium and identification of L. plantarum 299v was done on randomly selected colonies by a random amplification of polymorphic DNA (RAPD) typing. Results . A significant difference in cortisol levels was found between the treatment group and the placebo group ( P < 0.05), together with a significant increase in levels of lactobacilli in the treatment group compared with the placebo group ( P < 0.001). No significant changes were found for salivary IgA. Conclusion . A probiotic bacterium with ability to reduce symptoms of irritable bowel syndrome (IBS) prohibited increased levels of the stress marker cortisol during the examination period. The registration number of the study is NCT02974894, and the study is registered at ClinicalTrials.gov.
Oral Administration of Lactobacillus plantarum 299v Reduces Cortisol Levels in Human Saliva during Examination Induced Stress: A Randomized, Double-Blind Controlled Trial

PubMed Central

Andersson, Hannah; Tullberg, Cecilia; Ahrné, Siv; Hamberg, Kristina; Lazou Ahrén, Irini; Molin, Göran; Sonesson, Mikael

2016-01-01

Objective. To clarify the effect of Lactobacillus plantarum 299v on the salivary cortisol and salivary IgA levels in young adults under examination stress. Design. Forty-one students with an upcoming academic exam were included in a randomized double-blind, placebo-controlled study. The probiotic bacteria or the placebo product was administered in capsules once a day during 14 days. Saliva was collected and a perceived stress test was filled out at each sampling occasion. Saliva was collected for cortisol analysis by Electrochemiluminescence Immunoassay (ECLI) and salivary IgA was analysed by Enzyme-Linked Immunosorbent Assay (ELISA). Abundance of lactobacilli was evaluated by cultivation of saliva on selective medium and identification of L. plantarum 299v was done on randomly selected colonies by a random amplification of polymorphic DNA (RAPD) typing. Results. A significant difference in cortisol levels was found between the treatment group and the placebo group (P < 0.05), together with a significant increase in levels of lactobacilli in the treatment group compared with the placebo group (P < 0.001). No significant changes were found for salivary IgA. Conclusion. A probiotic bacterium with ability to reduce symptoms of irritable bowel syndrome (IBS) prohibited increased levels of the stress marker cortisol during the examination period. The registration number of the study is NCT02974894, and the study is registered at ClinicalTrials.gov. PMID:28101105
Erotic stimulus processing under amisulpride and reboxetine: a placebo-controlled fMRI study in healthy subjects.

PubMed

Graf, Heiko; Wiegers, Maike; Metzger, Coraline D; Walter, Martin; Grön, Georg; Abler, Birgit

2014-10-31

Impaired sexual function is increasingly recognized as a side effect of psychopharmacological treatment. However, underlying mechanisms of action of the different drugs on sexual processing are still to be explored. Using functional magnetic resonance imaging, we previously investigated effects of serotonergic (paroxetine) and dopaminergic (bupropion) antidepressants on sexual functioning (Abler et al., 2011). Here, we studied the impact of noradrenergic and antidopaminergic medication on neural correlates of visual sexual stimulation in a new sample of subjects. Nineteen healthy heterosexual males (mean age 24 years, SD 3.1) under subchronic intake (7 days) of the noradrenergic agent reboxetine (4 mg/d), the antidopaminergic agent amisulpride (200mg/d), and placebo were included and studied with functional magnetic resonance imaging within a randomized, double-blind, placebo-controlled, within-subjects design during an established erotic video-clip task. Subjective sexual functioning was assessed using the Massachusetts General Hospital-Sexual Functioning Questionnaire. Relative to placebo, subjective sexual functioning was attenuated under reboxetine along with diminished neural activations within the caudate nucleus. Altered neural activations correlated with decreased sexual interest. Under amisulpride, neural activations and subjective sexual functioning remained unchanged. In line with previous interpretations of the role of the caudate nucleus in the context of primary reward processing, attenuated caudate activation may reflect detrimental effects on motivational aspects of erotic stimulus processing under noradrenergic agents. © The Author 2015. Published by Oxford University Press on behalf of CINP.
Interaction between drug and placebo effects: a cross-over balanced placebo design trial.

PubMed

Hammami, Muhammad M; Al-Gaai, Eman A; Alvi, Syed; Hammami, Muhammad B

2010-11-19

The total effect of a medication is the sum of its drug effect, placebo effect (meaning response), and their possible interaction. Current interpretation of clinical trials' results assumes no interaction. Demonstrating such an interaction has been difficult due to lack of an appropriate study design. 180 adults were randomized to caffeine (300 mg) or placebo groups. Each group received the assigned intervention described by the investigators as caffeine or placebo, in a randomized crossover design. 4-hour-area-under-the-curve of energy, sleepiness, nausea (on 100 mm visual analog scales), and systolic blood pressure levels as well as caffeine pharmacokinetics (in 22 volunteers nested in the caffeine group) were determined. Caffeine drug, placebo, placebo-plus-interaction, and total effects were estimated by comparing outcomes after, receiving caffeine described as placebo to receiving placebo described as placebo, receiving placebo described as caffeine or placebo, receiving caffeine described as caffeine or placebo, and receiving caffeine described as caffeine to receiving placebo described as placebo, respectively. The placebo effect on area-under-the-curve of energy (mean difference) and sleepiness (geometric mean ratio) was larger than placebo-plus-interaction effect (16.6 [95% CI, 4.1 to 29.0] vs. 8.4 [-4.2 to 21.0] mm*hr and 0.58 [0.39 to 0.86] vs. 0.69 [0.49 to 0.97], respectively), similar in size to drug effect (20.8 [3.8 to 37.8] mm*hr and 0.49 [0.30 to 0.91], respectively), and its combination with the later was larger than total caffeine effect (29.5 [11.9 to 47.1] mm*hr and 0.37 [0.22 to 0.64]). Placebo-plus-interaction effect increased caffeine terminal half-life by 0.40 [0.12 to 0.68] hr (P=0.007). Drug and placebo effects of a medication may be less than additive, which influences the interpretation of clinical trials. The placebo effect may increase active drug terminal half-life, a novel mechanism of placebo action. ClinicalTrials.gov identification number - NCT00426010.
A brief history of placebos and clinical trials in psychiatry.

PubMed

Shorter, Edward

2011-04-01

The history of placebos in psychiatry can be understood only in the context of randomized controlled trials (RCTs). Placebo treatments are as old as medicine itself, and are particularly effective in dealing with psychosomatic symptoms. In psychiatry, placebos have mainly been featured in clinical drug trials. The earliest controlled trial in psychiatry (not involving drugs) occurred in 1922, followed by the first crossover studies during the 1930s. Meanwhile the concept of randomization was developed during the interwar years by British statistician Ronald A Fisher, and introduced in 3 trials of tuberculosis drugs between 1947 and 1951. These classic studies established the RCT as the gold standard in pharmaceutical trials, and its status was cemented during the mid-1950s. Nevertheless, while the placebo became established as a standard measure of drug action, placebo treatments became stigmatized as unethical. This is unfortunate, as they constitute one of the most powerful therapies in psychiatry. In recent years, moreover, the dogma of the placebo-controlled trial as the only acceptable data for drug licensing is also being increasingly discredited. This backlash has had 2 sources: one is the recognition that the US Food and Drug Administration has been too lax in permitting trials controlled with placebos alone, rather than also using an active agent as a test of comparative efficacy. In addition, there is evidence that in the hands of the pharmaceutical industry, the scientific integrity of RCTs themselves has been degraded into a marketing device. The once-powerful placebo is thus threatened with extinction.
The sodium glucose cotransporter 2 inhibitor empagliflozin does not prolong QT interval in a thorough QT (TQT) study

PubMed Central

2013-01-01

Background Empagliflozin is a potent, selective sodium glucose cotransporter 2 (SGLT2) inhibitor in development as an oral antidiabetic treatment. This QT interval study assessed potential effects of empagliflozin on ventricular repolarisation and other electrocardiogram (ECG) parameters. Methods A randomised, placebo-controlled, single-dose, double-blind, five-period crossover study incorporating a novel double-placebo period design to reduce sample size, while maintaining full statistical power. Treatments: single empagliflozin doses of 25 mg (therapeutic) and 200 mg (supratherapeutic), matching placebo and open-label moxifloxacin 400 mg (positive control). Triplicate 12-lead ECGs of 10 second duration were recorded at baseline and during the first 24 hours after dosing. The primary endpoint was mean change from baseline (MCfB) in the population heart rate-corrected QT interval (QTcN) between 1–4 hours after dosing. Results Thirty volunteers (16 male, 14 female, mean [range] age: 34.5 [18–52] years) were randomised. The placebo-corrected MCfB in QTcN 1–4 hours after dosing was 0.6 (90% CI: -0.7, 1.9) ms and -0.2 (-1.4, 0.9) ms for empagliflozin 25 mg and 200 mg, respectively, below the ICH E14 defined threshold of regulatory concern 10 ms. Assay sensitivity was confirmed by a placebo-corrected MCfB in QTcN 2–4 hours post-dose of 12.4 (10.7, 14.1) ms with moxifloxacin 400 mg. Empagliflozin tolerability was good for all volunteers; 23.3% experienced adverse events (AEs) with empagliflozin and 27.6% with placebo. The most frequent AE was nasopharyngitis. Conclusions/interpretation Single doses of empagliflozin 25 mg and 200 mg were not associated with QTcN prolongation and were well tolerated in healthy volunteers. Trial registration ClinicalTrials.gov: NCT01195675 PMID:23617452
Preventing ICU Subsyndromal Delirium Conversion to Delirium with Low Dose IV Haloperidol: A Double-Blind, Placebo-Controlled Pilot Study

PubMed Central

Al-Qadheeb, Nada S.; Skrobik, Yoanna; Schumaker, Greg; Pacheco, Manuel; Roberts, Russel; Ruthazer, Robin; Devlin, John W

2016-01-01

Objective To compare the efficacy and safety of scheduled low-dose, haloperidol vs. placebo for the prevention of delirium [Intensive Care Delirium Screening Checklist (ICDSC) ≥ 4)] administered to critically ill adults with subsyndromal delirium (ICDSC = 1-3). Design Randomized, double-blind, placebo-controlled trial. Setting Three 10-bed ICUs (2 medical; 1 surgical) at an academic medical center in the U.S. Patients Sixty-eight mechanically ventilated patients with subsyndromal delirium without complicating neurologic conditions, cardiac surgery or requiring deep sedation. Interventions Patients were randomly assigned to receive intravenous haloperidol 1 mg or placebo every six hours until either delirium (ICDSC ≥ 4 with psychiatric confirmation), therapy ≥ 10 days or ICU discharge occurred. Measurements and Main Results Baseline characteristics were similar between the haloperidol (n=34) and placebo (n=34) groups. A similar number of patients given haloperidol [12/34 (35%)] and placebo [8/34 (23%)] patients developed delirium (p=0.29). Haloperidol use reduced the hours per study day spent agitated (SAS ≥ 5) (p=0.008), but did not influence the proportion of 12-hour ICU shifts patients’ spent alive without coma (SAS ≤ 2) or delirium (p=0.36), the time to first delirium occurrence (p=0.22) nor delirium duration (p=0.26). Days of mechanical ventilation (p=0.80), ICU mortality (p=0.55) and ICU patient disposition (p=0.22) were similar in the two groups. The proportion of patients who developed QTc-interval prolongation (p=0.16), extrapyramidal symptoms (p=0.31), excessive sedation (p=0.31) or new-onset hypotension (p=1.0) that resulted in study drug discontinuation was comparable between the two groups. Conclusions Low-dose scheduled haloperidol, initiated early in the ICU stay, does not prevent delirium and has little therapeutic advantage in mechanically ventilated, critically ill adults with subsyndromal delirium. PMID:26540397
Cocoa polyphenols enhance positive mood states but not cognitive performance: a randomized, placebo-controlled trial.

PubMed

Pase, Matthew P; Scholey, Andrew B; Pipingas, Andrew; Kras, Marni; Nolidin, Karen; Gibbs, Amy; Wesnes, Keith; Stough, Con

2013-05-01

This study aimed to examine the acute and sub-chronic effects of cocoa polyphenols on cognition and mood. In a randomized, double-blind study, healthy middle-aged participants received a dark chocolate drink mix standardized to contain 500 mg, 250 mg or 0 mg of polyphenols (placebo) in a parallel-groups design. Participants consumed their assigned treatment once daily for 30 days. Cognition was measured with the Cognitive Drug Research system and self-rated mood with the Bond-Lader Visual Analogue Scale. Participants were tested at baseline, at 1, 2.5 and 4 h after a single acute dose and again after receiving 30 days of treatment. In total, 72 participants completed the trial. After 30 days, the high dose of treatment significantly increased self-rated calmness and contentedness relative to placebo. Mood was unchanged by treatment acutely while cognition was unaffected by treatment at all time points. This randomized controlled trial is perhaps the first to demonstrate the positive effects of cocoa polyphenols on mood in healthy participants. This provides a rationale for exploring whether cocoa polyphenols can ameliorate the symptoms associated with clinical anxiety or depression.
Mifepristone (RU 486) induces embryo expulsion in first trimester non-developing pregnancies: a prospective randomized trial.

PubMed

Lelaidier, C; Baton-Saint-Mleux, C; Fernandez, H; Bourget, P; Frydman, R

1993-03-01

This study was designed to investigate the use of oral mifepristone (RU 486) for the induction of natural expulsion of concepti in women with spontaneously interrupted pregnancy in the first trimester. It consisted of a double-blind placebo-controlled study of mifepristone (600 mg) against placebo. A total of 46 women consulting for interrupted pregnancy were diagnosed at ultrasound with no clinical sign of miscarriage. Measurements were made of the occurrence of natural expulsion, the frequency of complete expulsion, the need for subsequent surgical evacuation, analgesia and the need for transfusion. Natural expulsion occurred within 5 days in 82% of patients receiving mifepristone treatment versus 8% of placebo-treated patients (P < 0.001). All patients experienced bleeding after RU 486 and two needed emergency aspiration for haemorrhagic expulsion. The treatment failed in four patients, who underwent evacuation under local anaesthesia. In the control group, 19 patients underwent evacuation under local (n = 10) or general (n = 9) anaesthesia. It was concluded that a standard oral pilot dose of 600 mg of mifepristone induces natural expulsion in 82% of women with non-developing first trimester intrauterine pregnancies.
The vasopressin V(1b) receptor antagonist SSR149415 in the treatment of major depressive and generalized anxiety disorders: results from 4 randomized, double-blind, placebo-controlled studies.

PubMed

Griebel, Guy; Beeské, Sandra; Stahl, Stephen M

2012-11-01

These studies were designed to evaluate the efficacy and tolerability of the first nonpeptide vasopressin V(1b) receptor antagonist, SSR149415, in the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD). Studies were randomized 8-week, double-blind, placebo-controlled trials evaluating 100- and 250-mg twice daily doses of SSR149415, placebo, and escitalopram 10 mg/day or paroxetine 20 mg/day, conducted from August 2006 through February 2008. Participants met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for MDD or GAD. Baseline Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HDRS) total scores were ≥ 24 and 18, respectively, and in the GAD trial baseline Hamilton Anxiety Rating Scale (HARS) score was ≥ 22. Primary efficacy variables included changes from baseline in total score on HDRS or HARS and MADRS, and the secondary variable included changes in the Clinical Global Impressions-Severity of Illness score (CGI-S). A 4-week, double-blind, placebo-controlled study evaluating the effect of 100- and 250-mg twice daily doses of SSR149415 on the hypothalamic-pituitary-adrenal (HPA) axis in MDD patients was also conducted. In the GAD trial, SSR149415 did not separate from placebo on the primary (HARS-100 mg: P = .29; 250 mg: P = .21) and secondary (CGI-S-100 mg: P = .18; 250 mg: P = .24) outcome measures, while paroxetine demonstrated efficacy (HARS: P = .003; CGI-S: P = .01). In 2 MDD trials, SSR149415-treated patients did not show significant improvement from baseline on any outcome measure compared with placebo-treated patients (HDRS-100 mg: P = .21 and .48, respectively; 250 mg: P = .22 and P = .46, respectively; CGI-S-100 mg: P = .64 and P = .82, respectively; 250 mg: P = .33 and P = .08, respectively). In the third MDD study, SSR149415 250 mg (P = .04), but not escitalopram (P = .15), demonstrated significant improvement compared to placebo on the HDRS total score at week 8. SSR149415 had no deleterious effects on the HPA axis. These studies demonstrate that SSR149415 may not be useful for the treatment of GAD and that its antidepressant potential needs to be further evaluated. ClinicalTrials.gov identifiers: NCT00374166 (Sanofi ID number: DFI5880), NCT00361491 (Sanofi ID number: DFI5879), NCT00358631 (Sanofi ID number: DFI5878), NCT01606384 (Sanofi ID number: PDY5467). © Copyright 2012 Physicians Postgraduate Press, Inc.
Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and cravings

PubMed Central

Trigo, Jose M.; Lagzdins, Dina; Rehm, Jürgen; Selby, Peter; Gamaleddin, Islam; Fischer, Benedikt; Barnes, Allan J.; Huestis, Marilyn A.; Le Foll, Bernard

2016-01-01

Background There is currently no pharmacological treatment approved for cannabis dependence. In this proof of concept study, we assessed the feasibility/effects of fixed and self-titrated dosages of Sativex (1:1, Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD)) on craving and withdrawal from cannabis among nine community-recruited cannabis-dependent subjects. Methods Participants underwent an 8-week double-blind placebo-controlled trial (an ABACADAE design), with four smoke as usual conditions (SAU) (A) separated by four cannabis abstinence conditions (B–E), with administration of either self-titrated/fixed doses of placebo or Sativex (up to 108 mg THC/100 mg CBD). The order of medication administration during abstinence conditions was randomized and counterbalanced. Withdrawal symptoms and craving were assessed using the Cannabis Withdrawal Scale (CWS), Marijuana Withdrawal Checklist (MWC) and Marijuana Craving Questionnaire (MCQ). Medication use was assessed during the study by means of self-reports, vial weight control, toxicology and metabolite analysis. Cannabis use was assessed by means of self-reports. Results High fixed doses of Sativex were well tolerated and significantly reduced cannabis withdrawal during abstinence, but not craving, as compared to placebo. Self-titrated doses were lower and showed limited efficacy as compared to high fixed doses. Participants reported a significantly lower “high” following Sativex or placebo as compared to SAU conditions. Cannabis/medication use along the study, as per self-reports, suggests compliance with the study conditions. Conclusions The results found in this proof of concept study warrant further systematic exploration of Sativex as a treatment option for cannabis withdrawal and dependence. PMID:26925704

Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and cravings.

PubMed

Trigo, Jose M; Lagzdins, Dina; Rehm, Jürgen; Selby, Peter; Gamaleddin, Islam; Fischer, Benedikt; Barnes, Allan J; Huestis, Marilyn A; Le Foll, Bernard

2016-04-01

There is currently no pharmacological treatment approved for cannabis dependence. In this proof of concept study, we assessed the feasibility/effects of fixed and self-titrated dosages of Sativex (1:1, Δ(9)-tetrahydrocannabinol (THC)/cannabidiol (CBD)) on craving and withdrawal from cannabis among nine community-recruited cannabis-dependent subjects. Participants underwent an 8-week double-blind placebo-controlled trial (an ABACADAE design), with four smoke as usual conditions (SAU) (A) separated by four cannabis abstinence conditions (B-E), with administration of either self-titrated/fixed doses of placebo or Sativex (up to 108 mg THC/100 mg CBD). The order of medication administration during abstinence conditions was randomized and counterbalanced. Withdrawal symptoms and craving were assessed using the Cannabis Withdrawal Scale (CWS), Marijuana Withdrawal Checklist (MWC) and Marijuana Craving Questionnaire (MCQ). Medication use was assessed during the study by means of self-reports, vial weight control, toxicology and metabolite analysis. Cannabis use was assessed by means of self-reports. High fixed doses of Sativex were well tolerated and significantly reduced cannabis withdrawal during abstinence, but not craving, as compared to placebo. Self-titrated doses were lower and showed limited efficacy as compared to high fixed doses. Participants reported a significantly lower "high" following Sativex or placebo as compared to SAU conditions. Cannabis/medication use along the study, as per self-reports, suggests compliance with the study conditions. The results found in this proof of concept study warrant further systematic exploration of Sativex as a treatment option for cannabis withdrawal and dependence. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Multi-center randomized controlled trial of cognitive treatment, placebo, oxybutynin, bladder training, and pelvic floor training in children with functional urinary incontinence.

PubMed

van Gool, Jan D; de Jong, Tom P V M; Winkler-Seinstra, Pauline; Tamminen-Möbius, Tytti; Lax, Hildegard; Hirche, Herbert; Nijman, Rien J M; Hjälmås, Kelm; Jodal, Ulf; Bachmann, Hannsjörg; Hoebeke, Piet; Walle, Johan Vande; Misselwitz, Joachim; John, Ulrike; Bael, An

2014-06-01

Functional urinary incontinence causes considerable morbidity in 8.4% of school-age children, mainly girls. To compare oxybutynin, placebo, and bladder training in overactive bladder (OAB), and cognitive treatment and pelvic floor training in dysfunctional voiding (DV), a multi-center controlled trial was designed, the European Bladder Dysfunction Study. Seventy girls and 27 boys with clinically diagnosed OAB and urge incontinence were randomly allocated to placebo, oxybutynin, or bladder training (branch I), and 89 girls and 16 boys with clinically diagnosed DV to either cognitive treatment or pelvic floor training (branch II). All children received standardized cognitive treatment, to which these interventions were added. The main outcome variable was daytime incontinence with/without urinary tract infections. Urodynamic studies were performed before and after treatment. In branch I, the 15% full response evolved to cure rates of 39% for placebo, 43% for oxybutynin, and 44% for bladder training. In branch II, the 25% full response evolved to cure rates of 52% for controls and 49% for pelvic floor training. Before treatment, detrusor overactivity (OAB) or pelvic floor overactivity (DV) did not correlate with the clinical diagnosis. After treatment these urodynamic patterns occurred de novo in at least 20%. The mismatch between urodynamic patterns and clinical symptoms explains why cognitive treatment was the key to success, not the added interventions. Unpredictable changes in urodynamic patterns over time, the response to cognitive treatment, and the gender-specific prevalence suggest social stress might be a cause for the symptoms, mediated by corticotropin-releasing factor signaling pathways. © 2013 Wiley Periodicals, Inc.
Acetylcholinesterase inhibitors and memantine in bipolar disorder: A systematic review and best evidence synthesis of the efficacy and safety for multiple disease dimensions.

PubMed

Veronese, Nicola; Solmi, Marco; Luchini, Claudio; Lu, Ru-Band; Stubbs, Brendon; Zaninotto, Leonardo; Correll, Christoph U

2016-06-01

Acetylcholinesterase inhibitors (AceI) and memantine might prove useful in bipolar disorder (BD) given their neuroprotective and pro-cognitive effects, as highlighted by several case reports. We aimed to systematically review the efficacy and safety of AceI and memantine across multiple outcome dimensions in BD. Systematic PubMed and SCOPUS search until 04/17/2015 without language restrictions. Included were randomized controlled trials (RCTs), open label studies and case series of AceI or memantine in BD patients reporting quantitative data on depression, mania, psychotic symptoms, global functioning, or cognitive performance. We summarized results using a best-evidence based synthesis. Out of 214 hits, 12 studies (RCTs=5, other designs=7, total n=422) were included. Donepezil (studies=5; treated=102 vs. placebo=21): there was strong evidence for no effect on mania and psychotic symptoms; low evidence indicating no effect on depression. Galantamine (studies=3; treated=21 vs. controls=20) (placebo=10, healthy subjects=10): there was strong evidence for no effect on mania; moderate evidence for no effect on depression; low evidence for no effect on global functioning. Memantine (studies=4; treated=152 vs. placebo=88): there was conflicting evidence regarding efficacy for mania, depression and global functioning. Paucity of RCTs; small sample size studies; heterogeneous design, outcome and patient characteristics. There is limited but converging evidence of no effect of AceI in BD, and conflicting evidence about memantine in BD. Too few studies of mostly medium/low quality and lacking sufficient numbers of patients in specific mood states, especially mania, contributed data, focusing solely on short-term/medium-term treatment, necessitating additional high-quality research to yield more definite results. Copyright © 2016 Elsevier B.V. All rights reserved.
Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome.

PubMed

Pasquali, R; Gambineri, A; Biscotti, D; Vicennati, V; Gagliardi, L; Colitta, D; Fiorini, S; Cognigni, G E; Filicori, M; Morselli-Labate, A M

2000-08-01

Abdominal obesity and hyperinsulinemia play a key role in the development of the polycystic ovary syndrome (PCOS). Dietary-induced weight loss and the administration of insulin-lowering drugs, such as metformin, are usually followed by improved hyperandrogenism and related clinical abnormalities. This study was carried out to evaluate the effects of combined hypocaloric diet and metformin on body weight, fat distribution, the glucose-insulin system, and hormones in a group of 20 obese PCOS women [body mass index (BMI) > 28 kg/m2] with the abdominal phenotype (waist to hip ratio >0.80), and an appropriate control group of 20 obese women who were comparable for age and pattern of body fat distribution but without PCOS. At baseline, we measured sex hormone, sex hormone-binding globulin (SHBG), and leptin blood concentrations and performed an oral glucose tolerance test and computerized tomography (CT) at the L4-L5 level, to measure sc adipose tissue area (SAT) and visceral adipose tissue area. All women were then given a low-calorie diet (1,200-1,400 kcal/day) alone for one month, after which anthropometric parameters and CT scan were newly measured. While continuing dietary treatment, PCOS women and obese controls were subsequently placed, in a random order, on metformin (850 mg/os, twice daily) (12 and 8, respectively) or placebo (8 and 12, respectively), according to a double-blind design, for the following 6 months. Blood tests and the CT scan were performed in each woman at the end of the study while they were still on treatment. During the treatment period, 3 women of the control group (all treated with placebo) were excluded because of noncompliance; and 2 PCOS women, both treated with metformin, were also excluded because they became pregnant. Therefore, the women cohort available for final statistical analysis included 18 PCOS (10 treated with metformin and 8 with placebo) and 17 control women (8 treated with metformin and 9 with placebo). The treatment was well tolerated. In the PCOS group, metformin therapy improved hirsutism and menstrual cycles significantly more than placebo. Baseline anthropometric and CT parameters were similar in all groups. Hypocaloric dieting for 1 month similarly reduced BMI values and the waist circumference in both PCOS and control groups, without any significant effect on CT scan parameters. In both PCOS and control women, however, metformin treatment reduced body weight and BMI significantly more than placebo. Changes in the waist-to-hip ratio values were similar in PCOS women and controls, regardless of pharmacological treatment. Metformin treatment significantly decreased SAT values in both PCOS and control groups, although only in the latter group were SAT changes significantly greater than those observed during the placebo treatment. On the contrary, visceral adipose tissue area values significantly decreased during metformin treatment in both PCOS and control groups, but only in the former was the effect of metformin treatment significantly higher than that of placebo. Fasting insulin significantly decreased in both PCOS women and controls, regardless of treatment, whereas glucose-stimulated insulin significantly decreased only in PCOS women and controls treated with metformin. Neither metformin or placebo significantly modified the levels of LH, FSH, dehydroepiandrosterone sulphate, and progesterone in any group, whereas testosterone concentrations decreased only in PCOS women treated with metformin. SHBG concentrations remained unchanged in all PCOS women; whereas in the control group, they significantly increased after both metformin and placebo. Leptin levels decreased only during metformin treatment in both PCOS and control groups. (ABSTRACT TRUNCATED)
Analgesic effects of treatments for non-specific low back pain: a meta-analysis of placebo-controlled randomized trials.

PubMed

Machado, L A C; Kamper, S J; Herbert, R D; Maher, C G; McAuley, J H

2009-05-01

Estimates of treatment effects reported in placebo-controlled randomized trials are less subject to bias than those estimates provided by other study designs. The objective of this meta-analysis was to estimate the analgesic effects of treatments for non-specific low back pain reported in placebo-controlled randomized trials. Medline, Embase, Cinahl, PsychInfo and Cochrane Central Register of Controlled Trials databases were searched for eligible trials from earliest records to November 2006. Continuous pain outcomes were converted to a common 0-100 scale and pooled using a random effects model. A total of 76 trials reporting on 34 treatments were included. Fifty percent of the investigated treatments had statistically significant effects, but for most the effects were small or moderate: 47% had point estimates of effects of <10 points on the 100-point scale, 38% had point estimates from 10 to 20 points and 15% had point estimates of >20 points. Treatments reported to have large effects (>20 points) had been investigated only in a single trial. This meta-analysis revealed that the analgesic effects of many treatments for non-specific low back pain are small and that they do not differ in populations with acute or chronic symptoms.
Treatment of fatigue with methylphenidate, modafinil and amantadine in multiple sclerosis (TRIUMPHANT-MS): Study design for a pragmatic, randomized, double-blind, crossover clinical trial.

PubMed

Nourbakhsh, Bardia; Revirajan, Nisha; Waubant, Emmanuelle

2018-01-01

Fatigue is the most common symptom of multiple sclerosis (MS). Amantadine, modafinil and amphetamine-like stimulants are commonly used in clinical practice for treatment of fatigue; however, the evidence supporting their effectiveness is sparse and conflicting. To describe the design of a trial study funded by Patient-Centered Outcome Research Institute (PCORI) that will compare the efficacy of commonly used fatigue medications in patients with MS. The study is a randomized, placebo-controlled, crossover, four-sequence, four-period, double-blind, multicenter trial of three commonly used medications for the treatment of MS-related fatigue (amantadine, modafinil, methylphenidate) versus placebo in fatigued subjects with MS. Adult patients with MS, with an Expanded Disability Status Scale of <7.0 are eligible to participate. Participants will be randomized to one of four predefined sequences of medication administration. Each sequence comprises four 6-week periods of treatment with one of the 3 study drugs or placebo, and three 2-week washout periods between medication periods. 136 participants will be randomized over two years in two academic centers in the United States starting in the Summer 2017. Complete enrollment is expected by early 2019. The primary outcome of the study is the modified fatigue impact scale (MFIS) score while participants receive the maximally tolerated dose of each study medication (or placebo). Safety and tolerability of the medications and heterogeneity of treatment effect will also be assessed. Results of the proposed study will provide evidence-based and personalized treatment options for patients affected by MS-related fatigue. Clinicaltrials.gov registration number: NCT03185065. Copyright © 2017 Elsevier Inc. All rights reserved.
Effect of aromatherapy massage on menopausal symptoms: a randomized placebo-controlled clinical trial.

PubMed

Darsareh, Fatemeh; Taavoni, Simin; Joolaee, Soodabeh; Haghani, Hamid

2012-09-01

Menopause is a significant event in most women's lives because it marks the end of a woman's natural reproductive life. The purpose of this study was to determine the effect of aromatherapy massage on menopausal symptoms. A randomized placebo-controlled clinical trial was conducted at a menopausal clinic at a gynecology hospital in Tehran. The study population comprised 90 women who were assigned to an aromatherapy massage group, a placebo massage group, or a control group. Each participant in the aromatherapy massage group received 30-minute aromatherapy treatment sessions twice a week for 4 weeks with aroma oil, whereas participants in the placebo massage group received the same treatment with plain oil. No treatment was provided to participants in the control group. The outcome measures in this study were menopausal symptoms, as obtained through the Menopause Rating Scale. The mean baseline level of the menopausal score did not differ among all groups. However, after eight sessions of intervention, the Menopause Rating Scale score differed significantly among the three groups (P < 0.001). Post hoc analysis revealed that women in both the aromatherapy massage group and the placebo massage group had a lower menopausal score than the control group (P < 0.001). When the aromatherapy massage and the placebo massage groups were compared, the menopausal score for the aromatherapy massage group was found to be significantly lower (P < 0.001) than for the placebo group. The results of the study demonstrate that both massage and aromatherapy massage were effective in reducing menopausal symptoms. However, aromatherapy massage was more effective than only massage.
Dose-ranging study with the glucokinase activator AZD1656 as monotherapy in Japanese patients with type 2 diabetes mellitus.

PubMed

Kiyosue, A; Hayashi, N; Komori, H; Leonsson-Zachrisson, M; Johnsson, E

2013-10-01

To assess the glucose-lowering effects of monotherapy with the glucokinase activator AZD1656 in Japanese patients with type 2 diabetes mellitus. This was a randomized, double-blind, placebo-controlled study performed in Japan (NCT01152385). Patients (n = 224) were randomized to AZD1656 (40-200, 20-140 or 10-80 mg titrated doses) or placebo. The primary variable was the placebo-corrected change from baseline to 4 months in glycated haemoglobin (HbA1c). Effects on fasting plasma glucose (FPG) and safety were also assessed. HbA1c was reduced numerically from baseline by 0.3-0.8% with AZD1656 and by 0.1% with placebo over the first 2 months of treatment, after which effects of AZD1656 started to decline. The changes from baseline to 4 months in HbA1c were not significant for the AZD1656 40-200 mg group versus placebo [mean (95% CI) placebo-corrected change: -0.22 (-0.65, 0.20)%; p = 0.30]. Formal significance testing was not carried out for the other two AZD1656 dose groups. A higher percentage of patients on AZD1656 achieved HbA1c ≤ 7% after 4 months versus placebo, but responder rates were low. Results for FPG reflected those for HbA1c. Cases of hypoglycaemia were rare with AZD1656 (one patient) and no safety concerns were raised. Although initially favourable plasma glucose reductions were observed, there was a loss of effect over time with sustained AZD1656 treatment. The study design did not allow an evaluation of the reasons for this lack of long-term efficacy. © 2013 John Wiley & Sons Ltd.
Effect of Epsilon Aminocaproic Acid on Red-Cell Transfusion Requirements in Major Spinal Surgery

PubMed Central

Berenholtz, Sean M.; Pham, Julius Cuong; Garrett-Mayer, Elizabeth; Atchison, Christine W; Kostuik, John P.; Cohen, David B.; Nundy, Shantanu; Dorman, Todd; Ness, Paul M.; Klag, Michael J.; Pronovost, Peter J.; Kebaish, Khaled M.

2009-01-01

Study Design Randomized, placebo-controlled trial Objective To evaluate the efficacy of epsilon aminocaproic acid (EACA) to reduce the number of red-cell (RBC) transfusions in adult patients undergoing major spinal surgery. Summary of Background Data Reconstructive spinal surgery is associated with significant blood loss. The number of studies evaluating the efficacy of EACA in adult patients undergoing spinal surgery remains scarce and limited. Methods EACA (100 mg/kg) or placebo was administered to 182 adult patients after the induction of anesthesia followed by an infusion that was continued for 8 hours postoperatively. Primary end-points included total allogeneic RBC transfusions through postoperative day (POD) 8 and postoperative allogeneic plus autologus RBC transfusions through POD 8. Results Mean total allogeneic RBC transfusions were not statistically different between the groups (5.9 units EACA versus 6.9 units placebo; P=0.17). Mean postoperative RBC transfusions in the EACA group was less (2.0 units versus 2.8 units placebo; P=0.03). There was no significant difference in mean estimated intraoperative EBL (2938 cc EACA vs. 3273 cc placebo; P=0.32). Mean intensive care unit length of stay was decreased (EACA 1.8 days versus 2.8 days placebo; P=0.04). The incidence of thromboembolic complications was similar (2.2% EACA vs 6.6% placebo; P=0.15). Conclusions The difference in total allogeneic RBC transfusions between the groups was not statistically significant. EACA was associated with a 30% (0.8 units) reduction in postoperative RBC transfusions and a one-day reduction in ICU LOS, without an increased incidence of thromboembolic events. EACA may be considered for patients undergoing major spinal surgery. Larger studies are needed to evaluate the relationship between EACA and total RBC requirements. PMID:19730217
Mealtime glucose regulation with nateglinide in healthy volunteers: comparison with repaglinide and placebo.

PubMed

Kalbag, J B; Walter, Y H; Nedelman, J R; McLeod, J F

2001-01-01

This study was designed to compare the pharmacodynamic effects of single doses of nateglinide (A-4166), repaglinide, and placebo on mealtime insulin secretion and glycemic control in healthy subjects. Fifteen healthy volunteers participated in this open-label five-period crossover study. They received single 10-min preprandial doses of 120 mg nateglinide, 0.5 or 2 mg repaglinide, or placebo or 1 min preprandially of 2 mg repaglinide. Subjects received each dose only once, 48 h apart. Pharmacodynamic and pharmacokinetic assessments were performed from 0 to 12 h postdose. Nateglinide induced insulin secretion more rapidly than 2 and 0.5 mg repaglinide and placebo (10 min preprandial), with mean rates of insulin rise of 2.3, 1.3, 1.15, and 0.8 microU x ml(-1) x min(-1), respectively, over the 0- to 30-min postmeal interval. After peaking, insulin concentrations decreased rapidly in the nateglinide-treated group and were similar to placebo within 2 h postdose. After 2 mg repaglinide, peak insulin concentrations were delayed and returned to baseline more slowly than with nateglinide treatment. Nateglinide treatment produced lower average plasma glucose concentrations in the 0- to 2-h postdose interval than either dose of repaglinide and placebo (P < 0.05 vs. 0.5 mg repaglinide and placebo). Plasma glucose concentrations returned more rapidly to predose levels with nateglinide treatment than with either dose of repaglinide. Treatment with repaglinide produced a sustained hypoglycemic effect up to 6 h postdose. In this single-dose study in nondiabetic volunteers, nateglinide provided a more rapid and shorter-lived stimulation of insulin secretion than repaglinide, resulting in lower meal-related glucose excursions. If similar results are observed in diabetes, nateglinide may produce a more physiological insulin secretory response with the potential for a reduced risk of postabsorptive hypoglycemia.
Botulinum toxin type A in treatment of bilateral primary axillary hyperhidrosis: randomised, parallel group, double blind, placebo controlled trial

PubMed Central

Naumann, M; Lowe, N J

2001-01-01

Objectives To evaluate the safety and efficacy of botulinum toxin type A in the treatment of bilateral primary axillary hyperhidrosis. Design Multicentre, randomised, parallel group, placebo controlled trial. Setting 17 dermatology and neurology clinics in Belgium, Germany, Switzerland, and the United Kingdom. Participants Patients aged 18-75 years with bilateral primary axillary hyperhidrosis sufficient to interfere with daily living. 465 were screened, 320 randomised, and 307 completed the study. Interventions Patients received either botulinum toxin type A (Botox) 50 U per axilla or placebo by 10-15 intradermal injections evenly distributed within the hyperhidrotic area of each axilla, defined by Minor's iodine starch test. Main outcome measures Percentage of responders (patients with ⩾50% reduction from baseline of spontaneous axillary sweat production) at four weeks, patients' global assessment of treatment satisfaction score, and adverse events. Results At four weeks, 94% (227) of the botulinum toxin type A group had responded compared with 36% (28) of the placebo group. By week 16, response rates were 82% (198) and 21% (16), respectively. The results for all other measures of efficacy were significantly better in the botulinum toxin group than the placebo group. Significantly higher patient satisfaction was reported in the botulinum toxin type A group than the placebo group (3.3 v 0.8, P<0.001 at 4 weeks). Adverse events were reported by only 27 patients (11%) in the botulinum toxin group and four (5%) in the placebo group (P>0.05). Conclusion Botulinum toxin type A is a safe and effective treatment for primary axillary hyperhidrosis and produces high levels of patient satisfaction. What is already known on this topicPrimary hyperhidrosis is a chronic disorder that can affect any part of the body, especially the axillas, palms, feet, and faceCurrent treatments are often ineffective, short acting, or poorly toleratedWhat this study addsBotulinum toxin type A was significantly better than placebo on all measures of sweatingPatient satisfaction was high and few adverse events were reportedEffects of treatment remained apparent at 16 weeks PMID:11557704
A Randomized Study of Lubiprostone for Opioid-Induced Constipation in Patients with Chronic Noncancer Pain

PubMed Central

Cryer, Byron; Katz, Seymour; Vallejo, Ricardo; Popescu, Anca; Ueno, Ryuji

2014-01-01

Objective To evaluate the efficacy and safety of oral lubiprostone for relieving symptoms of opioid-induced constipation (OIC) in patients with chronic noncancer pain. Design Prospective, randomized, double-blind, placebo-controlled trial. Setting Seventy-nine US and Canadian centers. Subjects Patients aged ≥18 years with OIC, defined as <3 spontaneous bowel movements (SBMs) per week. Methods Patients received lubiprostone 24 mcg or placebo twice daily for 12 weeks. The primary endpoint was change from baseline in SBM frequency at week 8. Results Among randomized patients (N = 418; lubiprostone, N = 210; placebo, N = 208), most completed the study (lubiprostone, 67.1%; placebo, 69.7%). The safety and efficacy (intent-to-treat) populations included 414 (lubiprostone, N = 208; placebo, N = 206) and 413 (lubiprostone, N = 209; placebo, N = 204) patients, respectively. The mean (standard deviation) age was 50.4 (10.9) years; most patients were female (64.4%) and white (77.7%). Changes from baseline in SBM frequency rates were significantly higher at week 8 (P = 0.005) and overall (P = 0.004) in patients treated with lubiprostone compared with placebo. Pairwise comparisons showed significantly greater overall improvement for abdominal discomfort (P = 0.047), straining (P < 0.001), constipation severity (P = 0.007), and stool consistency (P < 0.001) with lubiprostone compared with placebo. Moreover, patients rated the effectiveness of lubiprostone as significantly (P < 0.05) better than placebo for 11 of 12 weeks. The most common treatment-related adverse events (AEs) with lubiprostone and placebo were nausea (16.8% vs 5.8%, respectively), diarrhea (9.6% vs 2.9%), and abdominal distention (8.2% vs 2.4%). No lubiprostone-related serious AEs occurred. Conclusion Lubiprostone effectively relieved OIC and associated signs and symptoms and was well tolerated in patients with chronic noncancer pain (http://clinicaltrials.gov/ct2/show/NCT00595946). PMID:24716835
Design of a Randomized Placebo-Controlled Trial to Assess Dabigatran and Omeprazole in Patients with Myocardial Injury after Noncardiac Surgery (MANAGE).

PubMed

Duceppe, Emmanuelle; Yusuf, Salim; Tandon, Vikas; Rodseth, Reitze; Biccard, Bruce M; Xavier, Denis; Szczeklik, Wojciech; Meyhoff, Christian S; Franzosi, Maria Grazia; Vincent, Jessica; Srinathan, Sadeesh K; Parlow, Joel; Magloire, Patrick; Neary, John; Rao, Mangala; Chaudhry, Navneet K; Mayosi, Bongani; de Nadal, Miriam; Popova, Ekaterine; Villar, Juan Carlos; Botto, Fernando; Berwanger, Otavio; Guyatt, Gordon; Eikelboom, John W; Sessler, Daniel I; Kearon, Clive; Pettit, Shirley; Connolly, Stuart J; Sharma, Mukul; Bangdiwala, Shrikant I; Devereaux, P J

2018-03-01

Worldwide approximately 200 million adults undergo major surgery annually, of whom 8 million are estimated to suffer a myocardial injury after noncardiac surgery (MINS). There is currently no trial data informing the management of MINS. Antithrombotic agents such as direct oral anticoagulants might prevent major vascular complications in patients with MINS. The Management of Myocardial Injury After Noncardiac Surgery (MANAGE) trial is a large international blinded randomized controlled trial of dabigatran vs placebo in patients who suffered MINS. We used a partial factorial design to also determine the effect of omeprazole vs placebo in reducing upper gastrointestinal bleeding and complications. Both study drugs were initiated in eligible patients within 35 days of suffering MINS and continued for a maximum of 2 years. The primary outcome is a composite of major vascular complications for the dabigatran trial and a composite of upper gastrointestinal complications for the omeprazole trial. We present the rationale and design of the trial and baseline characteristics of enrolled patients. The trial randomized 1754 patients between January 2013 and July 2017. Patients' mean age was 69.9 years, 51.1% were male, 14.3% had a history of peripheral artery disease, 6.6% had a history of stroke or transient ischemic attack, 12.9% had a previous myocardial infarction, and 26.0% had diabetes. The diagnosis of MINS was on the basis of an isolated ischemic troponin elevation in 80.4% of participants. MANAGE is the first randomized controlled trial to evaluate a potential treatment of patients who suffered MINS. Copyright © 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
Chinese herbal medicine (Ma Zi Ren Wan) for functional constipation: study protocol for a prospective, double-blinded, double-dummy, randomized controlled trial.

PubMed

Zhong, Linda L D; Cheng, Chung Wah; Chan, Yawen; Chan, King Hong; Lam, Ting Wa; Chen, Xiao Rui; Wong, Chi Tak; Wu, Justin C Y; Bian, Zhao Xiang

2013-11-04

Functional constipation is a common clinical complaint. Although the effectiveness of Ma Zi Ren Wan for alleviating functional constipation symptoms has been proven in a previous randomized placebo-controlled study, further evidence is needed to make clinical recommendations about Chinese herbal medicine. In particular, a comparison with conventional western medicine for functional constipation patients is needed. This is a prospective, double-blinded, double dummy, randomized, controlled trial. After a 2-week run-in period, eligible patients (Rome III) with excessive traditional Chinese medicine syndrome will randomly be assigned to the Chinese medicine arm (Ma Zi Ren Wan and western medicine placebo), western medicine arm (senna and Chinese medicine placebo) or placebo arm (Chinese medicine placebo and western medicine placebo). Patients will undergo an 8-week treatment and an 8-week follow-up. The primary outcome is the responder rate for complete spontaneous bowel movement (CSBM) during treatment. Patients with a mean increase of CSBM ≧1/week in comparison with their baselines are defined as responders. The secondary outcomes include responder rate during follow-up, changes of colonic transit as measured with radio-opaque markers, individual and global symptom assessments, and reported adverse effects. This study is the first study to compare a Chinese Herbal Medicine (Ma Zi Ren Wan) with a laxative that is commonly used in the clinical practice of western medicine, and with a placebo. This study will complete the investigation of Ma Zi Ren Wan for functional constipation, and should, therefore, suggest recommendations for clinical practice. Furthermore, the process of first conducting a systematic review, then implementing a dose determination study followed by a placebo-control trial, and finally, comparing traditional Chinese medicine with an active conventional medicine in a controlled trial can be a reference to other researches on Chinese medicine interventions in the future. NCT01695850.
Placebo-controlled study of the mite allergen-reducing effect of tannic acid plus benzyl benzoate on carpets in homes of children with house dust mite sensitization and asthma.

PubMed

Lau, Susanne; Wahn, Julia; Schulz, Gabriele; Sommerfeld, Christine; Wahn, Ulrich

2002-02-01

We studied the effect of a spray containing 1% benzyl benzoate, an acaricide, and 1% tannic acid ('Lowal'; a protein-denaturing substance), on concentrations of major allergens from house dust mite (HDM) species Dermatophagoides pteronyssinus and D. farinae (Der p 1 and Der f 1, respectively) in carpets. In a double-blind, placebo-controlled study with crossover design, 30 homes of children with HDM sensitization and asthma were included. All houses showed > or = 400 ng/g of Der p 1 + Der f 1 in carpet dust. The first treatment was performed on day 0 (group 1 active treatment, n = 15; group 2 placebo treatment, n = 15). After 2 and 8 weeks, dust samples were collected for quantification of mite allergens. After a 2-week washout period, the second treatment was performed (group 1 placebo treatment; group 2 active treatment). Again, carpet dust was collected after 2 and 8 weeks. Twenty-two of 30 families completed the trial: 14/15 in group 1 and eight of 15 in group 2. On day 0, there was no significant difference in mite allergen exposure between group 1 and group 2 (1,498 vs. 2,239 ng/g of Der p 1 + Der f 1, respectively). In group 1, the geometric mean for the difference of mite allergen concentration comparing day 0 and week 6 was 196 ng/g (95% CI: -7,161 and 8,401) for the first treatment (active) and 15 ng/g (95% CI: -1,079 and 1,292) for the second treatment (control). In group 2, the difference was 66 ng/g (95% CI: -398 and 1,515) for the first treatment (control) and 609 ng/g (95% CI: 186 and 9,264) for the second treatment (active). Comparing placebo and active treatment in total, there was a significant decrease following placebo treatment after 14 days (p = 0.026). After 8 weeks, active treatment was superior to placebo treatment (p = 0.049), but the allergen reduction achieved was < 20% (median 1,500 ng/g on day 0 vs. 1,250 ng/g after 8 weeks). We conclude that the slight mite allergen reduction on carpets achieved by the treatment with 'Lowal' is unlikely to achieve worthwhile clinical benefit either in the treatment of mite-sensitive patients or in primary or secondary prophylaxis.
Effects of alcohol and energy drink on mood and subjective intoxication: a double-blind, placebo-controlled, crossover study.

PubMed

Benson, Sarah; Scholey, Andrew

2014-07-01

There is concern that combining energy drinks with alcohol may 'mask' subjective intoxication leading to greater alcohol consumption. This study examines the effects of alcohol alone and combined with energy drink on objective and subjective intoxication and mood over the course of 3 h. Using a double-blind, placebo-controlled, balanced, crossover design, 24 participants (mean age 22.23 years) were administered with double placebo, 0.6 g/kg alcohol (mean peak blood alcohol content of 0.051%), 250 ml energy drink and alcohol/energy drink, according to a Latin square design, with a washout of >48 h. On each visit, they were breathalysed and rated themselves on a comprehensive battery of mood items at baseline and then at 45, 90 and 180 min post-drink. Blood alcohol and subjective intoxication were significantly increased following both alcohol alone and alcohol/energy drink. Both measures were statistically indistinguishable between alcohol conditions. In keeping with its (80 mg) caffeine content, the energy drink alone significantly increased self-rated 'alertness' and reduced 'depression-dejection' scores compared with the combined alcohol/energy drink. The alcohol/energy drink increased 'vigor' and 'contentment' at 45 min and decreased 'contentment' at 180 min. The co-ingestion of an energy drink with alcohol does not differently influence blood alcohol content recordings or subjective intoxication compared with alcohol alone, although some mood items are differentially affected. Copyright © 2014 John Wiley & Sons, Ltd.
The Effect of Pet Remedy on the Behaviour of the Domestic Dog (Canis familiaris).

PubMed

Taylor, Sienna; Madden, Joah

2016-10-25

Stress-affected behaviour in companion animals can have an adverse effect on animal health and welfare and their relationships with humans. This stress can be addressed using chemical treatments, often in conjunction with behavioural therapies. Here, we investigated the efficacy of one commercial pharmacological intervention, Pet Remedy, advertised as a natural stress relief product for mammals. We aimed to see whether the product lowered stress-affected behaviour in dogs placed in a non-familiar environment. Behavioural responses of 28 dogs were video recorded using a double-blind, placebo-controlled, and counterbalanced repeated measures design. Dogs were exposed to both a placebo and Pet Remedy plug-in diffuser for 30 min with an intervening period of approximately 7 days between conditions. Multivariate regression analysis identified no significant differences in behaviour in either the Pet Remedy or placebo condition. In conclusion, in the current study, Pet Remedy did not reduce behavioural indicators indicative of a stress response. To determine the effects of Pet Remedy, future research using a larger sample size and controlling for breed would be beneficial.
Evaluation of neurofeedback in ADHD: the long and winding road.

PubMed

Arns, Martijn; Heinrich, Hartmut; Strehl, Ute

2014-01-01

Among the clinical applications of neurofeedback, most research has been conducted in ADHD. As an introduction a short overview of the general history of neurofeedback will be given, while the main part of the paper deals with a review of the current state of neurofeedback in ADHD. A meta-analysis on neurofeedback from 2009 found large effect sizes for inattention and impulsivity and medium effects sizes for hyperactivity. Since 2009 several new studies, including 4 placebo-controlled studies, have been published. These latest studies are reviewed and discussed in more detail. The review focuses on studies employing (1) semi-active, (2) active, and (3) placebo-control groups. The assessment of specificity of neurofeedback treatment in ADHD is discussed and it is concluded that standard protocols such as theta/beta, SMR and slow cortical potentials neurofeedback are well investigated and have demonstrated specificity. The paper ends with an outlook on future questions and tasks. It is concluded that future controlled clinical trials should, in a next step, focus on such known protocols, and be designed along the lines of learning theory. Copyright © 2013 Elsevier B.V. All rights reserved.
Influence of the antiseptic agents polyhexanide and octenidine on FL cells and on healing of experimental superficial aseptic wounds in piglets. A double-blind, randomised, stratified, controlled, parallel-group study.

PubMed

Kramer, A; Roth, B; Müller, G; Rudolph, P; Klöcker, N

2004-01-01

The main target of the combination of octenidine with phenoxyethanol (Octenisept) is the antisepsis of acute wounds, whereas polyhexanide combined with polyethylene glycol in Ringer solution (Lavasept) is the agent of choice for antisepsis of chronic wounds and burns. Because comparative data for both agents on the effects on wound healing are lacking, we investigated the influence of preparations based on polyhexanide and octenidine versus placebo (Ringer solution) in experimental superficial aseptic skin wounds (n = 108) of 20 mm diameter, using a double-blind, randomised, stratified, controlled, parallel-group design in piglets. Computerised planimetry and histopathological methods were used for the assessment of wound healing. Histologically, no significant differences could be verified at any time between the 3 groups. However, in the early phase (day 9 after wounding), the octenidine-based product retarded wound contraction to a significantly greater extent than placebo and polyhexanide, whereas in the later phase (days 18 and 28), polyhexanide promoted contraction significantly more than did placebo and octenidine. The consequence is complete wound closure after 22.9 days using polyhexanide, in comparison to the placebo after 24.1 days (p < 0.05) and octenidine after 28.3 days (no statistical difference to placebo). This may be explained by the better tolerance of polyhexanide in vitro, which was demonstrated with dose and time dependence in cytotoxicity tests on human amnion cells. Copyright 2004 S. Karger AG, Basel
Lubiprostone neither decreases gastric and small-bowel transit time nor improves visualization of small bowel for capsule endoscopy: a double-blind, placebo-controlled study.

PubMed

Hooks, S Bennett; Rutland, Travis J; Di Palma, Jack A

2009-11-01

Lubiprostone, a selective activator of type 2 chloride channels, is approved for treatment of chronic idiopathic constipation and recently constipation-predominant irritable bowel syndrome. It has been suggested that lubiprostone has a prokinetic effect. This investigation was designed to evaluate lubiprostone as a preparation and propulsive agent for small-bowel capsule endoscopy. The PillCam Small Bowel capsule endoscopy system with the PillCam SB1 capsule and Rapid 5 software platform were used. The study was designed as a double-blind, placebo-controlled trial. Forty healthy adults. Gastric transit time (GTT), small-bowel transit time (SBTT), and adequacy of small-bowel cleansing preparation. The study subjects received 24 mug lubiprostone or placebo 30 minutes before PillCam capsule ingestion. Capsule endoscopy studies were read by 2 independent investigators unaware of the study medication received, and differences in interpretation were resolved by consensus. Anatomical landmarks were identified, and GTT and SBTT were calculated. Overall preparation quality assessment of the proximal, mid, and distal small bowel was determined by using a 4-step scale. The percentage of visualized bowel was determined by review of 10-minute video segments at 1-hour intervals after the capsule passed through the pylorus. In the lubiprostone group (n = 20), 2 subjects did not pass the capsule through the pylorus in the 8-hour battery life of the capsule. An additional 3 capsules did not pass into the colon. In the placebo group (n = 20), all capsules passed into the small bowel, but 1 did not pass into the colon. The subjects in whom the capsule did not pass into the small bowel were excluded from the small-bowel analysis. In the subjects in whom the capsule did reach the colon, the SBTT could not be calculated and they were excluded from SBTT analysis. The mean GTT in the lubiprostone group was 126 minutes and 43 minutes in the placebo group (P = .0095). The mean SBTT in the lubiprostone group was 188 minutes and 219 minutes in the placebo group (P = .130). The overall preparation assessment of the small bowel was not statistically significant between the 2 groups in the proximal, mid, or distal small bowel (proximal, P = .119; mid, P = .118; distal, P = .121). There was no significant difference in lubiprostone compared with placebo in the percentage of visualized small bowel. Some capsules did not leave the stomach or reach the cecum. Lubiprostone produced a significant increase in GTT but did not result in a significant decrease in SBTT compared with placebo. The administration of lubiprostone before capsule ingestion did not result in improved overall preparation of the small bowel for capsule endoscopy or increase the percentage of visualized small bowel. (The trial was registered at www.clinicaltrials.gov, identifier NCT00746395.).

An analysis of adaptive design variations on the sequential parallel comparison design for clinical trials.

PubMed

Mi, Michael Y; Betensky, Rebecca A

2013-04-01

Currently, a growing placebo response rate has been observed in clinical trials for antidepressant drugs, a phenomenon that has made it increasingly difficult to demonstrate efficacy. The sequential parallel comparison design (SPCD) is a clinical trial design that was proposed to address this issue. The SPCD theoretically has the potential to reduce the sample-size requirement for a clinical trial and to simultaneously enrich the study population to be less responsive to the placebo. Because the basic SPCD already reduces the placebo response by removing placebo responders between the first and second phases of a trial, the purpose of this study was to examine whether we can further improve the efficiency of the basic SPCD and whether we can do so when the projected underlying drug and placebo response rates differ considerably from the actual ones. Three adaptive designs that used interim analyses to readjust the length of study duration for individual patients were tested to reduce the sample-size requirement or increase the statistical power of the SPCD. Various simulations of clinical trials using the SPCD with interim analyses were conducted to test these designs through calculations of empirical power. From the simulations, we found that the adaptive designs can recover unnecessary resources spent in the traditional SPCD trial format with overestimated initial sample sizes and provide moderate gains in power. Under the first design, results showed up to a 25% reduction in person-days, with most power losses below 5%. In the second design, results showed up to a 8% reduction in person-days with negligible loss of power. In the third design using sample-size re-estimation, up to 25% power was recovered from underestimated sample-size scenarios. Given the numerous possible test parameters that could have been chosen for the simulations, the study's results are limited to situations described by the parameters that were used and may not generalize to all possible scenarios. Furthermore, dropout of patients is not considered in this study. It is possible to make an already complex design such as the SPCD adaptive, and thus more efficient, potentially overcoming the problem of placebo response at lower cost. Ultimately, such a design may expedite the approval of future effective treatments.
A Randomized Placebo-Controlled Trial of a School-Based Depression Prevention Program.

ERIC Educational Resources Information Center

Merry, Sally; McDowell, Heather; Wild, Chris J.; Bir, Julliet; Cunliffe, Rachel

2004-01-01

Objective: To conduct a placebo-controlled study of the effectiveness of a universal school-based depression prevention program. Method: Three hundred ninety-two students age 13 to 15 from two schools were randomized to intervention (RAP-Kiwi) and placebo programs run by teachers. RAP-Kiwi was an 11-session manual-based program derived from…
Effects of MPH-OROS on the Organizational, Time Management, and Planning Behaviors of Children with ADHD

ERIC Educational Resources Information Center

Abikoff, Howard; Nissley-Tsiopinis, Jenelle; Gallagher, Richard; Zambenedetti, Maurizio; Seyffert, Michael; Boorady, Roy; McCarthy, John

2009-01-01

A double-blind, placebo-controlled, crossover design study was done to evaluate the effects of methylphenidate-osmotic-release oral systems (MPH-OROS) on the organization, time management, and planning (OTMP) of children with attention deficit hyperactivity disorder (ADHD). Results show significant improvements on the OTMP of children with ADHD in…
Use of methotrexate in patients with uveitis.

PubMed

Ali, A; Rosenbaum, J T

2010-01-01

Methotrexate has been frequently employed to treat ocular inflammatory diseases including uveitis, scleritis, and orbital inflammatory disease. It is effective for intraocular lymphoma when given directly into the eye. No study has assessed its efficacy for eye disease in a randomised, placebo controlled design. This report reviews the literature relevant to methotrexate's utility in the treatment of ocular inflammatory disease.
Daily cranberry juice for the prevention of asymptomatic bacteriuria in pregnancy: A randomized, controlled pilot study

PubMed Central

Wing, Deborah A.; Rumney, Pamela J.; Preslicka, Christine; Chung, Judith H.

2008-01-01

Objective To compare daily cranberry juice cocktail to placebo during pregnancy on asymptomatic bacteriuria (ASB) and symptomatic urinary tract infections (UTIs). Study Design 188 women were randomized to cranberry or placebo in three treatment arms: A: Cranberry three times daily (n=58), B: Cranberry at breakfast, then placebo at lunch and dinner (n=67), C. Placebo three times daily (n=63). After 27.7% (52/188) of the subjects were enrolled, the dosing regimens were changed to twice daily dosing to improve compliance. Results There were 27 UTIs in 18 subjects in this cohort: 6 in 4 subjects in Group A, 10 in 7 subjects in Group B, and 11 in 7 subjects in Group C, p=0.71. There were 57% and 41% reductions in the frequency of ASB and all UTIs in the multiple daily dosing group, however, this study was not sufficiently powered at the alpha 0.05 level (CI 0.14–1.39 and 0.22–1.60, respectively, incidence rate ratios). 73/188 (38.8%) subjects withdrew, most for gastrointestinal upset. Conclusion These data suggest there may be a protective effect of cranberry ingestion against ASB and symptomatic UTIs in pregnancy. Further studies are planned to evaluate this effect. PMID:18707726
Probiotic prophylaxis in patients with predicted severe acute pancreatitis (PROPATRIA): design and rationale of a double-blind, placebo-controlled randomised multicenter trial [ISRCTN38327949

PubMed Central

Besselink, Marc GH; Timmerman, Harro M; Buskens, Erik; Nieuwenhuijs, Vincent B; Akkermans, Louis MA; Gooszen, Hein G

2004-01-01

Background Infectious complications are the major cause of death in acute pancreatitis. Small bowel bacterial overgrowth and subsequent bacterial translocation are held responsible for the vast majority of these infections. Goal of this study is to determine whether selected probiotics are capable of preventing infectious complications without the disadvantages of antibiotic prophylaxis; antibiotic resistance and fungal overgrowth. Methods/design PROPATRIA is a double-blind, placebo-controlled randomised multicenter trial in which 200 patients will be randomly allocated to a multispecies probiotic preparation (Ecologic 641) or placebo. The study is performed in all 8 Dutch University Hospitals and 7 non-University hospitals. The study-product is administered twice daily through a nasojejunal tube for 28 days or until discharge. Patients eligible for randomisation are adult patients with a first onset of predicted severe acute pancreatitis: Imrie criteria 3 or more, CRP 150 mg/L or more, APACHE II score 8 or more. Exclusion criteria are post-ERCP pancreatitis, malignancy, infection/sepsis caused by a second disease, intra-operative diagnosis of pancreatitis and use of probiotics during the study. Administration of the study product is started within 72 hours after onset of abdominal pain. The primary endpoint is the total number of infectious complications. Secondary endpoints are mortality, necrosectomy, antibiotic resistance, hospital stay and adverse events. To demonstrate that probiotic prophylaxis reduces the proportion of patients with infectious complications from 50% to 30%, with alpha 0,05 and power 80%, a total sample size of 200 patients was calculated. Conclusion The PROPATRIA study is aimed to show a reduction in infectious complications due to early enteral use of multispecies probiotics in severe acute pancreatitis. PMID:15456517
N-acetylcysteine for major depressive episodes in bipolar disorder.

PubMed

Magalhães, Pedro V; Dean, Olívia M; Bush, Ashley I; Copolov, David L; Malhi, Gin S; Kohlmann, Kristy; Jeavons, Susan; Schapkaitz, Ian; Anderson-Hunt, Murray; Berk, Michael

2011-12-01

In this report, we aimed to evaluate the effect of add-on N-acetylcysteine (NAC) on depressive symptoms and functional outcomes in bipolar disorder. To that end, we conducted a secondary analysis of all patients meeting full criteria for a depressive episode in a placebo controlled trial of adjunctive NAC for bipolar disorder. Twenty-four week randomised clinical trial comparing adjunctive NAC and placebo in individuals with bipolar disorder experiencing major depressive episodes. Symptomatic and functional outcome data were collected over the study period. Seventeen participants were available for this report. Very large effect sizes in favor of NAC were found for depressive symptoms and functional outcomes at endpoint. Eight of the ten participants on NAC had a treatment response at endpoint; the same was true for only one of the seven participants allocated to placebo. These results indicate that adjunctive NAC may be useful for major depressive episodes in bipolar disorder. Further studies designed to confirm this hypothesis are necessary.
Topical use of Matricaria recutita L (Chamomile) Oil in the Treatment of Monosymptomatic Enuresis in Children

PubMed Central

Sharifi, Hosein; Minaie, Mohammad Bagher; Qasemzadeh, Mohammad Javad; Ataei, Nematollah; Gharehbeglou, Mohammad; Heydari, Mojtaba

2015-01-01

Aim. To evaluate the efficacy of topical use of Matricaria recutita L oil in the treatment of enuresis in children. Methods. Eighty patients diagnosed as monosymptomatic nocturnal or daytime enuresis were allocated to receive Matricaria recutita L (chamomile) oil or placebo topically for 6 weeks in a double-blind randomized placebo-controlled trial with a parallel design. Patients were evaluated prior to and following 8 weeks of the intervention in terms of frequency of enuresis and any observed adverse events. Results. The mean frequency of enuresis at the first, second, and third 2 weeks was lower in the intervention group compared with the placebo group, and the differences were statistically significant (P < .001, P = .03, and P < .001, respectively). There was no report of any adverse event in the study groups. Conclusion. The findings of this study showed that the topical use of (chamomile) oil can decrease the frequency of nocturia in children with monosymptomatic nocturnal or daytime enuresis. PMID:26427789
Vitamin B-12-fortified toothpaste improves vitamin status in vegans: a 12-wk randomized placebo-controlled study.

PubMed

Siebert, Anne-Kathrin; Obeid, Rima; Weder, Stine; Awwad, Hussain M; Sputtek, Andreas; Geisel, Juergen; Keller, Markus

2017-03-01

Background: The oral application of vitamin B-12 may prevent its deficiency if the vitamin is absorbed via the mucosal barrier. Objectives: We studied the effect of the use of a vitamin B-12-fortified toothpaste on vitamin-status markers in vegans and assessed the efficiency of markers in the identification of vitamin-augmentation status. Design: In this 12-wk, double-blinded, randomized, placebo-controlled study, 76 vegans received either a placebo ( n = 34) or vitamin B-12 ( n = 42) toothpaste. Sixty-six subjects ( n = 30 in the placebo arm; n = 36 in the vitamin B-12 arm) completed the intervention. Serum and plasma concentrations of vitamin B-12, holotranscobalamin, total homocysteine (tHcy), and methylmalonic acid (MMA) were measured before and after the intervention. Results: Both postintervention concentrations of vitamin B-12 and holotranscobalamin and their changes over 12 wk were higher in the vitamin B-12 group (mean ± SD change: 81 ± 135 pmol/L for vitamin B-12 and 26 ± 34 pmol/L for holotranscobalamin) than in the placebo group (-27 ± 64 and -5 ± 17 pmol/L, respectively) after adjustment for baseline concentrations. Postintervention concentrations of MMA and their changes differed significantly between groups (MMA changes: -0.169 ± 0.340 compared with -0.036 ± 0.544 μmol/L in vitamin B-12 and placebo groups, respectively; P < 0.001). After adjustment for baseline tHcy, postintervention concentrations of tHcy tended to be lower ( P = 0.051), and the changes in tHcy (-0.7 ± 4.4 compared with 2.0 ± 5.6 μmol/L, respectively) were greater in the vitamin B-12 group than in the placebo group. Changes in vitamin B-12 markers were more prominent in vegans who reported that they had not taken vitamin B-12 supplements. Conclusion: Vitamin B-12 that is applied to the oral cavity via toothpaste enters the circulation and corrects the vitamin B-12 markers in the blood of vegans who are at higher risk of vitamin B-12 deficiency. This trial was registered at clinicaltrials.gov as NCT02679833. © 2017 American Society for Nutrition.
Probiotics for fibromyalgia: study design for a pilot double-blind, randomized controlled trial.

PubMed

Roman, Pablo; Estévez, Ángeles F; Sánchez-Labraca, Nuria; Cañadas, Fernando; Miras, Alonso; Cardona, Diana

2017-10-24

Fibromyalgia syndrome (FMS) is a chronic, generalized and diffuse pain disorder accompanied by other symptoms such as emotional and cognitive deficits. The FMS patients show a high prevalence of gastrointestinal symptoms. Recently it has been found that microbes in the gut may regulate brain processes through the gut-microbiota-brain axis, modulating thus affection, motivation and higher cognitive functions. Therefore, the use of probiotics might be a new treatment that could improve the physical, psychological and cognitive state in FMS; however, no evidence about this issue is available. This paper describes the design and protocol of a double-blind, placebo-controlled and randomized pilot study. We use validated questionnaires, cognitive task through E-Prime and biological measures like urine cortisol and stool fecal samples. The trial aim is to explore the effects of eight weeks of probiotics therapy in physical (pain, impact of the FMS and quality of life), emotional (depression, and anxiety) and cognitive symptoms (attention, memory, and impulsivity) in FMS patients as compared to placebo. This pilot study is the first, to our knowledge, to evaluate the effects of probiotics in FMS. The primary hypothesis was that FMS patients will show a better performance on cognitive tasks, and an improvement in emotional and physical symptoms. These results will contribute to a better understanding in the gut-brain axis. Here we present the design and protocol of the study.
The effects of the DDS-1 strain of lactobacillus on symptomatic relief for lactose intolerance - a randomized, double-blind, placebo-controlled, crossover clinical trial.

PubMed

Pakdaman, Michael N; Udani, Jay K; Molina, Jhanna Pamela; Shahani, Michael

2016-05-20

Lactose intolerance is a form of lactose maldigestion where individuals experience symptoms such as diarrhea, abdominal cramping, flatulence, vomiting and bowel sounds following lactose consumption. Lactobacillus acidophilus is a species of bacteria known for its sugar fermenting properties. Preclinical studies have found that Lactobacillus acidophilus supplementation may assist in breaking down lactose; however, no human clinical trials exist evaluating its efficacy in alleviating symptoms related to lactose intolerance. The aim of this randomized, double-blind, placebo-controlled, crossover study was to evaluate the effect of a proprietary strain of Lactobacillus acidophilus on relieving discomfort related to lactose intolerance. The study enrolled healthy volunteers between 18 and 75 years of age who complained of lactose intolerance. Screening visits included a lactose challenge visit to confirm eligibility based on a score of 10 or higher on subjective assessment of the following symptoms after lactose challenge: diarrhea, abdominal cramping, vomiting, audible bowel sounds, flatulence, and overall symptoms. Qualified subjects participated in a 2-arm crossover design, with each arm consisting of 4 weeks of intervention of either active or placebo product, with a 2-week washout period during crossover. The study product consisted of the DDS-1 strain of Lactobacillus acidophilus (Nebraska Cultures, Walnut Creek, California). The placebo was formulated from maltodextrin. Study participants were instructed to take the product once daily for 4 weeks. Data collected included subjective symptom scores related to lactose intolerance. Longitudinal comparison between the DDS-1 group and placebo group demonstrated statistically significant reductions in abdominal symptom scores during the 6-h Lactose Challenge at week 4 for diarrhea (p = 0.033), abdominal cramping (p = 0.012), vomiting (p = 0.0002), and overall symptom score (p = 0.037). No adverse events were reported. The present study has found that this unique DDS-1 strain of Lactobacillus acidophilus, manufactured by Nebraska Cultures, is safe to consume and improves abdominal symptom scores compared to placebo with respect to diarrhea, cramping, and vomiting during an acute lactose challenge.
Randomized, double-blind, placebo-controlled clinical trial of choline supplementation in school-aged children with fetal alcohol spectrum disorders1

PubMed Central

Risbud, Rashmi D; Mattson, Sarah N; Chambers, Christina D; Thomas, Jennifer D

2016-01-01

Background: Prenatal alcohol exposure results in a broad range of cognitive and behavioral impairments. Because of the long-lasting problems that are associated with fetal alcohol spectrum disorders (FASDs), the development of effective treatment programs is critical. Preclinical animal studies have shown that choline, which is an essential nutrient, can attenuate the severity of alcohol-related cognitive impairments. Objective: We aimed to translate preclinical findings to a clinical population to investigate whether choline supplementation can ameliorate the severity of memory, executive function, and attention deficits in children with FASDs. Design: In the current study, which was a randomized, double-blind, placebo-controlled clinical trial, we explored the effectiveness of a choline intervention for children with FASDs who were aged 5–10 y. Fifty-five children with confirmed histories of heavy prenatal alcohol exposure were randomly assigned to either the choline (n = 29) or placebo (n = 26) treatment arms. Participants in the choline group received 625 mg choline/d for 6 wk, whereas subjects in the placebo group received an equivalent dose of an inactive placebo treatment. Primary outcomes, including the performance on neuropsychological measures of memory, executive function, and attention and hyperactivity, were assessed at baseline and postintervention. Results: Compared with the placebo group, participants in the choline group did not differentially improve in cognitive performance in any domain. Treatment compliance and mean dietary choline intake were not predictive of treatment outcomes. Conclusions: Findings of the current study do not support that choline, administered at a dose of 625 mg/d for 6 wk, is an effective intervention for school-aged (5–10 y old) children with FASDs. This research provides important information about choline’s therapeutic window. Combined with other studies of choline and nutritional interventions in this population, this study emphasizes a further need for the continued study of the role of nutritional status and supplementation in children with FASDs and the contributions of nutrition to neurocognition. This trial was registered at clinicaltrials.gov as NCT01911299. PMID:27806977
The efficacy of cetirizine hydrochloride on the pruritus of cats with atopic dermatitis: a randomized, double-blind, placebo-controlled, crossover study.

PubMed

Wildermuth, Kerstin; Zabel, Sonja; Rosychuk, Rod A W

2013-12-01

Various antihistamines have been used in the management of feline atopic dermatitis, with variable reported benefit. To date, there have been no randomized, double-blind, placebo-controlled, crossover clinical trials on the use of this drug class in cats. To evaluate the clinical efficacy of cetirizine hydrochloride for the control of pruritus and dermatitis in cats diagnosed with atopic dermatitis. In this randomized, double-blind, placebo-controlled crossover clinical trial, 21 client-owned cats diagnosed with mild to moderate nonseasonal atopic dermatitis were randomly assigned to two groups. Cats in each group received either 1 mg/kg cetirizine hydrochloride or placebo once daily per os for 28 days followed by a 14 day wash-out period. Treatments were then crossed over, and cats received placebo or cetirizine hydrochloride for another 28 days. Owners marked a pruritus severity scale before inclusion in the study and weekly throughout the entire study period. Lesions were scored by the clinician using a Canine Atopic Dermatitis Extent and Severity Index (CADESI)-03 modified for the cat before enrolment and at day 28 of each treatment. Nineteen cats completed the study. There were no statistically significant differences between treatment with cetirizine hydrochloride and placebo for modified CADESI-03 or pruritus scores. This study suggests that cetirizine hydrochloride cannot be recommended for the management of feline atopic dermatitis. © 2013 ESVD and ACVD.
Clinical evaluation of liquid placebos for an herbal supplement, STW5, in healthy volunteers.

PubMed

Yoon, Saunjoo L; Grundmann, Oliver; Keane, Devan; Urbano, Theodore; Moshiree, Baharak

2012-10-01

Although clinical trials are needed to evaluate the efficacy of liquid herbal medicinal products, design of feasible placebos that mimic the appearance, taste, and smell of such products is particularly challenging. The design and feasibility of a liquid placebo for STW5, an herbal medicinal product used for various gastrointestinal problems, was explored in this study. Four sample products-STW5, a fresh and aged version of a placebo made from a seasoning mix (Maggi™), and a placebo with aged artificial flavor and food coloring-were compared in two organoleptic (sensory), single-blind trials with a total of 60 (N=60) healthy volunteers (n(1)=30, n(2)=30). The appearance, smell, and taste of each solution were evaluated using a Likert scale questionnaire. The liquid placebos evaluated were similar in regard to appearance, smell, and taste. However, participants indicated that for a clinical trial with STW5, the aged Maggi™ placebo would be more viable compared to the fresh Maggi placebo or the aged artificial food coloring placebo with licorice flavor. Participants also noted that the mint flavor and smell of STW5 was distinctly different from the placebo solutions. The trials were conducted in healthy volunteers, not in actual patients. The aged Maggi™ liquid mix may be more favorable as a placebo than the artificially created one. However, further adjustment will need to be made to the Maggi™ placebo to simulate the complex aromatic composition of STW5 for clinical studies in the future. Copyright © 2012 Elsevier Ltd. All rights reserved.
Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial.

PubMed

Cummings, Jeffrey L; Lyketsos, Constantine G; Peskind, Elaine R; Porsteinsson, Anton P; Mintzer, Jacobo E; Scharre, Douglas W; De La Gandara, Jose E; Agronin, Marc; Davis, Charles S; Nguyen, Uyen; Shin, Paul; Tariot, Pierre N; Siffert, João

Agitation is common among patients with Alzheimer disease; safe, effective treatments are lacking. To assess the efficacy, safety, and tolerability of dextromethorphan hydrobromide-quinidine sulfate for Alzheimer disease-related agitation. Phase 2 randomized, multicenter, double-blind, placebo-controlled trial using a sequential parallel comparison design with 2 consecutive 5-week treatment stages conducted August 2012-August 2014. Patients with probable Alzheimer disease, clinically significant agitation (Clinical Global Impressions-Severity agitation score ≥4), and a Mini-Mental State Examination score of 8 to 28 participated at 42 US study sites. Stable dosages of antidepressants, antipsychotics, hypnotics, and antidementia medications were allowed. In stage 1, 220 patients were randomized in a 3:4 ratio to receive dextromethorphan-quinidine (n = 93) or placebo (n = 127). In stage 2, patients receiving dextromethorphan-quinidine continued; those receiving placebo were stratified by response and rerandomized in a 1:1 ratio to dextromethorphan-quinidine (n = 59) or placebo (n = 60). The primary end point was change from baseline on the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (scale range, 0 [absence of symptoms] to 12 [symptoms occur daily and with marked severity]). A total of 194 patients (88.2%) completed the study. With the sequential parallel comparison design, 152 patients received dextromethorphan-quinidine and 127 received placebo during the study. Analysis combining stages 1 (all patients) and 2 (rerandomized placebo nonresponders) showed significantly reduced NPI Agitation/Aggression scores for dextromethorphan-quinidine vs placebo (ordinary least squares z statistic, -3.95; P < .001). In stage 1, mean NPI Agitation/Aggression scores were reduced from 7.1 to 3.8 with dextromethorphan-quinidine and from 7.0 to 5.3 with placebo. Between-group treatment differences were significant in stage 1 (least squares mean, -1.5; 95% CI, -2.3 to -0.7; P<.001). In stage 2, NPI Agitation/Aggression scores were reduced from 5.8 to 3.8 with dextromethorphan-quinidine and from 6.7 to 5.8 with placebo. Between-group treatment differences were also significant in stage 2 (least squares mean, -1.6; 95% CI, -2.9 to -0.3; P=.02). Adverse events included falls (8.6% for dextromethorphan-quinidine vs 3.9% for placebo), diarrhea (5.9% vs 3.1% respectively), and urinary tract infection (5.3% vs 3.9% respectively). Serious adverse events occurred in 7.9% with dextromethorphan-quinidine vs 4.7% with placebo. Dextromethorphan-quinidine was not associated with cognitive impairment, sedation, or clinically significant QTc prolongation. In this preliminary 10-week phase 2 randomized clinical trial of patients with probable Alzheimer disease, combination dextromethorphan-quinidine demonstrated clinically relevant efficacy for agitation and was generally well tolerated. clinicaltrials.gov Identifier: NCT01584440.
Dose finding with the sequential parallel comparison design.

PubMed

Wang, Jessie J; Ivanova, Anastasia

2014-01-01

The sequential parallel comparison design (SPCD) is a two-stage design recommended for trials with possibly high placebo response. A drug-placebo comparison in the first stage is followed in the second stage by placebo nonresponders being re-randomized between drug and placebo. We describe how SPCD can be used in trials where multiple doses of a drug or multiple treatments are compared with placebo and present two adaptive approaches. We detail how to analyze data in such trials and give recommendations about the allocation proportion to placebo in the two stages of SPCD.
Sarizotan as a treatment for dyskinesias in Parkinson's disease: a double-blind placebo-controlled trial.

PubMed

Goetz, Christopher G; Damier, Philippe; Hicking, Christine; Laska, Eugene; Müller, Thomas; Olanow, C Warren; Rascol, Olivier; Russ, Hermann

2007-01-15

The objective of this study is to conduct a dose-finding study of sarizotan in Parkinson's disease (PD) patients with dyskinesia to identify a safe dose and to identify a sensitive dyskinesia rating measure. Sarizotan is a novel compound with full 5-HT(1A) agonist properties and additional high affinity for D(3) and D(4) receptors. An open label study documented improvements in PD patients with levodopa-induced dyskinesia. There is no precedent for study designs or outcome measures in pivotal trials of antidyskinesia therapies. The approach used here was a multicenter, randomized, placebo-controlled, double-blind, parallel study. Included were PD patients optimized to levodopa and dopaminergic drugs with moderately disabling dyskinesias present greater than or equal to 25% of the waking day. Interventions included sarizotan 2, 4, or 10 mg/day or matching placebo, given in two doses. There were two outcome measures: the primary measure was change from baseline in diary-based on time without dyskinesia; the secondary measures were change from baseline in scores on the Abnormal Involuntary Movement Scale (AIMS), the composite score of Unified Parkinson's Disease Rating Scale (UPDRS) Items 32+33 (dyskinesia duration and disability) and total UPDRS. A total of 398 subjects were randomized, with 381 included in the intention-to-treat population. No significant changes occurred on sarizotan compared to placebo on any diary-based measure of dyskinesia or the AIMS score. The composite score of UPDRS Items 32+33 was significantly improved with 2 mg/day sarizotan, with a trend at 10 mg/day. Adverse events were not significantly different in sarizotan- and placebo-treated patients, but off time significantly increased with sarizotan 10 mg/day. Sarizotan 2 mg/day is a safe agent in PD patients with dyskinesia. To test its role in abating dyskinesia, future studies should focus on this dose and will use the composite score of UPDRS Items 32+33 as the primary outcome. (c) 2006 Movement Disorder Society.
A double-blind, placebo-controlled study on the effects of lutein and zeaxanthin on photostress recovery, glare disability, and chromatic contrast.

PubMed

Hammond, Billy R; Fletcher, Laura M; Roos, Franz; Wittwer, Jonas; Schalch, Wolfgang

2014-12-02

Past studies have shown that higher macular pigment optical density (MPOD) and lutein (L) and zeaxanthin (Z) supplementation are related to improvements in glare disability, photostress recovery, and chromatic contrast. This study assessed those links using a randomized, double-blind, placebo-controlled design. The visual effects of 1 year of supplementing L (10 mg/d) and Z (2 mg/d) were investigated. One hundred fifteen young, healthy subjects were recruited and randomized into the study (58 received placebo, 57 L+Z). Several dependent measures were collected at baseline and then once every 3 months: serum L and Z measured by HPLC chromatography; MPOD measured using customized heterochromatic flicker photometry; photostress recovery assessed by measuring the time needed to recover visual acquisition of a grating target after 30 seconds of an intense xenon white flash exposure; glare disability evaluated as the energy in a surrounding annulus necessary to veil a central grating target; and chromatic contrast assessed by measuring thresholds for a yellow grating target superposed on a 460-nm background. Macular pigment optical density increased significantly versus placebo at all eccentricities (10, 30, 60, and 105 minutes from the center of the macula). Serum L and Z also increased significantly by the first follow-up visit (at 3 months), and remained elevated throughout the intervention period of 1 year. Chromatic contrast and photostress recovery time improved significantly versus placebo. Glare disability was correlated with macular pigment density throughout the study period but did not increase significantly in the treated group. Daily supplementation with L+Z resulted in significant increase in serum levels and MPOD and improvements in chromatic contrast and recovery from photostress. These results are consistent with past studies showing that increasing MPOD leads to improved visual performance. (ClinicalTrials.gov number, NCT00909090.). Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers

PubMed Central

Taubel, Jorg; Naseem, Asif; Harada, Tomohiko; Wang, Duolao; Arezina, Radivoj; Lorch, Ulrike; Camm, A John

2010-01-01

AIMS To characterize the effects of levofloxacin on QT interval in healthy subjects and the most appropriate oral positive control treatments for International Conference on Harmonization (ICH) E14 QT/QTc studies. METHODS Healthy subjects received a single dose of levofloxacin (1000 or 1500 mg), moxifloxacin (400 mg) or placebo in a four-period crossover design. Digital 12-lead ECGs were recorded in triplicate. Measurement of QT interval was performed automatically with subsequent manual onscreen over-reading using electronic callipers. Blood samples were taken for determination of levofloxacin and moxifloxacin concentrations. RESULTS Mean QTcI (QT interval corrected for heart rate using a correction factor that is applicable to each individual) was prolonged in subjects receiving moxifloxacin 400 mg compared with placebo. The largest time-matched difference in QTcI for moxifloxacin compared with placebo was observed to be 13.19 ms (95% confidence interval 11.21, 15.17) at 3.5 h post dose. Prolonged mean QTcI was also observed in subjects receiving levofloxacin 1000 mg and 1500 mg compared with placebo. The largest time-matched difference in QTcI compared with placebo was observed at 3.5 h post dose for both 1000 mg and 1500 mg of levofloxacin [mean (95%) 4.42 ms (2.44, 6.39) in 1000 mg and 7.44 ms (5.47, 9.42) in 1500 mg]. A small increase in heart rate was observed with levofloxacin during the course of the study. However, moxifloxacin showed a greater increase compared with levofloxacin. CONCLUSIONS Both levofloxacin and moxifloxacin can fulfil the criteria for a positive comparator. The ICH E14 guidelines recommend a threshold of around 5 ms for a positive QT/QTc study. The largest time-matched difference in QTc for levofloxacin suggests the potential for use in more rigorous QT/QTc studies. This study has demonstrated the utility of levofloxacin on the assay in measuring mean QTc changes around 5 ms. PMID:20406223
Neural Correlates of Antidepressant-Related Sexual Dysfunction: A Placebo-Controlled fMRI Study on Healthy Males Under Subchronic Paroxetine and Bupropion

PubMed Central

Abler, Birgit; Seeringer, Angela; Hartmann, Antonie; Grön, Georg; Metzger, Coraline; Walter, Martin; Stingl, Julia

2011-01-01

Sexual dysfunction is a common side effect of selective serotonin reuptake inhibitors (SSRIs) like paroxetine in the treatment of depression, imposing a considerable risk on medication adherence and hence therapeutic success. Bupropion, a norepinephrine and dopamine reuptake inhibitor, is recommended as an alternative treatment without adverse effects concerning sexual arousal and libido. We investigated the neural bases of paroxetine-related subjective sexual dysfunction when compared with bupropion and placebo. We scanned 18 healthy, heterosexual males in a randomized, double-blind, within-subject design while watching video clips of erotic and nonerotic content under steady-state conditions after taking 20 mg of paroxetine, 150 mg of bupropion, and placebo for 7 days each. Under paroxetine, ratings of subjective sexual dysfunction increased compared with placebo or bupropion. Activation along the anterior cingulate cortex (ACC), including subgenual, pregenual, and midcingulate cortices, in the ventral striatum and midbrain was decreased when compared with placebo. In contrast, bupropion let subjective ratings and ACC activations unchanged and increased activity of brain regions including posterior midcingulate cortex, mediodorsal thalamus, and extended amygdala relative to placebo and paroxetine. Brain regions that have been related to the processing of motivational (ventral striatum), emotional, and autonomic components of erotic stimulation (anterior cingulate) in previous studies showed reduced responsiveness under paroxetine in our study. Drug effects on these regions may be part of the mechanism underlying SSRI-related sexual dysfunction. Increased activation under bupropion may point to an opposite effect that may relate to the lack of impaired sexual functioning. PMID:21544071

Neural correlates of antidepressant-related sexual dysfunction: a placebo-controlled fMRI study on healthy males under subchronic paroxetine and bupropion.

PubMed

Abler, Birgit; Seeringer, Angela; Hartmann, Antonie; Grön, Georg; Metzger, Coraline; Walter, Martin; Stingl, Julia

2011-08-01

Sexual dysfunction is a common side effect of selective serotonin reuptake inhibitors (SSRIs) like paroxetine in the treatment of depression, imposing a considerable risk on medication adherence and hence therapeutic success. Bupropion, a norepinephrine and dopamine reuptake inhibitor, is recommended as an alternative treatment without adverse effects concerning sexual arousal and libido. We investigated the neural bases of paroxetine-related subjective sexual dysfunction when compared with bupropion and placebo. We scanned 18 healthy, heterosexual males in a randomized, double-blind, within-subject design while watching video clips of erotic and nonerotic content under steady-state conditions after taking 20 mg of paroxetine, 150 mg of bupropion, and placebo for 7 days each. Under paroxetine, ratings of subjective sexual dysfunction increased compared with placebo or bupropion. Activation along the anterior cingulate cortex (ACC), including subgenual, pregenual, and midcingulate cortices, in the ventral striatum and midbrain was decreased when compared with placebo. In contrast, bupropion let subjective ratings and ACC activations unchanged and increased activity of brain regions including posterior midcingulate cortex, mediodorsal thalamus, and extended amygdala relative to placebo and paroxetine. Brain regions that have been related to the processing of motivational (ventral striatum), emotional, and autonomic components of erotic stimulation (anterior cingulate) in previous studies showed reduced responsiveness under paroxetine in our study. Drug effects on these regions may be part of the mechanism underlying SSRI-related sexual dysfunction. Increased activation under bupropion may point to an opposite effect that may relate to the lack of impaired sexual functioning.
Effect of nifedipine on choroidal blood flow regulation during isometric exercise.

PubMed

Schmidl, Doreen; Prinz, Ana; Kolodjaschna, Julia; Polska, Elzbieta; Luksch, Alexandra; Fuchsjager-Mayrl, Gabriele; Garhofer, Gerhard; Schmetterer, Leopold

2012-01-25

To determine whether nifedipine, an L-type calcium channel blocker, alters choroidal blood flow (ChBF) regulation during isometric exercise in healthy subjects. The study was carried out in a randomized, placebo-controlled, double-masked, two-way crossover design. Fifteen healthy male subjects were randomly assigned to receive either placebo or nifedipine on two different study days. Subfoveal ChBF was measured with laser Doppler flowmetry while the study participants performed isometric exercise (squatting). This was performed before drug administration and during infusion of nifedipine and placebo, respectively. Mean arterial pressure (MAP) and intraocular pressure (IOP) were measured noninvasively, and ocular perfusion pressure (OPP) was calculated as ⅔ MAP-IOP. MAP and OPP increased significantly during all squatting periods (P < 0.01). The increase in ChBF was less pronounced than the increase in OPP during isometric exercise. Nifedipine did not alter the OPP increase in response to isometric exercise, but it significantly augmented the exercise-induced increase in ChBF (P < 0.001 vs. placebo). Although ChBF increased by a maximum of 14.2% ± 9.2% during the squatting period when placebo was administered, the maximum increase during administration of nifedipine was 23.2% ± 7.2%. In conclusion, the data of the present study suggest that nifedipine augments the ChBF response to an experimental increase in OPP. In addition, it confirms that the choroidal vasculature has a significant regulatory capacity over wide ranges of OPPs during isometric exercise. (ClinicalTrials.gov number, NCT00280462.).
Evaluation of 5 Hour Energy Drink on the Blood Pressure and Electrocardiograph Parameters on Young Healthy Volunteers: A Randomized, Double Blind, Crossover, Placebo-Controlled Trial

DTIC Science & Technology

2014-02-11

Travis AFB CA INSTITUTIONAL REVIEW BOARD (IRB) ()~\\) Non-Exempt Study Final Report p3YVJ (Please 1J!J!£ all information. Use additional pages if...QTc interval after acute and chronic consumption. METHODS: This was a randomized, placebo controlled, crossover study enrolling young healthy volunteers...not on any medications. Subjects received the study drink (5 Hour Energy shot or placebo) twice daily separated by approximately 7 hours for the
An analysis of adaptive design variations on the sequential parallel comparison design for clinical trials

PubMed Central

Mi, Michael Y.; Betensky, Rebecca A.

2013-01-01

Background Currently, a growing placebo response rate has been observed in clinical trials for antidepressant drugs, a phenomenon that has made it increasingly difficult to demonstrate efficacy. The sequential parallel comparison design (SPCD) is a clinical trial design that was proposed to address this issue. The SPCD theoretically has the potential to reduce the sample size requirement for a clinical trial and to simultaneously enrich the study population to be less responsive to the placebo. Purpose Because the basic SPCD design already reduces the placebo response by removing placebo responders between the first and second phases of a trial, the purpose of this study was to examine whether we can further improve the efficiency of the basic SPCD and if we can do so when the projected underlying drug and placebo response rates differ considerably from the actual ones. Methods Three adaptive designs that used interim analyses to readjust the length of study duration for individual patients were tested to reduce the sample size requirement or increase the statistical power of the SPCD. Various simulations of clinical trials using the SPCD with interim analyses were conducted to test these designs through calculations of empirical power. Results From the simulations, we found that the adaptive designs can recover unnecessary resources spent in the traditional SPCD trial format with overestimated initial sample sizes and provide moderate gains in power. Under the first design, results showed up to a 25% reduction in person-days, with most power losses below 5%. In the second design, results showed up to a 8% reduction in person-days with negligible loss of power. In the third design using sample size re-estimation, up to 25% power was recovered from underestimated sample size scenarios. Limitations Given the numerous possible test parameters that could have been chosen for the simulations, the study’s results are limited to situations described by the parameters that were used, and may not generalize to all possible scenarios. Furthermore, drop-out of patients is not considered in this study. Conclusions It is possible to make an already complex design such as the SPCD adaptive, and thus more efficient, potentially overcoming the problem of placebo response at lower cost. Ultimately, such a design may expedite the approval of future effective treatments. PMID:23283576
Magnitude of blood pressure reduction in the placebo arms of modern hypertension trials: implications for trials of renal denervation.

PubMed

Patel, Hitesh C; Hayward, Carl; Ozdemir, Baris Ata; Rosen, Stuart D; Krum, Henry; Lyon, Alexander R; Francis, Darrel P; di Mario, Carlo

2015-02-01

Early phase studies of novel interventions for hypertension, such as renal sympathetic denervation, are sometimes single-armed (uncontrolled). We explored the wisdom of this by quantifying the blood pressure fall in the placebo arms of contemporary trials of hypertension. We searched Medline up to June 2014 and identified blinded, randomized trials of hypertension therapy in which the control arm received placebo medication or a sham (placebo) procedure. For nonresistant hypertension, we have identified all such trials of drugs licensed by the US Food and Drug Administration since 2000 (5 drugs). This US Food and Drug Administration-related restriction was not applied to resistant hypertension trials. This produced 7451 patients, who were allocated to a blinded control from 52 trials of nonresistant hypertension and 694 patients from 8 trials of resistant hypertension (3 drugs and 2 interventions). Systolic blood pressure fell by 5.92 mm Hg (95% confidence interval, 5.14-6.71; P<0.0001) in the nonresistant cohort and by 8.76 mm Hg (95% confidence interval, 4.83-12.70; P<0.0001) in the resistant cohort. Using metaregression, the falls were larger in trials that did not use ambulatory blood pressure monitoring as an inclusion criterion (z=2.84; P=0.0045), in those with higher baseline blood pressures (z=-0.3; P=0.0001), and in those where the patients were prescribed a continuous background of antihypertensives (z=-2.72; P=0.0065). The nontrivial magnitude of these apparent blood pressure reductions with perfectly ineffective intervention (placebo) illustrates that efficacy explorations of novel therapies for hypertension, once safety is established, should be performed with a randomized, appropriately controlled, and blinded design. © 2014 American Heart Association, Inc.
Treatment of post-myocardial infarction depressive disorder: a randomized, placebo-controlled trial with mirtazapine.

PubMed

Honig, Adriaan; Kuyper, Astrid M G; Schene, Aart H; van Melle, Joost P; de Jonge, Peter; Tulner, Dorien M; Schins, Annique; Crijns, Harry J G M; Kuijpers, Petra M J C; Vossen, Helen; Lousberg, Richel; Ormel, Johan

2007-01-01

To examine the antidepressant efficacy of a dual-acting antidepressant (mirtazapine) in patients with post-myocardial infarction (MI) depressive disorder. Antidepressants used in post MI trials with a randomized, double-blind, placebo-controlled design have been restricted to selective serotonin reuptake inhibitors (SSRIs). Antidepressant effects have been limited. In a prospective multicenter study, 2177 patients with MI were evaluated for depressive disorder during the first year post MI. Ninety-one patients who met the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for major or minor depressive disorder were randomized to a 24-week, double-blind, placebo-controlled trial. Antidepressant efficacy was tested using last-observation-carried-forward procedure and repeated measurements analysis using the SPPS mixed models approach, with as primary outcome reduction in depressive symptomatology on the 17-item Hamilton-Depression Rating Scale (Ham-D), and secondary outcomes the Beck Depression Inventory (BDI) and depression subscale of the Symptom Check List 90 items (dSCL-90) as well as the Clinical Global Impression (CGI) scale. Using the "last observation carried forward" (LOCF) method, mirtazapine did not show to be superior to placebo on the Ham-D, but did on the BDI, dSCL-90, and CGI scale over the acute treatment phase of 8 weeks (n = 91). Using mixed models analysis over the entire 24 weeks of treatment (n = 40), we did find a significant difference favoring mirtazapine to placebo on the Ham-D, BDI, and CGI, but on the dSCL-90, this difference was not significant. This trial shows efficacy of mirtazapine on primary and secondary depression measures. Mirtazapine seems to be safe in the treatment of post-MI depression.
Study protocol of Prednisone in episodic Cluster Headache (PredCH): a randomized, double-blind, placebo-controlled parallel group trial to evaluate the efficacy and safety of oral prednisone as an add-on therapy in the prophylactic treatment of episodic cluster headache with verapamil

PubMed Central

2013-01-01

Background Episodic cluster headache (ECH) is a primary headache disorder that severely impairs patient’s quality of life. First-line therapy in the initiation of a prophylactic treatment is verapamil. Due to its delayed onset of efficacy and the necessary slow titration of dosage for tolerability reasons prednisone is frequently added by clinicians to the initial prophylactic treatment of a cluster episode. This treatment strategy is thought to effectively reduce the number and intensity of cluster attacks in the beginning of a cluster episode (before verapamil is effective). This study will assess the efficacy and safety of oral prednisone as an add-on therapy to verapamil and compare it to a monotherapy with verapamil in the initial prophylactic treatment of a cluster episode. Methods and design PredCH is a prospective, randomized, double-blind, placebo-controlled trial with parallel study arms. Eligible patients with episodic cluster headache will be randomized to a treatment intervention with prednisone or a placebo arm. The multi-center trial will be conducted in eight German headache clinics that specialize in the treatment of ECH. Discussion PredCH is designed to assess whether oral prednisone added to first-line agent verapamil helps reduce the number and intensity of cluster attacks in the beginning of a cluster episode as compared to monotherapy with verapamil. Trial registration German Clinical Trials Register DRKS00004716 PMID:23889923
Acute effects of intoxication and arousal on approach / avoidance biases toward sexual risk stimuli in heterosexual men

PubMed Central

Simons, Jeffrey S.; Maisto, Stephen A.; Wray, Tyler B.; Emery, Noah N.

2015-01-01

This study tested the effects of alcohol intoxication and physiological arousal on cognitive biases toward erotic stimuli and condoms. Ninety-seven heterosexual men were randomized to 1 of 6 independent conditions in a 2 (high arousal or control) × 3 (alcohol target BAC = 0.08), placebo, or juice control) design and then completed a variant of the Approach Avoidance Task (AAT). The AAT assessed reaction times toward approaching and avoiding erotic stimuli and condoms with a joystick. Consistent with hypotheses, the alcohol condition exhibited an approach bias toward erotic stimuli, whereas the control and placebo groups exhibited an approach bias toward condom stimuli. Similarly, the participants in the high arousal condition exhibited an approach bias toward erotic stimuli and the low arousal control condition exhibited an approach bias toward condoms. The results suggest that acute changes in intoxication and physiological arousal independently foster biased responding towards sexual stimuli and these biases are associated with sexual risk intentions. PMID:25808719
Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-β1b (MIRACLE trial): study protocol for a randomized controlled trial.

PubMed

Arabi, Yaseen M; Alothman, Adel; Balkhy, Hanan H; Al-Dawood, Abdulaziz; AlJohani, Sameera; Al Harbi, Shmeylan; Kojan, Suleiman; Al Jeraisy, Majed; Deeb, Ahmad M; Assiri, Abdullah M; Al-Hameed, Fahad; AlSaedi, Asim; Mandourah, Yasser; Almekhlafi, Ghaleb A; Sherbeeni, Nisreen Murad; Elzein, Fatehi Elnour; Memon, Javed; Taha, Yusri; Almotairi, Abdullah; Maghrabi, Khalid A; Qushmaq, Ismael; Al Bshabshe, Ali; Kharaba, Ayman; Shalhoub, Sarah; Jose, Jesna; Fowler, Robert A; Hayden, Frederick G; Hussein, Mohamed A

2018-01-30

It had been more than 5 years since the first case of Middle East Respiratory Syndrome coronavirus infection (MERS-CoV) was recorded, but no specific treatment has been investigated in randomized clinical trials. Results from in vitro and animal studies suggest that a combination of lopinavir/ritonavir and interferon-β1b (IFN-β1b) may be effective against MERS-CoV. The aim of this study is to investigate the efficacy of treatment with a combination of lopinavir/ritonavir and recombinant IFN-β1b provided with standard supportive care, compared to treatment with placebo provided with standard supportive care in patients with laboratory-confirmed MERS requiring hospital admission. The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. Hospitalized adult patients with laboratory-confirmed MERS will be enrolled in this recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The trial is initially designed to include 2 two-stage components. The first two-stage component is designed to adjust sample size and determine futility stopping, but not efficacy stopping. The second two-stage component is designed to determine efficacy stopping and possibly readjustment of sample size. The primary outcome is 90-day mortality. This will be the first randomized controlled trial of a potential treatment for MERS. The study is sponsored by King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. Enrollment for this study began in November 2016, and has enrolled thirteen patients as of Jan 24-2018. ClinicalTrials.gov, ID: NCT02845843 . Registered on 27 July 2016.
Evaluation of the acoustic coordinated reset (CR®) neuromodulation therapy for tinnitus: study protocol for a double-blind randomized placebo-controlled trial.

PubMed

Hoare, Derek J; Pierzycki, Robert H; Thomas, Holly; McAlpine, David; Hall, Deborah A

2013-07-10

Current theories of tinnitus assume that the phantom sound is generated either through increased spontaneous activity of neurons in the auditory brain, or through pathological temporal firing patterns of the spontaneous neuronal discharge, or a combination of both factors. With this in mind, Tass and colleagues recently tested a number of temporally patterned acoustic stimulation strategies in a proof of concept study. Potential therapeutic sound regimes were derived according to a paradigm assumed to disrupt hypersynchronous neuronal activity, and promote plasticity mechanisms that stabilize a state of asynchronous spontaneous activity. This would correspond to a permanent reduction of tinnitus. The proof of concept study, conducted in Germany, confirmed the safety of the acoustic stimuli for use in tinnitus, and exploratory results indicated modulation of tinnitus-related pathological synchronous activity with potential therapeutic benefit. The most effective stimulation paradigm is now in clinical use as a sound therapy device, the acoustic coordinated reset (CR®) neuromodulation (Adaptive Neuromodulation GmbH (ANM), Köln, Germany). To measure the efficacy of CR® neuromodulation, we devised a powered, two-center, randomized controlled trial (RCT) compliant with the reporting standards defined in the Consolidated Standards of Reporting Trials (CONSORT) Statement. The RCT design also addresses the recent call for international standards within the tinnitus community for high-quality clinical trials. The design uses a between-subjects comparison with minimized allocation of participants to treatment and placebo groups. A minimization approach was selected to ensure that the two groups are balanced with respect to age, gender, hearing, and baseline tinnitus severity. The protocol ensures double blinding, with crossover of the placebo group to receive the proprietary intervention after 12 weeks. The primary endpoints are the pre- and post-treatment measures that provide the primary measures of efficacy, namely a validated and sensitive questionnaire measure of the functional impact of tinnitus. The trial is also designed to capture secondary changes in tinnitus handicap, quality (pitch, loudness, bandwidth), and changes in tinnitus-related pathological synchronous brain activity using electroencephalography (EEG). This RCT was designed to provide a confident high-level estimate of the efficacy of sound therapy using CR® neuromodulation compared to a well-matched placebo intervention, and uniquely in terms of sound therapy, examine the physiological effects of the intervention against its putative mechanism of action. ClinicalTrials.gov, NCT01541969.
Placebo effect in clinical trial design for irritable bowel syndrome.

PubMed

Shah, Eric; Pimentel, Mark

2014-04-30

Ongoing efforts to improve clinical trial design in irritable bowel syndrome have been hindered by high placebo response rates and ineffective outcome measures. We assessed established strategies to minimize placebo effect as well as the various ap-proaches to placebo effect which can affect trial design. These include genetic markers such as catechol-O-methyltransferase, opioidergic and dopaminergic neurobiologic theory, pre-cebo effect centered on expectancy theory, and side effect unblinding grounded on conditioning theory. We reviewed endpoints used in the study of IBS over the past decade including adequate relief and subjective global relief, emphasizing their weaknesses in fully evaluating the IBS condition, specifically their motility effects based on functional net value and relative benefit-harm based on dropouts due to adverse events. The focus of this review is to highlight ongoing efforts to improve clinical trial design which can lead to better outcomes in a real-world setting.
A Brief History of Placebos and Clinical Trials in Psychiatry

PubMed Central

Shorter, Edward

2013-01-01

The history of placebos in psychiatry can be understood only in the context of randomized controlled trials (RCTs). Placebo treatments are as old as medicine itself, and are particularly effective in dealing with psychosomatic symptoms. In psychiatry, placebos have mainly been featured in clinical drug trials. The earliest controlled trial in psychiatry (not involving drugs) occurred in 1922, followed by the first crossover studies during the 1930s. Meanwhile the concept of randomization was developed during the interwar years by British statistician Ronald A Fisher, and introduced in 3 trials of tuberculosis drugs between 1947 and 1951. These classic studies established the RCT as the gold standard in pharmaceutical trials, and its status was cemented during the mid-1950s. Nevertheless, while the placebo became established as a standard measure of drug action, placebo treatments became stigmatized as unethical. This is unfortunate, as they constitute one of the most powerful therapies in psychiatry. In recent years, moreover, the dogma of the placebo-controlled trial as the only acceptable data for drug licensing is also being increasingly discredited. This backlash has had 2 sources: one is the recognition that the US Food and Drug Administration has been too lax in permitting trials controlled with placebos alone, rather than also using an active agent as a test of comparative efficacy. In addition, there is evidence that in the hands of the pharmaceutical industry, the scientific integrity of RCTs themselves has been degraded into a marketing device. The once-powerful placebo is thus threatened with extinction. PMID:21507275
Nitroglycerin 0.4% ointment vs placebo in the treatment of pain resulting from chronic anal fissure: a randomized, double-blind, placebo-controlled study

PubMed Central

2013-01-01

Background Complications of chronic anal fissure (CAF) treatments are prompting interest in lower-risk therapies. This study was conducted to compare nitroglycerin (NTG) 0.4% ointment with placebo for pain associated with CAF. Methods In this randomized, double-blind, placebo-controlled trial, patients with one CAF and moderate-to-severe pain (≥50 mm on a 100 mm visual analog scale [VAS]) received 375 mg NTG 0.4% (1.5 mg active ingredient) or 375 mg placebo ointment applied anally every 12 hours for 21 days. The primary end point was change from baseline VAS score in 24-hour pain averaged over days 14–18. Review of data from patients who withdrew early was blinded to treatment. To control for the confounding effects of analgesics, all patients received 650 mg acetaminophen for headache prophylaxis before each application. Results A total of 247 patients were enrolled (NTG, n = 123; placebo, n = 124). The prespecified baseline observation carried forward (BOCF) analysis found no significant difference between groups; however, a last observation carried forward (LOCF) analysis showed a significant advantage for NTG. A post hoc analysis (LOCF/BOCF hybrid) demonstrated a significant adjusted mean difference of −7.0 mm in favor of NTG 0.4% (95% CI −13.6, –0.4; P = .038). Headache was the most common adverse event in the NTG (69.9%) and placebo (47.6%) groups. Conclusions This was the first placebo-controlled study that also controlled for the confounding effects of analgesics used to treat NTG-induced headache. In patients with moderate-to-severe CAF pain, NTG 0.4% ointment effectively reduced CAF pain compared with placebo. Trial registration ClinicalTrials.gov, NCT00522041 PMID:23815124
Effect of Transcutaneous Electrical Nerve Stimulation on Pain, Function, and Quality of Life in Fibromyalgia: A Double-Blind Randomized Clinical Trial

PubMed Central

Noehren, Brian; Dailey, Dana L.; Rakel, Barbara A.; Vance, Carol G.T.; Zimmerman, Miriam B.; Crofford, Leslie J.

2015-01-01

Background Fibromyalgia is a common chronic pain condition that has a significant impact on quality of life and often leads to disability. To date, there have been few well-controlled trials assessing the utility of nonpharmacological treatment modalities such as transcutaneous electrical nerve stimulation (TENS) in the management of pain and improvement in function in individuals with fibromyalgia. Objectives The purpose of this study will be to complete a long-term, multicenter study to assess the effects of TENS in women with fibromyalgia. Design This will be a phase II randomized, double-blind, placebo-controlled, multicenter clinical trial. Participants Three hundred forty-three participants with fibromyalgia will be recruited for this study. Intervention Participants will be randomly assigned to 1 of 3 groups: the intervention (TENS), placebo, or no treatment. After completing the randomized period, all participants will receive the intervention for 1 month. The participants will be asked to use TENS at the highest tolerable level for at least 2 hours daily during physical activity. Measurements The primary outcome will be pain with movement, with secondary outcomes assessing functional abilities, patient-reported outcomes, and quantitative sensory testing. Limitations Because having participants refrain from their typical medications is not practical, their usage and any change in medication use will be recorded. Conclusions The results of this study will provide some of the first evidence from a large-scale, double-blind, placebo-controlled trial on the effectiveness of TENS on pain control and quality-of-life changes in patients with fibromyalgia. PMID:25212518
Safety and Efficacy of ABT-089 in Pediatric Attention-Deficit/Hyperactivity Disorder: Results from Two Randomized Placebo-Controlled Clinical Trials

ERIC Educational Resources Information Center

Wilens, Timothy E.; Gault, Laura M.; Childress, Ann; Kratochvil, Christopher J.; Bensman, Lindsey; Hall, Coleen M.; Olson, Evelyn; Robieson, Weining Z.; Garimella, Tushar S.; Abi-Saab, Walid M.; Apostol, George; Saltarelli, Mario D.

2011-01-01

Objective: To assess the safety and efficacy of ABT-089, a novel alpha[subscript 4]beta[subscript 2] neuronal nicotinic receptor partial agonist, vs. placebo in children with attention-deficit/hyperactivity disorder (ADHD). Method: Two multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of children 6 through 12 years…
Probiotics [LGG-BB12 or RC14-GR1] versus placebo as prophylaxis for urinary tract infection in persons with spinal cord injury [ProSCIUTTU]: a study protocol for a randomised controlled trial.

PubMed

Lee, Bonsan Bonne; Toh, Swee-Ling; Ryan, Suzanne; Simpson, Judy M; Clezy, Kate; Bossa, Laetitia; Rice, Scott A; Marial, Obaydullah; Weber, Gerard; Kaur, Jasbeer; Boswell-Ruys, Claire; Goodall, Stephen; Middleton, James; Tudehope, Mark; Kotsiou, George

2016-04-16

Urinary tract infections [UTIs] are very common in people with Spinal Cord Injury [SCI]. UTIs are increasingly difficult and expensive to treat as the organisms that cause them become more antibiotic resistant. Among the SCI population, there is a high rate of multi-resistant organism [MRO] colonisation. Non-antibiotic prevention strategies are needed to prevent UTI without increasing resistance. Probiotics have been reported to be beneficial in preventing UTIs in post-menopausal women in several in vivo and in vitro studies. The main aim of this study is to determine whether probiotic therapy with combinations of Lactobacillus reuteri RC-14 + Lactobacillus rhamnosus GR-1 [RC14-GR1] and/or Lactobacillus rhamnosus GG + Bifidobacterium BB-12 [LGG-BB12] are effective in preventing UTI in people with SCI compared to placebo. This is a multi-site randomised double-blind double-dummy placebo-controlled factorial design study conducted in New South Wales, Australia. All participants have a neurogenic bladder as a result of spinal injury. Recruitment started in April 2011. Participants are randomised to one of four arms, designed for factorial analysis of LGG-BB12 and/or RC14-GR1 v Placebo. This involves 24 weeks of daily oral treatment with RC14-GR1 + LGG-BB12, RC14-GR1 + placebo, LGG-BB12 + placebo or two placebo capsules. Randomisation is stratified by bladder management type and inpatient status. Participants are assessed at baseline, three months and six months for Short Form Health Survey [SF-36], microbiological swabs of rectum, nose and groin; urine culture and urinary catheters for subjects with indwelling catheters. A bowel questionnaire is administered at baseline and three months to assess effect of probiotics on bowel function. The primary outcome is time from randomisation to occurrence of symptomatic UTI. The secondary outcomes are change of MRO status and bowel function, quality of life and cost-effectiveness of probiotics in persons with SCI. The primary outcome will be analysed using survival analysis of factorial groups, with Cox regression modelling to test the effect of each treatment while allowing for the other, assuming no interaction effect. Hazard ratios and Kaplan-Meier survival curves will be used to summarise results. If these probiotics are shown to be effective in preventing UTI and MRO colonisation, they would be a very attractive alternative for UTI prophylaxis and for combating the increasing rate of antibiotic resistance after SCI. Australian New Zealand Clinical Trials Registry [ ACTRN 12610000512022 ]. Date of registration: 21 June 2010.
Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial

PubMed Central

Mao, Jun J.; Xie, Sharon X.; Zee, Jarcy; Soeller, Irene; Li, Qing S.; Rockwell, Kenneth; Amsterdam, Jay D.

2015-01-01

Background We performed a proof of concept trial to evaluate relative safety and efficacy of Rhodiola rosea (R. rosea) versus sertraline for mild to moderate major depressive disorder. Hypothesis We hypothesize that R. rosea would have similar therapeutic effects as sertraline but with less adverse events. Study Design Phase II randomized placebo controlled clinical trial Methods 57 subjects were randomized to 12 weeks of standardized R. rosea extract, sertraline, or placebo. Changes over time in Hamilton Depression Rating (HAM-D), Beck Depression Inventory (BDI), and Clinical Global Impression Change (CGI/C) scores among groups were examined using mixed-effects models. Results Modest, albeit statistically non-significant, reductions were observed for HAM-D, BDI, and CGI/C scores for all treatment conditions with no significant difference between groups (p=0.79, p=0.28, and p=0.17, respectively). The decline in HAM-D scores was greater for sertraline (−8.2, 95% confidence interval [CI], −12.7 to −3.6) versus R. rosea (−5.1, 95% CI: −8.8 to −1.3) and placebo (−4.6, 95% CI: −8.6 to −0.6). While the odds of improving (versus placebo) were greater for sertraline (1.90 [0.44–8.20]; odds ratio [95% CI]) than R. rosea (1.39 [0.38–5.04]), more subjects on sertraline reported adverse events (63.2%) than R. rosea (30.0%) or placebo (16.7%) (p=0.012). Conclusions Although R. rosea produced less antidepressant effect versus sertraline, it also resulted in significantly fewer adverse events and was better tolerated. These findings suggest that R. rosea, although less effective than sertraline, may possess a more favorable risk to benefit ratio for individuals with mild to moderate depression. PMID:25837277
Efficacy and safety of lesogaberan in gastro-oesophageal reflux disease: a randomised controlled trial.

PubMed

Shaheen, Nicholas J; Denison, Hans; Björck, Karin; Karlsson, Maria; Silberg, Debra G

2013-09-01

Lesogaberan (AZD3355) is a novel γ-aminobutyric acid B-type receptor agonist designed to treat gastro-oesophageal reflux disease (GERD) by inhibiting transient lower oesophageal sphincter relaxations. A randomised, double-blind, placebo-controlled, multi-centre phase IIb study was performed to assess the efficacy and safety of lesogaberan as an add-on to proton pump inhibitor (PPI) therapy in patients with GERD who are partially responsive to PPI therapy (ClinicalTrials.gov reference: NCT01005251). In total, 661 patients were randomised to receive 4 weeks of placebo or 60, 120, 180 or 240 mg of lesogaberan twice daily, in addition to ongoing PPI therapy. Symptoms were measured using the Reflux Symptom Questionnaire electronic Diary. Response to treatment was defined as having an average of ≥ 3 additional days per week of not more than mild GERD symptoms during treatment compared with baseline. In the primary analysis, 20.9%, 25.6%, 23.5% and 26.2% of patients responded to the 60, 120, 180 and 240 mg twice daily lesogaberan doses, respectively, and 17.9% responded to placebo. The response to the 240 mg twice daily dose was statistically significantly greater than the response to placebo using a one-sided test at the predefined significance level of p < 0.1. However, the absolute increases in the proportions of patients who responded to lesogaberan compared with placebo were low. Lesogaberan was generally well tolerated, although six patients receiving lesogaberan developed reversible elevated alanine transaminase levels. In patients with GERD symptoms partially responsive to PPI therapy, lesogaberan was only marginally superior to placebo in achieving an improvement in symptoms.
Effect of a traditional syrup from Citrus medica L. fruit juice on migraine headache: A randomized double blind placebo controlled clinical trial.

PubMed

Jafarpour, Mehrnaz; Yousefi, Gholamhossein; Hamedi, Azadeh; Shariat, Abdolhamid; Salehi, Alireza; Heydari, Mojtaba

2016-02-17

In Persian ethnomedicine several herbal remedies and functional foods have been used to treat migraine headache which are mostly summarized in Qarabadin-e-kabir (Aghili-Shirazi MH, 1773). One of them is Citron syrup (Sharbat-e-Balang) containing edible Citrus medica L. fruit juice and sugar. The present study was designed to assess the efficacy and safety of Citron syrup on patients with migraine headache. Citron syrup was prepared as described in Qarabadin-e-kabir. In this double blind randomized placebo-controlled clinical trial, ninety patients with migraine headache were allocated to three parallel groups (Citron syrup, propranolol or placebo). Patients received 15ml of Citron syrup, placebo syrup or 20mg of propranolol tablet three times daily after a meal for 4 weeks. Primary outcomes were obtained from three measures: the frequency (per month), mean duration (hour) and mean intensity (visual analogue scale "VAS" 0-10 score) of headache attacks evaluated prior to and following 4 weeks of the intervention. Citron syrup was superior to placebo in reduction of headache attacks intensity (P<0.01) and duration (p<0.0001) and as effective as propranolol in patients with migraine headache (P>0.05). However, unlike propranolol, Citron syrup could not significantly reduce the frequency of attacks compared to placebo. No indication of any serious side effects from Citron syrup was observed. According to obtained results, Citron syrup as a traditional Persian remedy can be suggested as an effective treatment for decreasing pain intensity and duration of attacks in migraine headache and the effectiveness is comparable to propranolol. However, the syrup did not show significant effect on frequency of attacks. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Polyethylene glycol 3350 plus electrolytes for chronic constipation in children: a double blind, placebo controlled, crossover study

PubMed Central

Thomson, M A; Jenkins, H R; Bisset, W M; Heuschkel, R; Kalra, D S; Green, M R; Wilson, D C; Geraint, M

2007-01-01

Objectives To assess the efficacy and safety of polyethylene glycol 3350 plus electrolytes (PEG+E) for the treatment of chronic constipation in children. Design Randomised, double blind, placebo controlled crossover trial, with two 2‐week treatment periods separated by a 2‐week placebo washout. Setting Six UK paediatric departments. Participants 51 children (29 girls, 22 boys) aged 24 months to 11 years with chronic constipation (lasting ⩾3 months), defined as ⩽2 complete bowel movements per week and one of the following: pain on defaecation on 25% of days; ⩾25% of bowel movements with straining; ⩾25% of bowel movements with hard/lumpy stools. 47 children completed the double blind treatment. Main outcome measures Number of complete defaecations per week (primary efficacy variable), total number of complete and incomplete defaecations per week, pain on defaecation, straining on defaecation, faecal incontinence, stool consistency, global assessment of treatment, adverse events and physical examination. Results The mean number of complete defaecations per week was significantly higher for children on PEG+E than on placebo (3.12 (SD 2.05) v 1.45 (SD 1.20), respectively; p<0.001). Further significant differences in favour of PEG+E were observed for total number of defaecations per week (p = 0.003), pain on defaecation (p = 0.041), straining on defaecation (p<0.001), stool consistency (p<0.001) and percentage of hard stools (p = 0.001). Treatment related adverse events (all mild or moderate) occurred in similar numbers of children on PEG+E (41%) and placebo during treatment (45%). Conclusions PEG+E is significantly more effective than placebo, and appears to be safe and well tolerated in the treatment of chronic constipation in children. PMID:17626140

Chronic consumption of a low calorie, high polyphenol cranberry beverage attenuates inflammation and improves glucoregulation and HDL cholesterol in healthy overweight humans: a randomized controlled trial.

PubMed

Chew, Boon; Mathison, Bridget; Kimble, Lindsey; McKay, Diane; Kaspar, Kerrie; Khoo, Christina; Chen, C-Y Oliver; Blumberg, Jeffrey

2018-02-23

We studied the health benefits of low calorie cranberry beverage consumption on glucoregulation, oxidative damage, inflammation, and lipid metabolism in overweight but otherwise healthy humans. 78 overweight or obese men and women (30-70 years; BMI 27-35 kg/m 2 ) with abdominal adiposity (waist: hip > 0.8 for women and > 0.9 for men; waist: height ≥ 0.5) consumed 450 mL placebo or low calorie, high polyphenol cranberry extract beverage (CEB) daily for 8 week in a randomized, double-blind, placebo-controlled, parallel design trial. Blood and urine samples were collected after overnight fast at baseline and after 8 weeks of daily beverage consumption. Blood and urine samples were also collected during 3 oral glucose tolerance test (OGTT) challenges: (1) pre-intervention without the test beverages, (2) following a single dose of placebo or CEB at baseline (week 0), and (3) following a single dose of placebo or CEB at 8 week. Compared to placebo, a single CEB dose at baseline lowered endothelin-1 and elevated nitric oxide and the reduced:oxidized glutathione ratio (P < 0.05). Interferon-γ was elevated (P < 0.05) after a single CEB dose at baseline; however, after 8 week of CEB intervention, fasting C-reactive protein was lower (P < 0.05). CEB consumption for 8 week also reduced serum insulin and increased HDL cholesterol compared to placebo (P < 0.05). An acute dose of low calorie, high polyphenol cranberry beverage improved antioxidant status, while 8 week daily consumption reduced cardiovascular disease risk factors by improving glucoregulation, downregulating inflammatory biomarkers, and increasing HDL cholesterol.
Consistent and significant improvement of nighttime voiding frequency (nocturia) with silodosin in men with LUTS suggestive of BPH: pooled analysis of three randomized, placebo-controlled, double-blind phase III studies.

PubMed

Eisenhardt, Andreas; Schneider, Tim; Cruz, Francisco; Oelke, Matthias

2014-10-01

Nocturia is prevalent and bothersome in men with lower urinary tract symptoms suggestive of BPH (LUTS/BPH). α-Adrenoceptor antagonists without subtype selectivity have inconsistently shown significant effects on nocturia in these patients. We explored the effects of the α1A-adrenoceptor subtype-selective antagonist silodosin on nocturia by analyzing three placebo-controlled registration studies. Responses to question 7 of the IPSS questionnaire were analyzed for the entire study population and patients with ≥ 2 voids/night at baseline. Improvement/worsening rates for nocturia were calculated for once-daily silodosin 8 mg and placebo. Silodosin effects on the mean number of nocturnal voids were compared with placebo, and the number of patients in whom nocturia was reduced to <2 times was calculated. In total, 1,479 men were treated with silodosin or placebo; 1,266 men (85 %) had ≥ 2 voids/night at baseline. Compared to placebo, more men treated with silodosin reported about nocturia improvement (53.4 vs. 42.8 %, p < 0.0001) and fewer patients about worsening (9.0 vs. 14.3 %, p < 0.0001). Silodosin significantly reduced nocturia within each study and pooled cohort compared to placebo (p < 0.001). In men with ≥ 2 nocturnal voids at baseline, 61 and 49 % of patients with silodosin and placebo had reductions of ≥ 1 voids/night, respectively (p = 0.0003), and significantly more patients with silodosin had <2 nocturia episodes at study end compared to placebo (29.3 vs. 19.0 %; p = 0.0002). Although a weak impact on nocturia is already known from α-adrenoceptor antagonists without subtype selectivity, the individual placebo-controlled studies and the pooled data analysis showed that the α1A-adrenoceptor subtype-selective antagonist silodosin consistently and significantly improves nocturia in men with LUTS/BPH.
A Preliminary Study for Evaluating the Dose-Dependent Effect of d-Allulose for Fat Mass Reduction in Adult Humans: A Randomized, Double-Blind, Placebo-Controlled Trial.

PubMed

Han, Youngji; Kwon, Eun-Young; Yu, Mi Kyeong; Lee, Seon Jeong; Kim, Hye-Jin; Kim, Seong-Bo; Kim, Yang Hee; Choi, Myung-Sook

2018-01-31

d-allulose is a rare sugar with zero energy that can be consumed by obese/overweight individuals. Many studies have suggested that zero-calorie d-allulose has beneficial effects on obesity-related metabolism in mouse models, but only a few studies have been performed on human subjects. Therefore, we performed a preliminary study with 121 Korean subjects (aged 20-40 years, body mass index ≥ 23 kg/m²). A randomized controlled trial involving placebo control (sucralose, 0.012 g × 2 times/day), low d-allulose (d-allulose, 4 g × 2 times/day), and high d-allulose (d-allulose, 7 g × 2 times/day) groups was designed. Parameters for body composition, nutrient intake, computed tomography (CT) scan, and plasma lipid profiles were assessed. Body fat percentage and body fat mass were significantly decreased following d-allulose supplementation. The high d-allulose group revealed a significant decrease in not only body mass index (BMI), but also total abdominal and subcutaneous fat areas measured by CT scans compared to the placebo group. There were no significant differences in nutrient intake, plasma lipid profiles, markers of liver and kidney function, and major inflammation markers among groups. These results provide useful information on the dose-dependent effect of d-allulose for overweight/obese adult humans. Based on these results, the efficacy of d-allulose for body fat reduction needs to be validated using dual energy X-ray absorption.
Oral lysine clonixinate in the acute treatment of migraine: a double-blind placebo-controlled study.

PubMed

Krymchantowski, A V; Barbosa, J S; Cheim, C; Alves, L A

2001-03-01

Several oral nonsteroidal anti-inflammatory drugs (NSAIDs) are effective to treat migraine attacks. Lysine clonixinate (LC) is a NSAID derived from nicotinic acid that has proven to be effective in various pain syndromes such as renal colic and muscular pain. The aim of this double-blind, placebo-controlled study was to evaluate the efficacy of oral LC compared to placebo in the acute treatment of migraine. Sixty four patients with the diagnosis of migraine, according to the IHS criteria, were studied prospectively. Patients received LC or placebo once the headache reached moderate or severe intensity for 6 consecutive attacks. With regard to the moderate attacks, LC was superior than placebo after 1, 2 and 4 hours. The consumption of other rescue medications after 4 hours was significantly higher in the placebo group. With regard to the severe attacks, there was no difference between the active drug group and the placebo group concerning headache intensity and consumption of other rescue medications. We conclude that the NSAID lysine clonixinate is effective in treating moderately severe migraine attacks. It is not superior than placebo in treating severe migraine attacks.
A randomized, double blind, cross-over, placebo-controlled clinical trial to assess the effects of Candesartan on the insulin sensitivity on non diabetic, non hypertense subjects with dysglyce mia and abdominal obesity. "ARAMIA"

PubMed Central

López-Jaramillo, Patricio; Pradilla, Lina P; Lahera, Vicente; Sieger, Federico A Silva; Rueda-Clausen, Christian F; Márquez, Gustavo A

2006-01-01

Background The raising prevalence of type-2 diabetes mellitus and obesity has been recognized as a major problem for public health, affecting both developed and developing countries. Impaired fasting plasma glucose has been previously associated with endothelial dysfunction, higher levels of inflammatory markers and increased risk of developing insulin resistance and cardiovascular events. Besides life-style changes, the blockade of the renin-angiotensin system has been proposed as a useful alternative intervention to improve insulin resistance and decrease the number of new type-2 diabetes cases. The aim of this clinical trial is to study the effect of the treatment with Candesartan, an angiotensin II receptor antagonist, on the insulin resistance, the plasma levels of adipoquines, oxidative stress and prothrombotic markers, in a group of non diabetic, non hypertensive, dysglycemic and obese subjects. Methods and design A randomized, double blind, cross-over, placebo-controlled, clinical trial was designed to assess the effects of Candesartan (up to 32 mg/day during 6 months) on the Homeostasis Model Assessment (HOMA) index, lipid profile, protrombotic state, oxidative stress and plasma levels of inflammatory markers. The participants will be recruited in the "Fundación Cardiovascular de Colombia". Subjects who fullfil selection criteria will receive permanent educational, nutritional and exercise support during their participation in the study. After a 15 days-run-in period with placebo and life-style recommendations, the patients who have a treatment compliance equal or greater than 80% will be randomlly assigned to one of the treatment groups. Group A will receive Candesartan during 6 months and placebo during 6 months. Group B will receive placebo during the first 6 months, and then, Candesartan during the last 6 months. Control visits will be programed monthly and all parameters of interest will be evaluated every 6 months. Hypothesis Treatment with Candesartan, could improve the HOMA index, the response to the oral glucose tolerance test and reduce the plasma levels of adipoquines, oxidative stress and prothrombotic markers, in non diabetic, non hypertense subjects with dysglycemia and abdominal obesity, recruited from a population at high risk of developing insulin resistance. These effects are independent of the changes in arterial blood pressure. Trial registration: NCT00319202 PMID:16959033
Randomized study of placebo and framing information in direct-to-consumer print advertisements for prescription drugs.

PubMed

O'Donoghue, Amie C; Sullivan, Helen W; Aikin, Kathryn J

2014-12-01

Research suggests that quantitative information in direct-to-consumer (DTC) prescription drug ads may be helpful for consumers. The objective was to examine the effect of adding placebo rates and framing to DTC ads. In study 1, 2,000 Internet panel members with chronic pain participated in a randomized controlled experiment of DTC ads varying in placebo rate and framing. In study 2, 596 physicians ranked DTC ads varying in placebo rate and framing by how well they conveyed scientific information and their usefulness for patients. In study 1, participants who viewed placebo rates were able to recall them and use them to form certain perceptions. A mixed frame led to lower placebo rate recall and perceived efficacy. In study 2, overall, physicians preferred a placebo/single frame ad. Adding placebo rates to DTC ads may be useful for consumers. The evidence does not support using a mixed frame.
Can sequential parallel comparison design and two-way enriched design be useful in medical device clinical trials?

PubMed

Ivanova, Anastasia; Zhang, Zhiwei; Thompson, Laura; Yang, Ying; Kotz, Richard M; Fang, Xin

2016-01-01

Sequential parallel comparison design (SPCD) was proposed for trials with high placebo response. In the first stage of SPCD subjects are randomized between placebo and active treatment. In the second stage placebo nonresponders are re-randomized between placebo and active treatment. Data from the population of "all comers" and the subpopulations of placebo nonresponders then combined to yield a single p-value for treatment comparison. Two-way enriched design (TED) is an extension of SPCD where active treatment responders are also re-randomized between placebo and active treatment in Stage 2. This article investigates the potential uses of SPCD and TED in medical device trials.
A Randomized Placebo Controlled Trial Of Hypericum perforatum For Attention Deficit Hyperactivity Disorder In Children And Adolescents

PubMed Central

Weber, Wendy; Stoep, Ann Vander; McCarty, Rachelle L.; Weiss, Noel S.; Biederman, Joseph; McClellan, Jon

2008-01-01

Context Stimulant medication can effectively treat 60–70% of youth with attention deficit hyperactivity disorder. Yet, many parents seek out alternative therapies, and Hypericum perforatum is one of the top three botanicals used. Objective To determine the efficacy and safety of Hypericum perforatum for the treatment of attention deficit hyperactivity disorder in children. Design, Setting, and Participants A randomized double-blind placebo-controlled trial of 54 children was conducted between March 2005 and August 2006 at Bastyr University. A volunteer sample of children aged 6–17 years met DSM-IV criteria for attention deficit hyperactivity disorder by structured interview. Other medications for ADHD were not allowed during the trial. One patient in the placebo group withdrew due to an adverse event. Intervention Participants were randomized to receive 300 mg of Hypericum perforatum or a matched placebo three times daily for eight weeks. Main Outcome Measures ADHD Rating Scale-IV (0 to 54), Clinical Global Impression scales for Improvement and Severity (0 to 7), and adverse events Results No significant difference in the change of ADHD Rating Scale-IV score from baseline to week 8 was found between treatment and placebo groups (inattention improved 2.6 points Hypericum (95% CI −4.6 to −0.6) vs. 3.2 points placebo (95% CI −5.7 to −0.8), p = 0.68; hyperactivity improved 1.8 points Hypericum (95% CI −3.7 to 0.04) vs. 2.0 points placebo (95% CI −4.1 to 0.1), p = 0.89). There was also no significant difference between groups in the proportion of participants who met criteria for improvement (score of 2 or less) on the Clinical Global Impression Improvement Scale (Hypericum 44.4% (95% CI 25.5 to 64.7) vs. placebo 51.9% (95% CI 31.9 to 71.3), p = 0.59). No difference between groups was found in the number of participants who experienced adverse effects during the study period (Hypericum 40.7% (95% CI 22.4 to 61.2) vs. placebo 44.4% (95% CI 25.5 to 64.7), p = 0.78). Conclusions In this study, use of Hypericum perforatum for the treatment of attention deficit hyperactivity disorder over the course of eight weeks did not improve symptoms. PMID:18544723
Dietary nitrate improves vascular function in patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled study123

PubMed Central

Velmurugan, Shanti; Gan, Jasmine Ming; Rathod, Krishnaraj S; Khambata, Rayomand S; Ghosh, Suborno M; Hartley, Amy; Van Eijl, Sven; Sagi-Kiss, Virag; Chowdhury, Tahseen A; Curtis, Mike; Kuhnle, Gunter GC; Wade, William G; Ahluwalia, Amrita

2016-01-01

Background: The beneficial cardiovascular effects of vegetables may be underpinned by their high inorganic nitrate content. Objective: We sought to examine the effects of a 6-wk once-daily intake of dietary nitrate (nitrate-rich beetroot juice) compared with placebo intake (nitrate-depleted beetroot juice) on vascular and platelet function in untreated hypercholesterolemics. Design: A total of 69 subjects were recruited in this randomized, double-blind, placebo-controlled parallel study. The primary endpoint was the change in vascular function determined with the use of ultrasound flow-mediated dilatation (FMD). Results: Baseline characteristics were similar between the groups, with primary outcome data available for 67 patients. Dietary nitrate resulted in an absolute increase in the FMD response of 1.1% (an ∼24% improvement from baseline) with a worsening of 0.3% in the placebo group (P < 0.001). A small improvement in the aortic pulse wave velocity (i.e., a decrease of 0.22 m/s; 95% CI: −0.4, −0.3 m/s) was evident in the nitrate group, showing a trend (P = 0.06) to improvement in comparison with the placebo group. Dietary nitrate also caused a small but significant reduction (7.6%) in platelet-monocyte aggregates compared with an increase of 10.1% in the placebo group (P = 0.004), with statistically significant reductions in stimulated (ex vivo) P-selectin expression compared with the placebo group (P < 0.05) but no significant changes in unstimulated expression. No adverse effects of dietary nitrate were detected. The composition of the salivary microbiome was altered after the nitrate treatment but not after the placebo treatment (P < 0.01). The proportions of 78 bacterial taxa were different after the nitrate treatment; of those taxa present, 2 taxa were responsible for >1% of this change, with the proportions of Rothia mucilaginosa trending to increase and Neisseria flavescens (P < 0.01) increased after nitrate treatment relative to after placebo treatment. Conclusions: Sustained dietary nitrate ingestion improves vascular function in hypercholesterolemic patients. These changes are associated with alterations in the oral microbiome and, in particular, nitrate-reducing genera. Our findings provide additional support for the assessment of the potential of dietary nitrate as a preventative strategy against atherogenesis in larger cohorts. This trial was registered at clinicaltrials.gov as NCT01493752. PMID:26607938
Reduction of body fat and improved lipid profile associated with daily consumption of a Puer tea extract in a hyperlipidemic population: a randomized placebo-controlled trial

PubMed Central

Jensen, Gitte S; Beaman, Joni L; He, Yi; Guo, Zhixin; Sun, Henry

2016-01-01

Objective The goal for this study was to evaluate the effects of daily consumption of Puer tea extract (PTE) on body weight, body-fat composition, and lipid profile in a non-Asian population in the absence of dietary restrictions. Materials and methods A randomized, double-blind, placebo-controlled study design was used. A total of 59 overweight or mildly obese subjects were enrolled upon screening to confirm fasting cholesterol level at or above 220 mg/dL (5.7 mmol/dL). After giving informed consent, subjects were randomized to consume PTE (3 g/day) or placebo for 20 weeks. At baseline and at 4-week intervals, blood lipids, C-reactive protein, and fasting blood glucose were evaluated. A dual-energy X-ray absorptiometry scan was performed at baseline and at study exit to evaluate changes to body composition. Appetite and physical and mental energy were scored at each visit using visual analog scales (0–100). Results Consumption of PTE was associated with statistically significant weight loss when compared to placebo (P<0.05). Fat loss was seen for arms, legs, and the gynoid region (hip/belly), as well as for total fat mass. The fat reduction reached significance on within-group analysis, but did not reach between-group significance. Consumption of PTE was associated with improvements to lipid profile, including a mild reduction in cholesterol and the cholesterol:high-density lipoprotein ratio after only 4 weeks, as well as a reduction in triglycerides and very small-density lipoproteins, where average blood levels reached normal range at 8 weeks and remained within normal range for the duration of the study (P<0.08). No significant changes between the PTE group and the placebo group were seen for fasting glucose or C-reactive protein. A transient reduction in appetite was seen in the PTE group when compared to placebo (P<0.1). Conclusion The results from this clinical study showed that the daily consumption of PTE was associated with significant weight loss, reduced body mass index, and an improved lipid profile. PMID:27069360
Efficacy of maropitant in the prevention of delayed vomiting associated with administration of doxorubicin to dogs.

PubMed

Rau, S E; Barber, L G; Burgess, K E

2010-01-01

Vomiting, nausea, inappetence, and diarrhea are common delayed adverse effects of doxorubicin. Maropitant, a neurokinin-1 receptor antagonist, is known to prevent acute vomiting in dogs receiving cisplatin. To evaluate the efficacy of maropitant in preventing delayed vomiting after administration of doxorubicin to dogs. Fifty-nine dogs with cancer. This randomized, double-blind, placebo-controlled study used a cross-over design. Dogs were randomized into 1 of 2 treatment groups. Group A received maropitant after the 1st doxorubicin, and placebo after the 2nd. Group B received placebo first, and maropitant second. Maropitant (2 mg/kg) or placebo tablets were administered PO for 5 days after doxorubicin treatment. Owners completed visual analog scales based on Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events to grade their pet's clinical signs during the week after administration of doxorubicin. Statistical differences in gastrointestinal toxicosis and myelosuppression between maropitant and placebo treatments were evaluated. Significantly fewer dogs had vomiting (P=.001) or diarrhea (P=.041), and the severity of vomiting (P<.001) and diarrhea (P=.024) was less the week after doxorubicin when receiving maropitant compared with placebo. No differences were found between maropitant and placebo for other gastrointestinal and bone marrow toxicoses. Maropitant is effective in preventing delayed vomiting induced by doxorubicin. Its prophylactic use might improve quality of life and decrease the need for dose reductions in certain dogs. Copyright © 2010 by the American College of Veterinary Internal Medicine.
Hydrocortisone Cream to Reduce Perineal Pain after Vaginal Birth: A Randomized Controlled Trial.

PubMed

Manfre, Margaret; Adams, Donita; Callahan, Gloria; Gould, Patricia; Lang, Susan; McCubbins, Holly; Mintz, Amy; Williams, Sommer; Bishard, Mark; Dempsey, Amy; Chulay, Marianne

2015-01-01

To determine if the use of hydrocortisone cream decreases perineal pain in the immediate postpartum period. This was a randomized controlled trial (RCT), crossover study design, with each participant serving as their own control. Participants received three different methods for perineal pain management at three sequential perineal pain treatments after birth: two topical creams (corticosteroid; placebo) and a control treatment (no cream application). Treatment order was randomly assigned, with participants and investigators blinded to cream type. The primary dependent variable was the change in perineal pain levels (posttest minus pretest pain levels) immediately before and 30 to 60 minutes after perineal pain treatments. Data were analyzed with analysis of variance, with p < 0.05 considered significant. A total of 27 participants completed all three perineal pain treatments over a 12-hour period. A reduction in pain was found after application of both the topical creams, with average perineal pain change scores of -4.8 ± 8.4 mm after treatment with hydrocortisone cream (N = 27) and -6.7 ± 13.0 mm after treatment with the placebo cream (N = 27). Changes in pain scores with no cream application were 1.2 ± 10.5 mm (N = 27). Analysis of variance found a significant difference between treatment groups (F2,89 = 3.6, p = 0.03), with both cream treatments having significantly better pain reduction than the control, no cream treatment (hydrocortisone vs. no cream, p = 0.04; placebo cream vs. no cream, p = 0.01). There were no differences in perineal pain reduction between the two cream treatments (p = .54). This RCT found that the application of either hydrocortisone cream or placebo cream provided significantly better pain relief than no cream application.
Effects of Botanicals and Combined Hormone Therapy on Cognition in Postmenopausal Women

PubMed Central

Maki, Pauline M.; Rubin, Leah H.; Fornelli, Deanne; Drogos, Lauren; Banuvar, Suzanne; Shulman, Lee P.; Geller, Stacie E.

2009-01-01

Objective To characterize the effects of red clover, black cohosh, and combined hormone therapy on cognitive function in comparison to placebo in women with moderate to severe vasomotor symptoms. Design In a Phase II randomized, double-blind, placebo-controlled study, 66 midlife women (out of 89 from a parent study; mean age=53 y) with ≥ 35 weekly hot flashes were randomized to receive red clover (120 mg), black cohosh (128 mg), CEE/MPA (0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate), or placebo. Participants completed measures of verbal memory (primary outcome) and other cognitive measures (secondary outcomes) before and during the 12th treatment month. A subset of 19 women completed objective, physiological measures of hot flashes using ambulatory skin conductance monitors. Results There was no impact of either of the botanical treatments on any cognitive measure. Compared to placebo, CEE/MPA led to greater decline in verbal learning (one of five verbal memory measures). This effect just missed statistical significance (p=0.057) in unadjusted analyses, but reached significance (p=.02) after adjusting for vasomotor symptoms. Neither botanical treatment group showed a change in verbal memory that differed from the placebo group (ps>0.28), even after controlling for improvements in hot flashes. In secondary outcomes, CEE/MPA led to a decrease in immediate digit recall and an improvement in letter fluency. Only CEE/MPA significantly reduced objective hot flashes. Conclusions Results indicate no effects of a red clover (phytoestrogen) supplement or black cohosh on cognitive function. CEE/MPA reduces objective hot flashes but worsens some aspects of verbal memory. PMID:19590458
Lamotrigine Augmentation Versus Placebo in Serotonin Reuptake Inhibitors-Resistant Obsessive-Compulsive Disorder: A Randomized Controlled Trial

PubMed Central

Khalkhali, Mohammadrasoul; Zarrabi, Homa; Kafie, Moosa; Heidarzadeh, Abtin

2016-01-01

Objective: Serotonin reuptake inhibitors are frequently used in first-line treatments for patients with obsessive-compulsive disorder. Nevertheless, many of these patients do not respond well to initial therapy. The hypothesis of glutamatergic dysfunction in specific brain regions has been proposed in the pathophysiology of obsessive-compulsive disorder. This study was designed to evaluate the possible efficacy of lamotrigine, a glutamatergic agent in Serotonin reuptake inhibitors-resistant patients with obsessive-compulsive disorder. Method: This study was a 12-week, double blind, randomized, placebo-controlled trial of adjunctive fixed-doses of lamotrigine (100 mg) to Serotonin reuptake inhibitors therapy in obsessive-compulsive disorder. Eligible subjects who had a total Y-BOCS of 21 or above were randomly assigned to receive adjunctive treatment with either lamotrigine (n = 26), or placebo (n = 27). Response to lamotrigine was defined as clinical improvement (>25% decrease in the total Y-BOCS score), which was administered at weeks 0, 8 and 12. Results: At the endpoint (week 12), significant differences were observed in obsession, compulsion, and total Y-BOCS scores comparing lamotrigine to placebo (P = 0.01, 0.005 and 0.007 respectively). The mean reduction in obsession, compulsion and total scores in lamotrigine group was about 4.15, 4.50 and 8.73, respectively. Similarly, the mean reductions in the placebo group were 2.52, 2.56 and 5.07. Effect sizes for efficacy measureswerecalculatedbyCohen’sd, and it was calculated as 0.54 for the total YBOCS. Conclusion: Our findings provide evidence that this augmentation is well tolerated and may be an effective strategy for patients with refractory obsessive-compulsive disorder. PMID:27437007
Effect of an herbal/botanical supplement on strength, balance, and muscle function following 12-weeks of resistance training: a placebo controlled study

PubMed Central

2014-01-01

Background StemSport (SS; StemTech International, Inc. San Clemente, CA) contains a proprietary blend of the botanical Aphanizomenon flos-aquae and several herbal antioxidant and anti-inflammatory substances. SS has been purported to accelerate tissue repair and restore muscle function following resistance exercise. Here, we examine the effects of SS supplementation on strength adaptations resulting from a 12-week resistance training program in healthy young adults. Methods Twenty-four young adults (16 males, 8 females, mean age = 20.5 ± 1.9 years, mass = 70.9 ± 11.9 kg, stature = 176.6 ± 9.9 cm) completed the twelve week training program. The study design was a double-blind, placebo controlled parallel group trial. Subjects either received placebo or StemSport supplement (SS; mg/day) during the training. 1-RM bench press, 1-RM leg press, vertical jump height, balance (star excursion and center of mass excursion), isokinetic strength (elbow and knee flexion/extension) and perception of recovery were measured at baseline and following the 12-week training intervention. Results Resistance training increased 1-RM strength (p < 0.008), vertical jump height (p < 0.03), and isokinetic strength (p < 0.05) in both SS and placebo groups. No significant group-by-time interactions were observed (all p-values >0.10). Conclusions These data suggest that compared to placebo, the SS herbal/botanical supplement did not enhance training induced adaptations to strength, balance, and muscle function above strength training alone. PMID:24910543
Modafinil effects on cognitive function in HIV+ patients treated for fatigue: a placebo controlled study.

PubMed

McElhiney, Martin; Rabkin, Judith; Van Gorp, Wilfred; Rabkin, Richard

2010-06-01

Both mild cognitive impairment and fatigue are common among people with HIV/AIDS. This study examined the efficacy of modafinil for HIV+ patients who sought treatment for fatigue in a placebo-controlled double-blind 4-week trial. A battery of standard neuropsychological tests was administered at study entry and Week 4, and change in performance was compared for 59 patients receiving modafinil versus 44 patients receiving placebo. A significant effect on fatigue was observed. In addition, cognitive performance, as measured by a global change score, improved more in the modafinil than in the placebo group although the effect was not specific to any cognitive domain.
Acute effects of betahistine hydrochloride on food intake and appetite in obese women: a randomized, placebo-controlled trial1234

PubMed Central

Ali, Asem H; Yanoff, Lisa B; Stern, Elizabeth A; Akomeah, Abena; Courville, Amber; Kozlosky, Merel; Brady, Sheila M; Calis, Karim A; Reynolds, James C; Crocker, Melissa K; Barak, Nir; Yanovski, Jack A

2010-01-01

Background: Central nervous system histaminergic tone is thought to play a role in appetite regulation. In animal models, histamine receptor 1 (HRH1) agonists and histamine receptor 3 (HRH3) antagonists decrease food intake. Objective: The objective of this study was to examine the acute effects of betahistine hydrochloride (an HRH1 agonist and HRH3 antagonist) on food intakes and appetites. Design: The study was a proof-of-concept, randomized, double-blinded, placebo-controlled, dose-ranging study performed to examine the effects of betahistine in women with class I or II obesity [body mass index (BMI; in kg/m2) of 30–39.99]. After a 24-h placebo run-in period, subjects received a placebo (n = 19) or 48 (n = 19), 96 (n = 17), or 144 (n = 21) mg betahistine/d for 24 h. Treatment was followed by a buffet test meal to assess energy intake. Hunger, satiety, and desire to eat were measured after consuming the meal by using visual analog scales. Data were analyzed by using regression models with the assumption that there would be an increasing effect of betahistine doses. Analyses were adjusted for age, log fat and lean mass, food preferences, and intake during a buffet test meal obtained during the placebo run-in period. Results: Of the 79 obese women (mean ± SD age: 42 ± 11 y; BMI: 35 ± 3) enrolled in the study, 76 women completed the study. The betahistine dose did not significantly change intakes from those observed during the run-in period of the buffet test meal (P = 0.78). Hunger, fullness, and desire to eat (all P > 0.62) similarly showed no differences according to the betahistine dose. Conclusions: Betahistine did not produce an effect on food intakes or appetites. More potent histaminergic modulators may be required to elucidate the possible role of histaminergic pathways in human obesity. This trial was registered at clinicaltrials.gov as NCT00459992 PMID:20881066
Sibutramine promotes amygdala activity under fasting conditions in obese women.

PubMed

Oltmanns, Kerstin M; Heldmann, Marcus; Daul, Susanne; Klose, Silke; Rotte, Michael; Schäfer, Michael; Heinze, Hans-Jochen; Münte, Thomas F; Lehnert, Hendrik

2012-06-01

Sibutramine, a centrally-acting selective monoamine reuptake inhibitor, has been used as an appetite suppressant drug in obesity. To gain insight into the central nervous actions of sibutramine, brain responses to pictures of food items after sibutramine vs placebo application were assessed by functional magnetic resonance imaging (fMRI) in obese women. In a randomized double-blind crossover design, 10 healthy obese women (BMI 31.8-39.9 kg/m(2)) received 15 mg/d of sibutramine vs placebo for 14 d. Obese participants, and a group of 10 age-matched normal weight controls, viewed pictures of food items and control objects in hungry and satiated states while lying in the MR scanner. The paradigm followed a block design. In obese participants, fMRI measurements were conducted prior and after two weeks of daily sibutramine or placebo administration, whereas control participants were scanned only at one point in time. Upon food item presentation, obese participants showed increased brain activity in areas related to emotional and reward processing, perceptual processing, and cognitive control as compared to normal weight controls. Sibutramine exerted a divergent satiety-dependent effect on amygdala activity in obese participants, increasing activity in the hungry state while decreasing it under conditions of satiation. Our results demonstrate a modulatory influence of sibutramine on amygdala activity in obese women which may underlie the appetite suppressant effects of the drug.
Group-sequential three-arm noninferiority clinical trial designs

PubMed Central

Ochiai, Toshimitsu; Hamasaki, Toshimitsu; Evans, Scott R.; Asakura, Koko; Ohno, Yuko

2016-01-01

We discuss group-sequential three-arm noninferiority clinical trial designs that include active and placebo controls for evaluating both assay sensitivity and noninferiority. We extend two existing approaches, the fixed margin and fraction approaches, into a group-sequential setting with two decision-making frameworks. We investigate the operating characteristics including power, Type I error rate, maximum and expected sample sizes, as design factors vary. In addition, we discuss sample size recalculation and its’ impact on the power and Type I error rate via a simulation study. PMID:26892481
The effect of vitamin-mineral supplementation on juvenile delinquency among American schoolchildren: a randomized, double-blind placebo-controlled trial.

PubMed

Schoenthaler, S J; Bier, I D

2000-02-01

Numerous studies conducted in juvenile correctional institutions have reported that violence and serious antisocial behavior have been cut almost in half after implementing nutrient-dense diets that are consistent with the World Health Organization's guidelines for fats, sugar, starches, and protein ratios. Two controlled trials tested whether the cause of the behavioral improvements was psychological or biological in nature by comparing the behavior of offenders who either received placebos or vitamin-mineral supplements designed to provide the micronutrient equivalent of a well-balanced diet. These randomized trials reported that institutionalized offenders, aged 13 to 17 years or 18 to 26 years, when given active tablets produced about 40% less violent and other antisocial behavior than the placebo controls. However, generalization could not be made to typical schoolchildren without a controlled trial examining violence and antisocial behavior in public schools. To determine if schoolchildren, aged 6 to 12 years, who are given low dose vitamin-mineral tablets will produce significantly less violence and antisocial behavior in school than classmates who are given placebos. A stratified randomized, double-blind, placebo-controlled trial with pretest and post-test measures of antisocial behavior on school property. Two "working class," primarily Hispanic elementary schools in Phoenix, Arizona. Approximately half of the potential schoolchildren participated, i.e., 468 students aged 6 to 12 years. Daily vitamin-mineral supplementation at 50% of the U.S. recommended daily allowance (RDA) for 4 months versus placebo. The supplement was designed to raise vitamin-mineral intake up to the levels currently recommended by the National Academy of Sciences for children aged 6 to 11 years. Violent and nonviolent delinquency as measured by official school disciplinary records. Of the 468 students randomly assigned to active or placebo tablets, the 80 who were disciplined at least once between September 1st and May 1st served as the research sample. During intervention, the 40 children who received active tablets were disciplined, on average, 1 time each, a 47% lower mean rate of antisocial behavior than the 1.875 times each for the 40 children who received placebos (95% confidence interval, 29% to 65%, < 5 .020). The children who took active tablets produced lower rates of antisocial behavior in 8 types of recorded infractions: threats/fighting, vandalism, being disrespectful, disorderly conduct, defiance, obscenities, refusal to work or serve, endangering others, and nonspecified offenses. Poor nutritional habits in children that lead to low concentrations of water-soluble vitamins in blood, impair brain function and subsequently cause violence and other serious antisocial behavior. Correction of nutrient intake, either through a well-balanced diet or low-dose vitamin-mineral supplementation, corrects the low concentrations of vitamins in blood, improves brain function and subsequently lowers institutional violence and antisocial behavior by almost half. This paper adds to the literature by enabling previous research to be generalized from older incarcerated subjects with a history of antisocial behavior to a normal population of younger children in an educational setting.

Efficacy of dexpanthenol in skin protection against irritation: a double-blind, placebo-controlled study.

PubMed

Biro, Kathrin; Thaçi, Diamant; Ochsendorf, Falk R; Kaufmann, Roland; Boehncke, Wolf-Henning

2003-08-01

Dexpanthenol is popular in treating various dermatoses and in skin care, but few controlled clinical trials have been performed. We investigated the efficacy of dexpanthenol in skin protection against irritation in a randomized, prospective, double-blind, placebo-controlled study. 25 healthy volunteers (age 18-45 years) were treated for the inner aspect of both forearms with either Bepanthol Handbalsam containing 5% dexpanthenol or placebo x2 daily for 26 days. From day 15-22, sodium lauryl sulfate (SLS) 2% was applied to these areas x2 daily. Documentation comprised sebumetry, corneometry, pH value and clinical appearance (photographs). 21 volunteers completed the study, 3 were excluded because of non-compliance and 1 experienced a non-study-related, severe, adverse event. Only corneometry yielded a statistically significant difference, with decreased values following SLS challenge at the placebo sites (P < 0.05). Intraindividual comparisons showed superior results at the dexpanthenol-treated sites in 11 cases and in only 1 case at the placebo site. 6 volunteers experienced an irritant contact dermatitis, with more severe symptoms at the placebo site in 5 cases. In conclusion, dexpanthenol exhibits protective effects against skin irritation. The initiation of a study to evaluate the efficacy of dexpanthenol in preventing irritant occupational contact dermatitis under real workplace conditions is validated.
Suspected Nonceliac Gluten Sensitivity Confirmed in Few Patients After Gluten Challenge in Double-Blind, Placebo-Controlled Trials.

PubMed

Molina-Infante, Javier; Carroccio, Antonio

2017-03-01

A double-blind, placebo-controlled, gluten challenge has been proposed to confirm a diagnosis of nonceliac gluten sensitivity (NCGS) in patients without celiac disease who respond to a gluten-free diet. To determine the accuracy of this approach, we analyzed data from 10 double-blind, placebo-controlled, gluten-challenge trials, comprising 1312 adults. The studies varied in the duration of the challenge (range, 1 d to 6 wk), daily doses for the gluten challenge (range, 2-52 g; 3 studies administered <8 g/d), and composition of the placebo (gluten-free products, xylose, whey protein, rice, or corn starch containing fermentable carbohydrates). Most of the studies found gluten challenge to significantly increase symptom scores compared with placebo. However, only 38 of 231 NCGS patients (16%) showed gluten-specific symptoms. Furthermore, 40% of these subjects had a nocebo response (similar or increased symptoms in response to placebo). These findings reveal heterogeneity and potential methodology flaws among studies of gluten challenge, cast doubt on gluten as the culprit food component in most patients with presumptive NCGS, and highlight the importance of the nocebo effect in these types of studies. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
An adaptogenic role for omega-3 fatty acids in stress; a randomised placebo controlled double blind intervention study (pilot) [ISRCTN22569553

PubMed Central

Bradbury, Joanne; Myers, Stephen P; Oliver, Chris

2004-01-01

Background There is evidence for an adaptive role of the omega -3 fatty acid, docosahexaenoic acid (DHA) during stress. Mechanisms of action may involve regulation of stress mediators, such as the catecholamines and proinflammatory cytokines. Prevention of stress-induced aggression and hostility were demonstrated in a series of clinical trials. This study investigates whether perceived stress is ameliorated by DHA in stressed university staff. Methods Subjects that scored ≥ 17 on the Perceived Stress Scale were randomised into a 6-week pilot intervention study. The diet reactive group was supplemented with 6 g of fish oil containing 1.5 g per day DHA, while the placebo group was supplemented with 6 g a day of olive oil. The groups were compared with each other and a wider cross sectional study population that did not receive either active or placebo intervention. Results There was a significant reduction in perceived stress in both the fish oil and the placebo group from baseline. There was also a significant between-group difference between the fish oil group and the no-treatment controls in the rate of stress reduction (p < 0.05). However, there was not a significant between-group difference between the fish oil and the placebo group, nor the placebo group and the control group. These results are discussed in the context of several methodological limitations. The significant stress reductions in both the fish oil and the placebo group are considered in view of statistical regression, an effect likely to have been exaggerated by the time course of the study, a large placebo effect and the possibility of an active effect from the placebo. Conclusion There were significant differences (p < 0.05) in the fish oil group compared with no-treatment controls. This effect was not demonstrated in the placebo group. As a pilot study, it was not sufficiently powered to find the difference between the fish oil group and the placebo group significant. Further work needs to be undertaken to conclusively demonstrate these data trends. However, the findings from this research support the literature in finding a protective or 'adaptogenic' role for omega-3 fatty acids in stress. PMID:15566625
Effects of green tea catechin extract on serum lipids in postmenopausal women: a randomized, placebo-controlled clinical trial12

PubMed Central

Samavat, Hamed; Newman, April R; Wang, Renwei; Yuan, Jian-Min; Wu, Anna H; Kurzer, Mindy S

2016-01-01

Background: Green tea has been suggested to improve cardiovascular disease risk factors, including circulating lipid variables. However, current evidence is predominantly based on small, short-term randomized controlled trials conducted in diverse populations. Objective: The aim of this study was to examine the efficacy and impact of green tea extract (GTE) supplementation high in epigallocatechin gallate (EGCG) on blood lipids in healthy postmenopausal women. Design: This was an ancillary study of a double-blind, randomized, placebo-controlled, parallel-arm trial investigating the effects of a GTE supplement containing 1315 mg catechins (843 mg EGCG) on biomarkers of breast cancer risk. Participants were randomly assigned to receive GTE (n = 538) or placebo (n = 537) and were stratified by catechol-O-methyltransferase (COMT) genotype activity (high COMT compared with low or intermediate COMT genotype activity). They consumed either 4 GTE or identical placebo capsules daily for 12 mo. A total of 936 women completed this substudy. Circulating lipid panels including total cholesterol (TC), HDL cholesterol, and triglycerides were measured at baseline and at months 6 and 12. Results: Compared with placebo, 1-y supplementation with GTE capsules resulted in a significant reduction in circulating TC (−2.1% compared with 0.7%; P = 0.0004), LDL cholesterol (−4.1% compared with 0.9%; P < 0.0001) and non-HDL cholesterol (−3.1% compared with 0.4%; P = 0.0032). There was no change in HDL-cholesterol concentration, but triglyceride concentrations increased by 3.6% in the GTE group, whereas they decreased by 2.5% in the placebo group (P = 0.046). A significant reduction in TC was observed only among women with high (i.e., ≥200 mg/dL) baseline TC concentrations (P-interaction = 0.01) who consumed GTE capsules. The effect of GTE on the increase in triglycerides was mainly observed among obese women and statin users (P-interaction = 0.06). Conclusion: Supplementation with GTE significantly reduced circulating TC and LDL-cholesterol concentrations, especially in those with elevated baseline TC concentrations. This trial was registered at clinicaltrials.gov as NCT00917735. PMID:27806972
The safety of flavocoxid, a medical food, in the dietary management of knee osteoarthritis.

PubMed

Morgan, Sarah L; Baggott, Joseph E; Moreland, Larry; Desmond, Renee; Kendrach, Angela C

2009-10-01

This study was designed to determine the safety of a medical food, flavocoxid, a proprietary blend of free-B ring flavonoids and flavans from the root of Scutellaria baicalensis (Chinese skullcap) and the bark of Acacia catechu in the dietary management of knee osteoarthritis. The 12-week, randomized, double-blind, placebo-controlled trial in an academic medical center enrolled 59 patients with moderate osteoarthritis of at least one knee who were recruited who were classified as having "below average" to "a moderately above average cardiovascular risk" with a Framingham-based scoring tool. Subjects were randomized to flavocoxid 250 mg twice a day versus identical placebo. Safety measures, including recording of adverse events, incidence of serious adverse events, and results of routine laboratory values, were compared between the two groups. There were no major differences in the baseline demographic characteristics of the placebo and flavocoxid groups. With one exception no significant differences were found between the two groups with respect to adverse events by body system, blood pressure, or laboratory values. There was a significantly higher incidence of upper respiratory adverse events in the placebo group (35.4% vs. 5.8%, P = .0003). There were no intra- or inter-group differences in any of the laboratory parameters from study baseline to completion. Thus, flavocoxid is safe when used in a population with "below average" to "moderately above average cardiovascular risk" compared to placebo.
Placebo effects in a multiple sclerosis spasticity enriched clinical trial with the oromucosal cannabinoid spray (THC/CBD): dimension and possible causes.

PubMed

Di Marzo, Vincenzo; Centonze, Diego

2015-03-01

Regulatory authorities admit clinical studies with an initial enrichment phase to select patients that respond to treatment before randomization (Enriched Design Studies; EDSs). The trial period aims to prevent long-term drug exposure risks in patients with limited chances of improvement while optimizing costs. In EDSs for symptom control therapies providing early improvements and without a wash-out period, it is difficult to show further improvements and thus large therapeutic gains versus placebo. Moreover, in trials with cannabinoids, the therapeutic gains can be further biased in the postenrichment randomized phase because of carryover and other effects. The aims of the present review article are to examine the placebo effects in the enrichment and postenrichment phases of an EDS with Δ(9) -tetrahydrocannabinol and cannabidiol (THC/CBD) oromucosal spray in patients with multiple sclerosis (MS) spasticity and to discuss the possible causes of maintained efficacy after randomization in the placebo-allocated patients. The overall mean therapeutic gain of THC/CBD spray over placebo in resistant MS spasticity after 16 weeks can be estimated as a ~1.27-point improvement on the spasticity 0-10 Numerical Rating Scale (NRS; ~-20.1% of the baseline NRS score). We conclude that careful interpretation of the results of EDSs is required, especially when cannabinoid-based medications are being investigated. © 2014 John Wiley & Sons Ltd.
Duloxetine Inhibits Effects of MDMA (“Ecstasy") In Vitro and in Humans in a Randomized Placebo-Controlled Laboratory Study

PubMed Central

Nicola, Valentina G.; Vischer, Nerina; Donzelli, Massimiliano; Krähenbühl, Stephan; Grouzmann, Eric; Huwyler, Jörg; Hoener, Marius C.; Liechti, Matthias E.

2012-01-01

This study assessed the effects of the serotonin (5-HT) and norepinephrine (NE) transporter inhibitor duloxetine on the effects of 3,4–methylenedioxymethamphetamine (MDMA, ecstasy) in vitro and in 16 healthy subjects. The clinical study used a double-blind, randomized, placebo-controlled, four-session, crossover design. In vitro, duloxetine blocked the release of both 5-HT and NE by MDMA or by its metabolite 3,4-methylenedioxyamphetamine from transmitter-loaded human cells expressing the 5-HT or NE transporter. In humans, duloxetine inhibited the effects of MDMA including elevations in circulating NE, increases in blood pressure and heart rate, and the subjective drug effects. Duloxetine inhibited the pharmacodynamic response to MDMA despite an increase in duloxetine-associated elevations in plasma MDMA levels. The findings confirm the important role of MDMA-induced 5-HT and NE release in the psychotropic effects of MDMA. Duloxetine may be useful in the treatment of psychostimulant dependence. Trial Registration Clinicaltrials.gov NCT00990067 PMID:22574166
Effect of berberine on insulin resistance in women with polycystic ovary syndrome: study protocol for a randomized multicenter controlled trial.

PubMed

Li, Yan; Ma, Hongli; Zhang, Yuehui; Kuang, Hongying; Ng, Ernest Hung Yu; Hou, Lihui; Wu, Xiaoke

2013-07-18

Insulin resistance and hyperinsulinemia play a key role in the pathogenesis of polycystic ovary syndrome (PCOS), which is characterized by hyperandrogenism, ovulatory dysfunction, and presence of polycystic ovaries on pelvic scanning. Insulin resistance is significantly associated with the long-term risks of metabolic syndrome and cardiovascular disease. Berberine has effects on insulin resistance but its use in women with PCOS has not been fully investigated. In this paper, we present a research design evaluating the effects of berberine on insulin resistance in women with PCOS. This is a multicenter, randomized, placebo-controlled and double-blind trial. A total of 120 patients will be enrolled in this study and will be randomized into two groups. Berberine or placebo will be taken orally for 12 weeks. The primary outcome is the whole body insulin action assessed with the hyperinsulinemic-euglycemic clamp. We postulate that women with PCOS will have improved insulin resistance following berberine administration. This study is registered at ClinicalTrials.gov, NCT01138930.
Modafinil Improves Real Driving Performance in Patients with Hypersomnia: A Randomized Double-Blind Placebo-Controlled Crossover Clinical Trial

PubMed Central

Philip, Pierre; Chaufton, Cyril; Taillard, Jacques; Capelli, Aurore; Coste, Olivier; Léger, Damien; Moore, Nicholas; Sagaspe, Patricia

2014-01-01

Study Objective: Patients with excessive daytime sleepiness (EDS) are at high risk for driving accidents, and physicians are concerned by the effect of alerting drugs on driving skills of sleepy patients. No study has up to now investigated the effect of modafinil (a reference drug to treat EDS in patients with hypersomnia) on on-road driving performance of patients suffering from central hypersomnia. The objective is to evaluate in patients with central hypersomnia the effect of a wake-promoting drug on real driving performance and to assess the relationship between objective sleepiness and driving performance. Design and Participants: Randomized, crossover, double-blind placebo-controlled trial conducted among 13 patients with narcolepsy and 14 patients with idiopathic hypersomnia. Patients were randomly assigned to receive modafinil (400 mg) or placebo for 5 days prior to the driving test. Each condition was separated by at least 3 weeks of washout. Measurements: Mean number of Inappropriate Line Crossings, Standard Deviation of Lateral Position of the vehicle and mean sleep latency in the Maintenance of Wakefulness Test were assessed. Results: Modafinil reduced the mean number of Inappropriate Line Crossings and Standard Deviation of Lateral Position of the vehicle compared to placebo (F(1,25) = 4.88, P < 0.05 and F(1,25) = 3.87, P = 0.06 tendency). Mean sleep latency at the Maintenance of Wakefulness Test significantly correlated with the mean number of Inappropriate Line Crossings (r = -0.41, P < 0.001). Conclusions: Modafinil improves driving performance in patients with narcolepsy and idiopathic hypersomnia. The Maintenance of Wakefulness Test is a suitable clinical tool to assess fitness to drive in this population. Citation: Philip P; Chaufton C; Taillard J; Capelli A; Coste O; Léger D; Moore N; Sagaspe P. Modafinil improves real driving performance in patients with hypersomnia: a randomized double-blind placebo-controlled crossover clinical trial. SLEEP 2014;37(3):483-487. PMID:24587570
Normalizing effect of heroin maintenance treatment on stress-induced brain connectivity

PubMed Central

Walter, Marc; Gerber, Hana; Seifritz, Erich; Brenneisen, Rudolf; Wiesbeck, Gerhard A.; Riecher-Rössler, Anita; Lang, Undine E.; Borgwardt, Stefan

2015-01-01

Recent evidence has shown that a single maintenance dose of heroin attenuates psychophysiological stress responses in heroin-dependent patients, probably reflecting the effectiveness of heroin-assisted therapies for the treatment of severe heroin addiction. However, the underlying neural circuitry of these effects has not yet been investigated. Using a cross-over, double-blind, vehicle-controlled design, 22 heroin-dependent and heroin-maintained outpatients from the Centre of Substance Use Disorders at the University Hospital of Psychiatry in Basel were studied after heroin and placebo administration, while 17 healthy controls from the general population were included for placebo administration only. Functional magnetic resonance imaging was used to detect brain responses to fearful faces and dynamic causal modelling was applied to compute fear-induced modulation of connectivity within the emotional face network. Stress responses were assessed by hormone releases and subjective ratings. Relative to placebo, heroin acutely reduced the fear-induced modulation of connectivity from the left fusiform gyrus to the left amygdala and from the right amygdala to the right orbitofrontal cortex in dependent patients. Both of these amygdala-related connectivity strengths were significantly increased in patients after placebo treatment (acute withdrawal) compared to healthy controls, whose connectivity estimates did not differ from those of patients after heroin injection. Moreover, we found positive correlations between the left fusiform gyrus to amygdala connectivity and different stress responses, as well as between the right amygdala to orbitofrontal cortex connectivity and levels of craving. Our findings indicate that the increased amygdala-related connectivity during fearful face processing after the placebo treatment in heroin-dependent patients transiently normalizes after acute heroin maintenance treatment. Furthermore, this study suggests that the assessment of amygdala-related connectivity during fear processing may provide a prognostic tool to assess stress levels in heroin-dependent patients and to quantify the efficacy of maintenance treatments in drug addiction. PMID:25414039
Efficacy of polyglucosamine for weight loss-confirmed in a randomized double-blind, placebo-controlled clinical investigation.

PubMed

Pokhis, Karina; Bitterlich, Norman; Cornelli, Umberto; Cassano, Giuseppina

2015-01-01

The purpose of this clinical study was to ascertain whether low molecular weight chitosan polyglucosamine is able to produce significantly better weight loss than placebo. 115 participants were included in the study. We used a two-center randomized, double blind, placebo-controlled design. The participants followed a standard treatment (ST), which included the combination of a low-calorie diet achieved through creating a daily calorie deficit (500 cal) and an increased daily physical activity (7 MET-h/week). They were randomized to receive standard treatment plus placebo (ST + PL) or standard treatment plus polyglucosamine (ST + PG), respectively. Participants were instructed to take 2 × 2 tablets before the two meals containing the highest fat content for at least 24 weeks. Body weight, BMI, waist circumference and the time needed for a 5 % body weight reduction (5R) were taken as main variables. The average weight loss over a period of 25 weeks in the ITT population was 5.8 ± 4.09 kg in the ST + PG group versus 4.0 ± 2.94 kg in the ST + PL (pU = 0.023; pt = 0.010). After 25 weeks, 34 participants achieved 5R in the ST + PG group (64.1 %) compared to only 23 participants in the ST + PL group (42.6 %) (ITT) (p Fisher = 0.033). Weight loss through hypo-caloric diets have been found to be effective. The additional effect of PG in combination with standard treatment is able to produce significantly better weight loss than placebo. Participants treated with ST + PG showed a significant amount of weight loss, an additional 1.8 kg, compared to controls treated with ST + PL. Trial Registration at ClinicalTrials.gov: NCT02410785 Registered 07 April 2015.
Randomized double blind placebo-controlled trial of Saccharomyces cerevisiae CNCM I-3856 in irritable bowel syndrome: improvement in abdominal pain and bloating in those with predominant constipation.

PubMed

Spiller, Robin; Pélerin, Fanny; Cayzeele Decherf, Amélie; Maudet, Corinne; Housez, Béatrice; Cazaubiel, Murielle; Jüsten, Peter

2016-06-01

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by recurrent abdominal pain and/or discomfort. Probiotics have been reported to benefit IBS symptoms but the level of benefit remains quite unclear. This study was designed to assess the benefit of Saccharomyces cerevisiae I-3856 on IBS symptoms. A randomized, double blind, placebo-controlled trial has been performed in 379 subjects with diagnosed IBS. Subjects were randomly supplemented with the probiotics (1000 mg) or placebo for 12 weeks. Questionnaires (gastrointestinal symptoms, stools, wellbeing, and quality of life) were completed. Primary endpoint was percentage of responders defined as having a 50% decrease in the weekly average "intestinal pain/discomfort score" for at least 4 out of the last 8 weeks of the study. There was no overall benefit of S. cerevisiae I-3856 on IBS symptoms and wellbeing in the study population. Moreover, S. cerevisiae I-3856 was not statistically significant predictor of the responder status of the subjects (p > 0.05). Planned subgroup analyses showed significant effect in the IBS-C subjects: improvement of gastrointestinal symptoms was significantly higher in active group, compared to placebo, on abdominal pain/discomfort and bloating throughout the study and at the end of the supplementation. In this study, S. cerevisiae I-3856 at the dose of 1000 mg per day does not improve intestinal pain and discomfort in general IBS patients. However, it seems to have an effect in the subgroup with constipation which needs further studies to confirm (NCT01613456 in ClinicalTrials.gov registry).
Celecoxib Versus Placebo in Tonsillectomy: A Prospective, Randomized, Double-Blind Placebo-Controlled Trial.

PubMed

Van Daele, Douglas J; Bodeker, Kellie L; Trask, Douglas K

2016-10-01

Celecoxib is a cyclooxygenase-2-specific inhibitor indicated to treat acute pain and pain secondary to osteoarthritis and rheumatoid arthritis. Surgical models of acute pain have demonstrated superior pain relief to placebo. The objective of this study was to test the safety and efficacy of celecoxib for pain relief after tonsillectomy compared to placebo. Adult subjects were randomized to 200 mg celecoxib versus placebo with a loading dose the night before surgery then twice daily for 10 days. Subjects were instructed to supplement the study drug with hydrocodone/acetaminophen liquid or acetaminophen for pain as needed. Subjects completed a daily diary regarding their pain, nausea, vomiting, diet, and activity. Seventeen subjects enrolled. Intraoperative blood loss was similar between groups, and no subject had postoperative bleeding. Three patients returned to the emergency department for treatment, and 2 patients could not complete the diaries, all in the placebo group. Subjects in the placebo group required statistically significant (P < .05) higher doses of narcotic and acetaminophen to control pain. Pain and diet rating scores were slightly better in the celecoxib group compared to placebo. In this small cohort, celecoxib reduced postoperative narcotic and acetaminophen requirements compared to placebo without complications. © The Author(s) 2016.
Acute EGCG supplementation reverses endothelial dysfunction in patients with coronary artery disease.

PubMed

Widlansky, Michael E; Hamburg, Naomi M; Anter, Elad; Holbrook, Monika; Kahn, David F; Elliott, James G; Keaney, John F; Vita, Joseph A

2007-04-01

Epidemiological studies demonstrate an inverse relation between dietary flavonoid intake and cardiovascular risk. Recent studies with flavonoid-containing beverages suggest that the benefits of these nutrients may relate, in part, to improved endothelial function. We hypothesized that dietary supplementation with epigallocatechin gallate (EGCG), a major catechin in tea, would improve endothelial function in humans. We examined the effects of EGCG on endothelial function in a double blind, placebo-controlled, crossover design study. We measured brachial artery flow-mediated dilation by vascular ultrasound at six time points: prior to treatment with EGCG or placebo, two hours after an initial dose of EGCG (300 mg) or placebo, and after two weeks of treatment with EGCG (150 mg twice daily) or placebo. The order of treatments (EGCG or placebo) was randomized and there was a one-week washout period between treatments. A total of 42 subjects completed the study, and brachial artery flow-mediated dilation improved from 7.1 +/- 4.1 to 8.6 +/- 4.7% two hours after the first dose of 300 mg of EGCG (P = 0.01), but was similar to baseline (7.8 +/- 4.2%, P = 0.12) after two weeks of treatment with the final measurements made approximately 14 hours after the last dose. Placebo treatment had no significant effect, and there were no changes in reactive hyperemia or the response to sublingual nitroglycerin. The changes in vascular function paralleled plasma EGCG concentrations, which increased from 2.6 +/- 10.9 to 92.8 +/- 78.7 ng/ml after acute EGCG (P < 0.001), but were unchanged from baseline after two weeks of treatment (3.4 +/- 13.1 ng/ml). EGCG acutely improves endothelial function in humans with coronary artery disease, and may account for a portion of the beneficial effects of flavonoid-rich food on endothelial function.
Slow Wave Sleep Enhancement with Gaboxadol Reduces Daytime Sleepiness During Sleep Restriction

PubMed Central

Walsh, James K.; Snyder, Ellen; Hall, Janine; Randazzo, Angela C.; Griffin, Kara; Groeger, John; Eisenstein, Rhody; Feren, Stephen D.; Dickey, Pam; Schweitzer, Paula K.

2008-01-01

Study Objectives: To evaluate the impact of enhanced slow wave sleep (SWS) on behavioral, psychological, and physiological changes resulting from sleep restriction. Design: A double-blind, parallel group, placebo-controlled design was used to compare gaboxadol (GBX) 15 mg, a SWS-enhancing drug, to placebo during 4 nights of sleep restriction (5 h/night). Behavioral, psychological, and physiological measures of the impact of sleep restriction were assessed in both groups at baseline, during sleep restriction and following recovery sleep. Setting: Sleep research laboratory. Participants: Forty-one healthy adults; 9 males and 12 females (mean age: 32.0 ± 9.9 y) in the placebo group and 10 males and 10 females (mean age: 31.9 ± 10.2 y) in the GBX group. Interventions: Both experimental groups underwent 4 nights of sleep restriction. Each group received either GBX 15 mg or placebo on all sleep restriction nights, and both groups received placebo on baseline and recovery nights. Measurements and Results: Polysomnography documented a SWS-enhancing effect of GBX with no group difference in total sleep time during sleep restriction. The placebo group displayed the predicted deficits due to sleep restriction on the multiple sleep latency test (MSLT) and on introspective measures of sleepiness and fatigue. Compared to placebo, the GBX group showed significantly less physiological sleepiness on the MSLT and lower levels of introspective sleepiness and fatigue during sleep restriction. There were no differences between groups on the psychomotor vigilance task (PVT) and a cognitive test battery, but these measures were minimally affected by sleep restriction in this study. The correlation between change from baseline in MSLT on Day 6 and change from baseline in SWS on Night 6 was significant in the GBX group and in both groups combined. Conclusions: The results of this study are consistent with the hypothesis that enhanced SWS, in this study produced by GBX, reduces physiological sleep tendency and introspective sleepiness and fatigue which typically result from sleep restriction. Citation: Walsh JK; Snyder E; Hall J; Randazzo AC; Griffin K; Groeger J; Eisenstein R; Feren SD; Dickey P; Schweitzer PK. Slow Wave Sleep Enhancement with Gaboxadol Reduces Daytime Sleepiness During Sleep Restriction. SLEEP 2008;31(5):659–672. PMID:18517036
Randomised Controlled Trial (RCT) of cannabinoid replacement therapy (Nabiximols) for the management of treatment-resistant cannabis dependent patients: a study protocol.

PubMed

Bhardwaj, Anjali K; Allsop, David J; Copeland, Jan; McGregor, Iain S; Dunlop, Adrian; Shanahan, Marian; Bruno, Raimondo; Phung, Nghi; Montebello, Mark; Sadler, Craig; Gugusheff, Jessica; Jackson, Melissa; Luksza, Jennifer; Lintzeris, Nicholas

2018-05-18

The cannabis extract nabiximols (Sativex®) effectively supresses withdrawal symptoms and cravings in treatment resistant cannabis dependent individuals, who have high relapse rates following conventional withdrawal treatments. This study examines the efficacy, safety and cost-effectiveness of longer-term nabiximols treatment for outpatient cannabis dependent patients who have not responded to previous conventional treatment approaches. A phase III multi-site outpatient, randomised, double-blinded, placebo controlled parallel design, comparing a 12-week course of nabiximols to placebo, with follow up at 24 weeks after enrolment. Four specialist drug and alcohol outpatient clinics in New South Wales, Australia. One hundred forty-two treatment seeking cannabis dependent adults, with no significant medical, psychiatric or other substance use disorders. Nabiximols is an oromucosal spray prescribed on a flexible dose regimen to a maximum daily dose of 32 sprays; 8 sprays (total 21.6 mg tetrahydrocannabinol (THC) and 20 mg cannabidiol (CBD)) four times a day, or matching placebo, dispensed weekly. All participants will receive six-sessions of individual cognitive behavioural therapy (CBT) and weekly clinical reviews. Primary endpoints are use of non-prescribed cannabis (self-reported cannabis use days, urine toxicology), safety measures (adverse events and abuse liability), and cost effectiveness (incremental cost effectiveness in achieving additional Quality Adjusted Life Years). Secondary outcomes include, improvement in physical and mental health parameters, substance use other than cannabis, cognitive functioning and patient satisfaction measures. This is the first outpatient community-based randomised controlled study of nabiximols as an agonist replacement medication for treating cannabis dependence, targeting individuals who have not previously responded to conventional treatment approaches. The study and treatment design is modelled upon an earlier study with this population and more generally on other agonist replacement treatments (e.g. nicotine, opioids). Australian and New Zealand Clinical Trial Registry: ACTRN12616000103460 (Registered 1st February 2016).
Beneficial immunostimulatory effect of short-term Chlorella supplementation: enhancement of Natural Killer cell activity and early inflammatory response (Randomized, double-blinded, placebo-controlled trial)

PubMed Central

2012-01-01

Background In vitro and animal studies have demonstrated that Chlorella is a potent biological response modifier on immunity. However, there were no direct evidences for the effect of Chlorella supplementation on immune/inflammation response in healthy humans. Methods This study was designed for an 8-week randomized, double-blinded, placebo-controlled trial: 5g of Chlorella (n=23) or Placebo (n=28) as form of tablets. Mainly, cytotoxic activities of Natural killer (NK) cells and serum concentrations of interferon-γ, interleukin-1β and interleukin-12 were measured. Results After the 8-week, serum concentrations of interferon-γ (p<0.05) and interleukin-1β (p<0.001) significantly increased and that of interleukin-12 (p<0.1) tended to increase in the Chlorella group. The increments of these cytokines after the intervention were significantly bigger in the Chlorella group than those in the placebo group. In addition, NK cell activities (%) were significantly increased in Chlorella group, but not in Placebo group. The increments of NK cell activities (%) were also significantly bigger in the Chlorella group than the placebo group. Additionally, changed levels of NK cell activity were positively correlated with those of serum interleukin-1β (r=0.280, p=0.047) and interferon-γ (r=0.271, p<0.005). Signficantly positive correlations were also observed among the changed levels of serum cytokines; between interferon-γ and interleukin-1β (r=0.448, p<0.001), between interleukin-12 and interleukin-1β (r=0.416, p=0.003) and between interleukin-12 and interferon-γ (r=0.570, p<001). Conclusion These results may suggest a beneficial immunostimulatory effect of short-term Chlorella supplementation which enhances the NK cell activity and produces interferon-γ and interleukin-12 as well as interleukin-1β, the Th-1 cell-induced cytokines in healthy people. PMID:22849818
Randomised clinical trial: evaluation of the efficacy of mesalazine (mesalamine) suppositories in patients with ulcerative colitis and active rectal inflammation -- a placebo-controlled study.

PubMed

Watanabe, M; Nishino, H; Sameshima, Y; Ota, A; Nakamura, S; Hibi, T

2013-08-01

Mesalazine suppositories are recommended and widely used as the standard therapy in induction and maintenance of remission for proctitis. To evaluate the efficacy of mesalazine suppositories in patients with ulcerative colitis (UC) and rectal inflammation; and in patient groups categorised by the extent of lesions. This study was a phase III multicentre, randomised, double-blind, placebo-controlled, parallel-group study. Mild-to-moderate UC patients with rectal inflammation were randomly assigned either a 1 g mesalazine or placebo suppository. The suppository was administered in the rectum once daily for 4 weeks. The primary efficacy end point was the rate of endoscopic remission (mucosal score of 0 or 1) after 4 weeks. The endoscopic remission rates after 4 weeks in the mesalazine and placebo suppository groups were 81.5% and 29.7%, respectively, and the superiority of mesalazine to placebo was confirmed (P < 0.0001, chi-squared test). For proctitis, the endoscopic remission rates after 4 weeks were 83.8% and 36.1% in the mesalazine and placebo suppository groups, respectively, and the corresponding rates for all other types of UC were 78.6% and 21.4%, respectively. The superiority of mesalazine to placebo was confirmed in both subgroups (P < 0.0001, Fisher's exact test). The percentage of patients without bleeding was significantly higher in the mesalazine group than the placebo group from Day 3 of treatment (P = 0.0001, Fisher's exact test). The effectiveness of mesalazine suppositories in all types of UC patients with rectal inflammation was confirmed for the first time in a double-blind, placebo-controlled, parallel-group study (JapicCTI- 111421). © 2013 John Wiley & Sons Ltd.
[Extracorporeal shockwave therapy (ESWT) as therapeutic option in supraspinatus tendon syndrome? One year results of a placebo controlled study].

PubMed

Schmitt, J; Tosch, A; Hünerkopf, M; Haake, M

2002-07-01

Extracorporeal shock wave therapy (ESWT) is seen as a therapeutic option in the treatment of chronic supraspinatus tendinitis by some authors. To test whether ESWT comprising 3 x 2000 pulses with the positive energy flux density ED+ of 0.33 mJ/mm2 is clinically superior to a sham ESWT treatment, a prospective, randomized, single-blinded, placebo-controlled study with an independent observer was performed. Forty patients were treated either by verum ESWT or sham ESWT under local anesthesia. Target criteria were the age-corrected Constant score, pain at rest and during activity on a visual analogue scale, and subjective improvement. Patients who reported no subjective improvement after 12 weeks were deblinded and received verum ESWT if they had belonged to the placebo group (partial crossover). The results of the verum group lie within the range of results for ESWT published by other authors. Patients in the placebo group with local anesthetic showed equally good results. At 12 weeks, and 1 year after intervention, no difference could be found between the verum and placebo groups regarding Constant score, pain, shoulder function, or subjective improvement. The nonresponders to the placebo ESWT continued to show no improvement after receiving verum ESWT. This contradicts a specific ESWT effect. Based on the results of this placebo-controlled study, ESWT appears to have no clinically relevant effect on supraspinatus tendinitis. The study underlines the importance of a control group in evaluating new treatment methods for diseases with unknown natural history.
Adherence to placebo and mortality in the Beta Blocker Evaluation of Survival Trial (BEST).

PubMed

Pressman, Alice; Avins, Andrew L; Neuhaus, John; Ackerson, Lynn; Rudd, Peter

2012-05-01

Randomized controlled trials have reported lower mortality among patients who adhere to placebo compared with those who do not. We explored this phenomenon by reanalyzing data from the placebo arm of the Beta Blocker Evaluation of Survival Trial (BEST), a randomized, double-blind, placebo-controlled trial of bucindolol and mortality. Our primary aim was to measure and explain the association between adherence to placebo and total mortality among the placebo-allocated participants in the BEST trial. Secondary aims included assessment of the association between placebo adherence and cause-specific mortality. Participants with "higher placebo adherence" were defined as having taken at least 75% of their placebo study medication over the entire course of each individual's participation in the study, while those with "lower placebo adherence" took <75%. Primary outcome was in-study all-cause mortality. To account for confounding, we adjusted for all available modifiable, non-modifiable and psychosocial variables. Adherent participants had a significantly lower total mortality compared to less-adherent participants (HR=0.61, 95% Confidence Interval: 0.46-0.82). Adjusting for available confounders did not change the magnitude or significance of the estimates. When considering cause-specific mortality, CVD and pump failure showed similar associations. Analyses of the BEST trial data support a strong association between adherence to placebo study medication and total mortality. While probably not due to publication bias or simple confounding by healthy lifestyle factors, the underlying explanation for the association remains a mystery. Prospective examination of this association is necessary to better understand the underlying mechanism of this observation. Copyright © 2012 Elsevier Inc. All rights reserved.

Treatment of acute cerebral infarction with a choline precursor in a multicenter double-blind placebo-controlled study.

PubMed

Tazaki, Y; Sakai, F; Otomo, E; Kutsuzawa, T; Kameyama, M; Omae, T; Fujishima, M; Sakuma, A

1988-02-01

A multicenter double-blind placebo-controlled study of cytidine 5'-diphosphocholine (CDP-choline) was conducted to evaluate possible clinical benefits of the drug in patients with acute, moderate to severe cerebral infarction. The patients included also suffered from moderate to mild disturbances of consciousness, and all were admitted within 14 days of the ictus. Patients were allocated randomly to treatment with either CDP-choline (1,000 mg/day i.v. once daily for 14 days) or with placebo (physiological saline). One hundred thirty-three patients received CDP-choline treatment, and 139 received placebo. The group treated with CDP-choline showed significant improvements in level of consciousness compared with the placebo-treated group, and CDP-choline was an entirely safe treatment.
The effect of vilazodone on sexual function during the treatment of major depressive disorder.

PubMed

Clayton, Anita H; Kennedy, Sidney H; Edwards, John B; Gallipoli, Susan; Reed, Carol R

2013-10-01

Sexual dysfunction is common in major depressive disorder (MDD), and many serotonergic antidepressants adversely affect sexual function. Vilazodone, a novel serotonin (5-HT) reuptake inhibitor and 5-HT1A partial agonist approved for MDD, exerts its effects at the 5-HT transporter and at both presynaptic and postsynaptic 5-HT1A receptors. This mechanism may limit sexual dysfunction. To summarize effects of vilazodone (40 mg/day, with food) on sexual function in adults with MDD. Data sources were three Phase III studies: two 8-week, placebo-controlled studies (NCT00285376 and NCT00683592) and a 52-week open-label study (NCT00644358). Sexual function was assessed by analyzing changes from baseline to end of treatment (EOT) using validated measures. Arizona Sexual Experience Scale or Changes in Sexual Functioning Questionnaire. Population included 869 patients (vilazodone, 436; placebo, 433) from placebo-controlled studies and 599 patients from the open-label study. Sexual dysfunction prevalence was high (50%, men; 68%, women) before treatment and declined during treatment in vilazodone and placebo groups, indicating improvement on average. At EOT, stable/improved sexual function was observed in ≥91% of patients in placebo-controlled studies; treatment group differences in sexual dysfunction at EOT were not statistically significant for either sex. Differences vs. placebo in changes from baseline of sexual function scores were small and were generally not statistically significant; effect sizes (Cohen's D) were generally of low magnitude. In the placebo-controlled studies, 8.0% of vilazodone-treated patients and 0.9% of placebo-treated patients reported ≥1 sexual-function-related treatment-emergent adverse event (P<0.001). Half of men and two thirds of women with MDD had sexual dysfunction at baseline; sexual function improved on average in both vilazodone and placebo groups. Results suggest that vilazodone may have a small adverse impact on sexual function in adults with MDD relative to the high prevalence of sexual dysfunction at baseline. © 2012 International Society for Sexual Medicine.
Using alcohol intoxication goggles (Fatal Vision® goggles) to detect alcohol related impairment in simulated driving.

PubMed

McCartney, Danielle; Desbrow, Ben; Irwin, Christopher

2017-01-02

Fatal vision goggles (FVGs) are image-distorting equipment used within driver education programs to simulate alcohol-related impairment. However, there is no empirical evidence comparing the behavioral effects associated with wearing FVGs to alcohol intoxication. The purpose of this study was to determine the validity of FVGs in producing alcohol-related impairment in simulated driving. Twenty-two healthy males (age: 23 ± 3 years, mean ± SD) participated in a placebo-controlled crossover design study involving 4 experimental trials. In each trial, participants completed a baseline level simulated driving task followed by an experimental driving task, involving one of 4 treatments: (1) a dose of alcohol designed to elicit 0.080% breath alcohol concentration (BrAC; AB), (2) an alcohol placebo beverage (PB), (3) FVG (estimated % blood alcohol concentration [BAC] 0.070-0.100+), and (4) placebo goggles (PGs). The driving tasks included 3 separate scenarios lasting ∼5 min each; these were a simple driving scenario, a complex driving scenario, and a hazard perception driving scenario. Selected lateral control parameters (standard deviation of lane position [SDLP]; total number of lane crossings [LCs]) and longitudinal control parameters (average speed; standard deviation of speed [SDSP]; distance headway; minimum distance headway) were monitored during the simple and complex driving scenarios. Latency to 2 different stimuli (choice reaction time [CRT]) was tested in the hazard perception driving scenario. Subjective ratings of mood and attitudes toward driving were also provided during each of the trials. Neither placebo treatment influenced simulated driving performance. Mean BrAC was 0.060 ± 0.010% at the time of driving on the AB trial. Lateral control: In the simple driving scenario, SDLP and LC were not affected under any of the experimental treatments. However, in the complex driving scenario, significantly greater SDLP was observed on both the FVG and AB trials compared to their respective baseline drives. LC increased significantly from baseline on the AB trial only. Longitudinal control: Speed was not affected by any of the experimental treatments; however, SDSP increased significantly from baseline on the FVG trial. A significant reduction in distance headway and minimum distance headway was detected on the FVG trial compared to baseline. Hazard perception: Neither AB nor FVG trials were influential on CRT. Subjective mood ratings were significantly altered on the AB and FVG trials compared to baseline and placebo conditions. Participants reported reduced willingness and ability to drive under the active treatments (AB and FVG) than the placebo treatments (PB and PG). FVGs may have some utility in replicating alcohol-related impairment on specific driving performance measurements. Hence, the equipment may offer an alternative approach to researching the impact of alcohol intoxication on simulated driving performance among populations where the provision of alcohol would otherwise be unethical (e.g., prelicensed drivers).
Flexible Magnets Are Not Effective in Decreasing Pain Perception and Recovery Time After Muscle Microinjury

PubMed Central

Borsa, Paul A.; Liggett, Charles L.

1998-01-01

Objective: To assess the therapeutic effects of flexible magnets on pain perception, intramuscular swelling, range of motion, and muscular strength in individuals with a muscle microinjury. Design and Setting: This experiment was a single-blind, placebo study using a repeated-measures design. Subjects performed an intense exercise protocol to induce a muscle microinjury. After pretreatment measurements were recorded, subjects were randomly assigned to an experimental (magnet), placebo (imitation magnet), or control (no magnet) group. Posttreatment measurements were repeated at 24, 48, and 72 hours. Subjects: Forty-five healthy subjects participated in the study. Measurements: Subjects were measured repeatedly for pain perception, upper arm girth, range of motion, and static force production. Four separate univariate analyses of variances were used to reveal statistically significant mean (±SD) differences between variables over time. Interaction effects were analyzed using Scheffe post hoc analysis. Results: Analysis of variance revealed no statistically significant (P > .05) mean differences between conditions for any dependent pretreatment and posttreatment measurements. No significant interaction effects were demonstrated between conditions and times. Conclusions: No significant therapeutic effects on pain control and muscular dysfunction were observed in subjects wearing flexible magnets. ImagesFig 2.Fig 3. PMID:16558503
Considerations for development of surrogate endpoints for antifracture efficacy of new treatments in osteoporosis: a perspective.

PubMed

Bouxsein, Mary L; Delmas, Pierre D

2008-08-01

Because of the broad availability of efficacious osteoporosis therapies, conduct of placebo-controlled trials in subjects at high risk for fracture is becoming increasing difficult. Alternative trial designs include placebo-controlled trials in patients at low risk for fracture or active comparator studies, both of which would require enormous sample sizes and associated financial resources. Another more attractive alternative is to develop and validate surrogate endpoints for fracture. In this perspective, we review the concept of surrogate endpoints as it has been developed in other fields of medicine and discuss how it could be applied in clinical trials of osteoporosis. We outline a stepwise approach and possible study designs to qualify a biomarker as a surrogate endpoint in osteoporosis and review the existing data for several potential surrogate endpoints to assess their success in meeting the proposed criteria. Finally, we suggest a research agenda needed to advance the development of biomarkers as surrogate endpoints for fracture in osteoporosis trials. To ensure optimal development and best use of biomarkers to accelerate drug development, continuous dialog among the health professionals, industry, and regulators is of paramount importance.
Review article: Probiotics in gastrointestinal and liver diseases.

PubMed

Jonkers, D; Stockbrügger, R

2007-12-01

Probiotics, defined as live micro-organisms with beneficial effects for the host, are widely applied in gastrointestinal and liver diseases. To review the available evidence of clinical trials on probiotics in gastrointestinal and liver diseases, with a major focus on irritable bowel syndrome, inflammatory bowel disease, pancreatitis and chronic liver diseases. Evidence for the therapeutic or preventive application of particular probiotic strains is available for antibiotic-associated diarrhoea, rota-virus-associated diarrhoea and pouchitis. Results are encouraging for irritable bowel syndrome, ulcerative colitis and for reducing side effects by Helicobacter pylori eradication therapies, but are less clear for Crohn's disease, lactose intolerance and constipation. In general, for most of these patient groups, more placebo-controlled methodologically well-designed studies that pay attention to both clinical outcome and mechanistic aspects are required. The application in liver disease and pancreatitis is promising, but more human trials have to be awaited. Possible mechanisms of probiotics include modulation of the intestinal microbiota and the immune system, but different bacterial may have different effects. Further insight into disease entities and the functioning of probiotic strains is required to be able to select disease-specific strains, which have to be tested in well-designed placebo-controlled studies.
Mexiletine for Symptoms and Signs of Myotonia in Non-Dystrophic Myotonia: A Randomized Controlled Trial

PubMed Central

Statland, Jeffrey M; Bundy, Brian N; Wang, Yunxia; Rayan, Dipa Raja; Trivedi, Jaya R; Sansone, Valeria A; Salajegheh, Mohammad K; Venance, Shannon L.; Ciafaloni, Emma; Matthews, Emma; Meola, Giovanni; Herbelin, Laura; Griggs, Robert C; Barohn, Richard J; Hanna, Michael G

2012-01-01

Context Non-dystrophic myotonias (NDM) are rare diseases caused by mutations in skeletal muscle ion channels. Patients experience delayed muscle relaxation causing functionally-limiting stiffness and pain. Mexiletine-induced sodium channel blockade reduced myotonia in case studies and one single blind trial. As is common in rare diseases, larger studies of safety and efficacy have not previously been considered feasible. Objective To determine the effects of mexiletine for symptoms and signs of myotonia in NDM. Design, Setting, and Participation Fifty-nine patients with NDM participated in a randomized, double-blind, placebo-controlled two-period crossover study conducted between December 23, 2008 and March 30, 2011 at 7 neuromuscular referral centers in 4 countries, as part of the NIH-funded Rare Disease Clinical Research Network. Intervention Oral 200 mg mexiletine or placebo capsules three times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1 week wash-out between periods. Main Outcome Measures Patient-reported stiffness recorded on an interactive voice response diary (IVR) was the primary endpoint (1 ‘minimal’ to 9 ‘worst ever experienced’). Secondary endpoints included IVR-reported changes in pain, weakness, and tiredness, clinical myotonia assessment, quantitative grip myotonia, Individualized Neuromuscular Quality of Life (INQoL, percent of maximal detrimental impact), SF-36, electrophysiological exercise testing, and needle EMG. Results Mexiletine significantly improved patient-reported stiffness on the IVR. Because of a statistically significant interaction between treatment and period for this outcome, primary endpoint is presented by period (period 1 means were mexiletine 2.53 versus placebo 4.21, difference −1.68, 95% Confidence Interval [CI] −2.66, −0.706, P<0.001; period 2 means were mexiletine 1.60 versus placebo 5.27, difference −3.68, 95% CI −3.85, −0.139, P=0.04). Mexiletine improved the INQoL QOL score (mexiletine 14.0, placebo 16.7, difference −2.69, 95% CI −4.07, −1.30, P<0.001) and decreased handgrip myotonia on clinical exam (seconds: mexiletine 0.164, placebo 0.494, difference −0.330, 95% CI −0.633, −0.142, P<0.001). The most common adverse effect was gastrointestinal (9 mexiletine, 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 placebo, 1 mexiletine). One serious adverse event was determined to be not study-related. Conclusion In this preliminary study of patients with NDM, the use of mexiletine compared with placebo resulted in improved patient-reported stiffness over 4 weeks of treatment, despite some concern about the maintenance of blinding. Trial Registration Clinicaltrials.gov identifier: NCT 00832000 PMID:23032552
Motivation and expectancy influences in placebo responding: the mediating role of attention.

PubMed

Aigner, Carrie; Svanum, Soren

2014-12-01

Drawing upon research in perception and motivation, the current study proposes a motivation-attention model of placebo in which more motivated persons pay greater attention to placebo-related stimuli, directly influencing placebo response. We manipulated both motivation to respond to placebo and expectations of placebo response in a 2 × 2 design. Participants (N = 152) evaluated a series of placebo pheromones (slightly scented water) of potential romantic dates and made desirability ratings. Consistent with hypotheses, more highly motivated participants demonstrated greater placebo responses, as evidenced by higher desirability ratings of the "pheromone" and greater variability among ratings, when compared to less motivated participants. Moreover, the relation between motivation and placebo response was mediated by attention. Contrary to expectations, we found no effect for expectancy. These findings highlight the importance of motivation and the mediating factor of attention in placebo and support goal-oriented models of placebo. © 2014 International Union of Psychological Science.
N-Acetylcysteine in the Treatment of Pediatric Trichotillomania: A Randomized, Double-Blind, Placebo-Controlled Add-On Trial

ERIC Educational Resources Information Center

Bloch, Michael H.; Panza, Kaitlyn E.; Grant, Jon E.; Pittenger, Christopher; Leckman, James F.

2013-01-01

Objective: To examine the efficacy of N-acetylcysteine (NAC) for the treatment of pediatric trichotillomania (TTM) in a double-blind, placebo-controlled, add-on study. Method: A total of 39 children and adolescents aged 8 to 17 years with pediatric trichotillomania were randomly assigned to receive NAC or matching placebo for 12 weeks. Our primary…
Probiotic administration among free-living older adults: a double blinded, randomized, placebo-controlled clinical trial.

PubMed

Östlund-Lagerström, Lina; Kihlgren, Annica; Repsilber, Dirk; Björkstén, Bengt; Brummer, Robert J; Schoultz, Ida

2016-09-10

Diseases of the digestive system have been found to contribute to a higher symptom burden in older adults. Thus, therapeutic strategies able to treat gastrointestinal discomfort might impact the overall health status and help older adults to increase their overall health status and optimal functionality. The aim of this double-blinded, randomized, placebo-controlled clinical trial was to evaluate the effect of the probiotic strain Lactobacillus reuteri on digestive health and wellbeing in older adults. The study enrolled general older adults (>65 years). After eligibility screening qualified subjects (n = 290) participated in a 2-arm study design, with each arm consisting of 12 weeks of intervention of either active or placebo product. Primary outcome measure was set to changes in gastrointestinal symptoms and secondary outcome measures were changes in level of wellbeing, anxiety and stress. Follow up was performed at 8 and 12 weeks. No persistent significant effects were observed on the primary or secondary outcome parameters of the study. A modest effect was observed in the probiotic arm, were levels of stress decreased at week 8 and 12. Similarly, we found that subjects suffering from indigestion and abdominal pain, respectively, showed a significant decrease of anxiety at week 8 after probiotic treatment, but not at week 12. The RCT failed to show any improvement in digestive health after daily intake of a probiotic supplement containing L. reuteri. Neither was any significant improvement in wellbeing, stress or anxiety observed. Even though the RCT had a negative outcome, the study highlights issues important to take into consideration when designing trials among older adults. Clinicaltrials.gov/ NCT01837940 .
Evaluation of the anti-fatigue effects of a traditional herbal drug, Gongjin-dan, under insufficient sleep conditions: study protocol for a randomised controlled trial.

PubMed

Son, Mi Ju; Im, Hwi-Jin; Kim, Young-Eun; Ku, Boncho; Lee, Jun-Hwan; Son, Chang-Gue

2016-08-22

Many herbal medicines are traditionally used as anti-fatigue agents in east Asian countries; however, there is a dearth of clinical evidence supporting the anti-fatigue effects of such medicines and their mechanisms. This study is a feasibility trial to assess the clinical efficacy of Gongjin-dan (GJD) and verify its mechanisms by exploring fatigue outcomes, including endocrine and immunological biomarkers in humans. To investigate the anti-fatigue effects of GJD and the mechanism underlying these effects, a randomised, double-blind, placebo-controlled crossover clinical trial was designed. Participants (24 healthy male volunteers) will be hospitalised for 4 days (3 nights), during which acute fatigue and stress conditions will be induced by sleep deprivation, and GJD or a placebo will be administered (twice daily). The primary outcome will be changes in serum cortisol levels, measured in the morning, as an objective biomarker of sleep deprivation-induced fatigue and stress. The secondary outcomes will include: the Fatigue Severity Scale; the Brief Fatigue Inventory, and the Leeds Sleep Evaluation Questionnaire scores; levels of salivary cortisol, epinephrine, norepinephrine, oxidative stress-related biomarkers, homocysteine, and immunological factors; and heart rate variability. After a washout period of more than 4 weeks, a second treatment phase will commence in which participants who were previously administered the placebo will receive the drug and vice versa, following the same treatment regime as in the first phase. This study protocol provides a unique opportunity to enhance our understanding of fatigue and the effects of GJD on fatigue in terms of endocrine and immunological mechanisms by validating the study design and determining feasibility. Findings from this trial will help researchers to design a pilot or definitive clinical trial of traditional herbal medicine for chronic fatigue. Korean National Clinical Trial Registry CRIS; KCT0001681 , registered on 29 October 2015.
Tropomyosin Receptor Antagonism in Cylindromatosis (TRAC), an early phase trial of a topical tropomyosin kinase inhibitor as a treatment for inherited CYLD defective skin tumours: study protocol for a randomised controlled trial.

PubMed

Cranston, Amy; Stocken, Deborah D; Stamp, Elaine; Roblin, David; Hamlin, Julia; Langtry, James; Plummer, Ruth; Ashworth, Alan; Burn, John; Rajan, Neil

2017-03-07

Patients with germline mutations in a tumour suppressor gene called CYLD develop multiple, disfiguring, hair follicle tumours on the head and neck. The prognosis is poor, with up to one in four mutation carriers requiring complete surgical removal of the scalp. There are no effective medical alternatives to treat this condition. Whole genome molecular profiling experiments led to the discovery of an attractive molecular target in these skin tumour cells, named tropomyosin receptor kinase (TRK), upon which these cells demonstrate an oncogenic dependency in preclinical studies. Recently, the development of an ointment containing a TRK inhibitor (pegcantratinib - previously CT327 - from Creabilis SA) allowed for the assessment of TRK inhibition in tumours from patients with inherited CYLD mutations. Tropomysin Receptor Antagonism in Cylindromatosis (TRAC) is a two-part, exploratory, early phase, single-centre trial. Cohort 1 is a phase 1b open-labelled trial, and cohort 2 is a phase 2a randomised double-blinded exploratory placebo-controlled trial. Cohort 1 will determine the safety and acceptability of applying pegcantratinib for 4 weeks to a single tumour on a CYLD mutation carrier that is scheduled for a routine lesion excision (n = 8 patients). Cohort 2 will investigate if CYLD defective tumours respond following 12 weeks of treatment with pegcantratinib. As patients have multiple tumours, we intend to treat 10 tumours in each patient, 5 with active treatment and 5 with placebo. Patients will be allocated both active and placebo treatments to be applied randomly to tumours on the left or right side. The target is to treat 150 tumours in a maximum of 20 patients. Tumour volume will be measured at baseline and at 4 and 12 weeks. The primary outcome measure is the proportion of tumours responding to treatment by 12 weeks, based on change in tumour volume, with secondary measures based on adverse event profile, treatment compliance and acceptability, changes in tumour volume and surface area, patient quality of life and pain. Interventions for rare genetic skin diseases are often difficult to assess in an unbiased way due to small patient numbers and the challenges of incorporating adequate controls into trial design. Here we present a single-centre, randomised, placebo-controlled trial design that leverages the multiplicity of tumours seen in an inherited skin tumour syndrome that may inform the design of other studies in similar genetic diseases. International Standard Randomised Controlled Trial Number Registry, ISRCTN75715723 . Registered on 22 October 2014.
Omega-3 Fatty Acid Plasma Levels Before and After Supplementation: Correlations with Mood and Clinical Outcomes in the Omega-3 and Therapy Studies.

PubMed

Arnold, L Eugene; Young, Andrea S; Belury, Martha A; Cole, Rachel M; Gracious, Barbara; Seidenfeld, Adina M; Wolfson, Hannah; Fristad, Mary A

2017-04-01

To examine fatty acid profiles, their response to omega-3 fatty acid (Ω3) supplementation, and associations with clinical status and treatment response in youth with mood disorders. In a placebo-controlled 2X2 design, 7-14 year-olds (N = 95) in parallel pilot trials (depression N = 72; bipolar N = 23) were randomly assigned to 12 weeks of Ω3 supplementation (1.4 g eicosapentaenoic acid [EPA], 0.2 g docosahexaenoic acid [DHA], and 0.27 g other Ω3 per day); psychoeducational psychotherapy (PEP); their combination; or placebo (mainly oleic and linoleic acid) alone. Blood was drawn at baseline (N = 90) and endpoint (n = 65). Fatty acid levels were expressed as percent of total plasma fatty acids. Correlational and moderator/mediator analyses were done with SPSS Statistics 23. At baseline: (1) DHA correlated negatively with alpha-linolenic acid (ALA) (r = -0.23, p = 0.029); (2) Arachidonic acid (AA, Ω6) correlated negatively with global functioning (r = -0.24, p = 0.022); (3) Total Ω3 correlated negatively with age (r = -0.22, p = 0.036) and diastolic blood pressure (r = -0.31, p = 0.006). Moderation: Baseline ALA moderated response to Ω3 supplementation: ALA levels above the sample mean (lower DHA) predicted significantly better placebo-controlled response (p = 0.04). Supplementation effects: Compared to placebo, 2 g Ω3 per day increased EPA blood levels sevenfold and DHA levels by half (both p < 0.001). Body weight correlated inversely with increased EPA (r = -0.52, p = 0.004) and DHA (r = -0.54, p = 0.003) and positively with clinical mood response. Mediation: EPA increase baseline-to-endpoint mediated placebo-controlled global function and depression improvement: the greater the EPA increase, the less the placebo-controlled Ω3 improvement. Ω3 supplementation at 2 g/day increases blood levels substantially, more so in smaller children. A possible U-shaped response curve should be explored.
A diet containing whey protein, glutamine, and TGFbeta modulates gut protein metabolism during chemotherapy-induced mucositis in rats.

PubMed

Boukhettala, Nabile; Ibrahim, Ayman; Claeyssens, Sophie; Faure, Magali; Le Pessot, Florence; Vuichoud, Jacques; Lavoinne, Alain; Breuillé, Denis; Déchelotte, Pierre; Coëffier, Moïse

2010-08-01

Mucositis, a common side effect of chemotherapy, is characterized by compromised digestive function, barrier integrity and immune competence. Our aim was to evaluate the impact of a specifically designed diet Clinutren Protect (CP), which contains whey proteins, TGFbeta-rich casein, and free glutamine, on mucositis in rats. Mucositis was induced by three consecutive injections (day 0, day 1, day 2) of methotrexate (2.5 mg/kg). Rats had free access to CP or placebo diets from days -7 to 9. In the placebo diet, whey proteins and TGFbeta-rich casein were replaced by TGFbeta-free casein and glutamine by alanine. Intestinal parameters were assessed at day 3 and 9. Values, expressed as mean +/- SEM, were compared using two-way ANOVA. At day 3, villus height was markedly decreased in the placebo (296 +/- 11 microm) and CP groups (360 +/- 10 microm) compared with controls (464 +/- 27 microm), but more markedly in the placebo as compared to CP group. The intestinal damage score was also reduced in the CP compared with the placebo group. Glutathione content increased in the CP compared with the placebo group (2.2 +/- 0.2 vs. 1.7 +/- 0.2 micromol/g tissue). Gut protein metabolism was more affected in the placebo than in the CP group. The fractional synthesis rate was decreased in the placebo group (93.8 +/- 4.9%/day) compared with controls (121.5 +/- 12.1, P < 0.05), but not in the CP group (106.0 +/- 13.1). In addition, at day 9, rats exhibited improved body weight and food intake recovery in the CP compared to the placebo group. Clinutren Protect feeding reduces intestinal injury in the acute phase of methotrexate-induced mucositis in rats and improves recovery.
Effects of Oral L-Carnitine Administration in Narcolepsy Patients: A Randomized, Double-Blind, Cross-Over and Placebo-Controlled Trial

PubMed Central

Miyagawa, Taku; Kawamura, Hiromi; Obuchi, Mariko; Ikesaki, Asuka; Ozaki, Akiko; Tokunaga, Katsushi; Inoue, Yuichi; Honda, Makoto

2013-01-01

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, and rapid eye movement (REM) sleep abnormalities. A genome-wide association study (GWAS) identified a novel narcolepsy-related single nucleotide polymorphism (SNP), which is located adjacent to the carnitine palmitoyltransferase 1B (CPT1B) gene encoding an enzyme involved in β-oxidation of long-chain fatty acids. The mRNA expression levels of CPT1B were associated with this SNP. In addition, we recently reported that acylcarnitine levels were abnormally low in narcolepsy patients. To assess the efficacy of oral l-carnitine for the treatment of narcolepsy, we performed a clinical trial administering l-carnitine (510 mg/day) to patients with the disease. The study design was a randomized, double-blind, cross-over and placebo-controlled trial. Thirty narcolepsy patients were enrolled in our study. Two patients were withdrawn and 28 patients were included in the statistical analysis (15 males and 13 females, all with HLA-DQB1*06:02). l-carnitine treatment significantly improved the total time for dozing off during the daytime, calculated from the sleep logs, compared with that of placebo-treated periods. l-carnitine efficiently increased serum acylcarnitine levels, and reduced serum triglycerides concentration. Differences in the Japanese version of the Epworth Sleepiness Scale (ESS) and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) vitality and mental health subscales did not reach statistical significance between l-carnitine and placebo. This study suggests that oral l-carnitine can be effective in reducing excessive daytime sleepiness in narcolepsy patients. Trial Registration University hospital Medical Information Network (UMIN) UMIN000003760 PMID:23349733
Feasibility study of Transcutaneous Electrical Nerve Stimulation (TENS) for cancer bone pain.

PubMed

Bennett, Michael I; Johnson, Mark I; Brown, Sarah R; Radford, Helen; Brown, Julia M; Searle, Robert D

2010-04-01

This multicenter study assessed the feasibility of conducting a phase III trial of transcutaneous electrical nerve stimulation (TENS) in patients with cancer bone pain recruited from palliative care services. Eligible patients received active and placebo TENS for 1 hour at site of pain in a randomized crossover design; median interval between applications 3 days. Responses assessed at 30 and 60 minutes included numerical and verbal ratings of pain at rest and on movement, and pain relief. Recruitment, tolerability, adverse events, and effectiveness of blinding were also evaluated. Twenty-four patients were randomised and 19 completed both applications. The intervention was well tolerated. Five patients withdrew: 3 due to deteriorating performance status, and 2 due to increased pain (1 each following active and placebo TENS). Confidence interval estimation around the differences in outcomes between active and placebo TENS suggests that TENS has the potential to decrease pain on movement more than pain on rest. Nine patients did not consider that a placebo was used; the remaining 10 correctly identified placebo TENS. Feasibility studies are important in palliative care prior to undertaking clinical trials. Our findings suggest that further work is required on recruitment strategies and refining the control arm before evaluating TENS in cancer bone pain. Cancer bone pain is common and severe, and partly mediated by hyperexcitability. Animal studies suggest that Transcutaneous Electrical Nerve Stimulation can reduce hyperalgesia. This study examined the feasibility of evaluating TENS in patients with cancer bone pain in order to optimize methods before a phase III trial. Copyright 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.
A placebo-controlled study of the nasal decongestant effect of phenylephrine and pseudoephedrine in the Vienna Challenge Chamber.

PubMed

Horak, Friedrich; Zieglmayer, Petra; Zieglmayer, René; Lemell, Patrick; Yao, Ruji; Staudinger, Heribert; Danzig, Melvyn

2009-02-01

Studies on the efficacy of phenylephrine in the treatment of nasal congestion have yielded inconsistent results, notwithstanding its approval for this indication. To evaluate and compare the decongestant effect of a single dose of phenylephrine to placebo and pseudoephedrine in patients with seasonal allergic rhinitis. This randomized, placebo-controlled, 3-way crossover study evaluated patient-scored nasal congestion, peak nasal inspiratory flow, and rhinomanometry at more than 6 hours in 39 grass-sensitive patients exposed to grass pollen in the Vienna Challenge Chamber. Patients were dosed with immediate-release formulations of phenylephrine, 12 mg, pseudoephedrine, 60 mg, as a control, or placebo. Phenylephrine was not significantly different from placebo in the primary end point, mean change in nasal congestion score at more than 6 hours (P = .56), whereas pseudoephedrine was significantly more effective than both placebo (P < .01) and phenylephrine (P = .01). Phase 1 results showed a difference between phenylephrine and placebo that was 64% of the difference between pseudoephedrine and placebo, substantially greater than the 17% difference observed for all phases. Carryover bias due to patient recall of the pseudoephedrine effect may have influenced these results. Rhinomanometry and peak nasal inspiratory flow results were consistent with these data. Neither phenylephrine nor pseudoephedrine had an effect on the nonnasal symptoms. No adverse events were reported in this study. During a 6-hour observation period, a single dose of pseudoephedrine but not phenylephrine resulted in significant improvement in measures of nasal congestion. Neither phenylephrine nor pseudoephedrine had an effect on nonnasal symptoms.
An Alternative Treatment for Anxiety: A Systematic Review of Human Trial Results Reported for the Ayurvedic Herb Ashwagandha (Withania somnifera)

PubMed Central

Pratte, Morgan A.; Nanavati, Kaushal B.; Young, Virginia

2014-01-01

Abstract Objective: To assess existing reported human trials of Withania somnifera (WS; common name, ashwagandha) for the treatment of anxiety. Design: Systematic review of the literature, with searches conducted in PubMed, SCOPUS, CINAHL, and Google Scholar by a medical librarian. Additionally, the reference lists of studies identified in these databases were searched by a research assistant, and queries were conducted in the AYUSH Research Portal. Search terms included “ashwagandha,” “Withania somnifera,” and terms related to anxiety and stress. Inclusion criteria were human randomized controlled trials with a treatment arm that included WS as a remedy for anxiety or stress. The study team members applied inclusion criteria while screening the records by abstract review. Intervention: Treatment with any regimen of WS. Outcome measures: Number and results of studies identified in the review. Results: Sixty-two abstracts were screened; five human trials met inclusion criteria. Three studies compared several dosage levels of WS extract with placebos using versions of the Hamilton Anxiety Scale, with two demonstrating significant benefit of WS versus placebo, and the third demonstrating beneficial effects that approached but did not achieve significance (p=0.05). A fourth study compared naturopathic care with WS versus psychotherapy by using Beck Anxiety Inventory (BAI) scores as an outcome; BAI scores decreased by 56.5% in the WS group and decreased 30.5% for psychotherapy (p<0.0001). A fifth study measured changes in Perceived Stress Scale (PSS) scores in WS group versus placebo; there was a 44.0% reduction in PSS scores in the WS group and a 5.5% reduction in the placebo group (p<0.0001). All studies exhibited unclear or high risk of bias, and heterogenous design and reporting prevented the possibility of meta-analysis. Conclusions: All five studies concluded that WS intervention resulted in greater score improvements (significantly in most cases) than placebo in outcomes on anxiety or stress scales. Current evidence should be received with caution because of an assortment of study methods and cases of potential bias. PMID:25405876
Efficacy and safety of CP-945,598, a selective cannabinoid CB1 receptor antagonist, on weight loss and maintenance.

PubMed

Aronne, Louis J; Finer, Nick; Hollander, Priscilla A; England, Richard D; Klioze, Solomon S; Chew, Robert D; Fountaine, Robert J; Powell, Coralie M; Obourn, John D

2011-07-01

Three double-blind, placebo-controlled, three-parallel-group, multicenter phase 3 trials were conducted to assess the efficacy and safety of CP-945,598 for weight loss and weight-loss maintenance. Two trials were designed to be 2 years in duration (in obese and overweight patients) and one as a 1-year study (in obese and overweight patients with type 2 diabetes). However, the 2-year trials and the CP-945,598 development program were terminated before completion due to changing regulatory perspectives of CB1 receptor-related drugs. In total, 1,253 and 2,536 participants in the two 2-year multinational and North American studies were randomized to 10-mg CP-945,598 (n = 360; 718); 20-mg CP-945,598 (n = 534, 1,084) and placebo (n = 359, 734), respectively; and 975 participants were randomized to 10-mg CP-945,598 (n = 318); 20-mg CP-945,598 (n = 320); and placebo (n = 337) in the 1-year multinational diabetes trial. Baseline demographics were similar between treatment groups within each trial. One year of treatment with CP-945,598 resulted in a dose-related mean percentage reduction from baseline body-weight in all trials. A significant proportion of all participants also achieved 5% and 10% weight loss after 1 year. In participants with mainly well-controlled type 2 diabetes, the combination of lifestyle and CP-945,598 induced substantial improvements in glycemic control. The most frequent adverse events (AEs) for CP-945,598 were: diarrhea, nausea, nasopharyngitis, and headache. Self-reported experiences of anxiety and suicidal thoughts were higher with CP-945,598 than placebo, as were the incidence of depression and depressed mood. However, the reported increases in psychiatric symptoms were not consistently dose dependent.
Improvement in depression scores after 1 hour of light therapy treatment in patients with seasonal affective disorder.

PubMed

Reeves, Gloria M; Nijjar, Gagan Virk; Langenberg, Patricia; Johnson, Mary A; Khabazghazvini, Baharak; Sleemi, Aamar; Vaswani, Dipika; Lapidus, Manana; Manalai, Partam; Tariq, Muhammad; Acharya, Monika; Cabassa, Johanna; Snitker, Soren; Postolache, Teodor T

2012-01-01

The purpose of this study was to investigate possible rapid effects of light therapy on depressed mood in patients with seasonal affective disorder. Participants received 1 hour of bright light therapy and 1 hour of placebo dim red light in a randomized order crossover design. Depressed mood was measured at baseline and after each hour of light treatment using two self-report depression scales (Profile of Mood States-Depression-Dejection [POMS-D] subscale and the Beck Depression Inventory II [BDI-II]). When light effects were grouped for the two sessions, there was significantly greater reduction in self-report depression scores by -1.3 (p = 0.02) on the BDI-II and -1.2 (p = 0.02) on the POMS-D. A significant but modest improvement was detected after a single active light session. This is the first study, to our knowledge, to document an immediate improvement with light treatment using a placebo-controlled design with a clinical sample of depressed individuals.

Selenium and Prostate Cancer Prevention: Insights from the Selenium and Vitamin E Cancer Prevention Trial (SELECT)

PubMed Central

Nicastro, Holly L.; Dunn, Barbara K.

2013-01-01

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was conducted to assess the efficacy of selenium and vitamin E alone, and in combination, on the incidence of prostate cancer. This randomized, double-blind, placebo-controlled, 2 × 2 factorial design clinical trial found that neither selenium nor vitamin E reduced the incidence of prostate cancer after seven years and that vitamin E was associated with a 17% increased risk of prostate cancer compared to placebo. The null result was surprising given the strong preclinical and clinical evidence suggesting chemopreventive activity of selenium. Potential explanations for the null findings include the agent formulation and dose, the characteristics of the cohort, and the study design. It is likely that only specific subpopulations may benefit from selenium supplementation; therefore, future studies should consider the baseline selenium status of the participants, age of the cohort, and genotype of specific selenoproteins, among other characteristics, in order to determine the activity of selenium in cancer prevention. PMID:23552052
Myofascial Induction Effects on Neck-Shoulder Pain in Breast Cancer Survivors: Randomized, Single-Blind, Placebo-Controlled Crossover Design.

PubMed

Castro-Martín, Eduardo; Ortiz-Comino, Lucía; Gallart-Aragón, Tania; Esteban-Moreno, Bernabé; Arroyo-Morales, Manuel; Galiano-Castillo, Noelia

2017-05-01

To (1) investigate the immediate effects of myofascial induction (MI), with placebo electrotherapy as a control, on perceived pain, cervical/shoulder range of motion (ROM), and mood state in breast cancer survivors (BCSs) with shoulder/arm morbidity; and (2) examine the relationships between pain modifications and cervical/shoulder ROM on the side affected by breast cancer. Randomized, single-blind, placebo-controlled crossover study. Physical therapy laboratory. BCSs (N=21) who had a diagnosis of stage I-IIIA breast cancer and had completed adjuvant therapy (except hormonal treatment). During each session, the BCSs received either an MI (fascial unwinding) intervention focused on the upper limb area following the Pilat approach or placebo pulsed shortwave therapy (control group). Each session lasted 30 minutes, and an adequate washout period of 4 weeks between sessions was established. The visual analog scale (VAS) for pain and anxiety, shoulder-cervical goniometry for ROM, the Profile of Mood States for psychological distress, and the Attitudes Towards Massage Scale were used. An analysis of covariance (ANCOVA) revealed significant time × group interactions for VAS affected arm (P=.031) but not for VAS cervical (P=.332), VAS nonaffected arm (P=.698), or VAS anxiety (P=.266). The ANCOVA also revealed significant interactions for affected shoulder flexion (P<.001), abduction (P<.001), external rotation (P=.004), and internal rotation (P=.001). Significant interactions for affected cervical rotation (P=.022) and affected cervical lateral flexion (P=.038) were also found. A significant negative correlation was found between changes in VAS affected arm and shoulder/arm internal rotation ROM (r=-.46; P=.03). A single MI session decreases pain intensity and improves neck-shoulder ROM to a greater degree than placebo electrotherapy for BCSs experiencing pain. Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.
Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome.

PubMed

Burn, John; Bishop, D Timothy; Mecklin, Jukka-Pekka; Macrae, Finlay; Möslein, Gabriela; Olschwang, Sylviane; Bisgaard, Marie-Luise; Ramesar, Raj; Eccles, Diana; Maher, Eamonn R; Bertario, Lucio; Jarvinen, Heikki J; Lindblom, Annika; Evans, D Gareth; Lubinski, Jan; Morrison, Patrick J; Ho, Judy W C; Vasen, Hans F A; Side, Lucy; Thomas, Huw J W; Scott, Rodney J; Dunlop, Malcolm; Barker, Gail; Elliott, Faye; Jass, Jeremy R; Fodde, Ricardo; Lynch, Henry T; Mathers, John C

2008-12-11

Observational and epidemiologic data indicate that the use of aspirin reduces the risk of colorectal neoplasia; however, the effects of aspirin in the Lynch syndrome (hereditary nonpolyposis colon cancer) are not known. Resistant starch has been associated with an antineoplastic effect on the colon. In a randomized, placebo-controlled trial, we used a two-by-two design to investigate the effects of aspirin, at a dose of 600 mg per day, and resistant starch (Novelose), at a dose of 30 g per day, in reducing the risk of adenoma and carcinoma among persons with the Lynch syndrome. Among 1071 persons in 43 centers, 62 were ineligible to participate in the study, 72 did not enter the study, and 191 withdrew from the study. These three categories were equally distributed across the study groups. Over a mean period of 29 months (range, 7 to 74), colonic adenoma or carcinoma developed in 141 participants. Of 693 participants randomly assigned to receive aspirin or placebo, neoplasia developed in 66 participants receiving aspirin (18.9%), as compared with 65 receiving placebo (19.0%) (relative risk, 1.0; 95% confidence interval [CI], 0.7 to 1.4). There were no significant differences between the two groups with respect to the development of advanced neoplasia (7.4% and 9.9%, respectively; P=0.33). Among the 727 participants receiving resistant starch or placebo, neoplasia developed in 67 participants receiving starch (18.7%), as compared with 68 receiving placebo (18.4%) (relative risk, 1.0; 95% CI, 0.7 to 1.4). Advanced adenomas and colorectal cancers were evenly distributed in the two groups. The prevalence of serious adverse events was low, and the events were evenly distributed. The use of aspirin, resistant starch, or both for up to 4 years has no effect on the incidence of colorectal adenoma or carcinoma among carriers of the Lynch syndrome. (Current Controlled Trials number, ISRCTN59521990.) 2008 Massachusetts Medical Society
Transcranial direct current stimulation as a memory enhancer in patients with Alzheimer's disease: a randomized, placebo-controlled trial.

PubMed

Bystad, Martin; Grønli, Ole; Rasmussen, Ingrid Daae; Gundersen, Nina; Nordvang, Lene; Wang-Iversen, Henrik; Aslaksen, Per M

2016-03-23

The purpose of this study was to assess the efficacy of transcranial direct current stimulation (tDCS) on verbal memory function in patients with Alzheimer's disease. We conducted a randomized, placebo-controlled clinical trial in which tDCS was applied in six 30-minute sessions for 10 days. tDCS was delivered to the left temporal cortex with 2-mA intensity. A total of 25 patients with Alzheimer's disease were enrolled in the study. All of the patients were diagnosed according to National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association criteria. Twelve patients received active stimulation, and thirteen patients received placebo stimulation. The primary outcome measure was the change in two parallel versions of the California Verbal Learning Test-Second Edition, a standardized neuropsychological memory test normalized by age and gender. The secondary outcome measures were the Mini Mental State Examination, clock-drawing test, and Trail Making Test A and B. Changes in the California Verbal Learning Test-Second Edition scores were not significantly different between the active and placebo stimulation groups for immediate recall (p = 0.270), delayed recall (p = 0.052), or recognition (p = 0.089). There were nonsignificant differences in score changes on the Mini Mental State Examination (p = 0.799), clock-drawing test (p = 0.378), and Trail Making Test A (p = 0.288) and B (p = 0.093). Adverse effects were not observed. Compared with placebo stimulation, active tDCS stimulation in this clinical trial did not significantly improve verbal memory function in Alzheimer's disease. This study differs from previous studies in terms of the stimulation protocol, trial design, and application of standardized neuropsychological memory assessment. ClinicalTrials.gov identifier NCT02518412 . Registered on 10 August 2015.
Effects of a hops (Humulus lupulus L.) dry extract supplement on self-reported depression, anxiety and stress levels in apparently healthy young adults: a randomized, placebo-controlled, double-blind, crossover pilot study.

PubMed

Kyrou, Ioannis; Christou, Aimilia; Panagiotakos, Demosthenes; Stefanaki, Charikleia; Skenderi, Katerina; Katsana, Konstantina; Tsigos, Constantine

2017-04-01

The Humulus lupulus L. plant (hops) is used as a herbal medicinal product for anxiety/mood disorders. Our aim was to study the effects of a hops dry extract on self-reported depression, anxiety and stress levels in young adults. Apparently healthy young adults from our university completed the Depression Anxiety Stress Scale-21 (DASS-21) and those reporting at least mild depression, anxiety and stress were invited to complete the study intervention. This followed a randomized (1:1), placebo-controlled, double-blind, crossover design with two 4-week intervention periods (Melcalin hops or placebo; two 0.2 gr capsules once daily) separated by a 2-week wash-out. Anthropometric measurements, DASS-21 assessments and measurements of morning cortisol plasma levels were performed at the beginning and the end of the 4-week treatment periods. 36 participants (Females/Males: 31/5; age: 24.7±0.5 years) completed the study intervention (attrition: 6/42). No significant changes in body weight and composition or morning circulating cortisol were noted with the hops or placebo. Significantly decreased DASS-21 anxiety, depression and stress scores were documented with hops (9.2±7.3 vs. 5.1±5.9, 11.9±7.9 vs. 9.2±7.4, and 19.1±8.1 vs. 11.6±8.1; all p values <0.05), which were significantly greater compared to those caused by the placebo (all p values <0.05). In otherwise healthy young adults reporting at least mild depression, anxietyand stress symptoms, daily supplementation with a hops dry extract can significantly improve all these symptoms over a 4-week period. These beneficial effects agree with the indication of hops for anxiety/mood disorders and restlessness, as approved by the German Commission E.
Oxytocin Effect on Collective Decision Making: A Randomized Placebo Controlled Study.

PubMed

Hertz, Uri; Kelly, Maria; Rutledge, Robb B; Winston, Joel; Wright, Nicholas; Dolan, Raymond J; Bahrami, Bahador

2016-01-01

Collective decision making often benefits both the individuals and the group in a variety of contexts. However, for the group to be successful, individuals should be able to strike a balance between their level of competence and their influence on the collective decisions. The hormone oxytocin has been shown to promote trust, conformism and attention to social cues. We wondered if this hormone may increase participants' (unwarranted) reliance on their partners' opinion, resulting in a reduction in collective benefit by disturbing the balance between influence and competence. To test this hypothesis we employed a randomized double-blind placebo-controlled design in which male dyads self-administered intranasal oxytocin or placebo and then performed a visual search task together. Compared to placebo, collective benefit did not decrease under oxytocin. Using an exploratory time dependent analysis, we observed increase in collective benefit over time under oxytocin. Moreover, trial-by-trial analysis showed that under oxytocin the more competent member of each dyad was less likely to change his mind during disagreements, while the less competent member showed a greater willingness to change his mind and conform to the opinion of his more reliable partner. This role-dependent effect may be mediated by enhanced monitoring of own and other's performance level under oxytocin. Such enhanced social learning could improve the balance between influence and competence and lead to efficient and beneficial collaboration.
Attention Bias Modification for Major Depressive Disorder: Effects on Attention Bias, Resting State Connectivity, and Symptom Change

PubMed Central

Beevers, Christopher G.; Clasen, Peter C.; Enock, Philip M.; Schnyer, David M.

2015-01-01

Cognitive theories of depression posit that selective attention for negative information contributes to the maintenance of depression. The current study experimentally tested this idea by randomly assigning adults with Major Depressive Disorder (MDD) to four weeks of computer-based attention bias modification designed to reduce negative attention bias or four weeks of placebo attention training. Findings indicate that compared to placebo training, attention bias modification reduced negative attention bias and increased resting-state connectivity within a neural circuit (i.e., middle frontal gyrus and dorsal anterior cingulate cortex) that supports control over emotional information. Further, pre- to post-training change in negative attention bias was significantly correlated with depression symptom change only in the active training condition. Exploratory analyses indicated that pre- to post-training changes in resting state connectivity within a circuit associated with sustained attention to visual information (i.e., precuenus and middle frontal gyrus) contributed to symptom improvement in the placebo condition. Importantly, depression symptoms did not change differentially between the training groups—overall, a 40% decrease in symptoms was observed across attention training conditions. Findings suggest that negative attention bias is associated with the maintenance of depression; however, general attentional control may also maintain depression symptoms, as evidenced by resting state connectivity and depression symptom improvement in the placebo training condition. PMID:25894440
Less is More in Antidepressant Clinical Trials: A Meta-Analysis of the Effect of Visit Frequency on Treatment Response and Drop-out

PubMed Central

Rutherford, Bret R; Cooper, Timothy M.; Persaud, Amanda; Brown, Patrick J.; Sneed, Joel R.; Roose, Steven P.

2014-01-01

Objective We investigated how the number of follow-up visits affects response rates and drop-out among patients in antidepressant trials for Major Depressive Disorder (MDD). Data Sources Medline, PsycINFO, and PubMed were searched to identify trials contrasting antidepressants to placebo or active comparator in adults with depression. The index terms “depression—drug therapy,” “depressive disorder—drug therapy,” and “antidepressant agents,” in addition to the class and individual generic name of all antidepressants were combined using the ‘or’ operator. Results were limited to 1) English language articles, 2) publication year 1985 or later, 3) age group ≥ 18, and 4) publication types including clinical trials, controlled clinical trials, meta-analysis, multi-center study, randomized controlled trial, or review. Study Selection Included articles reported trials of approved antidepressant medications for MDD in outpatients aged 18–65, were 6–12 weeks in duration, and had response rates specified using a standardized measure. Trials were excluded for enrolling inpatients, pregnant women, psychotic subjects, or those with treatment-resistant depression. These criteria allowed 9,189 articles identified in the literature review to be narrowed to 111 reports. Data extraction Demographic characteristics, the number of study visits planned in each treatment cell, duration of active treatment, attrition rates, and response rates to medication and placebo were entered into a database. Results In a multilevel meta-analysis, active medication vs. placebo (OR 1.96, p < 0.001), active comparator vs. placebo-controlled study design (OR 1.82, p < 0.001), and longer vs. shorter duration (OR 1.87, p < 0.001) were associated with significantly increased odds of treatment response. After controlling for these variables, the number of study visits did not significantly influence response rates (OR 0.97, p = 0.877). The odds of drop-out were significantly decreased for active comparator vs. placebo-controlled trials (OR 0.67, p = 0.002) and longer vs. shorter duration trials (OR 0.54, p = 0.035), while increasing numbers of study visits significantly increased the odds of participant drop-out (OR 2.77, p < 0.001). Conclusion Visit schedules that are much more frequent than are commonly practiced in the community treatment of depression may increase the expense of clinical trials and make them less generalizable to standard clinical treatment. PMID:23945448
Long-Term Efficacy and Safety of Linagliptin in Patients With Type 2 Diabetes and Severe Renal Impairment

PubMed Central

McGill, Janet B.; Sloan, Lance; Newman, Jennifer; Patel, Sanjay; Sauce, Christophe; von Eynatten, Maximilian; Woerle, Hans-Juergen

2013-01-01

OBJECTIVE This placebo-controlled study assessed long-term efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in patients with type 2 diabetes and severe renal impairment (RI). RESEARCH DESIGN AND METHODS In this 1-year, double-blind study, 133 patients with type 2 diabetes (HbA1c 7.0–10.0%) and severe RI (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) at screening were randomized to linagliptin 5 mg (n = 68) or placebo (n = 65) once daily, added to existing background therapy. The primary efficacy end point was HbA1c change from baseline to week 12. Efficacy and safety end points were assessed after 1 year. RESULTS At week 12, adjusted mean HbA1c decreased by −0.76% with linagliptin and −0.15% with placebo (treatment difference, −0.60%; 95% CI −0.89 to −0.31; P < 0.0001). HbA1c improvements were sustained with linagliptin (−0.71%) over placebo (0.01%) at 1 year (treatment difference −0.72%, −1.03 to −0.41; P < 0.0001). Mean insulin doses decreased by −6.2 units with linagliptin and −0.3 units with placebo. Overall adverse event incidence was similar over 1 year (94.1 vs. 92.3%). Incidence of severe hypoglycemia with linagliptin and placebo was comparably low (three patients per group). Linagliptin and placebo had little effect on renal function (median change in eGFR, −0.8 vs. −2.2 mL/min/1.73 m2), and no drug-related renal failure occurred. CONCLUSIONS In patients with type 2 diabetes and severe RI, linagliptin provided clinically meaningful improvements in glycemic control with very low risk of severe hypoglycemia, stable body weight, and no cases of drug-related renal failure. The potential for linagliptin to spare insulin and provide long-term renal safety warrants further investigations. PMID:23033241
Sample size re-estimation and other midcourse adjustments with sequential parallel comparison design.

PubMed

Silverman, Rachel K; Ivanova, Anastasia

2017-01-01

Sequential parallel comparison design (SPCD) was proposed to reduce placebo response in a randomized trial with placebo comparator. Subjects are randomized between placebo and drug in stage 1 of the trial, and then, placebo non-responders are re-randomized in stage 2. Efficacy analysis includes all data from stage 1 and all placebo non-responding subjects from stage 2. This article investigates the possibility to re-estimate the sample size and adjust the design parameters, allocation proportion to placebo in stage 1 of SPCD, and weight of stage 1 data in the overall efficacy test statistic during an interim analysis.
Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial.

PubMed

Aggarwal, Swati P; Zinman, Lorne; Simpson, Elizabeth; McKinley, Jane; Jackson, Katherine E; Pinto, Hanika; Kaufman, Petra; Conwit, Robin A; Schoenfeld, David; Shefner, Jeremy; Cudkowicz, Merit

2010-05-01

In a pilot study, lithium treatment slowed progression of amyotrophic lateral sclerosis (ALS). We aimed to confirm or disprove these findings by assessing the safety and efficacy of lithium in combination with riluzole in patients with ALS. We did a double-blind, placebo-controlled trial with a time-to-event design. Between January and June, 2009, patients with ALS who were taking a stable dose of riluzole for at least 30 days were randomly assigned (1:1) by a centralised computer to receive either lithium or placebo. Patients, caregivers, investigators, and all site study staff with the exception of site pharmacists were masked to treatment assignment. The primary endpoint was the time to an event, defined as a decrease of at least six points on the revised ALS functional rating scale score or death. Interim analyses were planned for when 84 patients had been allocated treatment, 6 months later or after 55 events, and after 100 events. Analysis was by intention to treat. The stopping boundary for futility at the first interim analysis was a p value of at least 0.68. We used a log-rank test to compare the distributions of the time to an event between the lithium and placebo groups. This trial is registered with ClinicalTrials.gov, NCT00818389. At the first interim analysis, 22 of 40 patients in the lithium group had an event compared with 20 of 44 patients in the placebo group (log rank p=0.51). The hazard ratio of reaching the primary endpoint was 1.13 (95% CI 0.61-2.07). The study was stopped at the first interim analysis because criterion for futility was met (p=0.78). The difference in mean decline in the ALS functional rating scale score between the lithium group and the placebo group was 0.15 (95% CI -0.43 to 0.73, p=0.61). There were no major safety concerns. Falls (p=0.04) and back pain (p=0.05) were more common in the lithium group than in the placebo group. We found no evidence that lithium in combination with riluzole slows progression of ALS more than riluzole alone. The time-to-event endpoint and use of prespecified interim analyses enabled a clear result to be obtained rapidly. This design should be considered for future trials testing the therapeutic efficacy of drugs that are easily accessible to people with ALS. National Institute of Neurological Disorders and Stroke, ALS Association, and ALS Society of Canada. Copyright 2010 Elsevier Ltd. All rights reserved.
The effect of low-level laser in knee osteoarthritis: a double-blind, randomized, placebo-controlled trial.

PubMed

Hegedus, Béla; Viharos, László; Gervain, Mihály; Gálfi, Márta

2009-08-01

Low-level laser therapy (LLLT) is thought to have an analgesic effect as well as a biomodulatory effect on microcirculation. This study was designed to examine the pain-relieving effect of LLLT and possible microcirculatory changes measured by thermography in patients with knee osteoarthritis (KOA). Patients with mild or moderate KOA were randomized to receive either LLLT or placebo LLLT. Treatments were delivered twice a week over a period of 4 wk with a diode laser (wavelength 830 nm, continuous wave, power 50 mW) in skin contact at a dose of 6 J/point. The placebo control group was treated with an ineffective probe (power 0.5 mW) of the same appearance. Before examinations and immediately, 2 wk, and 2 mo after completing the therapy, thermography was performed (bilateral comparative thermograph by AGA infrared camera); joint flexion, circumference, and pressure sensitivity were measured; and the visual analogue scale was recorded. In the group treated with active LLLT, a significant improvement was found in pain (before treatment [BT]: 5.75; 2 mo after treatment : 1.18); circumference (BT: 40.45; AT: 39.86); pressure sensitivity (BT: 2.33; AT: 0.77); and flexion (BT: 105.83; AT: 122.94). In the placebo group, changes in joint flexion and pain were not significant. Thermographic measurements showed at least a 0.5 degrees C increase in temperature--and thus an improvement in circulation compared to the initial values. In the placebo group, these changes did not occur. Our results show that LLLT reduces pain in KOA and improves microcirculation in the irradiated area.
A Randomized, Phase 3 Trial of Naltrexone SR/Bupropion SR on Weight and Obesity-related Risk Factors (COR-II)

PubMed Central

Apovian, Caroline M; Aronne, Louis; Rubino, Domenica; Still, Christopher; Wyatt, Holly; Burns, Colleen; Kim, Dennis; Dunayevich, Eduardo

2013-01-01

Objective To examine the effects of naltrexone/bupropion (NB) combination therapy on weight and weight-related risk factors in overweight and obese participants. Design and Methods CONTRAVE Obesity Research-II (COR-II) was a double-blind, placebo-controlled study of 1,496 obese (BMI 30-45 kg/m2) or overweight (27-45 kg/m2 with dyslipidemia and/or hypertension) participants randomized 2:1 to combined naltrexone sustained-release (SR) (32 mg/day) plus bupropion SR (360 mg/day) (NB32) or placebo for up to 56 weeks. The co-primary endpoints were percent weight change and proportion achieving ≥5% weight loss at week 28. Results Significantly (P < 0.001) greater weight loss was observed with NB32 versus placebo at week 28 (−6.5% vs. −1.9%) and week 56 (−6.4% vs. −1.2%). More NB32-treated participants (P < 0.001) experienced ≥5% weight loss versus placebo at week 28 (55.6% vs. 17.5%) and week 56 (50.5% vs. 17.1%). NB32 produced greater improvements in various cardiometabolic risk markers, participant-reported weight-related quality of life, and control of eating. The most common adverse event with NB was nausea, which was generally mild to moderate and transient. NB was not associated with increased events of depression or suicidality versus placebo. Conclusion NB represents a novel pharmacological approach to the treatment of obesity, and may become a valuable new therapeutic option. PMID:23408728
Homeopathy for Depression - DEP-HOM: study protocol for a randomized, partially double-blind, placebo controlled, four armed study

PubMed Central

2011-01-01

Background Homeopathy is often sought by patients with depression. In classical homeopathy, the treatment consists of two main elements: the case history and the prescription of an individually selected homeopathic remedy. Previous data suggest that individualized homeopathic Q-potencies were not inferior to the antidepressant fluoxetine in a sample of patients with moderate to severe depression. However, the question remains whether individualized homeopathic Q-potencies and/or the type of the homeopathic case history have a specific therapeutical effect in acute depression as this has not yet been investigated. The study aims to assess the two components of individualized homeopathic treatment for acute depression, i.e., to investigate the specific effect of individualized Q-potencies versus placebo and to investigate the effect of different approaches to the homeopathic case history. Methods/Design A randomized, partially double-blind, placebo-controlled, four-armed trial using a 2 × 2 factorial design with a six-week study duration per patient will be performed. 228 patients diagnosed with major depression (moderate episode) by a psychiatrist will be included. The primary endpoint is the total score on the 17-item Hamilton Depression Rating Scale after six weeks. Secondary end points are: Hamilton Depression Rating Scale total score after two and four weeks; response and remission rates, Beck Depression inventory total score, quality of life and safety at two, four and six weeks. Statistical analyses will be by intention-to-treat. The main endpoint will be analysed by a two-factorial analysis of covariance. Within this model generalized estimation equations will be used to estimate differences between verum and placebo, and between both types of case history. Discussion For the first time this study evaluates both the specific effect of homeopathic medicines and of a homeopathic case taking in patients with depression. It is an attempt to deal with the challenges of homeopathic research and the results might be useful information in the current discussion about the evidence on homeopathy Trial registration ClinicalTrials.gov: NCT01178255 PMID:21320338
Antitussive effect of carcainium chloride in patients with chronic cough and idiopathic interstitial pneumonias: A pilot study.

PubMed

Lavorini, Federico; Spina, Domenico; Walker, Michael J; Franciosi, Lui; Page, Clive P; Fontana, Giovanni A

2016-10-01

Cough is a common presenting symptom in patients with idiopathic interstitial pneumonia (IIP); it is often disabling, and lacks effective treatment. Studies in animals suggest that carcainium chloride, a quaternary derivative of the local anesthetic lidocaine, is able to inhibit experimentally induced cough by a mechanism of action distinct from that of lidocaine. To determine the effectiveness of aerosolised carcainium chloride (VRP700) in controlling cough in patients with IIP. Eight female patients (mean age 71 years) with IIP were investigated in a double blind, randomised, placebo controlled crossover, adaptive contingency study design (EudraCT Number 2010-021350-19). The study consisted of a screening visit to assess the eligibility of patients, and two separated (48-72 h) study days. On the two study days, patients were randomised to receive either nebulized VRP700 (1.0 mg/kg) on the first study visit followed by nebulised placebo (sodium chloride 0.9%) on the second visit, or placebo on the first visit followed by VRP700 on the second visit. The primary endpoint was cough frequency over a 4-h assessment period; secondary endpoints were subjective cough-related level of discomfort as assessed by a visual analogue scale (VAS) and the subjective response to treatment as assessed by a quality of life question. Safety (ECG, spirometry, urine and blood tests) and adverse events occurring during the trial were also investigated. In all patients both VRP700 and placebo decreased cough frequency; however, mean decreases in cough frequency after treatment with VRP700 were significantly (P < 0.001) higher than with placebo. Similarly, mean reductions in VAS score were significantly (P < 0.001) higher after treatment with VRP 700 compared with placebo. All but one patient indicated that they felt better after receiving VRP700. No adverse events were reported during the study, nor were any changes in ECG variables, spirometry, urine and blood tests noted. The results of this exploratory study indicate that nebulised VRP700 improved cough and quality of life in hospitalised IIP patients with no significant side effects. A larger trial is warranted to assess these promising results. Copyright © 2016 Elsevier Ltd. All rights reserved.
Efficacy of etanercept in preventing relapse of uveitis controlled by methotrexate.

PubMed

Foster, C Stephen; Tufail, Fehma; Waheed, Nadia Khalida; Chu, David; Miserocchi, Elisabetta; Baltatzis, Stefanos; Vredeveld, Cindy M

2003-04-01

To evaluate the efficacy of etanercept vs placebo in preventing relapses of uveitis in patients taking methotrexate with control of uveitis and whose methotrexate dosage was being tapered. Patients with chronic or recurrent noninfectious uveitis with inflammation controlled by low-dose methotrexate were randomized to either the drug or placebo group in a double-masked manner, given a methotrexate taper schedule, and followed for 24 weeks. The main outcome measures were control of inflammation, visual acuity, and adverse reactions. Data were analyzed both as an attempt-to-treat analysis and an analysis only of those patients who completed the study. A total of 20 patients were randomized to the drug and placebo groups. Relapse of uveitis occurred in 3 of 10 patients in the treatment group and 5 of 10 patients in the control group. Two patients in the treatment group withdrew prematurely from the study due to adverse effects. There was no significant difference between the treatment and placebo groups with regard to the rate of relapse and the final visual acuity. No patient suffered from any irreversible, long-term morbidity or mortality. Etanercept has no significant efficacy over placebo in preventing relapses of uveitis in patients being tapered from methotrexate.
Effect of Intranasal Oxytocin Administration on Psychiatric Symptoms: A Meta-Analysis of Placebo-Controlled Studies

PubMed Central

Hofmann, Stefan G.; Fang, Angela; Brager, Daniel N.

2015-01-01

Clinical trials of intranasal administration of oxytocin for treating psychiatric problems have yielded mixed results. To conduct a quantitative review of placebo-controlled clinical trials of intranasally-administered oxytocin (OT) for psychiatric symptoms, manual and electronic searches using PubMed and PsycINFO were conducted. Of 1,828 entries, 16 placebo-controlled studies totaling 330 participants were included in the analysis. The overall placebo-controlled effect size was moderately strong (Hedges’ g = 0.67) and robust as suggested by the fail-safe N and funnel plot analysis. OT reduced symptoms of depression, anxiety, autism/repetitive behaviors, psychotic symptoms, and general psychopathology. In the combined sample, symptom reduction was moderated by frequency of administration. Publication year and diagnostic category did not moderate the effect of OT on the clinical outcome measures. We conclude that intranasal administration of OT is a potentially useful intervention for reducing psychiatric symptoms. However, more studies are needed to determine the best treatment target and to identify the mechanism of treatment change. PMID:26094200
Safety and efficacy of fenproporex for obesity treatment: a systematic review

PubMed Central

Paumgartten, Francisco José Roma; Pereira, Sabrina Schaaf Teixeira Costa; de Oliveira, Ana Cecilia Amado Xavier

2016-01-01

ABSTRACT OBJECTIVE To evaluate clinical evidence on the safety and efficacy of fenproporex for treating obesity. METHODS MEDLINE, LILACS and Cochrane Controlled Trials Register were searched as well as references cited by articles and relevant documents. Two authors independently assessed the studies for inclusion and regarding risk of bias, collected data, and accuracy. Eligible studies were all those placebo-controlled that provided data on the efficacy and safety of Fenproporex to treat obesity. RESULTS Only four controlled studies met the inclusion criteria. One randomized, placebo-controlled trial on Fenproporex was found on electronic databases. Three placebo-controlled studies (in non-indexed journals) were identified by hand-searching. Patients with cardiovascular and other comorbidities were excluded in all studies. Trials lasted from 40 to 364 days and doses ranged from 20 to 33.6 mg/d. All controlled studies found that weight loss among Fenproporex-treated patients was greater than that produced by the placebo, but drug effect was modest. Fenproporex produced additional weight reductions of 4.7 kg (one year), 3.8 kg (six months) and 1.55 kg (two months) in average, in relation to diet and exercise only (three trials). Insomnia, irritability, and anxiety were the most frequently reported side effects in the four studies. CONCLUSIONS There is a paucity of randomized, placebo-controlled trials on Fenproporex and those identified here present major methodological flaws. These studies suggest that Fenproporex is modestly effective in promoting weight loss. Nonetheless, they failed to provide evidence that it reduces obesity-associated morbidity and mortality. Data from these studies are insufficient to determine the risk-benefit profile of Fenproporex. Abuse potential and amphetamine-like adverse effects are causes for concern. PMID:27253901
A randomized, double-blind, placebo-controlled study of acetaminophen 1000 mg versus acetaminophen 650 mg for the treatment of postsurgical dental pain.

PubMed

Qi, Daniel S; May, Lisa G; Zimmerman, Brenda; Peng, Penny; Atillasoy, Evren; Brown, Jean D; Cooper, Stephen A

2012-12-01

Although acetaminophen is one of the oldest and most widely used of all analgesic drugs, the incremental benefit of the 1000-mg dose compared with the 650-mg dose has been questioned. The aim of this study was to assess the relative efficacy of acetaminophen 1000 mg versus acetaminophen 650 mg over a 6-hour period in patients experiencing at least moderate postsurgical dental pain. This single-center, randomized, double-blind, placebo-controlled, single-dose study enrolled patients aged 16 to 50 years who experienced at least moderate pain after surgical removal of impacted third molars. Each patient received either acetaminophen 1000 mg (n = 239), acetaminophen 650 mg (n = 241), or placebo (n = 60) when they had at least moderate pain and a score ≥50 on the 100-mm Visual Analog Scale (VAS) postsurgically. Pain intensity and pain relief were measured over 6 hours (VAS 0-100 mm). All 540 patients (52% female; age range, 16-30 years; 95% white) were included in the efficacy analysis. For the primary efficacy endpoint (weighted sum of the pain intensity difference from baseline [PID] and pain relief [PAR] scores over 6 hours [SPRID6]), acetaminophen 1000 mg demonstrated a 24% improvement compared with acetaminophen 650 mg (529.4 vs 427.3; P = 0.001). In addition, acetaminophen 650 mg was significantly superior compared with placebo (P < 0.001). The weighted sum of PID over 6 hours (SPID6), the weighted total pain relief over 6 hours (TOTPAR6), and the percentage of patients with >50% of the maximum possible TOTPAR6 score were significantly greater for patients treated with acetaminophen 1000 mg compared with those receiving acetaminophen 650 mg (P ≤ 0.006) or placebo (P < 0.001) and for patients treated with acetaminophen 650 mg compared with placebo (P < 0.001). Time to rescue, rescue rates through 4 and 6 hours, and patient global assessment demonstrated similar findings. Patients treated with acetaminophen 1000 mg or 650 mg had a significantly different distribution in times to confirmed perceptible and meaningful pain relief compared with those receiving placebo (P < 0.001). Adverse events were reported by 18.5% of patients, with no clinically important difference between active treatment groups and placebo. Acetaminophen 1000 mg provided clinically meaningful and statistically significantly greater efficacy in treating postsurgical dental pain compared with acetaminophen 650 mg and placebo. The outcomes of this study are limited to the single-dose design of this study. ClinicalTrials.gov identifier: NCT01115673. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.
Preladenant as an Adjunctive Therapy With Levodopa in Parkinson Disease: Two Randomized Clinical Trials and Lessons Learned.

PubMed

Hauser, Robert A; Stocchi, Fabrizio; Rascol, Olivier; Huyck, Susan B; Capece, Rachel; Ho, Tony W; Sklar, Peter; Lines, Christopher; Michelson, David; Hewitt, David

2015-12-01

Preladenant is an adenosine 2A receptor antagonist that reduced "off" time in a placebo-controlled phase 2b trial in patients with Parkinson disease (PD). We sought to confirm its efficacy in phase 3 trials. To evaluate preladenant as an adjunct to levodopa in patients with PD and motor fluctuations. Two 12-week, phase 3, randomized, placebo-controlled, double-blind trials performed from July 15, 2010, to April 16, 2013. The setting included neurology clinics, clinical research centers, and hospitals in the Americas, the European Union, Eastern Europe, India, and South Africa. Participants included patients with moderate to severe PD taking levodopa who were experiencing motor fluctuations. In trial 1, a total of 778 eligible patients were randomized to the addition of preladenant (2 mg, 5 mg, or 10 mg twice daily), placebo, or rasagiline mesylate (1 mg/d) in a 1:1:1:1:1 ratio. In trial 2, a total of 476 eligible patients were randomized to the addition of preladenant (2 mg or 5 mg twice daily) or placebo in a 1:1:1 ratio. The primary outcome measure was change in off time from baseline to week 12. In trial 1, neither preladenant nor rasagiline was superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were -0.10 hour (95% CI, -0.69 to 0.46 hour) for preladenant 2 mg twice daily, -0.20 hour (95% CI, -0.75 to 0.41 hour) for preladenant 5 mg twice daily, -0.00 hour (95% CI, -0.62 to 0.53 hour) for preladenant 10 mg twice daily, and -0.30 hour (95% CI, -0.90 to 0.26 hour) for rasagiline mesylate 1 mg/d. In trial 2, preladenant was not superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were -0.20 hour (95% CI, -0.72 to 0.35 hour) for preladenant 2 mg twice daily and -0.30 hour (95% CI, -0.86 to 0.21 hour) for preladenant 5 mg twice daily. Preladenant was well tolerated, with the most common adverse event that showed an increase over placebo in both trials being constipation (6%-8% for preladenant vs 1%-3% for placebo). In these phase 3 trials, preladenant did not significantly reduce off time compared with placebo. That the active control rasagiline also failed to demonstrate a significant reduction in off time suggests that issues of study design or conduct may have affected these trials. clinicaltrials.gov Identifier: NCT01155466 and NCT01227265.

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