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Marcus R.,Bristol Myers Squibb | Khan A.,Northwest Clinical Research Center | Khan A.,Duke University | Rollin L.,Bristol Myers Squibb | And 4 more authors.
Bipolar Disorders | Year: 2011

Objectives: To evaluate the efficacy and safety of aripiprazole (ARI) adjunctive to lithium (Li) or valproate (Val) (ARI+Li/Val) compared with placebo (PLB) adjunctive to Li or Val (PLB+Li/Val) as maintenance therapy for patients with bipolar I disorder who had an inadequate response to Li or Val monotherapy. Methods: Patients with a current manic/mixed episode received Li or Val for at least 2weeks. Those with an inadequate response [Young Mania Rating Scale (YMRS) total score ≥ 16 and ≤ 35% decrease from baseline at 2weeks] received adjunctive single-blind ARI plus mood stabilizer. Patients who achieved stability [YMRS and Montgomery-Åsberg Depression Rating Scale (MADRS) score ≤ 12] for 12 consecutive weeks were randomized to double-blind ARI (10-30 mg/day) or PLB+Li/Val. Relapse was monitored for 52weeks. Adverse events (AEs) were also evaluated. Results: A total of 337 patients were randomized to ARI+ Li/Val (n=168) or PLB+Li/Val (n=169). TheKaplan-Meier relapse rate at 52weeks was 17% with ARI+Li/Val and 29% with PLB+Li/Val. ARI+Li/Val significantly delayed time to any relapse compared with PLB+Li/Val; hazard ratio=0.54 (95% confidence interval: 0.33-0.89; log-rank p=0.014). The most common AEs ≥ 5%(ARI+Li/Val versus PLB+Li/Val) were headache (13.2% versus 10.8%), weight increase (9.0% versus 6.6%), tremor (6.0% versus 2.4%), and insomnia (5.4% versus 9.6%). Conclusions: Continuation of ARI+Li/Val treatment increased the time to relapse to any mood episode compared with Li or Val monotherapy, and was relatively well tolerated during the one-year study. These findings suggest that there is a long-term benefit in continuing ARI adjunctive to a mood stabilizer after sustained remission is achieved. © 2011 John Wiley and Sons A/S.

Khan A.,Northwest Clinical Research Center | Khan A.,Duke University | Brown W.A.,Brown University
World Psychiatry | Year: 2015

Although the early antidepressant trials which included severely ill and hospitalized patients showed substantial drug-placebo differences, these robust differences have not held up in the trials of the past couple of decades, whether sponsored by pharmaceutical companies or non-profit agencies. This narrowing of the drug-placebo difference has been attributed to a number of changes in the conduct of clinical trials. First, the advent of DSM-III and the broadening of the definition of major depression have led to the inclusion of mildly to moderately ill patients into antidepressant trials. These patients may experience a smaller magnitude of antidepressant-placebo differences. Second, drug development regulators, such as the U.S. Food and Drug Administration and the European Medicines Agency, have had a significant, albeit underappreciated, role in determining how modern antidepressant clinical trials are designed and conducted. Their concerns about possible false positive results have led to trial designs that are poor, difficult to conduct, and complicated to analyze. Attempts at better design and patient selection for antidepressant trials have not yielded the expected results. As of now, antidepressant clinical trials have an effect size of 0.30, which, although similar to the effects of treatments for many other chronic illnesses, such as hypertension, asthma and diabetes, is less than impressive. © 2015 World Psychiatric Association.

Hale M.,Gold Coast Research LLC | Khan A.,Northwest Clinical Research Center | Khan A.,Duke University | Kutch M.,Applied Clinical Intelligence LLC | Li S.,Neuromed Pharmaceuticals Inc.
Current Medical Research and Opinion | Year: 2010

Objective: This multicenter, double-blind, placebo-controlled study using a randomized withdrawal design evaluated the efficacy and safety of once-daily OROS hydromorphone ER in the treatment of opioid-tolerant patients with chronic moderate-to-severe low back pain (LBP). Main outcome measures: The primary efficacy assessment was mean change in pain intensity based on patient diary Numeric Rating Scale (NRS) scores from baseline to final visit of the 12-week double-blind phase. Secondary endpoints included mean change from baseline to each visit in patient diary NRS scores; and office NRS scores; time to treatment failure; Patient Global Assessment; rescue medication use; and Roland Morris Disability Questionnaire total scores. Clinical Trial Registration: ClinicalTrials.gov NCT00549042. Results: For the primary outcome measure, hydromorphone ER significantly reduced pain intensity compared to placebo (p<0.001). Median diary NRS score change from baseline to endpoint was significantly lower for hydromorphone ER (0.2 units) compared to placebo (1.2 units). A significantly higher proportion of hydromorphone ER (60.6) vs. placebo (42.9) patients had at least a 30 reduction in diary NRS pain score from screening to endpoint (p<0.01). Hydromorphone ER was well-tolerated, although 60 (13) discontinued during the enrichment phase for adverse events and more active (9, 6.7) than placebo (4, 3.0) patients discontinued treatment for adverse events during the randomized phase. Conclusions: These results provide evidence for the efficacy and safety of hydromorphone ER in opioid-tolerant patients with chronic moderate-to-severe LBP. Potential limitations include the shortened dose-conversion/titration phase, limiting the daily allowable dose of hydromorphone ER to 64mg, and the allowance of limited rescue medication throughout the entire double-blind phase. Other trial design elements such as the use of an enrichment phase and the inclusion of only opioid tolerant patients may limit the generalizabilty of these results. © 2010 Informa UK Ltd All rights reserved.

Mathews M.,Forest Research Institute | Gommoll C.,Forest Research Institute | Chen D.,Forest Research Institute | Nunez R.,Forest Research Institute | And 2 more authors.
International Clinical Psychopharmacology | Year: 2015

Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A partial agonist approved for major depressive disorder (MDD) treatment in adults. This was a 10-week, multicenter, double-blind, placebo-controlled and active-controlled, fixed-dose trial (NCT01473381). Adult patients with MDD (Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision criteria) were randomized 1:1:1:1 to vilazodone 20 or 40mg/day, citalopram 40mg/day, or placebo. Primary efficacy: Montgomery-Åsberg Depression Rating Scale (MADRS); secondary efficacy: Clinical Global Impressions-Severity and sustained response (MADRS total score≤12 for at least the last two consecutive double-blind visits). The intent-to-treat population comprised 1133 patients, (placebo=281; vilazodone 20mg/day=288; vilazodone 40mg/day=284; citalopram=280). MADRS and Clinical Global Impressions-Severity score change from baseline to week 10 was significantly greater for vilazodone 20mg/day, vilazodone 40mg/day, and citalopram versus placebo. Sustained response rates were numerically higher, but not significantly different, in all active treatment groups versus placebo. The most common adverse events (â‰15% of vilazodone patients, twice the rate of placebo) were diarrhea, nausea, vomiting (vilazodone 40mg/day only), and insomnia. Improved sexual function (Changes in Sexual Functioning Questionnaire scores) was seen in all groups; between-group differences were not significant. Vilazodone 20 and 40mg/day demonstrated efficacy and tolerability in the treatment of MDD. © 2015 Wolters Kluwer Health, Inc.

Khan A.,Northwest Clinical Research Center | Khan A.,Duke University | Faucett J.,Northwest Clinical Research Center | Brown W.A.,Brown University | Brown W.A.,Tufts University
Journal of Psychiatric Research | Year: 2014

The high failure rate of antidepressant clinical trials is due in part to a high magnitude of placebo response and considerable variance in placebo response. In some recent trials enhanced patient interview techniques consisting of Structured Interview Guide for the Montgomery-Asberg Depression Rating Scale (SIGMA) interviews, audiotaping of patient interviews and 'central' appraisal with Rater Applied Performance Scale (RAPS) criteria have been implemented in the hope of increasing reliability and thus reducing the placebo response. However, the data supporting this rationale for a change in patient interview technique are sparse.We analyzed data from depressed patients assigned to placebo in antidepressant clinical trials conducted at a single research site between 2008 and 2012. Three trials included 34 depressed patients undergoing SIGMA depression interviews with taping and RAPS appraisal and 4 trials included 128 depressed patients using traditional interview methods.Using patient level data we assessed the mean decrease in total MADRS scores and the variability of the decrease in MADRS scores in trials using SIGMA interviews versus trials using traditional interviews.Mean decrease in total MADRS score was significantly higher in the 3 trials that used SIGMA interviews compared to the 4 trials using traditional interviews (M=13.0 versus 8.3, t(df=160)=2.04, p=0.047). Furthermore, trials using SIGMA had a larger magnitude of response variance based on Levene's test for equality of variance (SD=12.3 versus 9.4, F=7.3, p=0.008).The results of our study suggest that enhanced patient interview techniques such as SIGMA interviews, audiotaping and RAPS appraisal may not result in the intended effect of reducing the magnitude of placebo response and placebo variance. © 2014 The Authors.

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