Northwest Clinical Research Center

Bellevue, WA, United States

Northwest Clinical Research Center

Bellevue, WA, United States
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Bakish D.,Ottawa Psychopharmacology Clinic | Bose A.,Forest Research Institute | Gommoll C.,Forest Research Institute | Chen C.,Forest Research Institute | And 5 more authors.
Journal of Psychiatry and Neuroscience | Year: 2014

Background: Major depressive disorder (MDD) is a global health concern. This study examined the efficacy, safety and tolerability of an extended-release (ER) formulation of levomilnacipran, an antidepressant approved for the treatment of MDD in adults. Methods: This 10- week (1-week placebo run-in period, 8-week double-blind treatment, 1-week down-taper), multicentre, double-blind, placebo- controlled, parallel-group, fixed-dose study was conducted between June 2011 and March 2012. Adult outpatients (age 18-75 yr) with MDD were randomly assigned (1:1:1) to placebo or to levomilnacipran ER 40 mg/day or 80 mg/day. For primary efficacy, we analyzed the Montgomery-Åsberg Depression Rating Scale (MADRS) change from baseline to week 8 using a mixed-effects model for repeatedmeasures approach on the intent-to-treat (ITT) population. For secondary efficacy, we used the Sheehan Disability Scale (SDS), and for safety, we examined adverse events and laboratory, vital sign/physical and electrocardiography findings. Results: The ITT population consisted of 185 patients in the placebo group, 185 in the levomilnacipran ER 40 mg/day group and 187 in the levomilnacipran ER 80 mg/ day group. Study completion rates were similar among the groups (76%-83%). On MADRS change from baseline the least squares mean difference (LSMD) and 95% confidence interval (CI) versus placebo was significant for levomilnacipran ER 40 mg/day (-3.3 [-5.5 to -1.1], p = 0.003) and 80 mg/day (-3.1, [-5.3 to -1.0], p = 0.004). On SDS change from baseline the LSMD (and 95% CI) versus placebo was also significant for levomilnacipran ER 40 mg/day (-1.8, 95% [-3.6 to 0], p = 0.046) and 80 mg/day (-2.7 [-4.5 to -0.9], p = 0.003). More patients in the levomilnacipran ER than the placebo group prematurely exited the study owing to adverse events; common adverse events (≥ 5% and ≥ double the rate of placebo) were nausea, dry mouth, increased heart rate, constipation, dizziness, hyperhidrosis, urinary hesitation and erectile dysfunction. Limitations: Limitations to our study included short treatment duration and lack of an active control arm. Conclusion: Levomilnacipran ER at doses of 40 mg/day and 80 mg/day demonstrated efficacy on symptomatic and functional measures of MDD and was generally well tolerated in this patient population. Clinical trial registration: NCT01377194. © 2014 Canadian Medical Association.

Khan A.,Northwest Clinical Research Center | Khan A.,Duke University | Faucett J.,Northwest Clinical Research Center | Lichtenberg P.,Hebrew University of Jerusalem | And 4 more authors.
PLoS ONE | Year: 2012

Background: Although previous meta-analyses have examined effects of antidepressants, psychotherapy, and alternative therapies for depression, the efficacy of these treatments alone and in combination has not been systematically compared. We hypothesized that the differences between approved depression treatments and controls would be small. Methods and Findings: The authors first reviewed data from Food and Drug Administration Summary Basis of Approval reports of 62 pivotal antidepressant trials consisting of data from 13,802 depressed patients. This was followed by a systematic review of data from 115 published trials evaluating efficacy of psychotherapies and alternative therapies for depression. The published depression trials consisted of 10,310 depressed patients. We assessed the percentage symptom reduction experienced by the patients based on treatment assignment. Overall, antidepressants led to greater symptom reduction compared to placebo among both unpublished FDA data and published trials (F = 38.5, df = 239, p<0.001). In the published trials we noted that the magnitude of symptom reduction with active depression treatments compared to controls was significantly larger when raters evaluating treatment effects were un-blinded compared to the trials with blinded raters (F = 2.17, df = 313, p<0.05). In the blinded trials, the combination of antidepressants and psychotherapy provided a slight advantage over antidepressants (p = 0.027) and psychotherapy (p = 0.022) alone. The magnitude of symptom reduction was greater with psychotherapies compared to placebo (p = 0.019), treatment-as-usual (p = 0.012) and waiting-list (p<0.001). Differences were not seen with psychotherapy compared to antidepressants, alternative therapies or active intervention controls. Conclusions: In conclusion, the combination of psychotherapy and antidepressants for depression may provide a slight advantage whereas antidepressants alone and psychotherapy alone are not significantly different from alternative therapies or active intervention controls. These data suggest that type of treatment offered is less important than getting depressed patients involved in an active therapeutic program. Future research should consider whether certain patient profiles might justify a specific treatment modality. © 2012 Khan et al.

Khan A.,Northwest Clinical Research Center | Khan A.,Duke University | Faucett J.,Northwest Clinical Research Center | Brown W.A.,Brown University
Psychopharmacology | Year: 2014

Rationale: Although newer interview methods such as Structured Interview Guide for the Montgomery-Asberg Depression Rating Scale (SIGMA; MADRS) with audiotaping and Rater Applied Performance Scale (RAPS) appraisal have been introduced to improve reliability of ratings in antidepressant clinical trials, there is limited evidence that these methods actually improve trial outcome.Objective: The objective of this study uis to evaluate outcome in four similarly designed trials of two recently approved antidepressants: two trials randomly used taped SIGMA interviews with RAPS appraisal and two trials used traditional semi-structured MADRS interviews.Methods: We reviewed data from patients who were screened (N=243) and randomized (N=148), evaluating the magnitude of change with placebo and antidepressants on mean total MADRS score.Results: Depressed patients assigned to placebo in trials using taped SIGMA interviews with RAPS appraisal had a significantly larger MADRS change score (M=-11.5±12.7) compared to patients assigned to placebo in trials using traditional semi-structured interviews (-5.4±8.9; F(df=1.57)=5.58, p=0.022). The error variance was also significantly larger in the placebo arm of trials using SIGMA interviews (F=5.43, p=0.023). Depressed patients assigned to antidepressants had similar outcome in all of the four trials.Conclusion: The recently suggested modifications in obtaining clinical data in antidepressant trials such as taped SIGMA interviews with RAPS rating appraisals may in fact result in a higher magnitude of placebo response and a lower magnitude of antidepressant-placebo differences compared to the traditional methods of collecting clinical data. These results were unexpected and indicate the necessity to test new methods prospectively, no matter how intuitively sensible they seem, prior to their implementation. © 2014 The Author(s).

Khan A.,Northwest Clinical Research Center | Khan A.,Duke University | Faucett J.,Northwest Clinical Research Center | Morrison S.,Northwest Clinical Research Center | And 2 more authors.
JAMA Psychiatry | Year: 2013

IMPORTANCE: There is concern that increased mortality risk among patients with psychiatric illness may be worsened by psychopharmacological agents. OBJECTIVES: To assess mortality risk among adult patients with a diagnosis of schizophrenia, depression, bipolar disorder, anxiety disorders, or attention-deficit/hyperactivity disorder participating in clinical trials conducted by pharmaceutical companies for US Food and Drug Administration (FDA) approval to market and to evaluate if psychopharmacological agents worsen this risk. DATA SOURCES: The FDA Summary Basis of Approval (SBA) reports of new drug applications and supplemental applications for 28 psychopharmacological agents approved between 1990 and 2011. STUDY SELECTION: The FDA SBA reports detailing exposure data from acute placebo-controlled trials and safety extension studies including 92 542 patients from 47 adult drug approval programs for treatment of schizophrenia, depression, bipolar disorder, anxiety disorders, or attention-deficit/hyperactivity disorder and SBA reports on combination and maintenance therapy programs for treatments of bipolar disorder. DATA EXTRACTION AND SYNTHESIS: We reviewed and synthesized mortality data from SBA reports that combined mortality rates across the clinical trials, including information on patient exposure years (PEY) for active treatments and placebo for individual indications. MAIN OUTCOMES AND MEASURES: Overall mortality rate per 100 000 PEY in relation to the psychiatric diagnosis of the patients participating in psychopharmacology clinical trials. Also, the overall mortality rates using PEY technique among patients assigned to psychopharmacological agents or placebo were evaluated. RESULTS: Overall, mortality risk was high and significantly associated with psychiatric diagnosis (χ42 = 1760; P < .001). Compared with the general adult population, patients with schizophrenia had the highest mortality risk (3.8-fold increase), followed by patients with depression (3.15-fold increase) and bipolar disorder (3.0-fold increase). The mortality risk was not increased when patients were assigned to psychotropic agents rather than placebo except for heterocyclic antidepressants. Suicide accounted for 109 of all 265 deaths (41.1%). CONCLUSIONS AND RELEVANCE: These data suggest that increased mortality rates reported in population studies are detectable among adult patients with psychiatric illnesses participating in psychopharmacological trials. Furthermore, 3- to 4-month exposure to modern psychotropic agents, such as atypical antipsychotic agents, selective serotonin reuptake inhibitors, and selective serotonin-norepinephrine reuptake inhibitors does not worsen this risk. Given the inherent limitations of the FDA SBA reports, further research is needed to support firm conclusions.

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.

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.

Khan A.,Northwest Clinical Research Center | Khan A.,Duke University | Sambunaris A.,Atlanta Institute of Medicine and Research | Edwards J.,Forest Research Institute | And 2 more authors.
International Clinical Psychopharmacology | Year: 2014

Vilazodone is a potent selective serotonin reuptake inhibitor and serotonin 1A receptor partial agonist approved for the treatment of major depressive disorder in adults. To assess the efficacy of vilazodone across a range of symptoms and severities of depression, data from two phase III, 8-week, randomized, double-blind, placebo-controlled trials were pooled for analysis. Overall improvement in depressive symptoms measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the 17-item Hamilton Depression Rating Scale was statistically significant (P<0.05) for vilazodone treatment compared with placebo as early as Week 1 and continued throughout double-blind treatment. Vilazodone treatment compared with placebo showed significant improvement on all 10 individual MADRS symptom items at end of treatment (P<0.01). Rates of response and remission were significantly greater in the vilazodone group relative to the placebo group, with numbers needed to treat ranging from eight to nine for response and 12-17 for remission. Between-group treatment differences in MADRS and the other outcome measures were similar among all depression subgroups, with no consistent pattern associated with depression severity. These findings support the efficacy of vilazodone across a broad range of depressive symptoms and severities for the treatment of major depressive disorder. Copyright © Lippincott Williams & Wilkins.

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.

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.

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: 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.

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