A bayesian dose-finding design adapting to efficacy and tolerability response.

We propose a new adaptive Bayesian design, explicitly modeling the trade-off between efficacy and tolerability in dose-finding studies. This design incorporates a continuous efficacy variable and a dichotomous tolerability variable. This adaptive design was developed in the context of a drug under development for treatment of major depression, but is easily extended to any setting with a continuous efficacy and a dichotomous tolerability or safety variable. The goal is to identify a target dose that was most efficacious while still being safe. Via simulations under various scenarios we show that our design performs extremely efficiently. Our design incorporates stopping rules, adaptive allocation, and dose-response estimation (for both efficacy and tolerability), among other features. We present various metrics from our simulation study, and conclude that this is an extremely efficient way of characterizing the risk-benefit profile of a drug during clinical development.

A 10-month, open-label evaluation of desvenlafaxine in outpatients with major depressive disorder.

BACKGROUND: The primary objective was to evaluate the long-term safety of desvenlafaxine (administered as desvenlafaxine succinate) during open-label treatment in adult outpatients with a primary DSM-IV diagnosis of major depressive disorder (MDD). METHOD: Depressed adult outpatients (≥ 18 years) who had completed 8-week, double-blind therapy (desvenlafaxine, venlafaxine extended release, or placebo) in a phase 3 study of desvenlafaxine for MDD received up to 10 months of open-label treatment with flexible-dose desvenlafaxine (200 to 400 mg/d). Safety assessments included physical examination, measurement of weight and vital signs, laboratory determinations, and 12-lead electrocardiogram recordings. Adverse events (AEs) and discontinuations due to AEs were monitored throughout the trial. The primary efficacy outcome was mean change from baseline on 17-item Hamilton Depression Rating Scale (HDRS-17) total score. The trial was conducted from August 2003 to March 2006. RESULTS: The safety population included 1,395 patients who took at least 1 dose of open-label desvenlafaxine. Treatment-emergent AEs were reported by 1,238 of 1,395 patients (89%) during the open-label, on-therapy period. Treatment-emergent AEs reported by 10% or more patients were headache, nausea, hyperhidrosis, dizziness, dry mouth, insomnia, upper respiratory infection, nasopharyngitis, and fatigue. Adverse events were the primary reason for study discontinuation in 296 of 1,395 patients (21%). Ten patients (< 1%) had serious AEs that were considered possibly, probably, or definitely related to the study drug during the on-therapy period. No deaths occurred during the study. CONCLUSIONS: Desvenlafaxine can be safely administered for up to 12 months. No new safety findings were observed in this study. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01309542.

How Adaptive Trial Designs can Increase Efficiency in Psychiatric Drug Development: A Case Study.

This paper uses a recently completed study to illustrate how adaptive trial designs can increase efficiency of psychiatric drug development. The design employed allowed a continuous reassessment of the estimated dose-response such that patients were randomized in a double-blind fashion to one of seven doses of the investigational drug, placebo, or active comparator. The study design also permitted early detection of futility allowing for early study termination. By using the adaptive trial design approach, only 202 patients were needed to make the determination of futility. In contrast, a conventional design would have required enrollment of 450 patients and considerably more time and expense to reach the same conclusion. Adaptive trial designs are important at this time when many pharmaceutical companies are abandoning the development of psychiatric medications because of the inefficiency of conventional approaches.

Adaptive Dc-optimal designs for dose finding based on a continuous efficacy endpoint.

We introduce a new optimal design for dose finding with a continuous efficacy endpoint. This design is studied in the context of a flexible model for the mean of the dose-response. The design incorporates aspects of both D- and c-optimality and can be used when the study goals under consideration include dose-response estimation, followed by identification of the target dose. Different optimality criteria are considered. Simulations are shown with results comparing our adaptive design to the fixed allocation (without adaptations). We show that both the estimation of dose-response and identification of the minimum effective dose are improved using our design.

Desvenlafaxine 50 and 100 mg/d in the treatment of major depressive disorder: an 8-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial and a post hoc pooled analysis of three studies.

BACKGROUND: Major depressive disorder (MDD) is a common, chronic illness associated with substantial disability and economic burden. Although a number of effective antidepressants are available, the need for new medications that are effective and well tolerated remains. OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of fixed-dose desvenlafaxine 50 and 100 mg/d with placebo for MDD. A post hoc pooled analysis was conducted to evaluate this study in the context of all similarly designed, completed studies with the 2 doses. METHODS: This was an 8-week, Phase III, randomized, double-blind, duloxetine-referenced, placebo-controlled, parallel-group trial conducted in 21 centers across the United States. Duloxetine was included for assay sensitivity as a positive control; the study was not designed or powered to compare desvenlafaxine with duloxetine. Participants were outpatients aged > or =18 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-defined MDD and a 17-item Hamilton Rating Scale for Depression (HAM-D(17)) score > or =20. Patients were randomly assigned at baseline to fixed-dose desvenlafaxine (50 or 100 mg/d), fixed-dose duloxetine (60 mg/d), or placebo. The primary outcome measure was HAM-D(17) total score at the final evaluation. Additional measures included the Clinical Global Impressions-Improvement (CGI-I) score, Montgomery Asberg Depression Rating Scale (MADRS) score, Clinical Global Impressions-Severity (CGI-S) score, and 6-item Hamilton Rating Scale for Depression, Bech version (HAM-D(6)). Tolerability assessments included discontinuation rates, adverse events (AEs), vital signs, and laboratory tests. The post hoc pooled analysis was performed using data from the current study and 2 previously published, positive studies that compared the efficacy and tolerability of desvenlafaxine 50 and 100 mg/d with placebo for MDD. The design and methodologies of the 2 studies were similar to the methodology of the current trial, other than not including a reference compound. RESULTS: Of the 925 patients who were screened, 287 did not meet entry criteria, and 638 patients enrolled in the study; the intent-to-treat (ITT) population included 615 patients who were evaluated for efficacy (mean [SD] age range, 38.8-40.7 [12.1-13.2] years; mean weight range, 83.3-87.0 [22.8-23.9] kg; female sex, 398 [64.7%]; white race, 458 [74.5%]). The primary end point did not reach significance based on the global F test for controlling multiplicity of the desvenlafaxine doses. Based on pairwise comparison, significantly greater improvements on the HAM-D(17) were observed in the desven-lafaxine 100 mg/d (-10.5; P = 0.028, unadjusted for multiple comparisons) and duloxetine 60 mg/d groups (-10.3; P = 0.047) compared with placebo (-8.7). Desvenlafaxine 100 mg/d and duloxetine 60 mg/d were associated with significantly better scores compared with placebo on the CGI-I, MADRS, CGI-S, and HAM-D(6). No significant differences were observed in any scale between the desvenlafaxine 50 mg/d and placebo groups. Discontinuation rates due to AEs were 5%, 7%, 13%, and 6% for the desvenlafaxine 50-mg/d, desvenlafaxine 100-mg/d, duloxetine 60-mg/d, and placebo groups, respectively. The ITT population from all 3 studies in the pooled analysis consisted of 1388 patients (mean [SD] age range, 38.8-45.7 [12.1-12.6] years; mean weight range, 73.1-87.0 [17.6-23.9] kg; female sex, 896 [64.6%]; white race, 1136 [81.8%]). Significantly greater improvements on the HAM-D(17) were observed for desvenlafaxine 50 mg/d (-11.5; P < 0.001) and 100 mg/d (-11.8; P < 0.001) versus placebo (-9.6). Both doses were significantly better than placebo on the CGI-I, MADRS, and HAM-D(6). CONCLUSIONS: The current study failed to meet its primary efficacy end point based on the a priori analysis plan. Desvenlafaxine was generally well tolerated. A post hoc pooled analysis of this trial and 2 previously published trials with both desvenlafaxine 50 and 100 mg/d found both doses to be effective for MDD compared with placebo. ClinicalTrials.gov Identifier: 00384033.

A placebo-controlled study evaluating the efficacy and safety of flexible-dose desvenlafaxine treatment in outpatients with major depressive disorder.

INTRODUCTION: This research compares the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) versus placebo in treating major depressive disorder. METHODS: In this randomized, double-blind study, outpatients with major depressive disorder > or =18 years of age received desvenlafaxine 200-400 mg/day or placebo for 8 weeks. Efficacy endpoints included (primary) change in 17-item Hamilton Rating Scale for Depression score at the final evaluation (last observation carried forward, analysis of covariance) and (secondary) Clinical Global Impressions-Improvement and -Severity of Illness scales. RESULTS: The difference between desvenlafaxine (n==) and placebo (n==) on the primary endpoint was not significant (-9.1 vs -7.5, P=.078). Week 8 observed cases (desvenlafaxine, n=80; placebo, n=94) results were significant (-10.7 vs -7.9, P=.008). Differences at the final evaluation (last observation carried forward) were significant for Clinical Global Impressions-Improvement (2.9 vs 2.5, P=.037) and Clinical Global Impressions-Severity of Illness (-1.9 vs -1.2, P=.041). Discontinuation rates due to adverse events (AEs) were 12% and 3% for desvenlafaxine and placebo, respectively (P=.008). The most frequently reported AE associated with desvenlafaxine was nausea (36% vs 9% [placebo]). CONCLUSION: In this study, the primary analysis did not show significant differences between desvenlafaxine and placebo; discontinuations due to AEs associated with the desvenlafaxine dose range may have contributed to the lack of statistical separation.

Adaptive designs for dose-finding studies based on sigmoid Emax model.

We propose an adaptive procedure for dose-finding in clinical trials when the primary efficacy endpoint is continuous. We model the mean of the efficacy endpoint, given the dose, as a four-parameter logistic function. The efficacy endpoint at each dose is distributed according to either a normal or a gamma distribution. We consider the cases of fixed variance and fixed coefficient of variation assuming them to be both known and unknown. The analytic formulae for the Fisher information matrix are obtained, which are used to build the locally and adaptive D-optimal designs.

Venlafaxine XR demonstrates higher rates of sustained remission compared to fluoxetine, paroxetine or placebo.

The combined serotonin-norepinephrine reuptake inhibitor, venlafaxine XR, has demonstrated significant response and remission in patients diagnosed with depression when measured with the Hamilton Depression Rating Scale (HAM-D). This pooled analysis of data from five studies compared the sustained remission of depressive symptoms in patients treated with venlafaxine XR, the selective serotonin reuptake inhibitors (SSRIs) fluoxetine or paroxetine, or placebo. Data from 1391 subjects enrolled in five active and placebo-controlled studies who met the DSM-III-R or DSM-IV criteria for major depressive disorder were analysed. Three treatment groups were compared: venlafaxine XR (n = 560), fluoxetine/paroxetine (n = 298) and placebo (n = 496). Mean treatment duration was 8 weeks. Responders were defined as those patients whose HAM-D-21 score decreased by > or = 50% from baseline. Remission was defined as a HAM-D-17 score < or = 7. Sustained remission was defined as maintenance of remission through week 8 or the end of treatment (if before week 8) and for > or = 2 weeks. Between-group rate comparisons in outcome measures were carried out using Fisher's exact and log-rank tests. Venlafaxine XR produced significantly higher rates of sustained remission in depressed patients compared to fluoxetine/paroxetine or placebo over this 8-week treatment period. As early as week 2, a significantly greater proportion of patients treated with venlafaxine achieved improved depression scores (remission and response). A significantly greater rate of remission and sustained remission occurred with venlafaxine compared to placebo. Remission was achieved earlier with venlafaxine and lasted throughout the remainder of the study. These results demonstrate that venlafaxine XR is more effective than fluoxetine/paroxetine for sustaining remission of depressive symptoms.