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

Abstract

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 ≥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 ≥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 Åsberg 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.