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.