Efficacy and safety of vortioxetine (Lu AA21004), 15 and 20 mg/day: a randomized, double-blind, placebo-controlled, duloxetine-referenced study in the acute treatment of adult patients with major depressive disorder

Abstract

This study assessed the efficacy, tolerability and safety of vortioxetine versus placebo in adults with recurrent major depressive disorder. This double-blind, randomized, placebo-controlled study included 608 patients [Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥ 26 and Clinical Global Impression - Severity score ≥ 4]. Patients were randomly assigned (1 : 1 : 1 : 1) to vortioxetine 15 mg/day, vortioxetine 20 mg/day, duloxetine 60 mg/day or placebo. The primary efficacy endpoint was change from baseline in MADRS total score at week 8 (mixed model for repeated measurements). Key secondary endpoints were: MADRS responders; Clinical Global Impression - Improvement scale score; MADRS total score in patients with baseline Hamilton Anxiety Rating Scale ≥ 20; remission (MADRS ≤ 10); and Sheehan Disability Scale total score at week 8. On the primary efficacy endpoint, both vortioxetine doses were statistically significantly superior to placebo, with a mean difference to placebo (n = 158) of -5.5 (vortioxetine 15 mg, P < 0.0001, n = 149) and -7.1 MADRS points (vortioxetine 20 mg, P < 0.0001, n = 151). Duloxetine (n = 146) separated from placebo, thus validating the study. In all key secondary analyses, both vortioxetine doses were statistically significantly superior to placebo. Vortioxetine treatment was well tolerated; common adverse events (incidence ≥ 5%) were nausea, headache, diarrhea, dry mouth and dizziness. No clinically relevant changes were seen in clinical safety laboratory values, weight, ECG or vital signs parameters. Vortioxetine was efficacious and well tolerated in the treatment of patients with major depressive disorder.

Trial registration: ClinicalTrials.gov NCT01140906.

Fig. 1

Flow chart of patient disposition. AEs, adverse events; APTS, all-patients-treated set; CGI-S, Clinical Global Impression – Severity; FAS, full-analysis set; LFU, lost to follow-up; LoE, lack of efficacy; MADRS, Montgomery–Åsberg Depression Rating Scale; NC, noncompliance; PV, protocol violation; WoC, patient consent withdrawn. *Three patients had a MADRS total score<26 and/or CGI-S score<4. **Patients with a valid postbaseline MADRS assessment. ‡Including one patient withdrawn from the FAS due to no postbaseline MADRS assessment.

Fig. 2

Estimated Montgomery–Åsberg Depression Rating Scale (MADRS) total scores from baseline to week 8 (FAS, MMRM by visit) and LOCF (FAS, ANCOVA). Patient numbers at each visit are shown below the x-axis for each treatment group. *P<0.05; **P<0.01; ***P<0.001 versus placebo. ANCOVA, analysis of covariance; DUL, duloxetine; FAS, full-analysis set; LOCF, last observation carried forward; MMRM, mixed model, repeated measures; PBO, placebo.

Fig. 3

Estimated Hamilton Rating Scale for Anxiety (HAM-A) total scores from baseline to week 8 (FAS, MMRM by visit) and LOCF (FAS, ANCOVA). Patient numbers at each visit are shown below the x-axis for each treatment group. **P<0.01; ***P<0.001 versus placebo. ANCOVA, analysis of covariance; DUL, duloxetine; FAS, full-analysis set; LOCF, last observation carried forward; MMRM, mixed model, repeated measures; PBO, placebo.

Fig. 4

Mean Discontinuation-Emergent Signs And Symptoms (DESS) total score at baseline (week 8), at 1 week (week 9) and 2 weeks (week 10) after tapered discontinuation of treatment (APCS, OC, ANCOVA). *P<0.05; ***P<0.001 versus placebo. ANCOVA, analysis of covariance; APCS, all-patients-completed set; OC, observed cases.