A randomised, double-blind, placebo-controlled, duloxetine-referenced study of the efficacy and safety of vortioxetine in acute treatment of MDD

OBJECTIVE: Vortioxetine (Lu AA21004) is an investigational multimodal antidepressant thought to work through a combination of 2 pharmacological modes of action: serotonin (5-HT) receptor activity modulation and 5-HT reuptake inhibition. This multi-national study assessed the efficacy, tolerability, and safety of 2 fixed doses of vortioxetine (15 and 20mg/day) versus placebo in adult patients with major depressive disorder (MDD). METHODS: This double-blind, randomised, fixed-dose, placebocontrolled, active reference 8-week study included 610 patients with a primary diagnosis of recurrent MDD with a current major depressive episode (MDE) >3 months in duration, a MADRS total score ?26 and a CGI-S score ?4. Patients were randomly assigned (1:1:1:1) to vortioxetine 15mg/day, vortioxetine 20mg/day, duloxetine 60mg/day (active reference), or placebo for 8 weeks. The primary efficacy endpoint was a mixed model for repeated measurements (MMRM) of the change from baseline in MADRS total score at Week 8 adjusting for multiplicity using a hierarchical testing procedure, analyzed separately for each dose. Key secondary endpoints at Week 8 were: MADRS responders; CGI-I score; MADRS total score in patients with baseline HAM-A ?20; remission (MADRS ?10); and Sheehan Disability Scale (SDS) total score. Safety and tolerability assessments included adverse events (AEs), clinical safety laboratory values, vital signs, weight, and ECG parameters. RESULTS: On the primary efficacy endpoint, both doses of vortioxetine were statistically significantly superior to placebo in mean change from baseline in MADRS total score at Week 8 (MMRM), with a mean treatment difference to placebo (n=158) of -5.6 (vortioxetine 15mg, p<0.0001, n=148) and -7.1 points (vortioxetine 20mg, p<0.0001, n=151). Duloxetine (n=146) separated from placebo, confirming assay sensitivity. Separation from placebo was seen from Week 2 onwards (vortioxetine 20mg and duloxetine) and Week 4 onwards (vortioxetine 15mg). In all predefined key secondary analyses, both doses of vortioxetine were statistically significantly superior to placebo. The withdrawal rate due to all reasons was 16.6% (15.8% placebo, 22.5% vortioxetine 15mg, 17.2% vortioxetine 20mg, and 10.9% duloxetine). Overall, treatment was well tolerated; the most commonly reported AEs (?5%) were nausea, headache, diarrhoea, dry mouth, dizziness and hyperhidrosis. No clinically relevant changes were seen in clinical safety laboratory values, weight, ECG or vital signs parameters. CONCLUSIONS: Vortioxetine (15 and 20mg/day) was efficacious and well tolerated in the treatment of adult patients with recurrent major depressive disorder. Trial Registration: This study has the ClinicalTrials.gov identifier NCT01140906. Commercial support: This study was funded by H Lundbeck A/S and the Takeda Pharmaceutical Company, Ltd.