Methods

Study design
This was a multicenter, open-label, flexible-dose, 52-week extension study of study participants who had completed one of two previous acute double-blind efficacy and safety trials that were conducted at 88 sites in Asia, Australia, Europe (NCT00735709) (Henigsberg et al., 2012), and the USA (NCT00672620) (Mahableshwarkar et al., 2013). In the US study, study participants were originally randomized to receive vortioxetine 2.5 mg, vortioxetine 5 mg, duloxetine 60 mg, or placebo once daily; those in the non-US study were randomized to receive vortioxetine 1 mg, vortioxetine 5 mg, vortioxetine 10 mg, or placebo once daily. Study participants completing one of these acute double-blind studies were eligible to continue treatment for 52 weeks in this open-label extension study, irrespective of their response to treatment at the end of week 8 of the acute efficacy studies if they were considered by the investigator to benefit from 52 weeks of treatment with vortioxetine. After baseline screening, all study participants were switched to vortioxetine 5 mg/day for the first week of the extension study, irrespective of their treatment assignment at the completion of the acute double-blind trials. Thereafter, the vortioxetine dose could be maintained at 5 mg/day, increased to a maximum of 10 mg/day, or decreased to 2.5 mg/day, on the basis of patient response and tolerability as determined by the investigator.
The study was approved by the ethics committee of each site and was carried out in accordance with the ethical principles outlined in the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice Guidelines. All enrolled study participants provided written informed consent before undergoing any study procedures.

Study visits
The visit schematic for the study is presented in Fig. 1. The baseline visit was the completion of the original lead-in study. At study visits during the treatment phase (weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 36, 44, and 52), assessments performed included physical examination (with measurement of vital signs and weight and 12-lead ECG), clinical laboratory tests, adverse event (AE) evaluation and concomitant medication use, and drug return assessment and accountability. Clinical assessments included the Columbia-Suicide Severity Rating Scale (C-SSRS), HAM-D24, Hamilton Anxiety Scale (HAM-A), Montgomery–Asberg Depression Rating Scale (MADRS), Clinical Global Impressions Scale – Severity of Illness Scale (CGI-S), 36-item Short-Form (SF-36), and the Sheehan Disability Scale (SDS). Assessments were repeated at the final study visit or the early termination visit. A follow-up safety call was made at least 4 weeks after the last dose of vortioxetine for any ongoing AEs, new AEs, new serious AEs, and concomitant medications.
Fig. 1  Study visit schematic. aDose adjustment up or down as appropriate on the basis of response and tolerability. FU, follow-up safety call.

Study participants
Inclusion criteria for the study included the completion of either of the lead-in trials immediately before enrollment in the extension study. The baseline visit must have been the same day as the completion of the preceding study. Study participants were required to have a primary diagnosis of MDD (classification code 296.xx) as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (American Psychiatric Association, 2000) at entry into the lead-in study and a clinical indication (in the opinion of the investigator) for 12 months of continued treatment. Study participants were required to be able to understand and comply with study instructions, and sexually active study participants of child-bearing potential had to agree to use appropriate contraception during the study and for 1 month afterward. Exclusion criteria included any concomitant diagnosis of other psychiatric disorders (e.g. mania, bipolar disorder, schizophrenia, etc.) before or during entry into either of the lead-in studies, risk for suicide, and/or a score of at least 5 points on item 10 (suicidal thoughts) on the MADRS. Study participants were also excluded if they experienced a continuing moderate or severe AE related to treatment from the original acute trial or were using disallowed medications.

Outcome variables
The primary objective was the safety and tolerability of vortioxetine, as assessed on the basis of AEs, vital signs and weight, ECGs, clinical laboratory values, and physical examination findings. AEs were assessed for severity (mild, moderate, or severe) and causal relationship with the study drug (probable, possible, or not related). Treatment-emergent adverse events (TEAEs) were defined as an AE with an onset that occurred after receiving the study drug and within 30 days after receiving the last dose of the study drug. Suicidal ideation and behavior were assessed as an exploratory variable utilizing the C-SSRS. Change in the severity of symptoms of depression and anxiety were assessed using the mean change from the open-label baseline in HAM-D24 total score (at all visits) and the mean change from baseline in the MADRS total score, HAM-A total score, and CGI-S at weeks 4, 24, and 52. Patient-reported outcomes included the SF-36 and the SDS.

Statistical analysis
The safety set included all study participants who received at least one dose of open-label study medication. The change in the severity of depressive symptoms was evaluated in study participants in the safety analysis who had been subjected to at least one post-open-label baseline evaluation [observed case (OC) data set]. Safety and efficacy data were summarized using descriptive statistics. The results were tabulated for all study participants enrolled in the open-label extension phase. Data were analyzed using the SAS System, version 9.1.3 (SAS Institute, Cary, North Carolina, USA).