Introduction: Buprenorphine/samidorphan (BUP/SAM) is an investigational opioid system modulator demonstrating efficacy versus placebo as an adjunctive treatment for major depressive disorder (MDD) and a consistent safety profile in placebo-controlled studies. Interim results from a 52-week, phase 3, BUP/SAM study (FORWARD-2) are reported.
Methods: FORWARD-2 (NCT02141399) enrolled patients from 4 placebo-controlled studies and de novo patients. Patients with a confirmed MDD diagnosis and history of inadequate response to antidepressant therapy (ADT) were treated with an established ADT for ≥8 weeks before receiving open-label, sublingual BUP/SAM 2mg/2mg adjunctive treatment for up to 52 weeks. Safety (primary objective), suicidal ideation or behavior (SIB), abuse potential, and withdrawal were assessed via adverse events (AEs), the Columbia Suicide Severity Rating Scale, and the Clinical Opiate Withdrawal Scale. Montgomery–Åsberg Depression Rating Scale (MADRS) scores and remission rates were assessed.
Results: Of 1454 patients, 49% completed the study, 11% discontinued due to AEs and 40% discontinued for other reasons as of the interim data cut. Nausea, headache, constipation, dizziness, and somnolence each occurred in ≥10% of patients. Increased SIB was not observed. Euphoria-related events (1.2%) and drug withdrawal (0.4%) were uncommon. Incidence of COWS score worsening from “No Withdrawal at Baseline” was low (5.5%). Mean MADRS scores improved from baseline and maintained until study end. Mean 52-week remission rate was 52.5%.
Conclusions: Long-term BUP/SAM treatment in patients with MDD was well tolerated with an AE profile consistent with placebo-controlled studies and showed durability of an antidepressant effect for up to 52 weeks.