Abstract
Esmethadone is under development as an adjunctive treatment for major depressive disorder in patients with inadequate response to standard antidepressants. In the phase 3 study REL-1017-301, esmethadone did not meet the primary endpoint of mean change from baseline (CFB) in Montgomery-Åsberg Depression Rating Scale (MADRS) at day 28, although it showed statistically significant results on the key secondary endpoint of response rate. Post hoc exploratory analyses suggested efficacy in patients with baseline MADRS greater than or equal to 35 (severe depression) (P = 0.006). The objective of this study was to enhance the reliability of these post hoc analyses through sensitivity analyses. (a) Sensitivity analyses for the primary endpoint using baseline MADRS cutoffs 31-37 showed larger treatment effects with higher baseline severity. Mixed model for repeated measures and per-protocol results were consistent. (b) CFB in MADRS was modeled for each treatment arm individually using all available data. The mean CFB in MADRS demonstrated separation between esmethadone and placebo arms for patients with a baseline score of 35 or higher. These exploratory, hypothesis-generating sensitivity analyses support the potential efficacy of esmethadone in patients with severe depression.