Zuranolone in Major Depressive Disorder (MDD): Minimal Important Difference (MID) and Meaningful Change Threshold (MCT) on the 17-item Hamilton Rating Scale for Depression (HAMD-17)

Abstract: Objective: WATERFALL (Phase 3; NCT04442490), adult patients with moderate to severe MDD who received zuranolone 50mg vs placebo showed statistically significant improvement in depressive symptoms (assessed by change from baseline [CFB] in HAMD-17 total score) at Day 15 (-1.7; p-value = 0.0141). Published HAMD-17 meaningful improvement estimates were based on more heterogenous MDD populations. The objectives were to establish a HAMD-17 MID for group-level data and patient-level MCT for moderate/severe MDD, and apply these to WATERFALL data. Methods: HAMD-17 MID was estimated using two distribution-based methods: one-half standard deviation (SD) for the pooled sample at baseline and one standard error of measurement (SEM; using a test re-test intra-class correlation coefficient). HAMD-17 MCT was calculated based on mean HAMD-17 improvement in patients with 1-unit improvement in Clinician Global Impressions of Severity response. Results: 537 patients were included. HAMD-17 MID estimates were -1.32 and -2.01 based on ½ SD and one SEM, respectively, with mean MID of -1.67. WATERFALL analysis estimates of mean difference in CFB HAMD-17 total score at Day 15 exceeded ½ SD and mean MID. The estimated HAMD-17 MCT was -9 points; a significantly greater proportion (p