OBJECTIVES

: Major depressive disorder (MDD) can have significant impact on health-related quality of life (HRQoL). A Phase 2, double-blind, randomized, placebo-controlled study of the investigational, orally-bioavailable GABA_A receptor positive allosteric modulator SAGE-217 in MDD assessed HRQoL using the Medical Outcomes Study Short Form-36 (SF-36v2) acute version.

METHODS

: Subjects (N=89) with MDD and a 17-item Hamilton Rating Scale for Depression (HAM-D) total score ≥ 22 were enrolled. Subjects were randomized 1:1 to receive 30 mg SAGE-217 or placebo on Days 1-14, with follow-up for 4 weeks. Depressive symptom reduction versus placebo was assessed by HAM-D total score change from baseline at Day 15. The SF-36v2 assessed patient reported differences in HRQoL. Comparisons to the general population used normative-based scoring; domain and summary scores with established minimally important differences (MID) were applied to determine clinical relevance. Safety and tolerability were assessed by standard safety parameters, including adverse event (AE) reporting.

RESULTS

: SAGE-217 achieved the Day 15 primary endpoint, with a greater least-squares mean reduction from baseline in HAM-D total score versus placebo (-17.4 versus -10.3; p<0.0001). At Day 15, SAGE-217 demonstrated statistically significant (p<0.05) increases in SF-36v2 least-squares mean scores versus placebo for general health (8.6 vs. 4.7), vitality (15.7 vs. 7.9), mental health (17.3 vs. 10.4), and mental component summary (20.2 vs. 12.8) scores. Bodily pain, general health, vitality, and physical component scores reached general population normative values for the SAGE-217 group. MID (2-3 points) was met for these scores, as well as social functioning and role emotional. There were no deaths, serious or severe AEs reported. The most common SAGE-217 group AEs reported (≥5%) included headache, dizziness, nausea, and somnolence.

CONCLUSIONS

: Subjects with MDD receiving SAGE-217 reported meaningful improvements in multiple domains of the SF-36v2, indicating significant improvements in HRQoL versus subjects receiving placebo in this randomized, double-blind study.