Efficacy and safety of zuranolone co-initiated with an antidepressant in adults with major depressive disorder: results from the phase 3 CORAL study

Abstract

Major depressive disorder (MDD) is a mental health disorder that can cause disability and functional impairment that standard-of-care (SOC) antidepressant therapies (ADTs) can take weeks to treat. Zuranolone is a neuroactive steroid and positive allosteric modulator of synaptic and extrasynaptic γ-aminobutyric acid (GABA) type A receptors approved as an oral, once-daily, 14-day treatment course in adults with postpartum depression and under investigation in adults with MDD. The phase 3 CORAL Study (NCT04476030) evaluated the efficacy and safety of zuranolone 50 mg co-initiated with SOC ADT (zuranolone+ADT) vs placebo co-initiated with SOC ADT (placebo+ADT) in adults with MDD. Patients were randomized 1:1 to once-daily, blinded zuranolone+ADT or placebo+ADT for 14 days, then continued open-label SOC ADT for 28 more days. The primary endpoint was change from baseline (CFB) in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score at Day 3. Among 425 patients in the full analysis set, CFB in HAMD-17 total score at Day 3 was significantly improved with zuranolone+ADT vs placebo+ADT (least squares mean [standard error], -8.9 [0.39] vs -7.0 [0.38]; p = 0.0004). The majority of patients receiving zuranolone+ADT that experienced treatment-emergent adverse events (TEAEs) reported mild or moderate events. The most common TEAEs present in ≥10% of patients in either zuranolone+ADT or placebo+ADT groups were somnolence, dizziness, headache, and nausea. These results demonstrate that zuranolone+ADT provided more rapid improvement in depressive symptoms compared with placebo+ADT in patients with MDD, with a safety profile consistent with previous studies. Clinical trial registration: ClinicalTrials.gov identifier: NCT04476030.

Fig. 1. Patient disposition.

ADT antidepressant therapy.

Fig. 2. Change from baseline in HAMD-17 total score.

Change from baseline in HAMD-17 total score at (A) Day 3 and (B) over the 14-day treatment period. Data are shown for the full analysis set using a mixed effects model for repeated measures. Change from baseline in HAMD-17 total score over the blinded treatment period was estimated using equal weights for the scheduled visits at Days 3, 8, 12, and 15. *p < 0.05. ADT antidepressant therapy, CFB change from baseline, HAMD-17 17-item Hamilton Rating Scale for Depression, LSM least squares mean, SE standard error.

Fig. 3. Improvement in depressive symptoms by time point and treatment group.

Change from baseline in (A) HAMD-17 total score and (B) HAMD-17 response and (C) HAMD-17 remission. HAMD-17 response was defined as a ≥50% reduction from baseline in HAMD-17 total score. HAMD-17 remission was defined as HAMD-17 total score ≤7. Data are shown for the full analysis set using a mixed effects model for repeated measures. Day 3 is the primary endpoint; all other time points were not adjusted for multiplicity, and p values are considered nominal. The vertical dashed line signifies the end of the treatment period and the final assessment of the primary endpoint. *p < 0.05. ADT antidepressant therapy, CFB change from baseline, HAMD-17 17-item Hamilton Rating Scale for Depression, LSM least squares mean, SE standard error.