Discussion
MDD, depression, treatment-resistant depression, depressive symptoms
SECONDARY, REMISSION
The CORAL Study was designed to assess the rapid improvement in depressive symptoms through co-initiation of zuranolone with an SOC ADT. The primary endpoint of CFB in HAMD-17 total score at D3 demonstrated significantly greater improvement in depressive symptoms with zuranolone+ADT vs placebo+ADT, providing clinical evidence for zuranolone as a potential rapid-acting treatment for patients with MDD who are initiating SOC ADTs. The effect size for the primary endpoint at D3 was 0.38. While not directly comparable, the reported mean effect size of varying primary endpoints for 34 ADT registration trials conducted after 2000 was 0.29 [The key secondary endpoint examined this temporal benefit with zuranolone+ADT more broadly, showing these improvements to be statistically significant over the full blinded treatment period, and not limited only to D3. Other secondary endpoints that were not nominally significant or part of the formal testing procedure showed that 53.4% of patients who received zuranolone+ADT achieved HAMD-17 response vs 49.2% of those receiving placebo+ADT at D15, with a median time to first response of 13 and 15 days, respectively; in addition, 29.1% and 21.8% of patients in the zuranolone+ADT and placebo+ADT groups, respectively, achieved HAMD-17 remission at D15. Most of the other secondary endpoints were not nominally significant.The rapid improvement in depressive symptoms experienced by patients receiving zuranolone+ADT was also clinically meaningful, which was quantified using the MCT. The MCT assesses patient-level clinical significance based on patients achieving a threshold CFB in HAMD-17, which was estimated for a similar patient population in the WATERFALL Study to be –9.0 [Patients administered zuranolone vs placebo, each co-initiated with an SOC ADT, experienced mild to moderate AEs consistent with the known safety profiles of the study drugs [A limitation of the CORAL Study is that these results may not be generalizable to all patients with MDD, as adults with treatment-resistant depression or those at significant risk of suicide (or attempted suicide within the current episode) were not enrolled. Another limitation of CORAL and other zuranolone studies is that a patient’s AE profile may have had an unblinding effect of revealing treatment with zuranolone+ADT. The large placebo response commonly observed in depression studies was also observed in CORAL [Given the considerable heterogeneity of MDD [