Brexanolone in Postpartum Depression: Post Hoc Analyses to Help Inform Clinical Decision-Making

Margaret E Gerbasi, Samantha Meltzer-Brody, Sarah Acaster, Moshe Fridman, Vijayveer Bonthapally, Paul Hodgkins, Stephen J Kanes, Adi Eldar-Lissai, Margaret E Gerbasi, Samantha Meltzer-Brody, Sarah Acaster, Moshe Fridman, Vijayveer Bonthapally, Paul Hodgkins, Stephen J Kanes, Adi Eldar-Lissai

Abstract

Background: Brexanolone (BRX) injection was approved by the United States Food and Drug Administration in 2019 for the treatment of adults with postpartum depression (PPD) based on two Phase 3 clinical trials. Materials and Methods: Data from the three trials were combined. PPD-specific 17-item Hamilton Rating Scale for Depression (HAMD-17) group-level minimal important difference (MID) and patient-level meaningful change (meaningful change threshold [MCT]) were estimated and applied to differences in BRX versus placebo (PBO) at hour 60 (primary endpoint) and day 30 (end of trial follow-up). Likelihood of HAMD-17 response and remission and Clinical Global Impression of Improvement (CGI-I) response for BRX versus PBO were assessed at hour 60 and as sustained through day 30 using relative risk. Associated number needed to treat (NNT) and number needed to harm (NNH) values were also estimated. Results: Two-hundred nine patients were included. The average HAMD-17 MID estimate was -2.1; the least-squared mean difference between BRX and PBO exceeded this at hour 60 and day 30. Minimal, moderate, and large MCTs were estimated to be -9, -15, and -20 points, respectively. Significantly more BRX-treated than PBO-treated patients achieved minimal, moderate, and large change (all ps < 0.05) at hour 60 and large meaningful response at day 30 (p < 0.05). BRX-treated patients were more likely to sustain HAMD-17 remission and CGI-I response through day 30 versus PBO. NNTs ranged from 4 to 8, with NNH of 97. Conclusions: BRX provided meaningful changes relative to PBO, rapid (hour 60), and sustained improvements (day 30) in PPD symptoms, low NNT, and large NNH. These results may help inform treatment decision-making. Clinicaltrials.gov registration numbers: NCT02614547, NCT02942004, and NCT02942017.

Keywords: brexanolone; meaningful change; number needed to harm; number needed to treat; postpartum depression.

Conflict of interest statement

Drs. Gerbasi, Bonthapally, Kanes, and Eldar-Lissai are employees of Sage Therapeutics, Inc. and own stock or stock options in the company. Dr. Hodgkins was an employee of Sage Therapeutics, Inc. at the time the study was conducted and owns stock/stock options in the company. Dr. Meltzer-Brody reports personal fees from MedScape and grants from Sage Therapeutics, Inc., awarded to the University of North Carolina (Chapel Hill, NC, USA) during the conduct of the brexanolone injection clinical trials and grants from Janssen, PCORI, and the NIH outside the submitted work. Ms. Acaster and Dr. Fridman are employees of Acaster Lloyd Consulting, Ltd. and AMF Consulting, respectively, which were paid by Sage Therapeutics to conduct the research reported in this manuscript.

Figures

FIG. 1.
FIG. 1.
Application of ½ SD and 1 SEM minimal important difference estimates to BRX versus PBO clinical trial data. The HAMD-17 group differences between BRX and PBO remain meaningful when applying estimates for the ½ SD estimate of minimal important difference and 1 SEM estimate of minimal important difference to the mean differences from hour 24 onward. LS, least-squares; BRX, brexanolone injection 90 μg/kg/h; HAMD-17, 17-item Hamilton Rating Scale for Depression; PBO, placebo; SD, standard deviation; SEM, standard error of measurement.
FIG. 2.
FIG. 2.
HAMD-17 patient-level meaningful change from baseline at hour 60 (A) and day 30 (B) with BRX versus PBO. Improvement cutoffs were −9, −15, and −20 for minimal, moderate, and large meaningful change, respectively. BRX, brexanolone injection 90 μg/kg/h; PBO, placebo injection.

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