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

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.

SUBMITTER: Gerbasi ME

PROVIDER: S-EPMC7957380 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBrexanolone injection, the first therapy approved by the US FDA for the treatment of postpartum depression (PPD) in adults, has been shown to produce a significantly greater decrease in the Hamilton Rating Scale for Depression (HAM-D) total score than placebo in randomised controlled trials (RCTs) of women with PPD.ObjectivesGiven the rapid effect of brexanolone injection (within 60 h) sustained throughout the length of the trials (30 days), we sought to compare its efficacy data against selective serotonin reuptake inhibitors (SSRIs), the class of antidepressants most commonly prescribed for PPD, using HAM-D and Edinburgh Postnatal Depression Scale (EPDS) outcomes from currently available RCTs.MethodsWe extracted data from 26 studies identified in a systematic literature review of pharmacological and pharmacological/nonpharmacological combination therapies in PPD. Six studies were suitable to form evidence networks through which to perform indirect treatment comparisons (ITCs) of HAM-D and EPDS outcomes between brexanolone and SSRIs. Having assessed the comparability and suitability of the available evidence for analysis, we discovered significant heterogeneity in the study designs, most notably in the placebo arms of the trials. We therefore conducted matching-adjusted indirect comparisons (MAICs) between brexanolone and the placebo arms of comparator studies, subsequently using the MAIC results of brexanolone versus placebo, and results for SSRIs versus placebo, to form ITCs of brexanolone versus SSRIs at three separate time points-day 3, week 4 and last observation. ITCs were calculated as the differences in change from baseline (CFB) in HAM-D and, separately, CFB in EPDS, between treatments, and reported with 95% confidence intervals (CIs).ResultsFor all time points, MAICs showed larger differences in CFB for brexanolone compared with SSRIs. Differences (95% CIs) between brexanolone and SSRIs were 12.79 (8.04-17.53) [day 3], 5.87 (- 1.62 to 13.37) [week 4] and 0.97 (- 6.35 to 8.30) [last observation] for the HAM-D. For the EPDS, the differences in CFB were 7.98 (5.32-10.64) [day 3], 6.35 (3.13-9.57) [week 4] and 4.05 (0.79-7.31) [last observation]. Other analytical approaches are also presented to demonstrate the similarity of results, using a network meta-analysis approach, and the importance of using the MAIC method to control for the important heterogeneity between placebo arms.ConclusionsAcknowledging the limitations of ITCs and this evidence base, when compared with SSRIs, these analyses suggest that brexanolone demonstrated larger differences in CFB for both patient- and clinician-reported PPD outcomes and at all investigated time points after adjusting for differences between placebos in the included studies.

Project description:BackgroundAdvance directives (AD) may promote preference-concordant care yet are absent in many patients with Chronic Obstructive Pulmonary Disease (COPD). In order to begin to inform AD discussions between clinicians and COPD patients, we constructed a decision tree to estimate the impact of alternative AD decisions on both quality and quantity of life (quality adjusted life years, QALYs).MethodsTwo aspects of the AD were considered, Do Not Intubate (DNI; i.e., no invasive mechanical ventilation) and Full Code (i.e., may use invasive mechanical ventilation). Model parameters were based on published estimates. Our model follows hypothetical patients with COPD to evaluate the effect of underlying COPD severity and of hypothetical patient-specific preferences (about long-term institutionalization and complications from invasive mechanical ventilation) on the recommended AD.ResultsOur theoretical model recommends endorsing the Full Code advance directive for patients who do not have strong preferences against having a potential complication from intubation (ETT complications) or being discharged to a long-term ECF. However, our model recommends endorsing the DNI advance directive for patients who do have strong preferences against having potential complications of intubation and are were willing to tradeoff substantial amounts of time alive to avoid ETT complications or permanent institutionalization. Our theoretical model also recommends endorsing the DNI advance directive for patients who have a higher probability of having complications from invasive ventilation (ETT).ConclusionsOur model suggests that AD decisions are sensitive to patient preferences about long-term institutionalization and potential complications of therapy, particularly in patients with severe COPD. Future work will elicit actual patient preferences about complications of invasive mechanical ventilation, and incorporate our model into a clinical decision support to be used for actual COPD patients facing AD decisions.

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

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