The Effects of Cyproheptadine on Severe COVID-19 From the I-SPY COVID Adaptive Platform Trial

<h3>Background</h3> Severe COVID-19 has been associated with hypercoagulability and platelet activation, which is known to result in excessive accumulation of serotonin. However, few studies have evaluated whether serotonergic blockade may improve clinical outcomes among those with COVID-19. <h3>Research Question</h3> Does cyproheptadine, an antiserotonergic drug most commonly used to treat serotonin syndrome, improve time to clinical recovery in patients with severe COVID-19? <h3>Study Design and Methods</h3> The Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis in COVID (I-SPY COVID) study is a phase 2, multicenter, adaptive, open-label randomized controlled trial designed to screen potential therapeutic agents rapidly to identify those with a high probability of improving outcomes for hospitalized critically ill patients with COVID-19. For this report, participants randomized to receive cyproheptadine 8 mg enterally every 8 hours for 10 days or until hospital discharge were compared with concurrently enrolled control patients who were treated with the standard of care regimen of dexamethasone and remdesivir and did not receive an investigational agent. Bayesian survival regression models were used to model the hazard functions for the 2 events of interest: (1) recovery (treating death as a competing event) and (2) overall death as a function of randomization arm and baseline COVID-19 level. <h3>Results</h3> From September through December 2021, 35 participants were randomized and consented to receive cyproheptadine and 61 concurrent control patients were eligible for analysis. At that point, futility criteria were met and the data monitoring committee halted further enrollment into the cyproheptadine arm. The posterior probability that cyproheptadine would increase the rate of recovery was 0.1% and the posterior probability that cyproheptadine would improve survival was 16.3%. <h3>Interpretation</h3> In an open-label phase 2 trial of adults critically ill with severe COVID-19, cyproheptadine did not improve recovery or survival compared with the standard of care. <h3>Clinical Trial Registration</h3> ClinicalTrials.gov; No.: NCT04488081; URL: www.clinicaltrials.gov