A Learning Health System Randomized Trial of Monoclonal Antibodies for Covid-19

Abstract

ABSTRACT Background: Neutralizing monoclonal antibodies (mAb) targeting SARS CoV2 decrease hospitalization and death in patients with mild to moderate Covid 19. Yet, their clinical use is limited, and comparative effectiveness is unknown. Methods: We present the first results of an ongoing, learning health system adaptive platform trial to expand mAb treatment to all eligible patients and evaluate the comparative effectiveness of available mAbs. The trial launched March 10, 2021. Results are reported as of June 25, 2021 due to the U.S. federal decision to pause distribution of bamlanivimab etesevimab; patient follow-up concluded on July 23, 2021. Patients referred for mAb who met Emergency Use Authorization criteria were provided a random mAb allocation of bamlanivimab, bamlanivimab etesevimab, or casirivimab imdevimab with a therapeutic interchange policy. The primary outcome was hospital-free days (days alive and free of hospital) within 28 days, where patients who died were assigned -1 day. The primary analysis was a Bayesian cumulative logistic model of all patients treated at an infusion center or emergency department, adjusting for treatment location, age, sex, and time. Inferiority was defined as a 99% posterior probability of an odds ratio < 1. Equivalence was defined as a 95% posterior probability that the odds ratio is within a given bound. Results: Prior to trial launch, 3.1% (502) of 16,345 patients who were potentially eligible by an automated electronic health record (EHR) screen received mAb. During the trial period, 23.2% (1,201) of 5,173 EHR-screen eligible patients were treated, a 7.5-fold increase. After including additional referred patients from outside the health system, a total of 1,935 study patients received mAb therapy (128 bamlanivimab, 885 bamlanivimab etesevimab, 922 casirivimab imdevimab). Mean age ranged from 55 to 57 years, half were female (range, 53% to 54%), and 17% were Black (range, 12% to 19%). Median hospital free days were 28 (IQR, 28 to 28) for each mAb group. Hospitalization varied between groups (bamlanivimab, 12.5%; bamlanivimab etesevimab, 14.7%, casirivimab imdevimab, 14.3%). Relative to casirivimab-imdevimab, the median adjusted odds ratios were 0.58 (95% credible interval (CI), 0.30 to 1.16) and 0.94 (95% CI, 0.72 to 1.24) for the bamlanivimab and bamlanivimab-etesevimab groups, respectively. These odds ratios yielded 91% and 94% probabilities of inferiority of bamlanivimab versus bamlanivimab etesevimab and casirivimab imdevimab respectively, and an 86% probability of equivalence between bamlanivimab etesevimab and casirivimab imdevimab, at the prespecified odds ratio bound of 0.25. Twenty one infusion related adverse events occurred in 0% (0/128), 1.4% (12/885), and 1.0% (9/922) of patients treated with bamlanivimab, bamlanivimab etesevimab, and casirivimab imdevimab, respectively. Conclusion: In non-hospitalized patients with mild to moderate Covid-19, bamlanivimab, compared to bamlanivimab etesevimab and casirivimab imdevimab, resulted in 91% and 94% probabilities of inferiority with regards to odds of improvement in hospital free days within 28 days. There was an 86% probability of equivalence between bamlanivimab etesevimab and casirivimab imdevimab at an odds ratio bound of 0.25. However, the trial was unblinded early due to federal distribution decisions, and no mAb met prespecified criteria for statistical inferiority or equivalence. (ClinicalTrials.gov, NCT04790786).