The comparative effectiveness of COVID-19 monoclonal antibodies: A learning health system randomized clinical trial

Abstract

Background: Monoclonal antibodies (mAb) that neutralize SARS-CoV-2 decrease hospitalization and death compared to placebo in patients with mild to moderate COVID-19; however, comparative effectiveness is unknown. We report the comparative effectiveness of bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab.

Methods: A learning health system platform trial in a U.S. health system enrolled patients meeting mAb Emergency Use Authorization criteria. An electronic health record-embedded application linked local mAb inventory to patient encounters and provided random mAb allocation. Primary outcome was hospital-free days to day 28. Primary analysis was a Bayesian model adjusting for treatment location, age, sex, and time. Inferiority was defined as 99% posterior probability of an odds ratio < 1. Equivalence was defined as 95% posterior probability the odds ratio is within a given bound.

Findings: Between March 10 and June 25, 2021, 1935 patients received treatment. Median hospital-free days were 28 (IQR 28, 28) for each mAb. Mortality was 0.8% (1/128), 0.8% (7/885), and 0.7% (6/922) for bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab, respectively. Relative to casirivimab-imdevimab (n = 922), median adjusted odds ratios were 0.58 (95% credible interval [CI] 0.30-1.16) and 0.94 (95% CI 0.72-1.24) for bamlanivimab (n = 128) and bamlanivimab-etesevimab (n = 885), respectively. These odds ratios yielded 91% and 94% probabilities of inferiority of bamlanivimab versus bamlanivimab-etesevimab and casirivimab-imdevimab, and an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab.

Interpretation: Among patients with mild to moderate COVID-19, bamlanivimab-etesevimab or casirivimab-imdevimab treatment resulted in 86% probability of equivalence. No treatment met prespecified criteria for statistical equivalence. Median hospital-free days to day 28 were 28 (IQR 28, 28) for each mAb.

Funding and registration: This work received no external funding. The U.S. government provided the reported mAb. This trial is registered at ClinicalTrials.gov, NCT04790786.

Conflict of interest statement

None of the authors have conflicts of interest to report.

Copyright © 2022 Elsevier Inc. All rights reserved.

Figures

Fig. 1

Epidemiology of Monoclonal Antibody Infusions. Panel A shows the number of mAb-infused patients among the EHR screen eligible. Panel B shows the proportion of mAb-infused patients among EHR screen eligible by White or Black race. Hispanic ethnicity, Other, and Unknown race are not shown due to small sample sizes. Panel C shows the number of mAb infusions per 1000 cases prior to March 10, 2021. Panel D shows the number of mAb infusions per 1000 cases after March 10, 2021. Zip codes with Interpretive example: Prior to the trial (panel A), mAb infusion was low. In panel B, the proportion of White and Black race infused among EHR-screen eligible patients increased. In the UPMC catchment in Pennsylvania, mAb infusions also increased in amount (darker, panel C, D) and in geographic distribution (more zip code areas colored) during OPTIMISE-C19.

Fig. 2

CONSORT Diagram. Due to pharmacy logistics, five patients who received bamlanivimab-etesevimab had been randomly assigned to casirivimab-imdevimab, and seven patients who received casirivimab-imdevimab had been randomly assigned to bamlanivimab-etesevimab. All infused patients who received bamlanivimab monotherapy had been randomly assigned to bamlanivimab monotherapy.  The FDA mAb policies changed over time, resulting in varying mAb availability and EUA eligibility criteria over time (Table S1 in Supplement, p 1).  .

Fig. 3

Hospital-Free Days to Day 28. Primary outcome is displayed as horizontally stacked proportions by monoclonal antibody type. Red represents worse values and blue represents better values. The median adjusted odds ratio from the primary analysis, using a Bayesian cumulative logistic model, were 0.58 (95% credible interval, 0.30–1.16) and 0.94 (95% credible interval, 0.72–1.24) for the bamlanivimab and bamlanivimab-etesevimab groups compared with the casirivimab-imdevimab group. 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 first prespecified bound. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)