Improving Precision and Power in Randomized Trials for COVID-19 Treatments Using Covariate Adjustment, for Binary, Ordinal, and Time-to-Event Outcomes

Time is of the essence in evaluating potential drugs and biologics for the treatment and prevention of COVID-19. There are currently over 400 clinical trials (phase 2 and 3) of treatments for COVID-19 registered on clinicaltrials.gov. Covariate adjustment is a statistical analysis method with potential to improve precision and reduce the required sample size for a substantial number of these trials. Though covariate adjustment is recommended by the U.S. Food and Drug Administration and the European Medicines Agency, it is underutilized, especially for the types of outcomes (binary, ordinal and time-to-event) that are common in COVID-19 trials. To demonstrate the potential value added by covariate adjustment in this context, we simulated two-arm, randomized trials comparing a hypothetical COVID-19 treatment versus standard of care, where the primary outcome is binary, ordinal, or time-to-event. Our simulated distributions are derived from two sources: longitudinal data on over 500 patients hospitalized at Weill Cornell Medicine New York Presbyterian Hospital, and a Centers for Disease Control and Prevention (CDC) preliminary description of 2449 cases. We found substantial precision gains from using covariate adjustment–equivalent to 9–21% reductions in the required sample size to achieve a desired power–for a variety of estimands (targets of inference) when the trial sample size was at least 200. We provide an R package and practical recommendations for implementing covariate adjustment. The estimators that we consider are robust to model misspecification.