Optimal design for phase 2 studies of SARS-CoV-2 antiviral drugs
Watson JA., Kissler S., Day NPJ., Grad Y., White NJ.
<jats:title>Abstract</jats:title><jats:p>There is no agreed methodology for pharmacometric assessment of candidate antiviral drugs in COVID-19. The most widely used measure of virological response in clinical trials so far is the time to viral clearance assessed by qPCR of viral nucleic acid in eluates from serial nasopharyngeal swabs. We posited that the rate of viral clearance would have better discriminatory value. Using a pharmacodynamic model fit to individual SARS-CoV-2 virus clearance data from 46 uncomplicated COVID-19 infections in a cohort of prospectively followed adults, we simulated qPCR viral load data to compare type 2 errors when using time to clearance and rate of clearance under varying antiviral effects, sample sizes, sampling frequencies and durations of follow-up. The rate of viral clearance is a uniformly superior endpoint as compared to time to clearance with respect to type 2 error, and it is not dependent on initial viral load or assay sensitivity. For greatest efficiency pharmacometric assessments should be conducted in early illness and daily qPCR samples should be taken over 7 to 10 days in each patient studied. Adaptive randomisation and early stopping for success permits more rapid identification of active interventions.</jats:p>