The Choice of Viral Load End Point in Early Phase Trials of COVID-19 Treatments Aiming to Reduce 28-Day Hospitalization and/or Death.

Abstract

Virologic end points are used in phase 2 trials for COVID-19 therapeutics, but they have not been established as surrogates for clinical end points. No meta-analysis using individual participant data (IPD) has been undertaken to identify viral load outcomes for which treatment effects are best associated with effects on hospitalization/death. This meta-analysis combined IPD from 23 COVID-19 treatment versus control comparisons to calculate R2, a surrogacy measure quantifying the relationship between the treatment effect on 28-day hospitalization/death and the treatment effect on the surrogate. R2 ranges from 0 to 1, with a strong relationship ≥ 0.72, moderate 0.49 < R2 < 0.72, and weak ≤ 0.49. We estimated R2 for various viral load outcomes at days 3, 5, and 7, including change-from-baseline, slope, average area under the curve minus baseline (AAUCMB), and a change of at least 0.5 log10 copies/mL from baseline to day 3. R 2 was numerically highest for the change-from-baseline to day 3 (0.53; 95% confidence interval [CI], .26-.79), slightly lower for change-from-baseline to day 5 (0.49; 95% CI, .24-.75) and numerically lower for change-from-baseline to day 7 (0.40; 95% CI, .15-.65). All were statistically significant. Our study is the first to use IPD, allowing us to evaluate viral load collected on various study days as a surrogate to clinical outcomes. Change in log10(viral load) from baseline to day 3 or day 5 are moderate surrogates for 28-day hospitalization/death and suitable primary end points in phase 2 clinical trials and are preferred over change-from-baseline to day 7. Slope and AAUCMB require more calculation but did not improve prediction so are not recommended.