The Journal of infectious diseases · 2025
The Choice of Viral Load End Point in Early Phase Trials of COVID-19 Treatments Aiming to Reduce 28-Day Hospitalization and/or Death.
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Mateja Allyson, Chu Eric, Murray Thomas A, Bramante Carolyn T, Moser Carlee, Givens Naomi, Abdelghany Mazin, Blair Chris, Chen Shuguang, Lat Prince Kumar, Harari Ofir, Kallewaard Nicole L, Macpherson Lisa Farmer, Boulware David R, Suñer Clara, Mitjà Oriol, Adam Stacey J, De Gruttola Victor, Hughes Michael D, Rubin Daniel, Smith Davey M, Potter Gail E
Аннотация
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
DISCUSSION: 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.
METHODS: 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.
RESULTS: 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.
DISCUSSION: 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.