{"doi":"10.1093/infdis/jiaf282","title":"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":"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.","journal":"The Journal of Infectious Diseases","year":2025,"id":538266,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9331,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1109695,"name":"Eric Chun‐Pu Chu","orcid":"0000-0002-0893-556X","position":1,"is_corresponding":false},{"id":387536,"name":"Thomas A. Murray","orcid":"0000-0003-2769-4957","position":2,"is_corresponding":false},{"id":49889,"name":"Carolyn T. Bramante","orcid":"0000-0001-5858-2080","position":3,"is_corresponding":false},{"id":419481,"name":"Carlee Moser","orcid":"0000-0001-5601-9112","position":4,"is_corresponding":false},{"id":1425284,"name":"Naomi Givens","orcid":null,"position":5,"is_corresponding":false},{"id":1424899,"name":"Mazin Abdelghany","orcid":"0000-0001-5192-8659","position":6,"is_corresponding":false},{"id":1425285,"name":"Chris Blair","orcid":null,"position":7,"is_corresponding":false},{"id":1424900,"name":"Shuguang Chen","orcid":"0000-0002-6284-6680","position":8,"is_corresponding":false},{"id":1425286,"name":"Prince Kumar Lat","orcid":null,"position":9,"is_corresponding":false},{"id":1424901,"name":"Ofir Harari","orcid":"0000-0002-2901-0558","position":10,"is_corresponding":false},{"id":1424902,"name":"Nicole L. Kallewaard","orcid":"0000-0002-9026-8865","position":11,"is_corresponding":false},{"id":376868,"name":"Lisa Macpherson","orcid":"0000-0003-3224-9233","position":12,"is_corresponding":false},{"id":267658,"name":"David R. Boulware","orcid":"0000-0002-4715-0060","position":13,"is_corresponding":false},{"id":1029306,"name":"Clara Suñer","orcid":"0000-0003-2581-8864","position":14,"is_corresponding":false},{"id":585053,"name":"Oriol Mitjà","orcid":null,"position":15,"is_corresponding":false},{"id":268630,"name":"Stacey J. Adam","orcid":"0000-0002-4590-5175","position":16,"is_corresponding":false},{"id":529228,"name":"Victor De Gruttola","orcid":null,"position":17,"is_corresponding":false},{"id":65752,"name":"Michael D. Hughes","orcid":"0000-0001-8562-2316","position":18,"is_corresponding":false},{"id":517467,"name":"Daniel J. Rubin","orcid":"0000-0002-6871-6246","position":19,"is_corresponding":false},{"id":36878,"name":"Davey M. 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