Publication date: Feb 17, 2025

Ensitrelvir, a severe acute respiratory syndrome coronavirus-2 main protease inhibitor, has demonstrated clinical and virologic efficacy in previous studies. In this global phase 3 trial, nonhospitalized adults with mild-to-moderate coronavirus disease 2019 (COVID-19) and symptom onset within 5 days were randomized (1:1) to receive once-daily ensitrelvir (375 mg day 1, 125 mg days 2-5) or blinded matching placebo. The primary endpoint was the restricted mean time to sustained (≥2 days) resolution of 15 COVID-19 symptoms, recorded in participant daily diaries, through day 29 in participants starting treatment within 3 days after symptom onset. Virologic efficacy and safety were assessed. Of 2093 participants, 1888 started treatment within 3 days after symptom onset. Mean time to symptom resolution was 12. 5 and 13. 1 days with ensitrelvir and placebo, respectively (difference, -0. 6 days; 95% confidence interval, -1. 38 to 0. 19; P = .14). On day 4, ensitrelvir reduced least-squares mean RNA by 0. 72 log10 copies/mL more than placebo (95% confidence interval, 0. 55-0. 90). Among those with positive viral cultures at enrollment, 274/287 (95. 5%) ensitrelvir-treated versus 210/280 (75. 0%) placebo-treated participants had negative cultures on day 4. RNA rebound was similar (

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