Luetkemeyer A.F.Chew K.W.Lacey S.Hughes M.D.Harrison L.J.Daar E.S.Eron J.Fletcher C.V.Greninger A.L.Hessinger D.Li J.Z.Mailhot D.Wohl D.Chayakulkeeree M.Mendoza J.L.A.Elistratova P.Makinde O.Morgan G.Portsmouth S.Uehara T.Smith D.Currier J.S.Mahidol University2025-07-282025-07-282025-06-15Clinical Infectious Diseases Vol.80 No.6 (2025) , 1235-124410584838https://repository.li.mahidol.ac.th/handle/20.500.14594/111427Background Ensitrelvir, a severe acute respiratory syndrome coronavirus-2 main protease inhibitor, has demonstrated clinical and virologic efficacy in previous studies. Methods 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. Results 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 (<1.5%) between groups. The proportion of participants with ≥1 adverse event was similar with ensitrelvir (61.5%) and placebo (60.6%). No treatment-related serious adverse events or deaths occurred. Three (0.3%) ensitrelvir-treated and 1 (0.1%) placebo-treated participants had COVID-19-related hospitalizations by day 29. Conclusions Despite the evidence of antiviral activity with ensitrelvir, this trial did not demonstrate a significant difference in time to sustained symptom resolution.MedicineArticleSCOPUS10.1093/cid/ciaf0292-s2.0-1050112468291537659139960062