Abstract

IMPORTANCE Treatment options for coronavirus disease 2019 (COVID-19) that can be used irrespective of risk factors for severe disease are warranted. OBJECTIVE To assess the efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19. DESIGN The phase 3 part of a phase 2/3, double-blind, randomized, placebo controlled study conducted from February 10 to July 10, 2022. SETTING A multicenter study conducted at 92 institutions in Japan, Vietnam, and South Korea. PARTICIPANTS Patients (aged 12 to <70 years) with mild-to-moderate COVID-19 within 120 hours of positive viral testing. INTERVENTIONS Patients were randomized (1:1:1) to receive once-daily ensitrelvir 125 mg (375 mg on day 1), 250 mg (750 mg on day 1), or placebo for 5 days. Among 1821 randomized patients, 1030 (347, 340, and 343 in the ensitrelvir 125-mg, ensitrelvir 250-mg, and placebo groups, respectively) were randomized in less than 72 hours of disease onset and assessed as the primary analysis population. MAIN OUTCOMES AND MEASURES The primary end point was the time to resolution of five COVID-19 symptoms (stuffy or runny nose, sore throat, cough, feeling hot or feverish, and low energy or tiredness). Other end points included virologic efficacy and safety. RESULTS The mean age was 35.7, 35.3, and 34.7 years, and 193 (55.6%), 185 (54.4%), and 174 (50.7%) patients were men in the ensitrelvir 125-mg, ensitrelvir 250-mg, and placebo groups, respectively (intention-to-treat, primary analysis population). A significant difference (P=.04 with a Peto-Prentice generalized Wilcoxon test stratified by vaccination history) was observed in the primary end point between ensitrelvir 125 mg and placebo in the primary analysis population (difference in median, -24.3 hours; 95% confidence interval, -78.7 to 11.7). Viral RNA levels on day 4 and time to negative viral titer demonstrated significant reduction vs placebo. The incidence of adverse events was 44.2%, 53.6%, and 24.8% in the ensitrelvir 125-mg, ensitrelvir 250-mg, and placebo groups, respectively. No treatment-related serious adverse events were reported. CONCLUSIONS AND RELEVANCE Treatment with ensitrelvir 125 mg demonstrated clinical and antiviral efficacy without new safety concerns. Generalizability to non-Asian populations should be confirmed. TRIAL REGISTRATION Japan Registry of Clinical Trials identifier: jRCT2031210350.