Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients With Mild-to-Moderate COVID-19: The SCORPIO-SR Randomized Clinical Trial
Authors: Yotsuyanagi Hiroshi , Ohmagari Norio , Doi Yohei , Yamato Masaya , Hoang Bac Nguyen , Cha Bong Ki , Imamura Takumi , Sonoyama Takuhiro , Ichihashi Genki , Sanaki Takao , Tsuge Yuko , Uehara Takeki , Mukae Hiroshi 
Published: July 2023

AbstractIMPORTANCETreatment options for coronavirus disease 2019 (COVID-19) that can be used irrespective of risk factors for severe disease are warranted.OBJECTIVETo assess the efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19.DESIGNThe phase 3 part of a phase 2/3, double-blind, randomized, placebo-controlled study conducted from February 10 to July 10, 2022.SETTINGA multicenter study conducted at 92 institutions in Japan, Vietnam, and South Korea.PARTICIPANTSPatients (aged 12 to <70 years) with mild-to-moderate COVID-19 within 120 hours of positive viral testing.INTERVENTIONSPatients 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 MEASURESThe 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.RESULTSThe 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 RELEVANCETreatment with ensitrelvir 125 mg demonstrated clinical and antiviral efficacy without new safety concerns. Generalizability to non-Asian populations should be confirmed.TRIAL REGISTRATIONJapan Registry of Clinical Trials identifier:jRCT2031210350.Key PointsQuestionCan ensitrelvir, an oral severe acute respiratory syndrome coronavirus 2 3C-like protease inhibitor, shorten the duration of symptoms in patients with mild-to-moderate COVID-19 irrespective of risk factors for severe disease?FindingsIn this phase 3 part of a phase 2/3, double-blind, randomized study SCORPIO-SR, a statistically significant difference was observed in the time to resolution of five COVID-19 symptoms between ensitrelvir 125 mg and placebo in patients randomized in less than 72 hours of disease onset. Viral RNA and viral titer demonstrated significant reduction vs placebo.MeaningEnsitrelvir 125 mg treatment shortened time to resolution of key COVID-19 symptoms.