Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients With Mild-to-Moderate COVID-19: The SCORPIO-SR Randomized Clinical Trial

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. Question Can 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? Findings In 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. Meaning Ensitrelvir 125 mg treatment shortened time to resolution of key COVID-19 symptoms. ### Competing Interest Statement Dr Yotsuyanagi has received consulting fees from Shionogi, lecture fees from Shionogi and ViiV Healthcare, and travel support from Shionogi outside the submitted work. He serves as an advisory board member for Shionogi and President of the Japanese Society of Infectious Diseases. Drs Ohmagari, Yamato, and Nguyen declare no conflict of interest. Dr Doi has received funding relevant to the submitted work from Shionogi and grants from Entasis; consulting fees from Gilead Sciences, Moderna, Shionogi, GSK, Meiji Seika, bioMerieux, and FujiFilm; and lecture fees from Gilead Sciences, Shionogi, MSD, and bioMerieux outside the submitted work. Dr Bong has received funding relevant to the submitted work from Ildong Pharmaceutical (partner of Shionogi for the development of ensitrelvir in the Republic of Korea) and grants from Hyundai Bioscience, Daewoong Pharmaceutical, and Asan Pharm outside the submitted work. Mr Imamura, Dr Sonoyama, Mr Ichihashi, Mr Sanaki, Ms Tsuge, and Dr Uehara are full-time employees of Shionogi and may own stocks or stock options. Dr Mukae has received funding relevant to the submitted work from Shionogi, consulting fees from Shionogi and MSD, and lecture fees from Shionogi, MSD, Gilead Sciences, AstraZeneca, Pfizer, and GSK outside the submitted work. ### Clinical Trial jRCT2031210350 ### Funding Statement This study was funded by Shionogi & Co., Ltd. and the Organization of the Ministry of Health, Labour and Welfare, Japan. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was reviewed and approved by the institutional review boards of all participating institutions listed in the List of Investigators in the Supplement. All patients or their legally acceptable representatives provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. 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