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

{ 'indexed': {'date-parts': [[2024, 2, 11]], 'date-time': '2024-02-11T11:31:30Z', 'timestamp': 1707651090869}, 'reference-count': 35, 'publisher': 'American Medical Association (AMA)', 'issue': '2', 'content-domain': {'domain': [], 'crossmark-restriction': False}, 'abstract': '<jats:sec><jats:title>Importance</jats:title><jats:p>Treatment options for COVID-19 are ' 'warranted irrespective of the presence of risk factors for severe ' 'disease.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>To assess the ' 'efficacy and safety of ensitrelvir in patients with mild to moderate ' 'COVID-19.</jats:p></jats:sec><jats:sec><jats:title>Design, Setting, and ' 'Participants</jats:title><jats:p>This phase 3 part of a phase 2/3, double-blind, ' 'placebo-controlled randomized clinical trial was conducted from February 10 to July 10, 2022, ' 'with a 28-day follow-up period, at 92 institutions in Japan, Vietnam, and South Korea. ' 'Patients (aged 12 to &amp;amp;lt;70 years) with mild to moderate COVID-19 within 120 hours of ' 'positive viral test results were ' 'studied.</jats:p></jats:sec><jats:sec><jats:title>Interventions</jats:title><jats:p>Patients ' 'were randomized (1:1:1) to receive 125 mg of once-daily ensitrelvir (375 mg on day 1), 250 mg ' 'of once-daily ensitrelvir (750 mg on day 1), or placebo for 5 ' 'days.</jats:p></jats:sec><jats:sec><jats:title>Main Outcomes and ' 'Measures</jats:title><jats:p>The primary end point was the time to resolution of the ' 'composite of 5 characteristic symptoms of SARS-CoV-2 Omicron infection, assessed using a ' 'Peto-Prentice generalized Wilcoxon test stratified by vaccination history. Virologic efficacy ' 'and safety were also ' 'assessed.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>A total of ' '1821 patients were randomized, of whom 1030 (347 in the 125-mg ensitrelvir group, 340 in the ' '250-mg ensitrelvir group, and 343 in the placebo group) were randomized in less than 72 hours ' 'of disease onset (primary analysis population). The mean (SD) age in this population was 35.2 ' '(12.3) years, and 552 (53.6%) were men. A significant difference was observed between the ' '125-mg ensitrelvir group and the placebo group (<jats:italic>P</jats:italic>\u2009=\u2009.04 ' 'with a Peto-Prentice generalized Wilcoxon test). The difference in median time was ' 'approximately 1 day between the 125-mg ensitrelvir group and the placebo group (167.9 vs ' '192.2 hours; difference, −24.3 hours; 95% CI, −78.7 to 11.7 hours). Adverse events were ' 'observed in 267 of 604 patients (44.2%) in the 125-mg ensitrelvir group, 321 of 599 patients ' '(53.6%) in the 250-mg ensitrelvir group, and 150 of 605 patients (24.8%) in the placebo ' 'group, which included a decrease in high-density lipoprotein level (188 [31.1%] in the 125-mg ' 'ensitrelvir group, 231 [38.6%] in the 250-mg ensitrelvir group, and 23 [3.8%] in the placebo ' 'group). No treatment-related serious adverse events were ' 'reported.</jats:p></jats:sec><jats:sec><jats:title>Conclusions and ' 'Relevance</jats:title><jats:p>In this randomized clinical trial, 125-mg ensitrelvir treatment ' 'reduced the time to resolution of the 5 typical COVID-19 symptoms compared with placebo in ' 'patients treated in less than 72 hours of disease onset; the absolute difference in median ' 'time to resolution was approximately 1 day. Ensitrelvir demonstrated clinical and antiviral ' 'efficacy without new safety concerns. Generalizability to populations outside Asia should be ' 'confirmed.</jats:p></jats:sec><jats:sec><jats:title>Trial ' 'Registration</jats:title><jats:p>Japan Registry of Clinical Trials Identifier: <jats:ext-link ' 'xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" ' 'xlink:href="https://jrct.niph.go.jp/en-latest-detail/jRCT2031210350">jRCT2031210350</jats:ext-link></jats:p></jats:sec>', 'DOI': '10.1001/jamanetworkopen.2023.54991', 'type': 'journal-article', 'created': {'date-parts': [[2024, 2, 9]], 'date-time': '2024-02-09T16:31:58Z', 'timestamp': 1707496318000}, 'page': 'e2354991', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients With Mild to Moderate COVID-19', 'prefix': '10.1001', 'volume': '7', 'author': [ { 'given': 'Hiroshi', 'family': 'Yotsuyanagi', 'sequence': 'first', 'affiliation': [ { 'name': 'The Institute of Medical Science, The University of Tokyo, ' 'Tokyo, Japan'}]}, { 'given': 'Norio', 'family': 'Ohmagari', 'sequence': 'additional', 'affiliation': [ { 'name': 'Disease Control and Prevention Center, National Center for ' 'Global Health and Medicine, Tokyo, Japan'}]}, { 'given': 'Yohei', 'family': 'Doi', 'sequence': 'additional', 'affiliation': [ { 'name': 'Division of Infectious Diseases, University of Pittsburgh School ' 'of Medicine, Pittsburgh, Pennsylvania'}, { 'name': 'Departments of Microbiology and Infectious Diseases, Fujita ' 'Health University School of Medicine, Toyoake, Japan'}]}, { 'given': 'Masaya', 'family': 'Yamato', 'sequence': 'additional', 'affiliation': [ { 'name': 'Infectious Diseases Center, Rinku General Medical Center, ' 'Izumisano, Japan'}]}, { 'given': 'Nguyen Hoang', 'family': 'Bac', 'sequence': 'additional', 'affiliation': [ { 'name': 'Endoscopic Surgery Training Center, University Medical Center, ' 'University of Medicine and Pharmacy, Ho Chi Minh City, ' 'Vietnam'}]}, { 'given': 'Bong Ki', 'family': 'Cha', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Internal Medicine, Chung-Ang Medical Health Care ' 'System Hyundae Hospital, Gyeonggi-do, Republic of Korea'}]}, { 'given': 'Takumi', 'family': 'Imamura', 'sequence': 'additional', 'affiliation': [ { 'name': 'Drug Development and Regulatory Science Division, Shionogi & Co, ' 'Ltd, Osaka, Japan'}]}, { 'given': 'Takuhiro', 'family': 'Sonoyama', 'sequence': 'additional', 'affiliation': [ { 'name': 'Drug Development and Regulatory Science Division, Shionogi & Co, ' 'Ltd, Osaka, Japan'}]}, { 'given': 'Genki', 'family': 'Ichihashi', 'sequence': 'additional', 'affiliation': [ { 'name': 'Drug Development and Regulatory Science Division, Shionogi & Co, ' 'Ltd, Osaka, Japan'}]}, { 'given': 'Takao', 'family': 'Sanaki', 'sequence': 'additional', 'affiliation': [{'name': 'Research Division, Shionogi & Co, Ltd, Toyonaka, Japan'}]}, { 'given': 'Yuko', 'family': 'Tsuge', 'sequence': 'additional', 'affiliation': [ { 'name': 'Drug Development and Regulatory Science Division, Shionogi & Co, ' 'Ltd, Osaka, Japan'}]}, { 'given': 'Takeki', 'family': 'Uehara', 'sequence': 'additional', 'affiliation': [ { 'name': 'Drug Development and Regulatory Science Division, Shionogi & Co, ' 'Ltd, Osaka, Japan'}]}, { 'given': 'Hiroshi', 'family': 'Mukae', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Respiratory Medicine, Nagasaki University Graduate ' 'School of Biomedical Sciences, Nagasaki, Japan'}]}], 'member': '10', 'published-online': {'date-parts': [[2024, 2, 9]]}, 'reference': [ { 'issue': '10323', 'key': 'zoi231613r2', 'doi-asserted-by': 'publisher', 'first-page': '437', 'DOI': '10.1016/S0140-6736(22)00017-4', 'article-title': 'Early assessment of the clinical severity of the SARS-CoV-2 omicron ' 'variant in South Africa: a data linkage study.', 'volume': '399', 'author': 'Wolter', 'year': '2022', 'journal-title': 'Lancet'}, { 'key': 'zoi231613r3', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.eclinm.2022.101455', 'article-title': 'Severe hospital events following symptomatic infection with Sars-CoV-2 ' 'Omicron and Delta variants in France, December 2021-January 2022: a ' 'retrospective, population-based, matched cohort study.', 'volume': '48', 'author': 'Auvigne', 'year': '2022', 'journal-title': 'EClinicalMedicine'}, { 'issue': '10332', 'key': 'zoi231613r4', 'doi-asserted-by': 'publisher', 'first-page': '1303', 'DOI': '10.1016/S0140-6736(22)00462-7', 'article-title': 'Comparative analysis of the risks of hospitalisation and death ' 'associated with SARS-CoV-2 omicron (B.1.1.529) and delta (B.1.617.2) ' 'variants in England: a cohort study.', 'volume': '399', 'author': 'Nyberg', 'year': '2022', 'journal-title': 'Lancet'}, { 'issue': '5', 'key': 'zoi231613r5', 'doi-asserted-by': 'publisher', 'first-page': '759', 'DOI': '10.1177/14034948221123163', 'article-title': 'Impact of Omicron on sick leave across industries: a population-wide ' 'study.', 'volume': '51', 'author': 'Grøsland', 'year': '2023', 'journal-title': 'Scand J Public Health'}, { 'issue': '11', 'key': 'zoi231613r6', 'doi-asserted-by': 'publisher', 'first-page': '373', 'DOI': '10.3390/tropicalmed7110373', 'article-title': 'Global distribution, dispersal patterns, and trend of several Omicron ' 'subvariants of SARS-CoV-2 across the globe.', 'volume': '7', 'author': 'Kopsidas', 'year': '2022', 'journal-title': 'Trop Med Infect Dis'}, { 'issue': '19', 'key': 'zoi231613r8', 'doi-asserted-by': 'publisher', 'first-page': '1813', 'DOI': '10.1056/NEJMoa2007764', 'article-title': 'Remdesivir for the treatment of Covid-19—final report.', 'volume': '383', 'author': 'Beigel', 'year': '2020', 'journal-title': 'N Engl J Med'}, { 'issue': '6', 'key': 'zoi231613r9', 'doi-asserted-by': 'publisher', 'first-page': '509', 'DOI': '10.1056/NEJMoa2116044', 'article-title': 'Molnupiravir for oral treatment of Covid-19 in nonhospitalized ' 'patients.', 'volume': '386', 'author': 'Jayk Bernal', 'year': '2022', 'journal-title': 'N Engl J Med'}, { 'issue': '15', 'key': 'zoi231613r10', 'doi-asserted-by': 'publisher', 'first-page': '1397', 'DOI': '10.1056/NEJMoa2118542', 'article-title': 'Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19.', 'volume': '386', 'author': 'Hammond', 'year': '2022', 'journal-title': 'N Engl J Med'}, { 'issue': '5', 'key': 'zoi231613r11', 'doi-asserted-by': 'publisher', 'first-page': '468', 'DOI': '10.1056/NEJMc2207519', 'article-title': 'Efficacy of antibodies and antiviral drugs against Omicron BA.2.12.1, ' 'BA.4, and BA.5 subvariants.', 'volume': '387', 'author': 'Takashita', 'year': '2022', 'journal-title': 'N Engl J Med'}, { 'issue': '7', 'key': 'zoi231613r12', 'doi-asserted-by': 'publisher', 'first-page': '942', 'DOI': '10.1016/S1473-3099(22)00365-6', 'article-title': 'Neutralisation sensitivity of SARS-CoV-2 omicron subvariants to ' 'therapeutic monoclonal antibodies.', 'volume': '22', 'author': 'Yamasoba', 'year': '2022', 'journal-title': 'Lancet Infect Dis'}, { 'issue': '7902', 'key': 'zoi231613r13', 'doi-asserted-by': 'publisher', 'first-page': '706', 'DOI': '10.1038/s41586-022-04474-x', 'article-title': 'Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and ' 'fusogenicity.', 'volume': '603', 'author': 'Meng', 'year': '2022', 'journal-title': 'Nature'}, { 'issue': '9', 'key': 'zoi231613r14', 'doi-asserted-by': 'publisher', 'first-page': '6499', 'DOI': '10.1021/acs.jmedchem.2c00117', 'article-title': 'Discovery of S-217622, a noncovalent oral SARS-CoV-2 3CL protease ' 'inhibitor clinical candidate for treating COVID-19.', 'volume': '65', 'author': 'Unoh', 'year': '2022', 'journal-title': 'J Med Chem'}, { 'issue': '7917', 'key': 'zoi231613r15', 'doi-asserted-by': 'publisher', 'first-page': '119', 'DOI': '10.1038/s41586-022-04856-1', 'article-title': 'Characterization and antiviral susceptibility of SARS-CoV-2 Omicron ' 'BA.2.', 'volume': '607', 'author': 'Uraki', 'year': '2022', 'journal-title': 'Nature'}, { 'issue': '679', 'key': 'zoi231613r16', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/scitranslmed.abq4064', 'article-title': 'S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load ' 'and ameliorates COVID-19 severity in hamsters.', 'volume': '15', 'author': 'Sasaki', 'year': '2023', 'journal-title': 'Sci Transl Med'}, { 'key': 'zoi231613r17', 'doi-asserted-by': 'publisher', 'first-page': '132', 'DOI': '10.1016/j.bbrc.2023.01.040', 'article-title': 'Ensitrelvir is effective against SARS-CoV-2 3CL protease mutants ' 'circulating globally.', 'volume': '645', 'author': 'Kawashima', 'year': '2023', 'journal-title': 'Biochem Biophys Res Commun'}, { 'issue': '4', 'key': 'zoi231613r18', 'doi-asserted-by': 'publisher', 'first-page': '402', 'DOI': '10.1016/S1473-3099(23)00070-1', 'article-title': 'Antiviral and bivalent vaccine efficacy against an omicron XBB.1.5 ' 'isolate.', 'volume': '23', 'author': 'Uraki', 'year': '2023', 'journal-title': 'Lancet Infect Dis'}, { 'issue': '10', 'key': 'zoi231613r19', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/aac.00697-22', 'article-title': 'A randomized phase 2/3 study of ensitrelvir, a novel oral SARS-CoV-2 ' '3C-like protease inhibitor, in Japanese patients with mild-to-moderate ' 'COVID-19 or asymptomatic SARS-CoV-2 infection: results of the phase 2a ' 'part.', 'volume': '66', 'author': 'Mukae', 'year': '2022', 'journal-title': 'Antimicrob Agents Chemother'}, { 'issue': '8', 'key': 'zoi231613r20', 'doi-asserted-by': 'publisher', 'first-page': '1403', 'DOI': '10.1093/cid/ciac933', 'article-title': 'Efficacy and safety of ensitrelvir in patients with mild-to-moderate ' 'COVID-19: the phase 2b part of a randomized, placebo-controlled, phase ' '2/3 study.', 'volume': '76', 'author': 'Mukae', 'year': '2023', 'journal-title': 'Clin Infect Dis'}, { 'issue': '20', 'key': 'zoi231613r21', 'doi-asserted-by': 'publisher', 'first-page': '2191', 'DOI': '10.1001/jama.2013.281053', 'article-title': 'World Medical Association Declaration of Helsinki: ethical principles ' 'for medical research involving human subjects.', 'volume': '310', 'author': 'World Medical Association', 'year': '2013', 'journal-title': 'JAMA'}, { 'issue': '8', 'key': 'zoi231613r22', 'doi-asserted-by': 'publisher', 'DOI': '10.1097/MD.0000000000033024', 'article-title': 'A phase 2/3 study of S-217622 in participants with SARS-CoV-2 infection ' '(Phase 3 part).', 'volume': '102', 'author': 'Yotsuyanagi', 'year': '2023', 'journal-title': 'Medicine (Baltimore)'}, { 'issue': '35', 'key': 'zoi231613r25', 'doi-asserted-by': 'publisher', 'first-page': '3455', 'DOI': '10.1200/JCO.19.01681', 'article-title': 'Methods for accommodating nonproportional hazards in clinical trials: ' 'ready for the primary analysis?', 'volume': '37', 'author': 'Freidlin', 'year': '2019', 'journal-title': 'J Clin Oncol'}, { 'issue': '10', 'key': 'zoi231613r26', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/aac.00632-22', 'article-title': 'Safety, tolerability, and pharmacokinetics of the novel antiviral agent ' 'ensitrelvir fumaric acid, a SARS-CoV-2 3CL protease inhibitor, in ' 'healthy adults.', 'volume': '66', 'author': 'Shimizu', 'year': '2022', 'journal-title': 'Antimicrob Agents Chemother'}, { 'key': 'zoi231613r27', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.lanepe.2022.100556', 'article-title': 'Severity of Omicron (B.1.1.529) and Delta (B.1.617.2) SARS-CoV-2 ' 'infection among hospitalised adults: a prospective cohort study in ' 'Bristol, United Kingdom.', 'volume': '25', 'author': 'Hyams', 'year': '2023', 'journal-title': 'Lancet Reg Health Eur'}, { 'issue': '10373', 'key': 'zoi231613r28', 'doi-asserted-by': 'publisher', 'first-page': '281', 'DOI': '10.1016/S0140-6736(22)02597-1', 'article-title': 'Molnupiravir plus usual care versus usual care alone as early treatment ' 'for adults with COVID-19 at increased risk of adverse outcomes ' '(PANORAMIC): an open-label, platform-adaptive randomised controlled ' 'trial.', 'volume': '401', 'author': 'Butler', 'year': '2023', 'journal-title': 'Lancet'}, { 'issue': '3', 'key': 'zoi231613r29', 'doi-asserted-by': 'publisher', 'first-page': '453', 'DOI': '10.1093/cid/ciac781', 'article-title': 'Effectiveness of molnupiravir in high-risk patients: a propensity score ' 'matched analysis.', 'volume': '76', 'author': 'Najjar-Debbiny', 'year': '2023', 'journal-title': 'Clin Infect Dis'}, { 'key': 'zoi231613r31', 'doi-asserted-by': 'publisher', 'author': 'Hammond', 'year': '2022', 'DOI': '10.1093/ofid/ofac492.994'}, { 'key': 'zoi231613r1', 'unstructured': 'World Health Organization. Classification of Omicron (B.1.1.529): ' 'SARS-CoV-2 variant of concern. Accessed October 2, 2023. ' 'https://www.who.int/news/item/26-11-2021-classification-of-omicron-(b.1.1.529)-sars-cov-2-variant-of-concern'}, { 'key': 'zoi231613r7', 'unstructured': 'World Health Organization. TAG-VE statement on Omicron sublineages BQ.1 ' 'and XBB. Accessed October 2, 2023. ' 'https://www.who.int/news/item/27-10-2022-tag-ve-statement-on-omicron-sublineages-bq.1-and-xbb'}, { 'key': 'zoi231613r23', 'unstructured': 'US Food and Drug Administration. Assessing COVID-19-related symptoms in ' 'outpatient adult and adolescent subjects in clinical trials of drugs and ' 'biological products for COVID-19 prevention or treatment. Accessed ' 'October 2, 2023. ' 'https://www.fda.gov/regulatory-information/search-fda-guidance-documents/assessing-covid-19-related-symptoms-outpatient-adult-and-adolescent-subjects-clinical-trials-drugs'}, { 'key': 'zoi231613r24', 'unstructured': 'Hiroshima Prefectural Health and Welfare Bureau. Findings from the ' 'analysis of J-SPEED (Surveillance in Post Extreme Emergencies and ' 'Disasters, Japan version) data: wave 7 analysis. Accessed October 2, ' '2023. https://www.mhlw.go.jp/content/10900000/000975398.pdf'}, { 'key': 'zoi231613r30', 'unstructured': 'ClinicalTrials.gov. Evaluation of Protease Inhibition for COVID-19 in ' 'Standard-Risk Patients (EPIC-SR). NCT05011513. Accessed October 2, 2023. ' 'https://clinicaltrials.gov/study/NCT05011513'}, { 'key': 'zoi231613r32', 'unstructured': 'US Food and Drug Administration. Meeting of the Antimicrobial Drugs ' 'Advisory Committee March 16, 2023: FDA Briefing Document. Accessed ' 'October 2, 2023. https://www.fda.gov/media/166197/download'}, { 'key': 'zoi231613r33', 'unstructured': 'ClinicalTrials.gov. A Study to Compare S-217622 With Placebo in ' 'Non-Hospitalized Participants With COVID-19 (SCORPIO-HR). NCT05305547. ' 'Accessed October 2, 2023. ' 'https://classic.clinicaltrials.gov/ct2/show/NCT05305547'}, { 'key': 'zoi231613r34', 'unstructured': 'ClinicalTrials.gov. Strategies and Treatments for Respiratory Infections ' '&; Viral Emergencies (STRIVE): Shionogi Protease Inhibitor. NCT05605093. ' 'Accessed October 2, 2023. https://clinicaltrials.gov/study/NCT05605093'}, { 'key': 'zoi231613r35', 'unstructured': 'ClinicalTrials.gov. A Phase 3 Study of S-217622 in Pediatric ' 'Participants Aged 6 to &lt;12 With SARS-CoV-2 Infection. jRCT2031230140. ' 'Accessed October 2, 2023. ' 'https://jrct.niph.go.jp/en-latest-detail/jRCT2031230140'}], 'container-title': 'JAMA Network Open', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://jamanetwork.com/journals/jamanetworkopen/articlepdf/2814871/yotsuyanagi_2024_oi_231613_1706809715.91975.pdf', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2024, 2, 9]], 'date-time': '2024-02-09T16:32:02Z', 'timestamp': 1707496322000}, 'score': 1, 'resource': {'primary': {'URL': 'https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2814871'}}, 'subtitle': ['The SCORPIO-SR Randomized Clinical Trial'], 'short-title': [], 'issued': {'date-parts': [[2024, 2, 9]]}, 'references-count': 35, 'journal-issue': {'issue': '2', 'published-print': {'date-parts': [[2024, 2, 5]]}}, 'URL': 'http://dx.doi.org/10.1001/jamanetworkopen.2023.54991', 'relation': {}, 'ISSN': ['2574-3805'], 'subject': ['General Medicine'], 'container-title-short': 'JAMA Netw Open', 'published': {'date-parts': [[2024, 2, 9]]}}