Abstract: ## BACKGROUND
Ensitrelvir, an oral inhibitor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease, is approved in Japan for the treatment of mild-tomoderate coronavirus disease 2019 (Covid-19). Previously, no antiviral agents were approved for postexposure prophylaxis in household contacts of patients with Covid-19.
METHODS
In this double-blind, randomized, placebo-controlled trial, we randomly assigned persons who were SARS-CoV-2-negative on local diagnostic testing but were household contacts of a patient with Covid-19 (the index patient) to receive either ensitrelvir (375 mg on day 1 and 125 mg daily on days 2 through 5) or placebo within 72 hours after symptom onset in the index patient. The primary end point was Covid-19 (defined by a central laboratory-confirmed positive reverse-transcriptase-polymerase-chain-reaction assay and the presence of ≥1 of 14 prespecified Covid-19 symptoms lasting ≥48 hours) by day 10 in a household contact in the modified intention-to-treat population (all the participants who underwent randomization, had a central laboratory-confirmed negative RT-PCR test for SARS-CoV-2 at baseline, and received at least one dose of the trial drug or placebo).
RESULTS
The modified intention-to-treat population included 1030 participants in the ensitrelvir group and 1011 in the placebo group. The mean age of the participants was 42.4 years; 71.1% had undergone randomization within 48 hours after symptom onset in the index patient, and 37.0% had at least one risk factor for severe Covid-19. The incidence of Covid-19 was lower in the ensitrelvir group than in the placebo group (2.9% vs. 9.0%; risk ratio, 0.33; 95% confidence interval [CI], 0.22 to 0.49; P<0.001). The incidence of adverse events during the trial was similar in the two groups (15.1% in the ensitrelvir group and 15.5% in the placebo group), as was the incidence of serious adverse events (0.2% in each group). No Covid-19-related hospitalizations or deaths were reported.
CONCLUSIONS
Ensitrelvir administered to household contacts of a patient with Covid-19 within 72 hours after symptom onset in the index patient was effective in preventing Covid-19 in the contacts. (Funded by Shionogi; SCORPIO-PEP Japan Registry for Clinical Trials number, jRCT2031230124; ClinicalTrials.gov number, NCT05897541.)
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Original Article
Ensitrelvir for Covid-19 Postexposure Prophylaxis in Household Contacts
F.G. Hayden, 1 M. Shinkai, 2 T.W. Clark, 3 A.F. Luetkemeyer, 4 P.E. Sax, 5 W.P. Hanage, 6 K.A. Gebo, 7 H. Ikematsu, 8 K. Izumikawa, 9 A. Fukushi, 10 S. Kezbor, 11 H. Sakaguchi, 10 S. Lacey, 12 G. Ichihashi, 10 N. Ohmagari, 13 and T. Uehara, 10 for the SCORPIO-PEP Study Team*
ABSTRACT
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The authors' full names, academic degrees, and affiliations are listed at the end of the article. Frederick G. Hayden can be contacted at fgh@ virginia . edu or at the Division of Infectious Diseases and International Health, P.O. Box 801342, University of Virginia Health System, Charlottesville, VA 22908.
*The SCORPIO-PEP study team members are listed in the Supplementary Appendix, available at NEJM.org.
This article was updated on May 14, 2026, at NEJM.org.
N Engl J Med 2026;394:1905-15. DOI: 10.1056/NEJMoa2509306 Copyright © 2026 Massachusetts Medical Society.
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