Ensitrelvir for Covid-19 Postexposure Prophylaxis in Household Contacts

Clinical Snapshot

Key Findings

• P Value: P<0.001

• Effect Size: 67% relative risk reduction

• Primary Outcome: Covid-19 incidence by day 10: 2.9% (ensitrelvir) vs 9.0% (placebo)

• Nnt Or Sensitivity: Number needed to treat: 16 (to prevent one Covid-19 case)

• Confidence Interval: Risk ratio 0.33 (95% CI: 0.22 to 0.49)

Clinical Application

Requires rapid identification and testing of contacts, 5-day oral treatment course Would require TGA approval for this indication. Cost-effectiveness analysis needed for PBS listing. Aligns with RACGP guidelines for household contact management Household contacts of Covid-19 patients who can be treated within 72 hours of index case symptom onset

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-to-moderate 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.).

References

1. 1.Hayden, F. G., Shinkai, M., Clark, T. W., Luetkemeyer, A. F., Sax, P. E., Hanage, W. P., Gebo, K. A., Ikematsu, H., Izumikawa, K., Fukushi, A., Kezbor, S., Sakaguchi, H., Lacey, S., Ichihashi, G., Ohmagari, N., & Uehara, T. (2026). Ensitrelvir for Covid-19 postexposure prophylaxis in household contacts. *New England Journal of Medicine*. https://doi.org/10.1056/NEJMoa2509306