Research Summary

Ensitrelvir Postexposure Prophylaxis Reduced COVID-19 Risk in Household Contacts

Edited by:
Ashton L. Stahl

Key Highlights

  • In the modified intention-to-treat population, COVID-19 by day 10 occurred in 2.9% of the ensitrelvir group versus 9% of the placebo group.
  • The phase 3, double-blind, randomized, placebo-controlled trial enrolled household contacts across the United States, Argentina, Japan, South Africa, and Vietnam.
  • Adverse event rates were similar with ensitrelvir and placebo, and no COVID–19–related hospitalizations or deaths were reported.
  • The authors reported that prophylactic benefit was generally consistent across most prespecified subgroups, including older adults and participants with risk factors for severe COVID-19.

Ensitrelvir significantly reduced the incidence of laboratory-confirmed COVID-19 among household contacts of patients with infection when started within 72 hours after symptom onset, according to the results of a phase 3 trial published in The New England Journal of Medicine. In the modified intention-to-treat population, COVID-19 developed by day 10 in 2.9% of participants assigned to ensitrelvir and 9.0% assigned to placebo, for a risk ratio of 0.33 (95% CI, 0.22-0.49; P < .001).

Researchers conducted a double-blind, randomized, placebo-controlled trial from June 2023 through mid-September 2024 in 5 countries. Household contacts aged 12 years or older were eligible if they tested negative locally for SARS-CoV-2 and were enrolled within 72 hours after symptom onset in the index patient. Participants were randomly assigned 1:1 to ensitrelvir, given as 375 mg on day 1 and 125 mg daily on days 2 through 5, or a matching placebo. The primary endpoint was laboratory-confirmed COVID-19 by day 10, defined as central laboratory RT-PCR positivity plus at least 1 of 14 prespecified symptoms lasting at least 48 hours.

Study Findings

The modified intention-to-treat population included 1,030 participants in the ensitrelvir group and 1,011 in the placebo group. The mean age was 42.4 years; 71.1% were enrolled within 48 hours after symptom onset in the index patient; 37.0% had at least 1 risk factor for severe COVID-19. In the full intention-to-treat population, the incidence of COVID-19 by day 10 was also lower with ensitrelvir than with placebo, at 4.4% versus 10.2% (risk ratio, 0.43; 95% CI, 0.32-0.59; P < .001).

For the key secondary end point of RT-PCR–confirmed SARS-CoV-2 infection regardless of symptoms, the incidence through day 10 was 14% with ensitrelvir and 21.5% with placebo in the modified intention-to-treat population (risk ratio, 0.66; 95% CI, 0.55-0.79).

Adverse events occurred in 15.1% of ensitrelvir recipients and 15.5% of placebo recipients; serious adverse events occurred in 0.2% of each group. The most common adverse events were headache, diarrhea, nasopharyngitis, cough, fatigue, and influenza. The researchers did not report any COVID-19–related hospitalizations or deaths.

Clinical Implications

According to the study authors, these findings suggest that prompt postexposure oral ensitrelvir prophylaxis was effective in preventing COVID-19 among household contacts, including those with risk factors for severe disease, without apparent safety concerns. They also stated that the findings suggest the potential effectiveness of ensitrelvir in reducing illness risk in other unprotected settings, such as outbreaks in acute and long-term care facilities.

The authors noted several limitations. They did not collect data on factors that can affect household transmission, including household size, masking, social distancing, and other public health measures. They also wrote that antiviral use in index patients may have reduced transmission risk and potentially affected estimates of prophylactic efficacy, particularly in Japan.

Expert Commentary

“In this trial, the prompt initiation of oral ensitrelvir postexposure prophylaxis was effective in preventing Covid-19 in household contacts, including those with risk factors for severe disease, without apparent safety concerns,” the researchers concluded.

Reference

Hayden FG, Shinkai M, Clark TW, et al; SCORPIO-PEP Study Team. Ensitrelvir for Covid-19 postexposure prophylaxis in household contacts. N Engl J Med. 2026;394(19):1905-1915. doi:10.1056/NEJMoa2509306