TOPLINE

Household contacts who started a 5-day regimen of ensitrelvir vs placebo within 72 hours of symptom onset in the index patient had a 67% lower risk for laboratory-confirmed COVID through day 10, with no new safety concerns identified.

METHODOLOGY

• Researchers conducted a phase 3 randomized trial across the US, Argentina, Japan, South Africa, and Vietnam to evaluate the efficacy and safety of ensitrelvir as postexposure prophylaxis in household contacts exposed to SARS-CoV-2.
• A total of 2041 household contacts aged 12 years or older (59.3% female) who tested negative for SARS-CoV-2 at baseline received at least one dose of ensitrelvir (n = 1030; 375 mg on day 1 and 125 mg daily on days 2-5) or a matching placebo (n = 1011) within 72 hours after symptom onset in the index patient (the first person with documented COVID in a household).
• Nasopharyngeal swabs were collected on days 1, 3, 6, 10, 15, 21, and 28 for reverse-transcription polymerase chain reaction testing for SARS-CoV-2.
• The primary efficacy endpoint was laboratory-confirmed COVID, defined as a positive test and the presence of at least one of the 14 prespecified COVID symptoms lasting at least 48 hours, occurring within 10 days of drug or placebo administration.
• Safety endpoints were adverse clinical and laboratory events.

TAKEAWAY

• By day 10, laboratory‑confirmed COVID occurred in 2.9% of participants who received ensitrelvir and in 9.0% of those who received placebo, corresponding to a 67% lower risk with ensitrelvir (risk ratio [RR], 0.33; P < .001).
• Fewer household contacts developed laboratory-confirmed COVID in the ensitrelvir group than in the placebo group through day 10, regardless of the symptoms (RR, 0.66; 95% CI, 0.55-0.79).
• The rates of adverse events were similar between groups (15.1% with ensitrelvir and 15.5% with placebo); the most common events were headache, diarrhea, nasopharyngitis, cough, fatigue, and influenza.
• Serious adverse events occurred in 0.2% of participants in each group, and no COVID-related hospitalizations or deaths were reported.

IN PRACTICE

“These findings suggest the potential effectiveness of ensitrelvir in reducing the risk of illness in other unprotected contexts, such as during outbreaks in acute and long-term care facilities,” the authors wrote.

SOURCE

The study was led by Frederick G. Hayden, MD, University of Virginia School of Medicine, Charlottesville, Virginia. It was published online on May 13, 2026, in The New England Journal of Medicine.

LIMITATIONS

Several factors that could influence the likelihood of household transmission were not captured. Participants taking medications contraindicated with ensitrelvir were excluded. In addition, follow‑up genome sequencing of samples from index patients was not performed.

DISCLOSURES

The trial was supported by Shionogi. Six authors reported being employees of Shionogi, and three of them also reported holding stocks in the company. Several authors reported receiving travel support, research grants or contracts, speaker or lecture fees, consulting roles, honoraria, and other ties with multiple pharmaceutical companies and institutions, including Shionogi.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.