Ensitrelvir Cuts Household COVID-19 Risk In Phase 3 Trial

Key Takeaways

• Lower symptomatic COVID-19 rates by day 10 were observed with ensitrelvir than with placebo in household contacts.
• The phase 3 randomized trial used oral ensitrelvir at 375 mg on day 1 and 125 mg on days 2 through 5, started within 72 hours after symptom onset in the index patient.
• Adverse-event rates were similar between groups, no COVID-related hospitalizations or deaths occurred, and ensitrelvir is approved in Japan for treatment and postexposure prevention in contacts.

A phase 3 randomized trial of ensitrelvir in household contacts evaluated oral postexposure prevention among people aged 12 years or older who tested negative and lived with a person with COVID-19. Treatment began within 72 hours after symptom onset in the index household case, and in the modified intention-to-treat population, confirmed symptomatic COVID-19 by day 10 occurred in 2.9% versus 9.0%, with a risk ratio of 0.33. The trial focused on early household postexposure prevention after known exposure in a shared home.

Investigators randomly assigned household contacts of infected patients to ensitrelvir 375 mg on day 1 and 125 mg on days 2 through 5 or to placebo. Eligible participants were 12 years or older, had a negative COVID-19 test at enrollment, and were living with the index patient. The primary endpoint was confirmed symptomatic COVID-19 by day 10 in a household member, assessed in a modified intention-to-treat population of 1,030 ensitrelvir recipients and 1,011 placebo recipients. The average age was 42.4 years, 71.1% were randomized within 48 hours, and 37.0% had at least one risk factor for severe disease. The study was therefore framed around early exposure within households.

In the intention-to-treat analysis, confirmed symptomatic infection through day 10 was 4.4% with ensitrelvir and 10.2% with placebo, yielding a risk ratio of 0.43. Lower infection rates were seen in both the modified intention-to-treat and intention-to-treat populations. Illnesses rose rapidly by day 2 in placebo recipients, while fewer events accrued with ensitrelvir through days 10 to 12. The trial ran in the United States, Japan, Argentina, South Africa, and Vietnam from June 2023 to September 2024. Generally similar patterns were observed across most subgroups, including older adults and participants with risk factors.

Adverse events occurred in 15.1% of ensitrelvir recipients and 15.5% of placebo recipients, while serious adverse events occurred in 0.2% of each group. No COVID-related hospitalizations or deaths occurred, and no imbalance in tolerability emerged between groups. Ensitrelvir is approved in Japan for mild-to-moderate COVID-19 treatment in people aged 12 years and older, and is also approved there for postexposure prevention in contacts.

The authors said the findings could indicate usefulness in other unprotected settings, including outbreaks in acute and long-term care facilities. Overall, safety frequencies were similar between groups within the regulatory context described for Japan.