Household Exposure Trial Finds Oral Antiviral Ensitrelvir to Show Strong Protection Against COVID-19

A new clinical trial published in The New England Journal of Medicine found that the oral antiviral drug ensitrelvir significantly reduced the risk of developing COVID-19 among household contacts of infected individuals, which marks a potential advance in post-exposure prevention strategies.

Ensitrelvir is an oral inhibitor of the SARS-CoV-2 3C-like protease, which has already been approved in Japan for the treatment of mild-to-moderate COVID-19. Thus, this double-blind, placebo-controlled trial enrolled more than 2,000 participants who had recently been exposed to COVID-19 within their households. All participants tested negative for SARS-CoV-2 at baseline but had been exposed to a confirmed index case within the previous 72 hours.

These participants were randomly assigned to receive either ensitrelvir or placebo shortly after the onset of symptoms in the infected household member. The treatment regimen consisted of a higher loading dose on day one, followed by a shorter course of daily dosing over the next 4 days. The primary outcome was the development of symptomatic, laboratory-confirmed COVID-19 within 10 days after exposure. These cases were confirmed using centralized PCR testing along with the presence of at least one COVID-19 symptom lasting two or more days.

Only 2.9% of participants in the treatment group developed COVID-19 when compared to 9.0% in the placebo group, which represented roughly two-thirds reduction in risk. This study reported a risk ratio of 0.33, which indicated significantly lesser incidence to develop symptomatic infection following household exposure. The findings were statistically robust, with a confidence interval well below 1.0 and a p-value of less than 0.001.

The safety profile of ensitrelvir was comparable to placebo. Adverse events occurred in roughly 15% of participants in both groups, and serious adverse events were rare, occurring in just 0.2% of participants in each arm. No COVID-19-related hospitalizations or deaths were reported during the trial.

Unlike vaccines, antiviral prophylaxis can act immediately to inhibit viral replication during the earliest stages of infection. Thus, these findings suggest this mechanism may explain the strong protective effect observed in the study. Additional studies will be required to determine how ensitrelvir performs in broader populations, including vaccinated individuals, different age groups, and settings outside household exposure.

Source:

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., & SCORPIO-PEP Study Team. (2026). Ensitrelvir for Covid-19 postexposure prophylaxis in household contacts. The New England Journal of Medicine, 394(19), 1905–1915. https://doi.org/10.1056/NEJMoa2509306