The SCORPIO-PEP trial evaluated ensitrelvir as postexposure prophylaxis for household contacts of Covid-19 patients and showed a significant reduction in symptomatic Covid-19 by day 10.
Introduction
The SCORPIO-PEP trial evaluated whether ensitrelvir, an oral antiviral agent, could prevent Covid-19 in people recently exposed to SARS-CoV-2 within their household. Household exposure remains one of the highest-risk settings for Covid-19 transmission, especially when close contacts occur before or shortly after diagnosis of the index patient.
Ensitrelvir is an oral inhibitor of the SARS-CoV-2 3C-like protease and is approved in Japan for the treatment of mild-to-moderate Covid-19. The SCORPIO-PEP trial tested whether giving ensitrelvir early after household exposure could reduce the risk of developing symptomatic Covid-19.
Study Design
The SCORPIO-PEP trial was a double-blind, randomized, placebo-controlled trial.
Participants were household contacts of a patient with Covid-19. Eligible contacts had to be SARS-CoV-2 negative on local diagnostic testing and were randomized within 72 hours after symptom onset in the index patient.
Participants were assigned to receive either:
Ensitrelvir: 375 mg on day 1, followed by 125 mg daily on days 2 through 5
Placebo
The modified intention-to-treat population included participants who were randomized, had a centrally confirmed negative RT-PCR test for SARS-CoV-2 at baseline, and received at least one dose of trial drug or placebo.
Patient Population
The modified intention-to-treat population included:
1030 participants in the ensitrelvir group
1011 participants in the placebo group
The mean age was 42.4 years. Most participants were randomized early after exposure, with 71.1% randomized within 48 hours after symptom onset in the index patient. In addition, 37.0% had at least one risk factor for severe Covid-19.
Primary Outcome
The primary endpoint of the SCORPIO-PEP trial was Covid-19 by day 10 in the household contact. Covid-19 was defined as a centrally confirmed positive RT-PCR test plus at least one prespecified Covid-19 symptom lasting at least 48 hours.
The incidence of Covid-19 was significantly lower with ensitrelvir:
Ensitrelvir: 2.9%
Placebo: 9.0%
This corresponded to a risk ratio of:
RR 0.33; 95% CI, 0.22 to 0.49; P<0.001
This means ensitrelvir reduced the relative risk of developing symptomatic Covid-19 by approximately 67% compared with placebo.
Safety Outcomes
Adverse events were similar between the two groups:
Adverse events:
Ensitrelvir: 15.1%
Placebo: 15.5%
Serious adverse events:
Ensitrelvir: 0.2%
Placebo: 0.2%
No Covid-19-related hospitalizations or deaths were reported in the trial.
Key Takeaway from the SCORPIO-PEP Trial
The SCORPIO-PEP trial showed that ensitrelvir, when given within 72 hours after symptom onset in the index Covid-19 patient, was effective in preventing symptomatic Covid-19 among household contacts.
The benefit was clinically meaningful, with Covid-19 occurring in 2.9% of participants receiving ensitrelvir compared with 9.0% receiving placebo. Importantly, the safety profile appeared similar to placebo, with low rates of serious adverse events.
Clinical Implications
The SCORPIO-PEP trial is important because postexposure prophylaxis has been a major unmet need in Covid-19 management. While vaccines reduce severe disease and treatment options exist for infected patients, fewer strategies have been available for preventing infection after a known high-risk exposure.
If approved more broadly, ensitrelvir could potentially offer an oral postexposure prophylaxis option for household contacts, particularly for people at higher risk of severe disease or those living with vulnerable family members.
Conclusion
In the SCORPIO-PEP trial, ensitrelvir significantly reduced the incidence of symptomatic Covid-19 among household contacts of infected patients. Given within 72 hours after symptom onset in the index patient, ensitrelvir reduced Covid-19 by day 10 without increasing adverse events compared with placebo.
Citation: Frederick G. Hayden et al. New England Journal of Medicine. 2026;394:1905-1915. DOI: 10.1056/NEJMoa2509306.
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