Household contacts exposed to severe acute respiratory syndrome coronavirus 2 were less likely to develop laboratory-confirmed symptomatic COVID-19 by day 10 after receiving a 5-day course of ensitrelvir, according to findings from the phase 3 SCORPIO-PEP trial published in The New England Journal of Medicine.
The trial was funded by Shionogi, and several researchers were employees of the sponsor who were involved in trial design, data collection, and data analysis. Ensitrelvir is approved in Japan for mild-to-moderate COVID-19 treatment and based on these findings, postexposure prophylaxis in household contacts aged 12 years or older, but it is not approved in the US.
In the modified intention-to-treat population, COVID-19 developed by day 10 in 30 of 1,030 participants who received ensitrelvir compared with 91 of 1,011 participants who received placebo, or 3% vs 9%. Researchers reported a risk ratio of 0.33 (95% confidence interval [CI] = 0.22–0.49; P < .001), corresponding to a 67% relative risk reduction.
The absolute risk reduction was 6.1 percentage points, yielding an estimated number needed to treat of approximately 16 to prevent 1 case of symptomatic COVID-19 by day 10, based on the reported event rates.
The double-blind, randomized, placebo-controlled trial enrolled household contacts aged 12 years or older in the US, Argentina, Japan, South Africa, and Vietnam from June 2023 through mid-September 2024. Eligible participants had negative local severe acute respiratory syndrome coronavirus 2 testing, had no fever or COVID-19 symptoms, and were enrolled within 72 hours following symptom onset in the index patient.
Participants were randomly assigned 1:1 to receive ensitrelvir 375 mg on day 1, followed by 125 mg daily on days 2 through 5 or placebo. The primary endpoint was COVID-19 by day 10, defined as central laboratory-confirmed reverse-transcriptase polymerase chain reaction positivity plus at least 1 of 14 prespecified COVID-19 symptoms lasting at least 48 hours.
The modified intention-to-treat analysis included randomized participants with negative baseline central laboratory reverse-transcriptase polymerase chain reaction results who received at least 1 study dose. The mean age was 42 years, 59% were female, 37% had at least 1 risk factor for severe COVID-19, and 71% underwent randomization within 48 hours following symptom onset in the index patient.
In the intention-to-treat population, COVID-19 developed by day 10 in 4% of participants assigned to ensitrelvir vs 10% assigned to placebo. Researchers reported a risk ratio of 0.43 (95% CI = 0.32–0.59; P < .001), corresponding to a 57% relative risk reduction.
In a secondary endpoint analysis, reverse-transcriptase polymerase chain reaction–confirmed severe acute respiratory syndrome coronavirus 2 infection regardless of symptoms occurred in 14% of ensitrelvir recipients vs 22% of placebo recipients, representing a 34% relative reduction in laboratory-confirmed infection among contacts, which the authors characterized as reduced within-household transmission.
Among participants with risk factors for severe illness, COVID-19 developed in 9 of 382 participants assigned to ensitrelvir and 37 of 374 assigned to placebo. However, the researchers noted that subgroup analyses and most secondary endpoints were not adjusted for multiplicity.
The findings differ from prior postexposure prophylaxis trials of nirmatrelvir–ritonavir and molnupiravir, which did not show statistically significant protection against COVID-19 in household contacts. The SCORPIO-PEP researchers suggested that earlier treatment initiation in the current trial, within 72 hours following symptom onset in the index patient, along with a stricter illness definition, may have contributed to the observed efficacy.
In post hoc analyses, viral loads and symptom scores appeared lower among ensitrelvir recipients who had infection at baseline or developed infection during postexposure prophylaxis. Genome sequencing identified amino acid substitutions that occurred during treatment in 2% of ensitrelvir-treated participants in the modified intention-to-treat population and 15% of ensitrelvir-treated participants who were reverse-transcriptase polymerase chain reaction positive at baseline.
The researchers noted that no amino acid substitutions related to ensitrelvir treatment were detected among placebo recipients, including among participants exposed to ensitrelvir-treated index patients, and they reported no evidence that treatment-emergent variants drove prophylaxis failures.
Adverse events occurred in 15% of ensitrelvir recipients and 16% of placebo recipients. Serious adverse events occurred in 0.2% of each group, and investigators assessed them as unrelated to ensitrelvir or placebo. No COVID-19 –related hospitalizations or deaths were reported.
Researchers observed declines in high-density lipoprotein cholesterol levels among ensitrelvir recipients that approached baseline levels by day 15.
The researchers emphasized that the trial evaluated prevention of symptomatic COVID-19 through day 10 and was not designed or powered to assess prevention of hospitalization or death.
The study population was highly immune, with more than 98% of household contacts testing positive for antinucleocapsid or antispike antibodies or both. The researchers said this may limit generalizability while also reflecting the current global immunologic landscape.
Additional limitations included a lack of data on household size, masking, distancing, and other public health measures. Antiviral use among index patients may also have reduced transmission risk, particularly in Japan, where 38% of index patients received antiviral treatment compared with approximately 6% in the US.
The trial also excluded pregnant patients, patients with recent severe acute respiratory syndrome coronavirus 2 infection or vaccination, and patients receiving contraindicated medications because ensitrelvir is a moderately strong cytochrome P450 3A inhibitor.
The authors wrote that the 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," according to Frederick G. Hayden, MD, of the Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, and colleagues.
The trial was supported by Shionogi. Full disclosures can be found in the published study.
