Background
Ensitrelvir is an oral SARS-CoV-2 3CL protease inhibitor, approved in Japan for the treatment of mild-moderate COVID-19. No approved antivirals have been proven efficacious as post-exposure prophylaxis (PEP) in household contacts (HHC) of index patients (IP) with COVID-19.
Methods
SCORPIO-PEP was a double-blind, placebo-controlled trial in HHC of IP with laboratory-confirmed COVID-19 conducted in the US, Japan, and other countries. HHC with negative local SARS-CoV-2 antigen or RT-PCR test were randomized 1:1 to receive either ensitrelvir (Day 1: 375mg, Day 2-5: 125mg), or placebo within 72 hours of symptom onset in the IP. The primary analysis population included HHC with central laboratory confirmed SARS-CoV-2 negativity by RT-PCR (mITT). The primary endpoint was the proportion of HHC who developed COVID-19 (RT-PCR positive and ≥1 of the 14 specified COVID-19 symptoms lasting for ≥48 hours) by Day 10. The secondary analysis population, which included HHC regardless of central laboratory RT-PCR results at baseline (ITT), was analyzed with the same endpoint.
Results
Between June 2023 and August 2024, 2,389 HHC were enrolled, of whom 2,041 constituted mITT (ensitrelvir n=1,030 vs. placebo n=1,011). In the mITT, the mean age was 42.4 years, 71.1% of HHC were randomized within 48 hours of IP symptom onset, and 37.0% had ≥1 high-risk factor (HR) for severe COVID-19. In the mITT population, the overall proportion of HHC developing confirmed COVID-19 was significantly lower in the ensitrelvir group (2.9%) than in the placebo group (9.0%), with a risk ratio of 0.33 (95%CI: 0.22-0.49; p<0.0001). In the ITT population (ensitrelvir n=1,194 vs. placebo n=1,193), similar ensitrelvir efficacy was observed with a risk ratio of 0.43 (95%CI: 0.32-0.59; p<0.0001). In the HHC with baseline SARS-CoV-2 positivity (ensitrelvir n=114 vs. placebo n=123), the risk ratio was 0.75 (95%CI: 0.46-1.23). In the ensitrelvir and placebo groups, the proportions developing treatment-emergent adverse events (TEAEs) (15.1% vs. 15.5%, respectively) or serious TEAEs (0.2% vs. 0.2%) were similar, as were the TEAEs observed in >1.5% of patients in either group: headache (2.9% vs. 2.5%), diarrhea (1.8% vs. 1.3%) and influenza (1.1% vs. 1.6%). There were no COVID-19 related hospitalizations or fatalities.
Conclusions
Administration of ensitrelvir to HHC <72 hours after the onset of IP symptoms was effective and generally well tolerated for PEP in HHC, including those with HR factors.