Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients With Mild to Moderate COVID-19: The SCORPIO-SR Randomized Clinical Trial

Abstract

Importance: Treatment options for COVID-19 are warranted irrespective of the presence of risk factors for severe disease.

Objective: To assess the efficacy and safety of ensitrelvir in patients with mild to moderate COVID-19.

Design, setting, and participants: This phase 3 part of a phase 2/3, double-blind, placebo-controlled randomized clinical trial was conducted from February 10 to July 10, 2022, with a 28-day follow-up period, at 92 institutions in Japan, Vietnam, and South Korea. Patients (aged 12 to <70 years) with mild to moderate COVID-19 within 120 hours of positive viral test results were studied.

Interventions: Patients were randomized (1:1:1) to receive 125 mg of once-daily ensitrelvir (375 mg on day 1), 250 mg of once-daily ensitrelvir (750 mg on day 1), or placebo for 5 days.

Main outcomes and measures: The primary end point was the time to resolution of the composite of 5 characteristic symptoms of SARS-CoV-2 Omicron infection, assessed using a Peto-Prentice generalized Wilcoxon test stratified by vaccination history. Virologic efficacy and safety were also assessed.

Results: A total of 1821 patients were randomized, of whom 1030 (347 in the 125-mg ensitrelvir group, 340 in the 250-mg ensitrelvir group, and 343 in the placebo group) were randomized in less than 72 hours of disease onset (primary analysis population). The mean (SD) age in this population was 35.2 (12.3) years, and 552 (53.6%) were men. A significant difference was observed between the 125-mg ensitrelvir group and the placebo group (P = .04 with a Peto-Prentice generalized Wilcoxon test). The difference in median time was approximately 1 day between the 125-mg ensitrelvir group and the placebo group (167.9 vs 192.2 hours; difference, -24.3 hours; 95% CI, -78.7 to 11.7 hours). Adverse events were observed in 267 of 604 patients (44.2%) in the 125-mg ensitrelvir group, 321 of 599 patients (53.6%) in the 250-mg ensitrelvir group, and 150 of 605 patients (24.8%) in the placebo group, which included a decrease in high-density lipoprotein level (188 [31.1%] in the 125-mg ensitrelvir group, 231 [38.6%] in the 250-mg ensitrelvir group, and 23 [3.8%] in the placebo group). No treatment-related serious adverse events were reported.

Conclusions and relevance: In this randomized clinical trial, 125-mg ensitrelvir treatment reduced the time to resolution of the 5 typical COVID-19 symptoms compared with placebo in patients treated in less than 72 hours of disease onset; the absolute difference in median time to resolution was approximately 1 day. Ensitrelvir demonstrated clinical and antiviral efficacy without new safety concerns. Generalizability to populations outside Asia should be confirmed.

Trial registration: Japan Registry of Clinical Trials Identifier: jRCT2031210350.

Figure 1.. CONSORT Flow Diagram

The intention-to-treat population comprised all patients who tested positive for SARS-CoV-2 RNA at baseline, as confirmed by reverse transcriptase–polymerase chain reaction (RT-PCR) testing of a nasopharyngeal swab sample. The modified intention-to-treat population comprised all patients who tested positive for SARS-CoV-2 RNA and who had a detectable SARS-CoV-2 titer at baseline.

Figure 2.. Time to Resolution of 5 COVID-19 Symptoms in the Intention-to-Treat Population

The analysis was performed for all patients who tested positive for SARS-CoV-2 RNA at baseline. Patients randomized in less than 72 hours of disease onset in the 125-mg ensitrelvir group were defined as the primary analysis population. A Peto-Prentice generalized Wilcoxon test was applied to test the statistical significance vs placebo. The test was stratified by SARS-CoV-2 vaccination history (yes or no) for patients randomized in less than 72 hours (A) and time from onset to randomization (<72 or ≥72 hours) and SARS-CoV-2 vaccination history (yes or no) for patients randomized within 120 hours (B). The 5 COVID-19 symptoms were stuffy or runny nose, sore throat, cough, feeling hot or feverish, and low energy or tiredness. In the primary analysis population (A), the median time to resolution of the 5 COVID-19 symptoms was 171.2 hours in the 250-mgensitrelvir group and 192.2 hours in the placebo group (difference, −21.0 hours; 95% CI, −73.8 to 7.2 hours). Among patients randomized within 120 hours of disease onset (B), the median difference in the time to resolution of the 5 COVID-19 symptoms between 125-mg ensitrelvir and placebo was −10.6 hours (95% CI, −56.9 to 21.3 hours).