Ensitrelvir for the Treatment of Nonhospitalized Adults with COVID-19: Results from the SCORPIO-HR, Phase 3, Randomized, Double-blind, Placebo-Controlled Trial

Abstract

Background: Ensitrelvir, a severe acute respiratory syndrome coronavirus-2 main protease inhibitor, has demonstrated clinical and virologic efficacy in previous studies.

Methods: In this global phase 3 trial, nonhospitalized adults with mild-to-moderate coronavirus disease 2019 (COVID-19) and symptom onset within 5 days were randomized (1:1) to receive once-daily ensitrelvir (375 mg day 1, 125 mg days 2-5) or blinded matching placebo. The primary endpoint was the restricted mean time to sustained (≥2 days) resolution of 15 COVID-19 symptoms, recorded in participant daily diaries, through day 29 in participants starting treatment within 3 days after symptom onset. Virologic efficacy and safety were assessed.

Results: Of 2093 participants, 1888 started treatment within 3 days after symptom onset. Mean time to symptom resolution was 12.5 and 13.1 days with ensitrelvir and placebo, respectively (difference, -0.6 days; 95% confidence interval, -1.38 to 0.19; P = .14). On day 4, ensitrelvir reduced least-squares mean RNA by 0.72 log10 copies/mL more than placebo (95% confidence interval, 0.55-0.90). Among those with positive viral cultures at enrollment, 274/287 (95.5%) ensitrelvir-treated versus 210/280 (75.0%) placebo-treated participants had negative cultures on day 4. RNA rebound was similar (<1.5%) between groups. The proportion of participants with ≥1 adverse event was similar with ensitrelvir (61.5%) and placebo (60.6%). No treatment-related serious adverse events or deaths occurred. Three (0.3%) ensitrelvir-treated and 1 (0.1%) placebo-treated participants had COVID-19-related hospitalizations by day 29.

Conclusions: Despite the evidence of antiviral activity with ensitrelvir, this trial did not demonstrate a significant difference in time to sustained symptom resolution.

Clinical trials registration number: NCT05305547.

Keywords: COVID-19; ensitrelvir; high risk; symptom resolution; viral rebound.

Graphical Abstract

Figure 1.

Randomization, treatment assignments, and follow-up (CONSORT flow diagram). Abbreviations: CONSORT, Consolidated Standards of Reporting Trials; mITT, modified intention-to-treat. *One participant was randomized to receive ensitrelvir but received placebo due to a dosing error.

Figure 2.

Antiviral efficacy as assessed by (A) Proportion of participants with SARS-CoV-2 RNA level <LLoQ (mITT population), and (B) Change in quantitative SARS-CoV-2 RNA level on D 4 and D 8 (mITT population). Abbreviations: ANCOVA, analysis of covariance; CI, confidence interval; D, day; LLoQ, lower limit of quantification; LSM, least-squares mean; mITT, modified intention-to-treat; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; ULoQ, upper limit of quantification. A, The proportion of participants with SARS-CoV-2 RNA levels below the LLoQ in the mITT population. Data are presented as percentage (%) ± 95% CI. B, The adjusted mean change in SARS-CoV-2 viral RNA from D 1 in the mITT population. ANCOVA was used to obtain the estimate of difference in mean and associated 95% CI adjusted for D 1. Participants who were alive and not hospitalized on D 4 or D 8 but who had missing RNA values (including due to loss to follow-up, samples not obtained, lost samples, and laboratory issues) on D 4 or D 8, respectively, were excluded. As the primary efficacy endpoint was not statistically significant, secondary endpoint results are descriptive. For quantitative analyses of log₁₀ SARS-CoV-2 RNA, D 1, D 4, and D 8 values were imputed. D 1, D 4, and D 8 values that were detected and were <LLoQ were imputed as 1.7 log₁₀ SARS-CoV-2 RNA; undetected values were imputed as 0.0; and values above ULoQ = 8.0 were imputed as 8.3 log₁₀ SARS-CoV-2 RNA.