Ensitrelvir for the Treatment of Nonhospitalized Adults with COVID-19: Results from the SCORPIO-HR, Phase 3, Randomized, Double-blind, Placebo-Controlled Trial
Anne F. Luetkemeyer, Kara W Chew, Stuart R. Lacey, Michael D. Hughes, Linda J. Harrison, Eric S. Daar, Joseph J. Eron, Courtney V. Fletcher, Alexander L. Greninger, Diane Hessinger, Jonathan Z. Li, David Mailhot, David A. Wohl, Methee Chayakulkeeree, J.L. Mendoza, Polina Elistratova, O. N. Makinde, Gareth Morgan, Simon Portsmouth, Takeki Uehara, Davey M. Smith, Judith S. Currier
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.