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 Lacey, Michael D Hughes, Linda J Harrison, Eric S Daar, Joseph Eron, Courtney V Fletcher, Alexander L Greninger, Diane Hessinger, Jonathan Z Li, David Mailhot, David Wohl, Methee Chayakulkeeree, Jose Luis, Accini Mendoza, Polina Elistratova, Oluwaseun Makinde, Gareth Morgan, Simon Portsmouth, Takeki Uehara, Davey Smith, Judith S Currier
doi:10.1093/cid/ciaf029/8017725
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 log 10 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.
Peto-Prentice's generalized Wilcoxon test is employed to compare the entire KM curve of time to symptom resolution between treatment groups. This test is often selected to increase the sensitivity of detecting a group difference in survival distributions in situations where the group difference in the KM curve is large during the early time points but decreases toward the end of a period. Abbreviations: CI, confidence interval; COVID-19, coronavirus disease 2019; IQR, interquartile range; KM, Kaplan-Meier; mITT, modified intention-to-treat; PCR, polymerase chain reaction. a Fifteen COVID-19 symptoms: stuffy nose, runny nose, sore throat, cough, low energy or tiredness, feeling hot or feverish, shortness of breath or difficulty breathing, chills or shivering, muscle or body aches, diarrhea, nausea, vomiting, headache, loss of taste, and loss of smell. The 6 targeted COVID-19 symptoms for the prespecified supportive analysis were stuffy nose, runny nose, sore throat, cough, low energy or tiredness, and feeling hot or feverish. b Supportive analyses were not part of the statistical hierarchy, were not adjusted for multiplicity, and should be interpreted in an exploratory manner. c The mITT2 population included all randomized participants who took ≥1 dose of ensitrelvir or placebo and who started intervention within 3 d of symptom onset with positive PCR results (above limit of detection) on day 1 (Supplementary Table 3 ).
Supplementary Data Supplementary materials are..
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