Antiviral efficacy of oral ensitrelvir versus oral ritonavir-boosted nirmatrelvir in COVID-19 (PLATCOV): an open-label, phase 2, randomised, controlled, adaptive trial

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Background Ensitrelvir is an oral antiviral treatment for COVID-19 with the same molecular target (the main protease) as ritonavir-boosted nirmatrelvir—the current oral first-line treatment. We aimed to compare the clinical antiviral effects of the two drugs. Methods In an open-label, phase 2, randomised, controlled, adaptive pharmacometric platform trial, low-risk adult outpatients aged 18–60 years with early symptomatic COVID-19 (<4 days of symptoms) were recruited from hospital acute respiratory infection clinics in Thailand and Laos. Patients were randomly assigned in blocks (block sizes depended on the number of interventions available) to one of eight treatment groups, including oral ensitrelvir and oral ritonavir-boosted nirmatrelvir at standard doses, both given for 5 days, and no study drug. The primary endpoint was the oropharyngeal SARS-CoV-2 viral clearance rate assessed between day 0 and day 5 in the modified intention-to-treat population (defined as patients with at least 2 days of follow-up). Patients had four oropharyngeal swabs taken on day 0 and two swabs taken daily from days 1 to 7, then on days 10 and 14. Viral clearance rates were derived under a Bayesian hierarchical linear model fitted to log 10 viral densities in standardised paired oropharyngeal swab eluates taken daily over the 5 days (14 samples). An individual patient data meta-analysis of all small molecule drugs evaluated in this platform trial using published results was also performed, adjusting for temporal trends in viral clearance. This trial is registered at ClinicalTrials.gov, NCT05041907. Findings Between March 17, 2023, and April 21, 2024, 604 of 903 patients enrolled were concurrently assigned to the three treatment groups (ensitrelvir n=202; ritonavir-boosted nirmatrelvir n=207; no study drug n=195). Median estimated SARS-CoV-2 clearance half-lives were 5·9 h (IQR 4·0–8·6) with ensitrelvir, 5·2 h (3·8–6·6) with nirmatrelvir, and 11·6 h (8·1–14·5) with no study drug. Viral clearance following ensitrelvir was 82% faster (95% credible interval 61–104) than no study drug and 16% slower (5–25) than ritonavir-boosted nirmatrelvir. In the meta-analysis of all unblinded small molecule drugs evaluated in the platform trial, nirmatrelvir and ensitrelvir had the largest antiviral effects (1157 patients). Viral rebound occurred in 15 (7%) of 207 patients in the nirmatrelvir group and 10 (5%) of 202 in the ensitrelvir group (p=0·45). Interpretation Both ensitrelvir and nirmatrelvir accelerate oropharyngeal SARS-CoV-2 viral clearance. Ensitrelvir is an effective alternative to currently available antivirals in treating COVID-19. Although COVID-19 is now generally a mild disease, it still causes substantial morbidity, particularly in vulnerable groups, and new variants or other coronaviruses could still emerge with pandemic potential. Safe effective and affordable antivirals are needed, and these are best assessed initially in pharmacometric platform trials assessing viral clearance. Funding Wellcome Trust through the COVID-19 Therapeutics Accelerator.

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