Molnupiravir or nirmatrelvir-ritonavir plus usual care versus usual care alone in patients admitted to hospital with COVID-19: a randomised, controlled, open-label, platform trial (RECOVERY)
HORBY PW., STAPLIN N., PETO L., EMBERSON JR., Campbell M., PESSOA-AMORIM G., Basnyat B., THWAITES L., Van Doorn R., Hamers RL., Nel J., Amuasi J., Stewart R., Ghosh D., Blencowe N., Desai P., Easom N., Majumdar J., Hine P., Chadwick D., Cooke G., Sarkar R., ESMAIL H., Baillie JK., Buch MH., Faust SN., Jaki T., Juszczak E., Jeffery K., KNIGHT M., Lim WS., Montgomery A., Mukherjee A., Mumford A., Rowan K., THWAITES G., MAFHAM M., HAYNES R., LANDRAY MJ.
Background: Molnupiravir and nirmatrelvir-ritonavir (Paxlovid) are oral antivirals that were assessed in separate treatment comparisons in the RECOVERY trial, a randomised, controlled, open-label, adaptive platform trial evaluating treatments for patients hospitalised with COVID-19 pneumonia. Methods: Adult participants could join the molnupiravir comparison, the nirmatrelvir-ritonavir comparison, or both. In each comparison, they were randomly allocated in a 1:1 ratio to the relevant antiviral (five days of molnupiravir 800mg twice daily or nirmatrelvir-ritonavir 300mg/100mg twice daily) in addition to usual care, or to usual care alone. The primary outcome was 28-day mortality, and secondary outcomes were time to discharge alive from hospital, and progression to invasive ventilation or death. Analysis was by intention-to-treat. Both comparisons were stopped because of low recruitment. ISRCTN50189673; clinicaltrials.gov NCT04381936. Findings: From January 2022 to May 2023, 923 patients were recruited to the molnupiravir comparison (445 allocated molnupiravir and 478 allocated usual care), and from March 2022 to May 2023, 137 patients were recruited to the nirmatrelvir-ritonavir comparison (68 allocated nirmatrelvir-ritonavir and 69 allocated usual care). Over three-quarters of the patients were vaccinated and had anti-spike antibodies at randomisation, and over two-thirds were receiving other SARS-CoV-2 antivirals. In the molnupiravir comparison, 74 (17%) patients allocated molnupiravir and 79 (17%) patients allocated usual care died within 28 days (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.68-1.28; p=0.66). In the nirmatrelvir-ritonavir comparison, 13 (19%) patients allocated nirmatrelvir-ritonavir and 13 (19%) patients allocated usual care died within 28 days (HR 1.02; 95% CI 0.47-2.23; p=0.96). In neither comparison was there evidence of any difference in the duration of hospitalisation or the proportion of patients progressing to invasive ventilation or death. Interpretation: Adding molnupiravir or nirmatrelvir-ritonavir to usual care was not associated with improvements in clinical outcomes. However, limited recruitment meant a clinically meaningful benefit of treatment could not be ruled-out, particularly for nirmatrelvir-ritonavir.