Molnupiravir or nirmatrelvir-ritonavir versus usual care in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Horby et al., medRxiv, doi:10.1101/2024.05.23.24307731, RECOVERY, NCT04381936

May 2024

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RECOVERY RCT showing no significant differences in mortality, ventilation, or discharge with either molnupiravir (923 patients) or paxlovid (137 patients). Viral load was improved with treatment but did not translate into clinical benefit, which may in part be due to side effects of treatment.

The treatment delay was notably shorter compared to other treatments in this trial - 4 and 5 days from onset for paxlovid and molnupiravir.

There was an exactly one year delay in publication after completion of recruitment. No press release or results are shown on the trial web site. In contrast, a press release was issued for the HCQ arm on the same day that recruitment ended. The one year delay may be a maximum delay due to EU Clinical Trials registration and associated regulatory requirements for the release of results within 12 months.

Concerns have been raised that the mutagenic mechanism of action may create dangerous variants or cause cancer1-9. Multiple analyses have identified variants potentially created by molnupiravir10-13.

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Study covers molnupiravir and paxlovid.

risk of death, 11.3% higher, RR 1.11, p = 0.55, treatment 57 of 445 (12.8%), control 55 of 478 (11.5%), COVID-19, day 28, Supp. Table 4.

risk of death, 7.0% lower, HR 0.93, p = 0.66, treatment 74 of 445 (16.6%), control 79 of 478 (16.5%), adjusted per study, all cause, multivariable, Cox proportional hazards, day 28.

risk of mechanical ventilation, 42.6% higher, RR 1.43, p = 0.59, treatment 8 of 445 (1.8%), control 6 of 476 (1.3%).

risk of no hospital discharge, 9.1% higher, RR 1.09, p = 0.46, treatment 126 of 445 (28.3%), control 124 of 478 (25.9%).

time to discharge, 11.1% higher, relative time 1.11, treatment 445, control 478.

viral load, 12.0% lower, relative load 0.88, p < 0.001, treatment mean 3.51 (±0.1) n=445, control mean 3.99 (±0.13) n=478.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

1. Swanstrom et al., Lethal mutagenesis as an antiviral strategy, Science, doi:10.1126/science.abn0048.science.org, doi.org.

2. Hadj Hassine et al., Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity, Viruses, doi:10.3390/v14040841.mdpi.com, doi.org.

3. Waters et al., Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the special case of molnupiravir, Environmental and Molecular Mutagenesis, doi:10.1002/em.22471.wiley.com, doi.org.

4. Huntsman, M., An assessment of the reproductive toxicity of the anti-COVID-19 drug molnupiravir using stem cell-based embryo models, Master's Thesis, scholarspace.manoa.hawaii.edu/items/cd11342c-b4dc-44c0-8b44-ce6e3369c40b.hawaii.edu.

5. Zibat et al., N4-hydroxycytidine, the active compound of Molnupiravir, promotes SARS-CoV-2 mutagenesis and escape from a neutralizing nanobody, iScience, doi:10.1016/j.isci.2023.107786.sciencedirect.com, doi.org.

6. Gruber et al., Molnupiravir increases SARS‐CoV‐2 genome diversity and complexity: A case‐control cohort study, Journal of Medical Virology, doi:10.1002/jmv.29642.wiley.com, doi.org.

7. Marikawa et al., An active metabolite of the anti-COVID-19 drug molnupiravir impairs mouse preimplantation embryos at clinically relevant concentrations, Reproductive Toxicology, doi:10.1016/j.reprotox.2023.108475.sciencedirect.com, doi.org.

8. Zhou et al., β-D-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells, The Journal of Infectious Diseases, doi:10.1093/infdis/jiab247.oup.com, doi.org.

9. Chamod et al., Molnupiravir Metabolite--N4-hydroxycytidine Causes Cytotoxicity and DNA Damage in Mammalian Cells in vitro: N4-hydroxycytidine Induced Cytotoxicity DNA Damage, Asian Medical Journal and Alternative Medicine, 23:3, asianmedjam.com/index.php/amjam/article/view/1448.asianmedjam.com.

10. Fountain-Jones et al., Effect of molnupiravir on SARS-CoV-2 evolution in immunocompromised patients: a retrospective observational study, The Lancet Microbe, doi:10.1016/S2666-5247(23)00393-2.sciencedirect.com, doi.org.

11. Sanderson et al., A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes, Nature, doi:10.1038/s41586-023-06649-6.nature.com, doi.org.

12. Kosakovsky Pond et al., Anti-COVID drug accelerates viral evolution, Nature, doi:10.1038/d41586-023-03248-3.nature.com, doi.org.

13. twitter.com, twitter.com/LongDesertTrain/status/1597353291868155906.twitter.com/LongDesertTrain/status/1597353291868155906.

Horby et al., 24 May 2024, Randomized Controlled Trial, multiple countries, preprint, 39 authors, trial NCT04381936 (history) (RECOVERY).

This Paper Molnupiravir All

open-label, platform trial

Prof Peter W Horby, Prof Martin, RECOVERY J Landray

doi:10.1101/2024.05.23.24307731

a randomised, controlled,

Declaration of interests The authors have no conflict of interest or financial relationships relevant to the submitted work to disclose. No form of payment was given to anyone to produce the manuscript. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. The Nuffield Department of Population Health at the University of Oxford has a staff policy of not accepting honoraria or consultancy fees directly or indirectly from industry (see https://www.ndph.ox.ac.uk/files/about/ndph-independenceof-research-policy-jun-20.pdf). Conflicts of interest No form of payment was given to anyone to produce the manuscript. The Nuffield Department of Population Health at the University of Oxford has a staff policy of not accepting honoraria or consultancy fees directly or indirectly from industry (see -0.68 (-1.29, -0.07) 0.03 RR=Hazard ratio for the outcomes of 28-day mortality and hospital discharge, and risk ratio for the outcome of receipt of invasive mechanical ventilation or death (and its subcomponents). CI=confidence interval. *Analyses exclude those on invasive mechanical ventilation at randomization. †Analyses exclude those on any form of ventilation at randomisation. ‡Analyses restricted to those on invasive mechanical ventilation at randomisation. §Analyses exclude those on haemodialysis or haemofiltration at randomisation.

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Late treatment
is less effective

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