Randomized Trial of Molnupiravir or Placebo in Patients ...

1 Published December 16, 2021. DOI: ORIGINAL ARTICLE. Randomized Trial of Molnupiravir or Placebo in Patients Hospitalized with Covid-19. Jos e R. Arribas, , Sanjay Bhagani, , Suzana M. Lobo, , , Ilsiyar Khaertynova, , Lourdes Mateu, , , Roman Fishchuk, , William Y. Park, , Khetam Hussein, , Sei Won Kim, , Jade Ghosn, ,11, Michelle L. Brown, , Ying Zhang, , Wei Gao, , Christopher Assaid, , Jay A. Grobler, , Julie Strizki, , Mary Vesnesky, , Amanda Paschke, , Joan R. Butterton, , Carisa De Anda, , on behalf of the MOVe-IN study group Abstract BACKGROUND Molnupiravir is an oral prodrug of b-D-N4-hydroxycytidine, active against SARS-CoV-2 in vitro and in animal models.

2 We report data from the phase 2 component of MOVe-IN, a clinical Trial evaluating Molnupiravir in Patients hospitalized with Covid-19. METHODS We conducted a Randomized , Placebo - controlled , double-blind phase 2/3. Trial in Patients 18 years old and older requiring in-hospital treatment for laboratory- con rmed Covid-19 with symptom onset 10 or fewer days before randomization. Partici- pants were randomly assigned to Placebo or Molnupiravir 200 mg, 400 mg, or 800 mg (1:1:1:1 ratio), twice daily for 5 days. Primary end points were safety and sustained recov- ery (participant alive and either not hospitalized or medically ready for discharge).

3 Through day 29. RESULTS Of 304 randomly assigned participants, 218 received at least one dose of mol- nupiravir and 75 of Placebo . At baseline, had at least one risk factor for severe Covid-19. Adverse events were reported in 121 of 218 ( ) Molnupiravir -treated and 46 of 75 ( ) Placebo -treated participants, with no apparent dose effect on adverse event rates and no evidence of hematologic toxicity based on prespeci ed adverse events. Of 16 con rmed deaths, most were in participants with severe Covid-19 ( ), with underlying comorbidities ( ), older than 60 years of age ( ), and/or symp- tom duration longer than 5 days ( ) at randomization.

4 Median time to sustained recovery was 9 days in all groups, with similar day 29 recovery rates ranging from The author af liations are listed at the end of the article. to Dr. De Anda can be contacted at or at CONCLUSIONS In this phase 2 Trial of Patients hospitalized with Covid-19, a 5-day Merck & Co. Inc., 309 N. Sumneytown Pike, North Wales, course of Molnupiravir up to 800 mg twice daily was not associated with dose-limiting PA 19454. For personal use only. No other uses without permission. Copyright 2021 Massachusetts Medical Society. side effects or adverse events, but did not demonstrate 15 countries globally (Table S1 in the Supplementary clinical bene t.)

5 (Funded by Merck Sharp Appendix). The Trial enrolled adult Patients requiring NCT04575584.) in-hospital treatment for laboratory-con rmed Covid-19. with sign/symptom onset 10 or fewer days before ran- domization. Key exclusion criteria were critical illness due to Covid-19 ( , respiratory failure [de ned as need for invasive or noninvasive mechanical ventilation, oxygen Introduction delivered by high- ow nasal cannula, or extracorporeal T. here is a need for safe, effective, and easily membrane oxygenation], shock, or multiorgan dysfunc- administered antiviral therapies to treat Patients tion/failure), severely immunocompromised persons who hospitalized for Covid-19; such treatments should are not expected to have a Covid-19 disease course and/or accelerate recovery times and reduce mortality.

6 Molnupir- clinical response to study treatment typical of the general avir is an orally administered, small-molecule ribonucleo- population, low platelet count (<100,000/ll or platelet side prodrug of b-D-N4-hydroxycytidine (NHC), which has transfusion 5 days prior), and SARS-CoV-2 vaccination. submicromolar potency against ribonucleic acid (RNA) Standard-of-care treatment with remdesivir and/or gluco- respiratory viruses, including 4 Molnupir- corticoids was permitted, but other immunomodulators avir is rapidly absorbed and converted into NHC, which (including interleukin-6 inhibitors and kinase inhibitors).

7 Is distributed systemically and phosphorylated intracellu- were prohibited for purposes of Covid-19 treatment. larly to NHC-triphosphate (NHC-TP).5 NHC-TP is incorpo- rated into the viral genome, which increases mismatch The study was conducted in accordance with principles of error rates during viral RNA replication. Once a tolerated Good Clinical Practice and was approved by the appropri- threshold of viral RNA errors has been exceeded, inhibi- ate institutional review boards/ethics committees and reg- tion of viral replication and production of noninfectious ulatory agencies. Written informed consent was obtained virus lead to viral ,3,6 In an animal model, mol- from all participants.

8 Full details of the Trial can be found nupiravir retained full ef cacy against SARS-CoV-2 var- in the protocol available online. The Trial was designed by iants of The favorable safety and tolerability sponsor (Merck & Co., Inc., Kenilworth, NJ) representa- pro le of Molnupiravir seen in preclinical studies and a tives. Safety oversight was performed by an independent phase 1 Trial provided the needed equipoise for further clin- data monitoring committee. Data were collected by inves- ical ,8 tigators and site personnel, analyzed by sponsor statisti- cians, and interpreted by the authors. The rst draft of the The potential of Molnupiravir as an antiviral treatment for manuscript was written with assistance of a medical writer Covid-19 is being evaluated in two phase 2/3 studies, one who is a sponsor employee, based on author guidance.

9 All in outpatients (MOVe-OUT trial9,10) and the other in hos- authors reviewed and edited subsequent versions, pitalized Patients (MOVe-IN Trial ). In this study, we report approved the submitted version, and vouch for the accu- safety, ef cacy, pharmacokinetic, and virology data from racy and completeness of the data and the delity of the the recently completed phase 2, dose- nding component Trial to the protocol, which is available with the full text of of MOVe-IN. this article at RANDOMIZATION AND INTERVENTIONS. Eligible participants were randomly assigned, via a cen- Methods tralized intervention randomization system, 1:1:1:1 to pla- cebo or Molnupiravir 200 mg, 400 mg, or 800 mg, Trial DESIGN AND PARTICIPANTS administered twice daily orally (or by an alternative route MOVe-IN (protocol MK-4482-001) was a Randomized , such as via nasogastric tube, for participants unable to Placebo - controlled , double-blind phase 2/3 Trial evaluating swallow study intervention capsules) for 5 days.

10 Randomi- safety and ef cacy of Molnupiravir in hospitalized adults zation was strati ed (block size: 4, the minimum block with Covid-19 ( NCT04575584). The size for a 4-arm Trial ) by time from sign/symptom onset to phase 2 component of MOVe-IN (initiated October 21, randomization ( 5 days or >5 days), age ( 60 years and 2020) was conducted at 65 hospitals/treatment centers in >60 years), and remdesivir use for the index Covid-19. NEJM EVIDENCE 2. For personal use only. No other uses without permission. Copyright 2021 Massachusetts Medical Society. infection before and/or at randomization (yes or no). Par- based on oxygen requirements, ranging from 1, minimal ticipants, investigators, and study staff (except unblinded or no symptoms, to 7, death ); Pulmonary Score (7- site pharmacists) remained blinded to allocation assign- point ordinal scale that focuses on Covid-19 disease sever- ment until study completion.