Background New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalization or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29. Results A total of 1433 participants underwent randomization; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, −6.8 percentage points; 95% confidence interval, −11.3 to −2.4; P=0.001). In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, −3.0 percentage points; 95% confidence interval, −5.9 to −0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group. Conclusions Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19. (Funded by Merck Sharp and Dohme; MOVe-OUT ClinicalTrials.gov number, NCT04575597 .)

NTIMICROBIALS AVAILABLE FOR treatment of complicated skin and skin structure infections (SSSIs) are generally efficacious, but antimicrobial resistance 1-7 and adverse effects limit their use. 1,8,9 Linezolid, an oxazolidinone, is the only drug approved for complicated SSSI caused by methicillinresistant Staphylococcus aureus (MRSA). Sporadic outbreaks of linezolidresistant strains of MRSA and enterococci, including those carrying a plasmid-borne cfr gene encoding the chloramphenicol/florfenicol resistance protein, have been reported. 10 Significant safety concerns with linezolid have emerged since it was approved in 2000 by the US Food and Drug Administration (FDA). 11 In 2010, the FDA issued a draft guidance for the development of systemic drugs to treat acute bacterial SSSIs (ABSSSIs) with recommendations for clinical response criteria and noninferiority trial design. 12,13 Given the time required to develop and obtain approval for a new chemical entity, trials demonstrating noninferiority to currently approved antimicrobials allow the development of new agents in advance of the selection of resistant pathogens in hospitals or in the community. Even within the same class of For editorial comment see p 609.

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Molnupiravir is an orally acting novel small-molecule prodrug that acts against Covid-19 by inducing viral mutations to a threshold beyond which it cannot replicate. In a small, double-blind, dose-escalation, trial in non-hospitalized adults with mild/moderate Covid-19 with symptom onset less than 7 days before trial randomization, molnupiravir had with no apparent dose-related effect on adverse events or laboratory tests in relation to dose or treatment. Of the participants receiving molnupiravir 3.1% were hospitalized or died compared with 5.4% treated with placebo.

Molnupiravir is an oral agent a metabolite of which has activity against SARS-CoV-2. In a controlled trial in adults hospitalized for Covid-19 who had symptoms for 10 days or less prior to randomization, patients received placebo (n=75) or varying doses of molnupiravir (n=218) administered twice-daily for 5 days. There was no impact of treatment on death. Median time to sustained recovery was 9 days in all groups, with day 29 recovery rates ranging from 81.5%-85.2%. There were no dose-limiting side effects or adverse events.