Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients

Abstract

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 [CI], -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% CI, -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.).

Figure 1. Randomization and Flow of Participants from Baseline through Day 29.

Figure 2. Time-to-Event Analysis of Hospitalization or Death through Day 29 in the Modified Intention-to-Treat Population.

Shown are Kaplan–Meier curves with 95% confidence intervals (𝙸 bars). X indicates censored values. Data for the single participant with unknown survival status and no hospitalization reported were censored on the day when the participant was last known to be alive. The inset shows the same data on an expanded y axis.

Figure 3. Incidence of Hospitalization or Death at Day 29 in the Modified Intention-to-Treat Population, According to Subgroup.

Shown are data for the primary end point in key subgroups of the modified intention-to-treat population. The 95% confidence intervals are based on the unstratified Miettinen and Nurminen method. Obesity was defined by a body-mass index of 30 or above. Data on baseline nucleocapsid antibody status are based on a nucleocapsid antibody assay and do not reflect previous vaccination status, since Covid-19 vaccines generate antibodies against the SARS-CoV-2 spike protein, not the SARS-CoV-2 nucleocapsid protein. Race and ethnic group were reported by the participants, who identified themselves from a set of available options. Each race or ethnic group category includes participants who identified themselves as belonging to that race or ethnic group only or as belonging to that race or ethnic group plus one or more other races or ethnic groups; thus, participants could be counted in more than one race or ethnic group category. Confidence intervals were not adjusted for multiple comparisons and may not be reproducible. For the Asian race group, the confidence interval was not calculated, in accordance with the analysis plan, owing to a sample size of less than 25 participants in either group. (See Fig. S3 for details on race and ethnic group.) Outcomes according to baseline clade are not shown here, since at the time of this report, clade sequencing had not yet been conducted for about 45% of all participants who underwent randomization.