A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus

Abstract

There is an urgent need for an effective, oral, direct-acting therapeutic to block transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and prevent progression to severe coronavirus disease 2019 (COVID-19). In a phase 2a double-blind, placebo-controlled, randomized, multicenter clinical trial, we evaluated the safety, tolerability, and antiviral efficacy of the nucleoside analog molnupiravir in 202 unvaccinated participants with confirmed SARS-CoV-2 infection and symptom duration <7 days. Participants were randomized 1:1 to receive molnupiravir (200 mg) or placebo and then 3:1 to receive molnupiravir (400 or 800 mg) or placebo, orally twice daily for 5 days. Antiviral activity was assessed by reverse transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2 RNA in nasopharyngeal swabs. Infectious virus was assessed by inoculation of cultured Vero cells with samples from nasopharyngeal swabs and was detected by RT-PCR. Time to viral RNA clearance (primary endpoint) was decreased in the 800-mg molnupiravir group (median 14 days) compared to the placebo group (median 15 days) (log rank P value = 0.013). Of participants receiving 800 mg of molnupiravir, 92.5% achieved viral RNA clearance compared with 80.3% of placebo recipients by study end (4 weeks). Infectious virus (secondary endpoint) was detected in swabs from 1.9% of the 800-mg molnupiravir group compared with 16.7% of the placebo group at day 3 of treatment (P = 0.016). At day 5 of treatment, infectious virus was not isolated from any participants receiving 400 or 800 mg of molnupiravir compared with 11.1% of placebo recipients (P = 0.034 and 0.027, respectively). Molnupiravir was well tolerated across all doses.

Fig. 1.. CONSORT diagram for the phase 2a trial.

Shown is the study flow chart for the phase 2a randomized, double-blind, placebo-controlled trial of multiple doses of molnupiravir in 202 nonhospitalized adults with recently diagnosed COVID-19 (ClinicalTrials.gov identifier: NCT04405570). Unvaccinated adults aged ≥18 years were eligible if they had a positive test for SARS-CoV-2 infection within 96 hours and had onset of symptoms of COVID-19 within 7 days at the time of treatment initiation (day 1). Antiviral activity, safety, and tolerability of molnupiravir were assessed for 28 days after treatment initiation. The modified intent to treat (mITT) population included all participants who were randomized into the study and had at least one post-baseline viral RNA assessment. The per protocol (PP) population included participants in the safety population who had no important protocol deviations leading to exclusion from the per protocol population and had completed the day 28 follow-up visit. The safety population included all participants who were randomized and took at least one dose of the study drug. Participants were analyzed according to the treatment they actually received. AE, adverse events.

Fig. 2.. SARS-CoV-2 infectivity and virology.

(A) Shown is a Kaplan-Meier plot of time to clearance of SARS-CoV-2 RNA by treatment: 200 mg molnupiravir (red), 400 mg molnupiravir (blue), 800 mg molnupiravir (cyan), or placebo (black). (B) Shown is the percentage of participants who were positive (red) for SARS-CoV-2 infectious virus at day 1 (baseline), day 3, and day 5 of treatment. Participants who were negative for SARS-CoV-2 infectious virus are in blue. Comparison was based on pooled placebo data. (C) Shown is the least squares mean change from baseline in SARS-CoV-2 RNA (log₁₀ copies/ml) for the modified intent to treat population at study days 3, 5, 7, and 14: 200 mg molnupiravir (red), 400 mg molnupiravir (blue), 800 mg molnupiravir (cyan), or placebo (black).