A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus
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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.
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SciScore for 10.1101/2021.06.17.21258639: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The protocol was approved by WCG institutional review board and written informed consent was obtained from each participant prior to study entry.
Consent: The protocol was approved by WCG institutional review board and written informed consent was obtained from each participant prior to study entry.Sex as a biological variable not detected. Randomization Randomization and Intervention: Participants were randomized 1:1 to 200 mg molnupiravir or matching placebo or 3:1 to molnupiravir (400 or 800 mg) or placebo. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Infectious virus isolation was … SciScore for 10.1101/2021.06.17.21258639: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The protocol was approved by WCG institutional review board and written informed consent was obtained from each participant prior to study entry.
Consent: The protocol was approved by WCG institutional review board and written informed consent was obtained from each participant prior to study entry.Sex as a biological variable not detected. Randomization Randomization and Intervention: Participants were randomized 1:1 to 200 mg molnupiravir or matching placebo or 3:1 to molnupiravir (400 or 800 mg) or placebo. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Infectious virus isolation was performed using Vero C1008 cells and assessed by quantitative RT-PCR of viral RNA in culture medium at 2 and 5 days post inoculation. Vero C1008suggested: ATCC Cat# CRL-1586, RRID:CVCL_0574)Software and Algorithms Sentences Resources Analyses were conducted using SAS Version 9.4 (SAS Institute Inc., Cary NC) and two-sided tests were performed using an alpha of 0.05 for treatment comparisons. SAS Institutesuggested: (Statistical Analysis System, RRID:SCR_008567)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Another limitation included imbalances in the randomization, with a greater proportion of seropositive individuals and a trend toward a lower viral load at baseline among those randomized to 800 mg molnupiravir compared to placebo. However, differences in infectious virus isolation at Day 5, time to clearance of viral RNA, and reductions in viral load from baseline to Day 5 remained significant when analysis was limited to participants who were antibody negative at baseline. Among participants who were negative for antibodies at baseline, there was no difference in baseline viral load between the 800 mg molnupiravir and placebo groups. An additional limitation is the use of pooled placebo in the analyses; however, differences in virus isolation and viral load reduction on Day 5 remained significant when analysis was limited to comparisons between 800 mg molnupiravir and concurrent placebo (Supplementary Table 7). These sensitivity analyses indicate that the antiviral efficacy demonstrated in this study is not due to imbalances in either seropositivity, trends in viral RNA level at baseline, or the use of a pooled placebo group. Currently, two combination intravenous monoclonal antibody cocktails have been granted emergency use authorization in an attempt to reduce nasopharyngeal SARS-CoV-2 RNA, medical visits, and hospitalizations; however, the logistical challenges of intravenous therapies limit timely administration to patients who may benefit most from these important trea...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04405570 Completed A Safety, Tolerability and Efficacy of Molnupiravir (EIDD-28… NCT04575597 Recruiting Efficacy and Safety of Molnupiravir (MK-4482) in Non-Hospita… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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