Making Statistical Sense of the Molnupiravir MOVe-OUT Clinical Trial

Abstract

Oral therapies for the early treatment of COVID-19 may prevent disease progression and health system overcrowding. A new oral therapeutic named molnupiravir has been promoted as providing an approximately 50% reduction in death or the need for hospitalization. The clinical trial evaluating this drug was stopped early at the recommendation of the Data Safety and Monitoring Board after approximately 50% of the sample had been recruited. At the point of discontinuing the trial, approximately 90% of the planned sample had been recruited and had available follow-up data accessible. We discuss issues about the study conduct, analysis, and interpretation, including 1) the authors and sponsors presented the interim analysis as the primary analysis; 2) communication between sponsors and the Data Safety and Monitoring Board was insufficient; 3) the treatment effects reverse when examining only the post-interim analysis population, and are substantially attenuated when examining the full data; 4) the choice of primary analysis is incorrect; 5) analysis of lost-to-follow-up patients favors the study drug; and 6) other known molnupiravir trials were not presented in the primary study findings. As a result of methodological and statistical concerns, it seems that external trials, separate from those supported by the sponsoring company, are required to determine the utility of this drug.

Real-world effectiveness of molnupiravir and nirmatrelvir/ritonavir against mortality, hospitalization, and in-hospital outcomes among community-dwelling, ambulatory COVID-19 patients during the BA.2.2 wave in Hong Kong: an observational study

“…28,30 In fact, the MOVe-OUT trial has been criticized for its premature termination, imbalances of patient characteristics between treatment and control groups at baseline, inconsistency in the results between interim and final analyses that could not be fully explained by differences in patient characteristics, and the dubious value of molnupiravir given its modest reduction in hospitalization or death rate that failed to reach statistical significance (HR=0•69, 95%CI=0•48-1•01). 3,[30][31][32][33] Accordingly, further studies are needed to confirm the realworld effectiveness of molnupiravir and nirmatrelvir/ritonavir in different healthcare settings and COVID-19 patient populations. Several clinical trials (namely RECOVERY and PANORAMIC) and observational studies of the two oral antivirals are ongoing, which will take into account the circulating Omicron variant and vaccination status of patients.…”

Molnupiravir Plus Usual Care Versus Usual Care Alone as Early Treatment for Adults with COVID-19 at Increased Risk of Adverse Outcomes (PANORAMIC): Preliminary Analysis from the United Kingdom Randomised, Controlled Open-Label, Platform Adaptive Trial

“…10 The reason for this difference has been debated. 13 Several Phase 3 trials have been conducted in India among non-hospitalized patients with reportedly mixed findings, 14 but to date the full peer-reviewed results have not been published. The AGILE CST-2 trial conducted in 180 vaccinated and unvaccinated participants showed that molnupiravir resulted in a faster time to a negative PCR test compared with placebo (8 days versus 11 days).…”

“…Estimates were similar for all subgroups. The observed median (IQR) time-to-first-recovery from randomisation was 9 (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) days in molnupiravir and 15 ( Interpretation In this preliminary analysis, we found that molnupiravir did not reduce already low hospitalisations/deaths among higher risk, vaccinated adults with COVID-19 in the community, but resulted in faster time to recovery, and reduced viral detection and load.…”

Molnupiravir’s authorisation should be re-evaluated after the Panoramic trial is reported

“…Molnupiravir reduced the risk of hospital admission or death by 52% versus placebo in the interim analysis but raised risk by 35% among patients subsequently evaluated 4. There was no clear explanation for this substantial disparity in treatment effects between the interim and final phases.…”