LETTERS

NPO Japan Institute ofPharmacovigilance, Tennoji-ku, Osaka,
Japan 543-0043
gec00724@nifty.com
Cite this as: BMJ 2022;377:o977
http://dx.doi.org/10.1136/bmj.o977
Published: 26 April 2022

MOLNUPIRAVIR’S PREMATURE AUTHORISATION

Imbalance in baseline characteristics in molnupiravir trials
Rokuro Hama medical doctor
Brophy emphasises the dangers of making decisions
based on a single prematurely terminated trial.1 The
molnupiravir trials have several more problems2 3:• The risk of hospital admission or death associatedwith molnupiravir was not significant in the all
randomised population when adjusted for sex(hazard ratio 0.69, 95% confidence interval 0.48
to 1.01).
• Molnupiravir may worsen covid-19 outcomes after
the interim analysis—simply calculating the rateof hospital admission or death in the populationof participants who were included in the final
analysis but not the interim analysis shows thatthe molnupiravir group had a non-significant
higher risk (6.2%) than the placebo group (4.7%).
• The Move-Out trial has serious imbalances inbaseline risk factors that favour molnupiravir.
Patients with chronic obstructive pulmonary
disease were assigned at a significantly lower rate
to the molnupiravir group (odds ratio 0.31,P=0.0043).4 The sum of the percentages of theparticipants with risk factors other than obesity
was significantly lower in the molnupiravir group(43.4%) than in the placebo group (51.8%) (OR0.71, P=0.019). With restriction to four risk factors(diabetes, chronic kidney disease, chronic
obstructive pulmonary disease, and active cancer),risk was almost 40% lower in the molnupiravirgroup (OR 0.61, P=0.0043).4 These findings
suggest that blinding might have been broken
before the interim analysis.

• Significant imbalances (except obesity) were also
observed in the all randomised population(OR=0.79, P=0.0314), which raises doubts about
fair randomisation.
• Contradictory results were seen in moderate tosevere covid-19. In subgroup analysis,
molnupiravir seemed significantly effective inpatients with moderate covid-19 and the effect size
was greater than in those with mild covid-19.5 But
two randomised controlled trials targeting
moderate covid-19 have been terminated becauseof futility.6• The Move-In trial also has a serious imbalance inseverity of covid-19 at baseline. Patients with score
6 covid-19 (admitted to hospital and given oxygenby non-invasive ventilation or high flow therapy)
were significantly less common in themolnupiravir groups (2.3%) than in the placebogroup (8.0%) (OR 0.27, P=0.025). But a
non-significant higher risk of death (6.0%) was
reported compared with placebo (2.7%) (OR 4.69,P=0.105). The ratio of mortality OR to OR ofthe bmj | BMJ 2022;377:o977 | doi: 10.1136/bmj.o977

baseline score 6 was 17.38 (95% confidence
interval 1.6 to 188.8) by Kolassa’s method.7
with irreversible• Molnupiravir has been associated5

myelosuppression in dogs and with DNA damage,bone marrow toxicity, and mutations in humans.8
Were the deaths observed in the Move-In trial3
associated with bone marrow toxicities?

Full clinical study reports of antivirals including
molnupiravir and remdesivir9 should be disclosed,
and a reanalysis is needed as in the systematicreviews on neuraminidase inhibitors.10
Competing interests: None declared.
Full response at: https://www.bmj.com/content/376/bmj.o443/rr.
1

Brophy JM. Molnupiravir’s authorisation was premature. BMJ
2022;376:o443. doi: 10.1136/bmj.o443 pmid: 35241455

2

Jayk Bernal A, Gomes da Silva MM, Musungaie DB, etalMOVe-OUT Study
Group. Molnupiravir for oral treatment of covid-19 in nonhospitalizedpatients. N Engl J Med 2022;386:509-20.
doi: 10.1056/NEJMoa2116044 pmid: 34914868

3

Arribas JR, Bhagani S, Lobo SM, etalRandomized trial of molnupiravir orplacebo in patients hospitalized with covid-19. NEJM Evid2022;1:EVIDoa2100044. doi: 10.1056/EVIDoa2100044.

4

MedCheck Editorial Team. Antivirals for COVID-19: molnupiravir (Lagevrio).
Doubt about efficacy due to serious baseline inbalance. Med Check in
English 2022;8:11-16. https://www.npojip.org/english/MedCheck/Med%20Check%20TIp-23-2022-04.pdf

5Medicines and Healthcare Products Regulatory Agency. Public assessment
report national procedure Lagevrio 200mg hard capsules (molnupiravir).
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1042560/Lagevrio_Public_Assessment_Report.pdf

6Singh AK, Singh A, Singh R, Misra A. Molnupiravir in COVID-19: A systematic
review of literature. Diabetes Metab Syndr 2021;15:102329.
doi: 10.1016/j.dsx.2021.102329 pmid: 34742052

7Kolassa S. Calculate 95% CI for ratio of odds ratio. https://stats.stackexchange.com/questions/471805/calculate-95-ci-for-ratio-of-odds-ratio

8

Kabinger F, Stiller C, Schmitzová J, etal. Mechanism of molnupiravir-induced
SARS-CoV-2 mutagenesis. Nat Struct Mol Biol 2021;28:740-6.
doi: 10.1038/s41594-021-00651-0 pmid: 34381216

9MedCheck Editorial Team. Remdesivir (trade name: Veklury). Most likely
ineffective for COVID-19. MedCheck in English 2020;6:39-45.
https://www.npojip.org/english/MedCheck/Med%20Check%20Tip-182020-08-21.pdf.

10Jefferson T, Jones MA, Doshi P, etal. Neuraminidase inhibitors for preventing
and treating influenza in healthy adults and children. Cochrane Database
Syst Rev 2012;1:CD008965.
doi: 10.1002/14651858.CD008965.pub4. pmid: 22258996

This article is made freely available for personal use in accordance with BMJ's
website terms and conditions for the duration of the covid-19 pandemic or until
otherwise determined by BMJ. You may download and print the article for any
lawful, non-commercial purpose (including text and data mining) provided that
all copyright notices and trade marks are retained.

1