MOVe-OUT (2021)
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Clinical Question
Does molnupiravir, started within 5 days of symptom onset of positive test, decrease hospitalizations and mortality in unvaccinated and non-hospitalized adults with confirmed COVID-19 and at least one risk factor for severe COVID-19?
Bottom Line
Molnupiravir is associated with lower risk of hospitalization or death at 29 days compared to placebo, based on interim analyses.
Major Points
Molnupiravir is a prodrug that generates an active form that introduces RNA mutations leading to the accumulation of errors over viral replication cycles. This provides a mechanism to combat RNA viruses, including SARS-CoV-2.
Guidelines
Design
- Multicenter, double-blind, parallel-group, randomized, placebo-controlled trial
- N = 1433
- Molnupiravir (n=716)
- Placebo (n=717)
- Setting: 107 sites in 20 countries
- Enrollment: May 6, 2021 to October 2, 2021
- Follow-up: all participants completed at least 29 days
- Analysis: Intention-to-treat
- Primary outcome: hospitalization or mortality
Population
Inclusion Criteria
- laboratory-confirmed COVID-19
- symptom onset or positive test within 5 days of enrollment
- at least one sign or symptom of COVID-19
- at least one risk factor for severe COVID-19: age >60 years, active cancer, chronic kidney disease, chronic obstructive pulmonary disease, obesity, heart failure, coronary artery disease, cardiomyopathy, or diabetes
- mild or moderate disease: defined based on WHO and FDA criteria
- Note: recruitment was ended early after an interim analysis at 50% enrollment due to evidence of efficacy
Exclusion Criteria
- anticipated need for hospitalization within next 48 hours
- dialysis or eGFR <30mL/min/1.73m2
- pregnancy or unwillingness to use contraception during intervention period and for at least 4 days after
- severe neutropenia (ANC < 500/mL)
- platelet count < 100,000/uL
- SARS-CoV-2 vaccination
- NOTE: use of supportive treatments with antipyretics, anyiinflmmatory agents, or glucocorticoids were allowed. Use of monoclonal antibodies or remdesivir was prohibited through day 29
Baseline Characteristics
- Median age: 43 years old
- Female sex: 51.3% (
- 53.6% molnupiravir
- 49.0% placebo
- % with symptoms or tests within 3 days of enrollement: 47.7%
Interventions
- Randomized to molnupiravir (800mg as 4x200mg capsules twice daily for 5 days) or placebo (identical-appearing pills and schedule)
Outcomes
Comparisons are molnupiravir vs. placebo.
Primary Outcomes
- Hospitalization or death through day 29
- 7.3% vs. 14.1% (difference 6.8 percentage points; 95% CI -11.3 to -2.4; P=0.001)
- rate of hospitalization or death through day 29
- HR 0.69; 95% CI 0.48 to 1.01
Secondary Outcomes
- COVID-associated hospitalizations
- 6.3% vs. 9.2% (difference 2.8 percentage points; 95% CI -5.7 to 0.0)
Subgroup Analysis
Comparisons are absolute risk reductions of molnupiravir vs. placebo (95% CI)
- By sex:
- Female: -3.6 (-7.4 to -0.2)
- Male: -1.9 (-6.5 to 2.8)
- By time since symptom onset:
- <=3 days: -1.0 (-5.2 to 3.2)
- >3 days: -4.8 (-9.0 to -0.7)
- By COVID-19 severity:
- mild: -2.4 (-5.9 to 1.0)
- moderate: -3.1 (-8.1 to 1.8)
- By baseline SARS-CoV-2 nucelocapsid antibody status:
- Positive: 2.3 (-1.7 to 7.1)
- Negative: -5.1 (-8.8 to -1.6)
- By risk factors for severe COVID-19:
- >60 years of age: -2.4 (-10.6 to 5.8)
- Obesity: -3.7 (-6.9 to -0.5)
- Diabetes: 1.4 (-8.2 to 11.1)
- Serious heart disease: -2.2 (-12.4 to 7.5)
- By Race:
- American indian or native american: -1.9 (-7.8 to 4.0)
- Asian: -2.4 (not calculated)
- Black: -4.2 (-11.1 to 2.2)
- White: -4.2 (-7.3 to -1.2)
- By baseline SARS-CoV-2 qualitiative assay:
- Detectable: -2.6 (-5.8 to 0.5)
- Undetectable: 0.0 (-7.1 to 6.7)
- Unknown: -12.7 (-29.9 to 2.9)
Adverse Events
- at least 1 advrse event: 30.4% vs 33.0% (difference -2.5%; 95% CI -7.4 to 2.3)
- at least 1 serious adverse event: 6.9% vs 9.6% (difference -2.7%; 95% CI -5.6 to 0.2)
- COVID-19 pneumonia: 6.3% vs 9.6%
- diarrhea: 2.3% vs 3.0%
- bacterial pneumonia: 2.0% vs 1.6%
- worsening COVID-19: 7.9% vs 9.8%
Criticisms
Funding
Merck Sharp and Dohme. ClinicalTrials.gov number, NCT04575597