Note: The risk of bias by domain corresponds to the highest risk of bias among outcomes by domain.
The overall risk of bias corresponds to the overall highest risk of bias assessed among outcomes.
| Bias | Author's judgement | Support for judgement |
| Randomization |
Low |
Quote: "Eligible, consenting participants were randomised by a suitably qualified and trained medical or research professional in equal allocation between molnupiravir and usual care using a secure, web-based randomisation system."
Comment: Allocation sequence random /probably random. Allocation sequence concealed Imbalances in baseline characteristics appear to be compatible with chance |
| Deviations from intervention |
Some concerns |
Quote: "Open label. Participants and members of the trial team responsible for recruitment/follow-up/monitoring of participants were aware of group assignment."
Comment: Unblinded study (participants and personnel/carers) Deviations from intended intervention arising because of the study context: No participant cross-over. No information on administration of co-interventions of interest: antivirals and corticosteroids. Biologics were reported. In the outpatient setting, we consider no important cointerventions of interest. Hence, no deviation arose because of the trial context HOSPITALIZATION OR DEATH. MORTALITY. SERIOUS ADVERSE EVENTS. Our analysis for the binary outcomes is an intention-to-treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention. Risk assessed to be low for the outcomes: Hospitalization or death. Mortality (D28). Serious adverse events. VIRAL NEGATIVE CONVERSION Participants were analyzed according to their randomized groups for the outcome viral negative conversion. Of note, 16 vs 16 participants were excluded from the analysis post-randomization because they were ineligible. This method was considered inappropriate to estimate the effect of assignment to intervention for this outcome. There was probably no substantial impact of failure to analyze participants according to their randomized groups. Risk assessed to be some concerns for the outcomes: Incidence of viral negative conversion (D7). |
| Missing outcome data |
High |
Comment: 25783 participants randomized; 25000 participants analyzed for hospitalization/death, mortality, serious adverse events.
HOSPITALIZATION OR DEATH. MORTALITY. SERIOUS ADVERSE EVENTS Data available for all or nearly all participants randomized. Of note: 126 vs 228 withdrew consent to access medical notes; 38 vs 63 withdrew for other reasons; 125 vs 171 were lost to follow up. Risk assessed to be low for the outcomes: Hospitalization or death. Mortality (D28). Serious adverse events. VIRAL NEGATIVE CONVERSION Comment: No information/unclear number of participants randomized for viral conversion; 75 participants analyzed. No information on whether data were available for all randomized participants. No evidence that the result is not biased. No information on whether missingness could or is likely to depend on the true value of the outcome. Risk assessed to be high for the outcomes: Incidence of viral negative conversion (D7). |
| Measurement of the outcome |
Some concerns |
Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups. Unblinded study (outcome assessor) MORTALITY, VIRAL NEGATIVE CONVERSION Observer-reported outcome not involving judgement. Risk assessed to be low for the outcomes: Mortality (D28). Incidence of viral negative conversion (D7). HOSPITALIZATION OR DEATH For this outcome, we consider that the assessment cannot possibly be influenced by knowledge of intervention assignment. Risk assessed to be low for the outcomes: Hospitalization or death. SERIOUS ADVERSE EVENTS The authors reported on adverse events and serious adverse events that may contain both clinically- and laboratory-detected events, which can be influenced by knowledge of the intervention assignment, but is not likely in the context of the pandemic. Risk assessed to be some concerns for the outcomes: Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan, registry were available (dated Nov 3, 2021).
Outcome pre-specified. Results were not selected from multiple outcome measurements or analyses of the data. Trial analyzed as pre-specified. Risk assessed to be low for the outcome: Hospitalization or death. Mortality (D28). Incidence of viral negative conversion (D7). Serious adverse events. |
| Overall risk of bias |
High |