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: “All participants were centrally randomly assigned (1:1) to receive either tixagevimab–cilgavimab or placebo using interactive response technology. Randomisation was stratified (using central blocked randomisation). An external third-party vendor (Signant Health; Blue Bell, PA, USA) was responsible for creating and housing the randomisation scheme.”
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: “Participants, investigators, and sponsor staff involved in the treatment or clinical evaluation and monitoring of the participants were masked to treatment-group assignments.”
Comment: Blinded study (participants and personnel/carers). MORTALITY. ADVERSE AND SERIOUS ADVERSE EVENTS Our analysis for the binary outcome 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: Mortality (D28). Adverse events. Serious adverse events. VIRAL NEGATIVE CONVERSION Participants were analyzed according to their randomized groups for the outcome. Of note, 294 vs 308 were excluded from the analysis post-randomization, of which 4 vs 3 were not due to missing data, rather because they did not receive the treatment. 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 |
Some concerns |
Comment: 910 participants randomized; 903 participants analyzed for mortality, adverse events and SAEs; 308 participants analyzed for viral conversion.
MORTALITY, ADVERSE AND SERIOUS ADVERSE EVENTS Data available for nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Adverse events. Serious adverse events. VIRAL NEGATIVE CONVERSION Data not available for all or nearly all participants randomized for viral conversion. No evidence that the result is not biased. Reasons: unknown. Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome due to balance between arms. Risk assessed to be some concerns for the outcome: Incidence of viral negative conversion (D7). |
| Measurement of the outcome |
Low |
Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups. Blinded study (outcome assessor). Risk assessed to be low for the outcomes: Mortality (D28), Incidence of viral negative conversion (D7), Adverse events, and Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan and prospective registry (dated January 25, 2021) were available.
Outcomes 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 outcomes: Mortality (D28), Incidence of viral negative conversion (D7), Adverse events, and Serious adverse events. |
| Overall risk of bias |
Some concerns |