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: “Patients were randomized 1:1:1 to 2.4 g REGEN-COV (1.2 g casirivimab and 1.2 g imdevimab), 8.0 g REGEN-COV (4.0 g casirivimab and 4.0 g imdevimab), or placebo as a single intravenous dose. Randomization was stratified by standard-of-care treatment (antiviral therapies, non-antiviral therapies; phase 1/2/3) and country (phase 2/3).”
Comment: Allocation sequence random. Allocation sequence concealed [Randomization must be centralized to stratify by country] Imbalances in baseline characteristics appear to be compatible with chance |
| Deviations from intervention |
Some concerns |
Preprint: “Double-blind study”, "The investigators, site personnel, and Regeneron Pharmaceuticals, Inc. were unaware of the treatment-group assignments."; Registry: "Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)"
Comment: Blinded study (participants and personnel/carers) MORTALITY. CLINICAL IMPROVEMENT. WHO SCORE 7 AND ABOVE. 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: Mortality (D28). Mortality (D60 or more). Clinical improvement (D28). Clinical improvement (D60 or more). WHO score 7 and above (D28). TIME TO CLINICAL IMPROVEMENT, TIME TO DEATH, TIME TO WHO SCORE 7 AND ABOVE. Participants were analyzed according to their randomized groups for the outcome. Of note, 59 (placebo), 51 (REGEN-COV 2.4g) and 57 (REGEN-COV 8.0g) participants were excluded from the analysis post-randomization because were not RT-PCR-positive (but were antigen positive) at baseline. 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 outcome: Time to clinical improvement. Time to death. Time to WHO score 7 and above. |
| Missing outcome data |
Some concerns |
Comment: 1364 participants randomized; 1197 participants analyzed for mortality D28, clinical improvement, time to clinical improvement, WHO score 7 and above.
Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: Participants were excluded from the analysis post-randomization because were not RT-PCR-positive (but were antigen positive) at baseline. MORTALITY, CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome because of balance between arms. Risk assessed to be some concerns for the outcomes: Mortality (D28). Mortality (D60 or more). Clinical improvement (D28). Clinical improvement (D60 or more). WHO score 7 and above (D28). TIME TO CLINICAL IMPROVEMENT. TIME TO DEATH. TIME TO WHO SCORE 7 AND ABOVE. This potential source of bias has been taken into account in domain 2 for the outcome: Time to clinical improvement. Risk assessed to be low for the outcome: Time to clinical improvement. Time to death. Time to WHO score 7 and above. |
| 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). Mortality (D60 and above). WHO score 7 and above (D28). Clinical improvement (D28). Clinical improvement (D60 or more). Time to clinical improvement. Time to death. Time to WHO score 7 and above. |
| Selection of the reported results |
Low |
MORTALITY D28, CLINICAL IMPROVEMENT D28. CLINICAL IMPROVEMENT D60 OR MORE. TIME TO CLINICAL IMPROVEMENT. WHO SCORE 7 AND ABOVE D28.
Comment: The prospective registry was available. The protocol was obtained from contact with authors. 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). Clinical improvement (D28). Clinical improvement (D60 or more). Time to clinical improvement. WHO score 7 and above (D28). MORTALITY D60 AND ABOVE. TIME TO DEATH. TIME TO WHO SCORE 7 AND ABOVE. Outcome data acquired from direct contact with authors. Analysis performed by the COVID-NMA. Risk assessed to be low for the outcome: Mortality (D60 or more). Time to death. Time to WHO score 7 and above. |
| Overall risk of bias |
Some concerns |