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: (protocol) "All participants will be centrally randomized using IRT. The IRT will be programmed with blind-breaking instructions."
Comment: Allocation sequence random. Allocation sequence concealed. |
| Deviations from intervention |
Low |
Quote: (registry) "Double (Participant, Investigator)" - (protocol) "An unblinded pharmacist (or unblinded designee) will be responsible for the dispensation of the study intervention and will endeavor to ensure that there are no differences in time taken to dispense between the different intervention arms. The IV bag should be prepared away from view of the blinded site staff and the participant."
Comment: Blinded study (participants and personnel/carers) MORTALITY. 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). Mortality (D60 or more). Serious adverse events. TIME TO DEATH Participants were analyzed according to their randomized groups for the outcome. Of note, 101 vs 99 participants were excluded from the analysis post-randomization for unknown reasons likely due to missing data which is accounted for in domain 3. This method was considered appropriate to estimate the effect of assignment to intervention for this outcome. Risk assessed to be low for the outcomes: Time to death. TIME TO CLINICAL IMPROVEMENT Participants were analyzed according to their randomized groups for the outcome. Of note, 85 vs 89 participants were excluded from the analysis post-randomization for unknown reasons likely due to missing data which is accounted for in domain 3. This method was considered appropriate to estimate the effect of assignment to intervention for this outcome. Risk assessed to be low for the outcomes: Time to clinical improvement. |
| Missing outcome data |
Some concerns |
Comment: 350 participants randomized; 342 participants analyzed (mortality D28); 341 participants analyzed (mortality D60 or more); 150 participants analyzed (time to death); 176 participants analyzed (time to clinical improvement); 347 participants analyzed (serious adverse events).
MORTALITY, SERIOUS ADVERSE EVENTS Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Serious adverse events. TIME TO DEATH Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: unknown (101 vs 99) No information on whether missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (similar proportions between arms) Risk assessed to be some concerns for the outcomes: Time to death. TIME TO CLINICAL IMPROVEMENT Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: unknown (85 vs 89) No information on whether missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (similar proportions between arms) Risk assessed to be some concerns for the outcome: Time to clinical improvement. |
| 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. Unclear blinding (outcome assessor) MORTALITY, TIME TO DEATH Observer-reported outcome not involving judgement. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death. TIME TO CLINICAL IMPROVEMENT Clinical improvement (defined as Time to First Discharge From Investigator Site) requires clinical judgement and could be affected by knowledge of intervention receipt, but it is not considered likely to in the context of a pandemic. Risk assessed to be some concerns for the outcomes: Time to clinical improvement. SERIOUS ADVERSE EVENTS The authors reported on serious adverse events that contain both clinically- and laboratory-detected events, which cannot be influenced by knowledge of the intervention assignment. Risk assessed to be low for the outcome: Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The retrospective protocol and statistical analysis plan were available (dated January 25th, 2021 and June 3rd, 2021, respectively). The prospective registry was available as well and consulted up to version dated (May 21, 2020).
MORTALITY (D60 OR MORE). SERIOUS ADVERSE EVENTS. 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 outcomes: Mortality (D60 or more). Serious adverse events. MORTALITY (D28). TIME TO DEATH. Outcome not pre-specified. No information on whether the result was selected from multiple outcome measurements or analyses of the data. Trial probably not analyzed as pre-specified. Risk assessed to be some concerns for the outcomes: Mortality (D28). Time to death. TIME TO CLINICAL IMPROVEMENT Outcome not pre-specified (different definition) No information on whether the result was selected from multiple outcome measurements or analyses of the data. Trial probably not analyzed as pre-specified. Risk assessed to be some concerns for the outcome: Time to clinical improvement. |
| Overall risk of bias |
Some concerns |