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 |
Some concerns |
Quote: “Randomisation was done with the Castor Electronic Data Capturing System (Castor EDC; Amsterdam, Netherlands) using variable block sizes (two, four, or six patients), stratified by study site. Allocation to study groups was done by Castor, and was not accessible to study investigators.”
Comment: Allocation sequence random. Allocation sequence concealed. Despite randomization, sex, obesity, diabetes, and cardiovascular disease were slightly unbalanced between the two groups. |
Deviations from intervention |
Some concerns |
Quote: “ Double-blind, placebo-controlled, clinical trial. Patients, medical staff, and investigators were masked to group assignment.”
Comment: Blinded study (participants and personnel/carers) MORTALITY, CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, AE, SAE 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). Clinical improvement (D28). WHO score 7 and above (D28). Adverse events. Serious adverse events. TIME TO DEATH, TIME TO WHO SCORE 7 AND ABOVE Participants were analyzed according to their randomized groups for the outcome time to death. Of note, 8 vs 7 participants were excluded from the analysis post-randomization because they did not receive at least one dose of the study drug or placebo due to withdrawal of consent before first dose, transfer to another hospital or due to medical error. 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 death. Time to WHO score 7 and above. |
Missing outcome data |
Low |
Comment: 400 participants randomized; 385 participants analyzed.
Data available for nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death. Clinical improvement (D28). WHO score 7 and above (D28). Time to WHO score 7 and above. Adverse events. Serious adverse events. |
Measurement of the outcome |
Low |
Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups. Probably blinded study (outcome assessor). Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death. Clinical improvement (D28). WHO score 7 and above (D28). Time to WHO score 7 and above. Adverse events. Serious adverse events. |
Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan and registry (2020-03-31) were available.
MORTALITY (D28). TIME TO DEATH. CLINICAL IMPROVEMENT (D28). WHO SCORE 7 AND ABOVE. TIME TO WHO SCORE 7 AND ABOVE. ADVERSE EVENTS. SERIOUS ADVERSE EVENTS. 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). Time to death. Clinical improvement (D28). WHO score 7 and above (D28). Time to WHO score 7 and above. Adverse events. Serious adverse events. MORTALITY (D60 OR MORE) Mortality (D60 or more) was not pre-specified in the registry, however, we do not consider the reporting of this outcome to be selective since mortality should be reported even if not planned. Results were probably 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) |
Overall risk of bias |
Some concerns |