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: "Randomization was carried out with stratification by site pharmacy (several clinical sites shared a site pharmacy, in
cases of geographical proximity) and disease severity. A flexible web-based randomization application was
developed, which was able to vary allocation according to stratum (i.e., pharmacy or disease severity). Using the
mass-weighted urn scheme (4,5), the underlying Active:Placebo sequence is generated to ensure an approximate 1:1
balance for each active versus pooled placebo comparison within strata throughout the trial. After confirming
eligibility and obtaining informed consent, designated personnel at the clinical sites used the application to verify
eligibility and obtain a study identification (SID) number for blinded agent/matching placebo. This “prescription”
was sent to the site pharmacy. The site pharmacist used a web-based pharmacy application to determine which
agent/placebo the SID corresponds to. The pharmacist was the only unblinded study member and prepared the
infusion bag for the patient."
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: "Double-blind" trial.
Comment: Blinded study (participants and personnel/carers). MORTALITY, CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, 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). Mortality (D60 or more). Clinical improvement (D60 or more). WHO score 7 and above (D28). Adverse events. Serious adverse events. TIME TO DEATH, TIME TO CLINICAL IMPROVEMENT Participants were analyzed according to their randomized groups for the outcome. Of note, 8 vs 3 participants were excluded from the analysis post-randomization because they did not receive the infusion. 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: Time to death. Time to clinical improvement. |
| Missing outcome data |
Some concerns |
Comment: 496 participants randomized; 485 participants analyzed; at least 6% (468/496) missing (depending on outcome).
Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: outcome not assessed or lost to follow up, and excluded due to non-receipt (for binary outcomes). Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome. Risk assessed to be some concerns for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death. Clinical improvement (D60 or more). Time to clinical improvement. WHO score 7 and above (D28). 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. Blinded study (outcome assessor). Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death. Clinical improvement (D60 or more). Time to clinical improvement. WHO score 7 and above (D28). Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan, and prospective registry were available (dated August 6, 2020).
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 (D28). Mortality (D60 or more). Time to death. Clinical improvement (D60 or more). Time to clinical improvement. WHO score 7 and above (D28). Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |