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: "The patients were sequentially randomly assigned by the Investigator in a 1:1 ratio to receive either C21 or placebo in blocks of four, with randomisation stratified by trial site. The randomisation sequence was generated by a statistician not involved in the rest of the trial, and the randomisation codes were kept in sealed envelopes at the trial sites."
Comment: Allocation sequence random. Allocation sequence concealed. |
| Deviations from intervention |
Low |
Quote: "Patients, care providers, those assessing outcomes and Sponsor staff were kept blinded until database lock had been performed for the complete trial"
Comment: Blinded study (participants, personnel/carers). 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). WHO score 7 and above (D28). Adverse events. Serious adverse events. |
| Missing outcome data |
Some concerns |
Comment: 106 participants randomized; 106 participants analyzed.
MORTALITY, ADVERSE and SERIOUS ADVERSE EVENTS Of note, 6 vs 13 participants had missing data Data not available for all participants randomized. No evidence that the result is not biased. Reasons: mechanical ventilation (1 vs 4), withdrawn consent (1 vs 4), discharged from hospital (4 vs 5) Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (same reasons for missingness between arms). Risk assessed to be some concerns for the outcomes: Mortality (D28). Adverse events. Serious adverse events. WHO SCORE 7 AND ABOVE Of note, 5 vs 9 participants had missing data Data not available for all participants randomized. No evidence that the result is not biased. Reasons: withdrawn consent (1 vs 4), discharged from hospital (4 vs 5) Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (same reasons for missingness between arms). Risk assessed to be some concerns for the outcome: WHO score 7 and above (D28). |
| 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). WHO score 7 and above (D28). Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The protocol, statistical analysis plan, and registry were available, but only the registry was prospective (dated June 29th, 2020).
MORTALITY Mortality outcome 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 not selected from multiple outcome measurements or analyses of the data. Trial analyzed as pre-specified. Risk assessed to be low for the outcome: Mortality (D28). WHO SCORE 7 AND ABOVE. ADVERSE EVENTS. SERIOUS ADVERSE EVENTS. Outcomes not pre-specified. No information on whether the result was selected from multiple outcome measurements or analyses of the data. No information on whether the trial was analyzed as pre-specified. Risk assessed to be some concerns for outcome: WHO score 7 and above (D28). Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |