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: “Using a stratified block randomization method with variable block sizes of 6 and 9, we randomly assigned patients in a 1:1:1 ratio to one of three treatment regimens. A 4-digits unique code was assigned to each eligible patient by a central allocation mechanism for subject identification on CRF forms. We applied sealed envelopes to protect the randomization sequence.”
Comment: Allocation sequence random Allocation sequence concealed Imbalances in baseline characteristics appear to be compatible with chance |
| Deviations from intervention |
Some concerns |
Quote: “Open-label”
Comment: Unblinded study (participants and personnel/carers) Deviations from intended intervention arising because of the study context: No participant cross-over. Administration of co-interventions of interest (biologics, antivirals and corticosteroids) was reported and not balanced between groups. This deviation was not balanced and could affect the outcome. Nevertheless, this domain was rated as some concern as it is impossible to distinguish deviation because of trial context and deviation because of intervention effect. MORTALITY 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 some concerns for the outcomes: Mortality (D28). TIME TO CLINICAL IMPROVEMENT, TIME TO WHO SCORE 7 AND ABOVE Participants were analyzed according to their randomized groups for time-to-event outcomes. Of note, 16 participants (Steroid + Azithromycin = 4, Azithromycin = 6, Lopinavir/Ritonavir = 6) were excluded from the analysis post-randomization because they were discharged on the first day of inclusion. 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 clinical improvement. Time to WHO score 7 and above |
| Missing outcome data |
Low |
Comment: 352 participants randomized; 336 participants analyzed.
Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Time to clinical improvement. Time to WHO score 7 and above |
| 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. Unblinded study (outcome assessor) MORTALITY Observer-reported outcome not involving judgement. Risk assessed to be low for the outcomes: Mortality (D28). TIME TO WHO SCORE 7 AND ABOVE For this outcome, we consider that the assessment cannot possibly be influenced by knowledge of intervention assignment. Risk assessed to be low for the outcomes: Time to WHO score 7 and above TIME TO CLINICAL IMPROVEMENT Clinical improvement (defined as being medically stable and ready for discharge from the hospital) requires clinical judgement and could be affected by knowledge of intervention receipt, but it not considered likely to in the context of a pandemic. Risk assessed to be some concerns for the outcomes: Time to clinical improvement. |
| Selection of the reported results |
Some concerns |
Comment: The registry was available (dated 2020-04-08).
MORTALITY Mortality outcome pre-specified. Results were not selected from multiple outcome measurements or analyses of the data. Trial analyzed as pre-specified. br/>Risk assessed to be low for the outcome: Mortality (D28). TIME TO CLINICAL IMPROVEMENT, TIME TO WHO SCORE 7 AND ABOVE Outcomes not pre-specified. No information on whether the results were 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: Time to clinical improvement. Time to WHO score 7 and above. |
| Overall risk of bias |
Some concerns |