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: "Participants were randomly assigned in a 1:1:1:1:1 ratio through computer-generated blocks of various sizes and stratified by administrative region and severity of illness at enrolment... Randomization was implemented in the electronic Case Report Form to ensure appropriate allocation concealment".
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. Chronic pulmonary diseases more common in the control arm (21%) than in the treatment arms (13%). |
| Deviations from intervention |
Low |
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 (antivirals, biologics, and corticosteroids) were reported and balanced between groups. Hence, deviations did not arise because of the trial context. 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). WHO score 7 and above. Adverse events. Serious adverse events. VIRAL NEGATIVE CONVERSION Participants were analyzed according to their randomized groups for the outcome. Of note, 64 vs 63 vs 66 vs 68 participants were excluded from the analysis post-randomization for reasons 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 outcome: Incidence of viral negative conversion (D7). TIME TO CLINICAL IMPROVEMENT Participants were analyzed according to their randomized groups for the outcome. Of note, 3 vs 3 vs 1 vs 3 participants were excluded from the analysis post-randomization due to ineligibility. This method was considered appropriate to estimate the effect of assignment to intervention for this outcome. Risk assessed to be low for the outcome: Time to clinical improvement. |
| Missing outcome data |
Some concerns |
Comment: 603 participants randomized; 593 participants analyzed for mortality, clinical improvement and WHO score 7 and above; 332 participants analyzed viral negative conversion; 589 participants analyzed for Adverse events and serious adverse events.
MORTALITY, (TIME TO) CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE Of note, 2 vs 1 vs 1 vs 1 participants were excluded from analysis due to no written consent. 1 vs 1 vs 0 vs 1 had a negative PCR and 1 participant previously treated with a study treatment. Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60). Clinical improvement. Time to clinical improvement. WHO score 7 and above (D28). ADVERSE and SERIOUS ADVERSE EVENTS Of note, 2 vs 1 vs 1 vs 1 participants were excluded from analysis due to no written consent. 1 vs 1 vs 0 vs 1 had a negative PCR and 1 participant previously treated with a study treatment. 0 vs 2 vs 2 vs 0 did not receive at least one dose of intervention. Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Adverse events. Serious adverse events. VIRAL NEGATIVE CONVERSION 64 vs 63 vs 66 vs 68 participants excluded. Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons for missing data unknown. 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 (equal proportion of missingness between arms). Risk assessed to be some concerns for the outcome: Incidence of viral negative conversion (D7). |
| 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, VIRAL NEGATIVE CONVERSION Mortality and viral negative conversion are observer-reported outcomes not involving judgement. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60). Incidence of viral negative conversion (D7). WHO SCORE 7 AND ABOVE For WHO score 7 and above, we consider that the assessment cannot possibly be influenced by knowledge of intervention assignment. Risk assessed to be low for the outcomes: WHO score 7 and above (D28). (TIME TO) CLINICAL IMPROVEMENT Clinical improvement (defined as improvement of 2 categories of the 7-point ordinal scale or hospital discharge within day 29) 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: Clinical improvement (D28). Time to clinical improvement. ADVERSE and SERIOUS ADVERSE EVENTS The authors reported on adverse events and serious adverse events that may contain both clinically- and laboratory-detected events, which can be influenced by knowledge of the intervention assignment, but is not likely in the context of the pandemic. Risk assessed to be some concerns for the outcomes: Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The protocol (statistical analysis plan dated June 8th, 2020) were retrospective. The prospective trial registry (dated March 20th, 2020) was available.
MORTALITY, VIRAL NEGATIVE CONVERSION, TIME TO CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, SAE 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). Mortality (D60). Incidence of viral negative conversion. Time to clinical improvement (D28). WHO score 7 and above (D28). Serious adverse events. CLINICAL IMPROVEMENT. ADVERSE EVENTS 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 outcome: Clinical Improvement. Adverse events. |
| Overall risk of bias |
Some concerns |