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 when 5 arms were initially implemented, and then in a 1:1 ratio to receive either standard of care (SoC, control arm) or SoC + remdesivir, once the other three treatment arms had been stopped for futility. Randomisation was performed in the electronic Case Report Form to ensure appropriate allocation concealment and used computer-generated blocks of various sizes"
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Low |
Quote: "open-label...Allocated treatment was not masked to participants nor study investigator"
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 were the intervention, corticosteroids was part of standard of care and biologics were reported as concomitant medications and were balanced between the groups. Hence, deviations did not arise because of the trial context. MORTALITY, CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, AE, SAE Our analysis for binary outcomes 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 (D60 or more). Clinical improvement (D28). WHO score 7 and above (D28). Adverse events. Serious adverse events. TIME TO CLINICAL IMPROVEMENT, TIME TO WHO SCORE 7 AND ABOVE Participants were analyzed according to their randomized groups for the outcome. Of note, 9 vs 5 participants were excluded from the analysis post-randomization (5 vs 3 without valid consent and 4 vs 1 due to ineligibility criteria (without confirmed positive PCR within 9 days before random assignment)). This method was considered appropriate to estimate the effect of assignment to intervention for this outcome. Risk assessed to be low for the outcomes: Time to clinical improvement. Time to score 7 and above. VIRAL NEGATIVE CONVERSION Participants were analyzed according to their randomized groups for the outcome. Of note, 202 vs 222 participants were excluded from the analysis post-randomization because of undectable viral loads. Nevertheless, 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). |
| Missing outcome data |
Low |
MORTALITY, (TIME TO) CLINICAL IMPROVEMENT, (TIME TO) WHO SCORE 7 AND ABOVE, AE, SAE
Comment: 857 participants randomized; 832 participants analyzed for efficacy; 824 participants analyzed for safety. Data available for nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D60 or more). Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Adverse events. Serious adverse events. VIRAL NEGATIVE CONVERSION Comment: 857 participants randomized; 419 participants analyzed Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: outcome only assessed in patients with a positive viral RNA test at baseline: 235 patients in the remdesivir arm and 212 patients in the standard of care arm. Missingness could not depend on the true value of the outcome. Risk assessed to be low 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. Observer-reported outcome not involving judgement. Risk assessed to be low for the outcome: Mortality (D60 or more). Time to death. Viral negative conversion. Time to viral negative conversion. (TIME TO) 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). CLINICAL IMPROVEMENT. TIME TO CLINICAL IMPROVEMENT. Clinical improvement (defined as hospital discharge) 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 |
MORTALITY, TIME TO CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, ADVERSE EVENT, SERIOUS ADVERSE EVENTS, NEGATIVE VIRAL CONVERSION..
Comment: The protocol (published in September 2020) and prospective trial registries (EudraCT March 9 2020, NCT March 20 2020) were available. Outcomes were 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 (D60 or more). WHO score 7 and above (D28). Adverse events. Serious adverse events. Incidence of viral negative conversion (D7). CLINICAL IMPROVEMENT. TIME TO WHO SCORE 7 AND ABOVE. Outcome not pre-specified in the registry. 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 (D28). Time to WHO Score 7 and above. |
| Overall risk of bias |
Some concerns |