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: "randomly assigned in a 1:1:1 ratio to receive up to a 5-day course of remdesivir, up to a 10-day course of remdesivir, or standard care. Randomization was not stratified. The randomization list was created and validated by the interactive web response system (IWRS) vendor. A dummy randomization list was provided in Microsoft Excel format to the biostatistician employed by the study sponsor for review. A separate list of sequential patient numbers within each treatment group was generated by the IWRS vendor. The randomization had a block size of 6. Based on the treatment from the randomization list, the IWRS provided the next sequential patient number to the site along with the treatment group assignment. The appropriate number of vials of open-label study drug were assigned to the patient. Sites did not have access to the randomization list and could not know the sequence of treatments."
Comment: Allocation sequence random. Allocation sequence concealed. Any imbalance in the baseline characteristics is compatible with chance. |
| Deviations from intervention |
Some concerns |
Comment: Unblinded study (participants and personnel/carers).
Deviations from intended intervention arising because of the study context: No participant cross-over Administration of co-intervention of interest, antivirals, corticosteroids and biologics were reported and balanced across arms. Hence, deviations did not arise because of the trial context. MORTALITY, CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, SAFETY OUTCOMES Data for the outcome were analyzed using 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). Clinical improvement (D28). 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, 4 vs 8 vs 0 participants were excluded from the analysis post-randomization because they did not receive the drug. This method was considered inappropriate to estimate the effect of assignment to intervention for this time-to-event 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 |
Low |
Comment: 596 participants randomized, 584 participants analyzed.
Data available for all or nearly all participants randomized. 4 vs 8 vs 0 did not start the treatment (not missing data; accounted for in domain 2). Risk assessed to be low for the outcomes: Mortality (D28). Time to death. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Adverse events. Serious adverse events. |
| Measurement of the outcome |
Some concerns |
Quote: "open label trial".
Comment: Method of measuring the outcome probably appropriate. Measurement or ascertainment of outcome probably does not differ between groups. Unblinded study (outcome assessor) MORTALITY, TIME TO DEATH, WHO SCORE 7 AND ABOVE, SAE Mortality is an observer-reported outcome not involving judgement. For WHO score 7 and above, we consider that the assessment cannot possibly be influenced by knowledge of intervention assignment. For serious adverse events (when it includes events not involving judgement e.g., laboratory measures), we consider that the assessment cannot possibly be influenced by knowledge of intervention assignment. Risk assessed to be low for outcomes: Mortality (D28). Time to death. WHO score 7 and above (D28). Serious adverse events. (TIME TO) CLINICAL IMPROVEMENT, ADVERSE EVENTS Clinical improvement requires clinical judgement and could be affected by knowledge of intervention receipt. Also, the authors reported on adverse events that contain both clinically- and laboratory-detected events. All these outcomes 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 outcomes: Clinical improvement (D28). Time to clinical improvement. Adverse events. |
| Selection of the reported results |
Some concerns |
Comment: Protocol, statistical analysis plan and registry were available.
The available protocol and SAP were dated April 29th, 2020 and June 26th, 2020 respectively, which is retrospective. Prospective versions of the registry were available but did not pre-specify any review-specific outcomes. 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 the outcomes: Mortality (D28). Time to death. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |