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 assigned to treatment or control in a 1:1 ratio using randomization stratified on the use of remdesivir and mechanical ventilation at entry using block randomization with variable block size.”
Quote (from contact with authors): "Randomization codes were generated using the R package blockrand, exported into an Excel spreadsheet and loaded into a REDCap database by the study statistician. Other study staff and investigators recruiting patients, as well as the potential study participants, remained blinded until patients were consented and enrolled. Once a study participant was enrolled, the study investigator used the REDCap randomization tool to reveal the arm assigned to that patient." Comment: Allocation sequence random. Allocation sequence concealed. |
| 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: both arms received the same standard or care (antivirals and corticosteroids) and randomization was stratified by remdesivir use. Biologics were the intervention. Hence, deviations did not arise because of the trial context. MORTALITY, CLINICAL IMPROVEMENT, ADVERSE EVENTS, SERIOUS ADVERSE EVENTS. 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 or more). Clinical improvement (D28). Clinical improvement (D60 or more). Adverse events. Serious adverse events. VIRAL NEGATIVE CONVERSION Participants were analyzed according to their randomized groups for the outcome. Of note, 26 vs 20 participants were excluded from the analysis post-randomization 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 outcomes: Incidence of viral negative conversion (D7). TIME TO DEATH, TIME TO CLINICAL IMPROVEMENT, TIME TO WHO SCORE 7 OR ABOVE. Participants were analyzed according to their randomized groups for the outcome. Risk assessed to be low for the outcomes: Time to death. Time to clinical improvement. Time to WHO score 7 or above. |
| Missing outcome data |
Some concerns |
MORTALITY. TIME TO DEATH. CLINICAL IMPROVEMENT. TIME TO CLINICAL IMPROVEMENT. TIME TO WHO SCORE 7 AND ABOVE. ADVERSE EVENTS, SERIOUS ADVERSE EVENTS.
Comment: 80 participants randomized; 78 participants analyzed (Mortality D28, Time to death), 79 participants analyzed (Clinical improvement D28, Clinical improvement D60 or more, Time to Clinical improvement, Time to WHO Score 7 and above, Adverse events, Serious adverse events); 77 participants analyzed (Mortality D60 or more) Data available for nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death. Clinical improvement (D28). Clinical improvement (D60 or more). Time to Clinical improvement. Time to WHO Score 7 and above. Adverse events. Serious adverse events. VIRAL NEGATIVE CONVERSION Comment: 80 participants randomized; 33 participants analyzed. Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: 1 vs 1 missing due to death, 22 vs 15 missing due to discharge, 3 vs 4 missing due to missed labs Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (similar reasons and proportion of missingness per arm) Risk assessed to be some concerns for the outcomes: 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, TIME TO DEATH, VIRAL NEGATIVE CONVERSION Observer-reported outcome not involving judgement. Risk assessed to be low for the outcomes: Mortality (D28). Time to death. Incidence of viral negative conversion D7). 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. CLINICAL IMPROVEMENT, TIME TO CLINICAL IMPROVEMENT. Clinical improvement (defined as ≥2-point improvement on WHO clinical progression scale or 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). Clinical improvement (D60 or more). Time to clinical improvement. ADVERSE EVENTS, 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 |
Low |
MORTALITY D28, TIME TO DEATH, SERIOUS ADVERSE EVENTS
Comment: The statistical analysis plan, supplemental material and registry were available (dated May 21, 2020). Outcome 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 outcome: Mortality (D28). Time to death. Serious adverse events. MORTALITY D60 OR MORE, CLINICAL IMPROVEMENT, TIME TO CLINICAL IMPROVEMEMNT, TIME TO WHO SCORE 7 OR ABOVE, ADVERSE EVENTS Outcome data acquired from direct contact with authors. Analysis performed by the COVID-NMA. Risk assessed to be low for the outcome: Viral negative conversion. Mortality D60 or more. Clinical improvement D28. Clinical improvement D60 or more. Time to clinical improvement. Time to WHO Score 7 and above. Adverse events. |
| Overall risk of bias |
Some concerns |