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 from the protocol: "The study will randomize participants 1:1 to placebo or investigational product. If additional arms are added to or dropped from the trial, randomization will proceed with an equal probability of assignment to each of the remaining arms. Randomization will be stratified by: Site; Severity of illness at enrollment (Severe disease: requiring mechanical ventilation or oxygen, a SpO2 /= 24 breaths/min); Mild-moderate disease: SpO2 > 94% and respiratory rate < 24 breaths/min without supplemental oxygen)."
"Enrollment and randomization of subjects is done online using the enrollment module of Advantage eClinical®. Eligible subjects will be randomized and assigned in a 1:1 ratio to either remdesivir or placebo, with stratification by site and disease severity (Mild/Moderate disease or Severe disease). The randomization is based on a variable blocked scheme to provide an approximately balanced allocation to the treatment groups during the study. If arms are added or removed later in the study, randomization will continue in an equal allocation manner." Comment: Allocation sequence probably concealed. Allocation sequence random. Baseline imbalances appear to be compatible with chance. |
| Deviations from intervention |
Low |
Quote: "The treatment will be prepared by the licensed pharmacist and administered by an unblinded study nurse. All follow-up safety and efficacy evaluations will be performed by blinded clinic staff."
Comment: It is unlikely that this lack of blinding (of the study nurse) would have led to deviations (by patients or staff) from the intended intervention. Blinded study (participants and personnel/carers) 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). Time to death. WHO score 7 and above (D28). Adverse events. Serious adverse events. |
| Missing outcome data |
Some concerns |
Comment: 1062 participants randomized; 1062 participants analyzed for mortality and time death; 1048 participants analyzed for adverse and serious adverse events; unclear number analyzed for WHO score 7 and above.
MORTALITY, TIME TO DEATH Data available for all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Time to death. ADVERSE EVENTS, SERIOUS ADVERSE EVENTS Data available for nearly all participants randomized. 1 vs 1 randomized to one drug and received the other; 10 vs 4 excluded because did not receive at least one dose of drug (not missing data hence not accounted for in this domain) Risk assessed to be low for the outcomes: Adverse events. Serious adverse events. WHO SCORE 7 AND ABOVE Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons for missing data: (obtained via contact with authors) ordinal score 8 denominators are n randomized 541 vs 521 but ordinal score 7 denominators are 487 vs 465; data missing for those participants with missing ordinal score data at visit. Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (same reasons and equal proportion of missingness between arms). Risk assessed to be some concerns for the outcome: WHO score 7 and above (D28). |
| Measurement of the outcome |
Low |
Quote: "All follow-up safety and efficacy evaluations will be performed by blinded clinic staff".
Method of measuring outcome probably appropriate. Measurement or ascertainment of outcome probably does not differ between groups. Blinded study (outcome assessor). Risk assessed to be low for the outcomes: Mortality (D28). Time to death. WHO score 7 and above (D28). Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The protocol, statistical analysis plan and registry were available. All had prospective versions which were consulted.
MORTALITY, WHO SCORE 7 AND ABOVE, SAFETY OUTCOMES Outcome presented and analyzed as 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). WHO score 7 and above (D28). Adverse events. Serious adverse events. TIME TO DEATH. 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: Time to death. |
| Overall risk of bias |
Some concerns |