Covid-19 Living Data

Trial NCT04345614
Publication CARDEA - Bruen C, Crit Care (2022) (published paper)
Primary outcome on the report: Time to recovery through Day 60, defined as meeting the criteria for category 6 (Hospitalized, not requiring supplemental oxygen or ongoing medical care), category 7 (Discharged, requiring supplemental oxygen), or category 8 (Discharged, not requiring supplemental oxygen) using an 8-point ordinal scale.

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: "randomization was stratified by baseline imputed PaO2/FiO2 ratio of >200 vs ≤200 through a central, concealed, web-based, automated system. The randomization schedule was created by an independent statistician with stratified block randomization method using SAS proc plan procedure." Comment: Allocation sequence random. Allocation sequence concealed.
Deviations from intervention	Some concerns	Comment: "double-blind" (report) "Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)" (trial registry) Comment: Blinded study (participants and personnel/carers). MORTALITY. CLINICAL IMRPOVEMENT. WHO SCORE 7 AND ABOVE. ADVERSE AND 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 (D60 or more). WHO Score 7 and above (D28). WHO score 7 and above (D60 or more). Adverse events. Serious adverse events. TIME TO DEATH. TIME TO WHO SCORE 7 AND ABOVE. Participants were analyzed according to their randomized groups for the outcome. Of note, 2 vs 1 participants were excluded from the analysis post-randomization because they did not receive any dose of study drug and 11 vs 9 were excluded because they did not meet the predefined efficacy criteria. This method was considered inappropriate to estimate the effect of assignment to intervention for this 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 WHO score 7 and above.
Missing outcome data	Some concerns	Comment: 284 participants randomized; 281 participants analyzed for efficacy D60 and safety; 261 participants analyzed for efficacy D30 and clinical improvement D60; 245 analyzed for WHO Score 7 and above. MORTALITY (D60 or more), ADVERSE AND SERIOUS ADVERSE EVENTS. Data available for nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D60 or more). Adverse events. Serious adverse events. MORTALITY (D28). CLINICAL IMPROVEMENT (D60 or more). Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: 11 vs 9 were patients with imputed Pa02/FiO2 >200. Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome; reasons and proportions of missing data between arms were similar. Risk assessed to be some concerns for the outcome: Mortality (D28). Clinical improvement (D60 or more). TIME TO DEATH. TIME TO WHO SCORE 7 AND ABOVE. Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: 11 vs 9 were patients with imputed Pa02/FiO2 >200 which were accounted for in domain 2. Missingness could not depend on the true value of the outcome. Risk assessed to be low for the outcome: Mortality (D28). Clinical improvement (D60 ore more). Time to death.Time to WHO score 7 and above. WHO SCORE 7 AND ABOVE. Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: 11 vs 9 were patients with imputed Pa02/FiO2 >200; 2 vs 6 missing for unknown reasons. Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome; reasons and proportions of missing data between arms were similar. Risk assessed to be some concerns for the outcome: WHO Score 7 and above (D28). WHO score 7 and above (D60 or more).
Measurement of the outcome	Low	Comment: Method of measuring the 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). Mortality (D60 or more). Time to death. Clinical improvement (D60 or more). WHO Score 7 and above (D28). WHO score 7 and above (D60 or more). Time to WHO score 7 and above. Adverse events. Serious adverse events.
Selection of the reported results	Some concerns	Comment: The prospective trial registry was available (dated 14 April 2020). MORTALITY. WHO SCORE 7 AND ABOVE (D28). SERIOUS ADVERSE EVENTS. 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 (D28). Mortality (D60 or more). Serious adverse events. TIME TO DEATH. CLINICAL IMPROVEMENT. TIME TO WHO SCORE 7 AND 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: Time to death. Clinical improvement (D60 or more).Time to WHO score 7 and above. Adverse events. WHO SCORE 7 AND ABOVE (D60). Outcome not pre-specified in the registry for the 60 days timepoint. 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: WHO Score 7 and above (D60).
Overall risk of bias	Some concerns