Trial NCT04505774
Publication ACTIV-4a - Berger JS, JAMA (2022) (published paper)
Primary outcome on the report: 1) Organ support–free days: evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and, for those who survived to hospital discharge, the number of days free of respiratory or cardiovascular organ support up to day 21 of the index hospitalization (range, −1 to 21 days; higher scores indicate less organ support and better outcomes); 2) Major bleeding by 28 days (as defined by the International Society on Thrombosis and Hemostasis).

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 concealed via a secure IxRS system (Worldwide Clinical Trials). Patients were randomized to receive a therapeutic dose of heparin plus a P2Y12 inhibitor or a therapeutic dose of heparin only (usual care) in an open-label fashion using a 1:1 ratio and permuted block sizes of 2 or 4. Patients were stratified by hospital site and severity of illness using a web-based system (eSocdat, Socar Research).”
Comment: Allocation sequence random. Allocation sequence concealed.
Imbalances in baseline characteristics appear to be compatible with chance.
Deviations from intervention
Low 		Quote: “None (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 - biologics, antivirals and corticosteroids reported and balanced between arms.
Hence, deviations did not arise because of the trial context.
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).
Missing outcome data
Low 		Comment: 562 participants randomized; 562 participants analyzed.
Data available for all or nearly all participants randomized.
Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Clinical improvement (D60 or more).
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
Mortality is an observer-reported outcome not involving judgement.
Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more).

CLINICAL IMPROVEMENT
Clinical improvement (defined as 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 (D60 or more).
Selection of the reported results
Low 		Comment: The protocol, statistical analysis plan and registry were available.
Outcomes 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: MMortality (D28). Mortality (D60 or more). Clinical improvement (D60 or more).
Overall risk of bias
Some concerns