Trial NCT04421027
Publication COV-BARRIER - Ely EW, Lancet Respir Med (2022) (published paper)
Primary outcome on the report: All-cause mortality by day 28 and day 60; number of ventilator-free days; overall improvement (assessed by odds of improvement in clinical status) on National Institute of Allergy and Infectious Disease Ordinal Scale (NIAID-OS) evaluated at days 4, 7, 10, 14, and 28; proportion of participants with at least 1-point improvement on the NIAID-OS or live discharge from the hospital at days 4, 7, 10, 14, and 28; duration of hospitalisation; and time to recovery through day 28.

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: “Randomisation was facilitated by a computer-generated random sequence using an interactive web-response system and was performed by a study investigator or designee. Participants were stratified at randomisation according to geographical region (Europe, USA, or the rest of the world). Participants, study staff, and investigators were masked to the study group assignment.”
Comment: Allocation sequence random.
Allocation sequence probably concealed.
Deviations from intervention
Low 		Quote: “Double-blind, placebo-controlled trial” “(Participant, Investigator)”
Comment: Blinded study (participants and personnel/carers)
Our analysis for the binary outcomes 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). Time to death. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Adverse events. Serious adverse events.
Missing outcome data
Low 		Comment: 101 participants randomized; 97 participants analyzed for Who score 7 and above and 101 analyzed for all other outcomes.
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). Time to clinical improvement. WHO score 7 and above (D28). Adverse events. Serious adverse events.
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 (D28). Time to clinical improvement. WHO score 7 and above (D28). Adverse events. Serious adverse events.
Selection of the reported results
Low 		Comment: The protocol and statistical analysis plan were available. The registry (dated June 9, 2020) was also available and utilised.
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: Mortality (D28). Mortality (D60 or more). 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
Low