Trial NCT04673162 ; EudraCT 2020-004323-16
Publication Salvarani C, Eur Respir J (2022) (published paper)
Primary outcome on the report: The duration of the patient hospitalisation, calculated as the interval of time between the randomisation and the hospital discharge without the need of supplementary oxygen during the first 30 days following randomisation.

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: “Random assignment was performed centrally at the Trials Center of the Policlinico San Martino-IRCCS in Genova, Italy, stratified by participating centers and type of noninvasive respiratory support [standard oxygen versus High Flow Nasal Cannula (HFNC) or noninvasive ventilation (NIV)]. Computer generated random lists were prepared using permuted balanced blocks of size 4 in random sequence. An Internet-based randomisation system ensured concealment of the treatment assignment until the patient had been registered in the system.”
Comment: Allocation sequence random. Allocation sequence concealed.
Imbalances in baseline characteristics appear to be compatible with chance.
Deviations from intervention
Low 		Quote: “Double-blind. Trial participants, investigators, study team care providers were unaware of the trial-group assignments until after all data queries were resolved and the database was locked.”
Comment: Blinded study (participants and personnel/carers).
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). Time to death. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Time to WHO score 7 and above. Adverse events. Serious adverse events.
Missing outcome data
Low 		Comment: 304 participants randomized; 298 participants analyzed for safety; 288 participants with complete follow up analyzed in consenting ITT (n = 301) for efficacy.
Data available for all or nearly all participants randomized.
Risk assessed to be low for the outcomes: Mortality (D28). Time to death. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Time to WHO score 7 and above. 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). Time to death. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Time to WHO score 7 and above. Adverse events. Serious adverse events.
Selection of the reported results
Low 		Comment: Two prospective registries 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: Mortality (D28). Time to death. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Time to WHO score 7 and above. Adverse events. Serious adverse events.
Overall risk of bias
Low