Trial NCT04331808
Publication CORIMUNO-TOCI-2 - Hermine O, Eur Respir J (2022) (published paper)
Primary outcome on the report: 1)The early co-primary outcome is the proportion of patients with a decrease of WHO score of at least 1 point at day 4.
2) The longer-term co-primary outcome is the cumulative incidence of successful tracheal extubation (defined as duration extubation > 48h) at day 14 if patients have been intubated before day 14 or removal of NIV or high flow (for > 48h) if they were included under oxygen by NIV or High flow (score 6) and remained without intubation. *

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: "Participants were randomly assigned in a 1:1 ratio to receive UC+TCZ or UC for TOCI-2 protocol, UC+SARI, or UC for SARI-2 protocol via a web-based secure centralized system. An independent statistician provided a computer-generated assignment randomization list stratified by center and blocked with varying block sizes unknown to the investigators"
Comment: Allocation sequence random.
Allocation sequence concealed.
Deviations from intervention
Low 		Quote: "open-label"
Comment: Unblinded study (participants and personnel/carers).
Deviations from intended intervention arising because of the study context:
No participant cross-over.
Information on administration of co-interventions of interest during study: antivirals (3 vs 2) and corticosteroids (17 vs 14) was available and well balanced between the groups. Biologics were the intervention.
Hence, deviations did not arise because of the trial context.

MORTALITY. CLINICAL IMPROVEMENT. 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 (D28). Clinical Improvement (D60). Adverse events. Serious adverse events.

TIME TO DEATH. TIME TO CLINICAL IMPROVEMENT
Participants were analyzed according to their randomized groups for the outcome.
Of note, 2 vs 3 participants were excluded from the analysis post-randomization because they withdrew consent. However, this will be assessed for in Rob3. This method was considered appropriate to estimate the effect of assignment to intervention for this outcome.
Risk assessed to be low for the outcome: Time to death. Time to clinical improvement.
Missing outcome data
Some concerns 		Comment: 97 participants randomized; 92 participants analyzed.
Data not available for all or nearly all participants randomized.
No evidence that the result is not biased.
Reasons: 2 vs 3 participants withdrew consent.
Missingness could depend on the true value of the outcome.
Not likely that missingness depended on the true value of the outcome.
Risk assessed to be some concerns for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death. Clinical improvement (D28). Clinical improvement (D60 or more). Time to clinical improvement. Adverse events. Serious adverse events.
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, TIME TO DEATH
Observer-reported outcome not involving judgement.
Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death.

(TIME TO) CLINICAL IMPROVEMENT
Clinical improvement 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 (D28). Clinical improvement (D60 or more). Time to clinical improvement.

ADVERSE and SERIOUS ADVERSE EVENTS
The authors reported on adverse events and serious adverse events that may contain both clinically- and laboratory-detected events, which can be influenced by knowledge of the intervention assignment, but is not likely in the context of the pandemic.
Risk assessed to be some concerns for the outcomes: Adverse events. Serious adverse events.
Selection of the reported results
Some concerns 		Comment: The prospective registry (March 31st, 2020) and prospective protocol (March 24, 2020) were available .

MORTALITY. TIME TO DEATH. CLINICAL IMPROVEMENT (D60). TIME TO CLINICAL IMPROVEMENT. ADVERSE AND SERIOUS ADVERSE EVENTS.
Outcome 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 outcome: Mortality (D28). Mortality (D60). Time to death. Time to clinical improvement. Clinical improvement (D60). Adverse events. Serious adverse events.

CLINICAL IMPROVEMENT (D28).
Outcomes not pre-specified in the registry.
No information on whether the result was selected from multiple outcome measurements or analyses of the data.
Trial not analyzed as pre-specified.
Risk assessed to be some concerns for the outcomes: Clinical improvement (D28).
Overall risk of bias
Some concerns