Trial NCT04546581
Publication ITAC (INSIGHT 013) - Polizzotto MN, Lancet (2022) (published paper)
Primary outcome on the report: An ordinal outcome based on the patient's clinical status on day 7. The seven categories of this outcome ranged from return to usual activities with no more than minimal symptoms due to COVID-19, to death. Primary safety outcome was a composite of death, serious adverse events, and grade 3 or 4 adverse events up to day 7.

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
Some concerns 		Quote: “Participants were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo. Randomisation was stratified by site pharmacy.”
Comment: Allocation sequence probably random. No information on allocation concealment.
Imbalances in baseline characteristics appear to be compatible with chance.
Deviations from intervention
Some concerns 		Quote: “Infusions were prepared by trial pharmacists and masked using opaque sleeves. All other investigators and research staff, and trial participants were masked to the treatment administered.”
Comment: Blinded study (participants and personnel/carers)

MORTALITY. CLINICAL IMPROVEMENT. WHO SCORE 7 AND ABOVE. SERIOUS ADVERSE EVENTS.
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). Clinical improvement (D28). WHO score 7 and above (D28). Serious adverse events.

TIME TO DEATH.
Participants were analyzed according to their randomized groups for the outcome.
Of note, 4 vs 8 participants were excluded from the analysis post-randomization because they did not receive the intervention and 2 vs 0 were ineligible. 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 due to small proportions and balance between groups.
Risk assessed to be some concerns for the outcomes: Time to death.
Missing outcome data
Low 		Comment: 593 participants randomized; 579 participants analyzed.
Data available for nearly all participants randomized.
Risk assessed to be low for the outcomes: Mortality (D28). Time to death. Clinical improvement (D28). WHO score 7 and above (D28). 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). WHO score 7 and above (D28). Serious adverse events.
Selection of the reported results
Low 		Comment: The protocol, statistical analysis plan and prospective 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: Mortality (D28). Time to death. Clinical improvement (D28). WHO score 7 and above (D28). Serious adverse events.
Overall risk of bias
Some concerns