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|
|Quote: “The randomization was performed by permuted block randomization and block sizes of 2, 4 and 6 used randomly. The statistician prepared a list of numbers for randomization. Sequentially numbered opaque envelopes were prepared according to the list and envelopes were delivered to the clinical investigators. The statistician that performed randomization and analysis was unaware regarding to treatment and follow-up of patients.”
Comment: Allocation sequence random. Allocation concealment unclear (sealing of envelopes).
|Deviations from intervention||
|Comment: Unblinded study (participants and personnel/carers)
Deviations from intended intervention arising because of the study context:
No participant cross-over.
Administration of all co-interventions of interest were reported: antivirals, biologics, corticosteroids.
Corticosteroid administration (61.9% vs 43.6% in the intervention vs control arms) and biologic administration (35.7% vs 25.6% in the intervention vs control arms).
This deviation was not balanced and could affect the outcome. Nevertheless, this domain was rated as some concern as it is impossible to distinguish deviation because of trial context and deviation because of intervention effect.
MORTALITY, WHO SCORE 7 AND ABOVE
Data for the outcome were analyzed using intention-to-treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention.
Risk assessed to be some concerns for the outcome: Mortality (D28). WHO score 7 and above (D28).
TIME TO DEATH, TIME TO CLINICAL IMPROVEMENT
Participants were analyzed according to their randomized groups for the outcome.
Of note, 4 vs 7 participants were excluded from the analysis post-randomization due to missing data which is accounted for in domain 3. This method was considered probably appropriate to estimate the effect of assignment to intervention for this outcome.
Risk assessed to be some concerns for the outcomes: Time to death. Time to clinical improvement.
|Missing outcome data||
|Comment: 92 participants randomized; 81 participants analyzed.
Data not available for all or nearly all participants randomized.
No evidence that the result is not biased.
Reasons for exclusions: entered another trial (0 vs 7), died before finishing the first week treatment (i.e., received <3 doses of IFN) (4 vs 0).
The reason for missing data is associated with the outcome for mortality. Although we do not agree with the reason for exclusion of these participants, for our review, since the event is known, we do not consider it missing data for Mortality outcome (total missing data still >5% of population; 7/92 participants). For the other outcomes, it is considered missing data (total missing data 11/92; >5% of population).
Missingness could depend on the true value of the outcome.
Likely that missingness depended on the true value of the outcome (different reasons and proportion of missingness between arms)
Risk assessed to be high for the outcomes: Mortality (D28). Time to death. Time to clinical improvement. WHO score 7 and above (D28).
|Measurement of the outcome||
|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
Mortality is an observer-reported outcome not involving judgement.
Risk assessed to be low for the outcomes: Mortality (D28). Time to death.
WHO SCORE 7 AND ABOVE
For WHO score 7 and above, we consider that the assessment cannot possibly be influenced by knowledge of intervention assignment.
Risk assessed to be low for the outcomes: WHO score 7 and above (D28).
TIME TO CLINICAL IMPROVEMENT
Clinical improvement (defined as time to at least 2-point improvement in ordinal scale or 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: Time to clinical improvement.
|Selection of the reported results||
|Comment: The protocol and statistical analysis plan were not available. The registry was available but retrospective (dated March 19th, 2020).
No information on whether the result was selected from multiple outcome measurements or analyses of the data.
No information on whether the trial was analyzed as pre-specified.
Risk assessed to be some concerns for the outcomes: Mortality (D28). Time to death. Time to clinical improvement. WHO score 7 and above (D28).
|Overall risk of bias||