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: “Consented patients enrolled in the study were randomly assigned to their treatment in a 2:1 fashion between reparixin and SOC, using an Interactive Response System (IRS). The randomization list was created by an independent statistician not involved in conducting the study. Randomization was stratified by site to ensure balanced assignment across treatment groups.”
Comment: Allocation sequence random. Allocation sequence concealed.
Imbalances in baseline characteristics appear to be compatible with chance.
|Deviations from intervention||
Comment: Unblinded study (participants and personnel/carers).
Deviations from intended intervention arising because of the study context:
No participant cross-over for analysis: participants are analyzed in the arms to which they were allocated.
Of note, 5/19 participants in the standard care group received reparixin as rescue medication.
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.
Of note, 1 vs 0 participant was excluded from the analysis post-randomization because they did not receive the drug. 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.
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 some concerns for the outcomes: Mortality (D28). Clinical improvement (D28). Adverse events. Serious adverse events.
|Missing outcome data||
|Comment: 56 participants randomized; 55 participants analyzed; 21/56 (38%) missing data for clinical improvement (D28); 11/56 (20%) missing data for other outcomes.
Data not available for nearly all participants randomized.
No evidence that the result is not biased.
Reasons: 2 vs 2 lost to FU in intervention and SC arms; 4 vs 1 transferred to another center; 1 vs 0 withdrew consent; and 1 did not receive reparixin.
Missingness could depend on the true value of the outcome.
Likely that missingness depended on the true value of the outcome for Clinical improvement (D28) since proportions missing were different (30% vs 53%).
Not likely that missingness depended on the true value of the outcome for the other outcomes.
Risk assessed to be high for the outcome: Clinical improvement (D28).
Risk assessed to be some concerns for the outcomes: Mortality (D28). Adverse events. Serious adverse events.
|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 is an observer-reported outcome not involving judgement.
Risk assessed to be low for the outcomes: Mortality (D28).
Clinical improvement (defined as a 2-point improvement on a clinical scale) 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).
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||
|Comment: The protocol, statistical analysis plan and registries (one prospective) were available.
Outcomes pre-specified in the registry and/or protocol.
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). Clinical improvement (D28). Adverse events. Serious adverse events.
|Overall risk of bias||