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: “Block randomisation was performed using a remote access Interactive Web Response System (IWRS), and was stratified according to disease severity [7-category ordinal scale (the COVID Outcomes Scale) recommended by the World Health Organization] and concomitant antiviral and/or anti-inflammatory medications.”
Comment: Allocation sequence random. Allocation sequence concealed. |
| Deviations from intervention |
Some concerns |
Quote: “Open-label”
Comment: Unblinded study (participants and personnel/carers) Deviations from intended intervention arising because of the study context: No participant cross-over. Administration of co-interventions of interest - biologics, antivirals and corticosteroids - reported and not balanced between groups. More patients in the Nafamostat arm received Umifenovir (25.0% vs 9.8%) and antivirals (67.3% vs 56.9%), while more patients in the SOC arms received anti-inflammatories (21.6% vs 11.5%), Baricitinib (17.6% vs 7.7%) and Olokizumab (5.9% vs 1.9%). br/>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. 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. Participants were analyzed according to their randomized groups for the outcome time to viral clearance. Of note, 1 vs participants were excluded from the analysis post-randomization because they did not receive the drug, and 0 vs. 1 because they did not have an ordinal scale outcome measurement. 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. Risk assessed to be some concerns for the outcomes: Mortality (D28). Time to viral negative conversion. Clinical improvement (D28). Adverse events. Serious adverse events. |
| Missing outcome data |
Low |
Comment: 104 participants randomized; 102 participants analyzed for efficacy; 103 participants analyzed for safety.
Data available for nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Time to viral negative conversion. Clinical improvement (D28). 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 VIRAL NEGATIVE CONVERSION Mortality and viral negative conversion are observer-reported outcomes not involving judgement. Risk assessed to be low for the outcomes: Mortality (D28). Time to viral negative conversion. CLINICAL IMPROVEMENT Clinical improvement (defined as an improvement of 2 points or more on the 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 outcome: 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 |
Some concerns |
Comment: The registry was retrospective (dated November 10, 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: Time to viral negative conversion. Clinical improvement (D28). Adverse events. Serious adverse events. Mortality outcome was not pre-specified in the registry, however, we do not consider the reporting of this outcome to be selective since mortality should be reported even if not planned. Results were probably 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). |
| Overall risk of bias |
Some concerns |