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: “Active drug and placebo tablets
were provided by the pharmacy at the Ghent University Hospital
in identical sealed, blinded, and consecutively numbered packages
following EudraLex Volume 4, Good Manufacturing Practice Annex
13, and Belgian circular 596 requirements. The unblinded study
personnel managed the allocation of the study medication of each
participant chronologically, according to the computer-generated
randomization list (www.randomization.com, random block size of
18) created by the pharmacy.”
Comment: Allocation sequence random. Allocation sequence probably concealed |
| Deviations from intervention |
Low |
Quote: "All study data were collected by blinded study personnel using Research Electronic Data Capture (REDCap) electronic data cap- ture tools hosted at Ghent University Hospital"; "Active drug and placebo tablets were provided by the pharmacy at the Ghent University Hospital" Comment: Blinded study (participants; study personnel giving the medication were unblinded, study personel blinded). CLINICAL IMPROVEMENT, 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: Clinical improvement (D28). Adverse events. TIME TO CLINICAL IMPROVEMENT Participants were analyzed according to their randomized groups for the outcome. Of note, 5/66 vs 1/30 participants were excluded from the analysis post-randomization because 3 vs 1 were hospitalized and 2 vs 0 stopped taking the intervention. 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 include all particpants randomized in the analysis. Risk assessed to be some concerns for the outcomes: Time to clinical improvement. |
| Missing outcome data |
Low |
Comment: 96 participants randomized; 90 participants analyzed.
Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: 4 participants were excluded because they did not complete the treatment due to clinical deterioration and hospitalization, 2 participants withdrew from the study. CLINICAL IMPROVEMENT.ADVERSE EVENTS Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (balanced between arms). Risk assessed to be low for the outcomes: Clinical improvement (D28). Adverse events. TIME TO CLINICAL IMPROVEMENT This source of bias has been taken into account in domain 2 for the outcome Time to clinical improvement. Risk assessed to be low for the outcomes: Time to clinical improvement. |
| Measurement of the outcome |
Low |
Quote: “All study data were collected by blinded study personnel using Research Electronic Data Capture (REDCap) electronic data capture tools hosted at Ghent University Hospital.”
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: Clinical improvement (D28). Time to clinical improvement. Adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The trial prospective registry was available (dated November 12,2020)
CLINICAL IMPROVEMENT, TIME TO CLINICAL IMPROVEMENT Outcome not pre-specified. No information on whether the result was selected from multiple outcome measurements or analyses of the data. Trial probably not analyzed as pre-specified. Risk assessed to be some concerns for the outcomes: Clinical improvement (D28). Time to clinical improvement. ADVERSE EVENTS Adverse evetns outcome was not pre-specified in the registry, however, we do not consider the reporting of this outcome to be selective since safety 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 outcomes: Adverse events |
| Overall risk of bias |
Some concerns |