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: “Patients were randomized at a 1:1 ratio to receive either
oral bromhexine in addition to standard therapy or standard
therapy alone. Subjects who were enrolled received
a trial number. Every single trial number was randomized
to either arm of the study through computer randomization.”
Comment: Allocation sequence random. No information on allocation concealment. |
| 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. No information on administration of co-interventions of interest: biologics, antivirals and corticosteroids. Hence, no information on whether deviations arose because of the trial context. MORTALITY, SERIOUS ADVERSE EVENTS Data for the outcome were analyzed using intention-to-treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention. VIRAL NEGATIVE CONVERSION Participants were analyzed according to their randomized groups for the viral negative conversion outcome. Of note, 11 vs 0 participants were excluded from the analysis post-randomization due to missing data which will be addressed in domain 3. This method was considered appropriate to estimate the effect of assignment to intervention. Risk assessed to be some concerns for the outcomes: Mortality (D28). Incidence of viral negative conversion (D7). Serious adverse events. |
| Missing outcome data |
High |
Comment: 111 patients randomized; 100 patients analyzed.
Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons for missing data: 9 patients in the treatment arm excluded from analysis because they declined to continue with the study drug after discharge; 2 others, also in the treatment arm, excluded because they did not have a PCR test on day 28. Missingness could depend on the true value of the outcome. Likely that missingness depended on the true value of the outcome (unequal proportion). Risk assessed to be high for the outcomes: Incidence of viral negative conversion (D7). Serious adverse events. Reasons for missing data regarding mortality outcome: 9 patients in the treatment arm excluded from analysis because they declined to continue with the study drug after discharge (it is unlikely that this reason would be related to a death outcome as the patient was discharged); 2 others, also in the treatment arm, excluded because they did not have a PCR test on day 28. Missingness could depend on the true value of the outcome. Unlikely that missingness depended on the true value of the mortality outcome. Risk assessed to be some concerns for the outcome: Mortality (D28). |
| 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 and viral negative conversion are observer-reported outcomes not involving judgement. Risk assessed to be low for the outcome: Mortality (D28). Incidence of viral negative conversion (D7) Also, the authors reported on serious adverse events that may contain both clinically- and laboratory-detected outcomes. This outcome 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: Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The protocol and statistical analysis plan were not available. The registry was retrospective. 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). Incidence of viral negative conversion (D7). Serious adverse events. |
| Overall risk of bias |
High |