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:"computer-generated variable blocks ranging from 4 to 8 patients per each center, and the code numbers for eligible patients were assigned in ascending sequential order."
Comment: Allocation sequence random. Unclear 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 were reported During the trial period, evidence of the ineffectiveness of hydroxychloroquine was published and a third ciclesonide plus hydroxychloroquine arm was combined with the ciclesonide alone arm. Eight patients in the ciclesonide group received oral HCQ treatment concomitantly for 10 days. Clinical failure was defined as the case of clinical deterioration requiring high-flow nasal oxygen or mechanical ventilation, resulting in salvage treatment with dexamethasone and remdesivir. 1/35 in the treatment arm and 5/26 in the SOC arm reached this endpoint. These deviations were 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, SERIOUS 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 some concerns for the outcomes: Mortality (D28). Incidence of viral negative conversion (D7). Serious adverse events. VIRAL NEGATIVE CONVERSION Participants were analyzed according to their randomized groups for the outcome. Of note, 12 participants were excluded from the analysis post-randomization, of which 2 were due to reasons other than missing data (issues with eligibility criteria). The remaining 10 were due to missing data and is accounted for in domain 3. This method was considered appropriate to estimate the effect of assignment to intervention for this outcome. Risk assessed to be some concerns for the outcomes: Incidence of viral negative conversion (D7). |
| Missing outcome data |
High |
Comment: 68 participants randomized, 61 participants analyzed for mortality and serious adverse events, 56 participants analyzed for viral negative conversion.
MORTALITY, SERIOUS ADVERSE EVENTS Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: 7 participants were excluded from the analyses because of issues with eligibility criteria (2 participants), withdrawal of consent (3 participants), or transfer to other hospitals within 3 days after study enrollment (2 participants). It is not clear which arms they were from. Missingness could depend on the true value of the outcome. No information on whether missingness is likely to depend on the true value of the outcome (but randomization is 1:1 and the number analyzed is 35 vs 26 hence it is more likely that there is an uneven proportion of missingness between arms). Risk assessed to be high for the outcomes: Mortality (D28). Serious adverse events. VIRAL NEGATIVE CONVERSION Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: 7 participants were excluded from the analyses because of issues with eligibility criteria (2 participants; accounted for in domain 2), withdrawal of consent (3 participants), or transfer to other hospitals within 3 days after study enrollment (2 participants). It is not clear which arms they were from. A further 1 vs 4 in the SOC arm were not included due to prior clinical progression. Missingness could depend on the true value of the outcome. No information on whether missingness is likely to depend on the true value of the outcome (but perhaps uneven proportion of missingness between arms based on 1 vs 4 clinical progression exclusion; also randomization is 1:1 and the number analyzed is 34 vs 22 hence it is more likely that there is an uneven proportion of missingness between arms). Risk assessed to be high for the outcome: Incidence of viral negative conversion (D7). |
| 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, VIRAL NEGATIVE CONVERSION Observer-reported outcome not involving judgement. Risk assessed to be low for the outcomes: Mortality (D28). Incidence of viral negative conversion (D7). 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: Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The registry was available dated June 24, 2021
VIRAL NEGATIVE CONVERSION, SERIOUS ADVERSE EVENTS Outcome pre-specified. 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 outcome: Incidence of viral conversion (D7). Serious adverse events. MORTALITY 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 |
High |