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 |
Protocol: "Randomization will be conducted through a password-protected, secure website using a
central, computer-based randomization program. Randomization will be at the patient level
and occur after data necessary to implement the inclusion and exclusion criteria have been
entered into the secure randomization website. The RAR will occur centrally as part of the computerized randomization process. Sites will receive the allocation status and will not be
informed of the randomization proportions. Each region will maintain its own computerbased
randomization program that is accessed by sites in that region but the RAR
proportions will be determined by a SAC and provided monthly to the administrator of each
region's randomization program who will update the RAR proportions."
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 information on co-interventions of interest: antivirals, biologics. Quote: "Among those assigned to the fixed-dose hydrocortisone group, 97% (n = 130/134) received at least 1 dose of hydrocortisone, an additional 1.5% (2/134) received an alternative systemic corticosteroid, and only 2 (1.5%) received no corticosteroid...Among those assigned to the no hydrocortisone group, 15% (15/99) received a systemic corticosteroid (6 of whom received hydrocortisone)" 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. Data for the binary outcomes were analyzed using 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 time-to-event outcome. Of note, 6 vs 7 participants were excluded from the analysis post-randomization because they withdrew consent. Nevertheless, we considered the analysis to be probably appropriate to estimate the effect of assignment to intervention for this time-to-event outcome. Risk assessed to be some concerns for the outcomes: Mortality (D28). Time to death. Serious adverse events. |
| Missing outcome data |
Low |
Comment: 251 participants randomized, 238 participants analyzed.
Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons for missing data: withdrawn consent Missing outcome data occurred due to documented reasons unrelated to the outcome. Missingness could not depend on the true value of the outcome. Risk assessed to be low for the outcomes: Mortality (D28). Time to death. 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 is an observer-reported outcome not involving judgement. Risk assessed to be low for the outcome: Mortality (D28). Time to death. Serious adverse events (severe neuromyopathy, fungemia, single cases of pneumonia, pulmonary embolism, elevated serum troponin, postoperative hemorrhage, intracranial hemorrhage, thrombocytopenia, ventricular tachycardia, and hypoglycemia) contain both clinically- and laboratory-detected outcomes, therefore it can be influenced by knowledge of the intervention assignment, but is not likely to. Risk assessed to be some concerns for the outcome: Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The protocol, statistical analysis plan and registry were available but 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). Time to death. Serious adverse events. |
| Overall risk of bias |
Some concerns |