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: “Patients were centrally randomized 1:1 by interactive response technology in a blinded manner.”
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Low |
Quote: “Investigators, who enrolled the patients, and the patients remained blinded to assigned study intervention throughout the study.”
Comment: Blinded study (participants and personnel/carers) MORTALITY, CLINICAL IMPROVEMENT 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: Mortality (D28). Mortality (D60). Clinical improvement (D28). Clinical improvement (D60). ADVERSE and SERIOUS ADVERSE EVENTS Participants were not analyzed according to their randomized groups for the outcome. Of note, 2 participants randomized to the control group were analyzed in the intervention group. Nevertheless, we considered the analysis to be probably appropriate to estimate the effect of assignment to intervention. Risk assessed to be low for the outcomes: Adverse events. Serious adverse events. TIME TO DEATH, TIME TO CLINICAL IMPROVEMENT Participants were analyzed according to their randomized groups for the outcome. This method was considered appropriate to estimate the effect of assignment to intervention. Risk assessed to be low for the outcomes: Time to death. Time to clinical improvement. |
| Missing outcome data |
Some concerns |
Comment: 806 participants randomized; 781 analyzed for Mortality (D28), 779 for clinical improvement (D28), 793 for adverse and serious adverse events, 759 for all other outcomes.
MORTALITY (D28) 781 participants analyzed. Data available for nearly all participants randomized. Risk assessed to be low for the outcome: Mortality (D28). CLINICAL IMPROVEMENT (D28) 779 participants analyzed. Data available for nearly all participants randomized. Risk assessed to be low for the outcome: Clinical improvement (D28). ADVERSE and SERIOUS ADVERSE EVENTS 793 participants analyzed. Data available for nearly all participants randomized. Risk assessed to be low for the outcomes: Adverse events. Serious adverse events. MORTALITY (D60 or more). TIME TO DEATH. CLINICAL IMPROVEMENT (D60 or more). TIME TO CLINICAL IMPROVEMENT. 759 participants analyzed. Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: lost to follow-up (8 vs 4), physician decision (5 vs 2), protocol deviation (3 vs 2), participant decision (8 vs 7). Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (balanced between groups). Risk assessed to be some concerns for the outcome: Mortality (D60 or more). Time to death. Clinical improvement (D60 or more). Time to clinical improvement. |
| Measurement of the outcome |
Low |
Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome does not differ between groups. Blinded study (outcome assessor). Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death. Clinical improvement (D28). Clinical improvement (D60 or more). Time to clinical improvement. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan, registry were available.
MORTALITY (D60 OR MORE), CLINICAL IMPROVEMENT, AE, SAE 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 outcomes: Mortality (D60 or more). Time to death. Clinical improvement (D28). Clinical improvement (D60 or more). Time to clinical improvement. Adverse events. Serious adverse events. MORTALITY (D28) 28-day all-cause mortality was a post-hoc outcome added to 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 outcomes: Mortality (D28). |
| Overall risk of bias |
Some concerns |