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: "Permuted block randomization was performed with a block size of 6 in a mixed sequential fashion. Randomization
was centrally performed through an allocation system
based upon a R free software environment. For the initial participants, random allocation was supervised by an unblinded statistician specifically designated by the Sponsor that did not participate in any patient-related activities and who was in either phone and email contact with a designated unblinded pharmacist from each participating site. Unblinded site personnel accessed the database with a non-delegable individual user and password in order to receive assignment information. As such, randomization results were concealed to the rest of the site research members. This procedure was maintained until the first twelve subjects were randomized in the study. From patient thirteen onwards randomization was stratified per participating site and directly performed by the unblinded pharmacist designated at each participating site through a close envelope method maintained in random order. Closed envelopes were only accessible to unblinded pharmacists and unblinded statisticians and concealed to all other personnel."
Comment: Allocation sequence random. Allocation sequence concealed. |
| Deviations from intervention |
Low |
Publication: “Randomization was supervised by a specifically designated sponsor team member who remained in contact with the designated
unblinded pharmacist from each participating site. Assignation was only revealed to the unblinded pharmacist and concealed to the rest of the site research members. Site pharmacist was responsible for
properly masking the intervention, handing the corresponding optically indistinguishable infusion bag to the blinded clinical team”
Registry: "Quadruple blind (Participant, Care Provider, Investigator, Outcomes Assessor)" Comment: Blinded study (participants and personnel/carers) 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 outcomes. Of note, 1 vs 1 participants were excluded from the analysis post-randomization because they did not receive the drug. Nevertheless, we considered the analysis to be probably appropriate to estimate the effect of assignment to intervention for the time-to-event outcomes. Risk assessed to be low for the outcomes: Mortality (D28). Time to death. Time to clinical improvement. WHO score 7 and above (D28). Clinical improvement (D28). Time to WHO score 7 and above. Adverse events. Serious adverse events. |
| Missing outcome data |
Low |
Comment: 245 participants randomized; 241 participants analyzed for efficacy outcomes; 243 participants analyzed for safety outcomes.
Data available for all or nearly all participants. Risk assessed to be low for the outcomes: Mortality (D28). Time to death. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28) Time to WHO score 7 and above. Adverse events. Serious adverse events. |
| Measurement of the outcome |
Low |
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: Mortality (D28). Time to death. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Time to WHO score 7 and above. Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The trial registry was available.
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 (D28).Clinical improvement (D28). Time to clinical improvement. Time to death, (time to) WHO score 7 and above and safety outcomes not pre-specified in the registry. 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: Time to death. WHO score 7 and above (D28). Time to WHO score 7 and above. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |