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: "Participants will be randomized to study drugs or placebo based on the arms that are actively enrolling at the time of randomization. Study drugs may be added or removed according to adaptive design and/or emerging evidence. When there are multiple study drugs available, randomization will occur based on appropriateness of each drug for the participant as determined by the study protocol and investigator and participant equipoise. Each participant will be required to randomize to at least one study drug versus placebo. The probability of placebo to treatment will remain the same regardless of eligibility decisions.
Eligible participants will be randomized (1:1), in a blinded fashion, to either the study drug arm or placebo arm in addition to standard of care. As additional study drugs are added, the randomization will be altered to leverage placebo data across arms. Participants will receive a complete supply study drug or placebo with the quantity depending on the study drug/placebo to which they are randomized."
Comment: Allocation sequence probably random. No information on allocation concealment. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: “Double blind (Participant, Care Provider). The participant and study teams will know which study drug the participant is allocated to, but will be blinded to study drug versus placebo because they will be matching.”
Comment: Blinded study (participants and personnel/carers). MORTALITY, HOSPITALIZATION OR DEATH, INCIDENCE OF WHO SCORE 7 OR ABOVE, ADVERSE EVENTS, 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 lowfor the outcomes: Mortality (D28). Hospitalization or death.WHO score 7 and above (D28).Adverse events. Serious adverse events. TIME TO CLINICAL IMPROVEMENT Participants were analyzed according to their randomized groups for the outcome. Of note, 59 vs 71 participants were excluded from the analysis post-randomization because they did not receive the drug due to the decentralized methods and home drug delivery employed in the study. This method was considered inappropriate to estimate the effect of assignment to intervention for this outcome. There was probably no substantial impact of failure to analyze participants according to their randomized groups. Risk assessed to be some concerns for the outcomes: Time to clinical improvement. |
| Missing outcome data |
Some concerns |
Comment: 1407 participants randomized; 1277 participants analyzed.
MORTALITY, HOSPITALIZATION OR DEATH, INCIDENCE OF WHO SCORE 7 OR ABOVE, ADVERSE EVENTS, SERIOUS ADVERSE EVENTS. Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: 59/715 vs 71/692 participants were excluded from the analysis post-randomization because they did not receive the drug due to the decentralized methods and home drug delivery employed in the study. Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome due to balance between group (balance between groups). Risk assessed to be some concerns for the outcomes: Mortality (D28). Hospitalization or death.WHO score 7 and above (D28).Adverse events. Serious adverse events. TIME TO CLINICAL IMPROVEMENT Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: 59/715 vs 71/692 participants were excluded from the analysis post-randomization because they did not receive the drug due to the decentralized methods and home drug delivery employed in the study. This potential source of bias has been taken into account in domain 2. Risk assessed to be low for the outcome: Time to clinical improvement. |
| 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). Hospitalization or death. WHO score 7 and above (D28). Adverse events. Serious adverse events. Time to clinical improvement. |
| Selection of the reported results |
Low |
Comment: The prospective registry was available (Dated May 13, 2021).
MORTALITY, HOSPITALIZATION OR DEATH, INCIDENCE OF WHO SCORE 7 OR ABOVE, TIME TO CLINICAL IMPROVEMENT outcomes 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 (D28). Hospitalization or death. WHO score 7 and above (D28). Time to clinical improvement. ADVERSE EVENTS, SERIOUS ADVERSE EVENTS Safety outcome were not pre-specified in the registry, however, we do not consider the reporting of this outcome to be selective since safety 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: Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |