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: “Randomization was generated by an independent methodologist with the randomize R package of the R software, using two blocks sizes (sized four and six, respectively), with random permutation. The block randomization was stratified by age into two groups (<75 years and ≥75 years). The Pharmacy Department of each institution held the random allocation sequence. Once a patient was enrolled, a prescription was sent to an un-blinded pharmacist who prepared the study drug, and dispensed it in opaque plastic bags containing a total volume of 100 ml and labeled for each participant.”
Comment: Allocation sequence random. Allocation sequence concealed. |
| Deviations from intervention |
Low |
Quote: “Double-blind. Once a patient was enrolled, a prescription was sent to an un-blinded pharmacist who prepared the study drug, and dispensed it in opaque plastic bags containing a total volume of 100 ml and labeled for each participant. Neither the medical team nor the nurses administering the treatment were aware of the content of the bags. Similarly, the physicians who assessed the primary and secondary outcomes, including adverse events, were blinded to treatment assignment.”
Comment: Blinded study (participants and personnel/carers) MORTALITY, (TIME TO) CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, AE, SAE Our analysis 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 ore more). Clinical improvement (D28). Clinical improvement (D60 or more). Time to clinical improvement. WHO score 7 and above (D28). WHO score 7 and above (D60 or more). Adverse events. Serious adverse events. VIRAL NEGATIVE CONVERSION Participants were analyzed according to their randomized groups for the outcome. Of note, 2 vs 3 participants were excluded from the analysis post-randomization likely due to missing data which is accounted for in domain 3. Risk assessed to be low for the outcomes: Incidence of viral negative conversion (D7). |
| Missing outcome data |
Some concerns |
Comment: 72 participants randomized; 71 participants analyzed for all outcomes except viral negative conversion (66 analyzed).
MORTALITY, (TIME TO) CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, AE, SAE Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 ore more). Clinical improvement (D28). Clinical improvement (D60 or more). Time to clinical improvement. WHO score 7 and above (D28). WHO score 7 and above (D60 or more). Adverse events. 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: 1 participant withdrew consent, unknown reasons for 5 participants Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome Risk assessed to be some concerns for the outcomes: Incidence of viral negative conversion (D7). |
| 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). Mortality (D60 ore more). Incidence of viral negative conversion (D7). Clinical improvement (D28). Clinical improvement (D60 or more). Time to clinical improvement. WHO score 7 and above (D28). WHO score 7 and above (D60 or more). Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol (dated April 24th, 2020), statistical analysis plan and registries (Eudra CT dated May 5th, 2020) were available.
MORTALITY. VIRAL NEGATIVE CONVERSION. WHO SCORE 7 AND ABOVE. ADVERSE AND SERIOUS ADVERSE EVENTS. 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). Incidence of viral negative conversion (D7). WHO score 7 and above (D28). Adverse events. Serious adverse events. MORTALITY (D60). (TIME TO) CLINICAL IMPROVEMENT. WHO SCORE 7 AND ABOVE (D60). Outcome data acquired from direct contact with authors. Analysis performed by the COVID-NMA. Risk assessed to be low for the outcome: Mortality (D60 or more). Clinical improvement (D28). Clinical improvement (D60 or more). Time to clinical improvement. WHO score 7 and above (D60 or more). |
| Overall risk of bias |
Some concerns |