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 performed using a web-response system after stratification by COVID-19 severity (mild or moderate), age, and CT severity at enrollment.”
Comment: Allocation sequence random. Allocation sequence probably concealed. |
| Deviations from intervention |
Some concerns |
Quote: “multicenter, open-labeled, randomized, active-controlled phase 3 trial”
Comment: Unblinded study (participants and personnel/carers). No participant cross-over. No information on administration of co-interventions of interest: biologics, antivirals and corticosteroids; antivirals were part of standard of care, but no information is reported on who received these. Hence, no information on whether deviations arose because of the trial context. Data for the outcome were analyzed using intention-to-treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention. Risk assessed to be some concerns for the outcomes: Incidence of viral negative conversion (D7). Time to viral negative conversion. Clinical improvement (D28). Time to clinical improvement. Adverse events. Serious adverse events. |
| Missing outcome data |
Some concerns |
Comment: 168 participants randomized; 168 participants analyzed for efficacy outcomes and 163 for safety outcomes.
Of note, 4 vs 1 discontinued the study (withdrew consent) before the first dose and 2 vs 2 discontinued the study (withdrew consent) after getting at least one dose. Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons provided for missing data: withdrew consent. 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). Time to viral negative conversion. Clinical improvement (D28). Time to clinical improvement. Adverse events. 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) (TIME TO) VIRAL NEGATIVE CONVERSION Viral negative conversion is an observer-reported outcome not involving judgement. Risk assessed to be low for the outcomes: Incidence of viral negative conversion (D7). Time to viral negative conversion. (TIME TO) CLINICAL IMPROVEMENT Clinical improvement (defined as a reduction of patient clinical status on at least 1 score according to WHO 8-Category Ordinal Scale for Clinical Improvement) requires clinical judgement and could be affected by knowledge of intervention receipt, but it not considered likely to in the context of a pandemic. Risk assessed to be some concerns for the outcomes: Clinical improvement (D28). Time to clinical improvement. ADVERSE and SERIOUS ADVERSE EVENTS The authors reported on adverse events and serious adverse events that may contain both clinically- and laboratory-detected events, which can be influenced by knowledge of the intervention assignment, but is not likely in the context of the pandemic. Risk assessed to be some concerns for the outcomes: Adverse events. Serious adverse events |
| Selection of the reported results |
Low |
Comment: The prospective protocol was available (dated May 8th, 2020 and edited on May 19th, 2020). The registry was available but retrospective (dated August 6th, 2020).
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 concerns for the outcomes: Incidence of viral negative conversion (D7). Time to viral negative conversion. Clinical improvement (D28). Time to clinical improvement. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |