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: The permuted block (four patients per block) randomization sequence, including stratification, was prepared by a statistician not involved in the trial, using SAS software, version 9.4 (SAS Institute). To minimize allocation bias, we performed allocation concealment with an interactive Web-based response system until randomization was finished on the system through a computer or phone.
Comment: Allocation sequence random. Allocation sequence concealed. |
| Deviations from intervention |
Some concerns |
Comment: Unblinded study (participants and personnel/carers).
Deviations from intended intervention arising because of the study context: [discuss cross-over and co-interventions below, e.g.] 2/99 were assigned to the lopinavir-ritonavir arm but did not receive the intervention, 1/100 was assigned to the standard care arm but received lopinavir-ritonavir). Deviations are too small to affect the outcome No information on administration of co-intervention of interest: biologics. Antivirals, and corticosteroids were reported. Hence, not enough information on whether deviations arose because of the trial context. MORTALITY, TIME TO DEATH, (TIME TO) CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE 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: Mortality (D28). Time to death. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). ADVERSE and SERIOUS ADVERSE EVENTS Participants were not analyzed according to their randomized groups for the outcome. Of note, 1 participant randomized to the control group was 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 some concerns for the outcomes: Adverse events. Serious adverse events. VIRAL NEGATIVE CONVERSION Participants were analyzed according to their randomized groups for the outcome. Of note, 30 vs 29 participants were excluded from the analysis post-randomization because they did not have any detectable viral RNA at baseline. This method was considered appropriate to estimate the effect of assignment to intervention for this outcome. Risk assessed to be some concerns for the outcomes: Incidence of viral negative conversion (D7) |
| Missing outcome data |
Low |
Comment: 199 participants randomized, 199 participants analyzed for mortality, time to death, (time to) clinical improvement and WHO score 7 and above outcomes; 194 participants analyzed for adverse and serious adverse events; 130 participants analyzed for viral negative conversion outcome.
MORTALITY, TIME TO DEATH, (TIME TO) CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Time to death. Clinical improvement (D28). Time to clinical improvement. WHO score 7 or above (D28). ADVERSE and SERIOUS ADVERSE EVENTS Data available for all or nearly all participants randomized. Of note, 3 participants died within 24 hours of admission and did not receive the drug. Risk assessed to be low for the outcomes: 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: no detectable viral RNA at baseline Missingness could not depend on the true value of the outcome. Risk assessed to be low for the outcome: Incidence of viral negative conversion (D7). |
| 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). MORTALITY, TIME TO DEATH, VIRAL NEGATIVE CONVERSION Mortality and viral negative conversion are observer-reported outcomes not involving judgement. Risk assessed to be low for the outcomes: Mortality (D28). Time to death. Incidence of viral negative conversion (D7). WHO SCORE 7 AND ABOVE For WHO score 7 and above, we consider that the assessment cannot possibly be influenced by knowledge of intervention assignment. Risk assessed to be low for the outcomes: WHO score 7 and above (D28). (TIME TO) CLINICAL IMPROVEMENT Clinical improvement (defined as improvement of two points (from the status at randomization) on a seven-category ordinal scale or live discharge from the hospital, whichever came first) 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 protocol was available (in Chinese with the final part presented in English regarding outcomes; the part that was in Chinese was examined by a native speaker). The statistical analysis plan was available.
Outcomes were pre-specified in the protocol and SAP as reported in the paper. 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). Time to death. Incidence of viral negative conversion (D7). Clinical improvement (D28). Time to clinical improvement. WHO score 7 or above (D28). Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |