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 enrolled patients were randomly allocated into two groups (1:1 allocation ratio) by an independent statistician using permuted blocks of 4 for all sites. The whole process of randomization was masked to all treating physicians. Patient unique identification number and treatment allocation codes were provided by a clinical research associate in sequentially numbered opaque envelopes."
Comment: The allocation sequence was random and concealed. |
| Deviations from intervention |
Some concerns |
Quote: "single-blind, randomized controlled phase II trial"
Comment: Single blinding (participants blinded and personnel/carers not blinded). Deviations from intended intervention arising because of the study context: No participant cross-over. Administration of co-interventions of interest were reported: antivirals and corticosteroids were balanced. Biologics (7 vs 11). This deviation was not balanced and could affect the outcome. Nevertheless, this domain was rated as some concern as it is impossible to distinguish deviation because of trial context and deviation because of intervention effect. MORTALITY, TIME TO DEATH, CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, AE, SAE 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. Time to clinical improvement. WHO score 7 and above (D28). Adverse events. Serious adverse events. TIME TO VIRAL NEGATIVE CONVERSION Participants were analyzed according to their randomized groups for the outcome. Of note, 26 participants were excluded from the analysis post-randomization because they tested negative at baseline. This was an exclusion of ineligible participants and was considered appropriate to estimate the effect of assignment to intervention for this outcome. Risk assessed to be some concerns for the outcome: Incidence of viral negative conversion (D7). Time to viral negative conversion. |
| Missing outcome data |
Some concerns |
Comment: 43 participants randomized; 41 participants analyzed for all outcomes except viral negative conversion (17 participants analyzed) and WHO score 7 and above (38 participants analyzed).
MORTALITY, TIME TO DEATH, CLINICAL IMPRORVEMENT, AE, SAE 1 patient excluded due to humoral immune deficiency post CAR T therapy and 1 patient withdrew consent. Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Time to death. Clinical improvement. Time to clinical improvement. 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: the remaining participants tested negative at baseline. Missingness could not depend on the true value of the outcome (accounted for in domain 2). Risk assessed to be low for the outcome: Incidence of viral negative conversion (D7). Time to viral negative conversion. WHO SCORE 7 AND ABOVE Data retrieved from contact with authors. Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reason for missingness unclear. No information on whether missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (similar proportion of missingness between arms). Risk assessed to be some concerns for outcomes: WHO score 7 and above (D28). |
| 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, TIME TO 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). Time to viral negative conversion. 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 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 |
Some concerns |
Comment: The protocol was available but was retrospective (dated March 8th, 2020). The prospective version of the registry (dated February 8th, 2020) was available but the only outcome listed was 'safety'.
MORTALITY, TIME TO CLINICAL IMPROVEMENT, TIME TO VIRAL NEGATIVE CONVERSION No information on whether the result was selected from multiple outcome measurements or analyses of the data. No information on whether the trial was analyzed as pre-specified. Risk assessed to be some concerns for the outcomes: Mortality (D28). Time to clinical improvement. Time to viral negative conversion. ADVERSE and SERIOUS ADVERSE EVENTS Outcome 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 outcome: Adverse events. Serious adverse events. TIME TO DEATH, VIRAL NEGATIVE CONVERSION, CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE Outcome data acquired from contact with authors. 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 outcome: Time to death. Incidence of viral negative conversion (D7). Clinical improvement (D28). WHO score 7 and above (D28). |
| Overall risk of bias |
Some concerns |