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: "patients were randomly assigned in a 2:1 ratio to receive either UC-MSCs or the placebo, in addition to standard care, using an interactive web response management system (IWRS). A permutated-block randomisation sequence that was stratified by the trial sites was generated and uploaded to the system."
Quote: "A barcode-based product management system (Product Identification Authentication and Tracking System, PIATS) was introduced in this study to manage and track the study products logistics, e.g., preparation, packaging, shipping, storage, and clinical administration to the patients. The application of PIATS could realize the blind label processing by non-informative unique barcodes of the clinical study drug. The concealment of the randomisation sequence could be ensured using PIATS and IWRS." Comment: Allocation sequence random. Allocation sequence concealed. |
| Deviations from intervention |
Low |
Quote: "Patients, investigators, and outcome assessors (independent central imaging reviewers) were all blinded to the treatment allocation. Blinding was also ensured by the product marking, with the UC-MSCs and the placebo having a similar appearance and packaging."
Comment: Blinded study (participants and personnel/carers). 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 low for the outcomes: Mortality (D28). Mortality (D60 or more). WHO score 7 and above (D28). Clinical improvement (D28). Adverse events. Serious adverse events. |
| Missing outcome data |
Some concerns |
Comment: 101 participants randomized; 100 participants analyzed for all outcomes except Mortality D60 or more (81 participants analyzed).
MORTALITY D28, CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, AE, SAE Data available for all or nearly all participants. Of note, one participant in the intervention group withdrew consent before treatments were administered and was not included in analyses. Risk assessed to be low for the outcomes: Mortality (D28). WHO score 7 and above (D28). Clinical improvement (D28). Adverse events. Serious adverse events. MORTALITY D60 OR MORE Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: Unknown 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 51/ 65 in MSC group vs 30/35 in placebo) Risk assessed to be some concerns for the outcomes: Mortality (D60 or more). |
| 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 or more). WHO score 7 and above (D28). Clinical improvement (D28) Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The protocol (dated June 1st, 2020 but included the history of changes), statistical analysis plan and registry (up to version dated March 6th, 2020) were available.
MORTALITY D28, AE, SAE 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 outcomes: Mortality (D28). Mortality (D60 or more). Adverse events. Serious adverse events. MORTALITY D60, CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE Different timepoint pre-specified (days 7, 14, 28), reported day 10 for clinical improvement and WHO score 7 and above. 3 month timepoint not pre-specified for mortality. No information on whether the result was selected from multiple outcome measurements or analyses of the data. Trial probably not analyzed as pre-specified. Risk assessed to be some concerns for the outcome: Mortality (D60 or more). Clinical improvement (D28). WHO score 7 and above (D28). |
| Overall risk of bias |
Some concerns |