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 |
High |
Quote: “This Phase 2 study is designed as a proof of concept study and will randomize 2:1 approximately 120 patients with COVID-19 associated acute hypoxemia: of which 80 patients will receive sargramostim plus standard of care, and 40 patients who will receive standard of care alone. ”
From contact with authors: "Not concealed" Comment: Allocation sequence probably random. Allocation sequence not concealed |
| Deviations from intervention |
Some concerns |
Quote: “Masking: None (Open Label)”
Comment: Unblinded study (participants and personnel/carers) Deviations from intended intervention arising because of the study context: No participant cross-over. Administration of co-interventions of interest: antivirals, corticosteroids, biologics was balanced between arms. Hence, no information on whether deviations arose because of the trial context. MORTALITY (D28). MORTALITY (D60 OR MORE). CLINICAL IMPROVEMENT (D60 OR MORE). WHO SCORE 7 AND ABOVE. ADVERSE EVENTS. SERIOUS ADVERSE EVENTS 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 some concerns for the outcomes: Mortality (D28). Mortality (D60 or more). Clinical improvement (D60 or more). WHO score 7 and above. Adverse events Serious adverse events. TIME TO DEATH Participants were probably analyzed according to their randomized groups for the outcome. This method was considered appropriate to estimate the effect of assignment to intervention for this outcome. Risk assessed to be low for the outcome: Time to death. |
| Missing outcome data |
Some concerns |
Comment: 122 participants randomized; 122 participants analyzed in ITT analysis.
Of note, 13 participants were lost to follow up or withdrew Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: Lost to follow up (5 vs 6), withdrawal by subject (2 vs 0) Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (balance between arms) Risk assessed to be some concerns for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death. Clinical improvement (D60 or more). WHO score 7 and above (D28). 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) MORTALITY, TIME TO DEATH Observer-reported outcome not involving judgement. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death. WHO SCORE 7 AND ABOVE For this outcome, 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). CLINICAL IMPROVEMENT Clinical improvement (defined as discharge) requires clinical judgement and could be affected by knowledge of intervention receipt, but it is not considered likely to in the context of a pandemic. Risk assessed to be some concerns for the outcomes: Clinical improvement (D60 or more) 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, statistical analysis plan, registry were available (dated June 2, 2020).
MORTALITY 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: Mortality (D28). Mortality (D60 or more). SERIOUS ADVERSE EVENTS Outcome not pre-specified in the version of the prospective registry dated August 18, 2020. 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: Serious adverse events TIME TO DEATH. CLINICAL IMPROVEMENT (D60 OR MORE). WHO SCORE 7 AND ABOVE. ADVERSE EVENTS. Outcome data acquired from direct contact with authors. Analysis performed by the COVID-NMA. Risk assessed to be low for the outcomes: Time to death. Clinical improvement (D60 or more). WHO score 7 and above (D28). Adverse events. |
| Overall risk of bias |
High |