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|
|Quote: "Randomisation was performed in an electronic case report form system (RedCap Database), 1:1 with random block sizes of 4, 6, or 8 subjects using tables generated from STATA (v16·1)"
Comment: Allocation sequence random. No information on allocation concealment.
|Deviations from intervention||
|Quote: “Open label”
"Patients, investigators, and health-care providers were not masked to study drug assignment."
Comment: Unblinded study (participants and personnel/carers).
Deviations from intended intervention arising because of the study context:
9 control patients were treated with progesterone due to clinical deterioration prior to Day 7 (n = 6, 27%) or absence of clinical improvement by Day 7 (n = 3, 14%). No information on whether this deviation was consistent with the trial protocol since the protocol was not available.
Administration of co-interventions of interest (antivirals, biologics, and corticosteroids) were reported. Slightly more patients in the control group received antivirals and corticosteroids (9/18 vs 15/22) and biologics (Tocilizumab: 1/18 vs 4/22; Convalescent plasma: 0/18 vs 2/22).
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.
Data for the outcome were analyzed using intention-to-treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention. The participants in the control group that received progesterone were analyzed with imputation (last observation carried forward) in the group they were randomized to.
Risk assessed to be some concerns for the outcomes: Mortality (D28). WHO score 7 and above (D28). Serious adverse events.
|Missing outcome data||
|Comment: 42 participants randomized; 40 participants analyzed.
Data available for nearly all participants randomized.
Risk assessed to be low for the outcomes: Mortality (D28). WHO score 7 and above (D28). Serious adverse events.
|Measurement of the outcome||
|Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups.
Unblinded study (outcome assessor)
Mortality is an observer-reported outcome not involving judgement.
Risk assessed to be low for the outcome: Mortality (D28).
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 outcome: WHO score 7 and above (D28).
SERIOUS ADVERSE EVENTS
The authors reported on serious adverse events that contained only laboratory-detected outcomes. Therefore, we consider that the assessment cannot possibly be influenced by knowledge of intervention assignment.
Risk assessed to be low for the outcome: Serious adverse events.
|Selection of the reported results||
|Comment: The trial registry was available (dated April 27th, 2020). The protocol and statistical analysis plan were not.
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).
WHO SCORE 7 AND ABOVE, SAE
Different timepoint in registry vs in paper. Furthermore, adverse events and serious adverse events were not pre-specified in the registry. The trial only reported on Grade 3 and 4 non-serious adverse events and serious adverse events without a definition.
No information on whether the results for were 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 outcomes: WHO score 7 and above (D28). Serious adverse events.
|Overall risk of bias||