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: “Enrolled patients were randomly assigned 1:1 to receive lenzilumab or matched placebo in addition to standard treatment per institutional guidelines at each site...A block randomisation
method implemented with a central randomisation
system (Rave Randomisation & Trial Supply Management;
Medidata, NY, USA) was used to assign patients to
treatment groups. Allocation of treatment was concealed
to all investigators, study personnel, and patients. The
investigational pharmacist was responsible for the
preparation of study drug for each patient and was
unmasked to the randomisation assignment.”
Comment: Allocation sequence random. Allocation sequenced concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: "double-blind" (report) "Masking: Double (Participant, Investigator)" (registry)
Comment: Blinded study (participants and personnel/carers) MORTALTIY, WHO SCORE 7 AND ABOVE, SERIOUS ADVERSE EVENTS: 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 low for the outcome: Mortality (D28).WHO score 7 and above (D28). Serious adverse events. TIME TO DEATH, TIME TO WHO SCORE 7 OR ABOVE: Participants were analyzed according to their randomized groups for the outcome. Of note, 25 vs 16 participants were excluded from the analysis post-randomization because they did not receive treatment: 7 vs. 1, Documented lack of supervision of the principal investigator or sub-investigator: 6 vs. 5, or Documented limitation to access of basic supportive care for COVID-19: 12 vs. 10. Additionally, 1 participant in the control arm received the intervention. This method was considered inappropriate to estimate the effect of assignment to intervention for these outcomes. There was probably no substantial impact of failure to analyze participants according to their randomized groups. Risk assessed to be some concerns for the outcomes: Time to death. Time to WHO score 7 and above. |
| Missing outcome data |
Low |
Comment: 520 participants randomized; 479 participants analyzed for efficacy; 512 participants analyzed for safety.
SERIOUS ADVERSE EVENTS Data available for nearly all participants randomized for safety. Risk assessed to be low for the outcome: Serious adverse events. Risk assessed to be low for the outcome: Serious adverse events. MORTALITY AND WHO SCORE 7 AND ABOVE Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons:18 vs 15 participants were excluded from the analysis post-randomization because of documented lack of supervision of the principal investigator or sub-investigator: 6 vs. 5, or documented limitation to access of basic supportive care for COVID-19: 12 vs. 10. Of note, 2 vs 1 participants withdrew from the study due to adverse events, 10 vs 10 were lost to follow-up. Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome. Risk assessed to be some concerns for the outcomes: Mortality (D28).WHO score 7 and above (D28). TIME TO DEATH AND TIME TO WHO SCORE 7 AND ABOVE For the outcomes Time to death and Time to WHO score 7 or above the missing data that were protocol exclusions were accounted for in domain 2. Risk assessed to be low for the outcomes: Time to death. Time to WHO score 7 and above. |
| 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). Time to death. WHO score 7 and above (D60 or more). Time to WHO score 7 and above. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The trial registry (prospective, dated April 17th, 2020) was available.
TIME TO WHO SCORE 7 AND ABOVE, SERIOUS ADVERSE EVENTS Outcomes 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: Time to WHO score 7 and above. Serious adverse events. TIME TO DEATH, WHO SCORE 7 AND ABOVE Outcomes not pre-specified before the start date of study period (2020-05-05). No information on whether the result was selected from multiple outcome measurements or analyses of the data. Trial not analyzed as pre-specified. Risk assessed to be some concerns for the outcome: Time to death. WHO score 7 and above (D28). MORTALITY Mortality outcome was not pre-specified in the registry, however, we do not consider the reporting of this outcome to be selective since mortality should be reported even if not planned. 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: Mortality (D28). |
| Overall risk of bias |
Some concerns |