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: "allocation using stratified randomisation by randomised permuted blocks" (report) "A randomization list will be prepared by the statistician responsible for the study, blind to the researchers. Patients will be randomized by 1: 1: 1 allocation using stratified randomization by randomized permuted blocks. Randomization will be stratified by age (people ≥60 and <60 years) and by time since the first vaccination dose (≥45 and <45 days)." (protocol)
Comment: Allocation sequence probably random. Allocation sequence probably concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: "All participants were vaccinated by health-care personnel who were aware of group allocation but were not otherwise involved in trial procedures or data collection. The patients were also aware of the arm of the study to which they were assigned." (report) "The study will be open but masked to the determination of the primary end point. This implies that both investigators and patients will be aware of the strategy assignment. " (protocol)
Comment: Unblinded study (participants and personnel/carers). Deviations from intended intervention arising because of the study context: No participant cross-over. Hence, deviations did not arise because of the trial context. Analysis of safety outcomes was intention-to-treat. As we are assessing the effect of assignment to intervention, the analysis method performed on these safety outcomes was considered appropriate. Risk assessed to be low for the outcomes: Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. Per-protocol analysis was performed on the immunogenicity outcomes. Reasons for exclusion were not provided, except that 4, 3, 5, 4, and 3 participants were "excluded" from the per-protocol analysis. As we are assessing the effect of assignment to intervention (intention-to-treat effect), we considered that the data were analyzed inappropriately. There was probably no substantial impact of failure to analyze participants according to their randomized assignment due to the small number of excluded partcipants. Risk assessed to be some concerns for the outcomes: Specific antibody GMT. Neutralizing antibody GMT. |
| Missing outcome data |
Low |
Comment: 540 participants randomized; 540 participants analyzed for safety; 524 participants analyzed for immunogenicity.
Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Specific antibody GMT. Neutralizing antibody GMT. Cellular response. Local adverse events. Systemic adverse events. 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. Quote: "The professionals of the central laboratory who make the determination of immunogenicity will not know the identification of the patient or the treatment scheme." (protocol) Outcome assessment was blinded for immunogenicity. Risk assessed to be low for the outcomes: Specific antibody GMT. Neutralizing antibody GMT. Outcome assessment was not blinded for safety. The authors reported on 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: Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan, and trial registry records were available.
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: Specific antibody GMT. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |