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: "Randomization was conducted with the use of an interactive Web-based response system"
Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. Risk assessed to be low |
Deviations from intervention |
Some concerns |
Quote: "observer-blinded" (report) “Masking: Triple (Participant, Care Provider, Investigator)” (registry)
Comment: Blinded study (participants, personnel, investigators). SAFETY All randomized participants who received at least one dose were analysed for safety outcomes. 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: Mortality. Adverse events.Serious adverse events. IMMUNOGENICITY Per-protocol analysis was performed on immunogenicity outcomes (as planned in the trial protocol). As we are assessing the effect of assignment to intervention (intention-to-treat effect), we considered that the data were analyzed inappropriately. Risk assessed as some concerns for the outcomes: Neutralizing antibody GMT. EFFICACY All randomized participants who received at least one dose were analysed for the outcome: Mortality. As we are assessing the effect of assignment to intervention, the analysis method performed on this otucome, was considered appropriate. Risk assessed to be low for the outcome: Mortality Per-protocol analysis as planned in the trial protocol) was performed on the outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. As we are assessing the effect of assignment to intervention (intention-to-treat effect), we considered that the data were analyzed inappropriately. Risk assessed as some concerns for the outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. |
Missing outcome data |
Some concerns |
Comment: 2264 participants randomized; 2260 participants analyzed for safety; 1983 participants analyzed for efficacy; 243 participants analyzed for immunogenicity.
SAFETY AND MORTALITY: Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality. Adverse events. Serious adverse events. IMMUNOGENICITY: Data not available for all or nearly all participants. No evidence that the result is not biased. Some reasons for missingness were protocol violations that were accounted for in domain 2; most reasons for missingness were due to use of a subset of participants selected using a simple random-sample selection procedure or due to no valid and determinate immunogenicity result from a blood sample obtained within 28 to 42 days after dose 2. Missingness due to no valid immunogenicity result could depend on the true value of the outcome; it was not reported how many participants were excluded for that reason. Risk assessed to be some concerns for the outcome: Neutralizing antibody GMTs. EFFICACY Data not available for all or nearly all participants. The large majority of reasons for missingness were protocol violations that were accounted for in domain 2. Risk assessed to be low for the outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. |
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: Confirmed symptomatic COVID-19. Severe or critical COVID-19. All-cause mortality. Neutralizing antibody GMTs. Adverse events. Serious adverse events. |
Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan and prospective registry (first posted online 30 April 2021) were available.
All outcomes were listed in the protocol. 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: Confirmed symptomatic COVID-19. Severe or critical COVID-19. All-cause mortality. Neutralizing antibody GMTs. Adverse events. Serious adverse events. |
Overall risk of bias |
Some concerns |