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: “stratified (block size 4) interactive web response system (IWRS) randomisation” "The statistician generated a sequence, according to which the drug was labelled. The drug and placebo were outwardly indistinguishable (packaging, label, and content). Investigators, participants, and all study staff were masked to group assignment."
Comment: 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: “Investigators, participants, and all study staff were masked to group assignment.”
Comment: Blinded study (participants, personnel/carers). EFFICACY and SAFETY Patients were excluded from analysis due to protocol violations such as vaccine administration error, not meeting eligibility criteria, receipt of other vaccines, error in date of second dose, skipped visits. As we are assessing the effect of assignment to intervention (intention-to-treat effect), we considered that the data were analyzed inappropriately. There was no substantial impact of failure to analyze participants according to their randomized assignment due to the small number. Risk assessed to be some concerns for the outcomes: Confirmed symptomatic COVID-19. Confirmed severe COVID-19. All-cause mortality. Cellular response. Neutralizing antibody GMT. Specific antibody GMT. Serious adverse events. IMMUNOGENICITY Not all participants were included in immunogenicity analyses because only a subsample were tested for logistical reasons in line with prospective registry. 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 all randomized assignment. Risk assessed to be some concerns for the outcomes: Cellular response. Neutralizing antibody GMT. Specific antibody GMT. Serious adverse events. |
| Missing outcome data |
Low |
Comment: Data from interim analysis.
21,977 participants randomized; 21,862 participants analyzed for safety. 19,866 participants analyzed for efficacy. EFFICACY and SAFETY Data available for >95% of population for safety and for 90% for efficacy outcomes. No evidence that the result is not biased. Patients were excluded because they violated the protocol or had not received the second dose and the bias had been taken into account in domain 2. Hence missingness was considered unrelated to the true value of the outcome. Risk assessed to be low for the outcomes: Confirmed symptomatic COVID-19. Confirmed severe COVID-19. All-cause mortality. Serious adverse events. IMMUNOGENICITY 58 to 456 participants were analyzed for immunogenicity outcomes. Immunogenicity data available for 0.3-2% of participants. No evidence that the result is not biased. Not all participants were included in immunogenicity analyses because only a subsample were tested for logistical reasons in line with prospective registry (this bias was addressed in domain 2). However, an even smaller sample than planned was reported, probably because this was an interim analysis. Hence, missingness is likely unrelated to the outcome. Risk assessed to be low for the outcomes: Specific antibody GMT. Neutralizing antibody GMT. Cellular response. |
| Measurement of the outcome |
Low |
Comment: Appropriate method of measuring the outcomes.
Measurement or ascertainment of outcomes does not differ between groups. Blinded study (outcome assessor). Risk assessed to be low for the outcomes: Confirmed symptomatic COVID-19. Confirmed severe COVID-19. All-cause mortality. Specific antibody seroconversion GMT. Neutralizing antibody GMT. Cellular response. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The prospective trial registry was available (August 28, 2020).
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. Confirmed severe COVID-19. All-cause mortality. Specific antibody GMT. Neutralizing antibody GMT. Cellular response. Serious adverse events. |
| Overall risk of bias |
Some concerns |