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 |
Published report: "Participants were randomly assigned in a 1:1 ratio, through the use of a centralized interactive response technology system, to receive vaccine or placebo. Assignment was stratified, on the basis of age and Covid-19 complications risk criteria, into the following risk groups: persons 65 years of age or older, persons younger than 65 years of age who were at heightened risk (at risk) for severe Covid-19, and persons younger than 65 years of age without heightened risk (not at risk)."
Sponsor Briefing: "The randomization will be in a blinded manner using a centralized Interactive Response Technology (IRT), in accordance with pregenerated randomization schedules" (protocol) Comment: Allocation sequence random. Allocation sequence concealed. Minor imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: "The investigator, study staff, study participants, site monitors, and Sponsor personnel (or its designees) will be blinded to the IP administered until study end" (protocol) “Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor” (registry)
Comment: Blinded study (participants, personnel, investigators). 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 outcomes: Mortality. Local adverse events. Systemic adverse events. Unsolicited adverse events. Withdrawals due to adverse events. Serious adverse events. Per-protocol analysis was performed on the efficacy outcomes (as planned in the trial protocol). Reasons for exclusions were balanced between treatment groups (1076 [7.1%] vs 1137 [6.8%]), with the majority of those excluded due to positive or unknown baseline SARS-CoV-2 status (631 vs 572). Other reasons: DID not receive any injection (29 vs 40), Received an incorrect injection (6 vs 7), Discontinued without receiveing second dose (168 vs 231), Received dose 2 out of dose 2 window (93 vs 109), Did not receive dose 2 or were out of window for per-protocol analysis (138 vs 154), Other major protocol deviation (11 vs 24). As we are assessing the effect of assignment to intervention (intent-to-treat effect), this domain was evaluated as some concerns for the efficacy outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. |
| Missing outcome data |
Low |
Comment: Data from interim analysis. 30,420 participants randomized; 29,235 to 30,351 participants analyzed for safety outcomes; 28,207 participants analysed for efficacy outcomes. Data available for >95% of population for safety outcomes. Data were available for 93% of efficacy population where most patients were excluded because the planned analysis was a per-protocol analysis and the bias had been taken into account in domain 2. Risk assessed to be low for outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. Mortality. Local adverse events. Systemic adverse events. Unsolicited adverse events. Withdrawals due to adverse events. Serious adverse events. |
| Measurement of the outcome |
Low |
Quote: “Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor” (registry) "COVID-19 Cases were adjudicated by a blinded committee" Comment: Blinded study (outcome assessor). Risk assessed to be low for the outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. Mortality. Local adverse events. Systemic adverse events. Unsolicited adverse events. Withdrawals due to adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol and registry were available. Results were not selected from multiple outcome measurements or analyses of the data. Trial analyzed appropriately for an interim analysis. Risk assessed to be low for the outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. Mortality. Local adverse events. Systemic adverse events. Unsolicited adverse events. Withdrawals due to adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |