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: "Vaccine and placebo were randomized at a 1:1 ratio and all sites accessed the same randomization lists through an IWRS provided by Cenduit (Durham, NC, USA)."
Comment: Allocation sequence random. Allocation sequence concealed. Minor imbalances in baseline characteristics appear to be compatible with chance. Risk assessed to be low. |
| Deviations from intervention |
Some concerns |
Quote: "Participants and all other study staff as well as monitors, lab technicians, and data management team remained unaware of the product allocation"
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 outcomes: Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. 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 these safety outcomes, 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-19. C Confirmed severe or critical COVID-19. 65 [1.0%] vs. 74 [1.2%] participants were excluded due to protocol violations, reasons for exclusions: Not eligible (0 vs. 1), Received 3rd dose or incorrect injection (11 vs. 8), Out of window for per-protocol analysis (54 vs. 65). 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 balance of the exclusions between arms. Risk assessed to be some concerns for the outcomes: Confirmed symptomatic COVID-19. Confirmed severe or critical COVID-19. |
| Missing outcome data |
Low |
Interim analysis.
Comment: 12,408 participants randomized; 12,396 participants analyzed for safety; 9823 participants analyzed for efficacy. SAFETY Data available for nearly all participants randomized for safety. Risk assessed to be low for the outcomes:Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. EFFICACY Data available for nearly all participants randomized for the oucome: Mortality Risk assessed to be low for the outcome: Mortality Data not available for all or nearly all participants randomized for the outcomes: Confirmed symptomatic COVID-19. Confirmed severe or critical COVID-19. 21% missing data. No evidence that the result is not biased. 1% (n=139) of the missing data were due to protocol violations described and accounted for in risk of bias domain 2. 20% (n=2446) of the missing data were due to the following reasons: Did not receive any injection (6 vs. 6), Did not receive dose 2 (711 vs. 751), Discontinued before 14 days after dose 2 (1 vs. 0), reported positive SARS-CoV-2 PCR test or COVID-19 cases prior to monitoring period (43 vs. 87), Did not enter case monitoring period at the data cutoff date (422 vs. 419). Most reasons for missingness were either due to the fact that this was an interim analysis and participants had not yet received a second dose or entered the monitoring period; missingness could not depend on the true value of the outcome. Risk assessed to be low for the outcomes: Confirmed symptomatic COVID-19. Confirmed severe or critical COVID-19. |
| 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. Severe or critical COVID. All-cause mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The prospective protocol, statistical analysis plan, and registry were available (24-Aug-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. Severe or critical COVID-19. All-cause mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |