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: "Randomisation into vaccine and placebo groups was done on day 0, at a 1:1 ratio in K1 and a 2:1 ratio in K2, using an interactive web response system (Omega-CRO, Ankara, Turkey)."
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: "Participants and practitioners were masked to the group allocation. The masking was removed in the event of a medical emergency requiring acute intervention, upon the responsible investigator's approval and the data and safety monitoring board's knowledge." "the placebo and study vaccine looked exactly the same, they were administered by staff masked to group allocation."
Comment: Blinded study (participants, staff, investigators). SAFETY All randomized participants who received at least one dose were analysed for safety outcomes, except for 4 participants who were excluded from all analyses because of protocol deviations (older than 59 years). 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 was performed on the efficacy outcomes (as planned in the trial protocol). 69 [1%] vs 86 [2.4%] participants were excluded from the efficacy analysis post-randomization because of protocol violations: positive for SARS-CoV-2 (60 [0.9%] 35 [1%]), unmasked before the second dose [due to emergency use authorisation and commencement of community vaccination] (4 [0.06%] vs 45 [1.3%]), received incorrect injection (1 [0.02%] vs 4 [0.1%]), had protocol violations (2 [0.03%] vs 0), pregnant (2 [0.03%] vs 1 [0.03%]), withdrawn by study investigator (0 vs 1 [0.03%]). As we are assessing the effect of assignment to intervention (intent-to-treat effect), this method was considered inappropriate to estimate the effect of assignment to intervention. Although reasons for exclusions were not balanced between treatment groups, there was probably no substantial impact of failure to analyze participants according to their randomized groups since the imbalance was due to unmasking and subsequent vaccination after emergency use authorization. Risk assessed to be some concerns for outcomes: Confirmed symptomatic COVID. Confirmed severe or critical COVID. |
| Missing outcome data |
Low |
Comment: 10218 participants randomized; 10214 participants analyzed for safety; 10029 participants analyzed for efficacy
Data available for nearly all participants randomized. Risk assessed to be low for the outcomes: Confirmed symptomatic COVID. Confirmed severe or critical COVID. Mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| 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. Risk assessed to be low for this outcome. Local adverse events. Systemic adverse events. Risk assessed to be low for this outcome. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol (dated 15 October 2020) and registry (dated 9 October 2020) were available. Although both were dated after study start date (15 September 2020), they were both dated before analysis would have started.
Results were not selected from multiple outcome measurements or analyses of the data. Interim analysis 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 |