Trial NCT04796896
Publication Creech CB, N Engl J Med, 2022
Primary outcome on the report: 1. Solicited local and systemic ARs through 7 days after each injection; 2. Unsolicited AEs through 28 days after each injection; 3. MAAEs through the entire study period; 4. SAEs through the entire study period; 5. AESIs, including MIS-C and myocarditis and/or pericarditis, through the entire study period; 6. The proportion of participants with a serum antibody level at day ≥57 antibody threshold of protection; 7. The GM value of serum antibody level and seroresponse rate from Study P204 vaccine recipients at day 57 compared with those from young adult (18≤25 years of age) vaccine recipients (day 57) in the clinical endpoint efficacy trial

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: “Children were randomly assigned with the use of a centralized interactive response technology system, in a 3:1 ratio.”
Comment: Allocation sequence random.
Allocation sequence concealed.
Imbalances in baseline characteristics appear to be compatible with chance.
Deviations from intervention
Some concerns 		Quote: Double-blind. “The trial participants and personnel were unaware of the trial-group assignments until the initiation of unblinding (on the date of the EUA); however, personnel who prepared and administered injections were aware of these assignments.”
Comment: Blinded study (participants and personnel/carers).
Safety analysis included those who received at least one dose of the intervention.
As we are assessing the effect of assignment to intervention, the analysis method performed on these safety outcomes, was considered appropriate.
Per-protocol analysis was performed on the efficacy outcomes.
Reasons for exclusion: Serological or virological evidence of prior SARS-CoV-2 infection at baseline; did not receive both planned injections, or received outside planned timing; major protocol deviations.
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 relative balance between groups.
Risk assessed to be low for the outcomes: Mortality. Local adverse events. Systemic adverse events. Adverse events.Serious adverse events.
Risk assessed to be some concerns for the outcomes: Confirmed COVID. Confirmed symptomatic COVID.
Missing outcome data
Low 		Comment: 4016 participants randomized; 3497 participants analyzed for efficacy; 3997-4002 participants analyzed for safety.
Data available for all or nearly all participants randomized for safety.
Data not available for all or nearly all participants randomized for efficacy.
No evidence that the result is not biased.
Reasons: Serological or virological evidence of prior SARS-CoV-2 infection at baseline; did not receive both planned injections, or received outside planned timing; major protocol deviations.
This potential source of bias has been taken into account in Domain 2.
Risk assessed to be low for the outcomes: Confirmed COVID. Confirmed symptomatic 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 COVID. Confirmed symptomatic COVID. Mortality. Local adverse events. Systemic adverse events. Adverse events.Serious adverse events.
Selection of the reported results
Low 		Comment: The protocol, statistical analysis plan and prospective registry were available.
Outcomes pre-specified.
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 COVID. Confirmed symptomatic COVID. Mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events.
Overall risk of bias
Some concerns