Trial NCT04796896
Publication Anderson E, N Engl J Med , 2022
Primary outcome on the report: Safety and reactogenicity of mRNA-1273 and to infer efficacy on the basis of the noninferiority of the serum antibody geometric mean concentrations and serologic responses among these children as compared with those among young adults.

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: "Random assignment of participants in part 2 of the study uses a centralized interactive response technology, in accordance with pre-generated randomization schedules."
Comment: Allocation sequence random
Allocation sequence concealed
Imbalances in baseline characteristics appear to be compatible with chance
Deviations from intervention
Some concerns 		Quote: “Part 2 was conducted in an observer-blind manner until emergency use authorization made all participants eligible for unblinding. Until the unblinding trigger, the investigator, study staff, study participants, study site monitors, and Sponsor personnel (or its designees) were blinded to the study vaccine administered, except a limited number of pharmacy personnel, accountable for preparing and administering, managing and documentation of mRNA-1273 (or placebo) to all participants and have no other study functions.”
Comment: Blinded study (participants and personnel/carers)

ALL CAUSE MORTALITY, LOCAL ADVERSE EVENTS, SYSTEMIC ADVERSE EVENTS, ADVERSE EVENTS, SERIOUS ADVERSE EVENTS
The analysis included participants 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.
Risk assessed to be low for the outcomes: Mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events.

CONFIRMED COVID, CONFIRMED SYMPTOMATIC COVID
Per-protocol analysis was performed on the efficacy outcomes.
Reasons for exclusion: 2 mRNA-1273 / 0 placebo participants were excluded due to an adverse event, 5 vs 15 entered open-label trial or crossed over; 0 vs 13 received EUA vaccine outside protocol; 0 vs 2 had a protocol violation and 5 vs 3 had other reason.
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 the small number who discontinued the trial in comparison to the overall n.
Risk assessed to be some concerns for the outcomes: Confirmed COVID. Confirmed symptomatic COVID.
Missing outcome data
Some concerns 		Comment: 4048 participants randomized; at least 3927 participants analyzed for safety outcomes; 3452 (85%) analyzed for efficacy outcomes.

ALL CAUSE MORTALITY, LOCAL ADVERSE EVENTS, SYSTEMIC ADVERSE EVENTS, ADVERSE EVENTS, SERIOUS ADVERSE EVENTS
Data available for all or nearly all participants randomized.
Risk assessed to be low for the outcomes: Mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events.

CONFIRMED COVID, CONFIRMED SYMPTOMATIC COVID
Data not available for all or nearly all participants randomized.
No evidence that the result is not biased.
Reasons: 8 mRNA-1273 / 0 placebo participants were lost to follow up; 2 vs 0 were withdrawn by physician; 46 vs 18 had consent withdrawn; 1 vs 0 had missing data. All other missing participants addressed in ROB 2.
Missingness could depend on the true value of the outcome.
Not likely that missingness depended on the true value of the outcome.
Risk assessed to be some concerns for the outcomes: Confirmed COVID. Confirmed symptomatic COVID.
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, registry were available (dated March 15, 2021).
Outcome 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 outcome: Confirmed COVID. Confirmed symptomatic COVID. Mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events.
Overall risk of bias
Some concerns