Trial NCT05049226
Publication Niyomnaitham S, medRxiv, 2022
Primary outcome on the report: 1) IgG levels against Anti-S RBD, at baseline, 28, 60 and 90 days after the third-dose/booster; 2) functional (neutralizing) humoral immune response, elicited by each regimen was also assessed by the PNA at baseline, 28, and 90 days post-third dose; 3) Third-dose vaccination safety and tolerability were evaluated at different intervals.

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
Some concerns 		Quote: “Prospective, multi-centre, randomized, observer-blinded Phase 2 study.”
Comment: Allocation sequence probably random.
No information on allocation concealment.
Imbalances in baseline characteristics appear to be compatible with chance.
Deviations from intervention
Some concerns 		Quote: “Observer blinded” “Double (Participant, Investigator)”
Comment: Blinded study (participants and personnel/carers).

MORTALITY, LOCAL ADVERSE EVENTS, SERIOUS ADVERSE EVENTS
Safety analyses included all randomized participants with at least one vaccination dose.
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. Serious adverse events.

NEUTRALIZING SEROCONVERSION RATE, NEUTRALIZING SEROCONVERSION RATE (>90D), NEUTRALIZING ANTIBODY GMT, NEUTRALIZING ANTIBODY GMT (>90D), NEUTRALIZING SEROCONVERSION RATE OMICRON, NEUTRALIZING ANTIBODY GMT OMICRON
Per-protocol analysis was performed on the immunogenicity outcomes.
Reasons for exclusion: nAb was only measured in a subgroup of participants.
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 between groups (sAb, nAb).
Risk assessed to be some concerns for the outcomes:Neutralizing seroconversion rate. Neutralizing seroconversion rate (>90 days) Neutralizing antibody GMT. Neutralizing antibody GMT (>90 days). Neutralizing seroconversion rate Omicron. Neutralizing antibody GMT Omicron.
Missing outcome data
Low 		Comment: 1243 participants randomized; 1243 participants analyzed for safety; 396-1233 participants analyzed for immunogenicity.

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

NEUTRALIZING SEROCONVERSION RATE, NEUTRALIZING SEROCONVERSION RATE (>90D), NEUTRALIZING ANTIBODY GMT, NEUTRALIZING ANTIBODY GMT (>90D), NEUTRALIZING SEROCONVERSION RATE OMICRON, NEUTRALIZING ANTIBODY GMT OMICRON
Data not available for all or nearly all participants randomized for immunogenicity.
No evidence that the result is not biased.
Reasons: sAb: COVID-19 infection, receipt of a fourth vaccine dose, immunocompromised state; nAb was only measured in a subgroup of participants.
Missingness could depend on the true value of the outcome.
Not likely that missingness depended on the true value of the outcome.
This potential source of bias has been taken into account in domain 2.
Risk assessed to be low for the outcomes: Neutralizing seroconversion rate. Neutralizing seroconversion rate (>90 days) Neutralizing antibody GMT. Neutralizing antibody GMT (>90 days). Neutralizing seroconversion rate Omicron.
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: Mortality. Neutralizing seroconversion rate. Neutralizing seroconversion rate (>90 days) Neutralizing antibody GMT. Neutralizing antibody GMT (>90 days). Neutralizing seroconversion rate Omicron. Local adverse events. Serious adverse events.
Selection of the reported results
Low 		Comment: The prospective registry was available (dated September 20, 2021).
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: Mortality. Neutralizing seroconversion rate. Neutralizing seroconversion rate (>90 days) Neutralizing antibody GMT. Neutralizing antibody GMT (>90 days). Neutralizing seroconversion rate Omicron. Local adverse events. Serious adverse events.
Overall risk of bias
Some concerns