Trial RPCEC00000347
Publication Toledo-Romani ME, Med, 2022
Primary outcome on the report: Percentage of subjects with seroconversion ≥4-fold the anti-RBD IgG pre-vaccination level. Serum samples were collected on days 0 (baseline) and 56 from all subjects; on days 14 and 70, blood samples were taken from 50% of the participants while samples from the other 50% were collected on days 42 and 84.

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: “Participants were randomly assigned at a 4:4:1 ratio to receive one of the two API batches of SOBERANA 02 or placebo (810 subjects; API 1: 354, API 2: 354 and 102 in the placebo group). Randomization was stratified in four 10-years age subgroups (from 19-29, 30-39, 40-49, 50-59 years), and one 21-years age subgroup (60-80 years).”
Comment: Allocation sequence probably random. No information on allocation concealment.
Imbalances in baseline characteristics appear to be compatible with chance.
Deviations from intervention
Low 		Quote: “Randomized, double blind, placebo controlled phase IIb clinical trial. Vaccine and placebo formulations were visually undistinguishable. All immunological evaluations were performed by external laboratories on blind samples.”
Comment: Blinded study (participants and personnel/carers)
Data for the safety outcomes were analyzed using intention-to-treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention.
Per-protocol analysis was performed on the immunogenicity outcomes.
Reasons for exclusion: losses to follow up who did not receive the designated number of doses.
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 of missing participants.
Risk assessed to be low for the outcomes: Mortality. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events.
Missing outcome data
Some concerns 		Comment: 810 participants randomized; 810 participants analyzed for safety outcomes; 752 participants analyzed for immunogenicity outcomes.
Safety data available for all participants randomized.
Risk assessed to be low for the outcomes: Mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events.
Immunogenicity data not available for all or nearly all participants randomized.
No evidence that the result is not biased.
Reasons: 52 (7.3%) vs. 6 (5.9%) did not complete the immunognicity analysis.
Missingness could depend on the true value of the outcome.
Not likely that missingness depended on the true value of the outcome because reasons and proportions for missing data between arms were similar.
Risk assessed to be some concerns for the outcome: Neutralizing antibody GMT.
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 antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events.
Selection of the reported results
Low 		Comment: The prospective registry was available (dated 17 December 2020).
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 outcomes: Mortality. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events.
Overall risk of bias
Some concerns