Trial NCT04551547
Publication Han B, Lancet Infect Dis, 2021
Primary outcome on the report: The primary safety endpoint was adverse reactions within 28 days after each injection in all participants who received at least one dose. The primary immunogenicity endpoint was seroconversion rate at 28 days after the second injection

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: "The randomisation codes for the phase 1 and phase 2 were generated by the randomisation statistician with the method of block randomisation using SAS software (version 9ยท4)."
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: "The vaccine and placebo were completely identical in appearance, and all participants, investigators, and laboratory staff were masked to group allocation"
Comment: Blinded study (participants, personnel, investigators).

LOCAL ADVERSE EVENTS. SYSTEMIC ADVERSE EVENTS. SERIOUS ADVERSE EVENTS.
All randomized participants who received at least one dose were analysed.
As we are assessing the effect of assignment to intervention, the analysis method performed was considered appropriate.
Risk assessed to be low for the outcomes: Adverse events. Serious adverse events.Local adverse events. Systemic adverse events

NEUTRALIZING ANTIBODY GMT
Per-protocol analysis was performed on the outcomes.
Reasons for exclusion: reason for exclusion were not reported by arm. "Seven participants were excluded because one received tetanus immunoglobulin at day 14 after the second dose, five did not have a blood sample taken at 28 days after the second dose, and one took a blood sample outside of the specified time window."
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.
Risk assessed to be some concerns for the outcomes: Neutralizing antibody GMT;
Missing outcome data
Low 		Comment: 552 participants randomized; 550 participants analyzed for safety; 462 participans analyzed for immunogenicity.

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

NEUTRALIZING ANTIBODY GMT
As per protocol, only participants randomized in phase 2 (N=480) were assessed for the immunogenicity outcomes;
Data available for nearly all participants randomized.
Risk assessed to be low for the outcome: Neutralizing antibody GMTs
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: Adverse events. Serious adverse events.Local adverse events. Systemic adverse events. Neutralizing antibody GMT.
Selection of the reported results
Low 		Comment: The prospective trial registry was available (September 16, 2020).
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: Adverse events. Serious adverse events. Local adverse events. Systemic adverse events. Neutralizing antibody GMT.
Overall risk of bias
Some concerns