Trial NCT04695652
Publication Hsieh SM, Lancet, 2021
Primary outcome on the report: 1) Immediate adverse events, solicited local and systemic adverse events up to 7 days after each injection, unsolicited adverse events up to 28 days after each injection, and any other adverse events, serious adverse events, adverse events of special interest, and vaccineassociated enhanced disease that occurred throughout the study period; 2) neutralising antibody titres on day 1 and day 57 in terms of GMTs, the GMT ratio, and the seroconversion rate; 2) Neutralising antibody titres on day 1 and day 57 in terms of GMTs, the GMT ratio, and the seroconversion rate

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: “Participants were randomly assigned (6:1) to receive either MVC-COV1901 or placebo. Randomisation was done centrally by use of an interactive web response system. The randomisation list by block (size 7 and 14) randomisation, stratified by age (≥20 to <65 years and ≥65 years), was generated by the randomisation biostatistician with unique randomisation identification numbers across all blocks and strata.”
Comment: Allocation sequence random. Allocation sequence concealed.
Imbalances in baseline characteristics appear to be compatible with chance.
Deviations from intervention
Some concerns 		Quote: “Participants and investigators were masked to group assignment. Since MVC-COV1901 and placebo are visually distinct, each trial site was assigned an unmasked study nurse, who was involved in the preparation, dispensing, administration, and accountability of the study intervention, but who had no involvement in the rest of the trial. To ensure that masking was achieved, study-specific training was done at all participating trial sites. Study staff who administered the intervention covered the syringes (physically by hand or with aluminium foil) to ensure participants were masked to the intervention.”
Comment: Blinded study (participants and personnel/carers)
Safety analysis was conducted on 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 immunogenicity outcomes in a pre-planned immunogenicity subset (N = 922 vaccine, 154 placebo).
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 similar and relatively balanced reasons for exclusion between groups (vaccine arm: 10/922 had major protocol deviations, 1/922 withdrew consent, 6/922 were lost to follow-up; 2/922 did not have a valid live virus neutralisation, pseudovirus neutralisation, or anti-spike IgG test result post-study intervention at the interim analysis; placebo arm: 1/154 became pregnant; 1/154 had a major protocol deviation, 2/154 were lost to follow-up).
Risk assessed to be low for the outcomes: Mortality. Local adverse events. Systemic adverse events. Adverse events. Withdrawals due to adverse events. Serious adverse events.
Risk assessed to be some concerns for the outcomes: Specific antibody GMT. Neutralizing antibody GMT.
Missing outcome data
Low 		Comment: 3854 participants randomized; 3844 participants analyzed for safety; 1053 participants analyzed for immunogenicity.
Data available for nearly all participants randomized for safety.
Data not available for all or nearly all participants randomized for immunogenicity.
No evidence that the result is not biased.
Reasons: analysis was performed in a pre-planned immunogenicity subset.
Missingness could not depend on the true value of the outcome.
Potential bias resulting from this has been taken into account in domain 2.
Risk assessed to be low for the outcomes: Mortality. Specific antibody GMT. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Withdrawals due to 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: Mortality. Specific antibody GMT. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Withdrawals due to adverse events. Serious adverse events.
Selection of the reported results
Low 		Comment: The protocol and statistical analysis plan (dated 2 June, 2021), and registry (submitted 31 December, 2020) were available. Outcomes were 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. Specific antibody GMT. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Withdrawals due to adverse events. Serious adverse events.
Overall risk of bias
Some concerns