Trial NCT04672395
Publication Bravo L, Lancet, 2022
Primary outcome on the report: Reactogenicity of the vaccine in an embedded phase 2 study, and the efficacy of SCB-2019 against COVID-19 in participants with no previous exposure to SARS-CoV-2 in the phase 3 study. 1) solicited local reactions and systemic adverse events for 7 days after each injection; 2) any unsolicited adverse events up to study day 43 (14 days after the second dose); 3) Safety is being assessed in an ongoing safety follow-up planned for 12 months after the second vaccination in the safety set that includes any participant who received at least one dose of vaccine or placebo; 4) first occurrence of RT-PCR-confirmed COVID-19 of any severity, with onset at least 14 days after the second vaccination

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 Cenduit Interactive Response Technology system (IQVIA, Durham, NC, USA) was used to randomly assign participants (1:1), using a block size of six, to receive two doses of either SCB-2019 or placebo. The randomisation lists were generated by external unmasked statisticians who played no further role in endpoint analyses.”
Comment: 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: “Study staff and the participants were masked to group assignment.”
Comment: Blinded study (participants and personnel/carers)
Data for unsolicited AEs and SAEs were analyzed using modified intention-to-treat analysis (those who received at least one dose). This method was considered appropriate to estimate the effect of assignment to intervention.
Reactogenicity outcomes were analyzed in the embedded Phase 2 population.
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.
Per-protocol analysis was performed on the efficacy outcomes where 8841 [58.6%] vs. 8978 [59.5%] participants were excluded.
Reasons for exclusion: did not receive any injection, baseline seropositive, missing baseline serology, not scheduled to receive a second dose, positive on RT-PCR for COVID-19 before day 14 after the second dose, received other COVID-19 vaccine, randomisation code broken, inclusion criteria deviations, randomisation errors, did not comply with schedule, deviations from pharmacy manual.
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 due to similar proportions and reasons for exclusion in the pre-planned per protocol analysis.
Risk assessed to be some concerns for the outcomes: Confirmed symptomatic COVID. Confirmed severe COVID.
Missing outcome data
Low 		Comment: 30174 participants randomized (1601 in the embedded Phase 2 reactogenicity set); 30128 participants analyzed for safety; 1589 participants analyzed for reactogenicity (Phase 2 reactogenicity set); 12,355 participants analyzed for efficacy.
Data available for all or nearly all participants randomized for safety and the Phase 2 reactogenicity set.
Data not available for all or nearly all participants randomized for efficacy, but this possible risk of bias was taken into account in domain 2.
Risk assessed to be low for the outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. Mortality. Local adverse events. Systemic adverse events. 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: Confirmed symptomatic COVID. Confirmed severe COVID. Mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events.
Selection of the reported results
Low 		Comment: The prospective registry was available.
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: Confirmed symptomatic COVID. Confirmed severe COVID. Mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events.
Overall risk of bias
Some concerns