Statistical analysis
HEPATITIS B, PERTUSSIS, PERTUSSIS, SECONDARY, HEP B, HEPATITIS B
For HepB, non-inferiority testing was based on the use of the two-sided 95% confidence interval (CI) of the difference of proportions of subjects with an anti-HBs Ab concentration ≥ 10 mIU/mL at day 84. The 95% CI of the difference was calculated using Wilson score method without continuity correction. Hepatitis B non-inferiority was considered demonstrated if the lower limit of the 95% CI of the difference of the two proportions (investigational formulation minus licensed formulation) was greater than minus 10%.For pertussis, non-inferiority testing was based on the use of aGMCs and their 95% CI, on both PT and FIM results. Adjusted GMCs were computed using analysis of covariance to adjust for baseline disparities and considering the correlation between pre- and post-vaccination concentration (log10-transformed), through an ANCOVA model using the pre-vaccination (day 0) concentration as a covariate for adjustment and the vaccine group. The 95% CI of ratio between vaccine groups aGMCs was calculated using normal approximation of the mean of log10-concentration. Pertussis non-inferiority was considered if the lower limits of the 95% CI of the ratio of adjusted GMCs for PT and for FIM antibodies were above 0.5 (less than a 2-fold reduction). Overall non-inferiority was concluded if both the pertussis (both PT and FIM) and Hep B non-inferiorities were demonstrated.Descriptive statistics were produced for each secondary endpoint. The safety and immunogenicity parameters were described with their 95% CI. Immunogenicity endpoints were summarized by vaccine groups and by time-points (pre and post primary series vaccination). For descriptive safety analyses, percentages were presented with their 95% CI (Clopper-Pearson method).The sample size was calculated based on primary study objectives, with an alpha level of 2.5% (one-sided hypotheses), a 10% non-inferiority clinical margin for the hepatitis B responses, a 2-fold decrease clinical margin for aGMC (aGMC ratio higher than 0.5) for pertussis responses (PT and FIM) and an assumption that 85% of enrolled subjects would fulfil the Per Protocol definitions in each group. Based on simulations, testing the null hypothesis on pertussis responses with a power of 91.5% (on aGMCs at Day 84), and assuming observed standard deviations of log10 (aGMCs) of 0.75 and 0.85, respectively on PT and FIM results, required a total of 195 evaluable subjects in each group. With such a sample size and an assumption of 95% of subjects with an anti-HBs Ab concentration ≥10 mIU/mL at D84, the power to demonstrate non-inferiority on HepB was 98.4% (using the Farrington and Manning method) meaning that the overall power of the trial was at least 90%. Considering a 15% of subjects non-evaluable at D84, a total of 460 subjects was included in the trial to reach the primary objective with an overall power of at least 90%.The primary immunogenicity analyses (non-inferiority testing) were performed on the per-protocol analysis set (PPAS) and confirmed on the full analyses set (FAS). The FAS was defined as the subset of enrolled subjects who received at least 1 dose of the study vaccines. The PPAS was defined as a subset of the FAS and comprised all subjects who had received the study vaccine and complied with all protocol-specified requirements and procedures. The secondary immunogenicity descriptive analyses were also performed on PPAS and FAS. In the FAS, subjects were analyzed by the vaccine group to which they were randomized. The safety analysis was performed on the safety analysis set (SafAS). The SafAS was defined for each stage of the trial as those subjects who have received at least 1 dose of the study vaccines. Subjects were analyzed after each dose according to the vaccine they received and after any dose according to the vaccine received at the first dose.The statistical analysis was conducted under the responsibility of Sanofi with SAS software, Version 9.4 (SAS Institute, Cary, NC, USA).