The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: Combined Reduced Antigen Content Diphtheria, Tetanus, Acellular Pertussis Vaccine Study Number: 106793 (DTPA-HBV-IPV-114) Title: Persistence of hepatitis B antibodies, immunogenicity and safety of GSK Biologicals hepatitis B vaccine Engerix -B Kinder (SKF103860) challenge dose in adolescents vaccinated with four doses of Infanrix hexa (SB217744) during infancy. Engerix -B Kinder (HBV): GlaxoSmithKline (GSK) Biologicals recombinant hepatitis B vaccine Infanrix hexa (DTPa-HBV-IPV/Hib): GSK Biologicals combined diphtheria-tetanus-acellular pertussis-hepatitis B- inactivated poliovirus and Haemophilus influenzae type b vaccine Rationale: The purpose of this study was to evaluate the persistence of antibodies against hepatitis B surface antigen (anti-hbs) concentrations in subjects 12 13 years of age previously vaccinated with four doses of DTPa-HBV-IPV/Hib in the first two years of life, the ability to mount an anamnestic response to the single HBV challenge dose and the safety of the single challenge dose of HBV vaccine. Phase: IV Study Period: 18-Feb-2014 to 23-Sep-2014 Study Design: Open-label, non-randomised, multi-centric, single-country study with a single group. Centres: 12 centres in Germany Indication: Antibody persistence and hepatitis B vaccine challenge in children aged 12 13 years, previously primed and boosted with 4 doses of DTPa-HBV-IPV/Hib vaccine as part of routine vaccination practice in Germany. Treatment: The study group was as follows: : Subjects who were previously primed and boosted with four doses of DTPa-HBV-IPV/Hib in the first two years of life, received a single dose of HBV vaccine. The HBV vaccine was administered intramuscularly into the deltoid of the non-dominant arm. Objectives: To assess the anti-hbs antibody response, in terms of subjects with antibody concentrations 100 miu/ml, to a single challenge dose of HBV vaccine in subjects 12 13 years of age, previously vaccinated with four doses of DTPa- HBV-IPV/Hib in the first two years of life. Primary Outcome Variable(s): Anti-HBs immune response. Anti-HBs antibody concentrations 100 miu/ml, one month after the single challenge dose of HBV vaccine. Secondary Outcome Variable(s): Anti-HBs antibody persistence at 12-13 years of age, after previous vaccination with DTPa-HBV-IPV/Hib. - Anti-HBs antibody concentrations 6.2 miu/ml, 10 miu/ml, 10 to < 100 miu/ml, 100 miu/ml and anti-hbs antibody concentrations before the single challenge dose of HBV vaccine. Anti-HBs immune response. - Anti-HBs antibody concentrations 6.2 miu/ml, 10 miu/ml and anti-hbs antibody concentrations one month after the single challenge dose of HBV vaccine. - Anamnestic response to the single challenge dose of HBV vaccine. Solicited local and general symptoms. - Occurrence of each solicited local and general symptoms during the 4-day (Day 0 3) follow-up period after the single challenge dose of HBV vaccine. Unsolicited Adverse Events (AEs) - Occurrence of unsolicited AEs during the 31-day (Day 0 30) follow-up period after the single challenge dose of HBV vaccine. Serious Adverse Events (SAEs) - Occurrence of SAEs after the single challenge dose of HBV vaccine up to study end. Statistical Methods: - The Analyses were performed on the Total Vaccinated cohort, the According-to-Protocol (ATP) cohort for immunogenicity and The ATP cohort for analysis of antibody persistence - The Total Vaccinated cohort included all subjects with documented administration of the study vaccine. - The ATP cohort for immunogenicity included all subjects who meet all eligibility criteria, who complied with the procedures and intervals defined in the protocol, who did not meet any of the elimination criteria during the study,
for whom post-vaccination immunogenicity results were available. - The ATP cohort for analysis of antibody persistence included all subjects who were aged 12-13 years at the time of enrolment, who have not received any additional dose of hepatitis B vaccine other than four doses of DTPa- HBV-IPV/Hib during first two years of life, with no evidence of hepatitis B infection or disease, for whom the serological results were available. Analysis of Immunogenicity: The analysis of immunogenicity was performed on the According to Protocol (ATP) cohort for immunogenicity and The ATP cohort for analysis of antibody persistence Seropositivity rates at pre-vaccination and one month post challenge dose time points were calculated with exact 95% CIs for anti-hbs antibody concentrations. GMCs at pre-vaccination and one month post challenge dose time points were tabulated with 95% CIs for anti-hbs antibody concentrations. Anamnestic Response to the challenge dose for Anti-HBs antibodies at one month post challenge dose was calculated with exact 95% CIs. Analysis of Safety : The analysis of safety was performed on the Total Vaccinated cohort. The percentages of subjects reporting each individual local and general solicited symptom within the 4-day (Days 0-3) following vaccination were tabulated, with exact 95% CI. The same tabulation was performed for grade 3 solicited symptoms and for general solicited symptoms assessed by the investigator as causally related to the study vaccine. The percentage of subjects with unsolicited AEs, classified by the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms, within the 31-day (Days 0-30) following vaccination was tabulated. The percentage of subjects with SAEs, classified by MedDRA preferred terms, was tabulated for the entire study period. Study Population: Healthy male or female subjects between, and including, 12 and 13 years of age at the time of the vaccination were included in the study. Subjects were excluded from the study if they received any investigational or nonregistered product other than the study vaccine(s) within 30 days preceding the booster dose, or planned receiving during the study period. Written informed consent obtained from the parent(s)/lar(s) of the subjects. Number of Subjects: Planned, N 300 Randomised, N (Total Vaccinated cohort) 300 Completed, n (%) 300 (100) Total Number Subjects Withdrawn, n (%) 0 (0.0) Withdrawn due to Adverse Events, n (%) 0 (0.0) Withdrawn due to Lack of Efficacy, n (%) 0 (0.0) Withdrawn for other reasons, n (%) 0 (0.0) Demographics N (Total Vaccinated cohort) 300 Females, n (%) 150 (50.0) Males, n (%) 150 (50.0) Mean Age, years (SD) 12.3 (0.5) Median 12 Minimum, Maximum 11, 14 White - Caucasian / European Heritage, n (%) 297 (99.0) Primary Outcome Results: Seropositivity rates, percentage of subjects with 10mIU/mL, 100mIU/mL and GMCs with 95%CI for anti-hbs antibody concentrations at one month post challenge dose time point (ATP cohort for analysis of immunogenicity) S+ 10 miu/ml 100 miu/ml GMC 95% CI 95% CI 95% CI 95% CI Group Timing N n % LL UL n % LL UL n % LL UL Value LL UL HBV Pre 291 203 69.8 64.1 75.0 176 60.5 54.6 66.1 61 21.0 16.4 26.1 22.4 18.2 27.5 Post 289 283 97.9 95.5 99.2 282 97.6 95.1 99.0 272 94.1 90.7 96.5 3502.6 2672.0 4591.5
GMC = geometric mean antibody concentration calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with concentration within the specified range S+=Seropositive for anti-hbs antibodies (concentrations above the assay cut-off 6.2 miu/ml) Pre=Blood sampling at pre-challenge dose time point Post=Blood sampling one month after the challenge dose Secondary Outcome Results: Seropositivity rates, percentage of subjects with 10mIU/mL, 10mIU/mL to <100mIU/mL, 100mIU/mL and GMCs with 95%CI for anti-hbs antibody concentrations at pre-challenge dose time point (ATP cohort for analysis of antibody persistence) Group Ti mi ng S+ 10 miu/ml 10 miu/ml to <100 100 miu/ml GMC miu/ml 95% CI 95% CI 95% CI 95% CI 95% CI N n % LL UL n % LL UL n % LL UL n % LL UL val LL UL ue HBV Pre 293 205 70.0 64.4 75.2 178 60.8 54.9 66.4 116 39.6 34.0 45.4 6 21. 16. 26. 22. 18.5 27.9 2 2 6 3 7 GMC = geometric mean antibody concentration calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with concentration within the specified range S+=Seropositive for anti-hbs antibodies (concentrations above the assay cut-off 6.2 miu/ml) =Blood sampling at pre-challenge dose time point Secondary Outcome Results: Anamnestic Response to the challenge dose for Anti-HBs antibodies one month after the challenge dose (ATP cohort for analysis of immunogenicity) Immune response to the challenge dose 95% CI Group Pre-vaccination N n % LL UL status HBV S- 87 80 92.0 84.1 96.7 S+ 200 197 98.5 95.7 99.7 Total 287 277 96.5 93.7 98.3 S-=Seronegative subjects (antibody concentration <6.2 miu/ml for anti-hbs) prior to vaccination S+=Seronegative subjects (antibody concentration 6.2 miu/ml for anti-hbs) prior to vaccination Total=Subjects either seropositive or seronegative at pre-vaccination Challenge dose response is defined as: For initially seronegative subjects antibody concentration greater than or equal to 10mIU/mL For initially seropositive subjects antibody concentration at least four times the pre-challenge antibody concentration N=Number of subjects with both pre- and post vaccination results available n/%=number/percentage of responders Secondary Outcome Results: Number(%) of subjects reporting solicited local symptoms during the 4-day (Days 0-3) post-vaccination period (Total vaccinated cohort) 95 % CI Symptom Intensity N n % LL UL Pain Any 300 132 44.0 38.3 49.8 Grade 3 300 1 0.3 0.0 1.8 Redness Any 300 70 23.3 18.7 28.5 >50 mm 300 0 0.0 0.0 1.2 Swelling Any 300 29 9.7 6.6 13.6 >50 mm 300 2 0.7 0.1 2.4
N = number of subjects with the documented dose n/% = number/percentage of subjects reporting the symptom at least once 95%CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit Any = all reports of the specified symptom irrespective of intensity grade and relationship to vaccination Grade 3 For Pain= Severe: Significant pain at rest. Prevents normal every day activities. Grade 3 For Redness/Swelling: >50mm Secondary Outcome Results: Number(%) of subjects reporting solicited general symptoms during the 4-day (Days 0-3) post-vaccination period (Total vaccinated cohort) 95 % CI Symptom Intensity/ N n % LL UL relationship Fatigue Any 300 73 24.3 19.6 29.6 Grade 3 300 6 2.0 0.7 4.3 Related 300 41 13.7 10.0 18.1 Gastrointestinal Any 300 34 11.3 8.0 15.5 Grade 3 300 4 1.3 0.4 3.4 Related 300 14 4.7 2.6 7.7 Headache Any 300 71 23.7 19.0 28.9 Grade 3 300 7 2.3 0.9 4.7 Related 300 40 13.3 9.7 17.7 Temperature/(Axillary) 37.5 C 300 7 2.3 0.9 4.7 >39.0 C 300 0 0.0 0.0 1.2 Related 300 4 1.3 0.4 3.4 N = number of subjects with the documented dose n/% = number/percentage of subjects reporting the symptom at least once 95% CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit Any: all reports of the specified symptom irrespective of intensity grade Grade 3 symptom: symptom that prevented normal activity Related: symptom assessed by the investigator as related to vaccination. Safety Results: Number (%) of subjects with AEs within the 31-day (Days 0-30) post-vaccination period (Total vaccinated cohort) Most frequent adverse events - On-Therapy (occurring within day 0-30 following vaccination) N = 300 Subjects with any AE(s), n (%) 44 (14.7) Upper respiratory tract infection 10 (3.3) Contusion 4 (1.3) Cough 3 (1.0) Gastroenteritis 3 (1.0) Headache 3 (1.0) Nasopharyngitis 3 (1.0) Abdominal pain upper 2 (0.7) Dislocation of vertebra 2 (0.7) Pyrexia 2 (0.7) Rash 2 (0.7) Rhinitis 2 (0.7) Seasonal allergy 2 (0.7) Vertigo 2 (0.7) Counting rule applied: As there were more than 30 subjects per treatment group and 3 groups, only the 10 most frequent events in each treatment group are to be listed. -: Implies that adverse event was not reported in the particular group or that the adverse event was reported in the particular group but did not fall within the pre-defined counting rule of 10 most frequent events for that group. Safety Results: Number (%) of subjects with SAE(s) reported during the entire study period (Total Vaccinated cohort)
Serious Adverse Events, n (%) [n assessed by the investigator to be related to study medication] All SAEs N = 300 Subjects with any SAE(s), n (%) [n related] 2 (0.7) [0] Contusion 1 (0.3) [0] Forearm fracture 1 (0.3) [0] Fatal SAEs Subjects with fatal SAE(s), n (%) [n related] 0 (0.0) [0] Conclusions: One month after the single challenge dose of HBV vaccine, 94.1% of the subjects had anti-hbs concentrations 100 miu/ml. The GMC for the respective cut-off was 3502.6 (LL: 2672.0; UL: 4591.5). Unsolicited symptoms were reported for 14.7% of subjects during the 31-day follow-up period. Two SAEs were reported during the study, which were not considered by the investigator to be causally related to the vaccination. No fatal SAEs were reported during the course of the study. Date updated: 24-June-2015