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. Study No.: 113954 (DTPa-HBV-IPV-126 BST:031) Title: Antibody persistence and immune memory against the hepatitis B antigen in 11-12 year old children, previously vaccinated with DTPa-HBV-IPV/Hib vaccine in study 217744/031. Infanrix hexa (DTPa-HBV-IPV/Hib): GlaxoSmithKline (GSK) Biologicals combined diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus and Haemophilus influenzae type b conjugate vaccine. Rationale: The aim of the study was to evaluate the long-term persistence of antibodies against hepatitis B and the immune response to a hepatitis B vaccine challenge in healthy children aged 11-12 years, previously vaccinated with DTPa-HBV- IPV/Hib vaccine or GSK Biologicals DTPa-IPV/Hib and HBV vaccines at the ages of 3, 5 and 11 months. Infanrix -IPV+Hib (DTPa-IPV/Hib): GSK Biologicals combined diphtheria, tetanus, acellular pertussis, inactivated poliovirus and Haemophilus influenzae type b conjugate vaccine. Engerix -B Kinder (HBV): GSK Biologicals hepatitis B vaccine. Phase: IV Study Period: 07 June 2010 to 26 November 2010 Study Design: Open-label, multicentre single country study with 2 parallel groups. Centres: 12 centres in Slovakia. Indication: Immunisation against hepatitis B Treatment: The study groups were as follows: received 3 doses of DTPa-HBV-IPV/Hib vaccine in the primary study and a challenge dose of HBV vaccine in this study. received 3 doses of DTPa-IPV/Hib and HBV vaccines in the primary study and a challenge dose of HBV vaccine in this study. The vaccine was administered as a single dose intramuscularly into the deltoid region of the non-dominant arm. Objectives: To assess the anti-hepatitis B (anti-hbs) antibody response to a challenge dose of HBV vaccine in subjects aged 11-12 years, vaccinated in infancy with 3 doses of DTPa-HBV-IPV/Hib or HBV vaccines at 3, 5 and 11 months of age Primary Outcome/Efficacy Variable: Anti-HBs antibody concentrations one month after a challenge dose of HBV vaccine: Percentage of subjects with anti-hbs antibody concentrations 100 miu/ml. Secondary Outcome/Efficacy Variable(s): Persistence and immune response to the study vaccine. Percentage of subjects with an anamnestic response* to a challenge dose. Anti-HBs antibody concentrations 3.3 miu/ml, 10 miu/ml, and 100 miu/ml before and one month after a challenge dose of HBV vaccine. Solicited local and general symptoms. Occurrence of solicited local symptoms during the 4-day (Day 0-3) follow-up period after a challenge dose of HBV vaccine. Occurrence of solicited general symptoms during the 4-day (Day 0-3) follow-up period after a challenge dose of HBV vaccine. Unsolicited adverse events (AEs). Occurrence of unsolicited symptoms during the 31-day (Day 0-30) follow-up period after a challenge dose of HBV vaccine. Serious adverse events (SAEs). Occurrence of SAEs after the challenge dose of HBV vaccine up to the study end. *Please refer to the Statistical Methods section for the definition of an anamnestic response Statistical Methods: The analyses were performed on the Total Vaccinated Cohort and the According-To-Protocol (ATP) cohort for Immunogenicity. The Total Vaccinated cohort included all subjects who received the challenge dose of HBV vaccine. The ATP cohort for analysis of immunogenicity included all evaluable subjects (i.e. those meeting all eligibility criteria, complied with the procedures defined in the protocol, with no elimination criteria met during the study) who had received
a challenge dose HBV vaccine and for whom immunogenicity data were available at the post-hbv challenge time point. Analysis of Immunogenicity: The analysis was performed on the ATP cohort for analysis of immunogenicity. For each group, prior to and one month after the challenge dose of HBV vaccine, the percentages of subjects with anti-hbs antibody concentrations 6.2 miu/ml, 10 miu/ml, between 10 miu/ml and < 100 miu/ml and 100 miu/ml and GMCs were calculated with 95% confidence interval (CI) The percentage of subjects with anamnestic response* was tabulated with 95% CI for each group and according to the prevaccination status of the subjects (< 6.2 miu/ml, 6.2 - <10 miu/ml, 10 miu/ml). *The anamnestic response was defined as At least (i.e. greater than or equal to) a 4-fold rise in post-challenge dose anti-hbs antibody concentrations in subjects seropositive** at the pre-challenge dose time point. Post-challenge dose anti-hbs antibody concentrations 10 miu/ml in subjects seronegative*** at the pre-challenge dose time point. **A seropositive subject is a subject with anti-hbs antibody concentration 6.2 miu/ml ***A seronegative subject is a subject with anti-hbs antibody concentration < 6.2 miu/ml. Analysis of Safety The analysis was performed on the Total Vaccinated cohort. The percentages of subjects reporting each individual local and general solicited symptom during the 4-day (Day 0 to Day 3) follow-up period after the challenge vaccination were tabulated with exact 95% CI, per group. The same tabulation was performed for grade 3 solicited symptoms and for solicited general symptoms assessed by the investigator as causally related to the study vaccination. The percentage of subjects with at least one report of unsolicited AE classified by the Medical Dictionary for Regulatory Activities (MedDRA) and reported within the 31-day (Day 0 to Day 30) follow-up period after the challenge vaccination was tabulated with exact 95% CI, per group. The occurrence of SAEs during the entire study period was tabulated according to MedDRA preferred terms. Study Population: Healthy male or female subject aged 11-12 years at the time of study entry (from and including the 11th birthday until and excluding the 13th birthday), who received all 3 doses of DTPa-HBV-IPV/Hib or DTPa-IPV/Hib and HBV vaccines in the primary study and who did not receive any hepatitis B (containing) vaccine since then. Written informed consent was obtained from the parents/guardians of the subject. Number of subjects Planned, N 135 129 Randomised, N (Total Vaccinated Cohort) 95 90 Completed, n (%) 95 (100) 90 (100) Total Number Subjects Withdrawn, n (%) 0 (0.0) 0 (0.0) Withdrawn due to Adverse Events, n (%) 0 (0.0) 0 (0.0) Withdrawn due to Lack of Efficacy, n (%) Not applicable Not applicable Withdrawn for other reasons, n (%) 0 (0.0) 0 (0.0) Demographics N (Total Vaccinated Cohort) 95 90 Females:Males 45:50 35:55 Mean Age, years (SD) 11.3 (0.46) 11.3 (0.47) Race, n (%) Not available Not available Primary Efficacy Results: Anti-HBs seropositivity rate, seroprotection rates and percentage of subjects with antibody concentrations equal to or above the specified cut-off values (ATP cohort for Immunogenicity) 6.2 miu/ml 10 miu/ml 10 and <100 miu/ml 100 miu/ml* GMC (miu/ml) 95% CI 95% CI 95% CI 95% CI Value 95% CI
Grou Timi N n % LL UL n % LL UL n % LL UL n % LL UL LL UL p ng HBV I PRE -C 95 53 55.8 45.2 66.0 46 48.4 38.0 58.9 32 33.7 24.3 44.1 14 14.7 8.3 23.5 13.5 9.7 18.7 POS 94 92 97.9 92.5 99.7 91 96.8 91.0 99.3 3 3.2 0.7 9.0 88 93.6 86.6 97.6 2528.6 1572.1 4067.1 T-C* HBV II PRE -C 89 57 64.0 53.2 73.9 52 58.4 47.5 68.8 35 39.3 29.1 50.3 17 19.1 11.5 28.8 17.8 12.4 25.4 POS 89 88 98.9 93.9 100 88 98.9 93.9 100 4 4.5 1.2 11.1 84 94.4 87.4 98.2 3815.1 2442.3 5959.5 T-C* Seropositivity = anti-hbs antibody concentration 6.2 miu/ml Seroprotection = anti-hbs antibody concentration 10 miu/ml 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 PRE-C = Pre challenge dose time point POST-C =Post challenge dose time point (one month later) *Primary Outcome Variable Secondary Outcome Variable(s): Anamnestic response to the HBV challenge dose stratified based on the pre-challenge dose status (ATP cohort for immunogenicity) Anamnestic response 95% CI Group Pre-vaccination N n % LL UL status HBV I S- ( <6.2 miu/ml ) 41 38 92.7 80.1 98.5 6.2--<10mIU/mL 7 7 100 59.0 100 10 miu/ml 46 46 100 92.3 100 Total 94 91 96.8 91.0 99.3 HBV II S- ( <6.2 miu/ml ) 32 31 96.9 83.8 99.9 6.2--<10mIU/mL 5 5 100 47.8 100 10 miu/ml 52 50 96.2 86.8 99.5 Total 89 86 96.6 90.5 99.3 Anamnestic response defined as: - For initially seronegative subjects, antibody concentration 10 miu/ml one month after post challenge dose - For initially seropositive subjects: antibody concentration at one month after post challenge dose 4 fold the pre-vaccination antibody concentration N = number of subjects with pre and post challenge dose results available n (%) = number (percentage) of subjects with antibody concentrations above the specified cut-off S- = seronegative subjects (antibody concentration < 6.2 miu/ml) Secondary Outcome Variable(s): Number (%) of subjects with solicited local symptom during the 4-day (Days 0-3) postvaccination period (Total Vaccinated Cohort) 95 % CI 95 % CI Symptom Intensity N N % LL UL N n % LL UL
Pain Any 95 30 31.6 22.4 41.9 90 24 26.7 17.9 37.0 Grade 3 95 1 1.1 0.0 5.7 90 1 1.1 0.0 6.0 Redness Any 95 25 26.3 17.8 36.4 90 22 24.4 16.0 34.6 >50 mm 95 0 0.0 0.0 3.8 90 0 0.0 0.0 4.0 Swelling Any 95 15 15.8 9.1 24.7 90 8 8.9 3.9 16.8 >50 mm 95 0 0.0 0.0 3.8 90 0 0.0 0.0 4.0 N = number of subjects with the documented dose. n (%) = number (percentage) of subjects reporting the symptom at least once Grade 3 pain= pain that prevented normal activity Any = any report of the specified symptom regardless the intensity Secondary Outcome Variable(s): Number (%) of subjects with solicited general symptom during the 4-day (Days 0-3) postvaccination period (Total Vaccinated Cohort) 95 % CI 95 % CI Symptom Intensity/Relationship N N % LL UL N n % LL UL Fatigue Any 95 23 24.2 16.0 34.1 90 22 24.4 16.0 34.6 Grade 3 95 1 1.1 0.0 5.7 90 0 0.0 0.0 4.0 Related 95 12 12.6 6.7 21.0 90 10 11.1 5.5 19.5 Gastrointestinal Any 95 9 9.5 4.4 17.2 90 9 10.0 4.7 18.1 Grade 3 95 0 0.0 0.0 3.8 90 0 0.0 0.0 4.0 Related 95 3 3.2 0.7 9.0 90 5 5.6 1.8 12.5 Headache Any 95 19 20.0 12.5 29.5 90 14 15.6 8.8 24.7 Grade 3 95 1 1.1 0.0 5.7 90 0 0.0 0.0 4.0 Related 95 7 7.4 3.0 14.6 90 3 3.3 0.7 9.4 Temperature/ (Axillary) >37.5 C 95 1 1.1 0.0 5.7 90 3 3.3 0.7 9.4 >39.0 C 95 0 0.0 0.0 3.8 90 0 0.0 0.0 4.0 Related 95 0 0.0 0.0 3.8 90 1 1.1 0.0 6.0 N = number of subjects with the documented dose n (%) = number (percentage) of subjects reporting the symptom at least once. Any = any report of the specified symptom regardless of intensity or relationship to vaccination Grade 3 symptom = symptom that prevented normal activity Related = general symptom assessed by the investigator to be causally related to the study vaccination Safety Results: Number (%) of subjects with unsolicited adverse events during the 31-day (Day 0-30) follow-up period after the challenge dose (Total Vaccinated Cohort) Most frequent adverse events - On-Therapy (occurring within Day 0-30 following vaccination) Subjects with any AE(s), n (%) 5 (5.3) 7 (7.8) Sinusitis 1 (1.1) 1 (1.1) Tonsillitis 1 (1.1) 1 (1.1) Bronchitis 1 (1.1) - Conjunctivitis 1 (1.1) - Erythema infectiosum - 1 (1.1) Headache 1 (1.1) - Infection 1 (1.1) - Laryngitis - 1 (1.1) Otitis media - 1 (1.1) Rhinitis - 1 (1.1) Tracheitis - 1 (1.1) Urticaria 1 (1.1) - Varicella - 1 (1.1) - : Adverse event absent Safety results: Number (%) of subjects with serious adverse events during the entire study period (Total Vaccinated cohort) Serious adverse event, n (%) [n considered by the investigator to be related to study medication]
All SAEs Subjects with any SAE(s), n (%) [n assessed by the investigator as related] 1 (1.1) [0] 0 (0.0) [0] Infection 1 (1.1) [0] 0 (0.0) [0] Fatal SAEs Subjects with fatal SAE(s), n (%) [n assessed by the investigator as related] 0 (0.0) [0] 0 (0.0) [0] Conclusion: One month after the administration of a challenge dose of HBV vaccine, 93.6% of subjects in and 94.4% of subjects in, who received DTPa-HBV-IPV/Hib vaccine or DTPa-IPV/Hib and HBV vaccine in the primary study, respectively, had anti-hbs antibody concentration 100 miu/ml. At least one unsolicited AE was reported for 5 (5.3%) and 7 (7.8%) subjects in HBV I and s, respectively, during the 31-day follow-up period after vaccination. One SAE was reported during the course of the study in the ; it was assessed by the investigator as not related to vaccination. No fatal SAEs were reported during the entire study period. Date updated: 16-January-2014