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.: 100551 (HAB-138 Ext: 028 Y11), 100552 (HAB-139 Ext: 028 Y12), 100553 (HAB-140 Ext: 028 Y13), 100554 (HAB-141 Ext: 028 Y14), 100555 (HAB-142 Ext: 028 Y15) Title: A double blind randomised, comparative study of the immunogenicity and reactogenicity of three different lots of GlaxoSmithKline Biologicals combined hepatitis A - hepatitis B vaccine when administered in healthy adults. Twinrix (HAB): GlaxoSmithKline (GSK) Biologicals combined hepatitis A and hepatitis B vaccine. Havrix (HAV): GSK Biologicals hepatitis A vaccine. Engerix (HBV): GSK Biologicals hepatitis B vaccine. Rationale: The aim of the long-term follow-up (LTFU) study was to evaluate the long-term persistence of humoral immune response from Year 11 to Year 15 after administration of the first dose of HAB vaccine [Study 208127/021 (HAB-028), primary vaccination]. The safety of the study vaccine was also assessed. The summary presents results for the LTFU period at Years 11, 12, 13, 14 and 15. Please refer to the HAB-028 CTRS for results on the primary study and to the 208127/115 & 119 CTRS for results on Months 108 & 120 (Years 9 and 10). Phase: III Study Period: LTFU at Year 11 (HAB-138): 24 November 2004 to 20 December 2004 LTFU at Year 12 (HAB-139): 16 November 2005 to 12 December 2005 LTFU at Year 13 (HAB-140): 10 November 2006 to 11 December 2006 LTFU at Year 14 (HAB-141): 27 September 2007 to 20 December 2007 LTFU at Year 15 (HAB-142): 21 October 2008 to 07 December 2009 Study Design: The long-term follow-up studies were open and self-contained. Centres: Single study centre in Belgium. Indication: Protection of healthy adults between 17 and 39 years of age, against hepatitis A and hepatitis B infection. Treatment: During the primary study (208127/021), the subjects received 3 doses of HAB vaccine (Lot 1, Lot 2 or Lot 3) according to a 0, 1, 6 month schedule. For the data analyses in the LTFU phase, the 3 groups were pooled. If a subject became seronegative for anti-hav (antibodies to hepatitis A virus) antibodies (i.e. concentrations < 15 miu/ml) or lost seroprotective concentrations for anti-hbs (antibodies to hepatitis B surface antigen) antibodies (i.e. concentrations < 10 miu/ml) at any of the long-term blood sampling time points (i.e. Years 11, 12, 13, 14 or 15), he/ she was offered an additional vaccine dose of HAB, HAV or HBV vaccine (administered between 6 to 12 months after the Year 15 time point). This was done in order to assess the immune memory after a primary three-dose schedule of HAB vaccine. The additional vaccine was administered intramuscularly into the deltoid region of the non-dominant arm. Objectives: For the long-term follow-up phase To evaluate anti-hav and anti-hbs antibody persistence at Years 11, 12, 13, 14 and 15 after the first vaccine dose of three-dose primary vaccination. For the additional vaccination phase To evaluate the immune memory 15 years after primary vaccination (with a three-dose vaccination schedule of HAB vaccine) in subjects who became seronegative for anti-hav antibodies (i.e. titres < 15 miu/ml) or lost seroprotective titres for anti-hbs antibodies (i.e. titres < 10 miu/ml) at the long-term blood sampling time point (i.e. Years 11, 12, 13, 14 or 15) and who received additional vaccine dose (administered between 6 to 12 months after the Year 15 time point). Primary Outcome/Efficacy Variable: For the long-term follow-up phase (at Years 11,12, 13, 14 and 15) Antibody persistence against the study vaccine antigens : - Anti-HAV: percentage of seropositive subjects and geometric mean concentrations (GMCs). - Anti-HBs: percentage of seropositive subjects, subjects with anti-hbs concentrations 10 miu/ml and GMCs. For the additional vaccination phase Immune response to the study vaccine antigen, before and one month after the additional vaccination: - Anti-HAV antibody concentrations (after an additional dose with HAV vaccine*). - Anti-HBs antibody concentrations (after an additional dose with HBV vaccine).
Anamnestic response to the additional vaccination. Anamnestic response for anti-hav antibody was defined as: - Anti-HAV antibody concentrations 15 miu/ml at one month post-additional vaccination in subjects, seronegative at the pre-additional vaccination time point. - At least a 2-fold increase in anti-hav antibody concentrations one month after the additional vaccination, in subjects having anti-hav antibody concentrations 100 miu/ml at the pre- additional vaccination time point. - At least a 4-fold increase in anti-hav antibody concentration one month after the additional vaccination, in seropositive subjects having anti-hav antibody concentrations < 100 miu/ml at the pre-additional vaccination time point. Anamnestic response for anti-hbs antibody was defined as: - Anti-HBs antibody concentrations 10 miu/ml at one month post-additional vaccination in subjects seronegative at the pre-additional vaccination time point. - At least a 4-fold increase in anti-hbs antibody concentrations, at one month post-additional vaccination in subjects seropositive at the pre-additional vaccination time point. Serious adverse events (SAEs): - SAEs which the subject experienced since the previous study visit were to be documented only if the SAE was assessed by the investigator to have a causal relationship to primary vaccination. SAEs related to study participation (blood sampling) and any event related to a lack of vaccine efficacy (i.e. hepatitis A infection or hepatitis B infection) were also to be documented. - Occurrence, intensity and relationship to vaccination of all SAEs following the administration of the additional vaccine dose. Outcome variables were not differentiated into primary and secondary in the study protocol, hence all outcome variables were considered as primary outcome variables. Secondary Outcome/Efficacy Variable:. Statistical Methods: The analyses were conducted on the Long-Term (LT) Total Vaccinated Cohort and the LT According-To-Protocol (LT-ATP) cohort for immunogenicity. The LT Total Vaccinated Cohort included all subjects (i.e. subjects who had received at least one dose of the study vaccine in the primary study) who returned for blood sampling at the particular long-term blood sampling time point (Year 11,12, 13, 14 or 15) and for whom serology results were available for anti-hav and/ or anti-hbs antibodies. The LT-ATP cohort for immunogenicity included subjects who returned at a particular blood sampling time point, the LT-ATP immunogenicity cohort (at that time point) included subjects who were included in the ATP immunogenicity cohort in the primary study, for whom serology results were available for that particular blood sampling time point and who were not eliminated either for vaccine administration forbidden in study protocol or for abnormal increase in anti-hav and/ or anti-hbs antibody titres, during the long-term follow-up. The definition of abnormal increase depended on the magnitude of the concentration at the previous time point (reference value). Abnormal increase in antibody concentrations was defined as a two-fold increase or more in antibody concentrations (when the antibody concentration at the reference time point was 100 miu/ml) or a four-fold increase or more in antibody concentrations (when the antibody concentration at the reference time point was < 100 miu/ml). Analysis of immunogenicity: The analysis of immunogenicity was performed on the LT-ATP cohort for immunogenicity. During the primary study, lot-to-lot consistency was demonstrated; therefore the analyses for the LT follow-up were presented for the. At each yearly blood sampling time point, anti-hav & anti-hbs seropositivity* rates and GMCs with their 95% confidence interval (CI) were tabulated; seroprotection** rates for anti-hbs with 95% CI were tabulated. Note: A decrease in the specificity of the anti-hb ELISA assay had been observed in some studies for low levels of antibody (10-100 miu/ml). The table shows updated results following complete retesting and reanalysis. *Seropositivity: for HAV antibodies was defined as antibody concentrations 15 miu/ml. for anti-hbs antibodies was defined as antibody concentrations 3.3 miu/ml for the in-house ELISA and 6.2 miu/ml for the ChemiLuminescence ImmunoAssay (CLIA). **Seroprotection for anti-hbs antibodies was defined as antibody concentrations 10 miu/ml. For subjects who received the additional vaccine dose between 6 to 12 months after Year 15 time point, the immunogenicity response was also tabulated.
Analysis of safety: The analysis of safety was performed on the LT Total Vaccinated Cohort. The occurrence of any SAE which the subject could have experienced since the last study visit was reported if the SAE was assessed by the investigator to have a causal relationship to primary vaccination; SAEs related to study participation (blood sampling) were tabulated. Finally, lack of vaccine efficacy (i.e. hepatitis A or hepatitis B infection) was also reported as SAE. For the additional vaccine dose: For subjects who received the additional vaccine dose between 6 to 12 months after Year 15 time point, the safety results were summarized. Study Population: Healthy male and female subjects between the ages of 17 and 39 years, seronegative for anti-hav, anti-hbs, anti-hepatitis B core antigen (anti-hbc) antibodies and/or hepatitis B surface antigen (HBsAg) at the time of first dose of primary vaccination. Written informed consent was obtained before each blood sampling visit of the LTFU study. Year 11 time point Number of subjects Planned, N Entered, N (LT Total Vaccinated Cohort) 37 Completed, n (%) 37 (100) Total Number Subjects Withdrawn, n (%) 0 (0.0) Withdrawn for other reasons, n (%) 0 (0.0) N (LT Total Vaccinated Cohort) 37 Females: Males 27:10 Mean Age, years (SD) 30.4 (3.08) White/Caucasian, n (%) 37(100) Year 12 time point Number of subjects Planned, N 40 Randomised, N (LT Total Vaccinated Cohort) Completed, n (%) 40 (100) Total Number Subjects Withdrawn, n (%) 0 (0.0) Withdrawn for other reasons, n (%) 0 (0.0) N (LT Total Vaccinated Cohort) 40 Females: Males 29:11 Mean Age, years (SD) 31.4 (2.95) White/Caucasian, n (%) 40 (100) Year 13 time point Number of subjects Planned, N 37 Randomised, N (LT Total Vaccinated Cohort) Completed, n (%) 37 (100) Total Number Subjects Withdrawn, n (%) 0 (0.0) Withdrawn for other reasons, n (%) 0 (0.0) N (LT Total Vaccinated Cohort) 37 Females: Males 28:9 Mean Age, years (SD) 31.9 (1.13) White/Caucasian 37 (100) Year 14 time point
Number of subjects Planned, N 43 Randomised, N (LT Total Vaccinated Cohort) Completed, n (%) 43 (100) Total Number Subjects Withdrawn, n (%) 0 (0.0) Withdrawn for other reasons, n (%) 0 (0.0) N (LT Total Vaccinated Cohort) 43 Females: Males 35:8 Mean Age, years (SD) 33.0 (1.42) White/Caucasian, n (%) 42 (97.7) Year 15 time point Number of subjects Planned*, N 50 Randomised, N (LT Total Vaccinated Cohort) Completed, n (%) 49 (98.0) Total Number Subjects Withdrawn, n (%) 1 (2.0) Withdrawn for other reasons, n (%) 1 (2.0) N (LT Total Vaccinated Cohort) 50 Females: Males 39:11 Mean Age, years (SD) 34.4 (2.66) White/Caucasian, n (%) 48 (96.0) Primary Efficacy Results: Seropositivity rates and GMCs (calculated on seropositive subjects) of anti-hav antibodies (LT ATP cohort for immunogenicity) Group Timing N S+ GMC (miu/ml) n % 95% CI Value 95% CI LL UL LL UL Pooled PIII(M7) 107 107 100 96.6 100 6591 5758 7545 PIII(M18) 86 86 100 95.8 100 1824 1524 2184 PIII(Year 2) 75 75 100 95.2 100 1330 1106 1600 PIII(Year 3) 54 54 100 93.4 100 1383 1094 1748 PIII(Year 4) 49 49 100 92.7 100 1164 934 1451 PIII(Year 5) 43 43 100 91.8 100 905 702 1166 PIII(Year 6) 40 40 100 91.2 100 977 723 1322 PIII(Year 6)* 40 40 100 91.2 100 769.7 568.6 1041.8 PIII(Year 7) 35 35 100 90.0 100 833.0 560.0 1239.2 PIII(Year 8) 35 35 100 90.0 100 597.5 422.7 844.4 PIII(Year 9) 28 28 100 87.7 100 573.0 386.4 849.6 PIII(Year 10) 29 29 100 88.1 100 674.6 455.1 1000.0 PIII(Year 11) 25 25 100 86.3 100 680.3 453.8 1019.9 PIII(Year 12) 28 28 100 87.7 100 602.7 420.8 863.2 PIII(Year 13) 23 23 100 85.2 100 601.5 408.7 885.4 PIII(Year 14) 24 24 100 85.8 100 524.7 368.7 746.5 PIII(Year 15)** 31 31 100 88.8 100 610.7 443.1 841.6 * There was a change of assay kit at Year 7 time point, thus for the sake of bridging, blood samples corresponding to Year 6 were re-tested with the new assay kit. **At Year 15, the ATP cohort was revised due to change in the elimination code based on CLIA N = number of subjects with available results
GMC = geometric mean concentrations calculated on seropositive subjects S+ = seropositivity for anti-hav antibodies defined as: antibody concentrations 33 miu/ml for time points PIII (M7) to PIII(Year 6) antibody concentrations 15 miu/ml for time points PIII (Year 6) to PIII(Year 15) (these cut-off values differ because of a change in assay kit) n (%) = number (percentage) of subjects with antibody concentration within the specified range 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PIII(Mx) = blood sampling after Dose 3, at Month x after first vaccine dose at primary study PIII(Year x) = blood sampling after Dose 3, at Year x after first vaccine dose at primary study Primary Efficacy Results: Seropositivity, seroprotection rates and GMCs, (calculated on seropositive subjects) of anti-hbs antibodies (LT ATP cohort for immunogenicity) # Group Timing N S+ 10 miu/ml GMC (miu/ml) n % 95% CI n % 95% CI Value 95% CI LL UL LL UL LL UL Pooled PIII(M7) 107 107 100 96.6 100 107 100 96.6 100 6601 5023 8675 PIII(M18) 86 86 100 95.8 100 85 98.8 93.7 100 710 511 986 PIII(Year 2) 75 75 100 95.2 100 73 97.3 90.7 99.7 476 331 686 PIII(Year 3) 54 53 98.1 90.1 100 52 96.3 87.3 99.5 383 250 585 PIII(Year 4) 49 48 98.0 89.1 99.9 46 93.9 83.1 98.7 410 255 661 PIII(Year 5) 43 42 97.7 87.7 99.9 40 93.0 80.9 98.5 330 187 584 PIII(Year 6) 40 38 95.0 83.1 99.4 38 95.0 83.1 99.4 322 197 527 PIII(Year 6)* 40 38 95.0 83.1 99.4 38 95.0 83.1 99.4 416.7 264.0 657.6 PIII(Year 7) 35 32 91.4 76.9 98.2 32 91.4 76.9 98.2 391.2 229.2 667.8 PIII(Year 8) 35 32 91.4 76.9 98.2 32 91.4 76.9 98.2 362.8 207.7 633.7 PIII(Year 9) 28 25 89.3 71.8 97.7 25 89.3 71.8 97.7 451.5 262.3 776.9 PIII(Year 10) 29 26 89.7 72.6 97.8 25 86.2 68.3 96.1 320.4 176.6 581.4 PIII(Year 11) 25 23 92.0 74.0 99.0 23 92.0 74.0 99.0 458.9 257.4 817.8 PIII(Year 12) 28 25 89.3 71.8 97.7 25 89.3 71.8 97.7 475.8 284.4 795.9 PIII(Year 13)** 23 20 87.0 66.4 97.2 20 87.0 66.4 97.2 163.3 99.7 267.3 PIII(Year 14) 24 21 87.5 67.6 97.3 21 87.5 67.6 97.3 149.1 94.8 234.5 PIII(Year 14) $ 24 21 87.5 67.6 97.3 21 87.5 67.6 97.3 242.8 127.0 464.3 PIII(Year 15) 31 28 90.3 74.2 98.0 28 90.3 74.2 98.0 210.9 121.5 366.2 * There was a change of assay kit at Year 7 time point, thus for the sake of bridging, blood samples corresponding to Year 6 were re-tested with the new assay kit. **From Year 13 to Year 14, anti-hbs antibody concentrations were tested with the in-house ELISA with cut-off 3.3 miu/ml $ There was a change of assay kit at Year 15 time-point, thus for the sake of bridging, blood samples corresponding to Year 14 were also re-tested with CLIA. S+ = Seropositivity for anti-hbs antibodies defined as : antibody concentrations 1.0 miu/ml for time points PIII (M7) to PIII(Year 6) antibody concentrations 3.3 miu/mlfor time points PIII(Year 6) to PIII(Year 14) antibody concentrations 6.2 miu/ml for time points PIII(Year 14 $ ) and PIII(Year 15) (these cut-off values differ because of a change in assay kit) N = number of subjects with available results n (%) = number (percentage) of subjects with antibody concentration within the specified range GMC = geometric mean concentrations calculated on seropositive subjects 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PIII(Mx) = blood sampling after Dose 3, at Month x after first vaccine dose at primary study PIII(Year x) = blood sampling after Dose 3, at Year x after first vaccine dose in primary study # A decrease in the specificity of the anti-hb ELISA assay had been observed in some studies for low levels of antibody (10-100 miu/ml). The table shows updated results following complete retesting and reanalysis. Primary Efficacy Results: Anti-HBs antibody concentrations before and one month for subjects* who received an additional vaccine dose of HBV (LT Total vaccinated Cohort)
Time point determining eligibility Anti-HBs (miu/ml) at time point determining eligibility (Year 11) Anti-HBs (miu/ml) preadditional vaccine dose Anti-HBs (miu/ml) at Day 30 post-additional vaccine dose Anamnestic response** Year 11 <3.3 <3.3 6548.1 Yes Year 11 <3.3 14.5 554.0 Yes *2 subjects received additional vaccine dose **anamnestic response for anti-hbs antibody is defined as - Anti-HBs antibody concentrations 10 miu/ml at one month post-additional dose in subjects seronegative at the pre-additional vaccination time-point. - At least a 4-fold increase in anti-hbs antibody concentrations, at one month post-additional dose in subjects seropositive at the pre-additional vaccination time-point. Primary Efficacy Results: Number (%) of subjects reporting solicited local symptoms during the 4-day (Days 0-3) postvaccination period (LT Total Vaccinated Cohort) Symptom Intensity N n % 95 % CI LL UL Pain Any 2 0 0.0 0.0 97.5 Grade 3 2 0 0.0 0.0 97.5 Redness Any 2 0 0.0 0.0 97.5 >20 mm 2 0 0.0 0.0 97.5 Swelling Any 2 0 0.0 0.0 97.5 >20 mm 2 0 0.0 0.0 97.5 N = Number of subjects with the administered dose n (%) = Number (percentage) of subjects reporting at least once the symptom 95%CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit Any = Incidence of a local symptom regardless of grade or relationship to vaccination Grade 3 pain = Symptom that prevented normal everyday activities Primary Efficacy Results: Number (%) of subjects reporting solicited general symptoms during the 4-day (Days 0-3) post-vaccination period (LT Total Vaccinated Cohort) Symptom Intensity/Relationship N n % 95 % CI LL UL Fatigue Any 2 1 50.0 2.5 100 Grade 3 2 0 0.0 0.0 97.5 Related 2 1 50.0 2.5 100 Fever/(Axillary) 37.5 C 2 0 0.0 0.0 97.5 >39.0 C 2 0 0.0 0.0 97.5 Related 2 0 0.0 0.0 97.5 Gastrointestinal Any 2 1 50.0 2.5 100 Grade 3 2 0 0.0 0.0 97.5 Related 2 1 50.0 2.5 100 Headache Any 2 0 0.0 0.0 97.5 Grade 3 2 0 0.0 0.0 97.5 Related 2 0 0.0 0.0 97.5 N = Number of subjects with the administered dose n (%) = Number (percentage) of subjects reporting at least once the symptom 95%CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit Any = Incidence of a general symptom irrespective of intensity grade or relationship to vaccinations Grade 3 = Symptom which prevented normal everyday activities Related = Symptom assessed by the investigator as causally related to study vaccination. Secondary Outcome variable(s):. Safety Results: Number (%) of subjects who received an additional vaccine dose after Year 15, with unsolicited adverse events (LT Total Vaccinated Cohort) Most frequent adverse events occurring during the 30-
day follow-up vaccination period after vaccination N=2 Subjects with any AE(s), n (%) 1 (50.0) Subjects with grade 3 AE(s), n (%) 0 (0.0) Subjects with related AE(s), n (%) 1 (50.0) Heaviness sensation above eyes 1 (50.0) procedures, or lack of vaccine efficacy, reported up to Year 11 (LT Total Vaccinated Cohort) N = 37 N = 37 procedures, or lack of vaccine efficacy, reported up to Year 12 (LT Total Vaccinated Cohort) N = 40 N = 40 procedures, or lack of vaccine efficacy, reported up to Year 13 (LT Total Vaccinated Cohort) N = 37 N = 37 procedures, or lack of vaccine efficacy, reported up to Year 14 (LT Total Vaccinated Cohort) N = 43 N = 43 procedures, or lack of vaccine efficacy, reported up to Year 15 (LT Total Vaccinated Cohort) N = 50 N = 50 Safety Results: Number (%) of subjects with serious adverse events occurring during the 30-day follow-up period after the additional vaccination dose (LT Total Vaccinated Cohort) N = 2
N = 2 Conclusion: From Year 11 to Year 15, all subjects had anti-hav antibody concentrations 15mIU/mL; at the same time points the GMC for anti-hav antibody was at least 524.7. Further, at least 87.0% of subjects had anti-hbs antibody concentrations 10 miu/ml from Year 11 to Year 15; the GMC for anti-hbs antibody was at least 149.1. Two subjects received an additional vaccine dose of HBV vaccine and showed an anamnestic response to the additional vaccination. No solicited local symptoms were reported and solicited general symptoms (fatigue and gastrointestinal symptoms) were reported by 2 subjects during the 4-day (Days 0-3) follow up period after the additional vaccine dose. Unsolicited adverse event was reported by 1 of the 2 subjects with the additional dose of the vaccine. No SAEs related to the primary vaccination or to the study procedures were reported during the LT follow-up studies up to Year 15. The publications listed below describe results for the primary study and the Long-Term Persistence study up to Month 120. Date updated: 20-March-2014