Study No.: Title: Rationale: Phase: Study Period: Study Design: Center: Indication: Treatment: Objective: Primary Outcome/Efficacy Variable:

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1 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.: (HAB-143 Ext:032 Y11), (HAB-144 Ext:032 Y12), (HAB-145 Ext:032 Y13), (HAB-146 Ext:032 Y14), (HAB-147 Ext:032 Y15) Title: A double-blind, randomized study to evaluate the immunogenicity and reactogenicity of three different lots of GlaxoSmithKline Biologicals' combined hepatitis A/hepatitis B vaccine in healthy adult volunteers. Twinrix (HAB): GlaxoSmithKline (GSK) Biologicals combined hepatitis A and 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 at Year 11 through to 15 after administration of the first dose of HAB vaccine (Study HAB-032, primary vaccination). The safety of the study vaccine was also assessed. Furthermore, in subjects who became seronegative for anti-hav antibodies (i.e. titers < 15 miu/ml) or lost seroprotective titers for anti-hbs antibodies (i.e. titers < 10 miu/ml) at the long-term blood sampling time points (i.e. Years 11, 12, 13, 14 or 15), immune memory was assessed by providing an additional vaccine dose of Havrix, Engerix -B or HAB vaccine. Havrix (HAV): GSK Biologicals hepatitis A vaccine Engerix -B (HBV): GSK Biologicals recombinant hepatitis B vaccine Phase: III Study Period: LTFU at Month 132 (HAB-143): 25 November 2004 to 17 December 2004 LTFU at Month 144 (HAB-144): 26 August, 2005 to 14 September, 2005 LTFU at Month 156 (HAB-145): 14 December 2006 to 09 March 2007 LTFU at Month 168 (HAB-146): 07 December 2007 to 05 February 2008 LTFU at Month 180 (HAB-147): 21 November 2008 to 09 January 2009 Study Design: Open follow-up. Center: Single study center in Belgium Indication: Immunization against hepatitis A and hepatitis B infection. Treatment: The study groups in the primary study were as follows: Group 1 received HAB vaccine lot 1 Group 2 received HAB vaccine lot 2 Group 3 received HAB vaccine lot 3 HAB vaccine was administered as an intramuscular injection in the deltoid region according to a Month 0, 1, 6 schedule. Note that the Pooled Group is the combination of Group 1, Group 2 and Group 3. Objective: To evaluate the anti-hepatitis A virus (anti-hav) and anti- hepatitis B surface antigen (anti-hbs) antibody persistence at Years 11, 12, 13, 14 and 15 after the first vaccine dose of three-dose primary vaccination. To evaluate the immune memory [after a primary three-dose schedule of HAB vaccine] in subjects who became seronegative for anti-hav antibodies (i.e. concentrations < 15 miu/ml) or had anti-hbs antibody concentrations < 10 miu/ml at the long-term blood sampling time point (i.e. Years 11, 12, 13, 14 or 15) and who received the additional vaccine dose at the subsequent blood sampling time point. Primary Outcome/Efficacy Variable: Immunogenicity: During the long-term follow-up (LTFU), at all time points: The seropositivity* rates and concentration of anti-hav antibodies. The seropositivity** rates, seroprotection*** rates and concentration of anti-hbs antibodies. * Seropositivity for HAV antibodies is defined as antibody concentrations 33 miu/ml until 72 months following first vaccination and 15mIU/mL after 72 months following vaccination. ** Seropositivity for anti-hbs antibodies is defined as antibody concentrations 1.0 miu/ml until 72 months following first vaccination, 3.3mIU/mL from 72 months until 168 months following first vaccination and 6.2 miu/ml from month 168 onwards. *** Seroprotection rate for anti-hbs antibodies is defined as the percentage of subjects with anti-hbs antibody concentrations 10 miu/ml. For subjects who received the additional vaccination: Immune response to the study vaccine antigen, before and one month after the additional vaccine dose:

2 Anti-HAV antibody concentrations (for an additional dose with HAV vaccine). Anti-HBs antibody concentrations (for an additional dose with HBV vaccine). Anamnestic response to the additional vaccine dose.* *Anamnestic response for anti-hbs antibody was 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. Anamnestic response for anti-hav antibody was defined as: Anti-HAV antibody concentrations 15 miu/ml at one month post-additional dose in subjects seronegative at the pre-additional vaccination time point. At least a 2-fold increase in anti-hav antibody concentrations, at one month post-additional dose in subjects having anti-hav antibody concentrations 100 miu/ml at the pre-additional vaccination time point. Or at least a 4-fold increase in anti-hav antibody concentrations at one month post-additional dose in seropositive subjects having anti-hav antibody concentrations< 100 miu/ml at the pre-additional vaccination time point. Safety: During the LTFU: Occurrence of serious adverse events (SAEs) causally linked to the primary vaccination or 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). For subjects who received the additional vaccination: Occurrence of solicited local/ general symptoms during the 4-day (Day 0 to Day 3) follow-up period after vaccination. Occurrence of unsolicited symptoms (local/ general) during the 30-day (Day 0 to Day 29) follow-up period after vaccination. Occurrence of SAEs during the follow-up period after vaccination (minimum 30 days) and any incidence which related to a lack of vaccine efficacy. Secondary Outcome/Efficacy Variable(s): The primary and secondary outcome variables were not differentiated in the study protocol; hence they were all considered as primary in this CTRS. Statistical Methods: The analyses were performed on the Long Term (LT) Total Cohort and the LT According-To-Protocol (LT ATP) cohort for immunogenicity. The LT Total Cohort included all subjects who returned at a specified follow-up study and who belonged to the Total Cohort of the primary vaccination course. The LT ATP cohort for immunogenicity included subjects from the ATP cohort for immunogenicity of the primary vaccination course, who returned for a specified follow-up study, for whom results were available for specified followup time points, who were not eliminated either for vaccine administration forbidden in study protocol or for abnormal increase in anti-hav and/ or anti-hbs antibody concentrations, 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 Total cohort and LT ATP cohort for immunogenicity. During the long term follow-up period, for each group and for pooled group, anti-hav and anti-hbs seropositivity rates and geometric mean concentrations (GMCs) with their 95% confidence interval (CI) were tabulated for all the blood sampling time points. For each group and for pooled group, seroprotection rates (SPR) for anti-hbs with 95% CI were tabulated for all blood sampling time points. No subject became seronegative for anti-hav antibodies (i.e. concentrations < 15 miu/ml) up to Year subjects lost seroprotective concentrations for anti-hbs antibodies (i.e. concentrations < 10 miu/ml) at Year 11 and Year 12, respectively, and were therefore eligible to receive the additional vaccine dose 1 year later.

3 Immunogenicity results and anamnestic response to the additional vaccine dose were tabulated for each subject who received an additional dose of HBV during the LTFU time-points. Note: A decrease in the specificity of the anti-hb ELISA assay had been observed in some studies for low levels of antibody ( miu/ml). The table shows updated results following complete retesting and reanalysis. Analysis of safety: The analysis of safety was performed on the LT Total Cohort. During the long term follow-up period, the occurrence of any SAE which the subject could have experienced since the last study visit was reported only if the SAE was assessed by the investigator as causally related to primary vaccination and related to study participation. Any incidence related to lack of vaccine efficacy (i. e. hepatitis A or hepatitis B infection) was also reported as SAE. For subjects who received the additional vaccine dose*, the incidence of solicited local and general symptoms occurring during the 4 days after the vaccination was tabulated with exact 95% CI. The same calculation was performed for symptoms of any intensity, those with intensity of grade 3, as well as for solicited general symptoms with relationship to vaccination. The percentage of subjects with at least one report of an unsolicited AE within the 30-day follow-up period was tabulated. SAEs were summarized during a follow-up period of minimum 30 days. Any incidence which related to a lack of vaccine efficacy was also reported as SAEs. *The 2 subjects that received additional dose were from groups 1 and 2 respectively. Study Population: Healthy adults who had participated in HAB-032 primary vaccination study. Written informed consent was obtained from each subject before each blood sampling visit of the LTFU study. Number of subjects (Year 15) Group 1 Group 2 Group 3 Pooled Group Planned, N Not applicable Not applicable Not applicable Not applicable Entered, N (LT Total Cohort) Completed, n (%) 18 (100) 16 (100) 17 (100) 51 (100) Total Number Subjects Withdrawn, n (%) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Withdrawn due to Adverse Events, n (%) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Withdrawn due to Lack of Efficacy, n (%) Not applicable Not applicable Not applicable Not applicable Withdrawn for other reasons, n (%) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Demographics (Year 15) Group 1 Group 2 Group 3 Pooled Group N (LT Total Cohort) Females : Males 15:3 12:4 14:3 41:10 Mean Age, years (SD) 35.4 (2.09) 38.8 (8.08) 35.2 (5.07) 36.4 (5.65) White/Caucasian, n (%) 18 (100) 16 (100) 17 (100) 51 (100) 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 Group 1 PIII(M18) PIII(M24) PIII(M36) PIII(M48) PIII(M60) PIII(M72) PIII(M72)* PIII(M84) PIII(M96) PIII(M108) PIII(M120) PIII(M132) PIII(M144) PIII(M156) PIII(M168) PIII(M180) # Group 2 PIII(M18)

4 PIII(M24) PIII(M36) PIII(M48) PIII(M60) PIII(M72) PIII(M72)* PIII(M84) PIII(M96) PIII(M108) PIII(M120) PIII(M132) PIII(M144) PIII(M156) PIII(M168) PIII(M180) # Group 3 PIII(M18) PIII(M24) PIII(M36) PIII(M48) PIII(M60) PIII(M72) PIII(M72)* PIII(M84) PIII(M96) PIII(M108) PIII(M120) PIII(M132) PIII(M144) PIII(M156) PIII(M168) PIII(M180) # Pooled PIII(M18) PIII(M24) PIII(M36) PIII(M48) PIII(M60) PIII(M72) PIII(M72)* PIII(M84) PIII(M96) PIII(M108) PIII(M120) PIII(M132) PIII(M144) PIII(M156) PIII(M168) PIII(M180) # * There was a change of assay kit at Month 84 time point, thus for the sake of bridging, blood samples corresponding to Month 72 were re-tested with the new assay kit. N = number of subjects with available results S+ = seropositivity for anti-hav antibodies 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

5 PIII(My) = blood sampling after Dose 3, at Month y after first vaccine dose at primary study # At Month 180, the ATP cohort for immunogenicity was revised due to change in the elimination code based on the new assay ChemiLuminescence ImmunoAssay (CLIA) for anti-hbs 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 Group 1 PIII(M18) PIII(M24) PIII(M36) PIII(M48) PIII(M60) PIII(M72) PIII(M72)* PIII(M84) PIII(M96) PIII(M108) PIII(M120) PIII(M132) PIII(M144) PIII(M156) PIII(M168) PIII(M168) $ PIII(M180) Group 2 PIII(M18) PIII(M24) PIII(M36) PIII(M48) PIII(M60) PIII(M72) PIII(M72)* PIII(M84) PIII(M96) PIII(M108) PIII(M120) PIII(M132) PIII(M144) PIII(M156) PIII(M168) PIII(M168) $ PIII(M180) Group 3 PIII(M18) PIII(M24) PIII(M36) PIII(M48) PIII(M60) PIII(M72) PIII(M72)* PIII(M84) PIII(M96) PIII(M108) PIII(M120) PIII(M132)

6 PIII(M144) PIII(M156) PIII(M168) PIII(M168) $ PIII(M180) Pooled PIII(M18) PIII(M24) PIII(M36) PIII(M48) PIII(M60) PIII(M72) PIII(M72)* PIII(M84) PIII(M96) PIII(M108) PIII(M120) PIII(M132) PIII(M144) PIII(M156) PIII(M168) PIII(M168) $ PIII(M180) * There was a change of assay kit at Month 84 time-point, thus for the sake of bridging, blood samples corresponding to Month 72 were re-tested with the new assay kit. From Month 156 to Month 168, anti-hbs antibody concentrations tested with the in-house assay with cut-off 3.3 miu/ml. $ There was a change of assay kit at Month 180 time-point, thus for the sake of bridging, blood samples corresponding to Month 168 were also re-tested with CLIA. From Month 168 onwards, anti-hbs antibody concentrations were tested with the CLIA assay with cut-off 6.2 miu/ml. N = number of subjects with available results S+ = seropositivity for anti-hbs antibodies 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(My) = blood sampling after Dose III, at Month y 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 ( miu/ml). The table shows updated results following complete retesting and reanalysis. Primary Efficacy Results: Anti-HBs antibody concentrations at time point determining eligibility, before and one month after the vaccination for subjects* who received an additional vaccine dose of HBV (LT Total cohort) Group Time point determining eligibility Time point when the additional vaccine dose was administered Anti-HBs (miu/ml) at time point determining eligibility Anti-HBs (miu/ml) pre additional vaccine dose Anti-HBs (miu/ml) post additional vaccine dose Anamnestic response** 1 Year 12 Year Yes 2 Year 11 Year Blood sample not taken 2138 Yes *The two subjects that received additional dose were from groups 1 and 2 respectively. **Anamnestic response for anti-hbs antibody was 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. The subject in Group 2 was withdrawn from the LT Cohort for immunogenicity because of non-compliance with the protocol. Primary Efficacy Results: Number (%) of subjects reporting solicited local symptoms during the 4-day (Days 0-3) follow-up

7 period after additional HBV vaccination (LT Total Cohort) Group 1 Group 2** 95 % CI 95 % CI Symptom Intensity N n % LL UL N n % LL UL Additional dose Pain Any Redness Any Swelling Any N= number of subjects with at least one 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 = occurrence of any local symptom regardless of intensity grade Grade 3 pain = adverse experience which prevented normal everyday activities Grade 3 redness and swelling = > 30mm and persisting more than 24 hours ** No information concerning solicited local symptoms was collected for subject belonging to Group 2. Primary Efficacy Results: Number (%) of subjects reporting solicited general symptoms during the 4-day (Days 0-3) follow-up period after additional HBV vaccination (LT Total Cohort). Group 1 Group 2 * 95 % CI 95 % CI Symptom Intensity/ Relationship N n % LL UL N n % LL UL Additional dose Fatigue Any Headache Any Malaise Any Nausea Any Vomiting Any Temperature > 37.4 C > 39.0 C N= number of subjects with at least one 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 = occurrence of any general symptom regardless of intensity grade or relationship to vaccination Grade 3 symptom = adverse experience which prevented normal everyday activities Related = general symptom assessed by the investigator as causally related to the study vaccination * No information concerning solicited general symptoms was collected for subject belonging to Group 2.

8 Secondary Outcome Variable(s): Not applicable. Safety results: Number (%) of subjects with unsolicited AEs after additional dose of HBV during the 30-day follow-up period (LT Total Cohort) Most frequent adverse events - On-Therapy (occurring within Days 0-29 following vaccination) Group 1 Group 2* Subjects with any AE(s), n (%) 1 (100) - Nasopharyngitis 1 (100) - * No information corresponding to unsolicited symptoms were collected for subject belonging to Group 2. Safety Results: Number (%) of subjects with serious adverse events related to the primary vaccination, to the LT study procedures or lack of vaccine efficacy, reported up to Year 15 (LT Total Cohort) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs Group 1 8 Group 2 6 Group 3 7 Pooled Group N= 51 Subjects with any SAE(s), n (%) [n 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] assessed by the investigator as related] Fatal SAEs Group 1 8 Group 2 6 Group 3 7 Pooled Group N= 51 Subjects with fatal SAEs, n (%) [n assessed by the investigator as related] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] Safety Results: Number (%) of subjects with serious adverse events after additional vaccination (LT Total Cohort) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs Group 1 Group 2 Subjects with any SAE(s), n (%) [n assessed by the investigator as related] 0 (0.0) [0] 1 (100) [0] Hallux valgus 0 (0.0) [0] 1 (100) [0] Fatal SAEs Group 1 Group 2 Subjects with fatal SAEs, n (%) [n assessed by the investigator as related] 0 (0.0) [0] 0 (0.0) [0] Conclusion: : For anti-hav antibodies, the humoral immune response persisted in 100% of the subjects up to Month 180 long-term followup time point; at Month 180, 96.6% of the subjects had anti-hbs antibody concentrations 10mIU/mL. No SAEs related to the primary vaccination or to the study procedures were reported during the LT follow-up study. Two subjects (one in each group) received an additional vaccination of HBV vaccine, one at the Year 12 and one at the Year 13 time point. One month after the additional dose, an anamnestic response was observed in both subjects and the anti-hbs antibody concentrations were mIU/mL for the subject in Group 1 and 2138 miu/ml for the subject in Group 2. During the 4-day follow-up period after the additional HBV vaccination, pain was the only solicited symptom reported by the subject of Group 1. During the 30-day follow-up period after the additional HBV vaccination, one unsolicited adverse event was reported by the subject belonging to Group 1. One SAE was reported by the subject in Group 2 after the additional vaccination. This was assessed by the investigator as unrelated to the additional HBV vaccination. Date updated: 20 March 2014