Study No.: Title: Rationale: Phase: Study Period: Study Design: Center: Indication: Treatment: Objectives:

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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.: /223 (HAV-223) / /224 (HAV-224) / (HAV-240 Ext.123 Year 11) / (HAV- 241 Ext.123 Year 12) / (HAV-242 Ext.123 Year 13) / (HAV-243 Ext. 123 Year 14) / (HAV- 244 Ext.123 Year 15) / (HAV- 123 Ext: Year 16) / (HAV-123 Ext: Year 17) / (HAV-123 Ext: Year 18) / (HAV-123 Ext: Year 19) / (HAV-123 Ext: Year 20) Title: Double-blind, randomized study to evaluate the immunogenicity and reactogenicity of three different lots of GlaxoSmithKline Biologicals' inactivated hepatitis A vaccine containing 1440 EL.U of antigen per ml and injected according to a 0, 6 month schedule in healthy adult subjects. Havrix (HAV): GlaxoSmithKline (GSK) Biologicals inactivated hepatitis A vaccine. Rationale: This study was conducted in 2 phases: a primary study and long-term follow-up (LTFU) study from Year 9 to Year 20. The aim of this LTFU study was to evaluate the persistence of humoral and cellular immune response and to assess the immunogenicity of an additional dose of HAV vaccine in subjects who had anti-hepatitis A (HAV) antibodies concentrations < 15 miu/ml. Phase: IV Study Period: Year 9 (Month 108): 14 January 2002 to 27 February 2002 Year 10 (Month 120): 27 November 2002 to 27 January 2003 Year 11 (Month 132): 16 January 2004 to 11 February 2004 Year 12 (Month 144): 10 November 2004 to 03 December 2004 Year 13 (Month 156): 27 October 2005 to 06 December 2005 Year 14 (Month 168): 09 November 2006 to 06 December 2006 Year 15 (Month 180): 27 September 2007 to 05 January 2009 Year 16 (Month 192): 21 October 2008 to 05 January 2009 Year 17 (Month 204): 03 November 2009 to 15 December 2009 Year 18 (Month 216): 29 November 2010 to 23 December 2010 Year 19 (Month 228): 8 February 2012 to 14 March 2012 Year 20 (Month 240): 07 March 2013 to 27 March 2013 Study Design: The primary study was a double-blind randomized study with 3 parallel groups receiving 3 different vaccine lots of HAV. This LTFU study was an open study with the same group allocation as in the primary study. Center: Single center in Belgium. Indication: Immunization against hepatitis A of healthy adults aged between 18 and 40 at the time of first vaccination. Treatment: The study groups were as follows: Lot 1 Group received 2 doses of HAV vaccine lot 1 Lot 2 Group received 2 doses of HAV vaccine lot 2 Lot 3 Group received 2 doses of HAV vaccine lot 3 As lot to lot consistency was assessed during the primary study, the 3 groups were pooled into the for data analyses during the LTFU study. No vaccine was administered during the LTFU study, except an additional dose of HAV vaccine which was offered to subjects who had anti-hav antibodies concentrations < 15 miu/ml at any of the long-term blood sampling time point. This additional vaccine dose was administered to the eligible subjects between 6 to 12 months after the Year 15 time point (if the subject had anti-hav antibodies < 15 miu/ml at any of the previous blood sampling time points [i.e. Years 11, 12, 13, 14 and 15]) or within a year following the time point when the subject had tested seronegative for anti-hav antibodies (i.e. Years 16, 17, 18, 19 and 20). The vaccine was administered intramuscularly in the deltoid muscle. Note: No additional vaccine dose was administered at the Years 16, 17, 18, 19 and 20 time points. Objectives: For the Year 9 and Year 10 time points: To evaluate the persistence of anti-hav antibodies and evaluate the persistence of cellular immune

2 response through blood samples taken 108 months and 120 months after the first vaccine dose of the 2- dose primary vaccination course in the primary study. For the Year 11 to Year 20 time points: To evaluate anti-hav antibody persistence at Years 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 after the first vaccine dose of 2-dose primary vaccination. To evaluate the immune memory (after a primary 2-dose schedule of HAV vaccine) in subjects having anti-hav antibodies (i.e. antibody concentrations) < 15 miu/ml during any of the long-term blood sampling time point (i.e. Years 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and who received the additional vaccine dose (administered between 6 to 12 months after the Year 15 time point and from Year 16 onwards, within one year after the time point that the subject tested seronegative for anti-hav antibodies) Primary Outcome/Efficacy Variable: Immunogenicity For all subjects: Seropositivity* rates and geometric mean concentrations (GMCs) (calculated on seropositive subjects) for anti- HAV antibodies at Year 9 to Year 20 in the pooled group. For subjects receiving the additional vaccine dose: Anti-HAV antibody response determined by seropositivity* rates and GMCs with 95% confidence intervals (CI) for anti-hav antibodies before, at Day 14 and Day 30 after the additional vaccine dose time point. *Seropositivity for anti-hav antibodies defined as antibody concentrations 20 miu/ml for Year 9 and Year 10 time points and 15 miu/ml for Year 11 to Year 20 time points. Secondary Outcome/Efficacy Variable(s): Safety For all subjects: Occurrence of pregnancies and pregnancy outcomes at Years 9 and 10 Occurrence of serious adverse events (SAEs) at Years 9 and 10 Occurrence of any events related to lack of vaccine efficacy (i.e. hepatitis A infection) from Year 11 to Year 20 Occurrence of SAEs assessed by the investigator as causally related to vaccination from Year 11 to Year 20 For subjects receiving the additional vaccine dose: Occurrence, intensity and relationship of each individual solicited local and general symptoms during the 4-day (Day 0 to Day 3) follow-up period after vaccination. Occurrence, intensity and relationship of subjects with at least 1 report of unsolicited adverse events (AEs), classified by the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms, during the 30-day (Day 0 to Day 29) follow-up period after vaccination. occurring during the follow-up period after additional vaccination. Pregnancies reported in female subjects who received the additional vaccination. Statistical Methods: The analyses were performed on the Long Term (LT) Total Cohort and the Long Term According to Protocol (LT ATP) cohort for immunogenicity. - The LT Total Cohort included all subjects who returned to the follow-up study and who had received at least 1 dose of the vaccine at the primary study. - The LT ATP cohort for immunogenicity included those subjects who returned to the follow-up study and who were included in the ATP cohort for immunogenicity of the primary study, who were not eliminated in the previous LTFU, who did not receive an extra study vaccine shot (or vaccine with equivalent antigen component) since the previous LTFU visit, who did not show abnormal increase in antibody concentrations since the previous LTFU visit, who had not reported any incidence of hepatitis A disease and who came back for LTFU blood samples within the acceptable time interval. Abnormal increase in antibody concentrations is defined as a 2-fold increase or more in antibody concentrations (when the antibody titer at the reference time point is 100 miu/ml) or a 4-fold increase or more in antibody concentrations (when the antibody titer at the reference time point is < 100 miu/ml)

3 Analysis of immunogenicity: The analyses were performed on the LT Total Cohort and the LT ATP cohort for immunogenicity. Seropositivity rates and GMCs (calculated on seropositive subjects) were tabulated with 95% confidence interval [CI] for anti-hav antibodies in the pooled group. At Year 15 and for each subject who received the additional vaccine dose at any of the long-term blood sampling time point (i.e. Years 11, 12, 13, 14 and 15), anti-hav antibody concentrations were tabulated at pre-vaccination and post-vaccination (before, at Day 14 and Day 30 after the additional vaccine dose) time points. Analysis of safety : The analyses were performed on the LT Total Cohort. For all subjects: in the pooled group at Year 9 and Year 10 and only the SAEs assessed by the investigator as causally related to vaccination from time points Year 11 to Year 20 were tabulated according to MedDRA preferred terms. The percentage of subjects with pregnancies and their outcomes were tabulated at Year 9 and Year 10. Any event which related to lack of vaccine efficacy (i.e. hepatitis A infection) was also reported from time points Year 11 to Year 20 At Year 15 and for subjects in the pooled group receiving the additional vaccine dose: 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 vaccination were tabulated; the same tabulation was performed for grade 3 symptoms and for solicited general symptoms assessed by the investigator as causally related to vaccination. The percentage of subjects with at least 1 report of unsolicited AE, classified by MedDRA preferred terms, during the 30-day (Day 0 to Day 29) follow-up period after vaccination was tabulated. The same tabulation was performed for grade 3 unsolicited AEs and for unsolicited AEs assessed by the investigator as causally related to vaccination. All SAEs and pregnancies occurring during the follow-up period after additional vaccination were also tabulated. Study Population: Healthy adults aged between 18 and 40 years old at the time of first vaccination. Subjects were in good health as determined by clinical examination and history taking and at study entry. Subjects were excluded if anti-hav antibodies were present at screening, if they presented with any acute disease at the moment of study entry, if they planned to simultaneously participate in any other clinical trial, and if any other vaccination or the administration of immunoglobulin occurred simultaneously. Subjects who returned for the LTFU visits were included if they had completed the primary vaccination. Subjects who received hepatitis A vaccination outside study were excluded from the study. If a subject received an additional vaccination at a previous time point, he/she was not eligible to participate in the subsequent long-term follow-up time points of the study. Written informed consent was obtained before the blood sampling visit each year Number of Subjects (LT Total Cohort): Year 9 (Month 108) Planned, N* 58 Entered, N (LT Total Cohort) 58 Completed, n (%) Total Number Subjects Withdrawn, n (%) Withdrawn due to Adverse Events, n (%) Withdrawn for other reasons, n (%) N (LT Total Cohort) 58 Females: Males 41: 17 Mean Age, years (SD) 36.8 (7.08) White/Caucasian, n (%) *Subjects who came back for the Year 9 time point Number of Subjects (LT Total Cohort): Year 10 (Month 120) Planned, N* 55 Entered, N (LT Total Cohort) 55 Completed, n (%) Total Number Subjects Withdrawn, n (%)

4 Withdrawn due to Adverse Events, n (%) Withdrawn for other reasons, n (%) N (LT Total Cohort) 55 Females: Males 36: 19 Mean Age, years (SD) 37.9 (7.36) White/Caucasian, n (%) *Subjects who came back for the Year 10 time point Number of Subjects (LT Total Cohort): Year 11 (Month 132) Planned, N* 64 Entered, N (LT Total Cohort) 64 Completed, n (%) 64 (100) N (LT Total Cohort) 64 Females: Males 42:22 Mean Age, years (SD) 39.1 (6.79) White/Caucasian, n (%) 64 (100) *Subjects who came back for the Year 11 time point Number of Subjects (LT Total Cohort): Year 12 (Month 144) Planned, N* 60 Entered, N (LT Total Cohort) 60 Completed, n (%) 60 (100) N (LT Total Cohort) 60 Females: Males 42:18 Mean Age, years (SD) 40.0 (6.95) White/Caucasian, n (%) 60 (100) *Subjects who came back for the Year 12 time point Number of Subjects (LT Total Cohort): Year 13 (Month 156) Planned, N* 71 Entered, N (LT Total Cohort) 71 Completed, n (%) 71 (100) N (LT Total Cohort) 71 Females: Males 48:23 Mean Age, years (SD) 40.3 (7.02) White/Caucasian, n (%) 71 (100) *Subjects who came back for the Year 13 time point Number of Subjects (LT Total Cohort): Year 14 (Month 168)

5 Planned, N* 66 Entered, N (LT Total Cohort) 66 Completed, n (%) 66 (100) N (LT Total Cohort) 66 Females: Males 48:18 Mean Age, years (SD) 41.1 (7.25) White/Caucasian, n (%) 66 (100) *Subjects who came back for the Year 14 time point Number of Subjects (LT Total Cohort): Year 15 (Month 180) Planned, N* 63 Entered, N (LT Total Cohort) 63 Completed, n (%) 63 (100) N (LT Total Cohort) 63 Females: Males 44:19 Mean Age, years (SD) 42.1 (7.10) White/Caucasian, n (%) 63 (100) *Subjects who came back for the Year 15 time point Number of Subjects (LT Total Cohort): Year 16 (Month 192) Planned, N* 78 Entered, N (LT Total Cohort) 78 Completed, n (%) 78 (100) N (LT Total Cohort) 78 Females: Males 56:22 Mean Age, years (SD) 42.3 (7.00) White/Caucasian, n (%) 78 (100) *Subjects who came back for the Year 16 time point Number of Subjects (LT Total Cohort): Year 17 (Month 204) Planned, N* 63 Entered, N (LT - Total Cohort) 63 Completed, n (%) 63 (100) N (LT Total Cohort) 63 Females: Males 45:18 Mean Age, years (SD) 43.6 (6.93) White/Caucasian, n (%) 63 (100)

6 *Subjects who came back for the Year 17 time point Number of Subjects (LT Total Cohort): Year 18 (Month 216) Planned, N* 52 Entered, N (LT Total Cohort) 52 Completed, n (%) 52 (100) N (LT Total Cohort) 52 Females: Males 35:17 Mean Age, years (SD) 44.1 (6.63) White/Caucasian, n (%) 52 (100) *Subjects who came back for the Year 18 time point Number of Subjects (LT Total Cohort): Year 19 (Month 228) Planned, N* 45 Entered, N (LT Total Cohort) 45 Completed, n (%) 45 (100) N (LT Total Cohort) 45 Females: Males 33:12 Mean Age, years (SD) 45.9 (6.61) White/Caucasian, n (%) 45 (100) *Subjects who came back for the Year 19 time point Number of Subjects (LT Total Cohort): Year 20 (Month 240) Planned, N* 50 Entered, N (LT Total Cohort) 50 Completed, n (%) 50 (100) N (LT Total Cohort) 50 Females: Males 37:13 Mean Age, years (SD) 46.3 (6.44) White/Caucasian, n (%) 50 (100) *Subjects who came back for the Year 20 time point Primary Efficacy Results: Seropositivity rates and GMCs (calculated on seropositive subjects) for 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 PII(M108)

7 Group PII(M120) PII(M132) PII(M132)* PII(M144) PII(M156) PII(M168) PII(M180) PII(M192) PII(M204) PII(M216) PII(M228) PII(M240) N = number of subjects with available results S+ = seropositivity for anti-hav antibodies n (%) = number (percentage) of subjects with anti-hav antibody titers 20 miu/ml for time points PII (M108) to PII (M132), number (percentage) of subjects with anti-hav antibody titers 15mIU/mL for time point PII(M132)* to PII (M240) GMC = geometric mean antibody concentration calculated on seropositive subjects 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PII (Mx) = post-vaccination blood sample obtained x months after the first vaccine dose (post-dose 2) of the 2-dose primary vaccination * The lab assay was changed at Month 132, thus the blood samples were tested with both the old and the new assay at that time point. Primary Efficacy Results Immune response to the HAV additional dose in subjects* with anti-hav antibody concentration < 15 miu/ml during any of the long-term blood sampling time points (i.e. Years 11, 12, 13, 14 or 15), and who received the additional vaccine dose (LT Total Cohort). Time point Anti-HAV (miu/ml) at time point Anti-HAV (miu/ml) pre additional dose Anti-HAV (miu/ml) at Day 14 post additional dose Anti-HAV (miu/ml) at Day 30 post additional dose Anamnestic response** Year 14 < Yes Year 14 < Yes * 2 subjects received additional vaccine dose ** anamnestic response is defined as - Anti-HAV antibody concentrations 15 miu/ml at 1 month post-additional dose in subjects seronegative at the pre-additional dose time point. - At least a 2-fold increase in anti-hav antibody concentrations 1 month after the additional dose, in subjects having anti-hav antibody concentrations 100 miu/ml at the pre-additional dose time point. - Or at least a 4-fold increase in anti-hav antibody concentrations 1 month after the additional dose, in seropositive subjects having anti-hav antibody concentrations < 100 miu/ml at the pre-additional dose time point. Secondary Outcome Variable(s): Incidence of solicited local symptoms during the 4 day (Days 0-3) follow-up period after the additional dose for subjects with anti-hav antibody concentration < 15 miu/ml during any of the long-term blood sampling time points (i.e. Years 11, 12, 13, 14 or 15), and who received the additional vaccine dose (LT Total Cohort). Symptom Intensity N =2 n % Pain Any Grade Redness Any Grade Swelling Any 0 0.0

8 Grade N = with completed sheets n (%) = number (percentage) of subjects for whom a specific symptom was reported Any = Incidence of a particular symptom regardless of intensity grade Grade 3 pain = symptom that prevented normal activities Secondary Outcome Variable(s): Incidence of solicited general symptoms during the 4 day (Days 0-3) follow-up period after the additional dose for subjects with anti-hav antibody concentration < 15 miu/ml during any of the long-term blood sampling time points (i.e. Years 11, 12, 13, 14 or 15), and who received the additional vaccine dose (LT Total Cohort). No solicited general symptoms were reported. Secondary Outcome Variable(s): Number (%) of subjects with pregnancies and their outcomes at Year 9 (LT Total Cohort). No pregnancy was reported. Secondary Outcome Variable(s): Number (%) of subjects with pregnancies and their outcomes at Year 10 (LT Total Cohort). Categories N = 5 n % Normal infant N = number of subjects with pregnancies n (%) = number (percentage) of subjects with pregnancies in a given category Secondary Outcome Variable(s): Pregnancies reported in female subjects who received the additional vaccination during the 30-day follow-up vaccination period. (LT Total Cohort). No pregnancies were reported Safety results: Number (%) of subjects with unsolicited AEs for subjects who received the additional vaccine dose between Year 11 and Year 15 (LT Total Cohort) Most frequent adverse events - On-Therapy (occurring within Days 0-29 following additional 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 (%) 0 (0.0) Influenza like illness 1 (50.0) Grade 3: event that produced significant impairment of functioning or incapacitation and was a definite hazard to the subject's health. Related: event assessed by the investigator as causally related to the study vaccination. Safety Results: Number (%) of subjects with SAEs, between Year 8 and Year 9 (LT Total Cohort) N = 58 N = 58 Subjects with fatal SAEs, n (%) [n assessed by the investigator as related] 0 (0.0) [0] Safety Results: Number (%) of subjects with SAEs, between Year 9 and Year 10 (LT Total Cohort) N = 55 Subjects with any SAE(s), n (%) [n assessed by the investigator as related] 4 (7.3) [0] Concussion 1 (1.8) [0] Arthralgia 1 (1.8) [0] Adenoma benign NOS 1 (1.8) [0] Deep vein thrombosis 1 (1.8) [0] N = 55

9 Subjects with fatal SAEs, n (%) [n assessed by the investigator as related] 0 (0.0) [0] Safety Results: Number (%) of subjects with SAEs causally related to the primary vaccination, between Year 10 and Year 11 (LT Total Cohort) N = 64 N = 64 Subjects with fatal SAEs, n (%) [n assessed by the investigator as related] 0 (0.0) [0] related to lack of vaccine efficacy between Year 11 and Year 12 (LT Total Cohort) N = 60 N = 60 Subjects with fatal SAEs, n (%) [n assessed by the investigator as related] 0 (0.0) [0] related to lack of vaccine efficacy between Year 12 and Year 13 (LT Total Cohort) N = 71 N = 71 related to lack of vaccine efficacy between Year 13 and Year 14 (LT Total Cohort) N = 66 N = 66 related to lack of vaccine efficacy between Year 14 and Year 15 (LT Total Cohort) N = 63 N = 63 related to lack of vaccine efficacy between Year 15 and Year 16 (LT Total Cohort) N = 78 N = 78

10 related to lack of vaccine efficacy between Year 16 and Year 17 (LT Total Cohort) N = 63 N = 63 related to lack of vaccine efficacy between Year 17 and Year 18 (LT Total Cohort) N = 52 N = 52 related to lack of vaccine efficacy between Year 18 and Year 19 (LT Total Cohort) N = 45 N = 45 related to lack of vaccine efficacy between Year 19 and Year 20 (LT Total Cohort) N = 50 N = 50 Safety Results: Number (%) of subjects with SAEs during additional vaccination period in subjects who received the extra dose between Year 11 and 15 (LT Total Cohort) N = 2 N = 2 Conclusion: All subjects who did not receive an additional dose of hepatitis A vaccine continued to remain seropositive for anti- HAV antibodies up to Year 20. At Year 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20, the GMC Values for anti-hav antibodies were 297.4, 363.2, 287.7, 270.4, 290.3, 242.3, 277.9, 301.7, and miu/ml, respectively. One subject reported an unsolicited AE (influenza like illness) after additional vaccination at Year 15. No additional

11 vaccine dose was administered at Years 16, 17, 18, 19 or 20. At Year 10 time point, 4 (7.3%) subjects reported one SAE; none of them was assessed by the investigators as related to the study vaccination. From Year 11 to Year 20 long-term follow-up, no SAEs assessed by investigator as causally related were reported. Date updated: 18-March-2014