Synopsis for study HAV-112 EXT M210 (110678) Pharmaceutical entrepreneur: GlaxoSmithKline GmbH & Co. KG Prinzregentenplatz 9 81675 Munich Germany Personal identifiable data of investigators (name / full postal address) are not published in this report, as consent according to Section 4a of the German Federal Act on Data Protection is not available for any of the investigators.
The study summarized below may involve approved and non-approved uses, formulations or treatment regimens. The results reported for any single study may not reflect the overall results obtained during all studies involving the same product. Before prescribing any product mentioned in this Register, healthcare professionals should consult the prescribing information for the product approved in their country. Name of company: GlaxoSmithKline Biologicals, Rixensart, Belgium Name of finished product: Havrix Name of active substance: Inactivated hepatitis A virus (Strain HM 175-RIT 4380) TABULAR FORMAT REFERRING TO PART OF THE DOSSIER Volume: Page: (for national authority only) Study No.: 110677 (HAV-112 EXT: MTH 198) and 110678 (HAV-112 EXT: MTH 210) Title of the study: Double-blind randomized study to evaluate the immunogenicity and reactogenicity of two different lots of GlaxoSmithKline Biologicals inactivated hepatitis A vaccine and injected according to a 0, 12 month schedule in healthy adult volunteers. Study period: Clinical phase: IV Study initiation date (Primary): 30 March 1992 Study completion date (Primary): 05 July 1993 Long-term follow-up start date [Month 198 (Year 16.5)]: 21 October 2008 Long-term follow-up completion date [Month 210 (Year 17.5)]: 08 December 2009 Objectives: The objectives of the primary study are stated in the primary study report 208109/108 (HAV-112). The objectives of the long-term follow-up study were: To evaluate anti-hav antibody persistence at Months 138, 150, 162, 174, 186, 198, 210, 222, 234 and 246, after the first vaccine dose of two-dose primary vaccination. To evaluate the immune memory (after a primary two-dose schedule of Havrix vaccine) in subjects with anti- HAV antibodies concentrations < 15 miu/ml during any of the long-term blood sampling time-points (i.e. Months 186, 198, 210, 222, 234 or 246) and who received the additional vaccine dose (administered within one year after the time point that the subject tested seronegative for anti-hav antibodies). Note: This report presents results for the Month 198 (Year 16.5) and Month 210 (Year 17.5) time-points. Study design: The primary study 208109/108 (HAV-112) was a double-blind, randomised study with two groups receiving two different lots of GlaxoSmithKline (GSK) Biologicals hepatitis A vaccine Havrix, according to a 0, 12 month schedule. The long-term follow-up (LTFU) studies from Year 16.5 to Year 17.5 were open-label with the same two groups. At each of the annual visits, one blood sample was collected from the subjects for anti-hepatitis A virus (HAV) antibody testing. Serious adverse events (SAEs) considered related to vaccination, study procedures or vaccine failure that had occurred since the last study visit were to be documented retrospectively. Additional vaccination phase: At Year 16.5 and Year 17.5, if a subject was found to be seronegative for anti-hav antibodies (i.e. anti-hav antibody concentrations < 15 miu/ml), an additional dose of Havrix was offered within 12 months following that time-point. Blood samples were collected prior to additional vaccine dose administration, 14 days and 30 days after the administration of the additional vaccine dose for anti-hav testing. Additional blood samples were collected from the subjects prior to additional vaccine dose administration and on Day 30 after vaccination for evaluating cell-mediated immunity (CMI). This was performed in an ancillary study sponsored and conducted separately by the investigator. The number of subjects enrolled at Year 16.5 and Year 17.5 is presented in Table 1. 110677 (HAV-112 EXT: MTH 198) and 110678 (HAV-112 EXT: MTH 210) 1
Table 1: Subject attrition per group in the primary study and at Years 16.5 and 17.5. Number of subjects Total Group 1 Group 2 Number of subjects enrolled in the primary study 194 96 98 Number of subjects included in the According-to-Protocol (ATP) 177 90 87 cohort for immunogenicity in the primary study Number of subjects who returned at Year 16.5 135 65 70 Number of subjects included in the Long-Term (LT)-ATP cohort 101 46 55 for immunogenicity at Year 16.5 Number of subjects who returned at Year 17.5 124 61 63 Number of subjects included in the LT-ATP cohort for 91 42 49 immunogenicity at Year 17.5 Number of subjects who received an additional vaccine dose 1 1 0 after Year 16.5 Group 1 received Havrix vaccine (Lot no.dha531a4) at 0, 12 months in the primary study Group 2 received Havrix vaccine (Lot no.dha541a4) at 0, 12 months in the primary study Diagnosis and criteria for inclusion: Subjects who participated in the primary study 208109/108 (HAV-112) and had expressed willingness to participate in a follow-up study were invited to this study. Written informed consent was obtained from the subjects at each follow-up visit prior to any study procedure. Study vaccine, dose, mode of administration, lot no.: Primary study: Vaccination schedule/site: In the primary study, each group received one of two different lots of GSK Biologicals inactivated hepatitis A vaccine, Havrix, as an intramuscular (IM) injection in the deltoid muscle of the non-dominant arm according to a 0, 12 month schedule. Vaccine dose/lot no.: Each 1 ml dose of Havrix contained inactivated hepatitis A virus adsorbed on to aluminium salt. Group 1 and Group 2 received Havrix vaccines, Lot nos. DHA531A4 and DHA541A4 (Expiry date: 30 October 1993), respectively. Additional vaccination phase (for Year 16.5): Vaccination schedule/site: If indicated, a single dose of GSK Biologicals Havrix was administered as an IM injection in the deltoid muscle of the non-dominant arm. Vaccine dose/lot no.: Each 1 ml dose of Havrix contained inactivated hepatitis A virus adsorbed on to aluminium salt (Lot no.: AHAVB194BH; Expiry date: May 2010). Duration of the study: Primary Study: 13 months; LTFU up to Year 17.5. Criteria for evaluation: LTFU phase: Immunogenicity: Seropositivity rates (percentage of subjects with anti-hav antibody concentrations 15 miu/ml * ) and anti-hav antibody concentrations were measured 16.5 and 17.5 years after the first dose of the primary vaccination course. * The seropositivity cut-off for HAV antibodies was defined as 20 miu/ml up to Year 11.5 and 15 miu/ml from Year 11.5 onwards. Safety: Any SAE that had occurred since the last study visit and was considered by the investigator to have a causal relationship to primary vaccination was to be documented retrospectively. Any event related to a lack of vaccine efficacy (i.e. hepatitis A infection) or any SAE related to study participation (blood sampling) was also to be reported. Additional vaccination phase: Immunogenicity: The immune response to the additional vaccine dose was evaluated by measuring seropositivity rates (percentage of subjects with anti-hav antibody concentrations 15 miu/ml) and anti-hav antibody concentrations before, 14 and 30 days after the additional vaccine dose. Safety: Solicited local and general symptoms were reported during a period of 4 days (Day 0 to Day 3) after the additional vaccine dose. Other (unsolicited) events, including SAEs were reported for a period of 30 days (Day 0 to Day 29) after the additional vaccine dose. Statistical methods: Cohorts definitions: LT-Total cohort included all subjects who returned for a particular follow-up study visit. The LT- ATP cohort for immunogenicity included all the subjects who returned at the given time-point and had not been eliminated due to violations. Demography: Demographic characteristics (i.e. age, gender and race) at Years 16.5 and 17.5 were tabulated per group and overall. 110677 (HAV-112 EXT: MTH 198) and 110678 (HAV-112 EXT: MTH 210) 2
Immunogenicity: LTFU phase: Antibody persistence up to Year 17.5: The primary analysis was performed on the LT-ATP cohort for immunogenicity and the secondary analysis was performed on the LT Total cohort. Anti-HAV antibody persistence was described per group and overall, as follows: Anti-HAV seropositivity rates and geometric mean concentrations (GMCs) with 95% confidence intervals (CI) were tabulated for the LT-ATP cohort for immunogenicity and the LT Total cohort. The distribution of anti-hav antibody concentrations was graphically represented using reverse cumulative distribution curves (RCCs) at both the long-term time-points for the LT-ATP cohort for immunogenicity. The evolution of GMCs for anti-hav antibodies from Day 15 to Year 17.5 was graphically represented for the LT-ATP cohort for immunogenicity. Additional vaccination phase Analysis of the immune response to an additional HAV vaccine dose: Immune response to the additional dose was evaluated in terms of seropositivity status, anti-hav antibody concentrations and anamnestic response. Anamnestic response was defined as follows: Post-vaccination anti-hav antibody concentrations 15 miu/ml in subjects seronegative (i.e. with anti- HAV antibody concentrations < 15 miu/ml) at the pre-vaccination time-point. At least (i.e. greater than or equal to) a 4-fold rise in post-vaccination anti- HAV antibody concentrations in subjects seropositive with anti-hav antibody concentration 15 miu/ml and < 100 miu/ml at the pre-vaccination time-point. At least (i.e. greater than or equal to) a 2-fold rise in post-vaccination anti- HAV antibody concentrations in seropositive subjects with anti-hav antibody concentration 100 miu/ml at the pre-vaccination timepoint. A listing summarising the individual immunogenicity results of subjects at pre-vaccination, 14 days and 30 days after the additional vaccine dose administration was generated. Safety: LTFU phase: The analysis was performed on the LT Total cohort. At each long-term visit, SAEs considered related to the primary vaccination, related to study participation (blood sampling) and any event related to a lack of vaccine efficacy (i.e. hepatitis A infection) that had occurred since the previous study visit were to be documented. Additional vaccination phase: For analysis of the response to the additional vaccine dose, all subjects who received the additional vaccine dose were considered. Solicited, unsolicited AEs and SAEs were summarised in an individual listing per subject. 110677 (HAV-112 EXT: MTH 198) and 110678 (HAV-112 EXT: MTH 210) 3
Summary: Demography: At Year 17.5, the mean age of the subjects for the LT-ATP cohort for immunogenicity for the Pooled group was 47.4 years with a standard deviation of 5.62 years. All subjects were of Caucasian origin and the majority (74.7%) were female. The gender distribution and age distribution observed at Year 17.5 were comparable to the distribution observed in the primary study and thereby representative of the original study cohort. Immunogenicity: The immunogenicity analysis was performed on the LT-ATP cohort for immunogenicity (primary analysis), and the LT Total cohort. Since lot-to-lot consistency was demonstrated in the primary study, the data are presented for the Pooled group (Group 1 and 2 combined). In the LT-ATP cohort for immunogenicity, at Year 17.5 the anti-hav seropositivity rate was 96.7% with a GMC of 369.3 miu/ml. Table 2: Seropositivity rates and GMCs (calculated on seropositive subjects) for anti-hav antibody concentrations, for the Pooled group up to Year 17.5 (LT-ATP cohort for immunogenicity) Timing N S+ 95% CI GMC 95% CI n % LL UL (miu/ml) LL UL PII(M13) 137 137 100 97.3 100 4730.4 4016.1 5571.8 Year 2 137 136 99.3 96.0 100 1636.9 1389.1 1928.9 Year 3 133 132 99.2 95.9 100 1084.0 904.2 1299.7 Year 4 126 125 99.2 95.7 100 994.8 821.2 1205.0 Year 5 126 125 99.2 95.7 100 756.7 619.4 924.6 Year 6.5 119 118 99.2 95.4 100 713.5 586.9 867.4 Year 7.5 119 115 96.6 91.6 99.1 836.2 698.6 1000.9 Year 8.5 109 108 99.1 95.0 100 615.6 505.9 749.1 Year 9.5 98 97 99.0 94.4 100 857.5 713.4 1030.7 Year 10.5 86 86 100 95.8 100 786.2 631.5 978.9 Year 11.5 79 77 97.5 91.2 99.7 748.1 614.3 911.1 Year 11.5* 85 82 96.5 90.0 99.3 378.6 304.3 471.0 Year 12.5 93 90 96.8 90.9 99.3 419.3 335.1 524.8 Year 13.5 101 98 97.0 91.6 99.4 342.2 270.8 432.5 Year 14.5 102 100 98.0 93.1 99.8 318.9 257.0 395.5 Year 15.5 98 95 96.9 91.3 99.4 353.1 284.0 439.1 Year 16.5 101 97 96.0 90.2 98.9 339.9 273.2 422.9 Year 17.5 91 88 96.7 90.7 99.3 369.3 294.0 463.9 N: number of subjects with available results n (%): number (percentage) of subjects seropositive for anti-hav antibodies S+: Seropositivity for anti-hav antibodies defined as antibody concentrations 20 miu/ml for time-points up to Year 11.5 15 miu/ml for time-points Year 11.5* to Year 17.5 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit GMC: geometric mean concentration calculated on seropositive subjects PII(M13): post-vaccination blood sample obtained 13 months after the first vaccine dose of primary vaccination Year 17.5: post-vaccination blood sample obtained 17.5 years after the first vaccine dose of primary vaccination * The laboratory assay was changed at Year 11.5, and the serum samples of Year 11.5 were re-tested with the new assay kit (with a cut-off of 15 miu/ml). Note: the difference in the number of subjects at Year 11.5 and Year 11.5* (using the new assay cut-off) is attributed to fewer subjects being eliminated for abnormal serology evolution during re-testing. Note: Subjects who received additional vaccination at a given time-point were considered as seronegative for immunogenicity analysis for all subsequent time-points for the LT-ATP cohort for immunogenicity. Antibody response to the additional vaccination: One subject was seronegative for anti-hav antibodies (concentrations < 15 miu/ml) at the Year 16.5 follow-up visit and received an additional vaccine dose of Havrix within 12 months after the visit. One month after receiving the additional vaccine dose, an anamnestic response to the additional vaccine dose was observed in the subject, which was indicative of immune memory. Table 3: Individual listings of the immune response to the additional hepatitis A vaccine dose Group Time-point Anti-HAV Anti-HAV Anti-HAV Anti-HAV Anti-HAV Anamnestic 110677 (HAV-112 EXT: MTH 198) and 110678 (HAV-112 EXT: MTH 210) 4
determining eligibility (miu/ml) at time-point determining eligibility (miu/ml) PI(M1)* (miu/ml) prior to additional vaccine dose (miu/ml) at Day 14 postadditional vaccine dose (miu/ml) at Day 30 postadditional vaccine dose response** 1 Year 16.5 <15 65 16 3222 4894 Yes Group 1 received Havrix vaccine (Lot no. DHA531A4) at 0, 12 months in the primary study and an additional dose of Havrix at Year 16.5 PI(M1)* = Post-primary Dose 1 (Month 1) blood sample, anti-hav concentration re-tested with new assay kit with a cut-off of 15 miu/ml ** Anamnestic response was defined as At least (i.e. greater than or equal to) a 4-fold rise in post-vaccination anti- HAV antibody concentrations in subjects seropositive with anti-hav antibody concentration 15 miu/ml and < 100 miu/ml at the pre-vaccination time-point. Safety: LTFU phase: Serious adverse events: No SAEs related to the primary vaccination, study procedures or vaccination failure were reported during the LTFU period (Year 16.5 and Year 17.5). There were no fatalities reported during the study period. Additional vaccination phase: Solicited adverse events: The subject who received additional vaccination reported pain of grade 1 intensity for a period of two days after the additional vaccination. There were no reports of solicited general adverse events for this subject. Unsolicited adverse events, SAEs and pregnancies: No unsolicited adverse events, SAEs or pregnancies were reported following the administration of additional vaccine dose. Important safety information received after the data lock point (database freeze date): none Conclusions: Almost all (96.7%) subjects were seropositive for anti-hav antibodies 17.5 years after a two dose primary vaccination with inactivated HAV vaccine in a 0, 12 months schedule. There were no reports of SAEs related to primary vaccination, study procedures or vaccination failure during the long-term follow-up visits. The subject who had become seronegative at Year 16.5 of follow-up and received a single additional vaccine dose had a marked increase in anti-hav antibody concentrations, exhibiting an anamnestic response to the additional vaccine dose. There were no new seronegative subjects at Year 17.5. No SAEs were reported following the additional Havrix vaccination. The additional dose of Havrix was well tolerated. Date of report: 11 January 2011 110677 (HAV-112 EXT: MTH 198) and 110678 (HAV-112 EXT: MTH 210) 5
Appendix 1 to Synopsis for study HAV-112 EXT M210 (110678) Overview of Protocol Amendments Excerpt from protocol including final amendment version 8 dated 27-May-2010
etrack study numbers and Abbreviated Titles Protocol Title: 110677 to 110681 (HAV-112 Ext M198 to M246) GlaxoSmithKline Biologicals Clinical Research & Development Eighth Protocol Amendment e-track study No. 100571 (HAV-235 EXT: 112 M138) e-track study No. 100572 (HAV-236 EXT: 112 M150) e-track study No. 100573 (HAV-237 EXT: 112 M162) e-track study No. 100574 (HAV-238 EXT: 112 M174) e-track study No. 100575 (HAV-239 EXT: 112 M186) e-track study No. 110677 (HAV-112 EXT: M198) e-track study No. 110678 (HAV-112 EXT: M210) e-track study No. 110679 (HAV-112 EXT: M222) e-track study No. 110680 (HAV-112 EXT: M234) e-track study No. 110681 (HAV-112 EXT: M246) Note: The CPMS no. of the main protocol and the e-track study nos. for the long-term follow-up studies differ [Primary protocol number: 208109/108 (HAV-112)]. Double-blind randomized study to evaluate the immunogenicity and reactogenicity of two different lots of GlaxoSmithKline Biologicals inactivated hepatitis A vaccine injected according to a 0, 12 month schedule in healthy adult volunteers. Amendment number: Amendment 1 (Dated: 05 June 1992) Amendment 2 (Dated: 01 December 1993) Amendment 3 (Dated: 07 July 1998) Amendment 4 (Dated: 18 April 2001) Amendment 5 (Dated: 10 October 2003) Amendment 6 (Dated: 22 October 2004) Amendment 7 (Dated: 01 September 2008) Amendment 8 (Dated: 27 May 2010) Amendment date: 27 May 2010 Rationale/background for changes: The protocol is being amended to clarify the following details of the additional vaccination phase for Months 186 to 246: Pregnancy in females will not be documented during the persistence phase of the study and will be documented only in those females who receive the additional vaccination dose. The text in the statistical analysis section has been modified to add clarity to analyses for subjects who receive additional vaccine dose at Months 186, 198, 210, 222 and 246. Subjects who receive an additional vaccination at a previous time point will not be eligible to participate in the subsequent long-term follow-up time points of the study. Additionally, changes have also been made to the study intervals for the long-term time points. Minor typographical corrections were done throughout the document. 110678 (HAV-112 EXT: M210) - 1 -
110677 to 110681 (HAV-112 Ext M198 to M246) GlaxoSmithKline Biologicals Clinical Research & Development GlaxoSmithKline Biologicals. Hepatitis A vaccine (HAVRIX) Protocol Number: 208109/108 (HAV-112) dated 17 February 1992 Seventh Amendment Date: 01 September 2008 e-track study No. 100571 (HAV-235 EXT: 112 M138) e-track study No. 100572 (HAV-236 EXT: 112 M150) e-track study No. 100573 (HAV-237 EXT: 112 M162) e-track study No. 100574 (HAV-238 EXT: 112 M174) e-track study No. 100575 (HAV-239 EXT: 112 M186) e-track study No. 110677 (HAV-112 EXT: M198) e-track study No. 110678 (HAV-112 EXT: M210) e-track study No. 110679 (HAV-112 EXT: M222) e-track study No. 110680 (HAV-112 EXT: M234) e-track study No. 110681 (HAV-112 EXT: M246) NOTE: THE CPMS NO. OF THE MAIN PROTOCOL AND THE E-TRACK STUDY NOS. FOR THE LONG-TERM FOLLOW-UP STUDIES DIFFER. Protocol Title: Double-blind randomized study to evaluate the immunogenicity and reactogenicity of two different lots of GlaxoSmithKline Biologicals. inactivated hepatitis A vaccine injected according to a 0, 12 month schedule in healthy adult volunteers. First Protocol Amendment Dated: 5 June 1992 Second Protocol Amendment Dated: 1 December 1993 Third Protocol Amendment Dated: 7 July 1998 Fourth Protocol Amendment Dated: 18 April 2001 Fifth Protocol amendment dated: 10 October 2003 Sixth Protocol Amendment Date: 22 October 2004 RATIONALE FOR CHANGES: The protocol is currently being amended to extend the long-term follow-up period of the study to evaluate the persistence of humoral immune response to primary hepatitis A vaccination for a period of five years (i.e. additional follow-up time points at Months 198, 210, 222, 234 and 246) and to reflect the changes with respect to the administration of an additional dose of HAV vaccine. Up to Month 186, subjects that have been identified as seronegative for anti-hav antibodies (i.e titers < 15mIU/ml) during any of the previous long-term time points (i.e Months 138, 150, 162, 174 or 186) will be offered an additional dose of HAVRIX. between 6 to 12 months after the Month 186 time point. Further, from Month 198 onwards, if a subject becomes seronegative to anti-hav antibodies, at any of the long term follow up time point (Month 198, 210, 222, 234 or 246), then the subject will be offered a HAVRIX.vaccine that will be administered within 12 months from that time-point. This additional vaccination will include three visits: pre-vaccination blood sampling and the vaccination visit and two post-vaccination blood sampling visits at Day 14 and Day 30. 110678 (HAV-112 EXT: M210) - 2 -
Appendix 2 to Synopsis for study HAV-112 EXT M210 (110678) List of study sites Belgium (click to hide all sites in Belgium) GSK Investigational Site Wilrijk,, 2610; Completed;