Synopsis of study HBV-314 BST 280 (108988)

Transcription

1 Synopsis of study HBV-314 BST 280 (108988) Pharmaceutical entrepreneur: GlaxoSmithKline GmbH & Co. KG Prinzregentenplatz 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.

2 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: Engerix -B Name of active substance: Recombinant hepatitis B surface antigen (HBsAg) TABULAR FORMAT REFERRING TO PART OF THE DOSSIER Volume: (for national authority only) Page: Study No.: HBV-314 BST 280 (108988) Title of the study: A phase IV, open, multicentric study to evaluate the immune response to a hepatitis B challenge dose in healthy subjects, 72 to 78 months after they received a primary vaccination course of GSK Biologicals Engerix -B (thiomersal-free or preservative-free) vaccine, in the primary study HBV-280. Study centres: The study was conducted at three centres (two centres in Belgium and one centre in Australia). Publication (reference): For the /280 (HBV-280) primary study; Heron L, Selkinova O, Moiseieva A, Damme P V, Wielen M, Levie K, Hoet B and Stoffel M. Immunogenicity, reactogenicity and safety of two-dose versus three-dose (standard care) hepatitis B immunisation of healthy adolescents aged years: A randomized controlled trial. Vaccine 25: 2007; Study period: Study start date: 28 November 2007 Clinical phase: IV Study completion date: 14 May 2008 Objectives: Primary: To assess the immune response to a challenge dose of hepatitis B vaccine administered in subjects who previously received a complete hepatitis B primary vaccination course, 72 to 78 months ago. Secondary: To evaluate the immunogenicity of a challenge dose of hepatitis B vaccine. To evaluate safety and reactogenicity of a challenge dose of hepatitis B vaccine in terms of: solicited symptoms that occurred during the 4-day (Day 0 to Day 3) follow-up period. unsolicited symptoms that occurred during the 31-day (Day 0 to Day 30) follow-up period. serious adverse events (SAEs) following the challenge dose administration. Study design: The subjects were primed as adolescents with Engerix-B vaccine in the primary study (HBV- 280). Group 1 received 2 doses of thiomersal-free Engerix-B vaccine at 0 and 6 months, with placebo at Month 1. Group 2 received 3 doses of preservative-free Engerix-B at 0, 1 and 6 months. During the long-term follow-up (LTFU) phase of this study, blood samples were taken 30, 42, 54 and 66 months after primary vaccination to evaluate the long-term (LT) persistence of the immune response. The current study was the challenge dose phase of the HBV-280 primary study and was an open, non-randomised, multi-centric study. All subjects in both the groups received a challenge dose of hepatitis B vaccine. Blood samples were drawn just before and one month after administration of the challenge dose. HBV-314 BST 280 (108988) 1

3 Table 1: Subject attrition per group Number of subjects Total Group 1 Group 2 Number of subjects in the Total cohort in the primary study Number of subjects included in the according-to-protocol (ATP) cohort for immunogenicity in the primary study Number of subjects enrolled in the challenge dose study Number of subjects who received challenge dose Number of subjects in the Total Vaccinated cohort for primary analysis of safety* Number of subjects in the ATP cohort for immunogenicity* * The primary analyses of safety and immunogenicity were performed using the data obtained from the 2 centres in Belgium. The 67 subjects enrolled in the Australian centre were not included in the primary analyses due to noncompliance with good clinical practice (GCP) at the Australian centre. Diagnosis and criteria for inclusion: Healthy male or female subjects who received the complete primary vaccination course in the HBV-280 primary study, with written informed consent obtained prior to the challenge dose study start. If the female subjects were of childbearing potential they were to have practiced adequate contraception for 30 days prior to vaccination, to have a negative pregnancy test and agreed to continue such precautions for 2 months after the hepatitis B challenge dose. Composition and description of vaccines: Primary study: Study vaccine, dose, mode of administration, lot no.: Vaccination schedule /site: Deep intramuscular (IM) injection in the deltoid muscle of the non-dominant arm according to a 0, 6 month schedule. A placebo dose was given at Month 1. Vaccine composition/ dose/ lot number: Each dose of GSK Biologicals thiomersal-free Engerix-B vaccine contained recombinant HBsAg and aluminium salt. Lot no.: DENS001A4 (expiry date: 28 February 2003). Reference vaccine/ Comparator, dose and mode of administration, lot no.: Vaccination schedule /site: Deep IM injection in the deltoid muscle of the non-dominant arm according to a 0, 1, 6 month schedule. Vaccine composition/ dose/ lot number: Each dose of GSK Biologicals preservative-free Engerix-B vaccine contained recombinant HBsAg and aluminium salt. Lot no.: ENG5010B2 (expiry date: 18 December 2003). Challenge dose study: Vaccination schedule /site: All subjects who were eligible to receive the challenge dose received a single dose of GSK Biologicals Engerix-B as a deep IM injection in the deltoid region of the non-dominant arm. Vaccine composition/ dose/ lot number: One dose of GSK Biologicals preservative-free Engerix-B vaccine contained HBsAg and aluminium salt. Lot number: AHBVB239B (expiry date: 31 May 2009). Duration of the study: Approximately one month per subject. Criteria for evaluation: Immunogenicity: Measurement of anti-hbs antibody concentrations, prior to and one month after the challenge dose of hepatitis B vaccine in all subjects. Safety: Recording of solicited local and general adverse events during the 4-day (Day 0 to Day 3) follow-up period after the challenge dose. Recording of unsolicited adverse events that occurred during the 31-day (Day 0 to Day 30) follow-up period after the challenge dose and SAEs during the entire study period. HBV-314 BST 280 (108988) 2

4 Statistical methods: Analysis of demography: Demographic characteristics (age in years, gender and race), cohort description and withdrawal status were tabulated. The mean age (with the median and standard deviation) was calculated for the two study groups and overall. A summary of the tracking log-sheets documenting reasons for non-participation in the challenge dose study was generated. Analysis of immunogenicity: The primary analysis was performed on the ATP cohort for immunogenicity including subjects from the 2 Belgian centres only. An analysis based on the total vaccinated cohort for Belgian subjects, the total vaccinated cohort for subjects from the Australian centre and the overall total vaccinated cohort was performed additionally. All analyses were performed overall and per group. The percentage of subjects with an anamnestic response to the hepatitis B vaccine challenge dose with exact 95% confidence intervals (CIs) was tabulated. An 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. Anti-HBs antibody concentrations 10 miu/ml at the post-challenge dose time-point, in subjects seronegative at the pre-challenge dose time-point. The following analyses were performed at the pre and post-challenge time-point: Anti-HBs geometric mean concentrations (GMCs) with 95% CIs were tabulated primarily for seropositive subjects and secondarily for all subjects. The percentage of subjects seropositive, seroprotected and the percentage of subjects with anti-hbs antibody concentrations 100 miu/ml with exact 95% CIs were tabulated. The distribution of anti-hbs antibody concentrations was presented using reverse cumulative distribution curves. An exploratory analysis of the immune response to the challenge dose stratified according to the post-primary and pre-challenge dose anti-hbs antibody concentration was performed. Analysis of safety: The primary analysis was performed on the total vaccinated cohort including subjects from the Belgian centres only. An analysis based on the total vaccinated cohort for subjects from the Australian centre and the overall total vaccinated cohort was performed in addition. Solicited local and general symptoms that were reported during the 4-day follow-up period after the challenge dose, as well as unsolicited events that were reported during the 31-day follow-up period after vaccination were tabulated. SAEs reported during the entire study period were to be described in detail. Summary: Demography results: The mean age of the subjects in the ATP cohort for immunogenicity was 19.4 years. The percentage of females was 48.6%. All subjects were White/ Caucasian. Immunogenicity results: Anamnestic response to the challenge dose: One month after receiving the hepatitis B vaccine challenge dose: All subjects in both groups had mounted an anamnestic response to the challenge dose. All subjects in both groups had anti-hbs antibody concentrations 10 miu/ ml. The percentage of subjects with anti-hbs antibody concentrations 100 miu/ ml was 94.3% in Group 1 and 95.2% in Group 2. Anti-HBs GMCs had increased approximately 108-fold in Group 1 and 95-fold in Group 2. HBV-314 BST 280 (108988) 3

5 Table 2: Percentage of subjects with anti-hbs antibody concentrations 3.3 miu/ ml, 10 miu/ ml, 100 miu/ ml and anti-hbs GMCs (calculated on seropositive subjects) one month after the administration of the challenge dose vaccine (ATP cohort for immunogenicity) Group Timing N 3.3 miu/ ml 10 miu ml 100 miu/ ml GMC n % 95% CI n % 95% CI n % 95% CI value 95% CI LL UL LL UL LL UL LL UL Group 1 Pre Post Group 2 Pre Post Pooled Pre Post Group 1 = received two doses of Engerix-B in the primary study Group 2 = received three doses of Engerix-B in the primary study N = number of subjects with available results; n (%) = number (percentage) of subjects with antibody concentrations above the specified cut-off; 95% CI = exact 95% confidence interval; LL = Lower limit; UL = Upper limit GMC = geometric mean concentrations, calculated on seropositive subjects (anti-hbs 3.3 miu/ml) Pooled = Pooled results of Group 1 and Group 2; Pre: Prior to the administration of the challenge dose Post: One month after the administration of the challenge dose Safety results: For the pooled groups Any symptom: At least one symptom (solicited or unsolicited, local or general) was reported by 67.5% (52/ 77) of subjects during the 4-day post-challenge dose follow-up period. At least one local symptom (solicited or unsolicited) was reported by 46.8% (36/77) of subjects. At least one general symptom (solicited or unsolicited) was reported by 49.4% (38/77) of subjects. Solicited local symptoms: Pain at the injection site was the most frequent solicited local symptom (reported by 33.8% of subjects). None of the reported local symptoms were of Grade 3 intensity. Solicited general symptoms: Fatigue was the most frequent solicited general symptom (reported by 33.8% of subjects). One subject (1.3%) reported fatigue of Grade 3 intensity. Table 3: Incidence and nature of symptoms reported during the 4-day (Days 0-3) post-vaccination period (Total Vaccinated cohort). Group 1 (N=55) Group 2 (N=22) Pooled (N=77) n % 95% CI n % 95% CI n % 95% CI LL UL LL UL LL UL Any symptom General symptoms Local symptoms Solicited local symptoms Pain Any M.A Redness (mm) Swelling (mm) Any mm M.A Any mm M.A Solicited general symptoms Fatigue Any Grade Related Fever/ (Axillary) Related M.A Any C HBV-314 BST 280 (108988) 4

6 ( C) >38.0 C Related >39.5 C Related M.A Gastro- All Intestinal symptoms Related Related M.A Headache All Related Related M.A Group 1 = received two doses of Engerix-B in the primary study Group 2 = received three doses of Engerix-B in the primary study N = number of subjects who received the vaccine n (%) = number (percentage) of subjects who reported the symptom at least once 95% CI = Exact 95% confidence interval; LL = Lower limit, UL = Upper limit Any = all reports of the specified symptom irrespective of intensity grade and relationship to vaccination Grade 3 pain, fatigue, gastrointestinal symptoms, headache = pain, fatigue, gastrointestinal symptoms, headache that prevented normal activity Related = symptoms considered by the investigator to have causal relationship to vaccination Grade 3 Related = adverse event which prevented normal everyday activities and was assessed as causally related to vaccination M.A. = symptoms for which the subjects received medical attention Pooled = Pooled results of Group 1 and Group 2 Unsolicited symptoms: At least one unsolicited symptom was reported by 31.2% (24/ 77) of subjects. Five of these (transient visual impairment, injection site paraesthesia, myalgia, allergic dermatitis and rash) were considered to be causally related to vaccination. Five subjects (6.5%) reported unsolicited symptoms of Grade 3 intensity. Only one of these (myalgia) was considered by the investigator to be causally related to the vaccination. All reported adverse events (AEs) resolved by the end of the study. Serious adverse events: None of the subjects reported SAEs during study period. Pregnancies: No pregnancies were reported during the study period. Conclusions: Subjects, primed as adolescents with 2 doses of thiomersal-free Engerix-B vaccine (Group 1) or 3 doses of preservative-free Engerix-B vaccine (Group 2) responded to a hepatitis B vaccine challenge dose administered 6 years later as follows: All subjects in both groups mounted an anamnestic response to the challenge dose. All subjects in both groups had anti-hbs antibody concentrations 10 miu/ ml one month after the challenge dose. The percentage of subjects who had anti-hbs antibody concentrations 100mIU/ ml was 94.3% in Group 1 (two-dose, 20 µg) and 95.2% in Group 2 (three-dose, 10 µg) one month after the challenge dose. Anti-HBs GMCs increased approximately 108-fold in Group 1 and 95-fold in Group 2. The challenge dose vaccine was well tolerated by the subjects with low incidence of Grade 3 symptoms. No SAEs were reported during the study period. Date of report: 23 June HBV-314 BST 280 (108988) 5

7 Appendix 1 to Synopsis for study HBV-314 BST 280 (108988) Overview of Protocol Amendments No protocol amendments were submitted for this study.

8 Appendix 2 to Synopsis for study HBV-314 BST 280 (108988) List of study sites Australia GSK Investigational Site Westmead, New South Wales, 2145; Completed; Belgium GSK Investigational Site Bruxelles,, 1200; Completed; GSK Investigational Site Wilrijk,, 2610; Completed;