In February 2013, GlaxoSmithKline (GSK) announced a ... › ctr-gsk-7381 › 111149 › e... ·...

In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register.

The following guiding principles have been applied to the disclosure: Information will be excluded in order to protect the privacy of patients and all namedpersons associated with the study

Patient data listings will be completely removed* to protect patient privacy. Anonymized

data from each patient may be made available subject to an approved research

proposal. For further information please see the Patient Level Data section of the GSK

Clinical Study Register.

Aggregate data will be included; with any direct reference to individual patients excluded

*Complete removal of patient data listings may mean that page numbers are no longer consecutively

numbered

CONFIDENTIAL

28 Aug 2009 - 1 -

GlaxoSmithKline Biologicals

Study titleChallenge dose administration of Twinrix� or comparator 4 years after primaryvaccination.

Study detailed titleA phase IV, open, multicentre, multicountry study to evaluate the immune response to achallenge dose of GSK Biologicals� Twinrix� vaccine versus monovalent hepatitis Aand B vaccines from different manufacturers in healthy and non-healthy adults aged > 41years, approximately 48 months after primary vaccination in study 100382 (HAB-160).

Clinical Study Report for Studies 111149 (HAB-160 BST) and111572 (HAB-168 BST: 160)(Development Phase IV)

Indication Studied: Persistence of immunity in healthy and non-healthy(including those taking medications) adults older than 41 years, four years after aprimary vaccination course with three doses of Twinrix.

Study initiation date: 14 January 2008Study completion date: 03 November 2008Data lock point: 06 May 2009Date of report: 28 August 2009Earlier Study Reports100382 (HAB-160) 18 October 2005100383 (HAB-161 Ext 160 Year 1) 22 February 2006100384 (HAB-162 Ext 160 Year 2) 08 May 2007100385 (HAB-163 Ext 160 Year 3) 20 October 2008

Sponsor Signatories: MD, Senior Manager, Clinical R&DPaediatric and Hepatitis Vaccine, GlaxoSmithKlineBiologicals

Director, Global Clinical R&D,Paediatric and Hepatitis Vaccines, GlaxoSmithKlineBiologicals

This study was performed in compliance with Good Clinical Practice including thearchiving of essential documents.Copyright 2009 the GlaxoSmithKline group of companies. All rights reserved.Unauthorised copying or use of this information is prohibited.

CONFIDENTIAL

111149 (HAB-160 BST) and 111572 (HAB-168 BST: 160)Final

28 Aug 2009 1dee3ccd006b780331b8eb2e76a0a4ca2

CONFIDENTIAL111149 (HAB-160 BST) and 111572 (HAB-168 BST: 160)

Final

28 Aug 2009 - 2 -

SYNOPSIS

Name of company: GlaxoSmithKlineBiologicals, Rixensart, BelgiumName of finished product:Twinrix�,Havrix�, Engerix�-BName of active substance: Hepatitis Aantigen (strain HM 175), RecombinantHepatitis B surface antigen (HBsAg)

TABULAR FORMATREFERRING TO PARTOF THE DOSSIER

Volume:

Page:

(for national authorityonly)

Title of the study: A phase IV, open, multicentre, multicountry study to evaluate the immune responseto a challenge dose of GSK Biologicals� Twinrix� vaccine versus monovalent hepatitis A and Bvaccines from different manufacturers in healthy and non-healthy adults aged > 41 years, approximately48 months after primary vaccination in study 100382 (HAB-160).Principal investigators: The Leiter der klinischen Prüfung was in Germany. The principalinvestigators were Prof. for Belgium and Dr. for Czech Republic.Study centres: The study was conducted in nine centres, of which seven were in Germany, one inBelgium and one in Czech Republic.Publication (reference): Van der Wielen M, Van Damme P, Chlibek R, Smetana J, von Sonnenburg F.Hepatitis A/B vaccination of adults over 40 years old: Comparison of three vaccine regimens and effectof influencing factors. Vaccine. 2006; 6176: 1-7.Study period: Study initiation date: 14 January 2008Study completion date: 03 November 2008

Clinical phase: IV

Objectives:Primary:To evaluate the anti-HAV and anti-HBs immune memory (in terms of anti-HAV and anti-HBs immuneresponse elicited by the challenge dose) in a population > 41 years of age (healthy and non-healthy),approximately 48 months after the first dose of the primary vaccination course.Secondary:• To evaluate the long-term persistence elicited by Twinrix, Engerix-B/Havrix and HBVAXPRO/

Vaqta, in terms of anti-HAV seropositivity rates and GMTs as well as anti-HBs seropositivity rates,seroprotection rates and GMTs at Month 48.

• To evaluate the immune response to the challenge dose, two weeks (Day 14) and one month (Day30) after vaccination.

• To retrospectively evaluate all serious adverse events (SAEs) with causal relationship tovaccination or referring to hepatitis A or B infection from the previous study visit up to Month 48.

• To evaluate safety and reactogenicity of the challenge dose in terms of:− solicited symptoms occurring during the 4-day (Day 0-3) follow-up period.− unsolicited symptoms occurring during the 31-day (Day 0-30) follow-up period.− all SAEs following the challenge dose administration.

Study design: The study was an open, multicentric study. The treatment groups in the challenge dosestudy were the same as in the HAB-160 primary study.• Twinrix Group received combined hepatitis A/ hepatitis B vaccine, Twinrix at 0, 1, 6 months• ENG+HAV Group received separate administrations of monovalent hepatitis B vaccine, Engerix -

B, at 0, 1, 6 months and monovalent hepatitis A vaccine, Havrix, at 0, 6 months.• HBVX+VAQ Group received separate administrations of monovalent hepatitis B vaccine,

HBVAXPRO, at 0, 1, 6 months and monovalent hepatitis A vaccine, Vaqta, at 0, 6 months.In the challenge dose study, all subjects received one dose of Twinrix, Engerix-B co-administered withHavrix or HBVAXPRO co-administered with Vaqta according to their randomisation in the primarystudy. Blood samples were taken from all subjects before, two weeks and one month after the challengedose administration.Note: The challenge dose study was described in a separate protocol (HAB-168 BST: 160 [111572]) forthe Belgian and Czech centres. For the German centres it was described in an amendment to the HAB-160 BST (111149) protocol.

111149 (HAB-160 BST) and 111572 (HAB-168 BST:160) Synopsis page 1 of 9

CONFIDENTIAL




Final

28 Aug 2009 - 3 -



Volume:

Page:


The eligibility criteria, study visit procedures and data collection were identical in the two studies andthe data are presented together in this report.Number of subjects:

Planned: 495 subjects

Enrolled and vaccinated: 506 subjects (172 in the Twinrix group, 170 in the ENG+HAV group and 164in the HBVX+VAQ group)

Completed: 503 subjects (169 in the Twinrix group, 170 in the ENG+HAV group and 164 in theHBVX+VAQ group)

Safety: Total vaccinated cohort: 506 subjects (172 in the Twinrix group, 170 in the ENG+HAV groupand 164 in the HBVX+VAQ group)

Immunogenicity: LT According-to-protocol (ATP) cohort for immunogenicity: 419 subjects (148 in theTwinrix group, 147 in the ENG+HAV group and 124 in the HBVX+VAQ group).

Immunogenicity: ATP cohort (Challenge dose): 498 subjects (167 in the Twinrix group, 168 in theENG+HAV group and 163 in the HBVX+VAQ group).

Diagnosis and criteria for inclusion: Subjects who completed the primary vaccination phase of theHAB-160 study, who did not receive an additional hepatitis A and/or B vaccine and from whom writteninformed consent was obtained. If the subject was female, she was to be of non-childbearing potential,i.e., either surgically sterilised or one year post-menopausal; or, if of childbearing potential, she was tobe abstinent or have used adequate contraceptive precautions for 30 days prior to vaccination, have anegative pregnancy test and was to agree to continue such precautions for two months after thevaccination.Study vaccine, dose, mode of administration, lot no.:Primary studyVaccination schedule /site: The Twinrix group received an intramuscular (IM) administration of Twinrixvaccine in the left deltoid region at 0, 1, 6 months.Vaccine composition/ dose/ lot number: GSK Biologicals� combined hepatitis A and hepatitis B vaccine(Twinrix) contained per 1.0 ml: at least 720 ELISA units of hepatitis A antigen (strain HM 175 RIT4380), 20 µg of recombinant hepatitis B surface antigen (HBsAg), 5 mg of 2-phenoxyethanol and 0.45mg of aluminium (as salt). Lot No.: HAB298A6.Challenge dose studyVaccination schedule /site: The Twinrix group received a single intramuscular (IM) administration ofTwinrix vaccine in the left deltoid region.Vaccine composition/ dose/ lot number: The composition of the vaccine is the same as above. Lot noAHABB087C.Reference vaccine /Comparator, dose and mode of administration, lot no.:Primary studyVaccination schedule/site:• ENG+HAV group received separate IM administrations of Engerix-B (at 0, 1, 6 months) and

Havrix (at 0, 6 months) in the primary study. Engerix-B was administered in the left deltoid regionand Havrix was administered in the right deltoid region.

• HBVX+VAQ group received separate IM administrations of HBVAXPRO (at 0, 1 and 6 months)and Vaqta (at 0, 6 months) in the primary study. HBVAXPRO was administered in the left deltoidregion and Vaqta was administered in the right deltoid region.


CONFIDENTIAL




Final

28 Aug 2009 - 4 -



Volume:

Page:


Vaccine composition /dose /lot number:• GSK Biologicals� monovalent hepatitis B vaccine, Engerix-B (Lot No.: ENG5424B6), contained

per 1.0 ml dose: 20 µg of recombinant HBsAg and 0.5 mg of aluminium as salt. GSK Biologicals�monovalent hepatitis A vaccine, Havrix (Lot No.: VHA800D6), contained per 1.0 ml dose: at least1440 ELISA units of hepatitis A antigen (strain HM 175), 0.5 mg of aluminium as salt and 5 mg of2-phenoxyethanol.

• Sanofi Pasteur MSD�s monovalent hepatitis B vaccine, HBVAXPRO (Lot No.: HS38310/HU31690) contained per 1.0 ml dose: 10 µg of HBsAg and 0.5 mg of aluminium as salt. SanofiPasteur MSD�s monovalent hepatitis A vaccine, Vaqta (Lot No.: HS41410), contained per 1.0 mldose: 50 IU of hepatitis A antigen (CR 326F strain) and 0.45 mg of aluminium as salt.

Challenge dose studyVaccination schedule/site:• ENG+HAV group received concomitantly Havrix (right deltoid region) and Engerix-B (left deltoid

region).• HBVX+VAQ group received concomitantly Vaqta (right deltoid region), and HBVAXPRO (left

deltoid region).Vaccine composition /dose /lot number:• The composition of the vaccines is the same as above. Lot no. Engerix-B: AHBVB388A, Havrix:

AHAVB108E, HBVAXPRO: DEXTA264AZ, Vaqta: DEXTA265AZ.Duration of treatment: The duration of primary phase of the study was approximately seven months foreach subject; the long-term follow-up was conducted for four years after the first dose of the primaryvaccination and the challenge dose phase of the study lasted approximately one month per subject.Criteria for evaluation:Immunogenicity /efficacy: Measurement of antibody concentrations against each vaccine antigen, prior tothe challenge dose and approximately two weeks and one month after the challenge dose in all subjects.Safety /reactogenicity:Recording of solicited local (pain, redness and swelling) and general (fever, fatigue, headache andgastrointestinal symptoms) adverse events by the subjects during a 4-day follow-up period (Day 0 to Day3) after the challenge dose vaccination. Recording of unsolicited adverse events that occurred during the31-day (Day 0 to Day 30) follow-up period after the challenge dose vaccination and Serious AdverseEvents (SAEs) during the entire study period.Statistical methods:Analyses were performed as per the protocol.Analysis of demographicsDemographic characteristics (age in years, gender and race), cohort description and withdrawal statuswere summarised using descriptive statistics. Mean, median and standard deviation was provided forcontinuous data such as age. All the demographic analyses were performed stratified based on the threestudy groups in the primary study and overall. A summary of the tracking log-sheet documenting reasonsfor non-participation in the challenge dose study was provided.Analysis of immunogenicityPersistence of antibody response (LT-ATP cohort for immunogenicity)• Seroprotection rates, seropositivity rates and GMCs for anti-HBs antibodies with 95% confidence

intervals were tabulated at Month 48.• Seropositivity rates and GMCs for anti-HAV antibodies with 95% CI were tabulated at Month 48.• Distribution of anti-HAV and anti-HBs antibody concentrations at Month 48 was presented using

reverse cumulative distribution curves.• GMC evolution curves for anti-HAV and anti-HBs antibodies were generated.


CONFIDENTIAL




Final

28 Aug 2009 - 5 -



Volume:

Page:


Response to challenge doseThe primary analysis was based on the ATP cohort for immunogenicity. Since the percentage of enrolledsubjects excluded from this ATP cohort was less than 5%, a second analysis based on the TotalVaccinated cohort was not performed.The following analyses were performed:• The percentage of subjects with anti-HAV anamnestic response to the challenge dose with exact

95% CIs was tabulated.(Anamnestic response was defined as anti-HAV antibody concentrations ≥ 15 mIU/ml at onemonth post-challenge dose in subjects, seronegative at the pre-challenge time point or at least a 2-fold increase in anti-HAV antibody concentrations one month after the challenge dose, in subjectshaving anti-HAV antibody concentrations ≥ 100 mIU/ml at the pre-challenge time point or at leasta 4-fold increase in antibody concentrations one month after the challenge dose, in seropositivesubjects having anti-HAV antibody concentrations < 100 mIU/ml at the pre-challenge time point).

• The percentage of subjects with anti-HBs anamnestic response to the challenge dose with exact95% CIs was tabulated.(Anamnestic response was defined as at least a 4-fold increase in anti-HBs antibody concentrations,at one month post-challenge dose in subjects seropositive at the pre-challenge time point or anti-HBs antibody concentrations ≥ 10 mIU/ml at one month post-challenge dose in subjectsseronegative at the pre-challenge time point).

• Anti-HAV and anti-HBs GMCs with 95% CIs were tabulated primarily for seropositive subjects andsecondarily for all subjects at the three time points.

• The percentage of subjects seropositive for anti-HAV antibodies (anti-HAV antibody concentrations≥ 15 mIU/ml) with exact 95% CI was tabulated at the three time points (the same was also tabulatedstratified based on the baseline characteristics).

• The percentage of subjects with anti-HBs antibody concentrations ≥ 3.3 mIU/ml , percentage ofsubjects with anti-HBs antibody concentrations ≥ 10 mIU/ml and ≥ 100 mIU/ml with exact 95% CIswere tabulated at the three time points (the same was also tabulated stratified based on the baselinecharacteristics).

• The distribution of anti-HAV and anti-HBs antibody concentrations was presented using reversecumulative distribution curves.

• The percentage of subjects with anti-HBs antibody concentrations ≥ 3.3 mIU/ml, ≥ 10 mIU/ml, ≥100 mIU/ml, 30 days after the challenge dose according to their pre-challenge dose status and postprimary status were tabulated.

• The anamnestic response to the HBV challenge dose stratified based on the pre-challenge and postprimary vaccination status was also tabulated.

• The relationship between anti-HBs or anti-HAV antibody concentrations observed after thechallenge dose and at the pre-challenge time point were graphically represented.

Analysis of safetyThe analysis was based on the Total vaccinated cohort. Since less than 5% of the enrolled subjects wereeliminated from the ATP cohort for safety analysis, a second analysis was not performed on the ATPcohort for safety.The percentage of subjects with at least one local adverse event (solicited and unsolicited), with at leastone general adverse event (solicited and unsolicited) and with any adverse event (solicited andunsolicited) during the 4-day (Day 0-3) follow-up period after the vaccination was tabulated with exact95% CI. Similar tabulations were done for Grade 3 symptoms.


CONFIDENTIAL




Final

28 Aug 2009 - 6 -



Volume:

Page:


• The percentage of subjects reporting each individual solicited symptom during the 4-day follow-upperiod with exact 95% CI, by type of adverse event; by severity (any grade, Grade 3 only); forgeneral symptoms: by relationship to vaccination (any relationship, related only) was tabulated.

• The occurrence of fever was tabulated per 0.5 °C cumulative increments as well as the occurrenceof fever (> 39.5 °C oral/axillary temperature) with causal relationship to vaccination.

• The percentage of subjects with at least one report of an unsolicited adverse event classified by theMedical Dictionary for Regulatory Activities (MedDRA) and reported within the 31-day (Day 0-30) follow-up period after vaccination was tabulated with exact 95% CI. The same tabulation wasperformed for Grade 3 unsolicited adverse events and for unsolicited adverse events with a causalrelationship to vaccination.

• The percentage of subjects who reported the start of at least one concomitant medication (i.e. anymedication, antipyretic medication, prophylactic antipyretics) during the 4-day and 31-day (Day 0-30) follow-up period after vaccination was tabulated (with exact 95% CI).

• Serious adverse events with causal relationship to vaccination or referring to hepatitis A or Binfection from the previous study visit up to Month 48 were retrospectively evaluated.

• All SAEs that were reported following the challenge dose administration were tabulated.Summary:Demography: The demographic profile of the three groups of subjects was comparable with respect tomean age, gender, racial distribution and BMI. The mean age of the subjects in the ATP cohort forimmunogenicity ranged from 58.4 years to 59.4 years in the three groups, 50.2% of subjects were maleand the population was predominantly (99.8%) White/ Caucasian.Immunogenicity:At Month 48 for the LT ATP cohort for persistence,• Anti-HAV seropositivity rates were 97.3% in the Twinrix group, 93.9% in the ENG+HAV group

and 96.0% in the HBVX+VAQ group.• The percentage of subjects with anti-HBs antibody concentrations ≥ 10 mIU/ml was 57.1% in the

Twinrix group, 40.1% in the ENG+HAV group and 26.6% in the HBVX+VAQ group.One month after the challenge dose administration for the ATP cohort for immunogenicity,• An anamnestic response to the hepatitis A containing challenge dose was mounted by 98.2% of

subjects in the Twinrix group, 97.6% in the ENG+HAV group and 99.4% of subjects in theHBVX+VAQ group.

• An anamnestic response to the hepatitis B antigen containing challenge dose was mounted by93.4% of subjects in the Twinrix group, 88.1% of subjects in the ENG+HAV group and 83.4% ofsubjects in the HBVX+VAQ group.

• Anti-HAV seropositivity rates were 99.4% in all three groups.• Anti-HBs seroprotection rates were 95.2%, 90.5% and 85.3% in the Twinrix group, ENG+HAV

group and HBVX+VAQ group, respectively.Table 1 Seropositivity rates and GMCs (calculated on seropositive subjects) for anti-HAV and anti-HBsantibodies and percentage of subjects with anti-HBs antibody concentration ≥ 10 mIU/ml at Month 48for the LT ATP cohort for immunogenicity.Group Timing N Anti-HBs antibodies Timing N Anti-HAV antibodies

≥≥≥≥ 3.3 mIU/ml ≥≥≥≥ 10 mIU/ml GMC ≥≥≥≥ 15 mIU/ml GMCn % n % Value 95% CI n % Value 95% CI

LL UL LL ULTwinrix PIII(M7) 181 168 92.8 166 91.7 1153.9 829.8 1604.7 PIII(M7) 181 176 97.2 2746.5 2256.3 3343.2

PIII(M12) 168 153 91.1 147 87.5 339.2 248.6 462.9 PIII(M12) 168 162 96.4 891.0 747.3 1062.2PIII(M24) 171 136 79.5 127 74.3 113.2 83.9 152.8 PIII(M24) 171 164 95.9 271.6 229.0 322.2

Table continued below


CONFIDENTIAL




Final

28 Aug 2009 - 7 -



Volume:

Page:


Group Timing N Anti-HBs antibodies Timing N Anti-HAV antibodies≥≥≥≥ 3.3 mIU/ml ≥≥≥≥ 10 mIU/ml GMC ≥≥≥≥ 15 mIU/ml GMC

n % n % Value 95% CI n % Value 95% CILL UL LL UL

PIII(M24)* 169 137 81.1 125 74.0 99.3 75.4 130.7 - - - - - - -PIII(M36) 163 124 76.1 104 63.8 72.1 53.1 98.0 PIII(M36) 163 158 96.9 216.9 182.6 257.6PIII(M48) 147 113 76.9 84 57.1 42.3 31.3 57.3 PIII(M48) 147 143 97.3 212.9 177.2 255.6

ENG+ PIII(M7) 182 152 83.5 145 79.7 491.2 342.3 704.9 PII(M7) 182 180 98.9 1394.3 1159.8 1676.1HAV PIII(M12) 168 134 79.8 124 73.8 149.4 106.4 209.7 PII(M12) 168 165 98.2 530.6 442.0 637.1

PIII(M24) 176 123 69.9 88 50.0 46.5 33.0 65.4 PII(M24) 176 170 96.6 209.9 176.3 249.8PIII(M24)* 175 129 73.7 99 56.6 40.8 30.4 54.9 - - - - - - -PIII(M36) 167 105 62.9 75 44.9 34.1 24.6 47.2 PII(M36) 167 159 95.2 185.4 155.7 220.7PIII(M48) 147 91 61.9 59 40.1 23.6 17.5 31.8 PII(M48) 147 138 93.9 165.7 137.7 199.4

HBVX+ PIII(M7) 176 137 77.8 125 71.0 179.1 128.5 249.7 PII(M7) 176 174 98.9 3707.2 3081.4 4460.2VAQ PIII(M12) 165 109 66.1 93 56.4 53.1 39.3 71.6 PII(M12) 165 164 99.4 1200.5 999.3 1442.1

PIII(M24) 167 74 44.3 50 29.9 21.3 15.5 29.4 PII(M24) 167 163 97.6 362.0 303.5 431.8PIII(M24)* 165 76 46.1 56 33.9 22.3 16.9 29.4 - - - - - - -PIII(M36) 153 67 43.8 45 29.4 18.9 14.1 25.3 PII(M36) 153 148 96.7 278.5 229.4 338.2PIII(M48) 124 64 51.6 33 26.6 13.7 10.6 17.7 PII(M48) 124 119 96.0 277.4 226.1 340.2

GMC = geometric mean antibody concentration calculated on subjects with concentration ≥ 15 mIU/ml or ≥ 3.3 mIU/mlN = number of subjects with available results; n/% = number/percentage of subjects with concentration within the specified range95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper LimitPIII(M7) to PIII(M24) = anti-HBs antibody concentrations tested with AUSAB® EIA /Abbott assay with cut-off 3.3mIU/mlPIII(M24)* onwards = anti-HBs antibody concentrations tested with the in-house assay with cut-off 3.3mIU/mlPII(M48) = Blood sampling after the second dose; 48 months after the first dose of primary vaccination course etcTable 2 Seropositivity rates and GMCs (calculated on seropositive subjects) for anti-HAV and anti-HBsantibodies and percentage of subjects with anti-HBs antibody concentration ≥ 10 mIU/ml before andfollowing the challenge dose for the ATP cohort for immunogenicity.

Group Timing N Anti-HBs antibodies N Anti-HAV antibodies≥≥≥≥ 3.3 mIU/ml ≥≥≥≥ 10 mIU/ml GMC ≥≥≥≥ 15 mIU/ml GMC

n % n % Value 95% CI n % Value 95% CILL UL LL UL

Twinrix Pre 167 128 76.6 93 55.7 40.3 30.0 54.2 167 162 97.0 212.2 177.5 253.7PI(D14) 167 162 97.0 160 95.8 8936.9 6071.1 13155.4 167 166 99.4 2255.0 1928.5 2636.8PI(D30) 167 161 96.4 159 95.2 7233.7 4868.2 10748.7 167 166 99.4 4062.0 3451.1 4781.0

ENG Pre 168 107 63.7 72 42.9 26.7 19.6 36.3 168 157 93.5 175.4 147.3 208.9+HAV PI(D14) 168 160 95.2 150 89.3 1521.0 1012.5 2285.0 168 167 99.4 1774.3 1493.5 2107.9

PI(D30) 168 162 96.4 152 90.5 1242.5 823.5 1874.8 168 167 99.4 3124.1 2630.4 3710.5HBVX Pre 163 90 55.2 50 30.7 15.4 12.2 19.5 163 158 96.9 308.4 255.6 372.1+VAQ PI(D14) 163 146 89.6 140 85.9 1222.4 821.3 1819.3 163 162 99.4 2712.9 2290.4 3213.3

PI(D30) 163 145 89.0 139 85.3 1075.1 717.2 1611.4 163 162 99.4 7481.6 6358.3 8803.3GMC = geometric mean antibody concentration calculated on subjects with concentration ≥ 15 mIU/ml or ≥ 3.3 mIU/mlN = number of subjects with available results; n/% = number/percentage of subjects with concentration within the specified range95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper LimitPIII(M48) = Blood sampling after the third dose; 48 months after the first dose of primary vaccination course etcPII(M48) = Blood sampling after the second dose; 48 months after the first dose of primary vaccination course etcPre = Prior to administration of challenge dose; PI (D14) = Two weeks after the administration of the challenge dosePI (D30) = One month after the administration of the challenge doseSafety /reactogenicity: The safety and reactogenicity analyses were performed on the Total vaccinatedcohort.Any symptoms:• At least one symptom (solicited or unsolicited, local or general) was reported by 44.2% of subjects

in the Twinrix group, 34.1% of subjects in the ENG+HAV group and 47.0% of subjects in theHBVX+VAQ group.


CONFIDENTIAL




Final

28 Aug 2009 - 8 -



Volume:

Page:


• At least one symptom of grade 3 intensity was reported by 2.3% of subjects in the Twinrix groupand 2.4% of subjects in the HBVX+VAQ group. No subjects reported a symptom of grade 3intensity in the ENG+HAV group.

Solicited local symptoms• Pain was the most frequently reported solicited local symptom reported by 24.4%, 20.6% and

28.0% of subjects in the Twinrix, the ENG+HAV and HBVX+VAQ groups, respectively.• Local symptoms of grade 3 intensity were reported by less than 1.3% of subjects.Solicited general symptoms• Fatigue was the most frequently reported solicited general symptom reported by 16.9%, 14.1% and

17.1% of subjects in the Twinrix, ENG+HAV and HBVX+VAQ groups, respectively.• Fatigue and gastrointestinal symptoms were the most frequently reported solicited general

symptom of grade 3 intensity in the Twinrix group; each symptom reported by 1.2% of subjects.• Solicited general symptoms that were considered to be causally related to vaccination were

reported by a maximum of 13.4% of subjects.Unsolicited symptoms• Unsolicited symptoms of grade 3 intensity were reported by 2.3%, 1.2% and 0.6% of subjects in

the Twinrix, ENG+HAV and HBVX+VAQ groups, respectively, during the 31-day follow-upperiod after the challenge dose

• Unsolicited symptoms considered by the investigator to be causally related to vaccination werereported by 2.3% and 0.6% of subjects in the Twinrix and ENG+HAV groups, during the 31-dayfollow-up period after the challenge dose. No subjects reported unsolicited symptoms that wereconsidered by the investigator to be causally related to vaccination in the HBVX+VAQ group.

Serious adverse events:Three subjects (one in the Twinrix group and two in the ENG+HAV group) reported SAEs during thestudy period.

The event was consideredby the investigator to be possibly related to vaccination. At the time of last contact, the outcome of thisevent was recorded as resolving/ recovering.

Both eventsresolved and were considered by the investigator to be unrelated to vaccination.

Pregnancies: No pregnancies were reported during the study period.Table 3 Reactogenicity results during the 4-day follow-up period after challenge dose administration forthe total vaccinated cohort.

Twinrix ENG+HAV HBVX+VAQN n % N n % N n %

Any symptom 172 76 44.2 170 58 34.1 164 77 47.0General symptoms 172 40 23.3 170 34 20.0 164 41 25.0Local symptoms 172 58 33.7 170 43 25.3 164 61 37.2Solicited local symptoms

N* n % N* n % N* n %Pain Any 172 42 24.4 170 35 20.6 164 46 28.0

Grade 3 172 0 0.0 170 0 0.0 164 1 0.6Redness Any 172 22 12.8 170 10 5.9 164 19 11.6(mm) ≥ 50 mm 172 0 0.0 170 0 0.0 164 0 0.0

Table continued overleaf.111149 (HAB-160 BST) and 111572 (HAB-168 BST:160) Synopsis page 7 of 9

CONFIDENTIAL




Final

28 Aug 2009 - 9 -



Volume:

Page:


Swelling Any 172 9 5.2 170 3 1.8 164 12 7.3(mm) ≥ 50 mm 172 2 1.2 170 0 0.0 164 1 0.6Solicited general symptoms

Twinrix ENG+HAV HBVX+VAQN* n % N* n % N* n %

Fatigue All 172 29 16.9 170 24 14.1 164 28 17.1Grade 3 172 2 1.2 170 0 0.0 164 0 0.0Related 172 23 13.4 170 19 11.2 164 22 13.4Grade 3*Related 172 1 0.6 170 0 0.0 164 0 0.0

Gastrointestinal All 172 5 2.9 170 8 4.7 164 5 3.0symptoms Grade 3 172 2 1.2 170 0 0.0 164 0 0.0

Related 172 1 0.6 170 6 3.5 164 4 2.4Grade 3*Related 172 1 0.6 170 0 0.0 164 0 0.0

Headache All 172 21 12.2 170 20 11.8 164 18 11.0Grade 3 172 1 0.6 170 0 0.0 164 0 0.0Related 172 15 8.7 170 16 9.4 164 14 8.5Grade 3*Related 172 1 0.6 170 0 0.0 164 0 0.0

Fever All >37.5°C) 172 2 1.2 170 0 0.0 164 2 1.2(Axillary >38.0°C 172 1 0.6 170 0 0.0 164 2 1.2temperature) >38.5°C 172 1 0.6 170 0 0.0 164 1 0.6(°°°°C) >39.0°C 172 0 0.0 170 0 0.0 164 0 0.0

>39.5°C 172 0 0.0 170 0 0.0 164 0 0.0Related 172 1 0.6 170 0 0.0 164 1 0.6>39.5°C*Related 172 0 0.0 170 0 0.0 164 0 0.0

N = number of subjects with the administered dose; N* = number of subjects with a documented dose (for solicited symptoms)n/% = number/percentage of subjects reporting at least once the symptom; 95%CI = Exact 95% confidence interval; LL = Lower Llimit, UL =Upper Limit; All = Solicited symptoms of any intensity; Grade 3 = Solicited symptoms that prevented normal activitiesRelated = Solicited symptoms that were considered to be causally related to vaccination; Grade3*Rel = Solicited symptoms of grade 3 intensitythat were considered to be causally related to vaccination.Conclusions:• At Month 48, anti-HAV seropositivity rates were 97.3% in the Twinrix group, 93.9% in the

ENG+HAV group and 96.0% in the HBVX+VAQ group with GMCs of 212.9 mIU/ml in theTwinrix group, 165.7 mIU/ ml in the ENG+HAV group and 277.4 mIU/ml in the HBVX+VAQgroup.

• At Month 48, the percentage of subjects with anti-HBs antibody concentrations ≥ 10 mIU/ml was57.1% in the Twinrix group, 40.1% in the ENG+HAV group and 26.6% in the HBVX+VAQ groupwith GMCs of 42.3 mIU/ml in the Twinrix group, 23.6 mIU/ ml in the ENG+HAV group and 13.7mIU/ml in the HBVX+VAQ group.

• One month after the challenge dose, an anamnestic response to the hepatitis A containing challengedose was mounted by 98.2% of subjects in the Twinrix group, 97.6% in the ENG+HAV group and99.4% of subjects in the HBVX+VAQ group.

• One month after the challenge dose, an anamnestic response to the hepatitis B antigen containingchallenge dose was mounted by 93.4% of subjects in the Twinrix group, 88.1% of subjects in theENG+HAV group and 83.4% of subjects in the HBVX+VAQ group.

• One month after the challenge dose, anti-HAV seropositivity rates were 99.4% in the three groups.• One month after the challenge dose, the percentage of subjects with anti-HBs antibody

concentrations ≥ 10 mIU/ml was 95.2% in the Twinrix group, 90.5% in the ENG+HAV group and85.3% in the HBVX+VAQ group.

• The vaccines used in the study were well tolerated when administered as a challenge dose with alow incidence of grade 3 solicited local and general symptoms (less than 1.3%).

• Three subjects reported SAEs during the study period. One was considered by the investigator to bepossibly related to vaccination.


CONFIDENTIAL




Final

28 Aug 2009 - 10 -



Volume:

Page:


References: Van der Wielen M, Van Damme P, Chlibek R, Smetana J, von Sonnenburg F. HepatitisA/B vaccination of adults over 40 years old: Comparison of three vaccine regimens and effect ofinfluencing factors. Vaccine. 2006; 6176: 1-7Date of report: 28 August 2009


CONFIDENTIAL




Final

28 Aug 2009 - 11 -

TABLE OF CONTENTS

PAGE

SYNOPSIS......................................................................................................................2

GLOSSARY OF TERMS ...............................................................................................22

TRADEMARKS .............................................................................................................23

1. ETHICS..................................................................................................................241.1. Independent Ethics Committee (IEC) or Institutional Review Board

(IRB) ...........................................................................................................241.2. Ethical conduct of the study ........................................................................241.3. Subject information and consent.................................................................24

2. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .......................242.1. Administrative structure ..............................................................................24

3. INTRODUCTION....................................................................................................24

4. STUDY OBJECTIVES............................................................................................264.1. Primary objectives ......................................................................................264.2. Secondary objectives..................................................................................26

5. INVESTIGATIONAL PLAN.....................................................................................275.1. Study design...............................................................................................27

5.1.1. Overall study design � Description...............................................275.2. Study procedures........................................................................................28

5.2.1. Outline of study procedures .........................................................285.2.2. Intervals between study visits ......................................................30

5.3. Selection of study population ......................................................................315.3.1. Inclusion criteria...........................................................................315.3.2. Exclusion criteria..........................................................................325.3.3. Elimination criteria .......................................................................325.3.4. Contraindications to subsequent doses of vaccine.......................325.3.5. Warnings and precautions ...........................................................335.3.6. Subject completion and withdrawal from study ............................35

5.3.6.1. Subject completion .....................................................355.3.6.2. Subject withdrawal from the study ..............................355.3.6.3. Subject withdrawal from administration of the

investigational product................................................365.4. Composition and administration of vaccines ...............................................36

5.4.1. Description of vaccines ................................................................365.4.2. Dosage and administration ..........................................................375.4.3. Treatment allocation and randomisation ......................................385.4.4. Blinding........................................................................................38

5.5. Prior and concomitant medication/vaccinations ..........................................385.6. Laboratory assays and time points .............................................................395.7. Assessment of immunogenicity variables....................................................39

5.7.1. Immunological correlates of protection.........................................395.8. Assessment of safety variables...................................................................40

CONFIDENTIAL




Final

28 Aug 2009 - 12 -

5.8.1. Adverse events............................................................................405.8.1.1. Solicited adverse events.............................................41

5.8.2. Evaluating adverse events and serious adverse events...............415.8.3. Serious adverse events ...............................................................44

5.8.3.1. Follow-up of adverse events and seriousadverse events and assessment of outcome..............45

5.8.3.2. Time frames for submitting serious adverseevent reports to GSK Biologicals ................................46

5.8.4. Pregnancy ...................................................................................475.9. Data quality assurance ...............................................................................475.10. Statistical methods......................................................................................48

5.10.1. Primary endpoint..........................................................................485.10.2. Secondary endpoints ...................................................................485.10.3. Determination of sample size.......................................................495.10.4. Study cohorts /data sets analysed ...............................................495.10.5. Derived and transformed data......................................................515.10.6. Analysis of demographics ............................................................525.10.7. Analysis of immunogenicity..........................................................525.10.8. Analysis of safety.........................................................................535.10.9. Interim analysis............................................................................54

5.11. Changes in the conduct of the study or planned analyses ..........................545.11.1. Protocol amendments..................................................................545.11.2. Other changes .............................................................................55

6. STUDY POPULATION RESULTS..........................................................................556.1. Study dates.................................................................................................556.2. Subject eligibility and attrition from the study ..............................................56

6.2.1. Number of subjects......................................................................566.2.2. Study completion and withdrawal from study ...............................566.2.3. Protocol deviations (Long-term follow-up up to Month 48) ...........576.2.4. Protocol deviations (Challenge dose phase) ................................58

6.3. Demographic characteristics.......................................................................606.3.1. ATP cohort for immunogenicity ....................................................606.3.2. Total vaccinated cohort................................................................61

7. IMMUNOGENICITY RESULTS ..............................................................................617.1. Data sets analysed .....................................................................................617.2. According-to-protocol analysis ....................................................................61

7.2.1. Persistence phase .......................................................................617.2.1.1. Anti-HAV antibody persistence ...................................617.2.1.2. Anti-HBs antibody persistence....................................64

7.2.2. Challenge dose phase .................................................................677.2.2.1. Anti-HAV antibody response.......................................677.2.2.2. Anti-HBs antibody response .......................................72

7.3. Total vaccinated cohort analysis .................................................................797.4. Immunogenicity conclusions .......................................................................79

8. SAFETY RESULTS................................................................................................808.1. Data sets analysed .....................................................................................808.2. Total vaccinated cohort analysis .................................................................80

8.2.1. Overall incidence of adverse events ............................................818.2.2. Solicited local adverse events......................................................81

CONFIDENTIAL




Final

28 Aug 2009 - 13 -

8.2.3. Solicited general adverse events .................................................828.2.4. Unsolicited adverse events ..........................................................83

8.3. According-to-protocol cohort analysis .........................................................858.4. Serious adverse events ..............................................................................85

8.4.1. Fatal events .................................................................................858.4.2. Non-fatal events...........................................................................86

8.5. Adverse events leading to premature discontinuation of studyvaccine and/or study...................................................................................86

8.6. Concomitant medications............................................................................868.7. Pregnancy ..................................................................................................878.8. Safety conclusions......................................................................................87

9. DISCUSSION AND OVERALL CONCLUSIONS ....................................................889.1. Discussion ..................................................................................................889.2. Overall conclusions.....................................................................................88

10. SUPPLEMENTS.....................................................................................................90

11. REFERENCES.....................................................................................................123

12. STUDY REPORT AUTHORS /CONTRIBUTING AUTHORS................................125

13. SERIOUS ADVERSE EVENTS............................................................................12613.1. SAE Summary Table ................................................................................12613.2. CIOMS......................................................................................................127

MODULAR APPENDICES

CONFIDENTIAL




Final

28 Aug 2009 - 14 -

LIST OF TABLES

PAGE

Table 1 List of study procedures: Twinrix Group .................................................28

Table 2 List of study procedures: Engerix-B/Havrix Group..................................29

Table 3 List of study procedures: HBVX+/VAQ Group ........................................30

Table 4 Intervals between study visits.................................................................31

Table 5 Vaccines used in the primary phase and challenge dose phaseand their composition .............................................................................37

Table 6 Dosage and Administration ....................................................................38

Table 7 Laboratory Assays .................................................................................39

Table 8 Serology Plan.........................................................................................39

Table 9 Solicited local adverse events ................................................................41

Table 10 Solicited general adverse events............................................................41

Table 11 Intensity scales for solicited symptoms...................................................42

Table 12 Precision achieved with 445 subjects for various expected valuesof challenge dose response, in terms of exact two-sided 95% CI ...........49

Table 13 Number of subjects entered, completed and withdrawn withreason for withdrawal (Total vaccinated cohort) .....................................56

Table 14 Subject attrition from the primary study up to Year 4 (Month 48)time point (LT ATP cohort for immunogenicity).......................................58

Table 15 Number of subjects enrolled into the challenge dose study aswell as the number excluded from ATP analyses with reasons forexclusion ................................................................................................59

Table 16 Summary of demographic characteristics (ATP cohort forimmunogenicity) .....................................................................................60

Table 17 Seropositivity rates and GMCs (calculated on seropositivesubjects) for anti-HAV antibodies (LT ATP cohort forimmunogenicity) .....................................................................................62

Table 18 Anti-HBs seropositivity rates, percentage of subjects withantibody concentrations greater than or equal to 10 mIU per mland GMCs (calculated on seropositive subjects) (LT ATP cohortfor immunogenicity)................................................................................65

CONFIDENTIAL




Final

28 Aug 2009 - 15 -

Table 19 Seropositivity rates and GMCs (calculated on seropositivesubjects) for anti-HAV antibodies before and after the challengedose (ATP cohort for immunogenicity) ...................................................68

Table 20 Anamnestic response to the challenge dose for anti-HAVantibodies (ATP cohort for immunogenicity) ...........................................69

Table 21 Seroprotection and seropositivity rates and GMCs calculated onseropositive subjects for anti-HBs antibodies before and after thechallenge dose (ATP cohort for immunogenicity) ...................................73

Table 22 Anamnestic response to the challenge dose for anti-HBsantibodies (ATP cohort for immunogenicity) ...........................................74

Table 23 Percentage of subjects with anti-HBs antibody concentrationsgreater than or equal to 3.3 mIU/ml, greater than or equal to 10mIU/ml, greater than or equal to 100 mIU/ml after the challengedose according to their post-primary vaccination status (ATPcohort for immunogenicity) .....................................................................78

Table 24 Percentage of subjects with anti-HBs antibody concentrationsgreater than or equal to 3.3 mIU/ml, greater than or equal to 10mIU/ml, greater than or equal to 100 mIU/ml after the challengedose according to their pre-challenge dose status (ATP cohortfor immunogenicity)................................................................................79

Table 25 Number and percentage of subjects who received the studyvaccine dose (Total vaccinated cohort for the Challenge dose)..............80

Table 26 Incidence and nature of symptoms (solicited and unsolicited)reported during the 4-day (Days 0-3) post-vaccination period(Total vaccinated cohort for the Challenge dose) ...................................81

Table 27 Percentage of subjects who reported solicited local symptomsduring the 4-day (Days 0-3) post-vaccination period (Totalvaccinated cohort for Challenge dose) ...................................................82

Table 28 Percentage of subjects who reported solicited general symptomsduring the 4-day (Days 0-3) post-vaccination period (Totalvaccinated cohort for Challenge dose) ...................................................83

Table 29 Percentage of subjects reporting the occurrence of grade 3unsolicited symptoms classified by MedDRA Primary SystemOrgan Class and Preferred Term during the 31-day (Days 0-30)post-vaccination period (Total vaccinated cohort for Challengedose)......................................................................................................84

Table 30 Percentage of subjects who reported the occurrence ofunsolicited symptoms classified by MedDRA Primary SystemOrgan Class and Preferred Term with causal relationship tovaccination, during the 31-day (Days 0-30) post-vaccinationperiod (Total vaccinated cohort for Challenge dose) ..............................85

CONFIDENTIAL




Final

28 Aug 2009 - 16 -

Table 31 Percentage of subjects who started to take the specifiedconcomitant medication at least once during the 4-day (Days 0-3) post-vaccination period (Total vaccinated cohort for theChallenge dose).....................................................................................87

CONFIDENTIAL




Final

28 Aug 2009 - 17 -

LIST OF FIGURES

PAGE

Figure 1 Reverse cumulative curves for anti-HAV antibody concentrationsat pre time point at Month 48 (LT ATP cohort for immunogenicity) .........63

Figure 2 GMC evolution curve of anti-HAV antibody concentrations fromprimary to Month 48 time point (LT ATP cohort forimmunogenicity) .....................................................................................64

Figure 3 Reverse cumulative curves for anti-HBs antibody concentrationsat Month 48 (LT ATP cohort for immunogenicity) ...................................66

Figure 4 GMC evolution curve of anti-HBs antibody concentrations fromprimary to Month 48 time point (LT ATP cohort forimmunogenicity) .....................................................................................67

Figure 5 Reverse cumulative distribution curves for anti-HAV antibodyconcentrations before the challenge dose (ATP cohort forimmunogenicity) .....................................................................................70

Figure 6 Reverse cumulative distribution curves for anti-HAV antibodyconcentrations, 30 days after the challenge dose (ATP cohort forimmunogenicity) .....................................................................................71

Figure 7 Reverse cumulative distribution curves for anti-HBs antibodyconcentrations at the pre-challenge dose (ATP cohort forimmunogenicity) .....................................................................................75

Figure 8 Reverse cumulative distribution curves for anti-HBs antibodyconcentrations, 30 days after the challenge dose (ATP cohort forimmunogenicity) .....................................................................................76

CONFIDENTIAL




Final

28 Aug 2009 - 18 -

LIST OF SUPPLEMENTS

PAGE

Supplement 1 Number of subjects by centre (Total vaccinated cohort) .........................90

Supplement 2 Summary of tracking log-sheets for all subjects initially enrolledin the primary study (Total Vaccinated Cohort).......................................91

Supplement 3 Number of subjects at each visit and list of withdrawn subjects(Total vaccinated cohort)........................................................................91

Supplement 4 Summary of demographic characteristics (ATP cohort for safety) ..........92

Supplement 5 Summary of demographic characteristics (Total vaccinatedcohort)....................................................................................................93

Supplement 6 GMC calculated on all subjects for anti-HAV antibodies beforeand after the challenge dose (ATP cohort for immunogenicity)...............94

Supplement 7 Seropositivity rates and GMCs (calculated on seropositivesubjects) for anti-HAV antibodies stratified by gender (ATPcohort for immunogenicity) .....................................................................95

Supplement 8 Seropositivity rates and GMCs (calculated on seropositivesubjects) for anti-HAV antibodies stratified by age (ATP cohortfor immunogenicity)................................................................................96

Supplement 9 Seropositivity rates and GMCs (calculated on seropositivesubjects) for anti-HAV antibodies stratified by BMI status (ATPcohort for immunogenicity) .....................................................................97

Supplement 10 Seropositivity rates and GMCs (calculated on seropositivesubjects) for anti-HAV antibodies stratified by smoking status(ATP cohort for immunogenicity) ............................................................98

Supplement 11 Seropositivity rates and GMCs (calculated on seropositivesubjects) for anti-HAV antibodies stratified by alcoholconsumption status (ATP cohort for immunogenicity).............................99

Supplement 12 Seropositivity rates and GMCs (calculated on seropositivesubjects) for anti-HAV antibodies stratified by concomitantmedication intake status (ATP cohort for immunogenicity) ...................100

Supplement 13 Seropositivity rates and GMCs (calculated on seropositivesubjects) for anti-HAV antibodies stratified by medical conditionstatus (ATP cohort for immunogenicity)................................................101

Supplement 14 Seropositivity rates and GMCs (calculated on seropositivesubjects) for anti-HAV antibodies stratified by diabetes status(ATP cohort for immunogenicity) ..........................................................102

CONFIDENTIAL




Final

28 Aug 2009 - 19 -

Supplement 15 Anti-HAV antibody concentrations between pre and postchallenge dose (ATP cohort for immunogenicity) .................................103

Supplement 16 Reverse cumulative distribution curves for anti-HAVantibody concentrations, 14 days after the challenge dose (ATPcohort for immunogenicity) ...................................................................104

Supplement 17 GMCs calculated on all subjects for anti-HBsantibodies (ATP cohort for immunogenicity) before and afterthe challenge dose .............................................................................105

Supplement 18 Reverse cumulative distribution curves for anti-HBsantibody concentrations, 14 days after the challenge dose (ATPcohort for immunogenicity) ...................................................................106

Supplement 19 Anti-HBs seropositivity rates, percentage of subjects withantibody concentrations greater than or equal to 10mIU/ml andgreater than or equal to 100mIU/ml and GMCs (calculated onseropositive subjects) stratified by gender (ATP cohort forimmunogenicity) ...................................................................................107

Supplement 20 Anti-HBs seropositivity rates, proportion of subjects withantibody concentrations greater than or equal to 10 mIU/ml andgreater than or equal to 100 mIU/ml and GMCs (calculated onseropositive subjects) stratified by age (ATP cohort forimmunogenicity) ...................................................................................108

Supplement 21 Anti-HBs seropositivity rates, proportion of subjects withantibody concentrations greater than or equal to 10 mIU/ml andgreater than or equal to 100 mIU/ml and GMCs (calculated onseropositive subjects) stratified by BMI status (ATP cohort forimmunogenicity) ...................................................................................109

Supplement 22 Anti-HBs seropositivity rates, percentage of subjects withantibody concentrations greater than or equal to 10 mIU/ml andgreater than or equal to 100 mIU/ml and GMCs (calculated onseropositive subjects) stratified by smoking status (ATP cohortfor immunogenicity)..............................................................................110

Supplement 23 Anti-HBs seropositivity rates, proportion of subjects withantibody concentrations greater than or equal to 10mIU/ml andgreater than or equal to 100 mIU/ml and GMCs (calculated onseropositive subjects) stratified by alcohol consumption status(ATP cohort for immunogenicity) ..........................................................111

Supplement 24 Anti-HBs seropositivity rates, percentage of subjects withantibody concentrations greater than or equal to 10mIU/ml andgreater than or equal to 100mIU/ml and GMCs (calculated onseropositive subjects) stratified by concomitant medication intakestatus (ATP cohort for immunogenicity)................................................112

Supplement 25 Anti-HBs seropositivity rates, percentage of subjects withantibody concentrations greater than or equal to 10mIU/ml and

CONFIDENTIAL




Final

28 Aug 2009 - 20 -

greater than or equal to 100mIU/ml and GMCs (calculated onseropositive subjects) stratified by medical condition status (ATPcohort for immunogenicity) ...................................................................113

Supplement 26 Anti-HBs seropositivity rates, percentage of subjects withantibody concentrations greater than or equal to 3.3mIU/ml,greater than or equal to 10mIU/ml and greater than or equal to100mIU/ml and GMCs (calculated on seropositive subjects)stratified by diabetes status (ATP cohort for immunogenicity) ..............114

Supplement 27 Anamnestic response to the challenge dose with ant-HBsantibody concentrations stratified based on the post-primaryvaccination status (ATP cohort for immunogenicity) .............................115

Supplement 28 Anamnestic response to the challenge dose for anti-HBsantibodies stratified based on the pre-challenge dose (ATPcohort for immunogenicity) ...................................................................116

Supplement 29 Anti-HBs antibody concentration between pre and postchallenge dose (ATP cohort for immunogenicity) .................................117

Supplement 30 Compliance in returning symptom sheets (Totalvaccinated cohort for the Challenge dose) ...........................................117

Supplement 31 Incidence and nature of grade 3 symptoms (solicited andunsolicited) reported during the 4-day (Days 0-3) post-vaccination period (Total vaccinated cohort for Challenge dose)..........118

Supplement 32 Incidence and nature of symptoms (solicited andunsolicited) with causal relationship to vaccination, reportedduring the 4-day (Days 0-3) post-vaccination period (Totalvaccinated cohort for Challenge dose) .................................................118

Supplement 33 Percentage of subjects who reported the occurrenceof unsolicited symptoms classified by MEDDRA PrimarySystem Organ Class and Preferred Term during the 31-day(Days 0-30) post-vaccination period (Total vaccinated cohort forChallenge dose)...................................................................................119

Supplement 34 Percentage of subjects who started to take the specifiedconcomitant medication at least once during the 31-day (Days 0-30) post-vaccination period (Total vaccinated cohort for theChallenge dose)...................................................................................121

Supplement 35 Percentage of subjects who took the specifiedconcomitant medication at least once during the 4-day (Days 0-3) post-vaccination period (Total vaccinated cohort for theChallenge dose)...................................................................................121

Supplement 36 Percentage of subjects who took the specifiedconcomitant medication at least once during the 31-day (Days 0-30) post-vaccination period (Total vaccinated cohort for theChallenge dose)...................................................................................122

CONFIDENTIAL




Final

28 Aug 2009 - 21 -

LIST OF ABBREVIATIONSAE Adverse event

ATP According-to-protocol

BMI Body mass index

CI Confidence interval

CEVAC Centre for Vaccinology, Ghent University and Hospital,Ghent, Belgium

eCRF Electronic Case Report Form

GMC Geometric mean concentration

GSK GlaxoSmithKline

HIV Human Immunodeficiency virus

IEC Independent Ethics Committee

IND Investigational New Drug

LT Long-term

IRB Institutional Review Board

MedDRA Medical Dictionary for Regulatory Activities

PFS Pre-filled syringes

RDE Remote data entry

SAE Serious adverse event

CONFIDENTIAL




Final

28 Aug 2009 - 22 -

GLOSSARY OF TERMS

Adverse event: Any untoward medical occurrence in a patient or clinicalinvestigation subject, temporally associated with the use of amedicinal product, whether or not considered related to themedicinal product.

An AE can therefore be any unfavorable and unintendedsign (including an abnormal laboratory finding), symptom,or disease (new or exacerbated) temporally associated withthe use of a medicinal product. For marketed medicinalproducts, this also includes failure to produce expectedbenefits (i.e. lack of efficacy), abuse or misuse.

Completed: Subjects who completed the last study visit.

Diary card: Cards given to the parents /guardians /subjects by theinvestigator to record adverse events following vaccination.

Eligible: Qualified for enrolment into the study based upon strictadherence to inclusion /exclusion criteria.

Evaluable: Meeting all eligibility criteria, complying with theprocedures defined in the protocol, and, therefore, includedin the analysis.

Subject(s): Term used throughout the protocol to denote an individualwho has been contacted in order to participate in the clinicalstudy, either as a recipient of the investigational product(s)or as a control.

Symptom sheet: Specific pages in the individual case report form onto whichthe investigator transcribed from the diary card and/or othersource documentation on solicited adverse event(s) reportedby the subject /parents /guardians (one sheet for solicitedlocal adverse events, one sheet for solicited general adverseevents).

CONFIDENTIAL




Final

28 Aug 2009 - 23 -

TRADEMARKS

The following trademarks are used in the present report.

Note: In the body of the Study Report (including the synopsis), the names of the vaccinesand/or medications will be written without the subscript symbol � or ®.

Trademarks of the GlaxoSmithKlinegroup of companies

generic description

Engerix�-B Hepatitis B vaccine.Havrix� Hepatitis A vaccineTwinrix� Combined hepatitis A and hepatitis B

vaccine.

Trademarks not owned by theGlaxoSmithKline group of companies

generic description

HBVAXPRO� Merck�s Hepatitis B vaccine.Vaqta� Merck�s Hepatitis A vaccine

CONFIDENTIAL




Final

28 Aug 2009 - 24 -

1. ETHICS

1.1. Independent Ethics Committee (IEC) or Institutional ReviewBoard (IRB)

The primary study protocol (HAB-160) dated 16 September 2003, first amendment dated28 August 2007, second amendment and the study protocol for the 111572 (HAB-168BST 160) study, both dated 25 January 2008, the informed consent and other informationthat required pre-approval were reviewed and approved by a national, regional, orinvestigational centre IEC.

1.2. Ethical conduct of the study

This study was conducted in accordance with "good clinical practice" (GCP) and allapplicable regulatory requirements, including, where applicable, the Declaration ofHelsinki.

1.3. Subject information and consent

Written informed consent was obtained from each subject prior to the performance of anystudy-specific procedures. Electronic case report forms (eCRF) were provided for eachsubject�s data to be recorded.

2. INVESTIGATORS AND STUDY ADMINISTRATIVESTRUCTURE

2.1. Administrative structure

This study was conducted by nine investigators in three countries: Germany, Belgiumand Czech Republic. The principal investigators for the study were Prof.

(Belgium) and Dr. (Czech Republic). The Leiter der KlinischenPrüfung was

3. INTRODUCTION

Hepatitis A and hepatitis B infections represent the most frequent forms of viralinfections of the liver. These diseases cause serious public health problems and affectcommunities worldwide. It has been recognised that vaccination is the only methodconferring long-term protection against HAV and HBV clinical disease and/or infection.GlaxoSmithKline Biologicals has developed a combined hepatitis A/hepatitis B vaccineTwinrix administered according to a 3-dose schedule (0, 1, 6 months). Several studies,conducted in mainly young subjects, have shown that the immunogenicity and safety ofTwinrix is at least as good as that of the monovalent vaccines Engerix-B and Havrixgiven concomitantly.

CONFIDENTIAL




Final

28 Aug 2009 - 25 -

The immune response after vaccination with GSK Biologicals combined hepatitis A andB vaccine as well as monovalent hepatitis A and B vaccines from different manufacturersis known to be influenced by several factors including age, gender and BMI [Reutter,1998, White, 1978]. The responses after immunisation of elderly individuals withhepatitis A and hepatitis B vaccines is a topic that is becoming increasingly relevant asthe number of aged people travelling to exotic destinations increases. Recent studies haveindicated that immune memory persists beyond the time at which anti-HBs antibodylevels may no longer be detectable and protects against clinically relevant disease. In caseof exposure to HBV antigen, this immune memory leads to a rapid and vigorous antibodyresponse [Bauer, 2006].

To document the immunogenicity of Twinrix in an older population, subjects aged 41years or more with a wide range in body weight and variable general health status wereenrolled into the primary study [GlaxoSmithKline Biologicals Report 100382]. Thispopulation mirrored the real-life > 41 year-old population. The study demonstrated thatthe combined hepatitis A/hepatitis B vaccine, Twinrix, induces superior hepatitis Bimmune response compared to monovalent vaccines Engerix-B (co-administered withHavrix) or HB VAX PRO (co-administered with Vaqta) in this population. Exploratoryanalysis showed that the vaccine received had the most significant influence on the anti-HBs antibody concentrations achieved at the post primary time-point, followed by age,BMI and gender. A similar exploratory analysis on anti-HAV antibody concentrationspost-primary vaccination showed that BMI had the most significant influence, followedby age, gender and vaccine received.

Persistence of anti-HAV and anti-HBs antibodies was evaluated in all groups one, twoand three years after the primary vaccination [GlaxoSmithKline Biologicals� Report100383, 100384 and 100385]. The vaccine received was shown to have the mostsignificant influence on the anti-HBs antibody persistence, followed by BMI, age andgender. A similar exploratory analysis on anti-HAV antibody persistence showed thatBMI had the most significant influence followed by age, gender and the vaccine received.

In the current study, data concerning the long-term (up to 48 months) anti-HBsseropositivity rates and seroprotection rates and the long-term anti-HAV seropositivityrate in this population was assessed. In addition, a single challenge dose of the samevaccine(s) as in the primary study was/were administered. Antibody concentrationsbefore, 14 and 30 days after this challenge dose were measured to evaluate the immunememory to the HAV and HBV antigens four years after primary vaccination.

At the request of the Czech authorities the challenge dose study was described in aseparate protocol (HAB-168 BST: 160 [111572]) for the Belgian and Czech centers. Forthe German centres it was described in an amendment to the HAB-160 BST (111149)protocol. The eligibility criteria, study visit procedures and data collection were identicalin the two studies and the data therefore was combined for analysis and this reportpresents the results of this combined analysis.

CONFIDENTIAL




Final

28 Aug 2009 - 26 -

4. STUDY OBJECTIVES

4.1. Primary objectives

To evaluate the anti-HAV and anti-HBs immune memory (in terms of anti-HAV andanti-HBs immune response elicited by the challenge dose) in a population > 41 years ofage (healthy and non-healthy), approximately 48 months after the first dose of theprimary vaccination course.

4.2. Secondary objectives

• To evaluate the long-term persistence elicited by Twinrix, Engerix-B/Havrix and HBVAX PRO/Vaqta, in terms of anti-HAV seropositivity rates and GMTs as well asanti-HBs seropositivity rates, seroprotection rates and GMTs at Month 48.

• To evaluate the immune response to the challenge dose, two weeks (Day 14) and onemonth (Day 30) after vaccination.

• To retrospectively evaluate all serious adverse events (SAEs) with causalrelationship to vaccination or referring to hepatitis A or B infection from theprevious study visit up to Month 48.

• To evaluate safety and reactogenicity of the challenge dose in terms of:

− solicited symptoms occurring during the 4-day (Day 0-3) follow-up period.

− unsolicited symptoms occurring during the 31-day (Day 0-30) follow-up period.

− all SAEs following the challenge dose administration.See Section 5.10 for details of the study endpoints.

CONFIDENTIAL




Final

28 Aug 2009 - 27 -

5. INVESTIGATIONAL PLAN

5.1. Study design

5.1.1. Overall study design – Description

Visit 10 One

month after Visit 8

Post-challenge BS

Visit 9 Two weeks after Visit 8 Post challenge BS

Visit 8 Month 48 Pre-challenge BS

Randomization (1:1:1), stratified by age, gender and BMI

Open Vaccination Visits

Persistence follow-up visits

Twinrix (N = 200)

Engerix-B/Havrix (N =200)

HB VAX PRO/Vaqta (N = 200)

Visit 1 Visit 4

Month 7

Visit 5 Month 12 Post-Vacc 3 BS



Screening

Day -21 to Day 0 Visit 2 Visit 3

Month 1 Month 6 Day 0 Post-Vacc 3

Vaccination: Twinrix or Eng/Hav* or HB/Vaqta**

Vaccination: Twinrix or Eng* or HB**


Pre-Vacc BS BS Vaccination:

Twinrix or Eng/Hav* or HB/Vaqta**

Challenge dose visits

BS: blood-sampling time-pointPre-Vacc: pre-vaccination; Post-Vacc 3: post-vaccination 3*Group Engerix-B (Eng) + Havrix (Hav)** Group HB VAX PRO (HB) + Vaqta

• Experimental design: open, multicentre study with three parallel groups.

• The study was self-contained.

• Treatment groups for the challenge dose study were the same as in the HAB-160primary study: all subjects received one dose of Twinrix, Engerix-B co-administeredwith Havrix or HBVAXPRO co-administered with Vaqta according to theirrandomisation in the primary vaccination study.

• Data collection: Remote data entry (RDE).

• Study duration: Approximately one month per subject after he/she received thechallenge dose.

• The challenge dose study was described in a separate protocol (HAB-168 BST: 160[111572]) for the Belgian and Czech centers. For the German centres it wasdescribed in an amendment to the HAB-160 (111149) protocol. The eligibilitycriteria, study visit procedures and data collection was identical in the two studiesand the data are presented together in this report.

CONFIDENTIAL




Final

28 Aug 2009 - 28 -

5.2. Study procedures

5.2.1. Outline of study procedures

The outline of study procedures for the three groups is presented in Table 1, Table 2 andTable 3.

Table 1 List of study procedures: Twinrix Group

Visit VISIT 8 VISIT 9 VISIT 10Timing Month 48 Day 14 after Month 48 Day 30 after Month 48Sampling time point Pre-challenge dose Post-challenge dose Post-challenge doseInformed consent ●Check inclusion criteria ●Check exclusion criteria ●Check elimination criteria ○ ○Check contraindications ●Check warnings and precautions ●Physical examination ○Recording of concomitant medication bysubjects on diary card

●

Transcription of concomitant medication ●Return of medication diary card ●Pre-vaccination body temperature ●Pregnancy test (urine test) ●Blood sampling for Ab determination (5 ml) ● ● ●Vaccination Twinrix ●Daily post-vaccination recording of solicitedsymptoms (Days 0�3) by subjects

●

Recording of non-serious adverse eventswithin 30 days post-vaccination, byinvestigator

●

Transcription of diary cards by investigator ●Reporting of SAEs ● ●Study Conclusion ●● study procedure that required documentation in the individual CRF or SAE form○ study procedure that did not require documentation in the individual CRF

CONFIDENTIAL




Final

28 Aug 2009 - 29 -

Table 2 List of study procedures: Engerix-B/Havrix Group


●

Transcription of concomitant medication ●Return of medication diary card ●Pre-vaccination body temperature ●Pregnancy test (urine test) ●Blood sampling for Ab determination (5 ml) ● ● ●Vaccination Engerix-BHavrix

●●

Daily post-vaccination recording of solicitedsymptoms (Days 0�3) by subjects

●


●

Transcription of diary cards by investigator ●Reporting of SAEs ● ●Study Conclusion ●● study procedure that required documentation in the individual CRF or SAE form○ study procedure that did not require documentation in the individual CRF

CONFIDENTIAL




Final

28 Aug 2009 - 30 -

Table 3 List of study procedures: HBVX+/VAQ Group


●

Transcription of concomitant medication ●Return of medication diary card ●Pre-vaccination body temperature ●Pregnancy test (urine test) ●Blood sampling for Ab determination(5 ml) ● ● ●

Vaccination HBVAXPROVaqta

●●

Daily post-vaccination recording ofsolicited symptoms (Days 0�3) bysubjects

●


●

Transcription of diary cards byinvestigator

●

Reporting of SAEs ● ●Study Conclusion ●● study procedure that required documentation in the individual CRF or SAE form○ study procedure that did not require documentation in the individual CRF

It was the investigator�s responsibility to ensure that the intervals between visits arestrictly followed. These intervals determine each subject�s evaluability in the according-to-protocol (ATP) analyses (see Sections 5.3.3 and 5.10.4 for details of criteria forevaluability and cohorts to be analysed).

5.2.2. Intervals between study visits

The intervals between study visits are given in Table 4.

CONFIDENTIAL




Final

28 Aug 2009 - 31 -

Table 4 Intervals between study visits

Study visits Protocol-defined interval Intervals used for inclusion inATP Immunogenicity cohort

Visit 1 → Visit 8 (Day 0 � Month 48) 48-60 months 46-60 monthsVisit 8 → Visit 9 (Month 48 � Day 14 afterchallenge dose)

14 ± 2 days 14 ± 2 days

Visit 8 → Visit 9 (Month 48 � Day 30 afterchallenge dose)

30-48 days 21-48 days

5.3. Selection of study population

All 590 subjects who completed the primary vaccination course in study HAB-160 wereinvited to participate in the challenge dose study. 276 subjects were expected to berecruited in the Belgian and Czech centres and 219 subjects in the German centres.

At the time of initiation of the study, the investigator was to contact ALL subjects whocompleted the primary vaccination course in the study 100382 (HAB-160). If at the timeof initiation of the challenge dose study, any subject declined participation, refusal wasdocumented as instructed on the �subject tracking document� provided by GSKBiologicals. The information was entered in the GSK Biologicals� clinical database foruse in identification of any safety issue(s) that may have prevented a subject�sparticipation.

See Section 5.10.3 for a detailed description of the criteria used in the estimation ofsample size for the challenge dose study.

5.3.1. Inclusion criteria

All subjects were to satisfy the following criteria at study entry:

• Subjects who the investigator believed that they could and would comply with therequirements of the protocol (e.g., completion of the diary cards, return for follow-upvisits) were enrolled in the study.

• A male or female who completed the primary vaccination phase of the HAB-160study.

• Written informed consent obtained from the subject.

• If the subject was female, she was to be of non-childbearing potential, i.e., eithersurgically sterilised or one year post-menopausal; or, if of childbearing potential, shewas to be abstinent or have used adequate contraceptive precautions (i.e., intrauterinecontraceptive device; oral/long term hormonal contraceptives; diaphragm or condomin combination with contraceptive jelly, cream or foam) for 30 days prior tovaccination, have a negative pregnancy test and was to agree to continue suchprecautions for two months after the vaccination.

CONFIDENTIAL




Final

28 Aug 2009 - 32 -

5.3.2. Exclusion criteria

The following criteria were checked at the time of study entry. If any applied, the subjectwas not included in the study:

• Use of any investigational or non-registered product (drug or vaccine) other than thestudy vaccines within 30 days preceding the challenge dose, or planned use duringthe study period.

• History of any hepatitis A or hepatitis B vaccination or infection since the primaryvaccination study.

• History of allergic disease or reactions likely to be exacerbated by any component ofthe vaccine.

• Acute disease at the time of enrolment. (Acute disease was defined as the presence ofa moderate or severe illness with or without fever. All vaccines could beadministered to persons with a minor illness such as diarrhoea, mild upperrespiratory infection with or without low-grade febrile illness, i.e., Oral/ axillarytemperature < 37.5°C) [37.0°C for Czech Republic only].

• Pregnant or lactating female.

5.3.3. Elimination criteria

The following criteria were checked at each visit subsequent to the first visit. If anybecame applicable during the study, it did not require withdrawal of the subject from thestudy but determined a subject�s evaluability in the ATP analysis.

• Use of any investigational or non-registered product (drug or vaccine) other than thestudy vaccine(s) during the study period.

5.3.4. Contraindications to subsequent doses of vaccine

The following events constituted absolute contraindications to administration of Twinrix,Engerix-B /Havrix, or HBVAXPRO/Vaqta; if any of these events had occurred during theprimary study HAB-160, the subject was not to receive the challenge dose of the vaccinesbut could continue other study procedures at the discretion of the investigator. Thesubject was to be followed up until resolution of the event:

• Anaphylactic reaction following the administration of vaccines.The following events constituted contraindications to administration of Twinrix, orEngerix-B/Havrix, or HBVAXPRO/Vaqta at that point in time; if any one of these eventsoccurred at the time scheduled for vaccination, the subject was vaccinated at a later date,within the time window specified, or withdrawn at the discretion of the investigator. Thesubject was followed until resolution of the event.

• Acute disease at the time of vaccination. (Acute disease was defined as the presenceof a moderate or severe illness with or without fever. All vaccines could beadministered to persons with a minor illness such as diarrhoea, mild upperrespiratory infection with or without low-grade febrile illness, i.e., Oral/ axillary

CONFIDENTIAL




Final

28 Aug 2009 - 33 -

temperature < 37.5°C [< 37.0°C for Czech Republic only] at the time ofvaccination.)

5.3.5. Warnings and precautions

Twinrix

• As with other vaccines, the administration of Twinrix is to be postponed in subjectssuffering from acute severe febrile illness.

• It is possible that subjects may be in the incubation period of a hepatitis A orhepatitis B infection at the time of vaccination. It is not known whether Twinrixwould prevent hepatitis A and hepatitis B in such cases.

• The vaccine does not prevent infection caused by other agents such as hepatitis Cand hepatitis E and other pathogens known to infect the liver.

• Twinrix is not recommended for post-exposure prophylaxis (e.g. needle stick injury).

• The vaccine has not been tested in patients with impaired immunity. Inhaemodialysis patients and persons with an impaired immune system, adequate anti-HAV and anti-HBs antibody concentrations might not have been obtained after theprimary immunisation course and such patients might therefore have requiredadministration of additional doses of vaccine.

• Twinrix is not to be administered intravenously under any circumstances.

Engerix-B

• Because of the long incubation period of hepatitis B it is possible for unrecognisedinfection to be present at the time of immunisation. The vaccine may not preventhepatitis B infection in such cases.

• The vaccine does not prevent infection caused by other pathogens known to infectthe liver such as hepatitis A, hepatitis C and hepatitis E virus.

• Thiomersal (an organomercuric compound) has been used in the manufacturingprocess of this medicinal product and residues of it are present in the final product.Therefore, sensitisation reactions may occur.

• Engerix-B is not to be administered in the buttock or intradermally since this couldresult in a lower immune response.

• Engerix-B is not to be administered intravascularly under any circumstances.

• As with all injectable vaccines, appropriate medical treatment and supervision isalways readily available in case of rare anaphylactic reactions following theadministration of the vaccine.

• As with any vaccine, a protective immune response may not be elicited in allvaccinees.

CONFIDENTIAL




Final

28 Aug 2009 - 34 -

Havrix

• It is possible that subjects may be in the incubation period of a hepatitis A infectionat the time of immunisation. It is not known whether Havrix (1440 ELISA Units)will prevent hepatitis A in such cases.

• In haemodialysis patients and in subjects with an impaired immune system, adequateanti-HAV antibody concentrations may not be obtained after a single dose of Havrix(1440 ELISA Units) and such patients may therefore require administration ofadditional doses of vaccine.

• As with all injectable vaccines, appropriate medical treatment is always readilyavailable for treatment in case of anaphylactic reactions following the administrationof the vaccine. For this reason, the vaccinee should remain under medicalsupervision for 30 minutes after immunisation.

• Havrix (1440 ELISA Units) is to be administered with caution to subjects withthrombocytopenia or a bleeding disorder since bleeding could occur following anintramuscular administration to these subjects.

• The vaccine should not be administered intramuscularly in the gluteal region orsubcutaneously/intradermally since administration by these routes may result in aless than optimal anti-HAV antibody response.

• Havrix (1440 ELISA Units) should under no circumstances be administeredintravenously.

HBVAXPRO

• Persons with immunodeficiency or those receiving immunosuppressive therapyrequire larger vaccine doses and respond less well than healthy individuals.

• Because of the long incubation period for hepatitis B, it is possible for unrecognisedinfection to be present at the time HBVAXPRO is given. HBVAXPRO may notprevent hepatitis B in such patients.

• Patients who develop symptoms suggestive of hypersensitivity after an injection arenot to receive further injections of HBVAXPRO.

• As with any parenteral vaccine, epinephrine (adrenaline) is available for immediateuse in case an anaphylactoid reaction occur. Any serious active infection is reasonfor delaying use of HBVAXPRO, except when, in the opinion of the physician,withholding the vaccine entailed a greater risk.

• Caution and appropriate care is to be exercised in administering the vaccine toindividuals with severely compromised cardiopulmonary status or to others in whoma febrile or systemic reaction can pose a significant risk.

CONFIDENTIAL




Final

28 Aug 2009 - 35 -

Vaqta

• As with all injectable vaccines, appropriate medical treatment and supervision isalways to be readily available in case of a rare anaphylactic event following theadministration of the vaccine.

• Testing for antibodies to hepatitis A prior to a decision on immunisation is to beperformed in patients born in areas of high endemicity and/or with a history ofjaundice.

• Vaqta did not cause immediate protection against hepatitis A, and there may be aperiod of 2 to 4 weeks before antibody induction occurred.

• Because of the long incubation period (approximately 20 to 50 days) for hepatitis A,it is possible for unrecognised hepatitis A infection to be present at the time thevaccine is given. The vaccine may not prevent hepatitis A in such individuals.

• Vaqta did not prevent hepatitis caused by infectious agents other than hepatitis Avirus.

• In subjects with an impaired immune system, adequate anti-HAV antibodyconcentrations may not be obtained. If the immunosuppression was due to medicaltreatment, vaccination is to be delayed if possible until the completion of therapy andimmune system recovery.

• The vaccine has been evaluated in human immunodeficiency virus (HIV) infectedadults. There are no data on the use of Vaqta in HIV infected subjects.

• As with any vaccine, vaccination with Vaqta may not result in a protective responsein all susceptible vaccinees.

• As no studies had been performed with Vaqta in subjects with liver disease, cautionis advised if administering the vaccine in these subjects.

5.3.6. Subject completion and withdrawal from study

5.3.6.1. Subject completion

A subject who returned for the concluding visit foreseen in the protocol was consideredto have completed the study.

5.3.6.2. Subject withdrawal from the study

From an analysis perspective, a �withdrawal� from the study was any subject who did notcome back for the concluding visit foreseen in the protocol.

A subject qualified as a �withdrawal� from the study when no study procedure hadoccurred, no follow-up had been performed and no further information had beencollected for this subject from the date of withdrawal/last contact.

Investigators were to make an attempt to contact those subjects who did not return forscheduled visits or follow-up.

CONFIDENTIAL




Final

28 Aug 2009 - 36 -

Information relative to the withdrawal was documented on the Study Conclusion screenof the eCRF. The investigator documented whether the decision to withdraw from thestudy was made by the subject or the investigator and which of the following possiblereasons was responsible for withdrawal:

• serious adverse event

• non-serious adverse event

• protocol violation (was to be specified)

• consent withdrawal, not due to an adverse event

• moved from the study area

• lost to follow-up

• other (was to be specified).

5.3.6.3. Subject withdrawal from administration of the investigational product

Not applicable.

5.4. Composition and administration of vaccines

5.4.1. Description of vaccines

The vaccines Twinrix, Engerix-B and Havrix to be used were developed andmanufactured by GSK Biologicals. The vaccines HBVAXPRO and Vaqta used in thisstudy were manufactured by Merck and Co Inc and marketed by Sanofi Pasteur MSD.

The Quality Control Standards and Requirements for these vaccines were described inseparate release protocols and the required approvals were obtained.

Commercial vaccines were assumed to have complied with the specifications given in themanufacturer's Summary of Product Characteristics.

The vaccine composition and the lot numbers of the vaccines used in the primary phaseand challenge dose phase of the study is presented in Table 5.

All subjects received a challenge dose of the same vaccine that they received in theprimary study.

CONFIDENTIAL




Final

28 Aug 2009 - 37 -

Table 5 Vaccines used in the primary phase and challenge dose phase andtheir composition

Vaccine Composition Presentation Primaryphase lotnumber

Challenge dosephase lot

number (Expirydate)

GSK Biologicals� combinedhepatitis A and hepatitis Bvaccine Twinrix Adult

Hepatitis A antigen (strain HM 175 RIT4380): at least 720 ELISA unitsHBsAg (Recombinant antigen): 20 µgAluminium (as salt): 0.45 mg2-phenoxyethanol: 5 mg

Pre-filledsyringes[PFS] (1.0ml)

HAB298A6 AHABB087C(30 Sep 2009)

GSK Biologicals�recombinant hepatitis Bvaccine, Engerix-B

HBsAg (Recombinant antigen): 20 µgAluminium (as salt): 0.5 mg

PFS (1.0 ml) ENG5424B6 AHBVB388A(30 NOV 2009)

GSK Biologicals�inactivated hepatitis Avaccine, Havrix

Hepatitis A antigen (strain HM 175): atleast 1440 ELISA UnitsAluminium (as salt): 0.5 mg2-phenoxyethanol: 5 mg

PFS (1.0 ml) VHA800D6 AHAVB108E (30APR 2009)

HBVAXPRO Hepatitis B (recombinant HBsAg): 10µgAluminium (as Al (OH)3): 0.5 mg

PFS (1.0 ml) HS38310 DEXTA264AZ(30 NOV 2009)

Vaqta Hepatitis A antigen (CR 326F strain):50 IUAluminium (as Al (OH) 3): 0.45 mg

PFS (1.0 ml) HS41410 DEXTA265AZ(30 SEP 2008)

5.4.2. Dosage and administration

All subjects (irrespective of their serological status) were given a challenge dose of thesame vaccine that they received in the primary study (HAB-160).

The vaccines were administered as an intramuscular injection in the deltoid region.

Subjects in the Twinrix group received Twinrix as an intramuscular injection in the leftdeltoid region, using a 23 gauze, 25 mm needle.

Subjects in the ENG+HAV group received concomitantly Havrix (right deltoid region)and Engerix-B (left deltoid region) using a 23 gauze, 25 mm needle.

Subjects in the HBVX+VAQ group received concomitantly Vaqta (right deltoid region),and HBVAXPRO (left deltoid region), administered according to the manufacturer�srecommendations using a 23 gauze, 25 mm needle.

An overview of the administration of the vaccines is presented in Table 6.

CONFIDENTIAL




Final

28 Aug 2009 - 38 -

Table 6 Dosage and Administration

Group Visit Day Vaccination Dose Route Site SideTwinrix 8 0 Twinrix 1st IM D L

Engerix-B 1st IM D LEngerix-B + Havrix 8 0Havrix 1st IM D R

HBVAXPRO 1st IM D LHBVAXPRO + Vaqta 8 0Vaqta 1st IM D R

The vaccinees were observed closely for at least 30 minutes, with appropriate medicaltreatment readily available in case of a rare anaphylactic reaction following theadministration of vaccines.

5.4.3. Treatment allocation and randomisation

The vaccines were numbered sequentially per group. The site took the lowest treatmentnumber available in the fridge of the vaccine group that the subject received in theprimary study (HAB-160). Subjects were administered the vaccine dose with the lowesttreatment number still available at the study centre. The treatment number was recordedby the investigator in the eCRF (treatment allocation).

5.4.4. Blinding

The study was conducted in an open manner.

5.5. Prior and concomitant medication/vaccinations

At each study visit/contact, the investigator questioned the subject about anymedication(s) taken.

All concomitant medication, with the exception of vitamins and/or dietary supplements,administered at any time during the period starting 7 days before the administration of thechallenge dose and ending at one month (minimum 30 days) after the challenge dose wasto be recorded by the subject. The investigator verified and completed the subject�srecords. The generic name of the medication (trade names were allowed for combinationdrugs, i.e., multi-component drugs), medical indication, total daily dose, route ofadministration, start and end dates of treatment, were transcribed into the medicationscreens of the eCRF for any medication taken up to one month after the challenge dose.

Any vaccine not foreseen in the study protocol administered in the period beginning 30days preceding the challenge dose and ending one month (minimum 30 days) after thechallenge vaccine dose, was to be recorded with trade name, route of administration anddate(s) of administration.

Any concomitant medication administered prophylactically in anticipation of reaction tothe vaccination was to be recorded in the eCRF with generic name of the medication(trade names were allowed for combination drugs only), total daily dose, route ofadministration, start and end dates of treatment and coded as �Prophylactic�.

CONFIDENTIAL




Final

28 Aug 2009 - 39 -

Concomitant medication administered for the treatment of an SAE was to be recorded inthe eCRF with generic name of the medication (trade names were allowed forcombination drugs only), medical indication (including which SAE), total daily dose,route of administration, start and end dates of treatment.

5.6. Laboratory assays and time points

At the time of vaccination, two weeks and one month after the administration of thechallenge dose, approximately 5 ml of whole venous blood was collected formeasurement of anti-HAV and anti-HBs antibody concentrations (Table 7).

Table 7 Laboratory Assays

Marker Assaymethod

Test Kit/Manufacturer

Assayunit

Assaycut-off

Laboratory

Anti-HAV EIA Enzygnost ® Anti-HAV*/DADE Behring mIU/ml 15 mIU/ml GSK Bio

Anti-HBs EIA In-house assay mIU/ml 3.3 mIU/ml CEVACEIA: Enzyme immunoassay.Centre for Vaccinology, Ghent University and Hospital, Ghent, Belgium

The GSK Biologicals� clinical laboratories have established a Quality System supportedby procedures. The activities of GSK Biologicals� clinical laboratories are auditedregularly for quality assessment by an internal (sponsor-dependent) but laboratory-independent Quality Department.

5.7. Assessment of immunogenicity variables

In case of insufficient blood sample volume to perform assays for all antibodies, thesamples were analysed according to the following priority ranking, detailed in Table 8.

Table 8 Serology Plan

Blood sampling time pointTiming Day/ Month Visit no. Marker Laboratory

siteNo.

subjectsAntigen Priority

ranking

Pre-challenge dose Day 0 8 Anti-HBsAnti-HAV GSK/ Cevac All Anti-HBs (1)

Anti-HAV (2)Two weeks post-challenge dose Day 14 9 Anti-HBs

Anti-HAV GSK/ Cevac All Anti-HBs (1)Anti-HAV (2)

One MonthPost-challenge dose Day 30 10 Anti-HBs

Anti-HAV GSK/ Cevac All Anti-HBs (1)Anti-HAV (2)

5.7.1. Immunological correlates of protection

No correlate of protection has been demonstrated so far for hepatitis A, however based oninformation gathered from passive immunisation studies, a subject is consideredprotected as soon as antibodies are detectable.

CONFIDENTIAL




Final

28 Aug 2009 - 40 -

For hepatitis B, an antibody concentration ≥ 10 mIU/ml is considered to be seroprotective[Centre for Disease Control, 1991, World Health Organisation, 1988].

5.8. Assessment of safety variables

5.8.1. Adverse events

An AE was any untoward medical occurrence in a clinical investigation subject,temporally associated with the use of a medicinal product, whether or not consideredrelated to the medicinal product.

An AE was therefore any unfavourable and unintended sign (including an abnormallaboratory finding), symptom, or disease (new or exacerbated) temporally associated withthe use of a medicinal product. For marketed medicinal products, this also includedfailure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.

Examples of an AE include:

• Significant or unexpected worsening or exacerbation of the condition/indicationunder study.

• Exacerbation of a chronic or intermittent pre-existing condition including either anincrease in frequency and/or intensity of the condition.

• New conditions detected or diagnosed after investigational product administrationeven though it may have been present prior to the start of the study.

• Signs, symptoms, or the clinical sequelae of a suspected interaction.

• Signs, symptoms, or the clinical sequelae of a suspected overdose of eitherinvestigational product or a concurrent medication (overdose per se was not reportedas an AE/SAE).

• Significant failure of expected pharmacological or biological action.

Examples of an AE DO NOT include:

• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition thatlead to the procedure was an AE.

• Situations where an untoward medical occurrence did not occur (social and/orconvenience admission to a hospital).

• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) presentor detected at the start of the study that did not worsen.

• For therapeutic studies, the disease/disorder being studied, or expected progression,signs, or symptoms of the disease/disorder being studied, unless more severe thanexpected for the subject�s condition.

AEs may have included pre- or post-treatment events that occurred as a result ofprotocol-mandated procedures (i.e. invasive procedures, modification of subject�sprevious therapeutic regimen).

CONFIDENTIAL




Final

28 Aug 2009 - 41 -

N.B. AEs to be recorded as endpoints (solicited events) are described in Section 5.10.2.All other AEs were recorded as UNSOLICITED AES.

Example of events to be recorded in the medical history section of the eCRF:

• Pre-existing conditions or signs and/or symptoms present in a subject prior to thestart of the study (i.e. prior to the first study vaccination).

5.8.1.1. Solicited adverse events

A 4-day (Day 0-3) follow-up of solicited local adverse events at the injection site andsolicited general adverse events was performed after vaccination. Data concerning thefollowing adverse events were solicited using diary cards provided by the sponsor. SeeTable 9 and Table 10 for details of the local and general adverse events that weresolicited.

Solicited local (injection site) AEs

Table 9 Solicited local adverse events

Pain at injection siteRedness at injection siteSwelling at injection site

Solicited general AEs

Table 10 Solicited general adverse events

FatigueFeverGastrointestinal symptoms �

Headache�Gastrointestinal symptoms included nausea, vomiting, diarrhoea and/or abdominal pain

N.B. Temperature was to be recorded in the evening. If additional temperaturemeasurements were performed at other times of day, the highest temperature wasrecorded.

5.8.2. Evaluating adverse events and serious adverse events

Assessment of intensity

Intensity of the following AEs was assessed as described in Table 11.

CONFIDENTIAL




Final

28 Aug 2009 - 42 -

Table 11 Intensity scales for solicited symptoms

Adverse Event Intensity grade ParameterPain at injection site 0 Absent

1 Painful on touch2 Painful when limb was moved3 Pain that prevented normal activity

Redness at injection site Recorded greatest surface diameter in mmSwelling at injection site Recorded greatest surface diameter in mmFever* Record temperature in °C / °FHeadache 0 Normal

1 Headache that was easily tolerated2 Headache that interfered with normal activity3 Headache that prevented normal activity

Fatigue 0 Normal1 Fatigue that was easily tolerated2 Fatigue that interfered with normal activity3 Fatigue that prevented normal activity

Gastrointestinal symptoms 0 Gastrointestinal symptoms normal(nausea, vomiting, diarrhoea 1 Gastrointestinal symptoms that were easily toleratedand/or abdominal pain) 2 Gastrointestinal symptoms that interfered with normal

activity3 Gastrointestinal symptoms that prevented normal activity

* Fever was defined as axillary temperature ≥37.5°C/oral temperature ≥ 37.5°C (> 37.0 °C for Czech Republic only)

The maximum intensity of local injection site redness/swelling was scored at GSKBiologicals as follows:

0 : Absent1 : ≥ 1 and < 10 mm2 : ≥ 10 and < 50 mm3 : ≥ 50 mm

The intensity of fever was scored at GSK Biologicals in 0.5°C increments. Oral/axillarytemperature > 39.5°C was scored as fever of Grade 3 intensity.

The investigator made an assessment of the maximum intensity that occurred over theduration of the event for all other AEs, i.e. unsolicited symptoms, including SAEsreported during the study. The assessment was based on the investigator�s clinicaljudgement.

The intensity of each AE and SAE recorded in the eCRF or SAE Report screens, asapplicable, was assigned to one of the following categories:

CONFIDENTIAL




Final

28 Aug 2009 - 43 -

1 (mild) = An AE which was easily tolerated by the subject, causing minimaldiscomfort and not interfering with everyday activities.

2 (moderate) = An AE which was sufficiently discomforting to interfere withnormal everyday activities.

3 (severe) = An AE which prevented normal, everyday activities. (In adults,such an AE for example, prevented attendance at work andnecessitated the administration of corrective therapy.)

An AE that was assessed as Grade 3 (severe) was not to be confused with a SAE.Grade 3 was a category utilised for rating the intensity of an event; and both AEs andSAEs could be assessed as Grade 3. An event was defined as �serious� when it met oneof the pre-defined outcomes as described in Section 5.8.3.

Assessment of causality

The definitions for �NO� and �YES� were written in such a way that all events that wereattributed a �NO� could be pooled with events which in the primary vaccination studywere determined to be �not related� or �unlikely to be related� to vaccination. Thoseevents that were attributed a �YES� could be pooled with those events that in the pastwere determined to have a �suspected� or �probable� relationship to vaccination in theprimary vaccination study.

The investigator was obligated to assess the relationship between investigational productand the occurrence of each AE/SAE. The investigator used clinical judgement todetermine the relationship. Alternative causes, such as natural history of the underlyingdiseases, concomitant therapy, other risk factors and the temporal relationship of theevent to the investigational product were considered and investigated. The investigatoralso consulted the Investigator Brochure and/or Product Information, for marketedproducts, in the determination of his/her assessment.

There might have been situations when a SAE had occurred and the investigator hadminimal information to include in the initial report to GSK Biologicals. However, it wasvery important that the investigator always made an assessment of causality for everyevent prior to submission of the SAE to GSK Biologicals. The investigator might havechanged his/her opinion of causality in light of follow-up information, amending the SAEinformation accordingly. The causality assessment was one of the criteria used whendetermining regulatory reporting requirements.

In case of concomitant administration of multiple vaccines, it might not have beenpossible to determine the causal relationship of general AEs to the individual vaccinesadministered. The investigator, therefore, assessed whether the AE could be causallyrelated to vaccination rather than to the individual vaccines.

All solicited local (injection site) reactions were considered causally related tovaccination. Causality of all other AEs was assessed by the investigator using thefollowing question:

CONFIDENTIAL




Final

28 Aug 2009 - 44 -

Was there a reasonable possibility that the AE may have been caused by theinvestigational product?

NO : The AE was not causally related to administration of the studyvaccine(s). There were other, more likely causes and administrationof the study vaccine(s) was not suspected to have contributed to theAE.

YES : There was a reasonable possibility that the vaccine(s) contributed tothe AE.

Non-serious and serious AEs were evaluated as two distinct events. If an event met thecriteria to be determined �serious�, it was examined by the investigator to the extent to beable to determine ALL contributing factors applicable to each serious adverse event.

Other possible contributors included:

• Medical history

• Other medication

• Protocol required procedure

• Other procedure not required by the protocol

• Lack of efficacy of the vaccine(s), if applicable

• Erroneous administration

• Other cause (to be specified).

5.8.3. Serious adverse events

A serious adverse event (SAE) was any untoward medical occurrence that:

a. resulted in death,

b. was life-threatening,

NOTE: The term 'life-threatening' in the definition of 'serious' referred to an event inwhich the subject was at risk of death at the time of the event. It did not refer to an event,which hypothetically might have caused death, if it were more severe.

c. required hospitalisation or prolongation of existing hospitalisation,

NOTE: In general, hospitalisation signified that the subject had been detained (usuallyinvolving at least an overnight stay) at the hospital or emergency ward for observationand/or treatment that would not have been appropriate in the physician�s office or out-patient setting. Complications that occurred during hospitalisation were AEs. If acomplication prolonged hospitalisation or fulfilled any other serious criteria, the eventwas serious. When in doubt as to whether �hospitalisation� occurred or was necessary,the AE was considered serious.

Hospitalisation for elective treatment of a pre-existing condition that did not worsen frombaseline was not considered an AE.

CONFIDENTIAL




Final

28 Aug 2009 - 45 -

d. resulted in disability/incapacity, or

NOTE: The term disability meant a substantial disruption of a person�s ability to conductnormal life functions. This definition was not intended to include experiences of relativelyminor medical significance such as uncomplicated headache, nausea, vomiting,diarrhoea, influenza, and accidental trauma (e.g. sprained ankle) which may haveinterfered or prevented everyday life functions but did not constitute a substantialdisruption.e. was a congenital anomaly/birth defect in the offspring of a study subject.

Medical or scientific judgement was exercised in deciding whether reporting wasappropriate in other situations, such as important medical events that may not have beenimmediately life-threatening or resulted in death or hospitalisation but may havejeopardised the subject or may have required medical or surgical intervention to preventone of the other outcomes listed in the above definition. These were also consideredserious. Examples of such events were invasive or malignant cancers, intensive treatmentin an emergency room or at home for allergic bronchospasm, blood dyscrasias orconvulsions that did not result in hospitalisation.

f. Any signs of suspected or confirmed hepatitis A or hepatitis B. The signs andsymptoms, clinical sequelae resulting from lack of clinical efficacy or both were tobe reported. Any signs of suspected or confirmed hepatitis A or hepatitis B since thelast follow up visit (HAB-160 Year 3) till the end of the study (30 days afterchallenge dose) were to be reported as an SAE.

5.8.3.1. Follow-up of adverse events and serious adverse events andassessment of outcome

After the initial AE/SAE report, the investigator was required to proactively follow eachsubject and provide further information to GSK Biologicals on the subject�s condition.

All AEs and SAEs documented at a previous visit/contact and designated as notrecovered/not resolved or recovering/resolving were reviewed at subsequentvisits/contacts.

Investigators followed-up subjects:

• with SAEs or subjects withdrawn from the study as a result of an AE, until the eventhad resolved, subsided, stabilised, disappeared, the event was otherwise explained, orthe subject was lost to follow-up;

• or, in the case of other non-serious AEs, until they completed the study or they werelost to follow-up.

For the long-term follow-up visit (Month 48)

Investigators followed-up subjects:

• with SAEs considered related to vaccination or with confirmed or suspected hepatitisA or B infection (in this study reported as SAE, as defined per protocol), until the

CONFIDENTIAL




Final

28 Aug 2009 - 46 -

event had resolved, subsided, stabilised, disappeared, the event was otherwiseexplained, or the subject was lost to follow-up.

Clinically significant laboratory abnormalities were followed up until they returned tonormal, or a satisfactory explanation was provided. Additional information (including butnot limited to laboratory results) relative to the subsequent course of such an abnormalitynoted for any subject was made available to the Study Monitor.

GSK Biologicals may have requested that the investigator perform or arrange for theconduct of supplemental measurements and/or evaluations to elucidate as fully aspossible the nature and/or causality of the AE or SAE. The investigator was obliged toassist. If a subject died during participation in the study or during a recognised follow-upperiod, GSK Biologicals was to be provided with a copy of any available post-mortemfindings, including histopathology.

New or updated information was recorded on the originally completed screens in theeCRF. The updated SAE Report screens in the eCRF were resent to GSK Biologicalswithin 24 hours of receipt of the follow-up information.

In case the electronic SAE reporting system did not work or after freezing of the subject'seCRF, paper SAE Report Forms and the facsimile (Fax) system were used to reportSAEs.

Outcome of any non-serious AE occurring within one month (minimum 30 days) post-vaccination (i.e. unsolicited AE) or any SAE reported during the entire study wereassessed as:

• Recovered/resolved

• Not recovered/not resolved

• Recovering/resolving

• Recovered with sequelae/resolved with sequelae

• Fatal (SAEs only).

5.8.3.2. Time frames for submitting serious adverse event reports to GSKBiologicals

SAEs were reported promptly to GSK once the investigator determined that the event metthe protocol definition of an SAE. The investigator completed and submitted relevantinformation on the SAEs in the SAE screens in eCRF WITHIN 24 HOURS OF HIS/HERBECOMING AWARE OF THESE EVENTS. Additional or follow-up information relating to theinitial SAE report was also completed and submitted in the SAE screens in eCRF within24 hours of receipt of such information

When paper SAE Report Form was used as back-up system (if electronic SAE reportingsystem did not work or after freezing of the subject's eCRF), the investigator faxed theSAE reports to GSK Biologicals� Central Safety for Serious Adverse Event Reporting.During the study, the investigator updated the SAE screens in eCRF once the electronic

CONFIDENTIAL




Final

28 Aug 2009 - 47 -

system was working again (and not later than 24 hours) and before using it to reportadditional information.

5.8.4. Pregnancy

Subjects who became pregnant during the study period (up to and including one monthafter receiving the vaccine dose) could continue other study procedures at the discretionof the investigator.

The investigator, or his/her designee, was to collect the pregnancy information on anysubject who became pregnant while participating in this study. The investigator, orhis/her designee, was to record pregnancy information on the Pregnancy Report Formand submit it to GSK within 24 hours of learning of a subject's pregnancy. The subjectwas to be followed up to determine the outcome of the pregnancy. At the end of thepregnancy, whether that was full-term or premature, information on the status of themother and child was to be forwarded to GSK. Generally, follow-up was to be no longerthan six to eight weeks following the estimated delivery date.

While pregnancy itself was not considered an AE or SAE, any pregnancy complication orelective termination of a pregnancy for medical reasons was to be recorded as an AE or aSAE.

A spontaneous abortion was always to be considered as a SAE. Furthermore, any SAEthat occurred as a result of a post-study pregnancy AND considered reasonably related intime to receipt of the investigational product by the investigator, was reported to GSKBiologicals. While the investigator was not obligated to actively seek this informationfrom former study participants, he/she might have learnt of a pregnancy throughspontaneous reporting.

Information on pregnancies identified during the screening phase/prior to vaccineadministration was not to be collected; this information was not to be communicated tosafety.

5.9. Data quality assurance

To ensure that the study procedures conformed across all investigator centres, theprotocol, case report form and safety reporting were reviewed with the investigators andhis/her/their personnel responsible for the conduct of the study by the Companyrepresentative(s) prior to study start.

Adherence to the protocol requirements and verification of data generation accuracy wereachieved through monitoring visits to each investigator site. Computer checks andblinded review of subject tabulations were performed to ensure consistency of eCRFcompletion. All procedures were performed according to methodologies detailed inGlaxoSmithKline Biologicals Standard Operating Procedures (SOPs).

Independent Audit statement:

• No study specific audits were performed for this study.

CONFIDENTIAL




Final

28 Aug 2009 - 48 -

5.10. Statistical methods

All analyses were performed as specified in the protocol and in the reporting and analysisplan.

The statistical analyses were performed using the Statistical Analysis Systems version 9.1on Windows XP Professional and StatXact-7.0 procedure on SAS.

5.10.1. Primary endpoint

• Anti-HAV immune response (anamnestic) to the challenge dose was defined as:

− Anti-HAV antibody concentrations ≥ 15 mIU/ml at one month post-challengedose in subjects, seronegative at the pre-challenge time point.

− At least a 2-fold increase in anti-HAV antibody concentrations one month afterthe challenge dose, in subjects having anti-HAV antibody concentrations ≥ 100mIU/ml at the pre-challenge time point.

− or at least a 4-fold increase in anti-HAV antibody concentrations one month afterthe challenge dose, in seropositive subjects having anti-HAV antibodyconcentrations < 100 mIU/ml at the pre-challenge time point.

• Anti-HBs antibody response (anamnestic) to the challenge dose was defined as:

− Anti-HBs antibody concentrations ≥ 10 mIU/ml at one month post-challengedose in subjects seronegative at the pre-challenge time point.

− At least a 4-fold increase in anti-HBs antibody concentrations, at one month post-challenge dose in subjects seropositive at the pre-challenge time point.

5.10.2. Secondary endpoints

Immunogenicity

• Anti-HAV seropositivity rates and GMCs, as well as anti-HBs seropositivity rates,seroprotection rates and GMCs at Month 48.

• Percentage of subjects with anti-HAV antibody titres ≥ 15 mIU/ml and GMCscalculated on seropositive subjects, two weeks and one month after the challengedose.

• Percentage of subjects with anti-HBs antibody titres ≥ 3.3 mIU/ml, ≥ 10 mIU/ml, ≥100 mIU/ml and anti-HBs geometric mean concentrations (GMCs) calculated onseropositive subjects, two weeks and one month after the challenge dose.

Reactogenicity

• Occurrence and intensity of solicited local symptoms in the 4-day (Day 0-3) follow-up period after the challenge dose.

• Occurrence, intensity and relationship of solicited general symptoms in the 4-day(Day 0-3) follow-up period after the challenge dose.

Safety

CONFIDENTIAL




Final

28 Aug 2009 - 49 -

• Retrospective recording of all SAEs with causal relationship to vaccination orreferring to hepatitis A or B infection that occurred since the last study visit of theHAB-160 long-term follow-up study.

• Occurrence, intensity and relationship to vaccination of unsolicited symptomsreported during the 31-day (Day 0-30) follow-up period after the challenge dose.

• Occurrence, intensity and relationship to vaccination of all SAEs following theadministration of the challenge dose.

5.10.3. Determination of sample size

The sample size for the challenge dose study was not estimated using any power basedcomputations.

A total of 596 subjects were enrolled in the primary study of which 590 subjectscompleted the study and 583 subjects participated in the long-term follow up visit atMonth 24 (Year 2). Thus, considering a drop-out rate of 15% from the Month 24 timepoint, about 495 subjects were expected to participate in the challenge dose study and anevaluable 445 subjects. Of these, 276 subjects were expected to be recruited in theBelgian and Czech centres. 219 subjects were expected to be recruited in the Germancentres.

Table 12 provides the precision achieved with a sample of 445 subjects, for variouspossible expected values of response (ranging from 80% to 95%) to the challenge dose interms of exact 95% confidence interval.

Table 12 Precision achieved with 445 subjects for various expected values ofchallenge dose response, in terms of exact two-sided 95% CI

Subjects with challenge dose response as defined in Primary endpoint

Exact 95% CI

No. of Subjects expected (N)

n %LL UL

356 80.0 76.0 83.6379 85.2 81.5 88.3402 90.3 87.2 92.9

445

424 95.3 92.9 97.1n = No. of subjects with challenge dose response% = (n/N)*100; LL = Lower limit; UL = Upper limit

5.10.4. Study cohorts /data sets analysed

Five study cohorts were defined for the purpose of analysis:

• Long-term (LT) Total vaccinated cohort

• LT ATP cohort for analysis of immunogenicity

• Total vaccinated cohort (challenge dose)

• ATP cohort for analysis of safety (challenge dose)

CONFIDENTIAL




Final

28 Aug 2009 - 50 -

• ATP cohort for analysis of immunogenicity (challenge dose)

LT Total vaccinated cohort

The LT Total vaccinated cohort included all subjects who received at least one dose ofthe study vaccine in the primary study and who returned for the Month 48 bloodsampling time point.

LT ATP cohort for analysis of immunogenicity

For subjects who returned at the Month 48 time point, the ATP-LT cohort (at that timepoint) included those who were included in the primary ATP immunogenicity analysis,who did not receive hepatitis A or hepatitis B vaccine not specified in the study protocoland who were not eliminated for abnormal increase� in antibody titre during follow-upperiod.

� Note: the criteria of an antibody (anti-HAV or anti-HBs) concentration abnormalincrease depended on the magnitude of antibody level reached at first time point (i.e. thereference value). The case of an abnormal antibody concentration increase was defined asa two-fold increase or more in antibody concentrations (when the antibody concentrationsat the reference time point was ≥ 100 mIU/ml) or a four-fold increase or more in antibodyconcentrations (when the antibody concentrations at the reference time point was < 100mIU/ml). This code was assigned to eliminate from the analysis subjects who could havebeen infected by the hepatitis A or hepatitis B virus, or who could have received avaccine dose not specified in the protocol during the study.

Total vaccinated cohort (challenge dose)

The Total Vaccinated cohort included all subjects who received the challenge dose:

• a safety analysis based on the Total vaccinated cohort included all vaccinatedsubjects.

• an immunogenicity analysis based on the Total vaccinated cohort included allvaccinated subjects for whom immunogenicity data was available.

ATP cohort for analysis of safety (challenge dose)

The ATP cohort for safety included all eligible subjects:

• who received the complete primary hepatitis B and hepatitis A vaccination course inthe HAB-160 primary study.

• who received the challenge dose.

• who did not receive a vaccine not specified or forbidden in the protocol

ATP cohort for analysis of immunogenicity (Challenge dose)

The ATP cohort for analysis of immunogenicity included all evaluable subjects includedin the ATP cohort for analysis of safety ((i.e. those meeting all eligibility criteria,complying with the procedures and intervals defined in the protocol, with no elimination

CONFIDENTIAL




Final

28 Aug 2009 - 51 -

criteria during the study) who received the challenge dose and for whom data concerningimmunogenicity endpoint measures for at least one antigen was available at the post-challenge dose time point. The interval between Visit 8 (pre-challenge dose) and Visit 10(post-challenge dose time point) considered for inclusion of a subject in the ATP cohortfor immunogenicity was 21 to 48 days.

5.10.5. Derived and transformed data

Immunogenicity:

• The cut-off value was defined by the laboratory before the analysis and is describedin Section 5.6. The cut-off value for anti-HAV assay was 15 mIU/ml; the cut-offvalue for anti-HBs assay was 3.3 mIU/ml.

• A seronegative subject was a subject whose concentration was below the cut-offvalue.

• A seropositive subject was a subject whose concentration was greater than or equalto the cut-off value.

• Seropositivity rate was defined as the percentage of subjects with antibodyconcentrations greater than or equal to the cut-off value.

• Anti-HBs seroprotection rate was defined as the percentage of subjects with anti-HBs antibody concentrations ≥ 10 mIU/ml.

• The GMC calculations were performed by taking the anti-log of the mean of the logtransformation of antibody concentrations equal to or above the seropositivity level(i.e. 15 mIU/ml for anti-HAV and 3.3 mIU/ml for anti-HBs).

• If GMC had to be calculated on all subjects (as supplement), subjects whose antibodyconcentrations were below the assay cut-off were assigned an arbitrary value of halfthe cut-off.

• Anti-HAV anamnestic response to the challenge dose was defined as:

− Anti-HAV antibody concentrations ≥ 15 mIU/ml at one month post-challengedose in subjects, seronegative at the pre-challenge time point.

− At least a 2-fold increase in anti-HAV antibody concentrations one month afterthe challenge dose, in subjects having anti-HAV antibody concentrations ≥ 100mIU/ml at the pre-challenge time point or at least a 4-fold increase in antibodyconcentrations one month after the challenge dose, in seropositive subjectshaving anti-HAV antibody concentrations < 100 mIU/ml at the pre-challengetime point.

• Anti-HBs anamnestic response to the challenge dose was defined as

− At least a 4-fold increase in anti-HBs antibody concentrations, at one month post-challenge dose in subjects seropositive at the pre-challenge time point.

− Anti-HBs antibody concentrations ≥ 10 mIU/ml at one month post-challengedose in subjects seronegative at the pre-challenge time point.

CONFIDENTIAL




Final

28 Aug 2009 - 52 -

• For a given subject and a given immunogenicity measurement, missing or non-evaluable measurements were not replaced. Therefore, an analysis excluded subjectswith missing or non-evaluable measurements.

Safety/ Reactogenicity:

• For the analysis of solicited symptoms, missing or non-evaluable measurements werenot replaced. Therefore the analysis of the solicited symptoms based on the Totalvaccinated cohort included only subjects with documented safety data (i.e. symptomscreen completed).

• For the analysis of unsolicited adverse events/concomitant medication, all vaccinatedsubjects were considered and subjects who did not report an event were consideredas subjects without an event.

5.10.6. Analysis of demographics

Demographic characteristics (age in years, gender and race), cohort description,withdrawal status were summarised using descriptive statistics:

• Mean, median, standard deviation was provided for continuous data such as age.All the demographic analyses were performed stratified based on the three study groupsin the primary study and overall.

A summary of the tracking log-sheet documenting reasons for non-participation in thechallenge dose study was provided.

5.10.7. Analysis of immunogenicity

Persistence of antibody response (LT-ATP cohort for immunogenicity)

Seroprotection rates, seropositivity rates and GMCs for anti-HBs antibodies with 95%confidence intervals were tabulated at Month 48.

Seropositivity rates and GMCs for anti-HAV antibodies with 95% CI, were tabulated atMonth 48.

Distribution of anti-HAV and anti-HBs antibody concentrations at Month 48 waspresented using reverse cumulative distribution curves.

GMC evolution curves for anti-HAV and anti-HBs antibodies for the LT-ATP cohort forimmunogenicity were generated.

CONFIDENTIAL




Final

28 Aug 2009 - 53 -

Response to challenge dose

The primary analysis was based on the ATP cohort for immunogenicity. Since thepercentage of enrolled subjects excluded from this ATP cohort was less than 5% a secondanalysis based on the Total Vaccinated cohort was not performed.

The following analyses were performed at the post-challenge dose time points for eachtreatment group:

• The percentage of subjects with an anamnestic anti-HAV response to the challengedose with exact 95% CIs was tabulated.

• The percentage of subjects with an anamnestic anti-HBs response to the challengedose with exact 95% CIs was tabulated.

• Anti-HAV and anti-HBs GMCs with 95% CIs were tabulated primarily forseropositive subjects and secondarily for all subjects.

• The percentage of subjects seropositive for anti-HAV antibodies (anti-HAV antibodyconcentrations ≥ 15 mIU/ml), with exact 95% CI was tabulated (the same was alsotabulated stratified based on the baseline characteristics).

• The percentage of subjects with anti-HBs antibody concentrations ≥ 3.3 mIU/ml ,percentage of subjects with anti-HBs antibody concentrations ≥ 10 mIU/ml and ≥ 100mIU/ml, with exact 95% CIs were tabulated (the same was also tabulated stratifiedbased on the baseline characteristics).

• The distribution of anti-HAV and anti-HBs antibody concentrations was presentedusing reverse cumulative distribution curves.

• The percentage of subjects with anti-HBs antibody concentrations ≥ 3.3 mIU/ml, ≥10 mIU/ml, ≥ 100 mIU/ml after the challenge dose according to their pre-challengedose status and post primary status were tabulated.

• The anamnestic response to the HBV challenge dose stratified based on the pre-challenge and post primary vaccination status was also tabulated.

• The relationship between anti-HBs or anti-HAV antibody concentrations observedafter the challenge dose and at the pre-challenge time point were graphicallyrepresented.

5.10.8. Analysis of safety

The analysis was based on the Total vaccinated cohort. Since less than 5% of the enrolledsubjects were eliminated from the ATP cohort for safety analysis, a second analysis wasnot performed on the ATP cohort for safety.

CONFIDENTIAL




Final

28 Aug 2009 - 54 -

• The percentage of subjects with at least one local adverse event (solicited andunsolicited), with at least one general adverse event (solicited and unsolicited) andwith any adverse event (solicited and unsolicited) during the 4-day (Day 0-3) follow-up period after the vaccination was tabulated with exact 95% CI. Similar tabulationswere done for Grade 3 symptoms.

• The percentage of subjects reporting each individual solicited symptom during the 4-day follow-up period with exact 95% CI, by type of adverse event; by severity (anygrade, Grade 3 only); for general symptoms: by relationship to vaccination (anyrelationship, related only) was tabulated.

• The occurrence of fever was tabulated per 0.5 °C cumulative increments as well asthe occurrence of fever (> 39.5 °C oral/axillary temperature) with causal relationshipto vaccination.

• The percentage of subjects with at least one report of an unsolicited adverse eventclassified by the Medical Dictionary for Regulatory Activities (MedDRA) andreported within the 31-day (Day 0-30) follow-up period after vaccination wastabulated with exact 95% CI. The same tabulation was performed for Grade 3unsolicited adverse events and for unsolicited adverse events with a causalrelationship to vaccination.

• The percentage of subjects who reported the start of at least one concomitantmedication (i.e. any medication, antipyretic medication, prophylactic antipyretics)during the 4-day and 31-day (Day 0-30) follow-up period after vaccination wastabulated (with exact 95% CI).

• Serious adverse events with causal relationship to vaccination or referring to hepatitisA or B infection from the previous study visit up to Month 48 were retrospectivelyevaluated.

• All SAEs that were reported following the challenge dose administration weretabulated.

5.10.9. Interim analysis

No interim analysis was performed for this study.

5.11. Changes in the conduct of the study or planned analyses

5.11.1. Protocol amendments

The protocol (HAB-160 primary study) was amended on 28 August 2007 to reflect thatall subjects were to receive a challenge dose of the vaccine they had received in theprimary vaccination, approximately 12 months after the Year 3 long-term follow-up time-point. It also described the blood sampling post-challenge dose to be done two weeks andone month (Day 30) later to evaluate the anti-HAV and anti-HBs antibody response.

The protocol was amended again on 25 January 2008 to reflect the description of thechallenge dose phase of this study in a separate protocol (HAB-168 BST: 160 [111572])for the Czech and Belgian centres that participated in the primary study HAB-160. The

CONFIDENTIAL




Final

28 Aug 2009 - 55 -

eligibility criteria, study visit procedures and data collection were identical for allparticipating centres (in Germany, the Czech Republic and Belgium) and the challengedose phase data from the three centres were to be combined for analysis.

An administrative change was done on 28 March 2008 to reflect the change in Leiter derklinischen Prüfung (LKP) for the study in the German centres.

5.11.2. Other changes

Reactogenicity:

• For tables on solicited adverse event, fever was defined as >37.5°C, howeveraccording to the protocol temperature >37°C was considered as fever in the CzechRepublic. At the time of study start, this Czech specific definition was revised andfever was defined as >37.5°C in this country as well.

Immunogenicity:

• Anti-HAV and anti-HBs GMCs with 95% CIs stratified based on the baselinecharacteristics were tabulated only on seropositive subjects and not on all subjects.

The following additional analyses were performed:

• The percentage of subjects with anti-HBs antibody concentrations ≥ 3.3 mIU/ml, ≥10 mIU/ml, ≥ 100 mIU/ml after the challenge dose according to their pre-challengedose status and post primary status was tabulated.

• The anamnestic response to the challenge dose for anti-HBs antibody concentrationsstratified based on the pre-challenge and post primary vaccination status was alsocalculated.

• The distribution of anti-HAV and anti-HBs antibody concentrations was graphicallypresented using RCCs for the LT-ATP cohort for immunogenicity.

• GMC evolution curves for anti-HAV and anti-HBs antibodies for the LT-ATP cohortfor immunogenicity were generated.

• Anti-HAV and anti-HBs seropositivity rates and GMCs stratified based on thebaseline characteristics for the ATP cohort of immunogenicity were tabulated. Allstratification was based on the primary study.

6. STUDY POPULATION RESULTS

6.1. Study dates

The first subject was enrolled in the study on 14 January 2008 and the last study visit wason 03 November 2008.

CONFIDENTIAL




Final

28 Aug 2009 - 56 -

6.2. Subject eligibility and attrition from the study

6.2.1. Number of subjects

A total of 506 subjects (172 in the Twinrix group, 170 subjects in the ENG+HAV groupand 164 subjects in the HBVX+VAQ group) were enrolled into the study.

The number of subjects per centre for the total vaccinated cohort is presented inSupplement 1.

The summary of tracking log-sheets for all subjects initially enrolled in the primary studyfor the total vaccinated cohort is presented in Supplement 2.

6.2.2. Study completion and withdrawal from study

The number of subjects enrolled, completed or withdrawn from the study is presented inTable 13.

Of the 506 subjects who were enrolled into the study, 503 subjects completed the studyand three subjects withdrew. The reasons for withdrawal are stated below.

•

• The subjectreceived the challenge dose but did not come back for the blood sampling visit, onemonth after the challenge dose.

• The subject received the challenge dose but did not return for the blood

sampling visit, one month after the challenge dose.Table 13 Number of subjects entered, completed and withdrawn with reason

for withdrawal (Total vaccinated cohort)

Twinrix Eng+HAV HBVX+VAQ TotalNumber of subjects enrolled 172 170 164 506Number of subjects completed 169 170 164 503Number of subjects withdrawn 3 0 0 3Reasons for withdrawal:Serious Adverse Event 1 0 0 1Lost to follow-up (subjects with complete vaccination course) 1 0 0 1Others 1 0 0 1Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseEnrolled = number of subjects who were vaccinated in the studyCompleted = number of subjects who completed last study visitWithdrawn = number of subjects who did not come for the last visit

CONFIDENTIAL




Final

28 Aug 2009 - 57 -

The number of subjects at each visit and list of withdrawn subjects for the totalvaccinated cohort is presented in Supplement 3.

6.2.3. Protocol deviations (Long-term follow-up up to Month 48)

The subject attrition from the primary study up to Year 4 (Month 48) for the LT ATPcohort for immunogenicity is presented in Table 14.

Subjects are listed in Table 14 based on the lowest elimination code as more than oneelimination code could be assigned to the same subject and between brackets subjects arelisted based on all elimination codes.

A total of 596 subjects were enrolled in the total vaccinated cohort in the primary study.

A total of 506 subjects returned for blood sampling at Month 48. Of these, 72 subjectswere eliminated at previous long-term time points. Fifteen subjects (two each in theTwinrix group and ENG+HAV group and eleven subjects in the HBVX+VAQ group)were assigned the elimination code 3120 for abnormal increase in ant-HAV or anti-HBsantibody concentrations between Year 3 and Year 4.

Thus, a total of 419 subjects were included in the LT ATP cohort for immunogenicity atMonth 48 (Year 4).

CONFIDENTIAL




Final

28 Aug 2009 - 58 -

Table 14 Subject attrition from the primary study up to Year 4 (Month 48) timepoint (LT ATP cohort for immunogenicity)

Title Total Twinrix Eng+HAV HBVX+VAQN n s % N n s N n s N n s

Number of subjects in the Total Vaccinated Cohortin the primary study

596 100 199 200 197

Number of subjects included in the ATPimmunogenicity cohort in the primary study

589 91.4 183 184 178

Number of subjects returning for blood sampling atYear 2 (Month 24)

583 97.8 193 196 194

Number of subjects included in the long-term ATPanalysis of immunogenicity at Year 2 (Month 24)

514 86.2 171 176 167

Number of subjects returning for blood sampling atYear 3 ( Month 36)

577 96.8 189 196 192


483 81.0 163 167 153

Number of subjects at Year 4 (Month 48) 506 84.9 172 170 164Number of subjects who returned at Year 4 (Month48) but were previously eliminated

72 22 21 29

Number of subjects with abnormal increase inantibody concentrations during the long-termfollow-up (Code 3120) at Year 4 (Month 48)

15 17 2 3 2 2 11 12


419 70.3 148 147 124

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseN: Number of subjects in the considered category.Note: Subjects may have more than one elimination code assignedn = number of subjects with the elimination code assigned excluding subjects who have been assigned a lowerelimination code or who have received the elimination code in the previous time-points including primary studys = number of subjects with the elimination code assigned% = percentage of subjects in the considered category relative to the Total Vaccinated Cohort of the primary study

6.2.4. Protocol deviations (Challenge dose phase)

The number of subjects enrolled into the challenge dose study as well as the numberexcluded from ATP immunogenicity analyses with reasons for exclusion is presented inTable 15.

A total of 506 subjects were enrolled and vaccinated in the study. Of these, one subject inthe ENG+HAV group was assigned the elimination code 1070 since the study vaccinewas not administered according to protocol.

Thus, 505 subjects were included in the ATP cohort for safety.

Of the 505 subjects, seven subjects were eliminated from the ATP cohort forimmunogenicity for the following reasons:

CONFIDENTIAL




Final

28 Aug 2009 - 59 -

•

•

• Five subjects (three subjects in the Twinrix group, one subject each in theENG+HAV group and HBVX+VAQ group) were assigned the elimination code2100.

−

−

−

Table 15 Number of subjects enrolled into the challenge dose study as wellas the number excluded from ATP analyses with reasons forexclusion

Total Twinrix Eng+HAV HBVX+VAQTitle n s % n s n s n s

Total enrolled cohort 506 172 170 164Total cohort 506 172 170 164Total vaccinated cohort 506 100 172 170 164Study vaccine dose not administeredaccording to protocol (code 1070)

1 1 0 0 1 1 0 0

ATP cohort for safety 505 99.8 172 169 164Initially seropositive or initially unknownantibody status (code 2020)

1 1 1 1 0 0 0 0

Non compliance with blood samplingschedule (including wrong and unknowndates (code 2090)

1 1 1 1 0 0 0 0

Essential serological data missing (code2100)

5 5 3 3 1 1 1 1

ATP cohort for immunogenicity 498 98.4 167 168 163Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phase Note: Subjects may have more than one elimination code assignedn = number of subjects with the elimination code assigned excluding subjects who have been assigned a lowerelimination code numbers = number of subjects with the elimination code assigned% = percentage of subjects in the considered ATP cohort relative to the Total vaccinated cohort

CONFIDENTIAL




Final

28 Aug 2009 - 60 -

6.3. Demographic characteristics

6.3.1. ATP cohort for immunogenicity

The summary of demographic characteristics for the ATP cohort for immunogenicity ispresented in Table 16.

The demographic profile of the three groups of subjects was comparable with respect tomean age, gender, racial distribution and BMI. The mean age ranged from 58.4 years to59.4 years in the three groups, 50.2% of subjects were male and the population waspredominantly (99.8%) White/ Caucasian. The mean BMI of the subjects in the threegroups was 28.3 kg/m².

Table 16 Summary of demographic characteristics (ATP cohort forimmunogenicity)

TwinrixN = 167

Eng+HAVN = 168

HBVX+VAQN = 163

TotalN = 498

Characteristics Categories Value Value Value ValueAge (years) Mean 58.4 59.4 59.2 59.0

SD 8.75 10.2 9.15 9.38Median 57.0 58.0 59.0 58.0Minimum 44 41 45 41Maximum 84 86 83 86

Height (cm) Mean 169.5 169.8 169.1 169.5SD 8.39 8.36 8.28 8.33Median 170.0 170.0 168.0 169.0

Weight (kg) Mean 80.8 82.1 81.3 81.4SD 14.99 18.28 17.24 16.86Median 79.0 79.7 80.0 79.6

BMI (kg/m²) Mean 28.1 28.4 28.3 28.3SD 4.62 5.90 5.17 5.25Median 27.6 26.9 27.7 27.4

n % n % n % n %Gender Female 82 49.1 82 48.8 84 51.5 248 49.8

Male 85 50.9 86 51.2 79 48.5 250 50.2Race Black 0 0.0 0 0.0 1 0.6 1 0.2

White/Caucasian 167 100 168 100 162 99.4 497 99.8Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseN = total number of subjectsn/% = number / percentage of subjects in a given categoryValue = value of the considered parameterSD = standard deviation

The summary of demographic characteristics for the ATP cohort for safety is presented inSupplement 4.

CONFIDENTIAL




Final

28 Aug 2009 - 61 -

6.3.2. Total vaccinated cohort

The summary of demographic characteristics for the total vaccinated cohort is presentedin Supplement 5.

The demographic characteristics of the total vaccinated cohort were similar to thoseobserved in the ATP cohort for immunogenicity.

7. IMMUNOGENICITY RESULTS

7.1. Data sets analysed

The primary analysis was based on the LT-ATP cohort for the persistence analyses andon the ATP cohort for immunogenicity for the challenge dose response. Since thepercentage of enrolled subjects excluded from this ATP cohort was less than 5%, asecondary analysis based on the Total Vaccinated cohort was not performed tocomplement the ATP analysis. See Section 5.10.4 for the definition of the cohortsidentified for analyses and Section 6.2 for eligibility for analyses.

7.2. According-to-protocol analysis

7.2.1. Persistence phase

7.2.1.1. Anti-HAV antibody persistence

The anti-HAV seropositivity rates and GMCs (calculated on seropositive subjects) foranti-HAV antibodies for the LT ATP cohort for immunogenicity are presented in Table17.

The reverse cumulative curves for anti-HAV antibody concentrations at Month 48 for theLT ATP cohort for immunogenicity are presented in Figure 1.

The GMC evolution curves of anti-HAV antibody concentrations from primary to Month48 time point for the LT ATP cohort for immunogenicity are presented in Figure 2.

At Month 48,

• Anti-HAV seropositivity rates were 97.3% in the Twinrix group, 93.9% in theENG+HAV group and 96.0% in the HBVX+VAQ group.

• Anti-HAV GMC evolution curves showed high decay rates in the first year afterprimary vaccination while there was only a marginal decrease in the anti-HAVGMCs from Year 3 to Year 4 in all three groups (See Figure 2).

CONFIDENTIAL




Final

28 Aug 2009 - 62 -

Table 17 Seropositivity rates and GMCs (calculated on seropositive subjects)for anti-HAV antibodies (LT ATP cohort for immunogenicity)

S+ GMC95% CI 95% CI

Group Timing Nn %

LL ULvalue

LL ULPIII(M7) 181 176 97.2 93.7 99.1 2746.5 2256.3 3343.2PIII(M12) 168 162 96.4 92.4 98.7 891.0 747.3 1062.2PIII(M24) 171 164 95.9 91.7 98.3 271.6 229.0 322.2PIII(M36) 163 158 96.9 93.0 99.0 216.9 182.6 257.6

Twinrix

PIII(M48) 147 143 97.3 93.2 99.3 212.9 177.2 255.6PII(M7) 182 180 98.9 96.1 99.9 1394.3 1159.8 1676.1PII(M12) 168 165 98.2 94.9 99.6 530.6 442.0 637.1PII(M24) 176 170 96.6 92.7 98.7 209.9 176.3 249.8PII(M36) 167 159 95.2 90.8 97.9 185.4 155.7 220.7

Eng+HAV

PII(M48) 147 138 93.9 88.7 97.2 165.7 137.7 199.4PII(M7) 176 174 98.9 96.0 99.9 3707.2 3081.4 4460.2PII(M12) 165 164 99.4 96.7 100 1200.5 999.3 1442.1PII(M24) 167 163 97.6 94.0 99.3 362.0 303.5 431.8PII(M36) 153 148 96.7 92.5 98.9 278.5 229.4 338.2

HBVX+VAQ

PII(M48) 124 119 96.0 90.8 98.7 277.4 226.1 340.2Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseGMC = geometric mean antibody concentration calculated on subjects with concentration ≥15 mIU/mlN = number of subjects with available resultsSeropositivity: Subjects with anti-HAV antibody concentrations ≥ 15 mIU/mln/% = number/percentage of subjects with concentration within the specified range95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper LimitPIII(M48) = Blood sampling after the third dose; 48 months after the first dose of primary vaccination course etcPII(M48) = Blood sampling after the second dose; 48 months after the first dose of primary vaccination course etc

CONFIDENTIAL




Final

28 Aug 2009 - 63 -

Figure 1 Reverse cumulative curves for anti-HAV antibody concentrations atpre time point at Month 48 (LT ATP cohort for immunogenicity)

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAX PRO and Vaqta in the primary study and in thechallenge phase

CONFIDENTIAL




Final

28 Aug 2009 - 64 -

Figure 2 GMC evolution curve of anti-HAV antibody concentrations fromprimary to Month 48 time point (LT ATP cohort for immunogenicity)

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phase

7.2.1.2. Anti-HBs antibody persistence

Anti-HBs seropositivity rates, percentage of subjects with antibody concentrations ≥ 10mIU/ ml and GMCs (calculated on seropositive subjects) for the LT ATP cohort forimmunogenicity are presented in Table 18.

The reverse cumulative curves for anti-HBs antibody concentrations at Month 48 for theLT ATP cohort for immunogenicity are presented in Figure 3.

The GMC evolution curve for anti-HBs antibody concentrations from primary to theMonth 48 time point for the LT ATP cohort for immunogenicity are presented in Figure4.

CONFIDENTIAL




Final

28 Aug 2009 - 65 -

At Month 48,

• Anti-HBs seropositivity rates were 76.9% in the Twinrix group, 61.9% in theENG+HAV group and 51.6% in the HBVX+VAQ group.

• The percentage of subjects with anti-HBs antibody concentrations ≥ 10 mIU/ml was57.1% in the Twinrix group, 40.1% in the ENG+HAV group and 26.6% in theHBVX+VAQ group.

• Anti-HBs GMC evolution curves showed high decay rates in the first year afterprimary vaccination while there was only a small decrease (0.59-0.75 fold) fromYear 3 to Year 4 in the three groups.

Table 18 Anti-HBs seropositivity rates, percentage of subjects with antibodyconcentrations greater than or equal to 10 mIU per ml and GMCs(calculated on seropositive subjects) (LT ATP cohort forimmunogenicity)

S+ ≥≥≥≥ 10 mIU/ml GMC95% CI 95% CI 95% CI

Group Timing Nn %

LL ULn %

LL ULvalue

LL ULPIII(M7) 181 168 92.8 88.0 96.1 166 91.7 86.7 95.3 1153.9 829.8 1604.7PIII(M12) 168 153 91.1 85.7 94.9 147 87.5 81.5 92.1 339.2 248.6 462.9PIII(M24) 171 136 79.5 72.7 85.3 127 74.3 67.0 80.6 113.2 83.9 152.8PIII(M24)* 169 137 81.1 74.3 86.7 125 74.0 66.7 80.4 99.3 75.4 130.7PIII(M36) 163 124 76.1 68.8 82.4 104 63.8 55.9 71.2 72.1 53.1 98.0

Twinrix

PIII(M48) 147 113 76.9 69.2 83.4 84 57.1 48.7 65.3 42.3 31.3 57.3PIII(M7) 182 152 83.5 77.3 88.6 145 79.7 73.1 85.3 491.2 342.3 704.9PIII(M12) 168 134 79.8 72.9 85.6 124 73.8 66.5 80.3 149.4 106.4 209.7PIII(M24) 176 123 69.9 62.5 76.6 88 50.0 42.4 57.6 46.5 33.0 65.4PIII(M24)* 175 129 73.7 66.5 80.1 99 56.6 48.9 64.0 40.8 30.4 54.9PIII(M36) 167 105 62.9 55.1 70.2 75 44.9 37.2 52.8 34.1 24.6 47.2

Eng+HAV

PIII(M48) 147 91 61.9 53.5 69.8 59 40.1 32.1 48.5 23.6 17.5 31.8PIII(M7) 176 137 77.8 71.0 83.7 125 71.0 63.7 77.6 179.1 128.5 249.7PIII(M12) 165 109 66.1 58.3 73.2 93 56.4 48.4 64.1 53.1 39.3 71.6PIII(M24) 167 74 44.3 36.6 52.2 50 29.9 23.1 37.5 21.3 15.5 29.4PIII(M24)* 165 76 46.1 38.3 54.0 56 33.9 26.8 41.7 22.3 16.9 29.4PIII(M36) 153 67 43.8 35.8 52.0 45 29.4 22.3 37.3 18.9 14.1 25.3

HBVX+VAQ

PIII(M48) 124 64 51.6 42.5 60.7 33 26.6 19.1 35.3 13.7 10.6 17.7Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseGMC = geometric mean antibody concentration calculated on subjects with concentration ≥ 3.3 mIU/mlN = number of subjects with available resultsS+ : Seropositivity for anti-HBs antibodies defined as antibody concentrations ≥ 3.3 mIU/mlValue = value of the considered parametern/% = number/percentage of subjects with concentration within the specified range95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper LimitPIII(M7) to PIII(M24) = anti-HBs antibody concentrations tested with AUSAB ® EIA /Abbott assay with cut-off3.3mIU/mlPIII(M24)* onwards = anti-HBs antibody concentrations tested with the in-house assay with cut-off 3.3mIU/mlPIII(M48) = Blood sampling after the third dose; 48 months after the first dose of primary vaccination course etc

CONFIDENTIAL




Final

28 Aug 2009 - 66 -

Figure 3 Reverse cumulative curves for anti-HBs antibody concentrations atMonth 48 (LT ATP cohort for immunogenicity)


CONFIDENTIAL




Final

28 Aug 2009 - 67 -

Figure 4 GMC evolution curve of anti-HBs antibody concentrations fromprimary to Month 48 time point (LT ATP cohort for immunogenicity)

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phasePIII(M7) to PIII(M24) = anti-HBs antibody concentrations tested with AUSAB ® EIA /Abbott assay with cut-off3.3mIU/mlPIII(M24)* onwards = anti-HBs antibody concentrations tested with the in-house assay with cut-off 3.3mIU/ml

7.2.2. Challenge dose phase

7.2.2.1. Anti-HAV antibody response

Seropositivity rates and GMCs (calculated on seropositive subjects) for anti-HAVantibodies before and after the challenge dose for the ATP cohort for immunogenicity arepresented in Table 19. The anamnestic response to the challenge dose for anti-HAVantibodies for the ATP cohort for immunogenicity is presented in Table 20.

The reverse cumulative curves for anti-HAV antibody concentrations, before and 30 daysafter the challenge dose for the ATP cohort for immunogenicity are presented in Figure 5and Figure 6, respectively.

CONFIDENTIAL




Final

28 Aug 2009 - 68 -

• Anti-HAV seropositivity rates were 99.4% at Day 14 and Day 30 after the challengedose, in all three groups.

• The increase in anti-HAV GMCs from the pre-challenge to the post-challenge timepoint ranged between 17.8-fold to 24.9-fold in the three groups.

• An anamnestic response to the hepatitis A containing challenge dose was mountedby 98.2% of subjects in the Twinrix group, 97.6% in the ENG+HAV group and99.4% of subjects in the HBVX+VAQ group (See Table 20).

Table 19 Seropositivity rates and GMCs (calculated on seropositive subjects)for anti-HAV antibodies before and after the challenge dose (ATPcohort for immunogenicity)

≥≥≥≥ 15 mIU/ml GMC95% CI 95% CI

Group Timing N n % LL UL value LL ULPre 167 162 97.0 93.2 99.0 212.2 177.5 253.7PI(D14) 167 166 99.4 96.7 100 2255.0 1928.5 2636.8

Twinrix

PI(D30) 167 166 99.4 96.7 100 4062.0 3451.1 4781.0Pre 168 157 93.5 88.6 96.7 175.4 147.3 208.9PI(D14) 168 167 99.4 96.7 100 1774.3 1493.5 2107.9

Eng+HAV

PI(D30) 168 167 99.4 96.7 100 3124.1 2630.4 3710.5Pre 163 158 96.9 93.0 99.0 308.4 255.6 372.1PI(D14) 163 162 99.4 96.6 100 2712.9 2290.4 3213.3

HBVX+VAQ

PI(D30) 163 162 99.4 96.6 100 7481.6 6358.3 8803.3Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseGMC = geometric mean antibody concentration calculated on subjects with concentration.≥ 15 mIU/mLN = number of subjects with available resultsn/% = number/percentage of subjects with antibody concentrations above the specified cut-off95% CI; LL, UL = exact 95% confidence interval; lower and upper limitsPre = Prior to administration of challenge dosePI (D14) = Two weeks after the administration of the challenge dosePI (D30) = One month after the administration of the challenge dose

CONFIDENTIAL




Final

28 Aug 2009 - 69 -

Table 20 Anamnestic response to the challenge dose for anti-HAV antibodies(ATP cohort for immunogenicity)

Anamnestic response to the challenge dose95% CI

Group Pre-vaccination status N n % LL UL

S- 5 4 80.0 28.4 99.5S+ (<100mIU/ml) 39 39 100 91.0 100S+ (≥100mIU/ml) 123 121 98.4 94.2 99.8

Twinrix

Total 167 164 98.2 94.8 99.6S- 11 10 90.9 58.7 99.8S+ (<100mIU/ml) 51 49 96.1 86.5 99.5S+ (≥100mIU/ml) 106 105 99.1 94.9 100

Eng + Hav

Total 168 164 97.6 94.0 99.3S- 5 4 80.0 28.4 99.5S+ (<100mIU/ml) 29 29 100 88.1 100S+ (≥100mIU/ml) 129 129 100 97.2 100

HBVX + VAQ

Total 163 162 99.4 96.6 100Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseS- = seronegative subjects (antibody concentration < 15 mIU/ml for anti-HAV) prior to vaccinationS+ = seropositive subjects (antibody concentration ≥ 15 mIU/ml for anti-HAV) prior to vaccinationTotal = subjects either seropositive or seronegative at pre-vaccinationChallenge Dose response defined as: For initially seronegative subjects, antibody concentration greater than or equal the cut-off (≥ 15 mIU/ml) For initially seropositive subjects with pre-vaccination antibody concentration < 100 mIU/ml: antibody concentrationat least four times the pre-vaccination antibody concentration For initially seropositive subjects with pre-vaccination antibody concentration ≥ 100 mIU/ml: antibody concentration at least two times the pre-vaccination antibody concentrationN = number of subjects with both pre- and post-vaccination results availablen/% = number/percentage of responders95% CI = exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit

CONFIDENTIAL




Final

28 Aug 2009 - 70 -

Figure 5 Reverse cumulative distribution curves for anti-HAV antibodyconcentrations before the challenge dose (ATP cohort forimmunogenicity)


CONFIDENTIAL




Final

28 Aug 2009 - 71 -

Figure 6 Reverse cumulative distribution curves for anti-HAV antibodyconcentrations, 30 days after the challenge dose (ATP cohort forimmunogenicity)


The GMCs calculated on all subjects for anti-HAV antibodies before and after thechallenge dose for the ATP cohort for immunogenicity are presented in Supplement 6.

The seropositivity rates and GMCs (calculated on seropositive subjects) for anti-HAVantibodies stratified by gender, age, BMI, smoking status, alcohol consumption,concomitant medication, medical condition status and diabetes status, one month after thechallenge dose for the ATP cohort for immunogenicity are presented in Supplement 7 toSupplement 14.

The correlation between anti-HAV antibody concentrations at the pre and post challengedose time points for the ATP cohort for immunogenicity is presented in Supplement 15.

The reverse cumulative curves for anti-HAV antibody concentrations 14 days after thechallenge dose for the ATP cohort for immunogenicity are presented in Supplement 16.

CONFIDENTIAL




Final

28 Aug 2009 - 72 -

7.2.2.2. Anti-HBs antibody response

Overall per group analysis

The seroprotection, seropositivity rates and GMCs calculated on seropositive subjects foranti-HBs antibody concentrations before and after the challenge dose for the ATP cohortfor immunogenicity are presented in Table 21.

The percentage of subjects with an anamnestic response to the challenge dose for anti-HBs antibodies for the ATP cohort for immunogenicity is presented in Table 22.

The reverse cumulative distribution curves for anti-HBs antibody concentrations at thepre-challenge dose and one month after the challenge dose for the ATP cohort forimmunogenicity are presented in Figure 7 and Figure 8, respectively.

One month after the challenge dose,

• An anamnestic response to the hepatitis B antigen containing challenge dose wasmounted by 93.4% of subjects in the Twinrix group, 88.1% of subjects in theENG+HAV group and 83.4% of subjects in the HBVX+VAQ group.

• Anti-HBs seropositivity rates were 96.4%, 96.4% and 89.0% in the Twinrix group,ENG+HAV group and HBVX+VAQ group, respectively.

• Anti-HBs seroprotection rates were 95.2%, 90.5% and 85.3% in the Twinrix group,ENG+HAV group and HBVX+VAQ group, respectively.

• The percentage of subjects with anti-HBs antibody concentrations ≥ 100 mIU/ mlwas 90.4%, 76.8% and 68.7% in the Twinrix group, ENG+HAV group andHBVX+VAQ group, respectively.

• Anti-HBs GMCs were 7233.7 mIU/ml, 1242.5 mIU/ml and 1075.1 mIU/ml in theTwinrix, ENG+HAV and HBVX+VAQ groups, respectively.

• The increase in anti-HBs GMCs between the pre-challenge time point and the post-challenge time point ranged between 46.5-fold to 179.5-fold in the three groups.

At Day 14 after the challenge dose, very similar anti-HBs concentrations were observedin all groups, indicating a rapid humoral response to the challenge dose.

• Anti-HBs seropositivity rates were 97%, 95.2% and 89.6% in the Twinrix group,ENG+HAV group and HBVX+VAQ group, respectively.

• Anti-HBs seroprotection rates were 95.8%, 89.3% and 85.9% in the Twinrix group,ENG+HAV group and HBVX+VAQ group, respectively.

• The percentage of subjects with anti-HBs antibody concentrations ≥ 100 mIU/ mlwas 91.6%, 81.5% and 72.4% of subjects in the Twinrix group, ENG+HAV groupand HBVX+VAQ group, respectively.

CONFIDENTIAL




Final

28 Aug 2009 - 73 -

• Anti-HBs GMCs were 8936.9 mIU/ml, 1521.0 mIU/ml and 1222.4 mIU/ml in theTwinrix, ENG+HAV and HBVX+VAQ groups, respectively.

Table 21 Seroprotection and seropositivity rates and GMCs calculated onseropositive subjects for anti-HBs antibodies before and after thechallenge dose (ATP cohort for immunogenicity)

≥≥≥≥ 3.3 mIU/ml ≥≥≥≥ 10 mIU/ml ≥≥≥≥ 100 mIU/ml GMC95% CI 95% CI 95% CI

Group Timing N n % LL UL n % LL UL n % LL UL value LL ULPre 167 128 76.6 69.5 82.8 93 55.7 47.8 63.4 35 21.0 15.1 27.9 40.3 30.0 54.2PI(D14) 167 162 97.0 93.2 99.0 160 95.8 91.6 98.3 153 91.6 86.3 95.3 8936.9 6071.1 13155.4

Twinrix

PI(D30) 167 161 96.4 92.3 98.7 159 95.2 90.8 97.9 151 90.4 84.9 94.4 7233.7 4868.2 10748.7Pre 168 107 63.7 55.9 71.0 72 42.9 35.3 50.7 19 11.3 6.9 17.1 26.7 19.6 36.3PI(D14) 168 160 95.2 90.8 97.9 150 89.3 83.6 93.5 137 81.5 74.8 87.1 1521.0 1012.5 2285.0

Eng+HAV

PI(D30) 168 162 96.4 92.4 98.7 152 90.5 85.0 94.5 129 76.8 69.7 82.9 1242.5 823.5 1874.8Pre 163 90 55.2 47.2 63.0 50 30.7 23.7 38.4 9 5.5 2.6 10.2 15.4 12.2 19.5PI(D14) 163 146 89.6 83.8 93.8 140 85.9 79.6 90.8 118 72.4 64.9 79.1 1222.4 821.3 1819.3

HBVX+VAQ

PI(D30) 163 145 89.0 83.1 93.3 139 85.3 78.9 90.3 112 68.7 61.0 75.7 1075.1 717.2 1611.4Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseGMC = geometric mean antibody concentration calculated on subjects with concentration ≥ 3.3 mIU/mLN = number of subjects with available resultsn/% = number/percentage of subjects with antibody concentrations above the specified cut-off95% CI = exact 95% confidence interval; LL = Lower Limit; UL = Upper LimitPre = Prior to administration of challenge dosePI (D14) =Two weeks after the administration of challenge dosePI (D30) = One month after the administration of challenge dose

CONFIDENTIAL




Final

28 Aug 2009 - 74 -

Table 22 Anamnestic response to the challenge dose for anti-HBs antibodies(ATP cohort for immunogenicity)

Booster response95% CI

Group Pre-vaccination status N n % LL ULS- 39 32 82.1 66.5 92.5S+ 128 124 96.9 92.2 99.1

Twinrix

Total 167 156 93.4 88.5 96.7S- 61 50 82.0 70.0 90.6S+ 107 98 91.6 84.6 96.1

Eng+HAV

Total 168 148 88.1 82.2 92.6S- 73 53 72.6 60.9 82.4S+ 90 83 92.2 84.6 96.8

HBVX + VAQ

Total 163 136 83.4 76.8 88.8Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseS- = seronegative subjects (antibody concentration < 3.3 mIU/ml for anti-HBs antibodies) prior to vaccinationS+ = seropositive subjects (antibody concentration ≥ 3.3 mIU/ml for anti-HBs antibodies) prior to vaccinationTotal = subjects either seropositive or seronegative at pre-vaccinationBooster response defined as : For initially seronegative subjects, antibody concentration ≥ 10 mIU/ml at PI(D30) For initially seropositive subjects : antibody concentration at PI(D30) ≥ 4 fold the pre-vaccination antibodyconcentrationN = number of subjects with both pre- and post-vaccination results availablen/% = number/percentage of responders95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit

CONFIDENTIAL




Final

28 Aug 2009 - 75 -

Figure 7 Reverse cumulative distribution curves for anti-HBs antibodyconcentrations at the pre-challenge dose (ATP cohort forimmunogenicity)


CONFIDENTIAL




Final

28 Aug 2009 - 76 -

Figure 8 Reverse cumulative distribution curves for anti-HBs antibodyconcentrations, 30 days after the challenge dose (ATP cohort forimmunogenicity)


The GMCs calculated on all subjects for anti-HBs antibodies before and after thechallenge dose for the ATP cohort for immunogenicity are presented in Supplement 17.

The reverse cumulative distribution curves for anti-HBs antibody concentrations 14 daysafter the challenge dose for the ATP cohort for immunogenicity are presented inSupplement 18.

The seropositivity rates and GMCs (calculated on seropositive subjects) for anti-HBsantibodies stratified by gender, age, BMI, smoking status, alcohol consumption,concomitant medication, medical condition status and diabetes status, before, 14 days andone month after the challenge dose for the ATP cohort for immunogenicity are presentedfrom Supplement 19 to Supplement 26.

CONFIDENTIAL




Final

28 Aug 2009 - 77 -

Analysis stratified based on the anti-HBs antibody concentrations after primaryvaccination and before the challenge dose administration (Exploratory analysis)

In order to evaluate whether the anti-HBs concentrations that were reached following theprimary vaccination course and/or the anti-HBs concentrations at the time of challengedose administration would affect the response to this challenge dose, an exploratoryanalysis was performed where subjects were stratified based on their post-primary andpre-challenge dose anti-HBs concentrations.

The percentage of subjects with anti-HBs antibody concentrations ≥ 3.3 mIU/ml, ≥ 10mIU/ml and ≥ 100 mIU/ml after the challenge dose stratified according to their post-primary vaccination status for the ATP cohort for immunogenicity is presented in Table23.

• The percentage of subjects who had anti-HBs antibody concentrations < 3.3 mIU/mlat the post-primary time point and achieved anti-HBs antibody concentrations ≥ 10mIU/ ml following the challenge dose was 33.3%, 53.3% and 42.9% in the Twinrix,ENG+HAV and HBVX+VAQ groups, respectively.

• The percentage of subjects that had anti-HBs antibody concentrations < 3.3 mIU/mlat the post-primary time point and demonstrated an anamnestic response to thechallenge dose was 33.3% , 46.7% and 37.1% in the Twinrix, ENG+HAV andHBVX+VAQ groups, respectively (See Supplement 27).

CONFIDENTIAL




Final

28 Aug 2009 - 78 -

Table 23 Percentage of subjects with anti-HBs antibody concentrationsgreater than or equal to 3.3 mIU/ml, greater than or equal to 10mIU/ml, greater than or equal to 100 mIU/ml after the challenge doseaccording to their post-primary vaccination status (ATP cohort forimmunogenicity)

Post-challenge dose (Day 30)≥≥≥≥ 3.3 mIU/ml ≥≥≥≥ 10 mIU/ml ≥≥≥≥ 100 mIU/ml GMC

95% CI 95% CI 95% CIGroup Post primary

vaccinationstatus

N n % LL UL n % LL UL n % LL UL value LL UL

<3.3 mIU/ml 9 3 33.3 7.5 70.1 3 33.3 7.5 70.1 2 22.2 2.8 60.0 6.3 1.3 31.63.3 - <10 mIU/ml 2 2 100 15.8 100 1 50.0 1.3 98.7 0 0.0 0.0 84.2 11.6 0.0 10313.810 - <100 mIU/ml 17 17 100 80.5 100 16 94.1 71.3 99.9 11 64.7 38.3 85.8 211.2 73.8 604.2Twinrix≥100 mIU/ml 139 139 100 97.4 100 139 100 97.4 100 138 99.3 96.1 100 13426.6 9573.0 18831.3<3.3 mIU/ml 30 24 80.0 61.4 92.3 16 53.3 34.3 71.7 4 13.3 3.8 30.7 15.7 7.9 31.13.3 - <10 mIU/ml 5 5 100 47.8 100 5 100 47.8 100 3 60.0 14.7 94.7 144.5 23.5 886.810 - <100 mIU/ml 32 32 100 89.1 100 30 93.8 79.2 99.2 22 68.8 50.0 83.9 366.7 181.1 742.5

Eng +Hav

≥100 mIU/ml 101 101 100 96.4 100 101 100 96.4 100 100 99.0 94.6 100 5029.9 3516.4 7194.8<3.3 mIU/ml 35 20 57.1 39.4 73.7 15 42.9 26.3 60.6 4 11.4 3.2 26.7 9.3 4.8 18.23.3 - <10 mIU/ml 11 9 81.8 48.2 97.7 8 72.7 39.0 94.0 4 36.4 10.9 69.2 47.0 10.2 215.510 - <100 mIU/ml 37 37 100 90.5 100 37 100 90.5 100 26 70.3 53.0 84.1 460.4 251.4 843.1

HBVX +VAQ

≥100 mIU/ml 80 79 98.8 93.2 100 79 98.8 93.2 100 78 97.5 91.3 99.7 4548.5 3084.0 6708.6Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseGMC = geometric mean antibody concentration, calculated for all subjects. Antibody concentrations below the cut-off of the assays were given an arbitrary value of one half the cut-off for the purpose of calculating the GMCN = number of subjects with available resultsn/% = number/percentage of subjects with antibody concentrations above the specified cut-off95% CI; LL, UL = exact 95% confidence interval; lower and upper limitsStratification based on primary study

The percentage of subjects with anti-HBs antibody concentrations ≥ 3.3 mIU/ml, ≥ 10mIU/ml and ≥ 100 mIU/ml after the challenge dose stratified according to the pre-challenge dose status for the ATP cohort for immunogenicity is presented in Table 24.

• The percentage of subjects that had anti-HBs antibody concentrations < 3.3 mIU/mlat the pre-challenge time point and achieved anti-HBs antibody concentrations ≥ 10mIU/ ml after the challenge dose was 82.1% in the Twinrix group, 82.0% in theENG+HAV group and 72.6% in the HBVX+VAQ group.

• A significant positive correlation between antibody concentrations before andfollowing the challenge dose was observed (refer to correlation graph Supplement29).

CONFIDENTIAL




Final

28 Aug 2009 - 79 -

Table 24 Percentage of subjects with anti-HBs antibody concentrationsgreater than or equal to 3.3 mIU/ml, greater than or equal to 10mIU/ml, greater than or equal to 100 mIU/ml after the challenge doseaccording to their pre-challenge dose status (ATP cohort forimmunogenicity)

≥≥≥≥ 3.3 mIU/ml ≥≥≥≥ 10 mIU/ml ≥≥≥≥ 100 mIU/ml GMC95% CI 95% CI 95% CI

Group Pre-challenge

dose status


<3.3 mIU/ml 39 33 84.6 69.5 94.1 32 82.1 66.5 92.5 26 66.7 49.8 80.9 188.6 78.7 452.03.3 - <10mIU/ml

35 35 100 90.0 100 34 97.1 85.1 99.9 32 91.4 76.9 98.2 1590.1 861.1 2936.1Twinrix

≥10mIU/ml 93 93 100 96.1 100 93 100 96.1 100 93 100 96.1 100 34370.4 24503.7 48209.9<3.3 mIU/ml 61 56 91.8 81.9 97.3 50 82.0 70.0 90.6 35 57.4 44.1 70.0 156.8 82.3 298.73.3 - <10mIU/ml

35 34 97.1 85.1 99.9 30 85.7 69.7 95.2 25 71.4 53.7 85.4 375.0 167.0 842.2Eng +Hav

≥10mIU/ml 72 72 100 95.0 100 72 100 95.0 100 69 95.8 88.3 99.1 7398.1 4618.0 11851.9<3.3 mIU/ml 73 57 78.1 66.9 86.9 53 72.6 60.9 82.4 35 47.9 36.1 60.0 91.1 45.6 182.13.3 - <10mIU/ml

40 38 95.0 83.1 99.4 37 92.5 79.6 98.4 32 80.0 64.4 90.9 873.2 421.5 1809.1HBVX +VAQ

≥10mIU/ml 50 50 100 92.9 100 49 98.0 89.4 99.9 45 90.0 78.2 96.7 4524.8 2397.7 8538.9Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseGMC = geometric mean antibody concentration, calculated for all subjects. Antibody concentrations below the cut-off ofthe assays were given an arbitrary value of one half the cut-off for the purpose of calculating the GMC.N = number of subjects with available resultsn/% = number/percentage of subjects with antibody concentrations above the specified cut-off95% CI; LL, UL = exact 95% confidence interval; lower and upper limits

The anamnestic response to the challenge dose for anti-HBs antibodies stratified based onthe post-primary vaccination status and the pre-challenge dose for the ATP cohort forimmunogenicity is presented in Supplement 27 and Supplement 28, respectively.

7.3. Total vaccinated cohort analysis

Since the percentage of enrolled subjects excluded from this ATP cohort are less than5%, a secondary analysis based on the Total Vaccinated cohort was not performed tocomplement the ATP analysis.

7.4. Immunogenicity conclusions

• At Month 48, anti-HAV seropositivity rates were 97.3% in the Twinrix group, 93.9%in the ENG+HAV group and 96.0% in the HBVX+VAQ group with GMCs of 212.9mIU/ml in the Twinrix group, 165.7 mIU/ ml in the ENG+HAV group and 277.4mIU/ml in the HBVX+VAQ group.

• At Month 48, the percentage of subjects with anti-HBs antibody concentrations ≥ 10mIU/ml was 57.1% in the Twinrix group, 40.1% in the ENG+HAV group and 26.6%

CONFIDENTIAL




Final

28 Aug 2009 - 80 -

in the HBVX+VAQ group with GMCs of 42.3 mIU/ml in the Twinrix group, 23.6mIU/ ml in the ENG+HAV group and 13.7 mIU/ml in the HBVX+VAQ group.

• One month after the challenge dose, an anamnestic response to the hepatitis Acontaining challenge dose was mounted by 98.2% of subjects in the Twinrix group,97.6% in the ENG+HAV group and 99.4% of subjects in the HBVX+VAQ group.

• One month after the challenge dose, an anamnestic response to the hepatitis Bantigen containing challenge dose was mounted by 93.4% of subjects in the Twinrixgroup, 88.1% of subjects in the ENG+HAV group and 83.4% of subjects in theHBVX+VAQ group.

• One month after the challenge dose, anti-HAV seropositivity rates were 99.4% in thethree groups.

• One month after the challenge dose, the percentage of subjects with anti-HBsantibody concentrations ≥ 10 mIU/ml was 95.2% in the Twinrix group, 90.5% in theENG+HAV group and 85.3% in the HBVX+VAQ group.

8. SAFETY RESULTS

8.1. Data sets analysed

The analysis was based on the Total Vaccinated cohort. Since only 0.2% of the enrolledsubjects were eliminated from the ATP cohort for safety analysis, a secondary analysiswas not performed on the ATP cohort for safety. See Section 5.10.4 for the definition ofthe cohorts identified for analyses and Section 6.2 for eligibility for analyses.

8.2. Total vaccinated cohort analysis

The number and percentage of subjects who received the challenge dose is presented inTable 25.

A total of 506 subjects were enrolled into the study and all subjects received thechallenge dose.

Table 25 Number and percentage of subjects who received the study vaccinedose (Total vaccinated cohort for the Challenge dose)

Twinrix (N = 172) Eng+HAV (N = 170) HBVX+VAQ (N = 164) Total (N = 506)n % n % n % n %

172 100 170 100 164 100 506 100Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseN = number of subjects in each group or in total included in the considered cohortn/% = number/percentage of subjects receiving the dose

The compliance in returning symptom sheets for the Total vaccinated cohort for theChallenge dose is presented in Supplement 30.

CONFIDENTIAL




Final

28 Aug 2009 - 81 -

8.2.1. Overall incidence of adverse events

The incidence and nature of symptoms (solicited and unsolicited) reported during the 4-day (Days 0-3) post-vaccination period for the Total vaccinated cohort for the Challengedose is presented in Table 26.

• At least one symptom (solicited or unsolicited, local or general) was reported by44.2% of subjects in the Twinrix group, 34.1% of subjects in the ENG+HAV groupand 47.0% of subjects in the HBVX+VAQ group.

• At least one symptom of grade 3 intensity was reported by 2.3% of subjects in theTwinrix group and 2.4% of subjects in the HBVX+VAQ group. No subjects reporteda symptom of grade 3 intensity in the ENG+HAV group (See Supplement 31).

Table 26 Incidence and nature of symptoms (solicited and unsolicited)reported during the 4-day (Days 0-3) post-vaccination period (Totalvaccinated cohort for the Challenge dose)

Any symptom General symptoms Local symptoms95% CI 95% CI 95% CI

Group N n % LL UL N n % LL UL N n % LL ULTwinrix 172 76 44.2 36.6 51.9 172 40 23.3 17.2 30.3 172 58 33.7 26.7 41.3Eng+HAV 170 58 34.1 27.0 41.8 170 34 20.0 14.3 26.8 170 43 25.3 19.0 32.5HBVX+VAQ 164 77 47.0 39.1 54.9 164 41 25.0 18.6 32.3 164 61 37.2 29.8 45.1Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseN = number of subjects with the administered dosen/% = number/percentage of subjects presenting at least one type of symptom whatever the study vaccineadministered95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit

The incidence and nature of grade 3 symptoms and causally related symptoms (solicitedand unsolicited) reported during the 4-day (Days 0-3) post-vaccination period for theTotal vaccinated cohort for the Challenge dose) is presented in Supplement 31 andSupplement 32, respectively.

8.2.2. Solicited local adverse events

All solicited local symptoms are considered to be causally related to vaccination.

The percentage of subjects who reported solicited local symptoms during the 4-day (Days0-3) post-vaccination period for the Total vaccinated cohort for the Challenge dose ispresented in Table 27.

• Pain was the most frequently reported solicited local symptom reported by 24.4%,20.6% and 28.0% of subjects in the Twinrix, the ENG+HAV and HBVX+VAQgroups, respectively.

• Local symptoms of grade 3 intensity were reported by less than 1.3% of subjects.

CONFIDENTIAL




Final

28 Aug 2009 - 82 -

Table 27 Percentage of subjects who reported solicited local symptomsduring the 4-day (Days 0-3) post-vaccination period (Totalvaccinated cohort for Challenge dose)

Twinrix Eng+HAV HBVX+VAQ95 % CI 95 % CI 95 % CI

Symptom Type N n % LL UL N n % LL UL N n % LL ULPain All 172 42 24.4 18.2 31.5 170 35 20.6 14.8 27.5 164 46 28.0 21.3 35.6

Grade 3 172 0 0.0 0.0 2.1 170 0 0.0 0.0 2.1 164 1 0.6 0.0 3.4Redness (mm) All 172 22 12.8 8.2 18.7 170 10 5.9 2.9 10.6 164 19 11.6 7.1 17.5

≥ 50 mm 172 0 0.0 0.0 2.1 170 0 0.0 0.0 2.1 164 0 0.0 0.0 2.2Swelling (mm) All 172 9 5.2 2.4 9.7 170 3 1.8 0.4 5.1 164 12 7.3 3.8 12.4

≥ 50 mm 172 2 1.2 0.1 4.1 170 0 0.0 0.0 2.1 164 1 0.6 0.0 3.4Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseN= number of subjects with the documented dosen/% = number/percentage of subjects reporting at least once the symptom95%CI = Exact 95% confidence interval; LL = Lower Limit, UL = Upper LimitAll = Solicited local symptoms of any intensityGrade 3 pain: Pain that prevented normal activities.

8.2.3. Solicited general adverse events

The percentage of subjects who reported solicited general symptoms during the 4-day(Days 0-3) post-vaccination period for the Total vaccinated cohort for the challenge doseis presented in Table 28.

• Fatigue was the most frequently reported solicited general symptom reported by16.9%, 14.1% and 17.1% of subjects in the Twinrix, ENG+HAV and HBVX+VAQgroups, respectively.

• Fatigue and gastrointestinal symptoms were the most frequently reported solicitedgeneral symptom of grade 3 intensity in the Twinrix group; each symptom reportedby 1.2% of subjects.

• No grade 3 solicited general symptoms were reported by subjects in the ENG+HAVgroup and HBVX+VAQ group.

• Solicited general symptoms that were considered to be causally related tovaccination were reported by a maximum of 13.4% of subjects.

CONFIDENTIAL




Final

28 Aug 2009 - 83 -

Table 28 Percentage of subjects who reported solicited general symptomsduring the 4-day (Days 0-3) post-vaccination period (Totalvaccinated cohort for Challenge dose)

Twinrix Eng+HAV HBVX+VAQ95 % CI 95 % CI 95 % CI

Symptom Type N n % LL UL N n % LL UL N n % LL ULFatigue All 172 29 16.9 11.6 23.3 170 24 14.1 9.3 20.3 164 28 17.1 11.7 23.7

Grade 3 172 2 1.2 0.1 4.1 170 0 0.0 0.0 2.1 164 0 0.0 0.0 2.2Related 172 23 13.4 8.7 19.4 170 19 11.2 6.9 16.9 164 22 13.4 8.6 19.6Grade 3*Rel 172 1 0.6 0.0 3.2 170 0 0.0 0.0 2.1 164 0 0.0 0.0 2.2

Gastrointestinal All 172 5 2.9 1.0 6.7 170 8 4.7 2.1 9.1 164 5 3.0 1.0 7.0Grade 3 172 2 1.2 0.1 4.1 170 0 0.0 0.0 2.1 164 0 0.0 0.0 2.2Related 172 1 0.6 0.0 3.2 170 6 3.5 1.3 7.5 164 4 2.4 0.7 6.1Grade 3*Rel 172 1 0.6 0.0 3.2 170 0 0.0 0.0 2.1 164 0 0.0 0.0 2.2

Headache All 172 21 12.2 7.7 18.1 170 20 11.8 7.3 17.6 164 18 11.0 6.6 16.8Grade 3 172 1 0.6 0.0 3.2 170 0 0.0 0.0 2.1 164 0 0.0 0.0 2.2Related 172 15 8.7 5.0 14.0 170 16 9.4 5.5 14.8 164 14 8.5 4.7 13.9Grade 3*Rel 172 1 0.6 0.0 3.2 170 0 0.0 0.0 2.1 164 0 0.0 0.0 2.2

Temperature/(Axillary) All (>37.50C) 172 2 1.2 0.1 4.1 170 0 0.0 0.0 2.1 164 2 1.2 0.1 4.3(°C) >38.00C 172 1 0.6 0.0 3.2 170 0 0.0 0.0 2.1 164 2 1.2 0.1 4.3

>38.50C 172 1 0.6 0.0 3.2 170 0 0.0 0.0 2.1 164 1 0.6 0.0 3.4>39.00C 172 0 0.0 0.0 2.1 170 0 0.0 0.0 2.1 164 0 0.0 0.0 2.2>39.50C 172 0 0.0 0.0 2.1 170 0 0.0 0.0 2.1 164 0 0.0 0.0 2.2Related 172 1 0.6 0.0 3.2 170 0 0.0 0.0 2.1 164 1 0.6 0.0 3.4>39.50C.*Rel 172 0 0.0 0.0 2.1 170 0 0.0 0.0 2.1 164 0 0.0 0.0 2.2

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseN = number of subjects with the documented dosen/% = number/percentage of subjects reporting at least once the symptom95%CI = Exact 95% confidence interval; LL = Lower Limit, UL = Upper LimitAll = Solicited general symptoms of any intensityGrade 3 = Solicited general symptoms that prevented normal activitiesRelated = Solicited general symptoms that were considered to be causally related to vaccinationGrade3*Rel = Solicited general symptoms of grade 3 intensity that were considered to be causally related tovaccination.

8.2.4. Unsolicited adverse events

The percentage of subjects who reported the occurrence of grade 3 and causally relatedunsolicited symptoms classified by MedDRA Primary System Organ Class and PreferredTerm during the 31-day (Days 0-30) post-vaccination period for the Total vaccinatedcohort for the challenge dose is presented in Table 29 and Table 30, respectively.

• Unsolicited symptoms were reported by 16.3%, 5.9% and 12.8% of subjects in theTwinrix, ENG+HAV and HBVX+VAQ groups, respectively, during the 31-dayfollow-up period after the challenge dose (See Supplement 33).

• Unsolicited symptoms of grade 3 intensity were reported by 2.3%, 1.2% and 0.6% ofsubjects in the Twinrix, ENG+HAV and HBVX+VAQ groups, respectively, duringthe 31-day follow-up period after the challenge dose (See Table 29).

CONFIDENTIAL




Final

28 Aug 2009 - 84 -

• Unsolicited symptoms considered by the investigator to be causally related tovaccination was reported by 2.3% and 0.6% of subjects in the Twinrix andENG+HAV groups, during the 31-day follow-up period after the challenge dose. Nosubjects in the HBVX+VAQ group reported unsolicited symptoms that wereconsidered by the investigator to be causally related to vaccination (See Table 30).

Table 29 Percentage of subjects reporting the occurrence of grade 3unsolicited symptoms classified by MedDRA Primary System OrganClass and Preferred Term during the 31-day (Days 0-30) post-vaccination period (Total vaccinated cohort for Challenge dose)

Twinrix N = 172

Eng+HAV N = 170

HBVX+VAQ N = 164

95% CI 95% CI 95% CIPrimary System Organ

Class (CODE)Preferred Term

(CODE)n % LL UL n % LL UL n % LL UL

At least one symptom 4 2.3 0.6 5.8 2 1.2 0.1 4.2 1 0.6 0.0 3.4Gastrointestinal disorders(10017947)

Abdominal pain upper(10000087)

1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2

General disorders andadministration siteconditions (10018065)

Influenza like illness(10022004)

0 0.0 0.0 2.1 1 0.6 0.0 3.2 0 0.0 0.0 2.2

Injury, poisoning andprocedural complications(10022117)

Fracture (10017076) 0 0.0 0.0 2.1 0 0.0 0.0 2.1 1 0.6 0.0 3.4

Musculoskeletal andconnective tissue disorders

Back pain (10003988) 1 0.6 0.0 3.2 1 0.6 0.0 3.2 0 0.0 0.0 2.2

(10028395) Myalgia (10028411) 1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2Renal and urinary disorders(10038359)

Nephritis interstitial(10029134)

1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseAt least one symptom = at least one symptom experienced (regardless of the MedDRA Preferred Term)N = number of subjects with at least one administered dosen/% = number/percentage of subjects reporting at least once the symptom95% CI= exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit

CONFIDENTIAL




Final

28 Aug 2009 - 85 -

Table 30 Percentage of subjects who reported the occurrence of unsolicitedsymptoms classified by MedDRA Primary System Organ Class andPreferred Term with causal relationship to vaccination, during the31-day (Days 0-30) post-vaccination period (Total vaccinated cohortfor Challenge dose)

Twinrix N = 172

Eng+HAV N = 170

HBVX+VAQ N = 164

95% CI 95% CI 95% CIPrimary System Organ Class

(CODE)Preferred Term


At least one symptom 4 2.3 0.6 5.8 1 0.6 0.0 3.2 0 0.0 0.0 2.2General disorders andadministration site conditions(10018065)

Injection sitehaematoma(10022066)

1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2

Injection sitehaemorrhage(10022067)

1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2

Musculoskeletal and connectivetissue disorders (10028395)

Myalgia(10028411)

1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2

Nervous system disorders(10029205)

Somnolence(10041349)

0 0.0 0.0 2.1 1 0.6 0.0 3.2 0 0.0 0.0 2.2

Renal and urinary disorders(10038359)


1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2


The percentage of subjects who reported the occurrence of unsolicited symptomsclassified by MedDRA Primary System Organ Class and Preferred Term during the 31-day (Days 0-30) post-vaccination period for the Total vaccinated cohort for Challengedose is presented in Supplement 33.

8.3. According-to-protocol cohort analysis

The analysis on the ATP cohort for safety was not done since only 0.2% of subjects wereeliminated from the total vaccinated cohort.

8.4. Serious adverse events

The serious adverse event (SAE) Summary Table(s) is in Section 13.1 and the SAECIOMS are in Section 13.2.

8.4.1. Fatal events

No deaths were reported in the study.

CONFIDENTIAL




Final

28 Aug 2009 - 86 -

8.4.2. Non-fatal events

Three subjects (one in the Twinrix group and two in the ENG+HAV group) reportedSAEs during the study period.

The event was considered by the investigator to bepossibly related to vaccination. At the time of last contact the outcome of this event wasrecorded as resolving/ recovering.

Both events resolved andwere considered by the investigator to be unrelated to vaccination. T See details inSection 13.1.

8.5. Adverse events leading to premature discontinuation ofstudy vaccine and/or study

8.6. Concomitant medications

The percentage of subjects who started to take the specified concomitant medication atleast once during the 4-day (Days 0-3) post-vaccination period for the total vaccinatedcohort for the challenge dose is presented in Table 31.

• The percentage of subjects who started to take at least one concomitant medicationduring the 4-day (Day 0 to Day 3) follow-up period after the challenge dose was7.6%, 4.7% and 4.3% in the Twinrix, ENG+HAV and HBVX+VAQ groups,respectively.

• The percentage of subjects who started to take at least one antipyretic medicationduring the 4-day follow-up period after the challenge dose was 4.1% in the Twinrixgroup and 1.8% each in the, ENG+HAV and HBVX+VAQ groups. None of theseantipyretics were prophylactic.

CONFIDENTIAL




Final

28 Aug 2009 - 87 -

Table 31 Percentage of subjects who started to take the specifiedconcomitant medication at least once during the 4-day (Days 0-3)post-vaccination period (Total vaccinated cohort for the Challengedose)

Twinrix ENG+HAV HBVX+VAQ95% CI 95% CI 95% CI

N n % LL UL N n % LL UL N n % LL ULAny 172 13 7.6 4.1 12.6 170 8 4.7 2.1 9.1 164 7 4.3 1.7 8.6Any antipyretic 172 7 4.1 1.7 8.2 170 3 1.8 0.4 5.1 164 3 1.8 0.4 5.3Prophylactic antipyretic 172 0 0.0 0.0 2.1 170 0 0.0 0.0 2.1 164 0 0.0 0.0 2.2Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseN= number of subjects with the administered dosen/%= number/percentage of subjects who started to take the specified concomitant medication at least once during thementioned period95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit

The percentage of subjects who started to take the specified concomitant medication atleast once during the 31-day (Days 0-30) post-vaccination period for the total vaccinatedcohort for the challenge dose is presented in Supplement 34.

The percentage of subjects who took the specified concomitant medication at least onceduring the 4-day (Days 0-3) post-vaccination period for the Total vaccinated cohort forthe challenge dose is presented in Supplement 35.

The percentage of subjects who took the specified concomitant medication at least onceduring the 31-day (Days 0-30) post-vaccination period for the Total vaccinated cohort forthe Challenge dose is presented in Supplement 36.

8.7. Pregnancy

No pregnancies were reported during the study.

8.8. Safety conclusions

• The vaccines used in the study were well tolerated when administered as a challengedose with a low incidence of grade 3 solicited local and general symptoms (less than1.3%).

• Three subjects reported SAEs during the study period. One was considered by theinvestigator to be possibly related to vaccination.

CONFIDENTIAL




Final

28 Aug 2009 - 88 -

9. DISCUSSION AND OVERALL CONCLUSIONS

9.1. Discussion

The study aimed to assess the persistence of the humoral response as well as the immunememory to a primary vaccination with either a combined hepatitis A and B vaccine(Twinrix) or concomitant administrations of monovalent hepatitis A vaccine (Havrix orVaqta) or monovalent hepatitis B vaccines (Engerix-B or HBVAXPRO) in an elderlypopulation.

As described in other long term follow up studies after primary vaccination againsthepatitis, antibody concentrations and seroprotection rates declined gradually over thefour years of follow-up. Anti-HAV seropositivity rates remained high in all groups butthe anti-HBs antibody concentrations ≥ 10 mIU/ml declined to 57.1% in the Twinrixgroup, 40.1% in the ENG+HAV group and 26.6% in the HBVX+VAQ group. As wasobserved following the primary vaccination course, anti-HBs concentrations remainedhighest in the Twinrix group throughout the follow-up period.

In order to evaluate the immune memory four years after the primary vaccination, allsubjects received a single challenge dose of the same vaccine(s) they were primed with.An anamnestic response to the HAV and the HBV antigen component was observed inthe vast majority of subjects (at least 97.6% for HAV and 83.4% for HBV). Although theanti-HBs concentrations and seroprotection rates had declined significantly in all groups(see above), a vigorous (higher than post-primary) and fast (within 14 days) anti-HBsresponse to the challenge dose was observed. This indicates that the immune memory tothe HBsAg was still present. As was observed following the primary vaccination courseand during the long term follow up, the anti-HBs response to the challenge dose washighest in the Twinrix group with a post-challenge dose seroprotection rate of 95.2% anda GMC of 7233.7 mIU/ml.

The results of the exploratory analysis indicated that among the nine subjects who did notdemonstrate an antibody response to the primary vaccination course, a third responded tothe challenge dose which was given four years later.

9.2. Overall conclusions

• At Month 48, anti-HAV seropositivity rates were 97.3% in the Twinrix group, 93.9%in the ENG+HAV group and 96.0% in the HBVX+VAQ group with GMCs of 212.9mIU/ml in the Twinrix group, 165.7 mIU/ ml in the ENG+HAV group and 277.4mIU/ml in the HBVX+VAQ group.

• At Month 48, the percentage of subjects with anti-HBs antibody concentrations ≥ 10mIU/ml was 57.1% in the Twinrix group, 40.1% in the ENG+HAV group and 26.6%in the HBVX+VAQ group with GMCs of 42.3 mIU/ml in the Twinrix group, 23.6mIU/ ml in the ENG+HAV group and 13.7 mIU/ml in the HBVX+VAQ group.

CONFIDENTIAL




Final

28 Aug 2009 - 89 -

• One month after the challenge dose, an anamnestic response to the hepatitis Acontaining challenge dose was mounted by 98.2% of subjects in the Twinrix group,97.6% in the ENG+HAV group and 99.4% of subjects in the HBVX+VAQ group.

• One month after the challenge dose, an anamnestic response to the hepatitis Bantigen containing challenge dose was mounted by 93.4% of subjects in the Twinrixgroup, 88.1% of subjects in the ENG+HAV group and 83.4% of subjects in theHBVX+VAQ group.

• One month after the challenge dose, anti-HAV seropositivity rates were 99.4% in thethree groups.

• One month after the challenge dose, the percentage of subjects with anti-HBsantibody concentrations ≥ 10 mIU/ml was 95.2% in the Twinrix group, 90.5% in theENG+HAV group and 85.3% in the HBVX+VAQ group.

• The vaccines used in the study were well tolerated when administered as a challengedose with a low incidence of grade 3 solicited local and general symptoms (less than1.3%).

• Three subjects reported SAEs during the study period. One was considered by theinvestigator to be possibly related to vaccination.

CONFIDENTIAL




Final

28 Aug 2009 - 90 -

10. SUPPLEMENTS

Supplement 1 Number of subjects by centre (Total vaccinated cohort)

Centre Twinrix group Eng+HAV group HBVX+VAQ group Totaln n n n %13 9 12 34 6.710 9 10 29 5.716 13 13 42 8.311 12 10 33 6.515 14 11 40 7.98 10 7 25 4.93 3 4 10 2.0

18 13 11 42 8.378 87 86 251 49.6

All 172 170 164 506 100Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phasen = number of subjects included in each group or in total for a given centre or for all centresAll = sum of all subjects in each group or in total (sum of all groups)% = n/All x 100Centre = GSK Biologicals assigned centre numberCentres to correspond to German centresCentre corresponds to the Belgian centreCentre corresponds to the Czech Republic

CONFIDENTIAL




Final

28 Aug 2009 - 91 -

Supplement 2 Summary of tracking log-sheets for all subjects initiallyenrolled in the primary study (Total Vaccinated Cohort)

TwinrixN = 199

Eng + HavN = 200

HBVX + VAQ N = 197

Total N = 596

n % n % n % n %Not participating in booster study 27 13.6 31 15.5 32 16.2 90 15.1Not eligible 3 1.5 1 0.5 3 1.5 7 1.2Lost to follow-up 5 2.5 6 3.0 7 3.6 18 3.0Not willing to participate due to AE or SAE 0 0.0 1 0.5 0 0.0 1 0.2Not willing to participate for other reason 7 3.5 15 7.5 11 5.6 33 5.5Died 8 4.0 2 1.0 3 1.5 13 2.2Missing 4 2.0 6 3.0 8 4.1 18 3.0Enrolled in booster study* 172 86.4 169 84.5 165 83.8 506 84.9Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseN = number of subjects enrolled in the initial studyn/% = number/percentage of subjects in a given category

Supplement 3 Number of subjects at each visit and list of withdrawnsubjects (Total vaccinated cohort)

Group VISIT N WithdrawnSubject numbers

Reason for withdrawal

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseN = number of subjects in each vaccine group

CONFIDENTIAL



This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level

Data section of the Sponsor Clinical Study Register.


Final

28 Aug 2009 - 92 -

Supplement 4 Summary of demographic characteristics (ATP cohort forsafety)

TwinrixN = 172

Eng+HAVN = 169

HBVX+VAQN = 164

TotalN = 505







Male 87 50.6 86 50.9 79 48.2 252 49.9Race Black 0 0.0 0 0.0 1 0.6 1 0.2

White/Caucasian 172 100 169 100 163 99.4 504 99.8Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAX PRO and Vaqta in the primary study and in thechallenge phaseN = total number of subjectsn/% = number / percentage of subjects in a given categoryValue = value of the considered parameterSD = standard deviation

CONFIDENTIAL




Final

28 Aug 2009 - 93 -

Supplement 5 Summary of demographic characteristics (Total vaccinatedcohort)

TwinrixN = 172

Eng+HAVN = 170

HBVX+VAQN = 164

TotalN = 506







Male 87 50.6 87 51.2 79 48.2 253 50.0Race Black 0 0.0 0 0.0 1 0.6 1 0.2

White/Caucasian 172 100 170 100 163 99.4 505 99.8Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseN = total number of subjectsn/% = number / percentage of subjects in a given categoryValue = value of the considered parameterSD = standard deviation

CONFIDENTIAL




Final

28 Aug 2009 - 94 -

Supplement 6 GMC calculated on all subjects for anti-HAV antibodies beforeand after the challenge dose (ATP cohort for immunogenicity)

GMC95% CI

Group Timing N Value LL ULPre 167 192.0 158.1 233.1PI(D14) 167 2179.3 1839.6 2581.7

Twinrix

PI(D30) 167 3911.7 3273.0 4675.1Pre 168 142.7 116.6 174.6PI(D14) 168 1717.5 1430.4 2062.2

Eng+HAV

PI(D30) 168 3014.0 2504.7 3626.8Pre 163 275.2 223.6 338.6PI(D14) 163 2616.6 2179.6 3141.2

HBVX+VAQ

PI(D30) 163 7171.2 5977.7 8603.1Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseGMC = geometric mean antibody concentration, calculated for all subjectsN = number of subjects with available results 95% CI; LL, UL = exact 95% confidence interval; lower and upper limitsPre = Prior to administration of challenge dosePI (D14) = Two weeks after the administration of challenge dosePI (D30) = One month after the administration of challenge dose

CONFIDENTIAL




Final

28 Aug 2009 - 95 -

Supplement 7 Seropositivity rates and GMCs (calculated on seropositivesubjects) for anti-HAV antibodies stratified by gender (ATP cohortfor immunogenicity)

≥≥≥≥ 15 mIU/ml GMC95% CI 95% CI

Group Timing N n % LL UL value LL ULPre 82 80 97.6 91.5 99.7 268.6 206.2 349.8Twinrix/FPost 82 81 98.8 93.4 100 4541.5 3688.7 5591.5Pre 85 82 96.5 90.0 99.3 168.6 133.2 213.5Twinrix/MPost 85 85 100 95.8 100 3652.2 2841.2 4694.8Pre 82 78 95.1 88.0 98.7 227.4 176.5 293.1Eng+HAV/FPost 82 81 98.8 93.4 100 4413.4 3492.8 5576.6Pre 86 79 91.9 83.9 96.7 135.8 107.7 171.1Eng+HAV/MPost 86 86 100 95.8 100 2256.4 1783.9 2854.1Pre 84 83 98.8 93.5 100 455.9 351.6 591.0HBVX+VAQ/FPost 84 84 100 95.7 100 9389.4 7584.0 11624.7Pre 79 75 94.9 87.5 98.6 200.1 157.1 254.9HBVX+VAQ/MPost 79 78 98.7 93.1 100 5858.1 4605.7 7451.2

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phase/F: Female subjects/M: Male subjectsN: total number of subjects with available resultsn (%): number (percentage) of subjects with anti-HAV antibody concentrations ≥ 15 mIU/mlGMCs: geometric mean concentrations calculated on subjects with anti-HAV antibody concentrations ≥ 15 mIU/ml95% CI: 95% confidence intervals; LL: Lower Limit; UL: Upper LimitPre: Blood sampling done prior to administration of challenge dosePost: Blood sampling done one month after administration of challenge dose

CONFIDENTIAL




Final

28 Aug 2009 - 96 -

Supplement 8 Seropositivity rates and GMCs (calculated on seropositivesubjects) for anti-HAV antibodies stratified by age (ATP cohort forimmunogenicity)

≥≥≥≥ 15 mIU/ml GMC95% CI 95%CI

Group Timing N

n % LL UL Value LL ULPre 63 62 98.4 91.5 100 270.9 202.8 361.9Twinrix/A1Post 63 63 100 94.3 100 5464.2 4294.1 6953.2Pre 59 57 96.6 88.3 99.6 213.6 157.1 290.4Twinrix/A2Post 59 59 100 93.9 100 3710.7 2828.4 4868.2Pre 45 43 95.6 84.9 99.5 148.0 105.9 206.7Twinrix/A3Post 45 44 97.8 88.2 99.9 2999.3 2114.6 4253.9Pre 58 56 96.6 88.1 99.6 233.9 168.6 324.5Eng+HAV/A1Post 58 58 100 93.8 100 3496.0 2653.8 4605.4Pre 55 52 94.5 84.9 98.9 185.9 140.0 246.9Eng+HAV/A2Post 55 54 98.2 90.3 100 3616.8 2689.6 4863.5Pre 55 49 89.1 77.8 95.9 118.7 90.3 156.1Eng+HAV/A3Post 55 55 100 93.5 100 2403.3 1730.4 3337.7Pre 55 55 100 93.5 100 449.7 321.3 629.4HBVX+VAQ/A1Post 55 55 100 93.5 100 9665.8 7643.8 12222.5Pre 53 53 100 93.3 100 261.3 182.1 374.9HBVX+VAQ/A2Post 53 53 100 93.3 100 7832.1 6022.6 10185.1Pre 55 50 90.9 80.0 97.0 242.8 188.0 313.6HBVX+VAQ/A3Post 55 54 98.2 90.3 100 5510.3 3937.8 7710.7

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phase/A1: Subjects aged ≤ 50 years of age/A2: Subjects aged between and including, 51 to 60 years of age/A3: Subjects aged ≥ 61 years of ageAge: Age at first vaccine dose in the primary time pointN: number of subjects with available resultsn (%): number (percentage) of subjects with anti-HAV antibody concentration ≥ 15 mIU/mlGMC: Geometric mean concentrations calculated on subjects with anti-HAV antibody concentrations ≥ 15 mIU/ml95% CI: 95% confidence interval; LL: Lower Limit, UL: Upper LimitPre: Blood sampling done prior to administration of challenge dosePost: Blood sampling done one month after administration of challenge dose�AGE: Stratification based on data collected in the primary study

CONFIDENTIAL




Final

28 Aug 2009 - 97 -

Supplement 9 Seropositivity rates and GMCs (calculated on seropositivesubjects) for anti-HAV antibodies stratified by BMI status (ATPcohort for immunogenicity)

≥ 15 mIU/ml GMC95% CI 95%CI

Group Timing N

n % LL UL Value LL ULPre 51 51 100 93.0 100 301.2 217.2 417.5Twinrix/B1Post 51 51 100 93.0 100 5774.7 4649.9 7171.7Pre 62 61 98.4 91.3 100 203.9 158.1 263.0Twinrix/B2Post 62 62 100 94.2 100 3791.6 2865.6 5016.8Pre 54 50 92.6 82.1 97.9 155.9 109.5 221.9Twinrix/B3Post 54 53 98.1 90.1 100 3138.4 2265.8 4347.2Pre 53 50 94.3 84.3 98.8 237.6 171.0 330.1Eng+HAV/B1Post 53 53 100 93.3 100 3456.6 2436.0 4904.8Pre 55 53 96.4 87.5 99.6 201.9 154.2 264.3Eng+HAV/B2Post 55 55 100 93.5 100 3650.7 2931.6 4546.4Pre 60 54 90.0 79.5 96.2 115.4 86.2 154.5Eng+HAV/B3Post 60 59 98.3 91.1 100 2467.3 1796.8 3388.0Pre 53 52 98.1 89.9 100 577.9 432.4 772.3HBVX+VAQ/B1Post 53 53 100 93.3 100 10418.8 7974.1 13613.1Pre 50 49 98.0 89.4 99.9 273.8 191.3 391.9HBVX+VAQ/B2Post 50 50 100 92.9 100 8039.6 6112.2 10574.8Pre 60 57 95.0 86.1 99.0 192.6 146.1 253.9HBVX+VAQ/B3Post 60 59 98.3 91.1 100 5227.8 3935.7 6944.1

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phase/B1: Subjects with BMI < 25 kg/m2 (Healthy)/B2: Subjects with BMI 25 kg/ m2 to < 30 kg/ m2 (Overweight)/B3: Subjects with BMI ≥ 30 kg/ m2 (Obese)N: number of subjects with available resultsn (%): number (percentage) of subjects with anti-HAV antibody concentration ≥ 15 mIU/mlGMC: Geometric mean concentrations calculated on subjects with anti-HAV antibody concentrations ≥ 15 mIU/ml95% CI: 95% confidence interval; LL: Lower Limit, UL: Upper LimitBMI: Stratification based on data collected in the primary studyPre: Blood sampling done prior to administration of challenge dosePost: Blood sampling done one month after administration of challenge dose

CONFIDENTIAL




Final

28 Aug 2009 - 98 -

Supplement 10 Seropositivity rates and GMCs (calculated on seropositivesubjects) for anti-HAV antibodies stratified by smoking status (ATPcohort for immunogenicity)


Group Timing N

n % LL UL Value LL ULPre 43 41 95.3 84.2 99.4 197.1 134.5 288.6Twinrix/SYPost 43 42 97.7 87.7 99.9 3482.9 2580.4 4701.0Pre 124 121 97.6 93.1 99.5 217.6 177.4 266.9Twinrix/SNPost 124 124 100 97.1 100 4279.2 3522.7 5198.1Pre 53 51 96.2 87.0 99.5 201.5 150.2 270.3Eng+HAV/SYPost 53 53 100 93.3 100 3586.1 2626.9 4895.4Pre 115 106 92.2 85.7 96.4 164.1 131.9 204.2Eng+HAV/SNPost 115 114 99.1 95.3 100 2930.1 2378.7 3609.4Pre 30 29 96.7 82.8 99.9 281.4 175.9 450.1HBVX+VAQ/SYPost 30 30 100 88.4 100 6915.8 4711.4 10151.5Pre 133 129 97.0 92.5 99.2 314.8 255.8 387.4HBVX+VAQ/SNPost 133 132 99.2 95.9 100 7616.5 6350.0 9135.6

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phase/SY: Subjects who smoke/SN: Subjects who do not smokeN: number of subjects with available resultsn (%): number (percentage) of subjects with anti-HAV antibody concentration ≥ 15 mIU/mlGMC: Geometric mean concentrations calculated on subjects with anti-HAV antibody concentrations ≥ 15 mIU/ml95% CI: 95% confidence intervals; LL: Lower Limit, UL: Upper LimitSmoking Status: Stratification based on data collected in the primary studyPre: Blood sampling done prior to administration of challenge dosePost: Blood sampling done one month after administration of challenge dose

CONFIDENTIAL




Final

28 Aug 2009 - 99 -

Supplement 11 Seropositivity rates and GMCs (calculated on seropositivesubjects) for anti-HAV antibodies stratified by alcohol consumptionstatus (ATP cohort for immunogenicity)


Group Timing N

n % LL UL Value LL ULPre 103 98 95.1 89.0 98.4 213.3 167.1 272.4Twinrix/L1Post 103 102 99.0 94.7 100 3735.4 2973.9 4691.9Pre 54 54 100 93.4 100 217.5 162.4 291.3Twinrix/L2Post 54 54 100 93.4 100 5062.9 3974.8 6448.7Pre 10 10 100 69.2 100 176.3 89.4 347.4Twinrix/L3Post 10 10 100 69.2 100 2907.4 1759.7 4803.8Pre 100 94 94.0 87.4 97.8 171.9 135.8 217.5Eng+HAV/L1Post 100 99 99.0 94.6 100 3270.3 2583.1 4140.4Pre 62 58 93.5 84.3 98.2 182.3 139.7 237.9Eng+HAV/L2Post 62 62 100 94.2 100 2965.8 2272.7 3870.2Pre 6 5 83.3 35.9 99.6 165.2 24.6 1111.2Eng+HAV/L3Post 6 6 100 54.1 100 2514.7 822.6 7687.3Pre 93 89 95.7 89.4 98.8 332.1 255.5 431.7HBVX+VAQ/L1Post 93 92 98.9 94.2 100 7798.4 6288.7 9670.5Pre 56 55 98.2 90.4 100 286.5 212.2 386.8HBVX+VAQ/L2Post 56 56 100 93.6 100 7827.9 5937.1 10320.9Pre 14 14 100 76.8 100 257.2 125.2 528.1HBVX+VAQ/L3Post 14 14 100 76.8 100 4753.4 2455.7 9201.3

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phase/L1: Subjects who do not consume or mildly consume alcohol (0 - 3)/L2: Subjects who consume alcohol moderately (4 - 21)/L3: Subjects who consume alcohol heavily (> 21)N: number of subjects with available resultsn (%): number (percentage) of subjects with anti-HAV antibody concentration ≥ 15 mIU/mlGMC: Geometric mean concentrations calculated on subjects with anti-HAV antibody concentrations ≥ 15 mIU/ml95% CI: 95% confidence intervals; LL: Lower Limit, UL: Upper LimitAlcohol Consumption: Stratification based on data collected in the primary studyPre: Blood sampling done prior to administration of challenge dosePost: Blood sampling done one month after administration of challenge dose

CONFIDENTIAL




Final

28 Aug 2009 - 100 -

Supplement 12 Seropositivity rates and GMCs (calculated on seropositivesubjects) for anti-HAV antibodies stratified by concomitantmedication intake status (ATP cohort for immunogenicity)


Group Timing N

n % LL UL Value LL ULPre 154 149 96.8 92.6 98.9 196.5 164.7 234.5Twinrix/MYPost 154 153 99.4 96.4 100 3978.1 3347.6 4727.4Pre 13 13 100 75.3 100 512.7 210.3 1250.1Twinrix/MNPost 13 13 100 75.3 100 5192.6 3135.8 8598.6Pre 154 143 92.9 87.6 96.4 174.9 145.5 210.3Eng+HAV/MYPost 154 153 99.4 96.4 100 3118.5 2598.0 3743.4Pre 14 14 100 76.8 100 180.5 96.8 336.3Eng+HAV/MNPost 14 14 100 76.8 100 3186.0 1840.9 5514.0Pre 152 147 96.7 92.5 98.9 317.4 260.9 386.1HBVX+VAQ/MYPost 152 151 99.3 96.4 100 7690.5 6526.5 9062.1Pre 11 11 100 71.5 100 210.1 101.0 437.3HBVX+VAQ/MNPost 11 11 100 71.5 100 5125.9 2027.0 12962.0

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phase/MY: Subjects who took concomitant medication/MN: Subjects who did not take any concomitant medicationN: number of subjects with available resultsn (%): number (percentage) of subjects with anti-HAV antibody concentration ≥ 15 mIU/mlGMC: Geometric mean concentrations calculated on subjects with anti-HAV antibody concentrations ≥ 15 mIU/ml95% CI: 95% confidence intervals; LL: Lower Limit, UL: Upper LimitConcomitant Medication intake status: Stratification based on data collected in the primary studyPre: Blood sampling done prior to administration of challenge dosePost: Blood sampling done one month after administration of challenge dose

CONFIDENTIAL




Final

28 Aug 2009 - 101 -

Supplement 13 Seropositivity rates and GMCs (calculated on seropositivesubjects) for anti-HAV antibodies stratified by medical conditionstatus (ATP cohort for immunogenicity)


Group Timing N

n % LL UL Value LL ULPre 12 12 100 73.5 100 315.3 153.7 646.9Twinrix/PPost 12 12 100 73.5 100 3912.1 2166.4 7064.5Pre 134 129 96.3 91.5 98.8 195.4 159.4 239.5Twinrix/CPost 134 133 99.3 95.9 100 3828.5 3162.5 4634.8Pre 21 21 100 83.9 100 281.1 178.5 442.9Twinrix/NPost 21 21 100 83.9 100 6037.9 4416.1 8255.2Pre 21 21 100 83.9 100 177.1 110.6 283.6Eng+HAV/PPost 21 21 100 83.9 100 3669.2 2559.0 5261.2Pre 128 117 91.4 85.1 95.6 161.6 131.0 199.5Eng+HAV/CPost 128 127 99.2 95.7 100 2938.2 2378.3 3630.1Pre 19 19 100 82.4 100 287.2 197.6 417.6Eng+HAV/NPost 19 19 100 82.4 100 3941.1 2609.6 5952.1Pre 14 14 100 76.8 100 463.3 242.6 884.7HBVX+VAQ/PPost 14 14 100 76.8 100 6031.5 3387.7 10738.7Pre 130 125 96.2 91.3 98.7 296.8 238.6 369.1HBVX+VAQ/CPost 130 129 99.2 95.8 100 7388.6 6098.7 8951.3Pre 19 19 100 82.4 100 294.0 182.6 473.2HBVX+VAQ/NPost 19 19 100 82.4 100 9545.6 7068.1 12891.4

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phase/P: Subjects who had a medical condition in the past/C; Subjects who had a current medical condition/N: Subjects who did not have any medical conditionN: number of subjects with available resultsn (%): number (percentage) of subjects with anti-HAV antibody concentration ≥ 15 mIU/mlGMC: Geometric mean concentrations calculated on subjects with anti-HAV antibody concentrations ≥ 15 mIU/ml95% CI: 95% confidence intervals; LL: Lower Limit, UL: Upper Limit�Medical condition: stratification based on the data collected in the primary studyPre: Blood sampling done prior to administration of challenge dosePost: Blood sampling done one month after administration of challenge dose

CONFIDENTIAL




Final

28 Aug 2009 - 102 -

Supplement 14 Seropositivity rates and GMCs (calculated on seropositivesubjects) for anti-HAV antibodies stratified by diabetes status (ATPcohort for immunogenicity)


Group Timing N

n % LL UL Value LL ULPre 13 10 76.9 46.2 95.0 92.1 35.0 242.5Twinrix/DYPost 13 13 100 75.3 100 1644.6 617.3 4381.9Pre 109 108 99.1 95.0 100 201.5 161.9 250.9Twinrix/DNPost 109 108 99.1 95.0 100 4320.2 3660.4 5098.9Pre 13 11 84.6 54.6 98.1 136.4 62.3 298.5Eng+HAV/DYPost 13 13 100 75.3 100 1943.1 752.5 5017.3Pre 107 100 93.5 87.0 97.3 160.5 127.4 202.1Eng+HAV/DNPost 107 106 99.1 94.9 100 3220.6 2605.8 3980.5Pre 17 15 88.2 63.6 98.5 189.2 105.8 338.4HBVX+VAQ/DYPost 17 17 100 80.5 100 3040.6 1618.8 5711.2Pre 103 100 97.1 91.7 99.4 324.4 255.4 412.0HBVX+VAQ/DNPost 103 102 99.0 94.7 100 8627.1 7116.6 10458.1

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phase/DY = Diabete/Yes/DN = Diabete/NoN: number of subjects with available resultsn (%): number (percentage) of subjects with anti-HAV antibody concentration ≥ 15 mIU/mlGMC: Geometric mean concentrations calculated on subjects with anti-HAV antibody concentrations ≥ 15 mIU/ml95% CI: 95% confidence intervals; LL: Lower Limit, UL: Upper LimitDiabetes: stratification based on the data collected in the primary studyPre: Blood sampling done prior to administration of challenge dosePost: Blood sampling done one month after administration of challenge doseStratification based on primary study

CONFIDENTIAL




Final

28 Aug 2009 - 103 -

Supplement 15 Anti-HAV antibody concentrations between pre and postchallenge dose (ATP cohort for immunogenicity)

Ant i -HAV ant i body concent rat i ons (MI U/ ML)

Post Chal l enge

1

10

100

1000

10000

100000

Pre Chal l enge

1 10 100 1000 10000 100000


CONFIDENTIAL




Final

28 Aug 2009 - 104 -

Supplement 16 Reverse cumulative distribution curves for anti-HAV antibodyconcentrations, 14 days after the challenge dose (ATP cohort forimmunogenicity)


CONFIDENTIAL




Final

28 Aug 2009 - 105 -

Supplement 17 GMCs calculated on all subjects for anti-HBs antibodies(ATP cohort for immunogenicity) before and after the challengedose

GMC95% CI

Group Timing N Value LL ULPre 167 19.1 14.1 26.0PI(D14) 167 6908.7 4462.7 10695.5

Twinrix

PI(D30) 167 5352.0 3411.2 8397.0Pre 168 9.7 7.3 12.9PI(D14) 168 1098.9 703.1 1717.5

Eng+HAV

PI(D30) 168 980.7 632.4 1520.9Pre 163 5.7 4.6 7.0PI(D14) 163 613.6 382.0 985.8

HBVX+VAQ

PI(D30) 163 525.6 325.9 847.8Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseGMC=geometric mean antibody concentration, calculated for all subjects.N = number of subjects with available results95% CI: 95% confidence intervals; LL: Lower Limit, UL: Upper LimitPre = Prior to administration of challenge dosePI (D14) = Two weeks after the administration of challenge dosePI (D30) = One month after the administration of challenge dose

CONFIDENTIAL




Final

28 Aug 2009 - 106 -

Supplement 18 Reverse cumulative distribution curves for anti-HBs antibodyconcentrations, 14 days after the challenge dose (ATP cohort forimmunogenicity)


CONFIDENTIAL




Final

28 Aug 2009 - 107 -

Supplement 19 Anti-HBs seropositivity rates, percentage of subjects withantibody concentrations greater than or equal to 10mIU/ml andgreater than or equal to 100mIU/ml and GMCs (calculated onseropositive subjects) stratified by gender (ATP cohort forimmunogenicity)

S+ ≥ 10 mIU/ml ≥ 100 mIU/ml GMC95% CI 95% CI 95%CI 95%CI

Group Timing N

n % LL UL n % LL UL n % LL UL Value LL ULPre 82 66 80.5 70.3 88.4 53 64.6 53.3 74.9 24 29.3 19.7 40.4 54.6 36.4 81.8Twinrix/FPost 82 79 96.3 89.7 99.2 78 95.1 88.0 98.7 74 90.2 81.7 95.7 9431.8 5154.1 17259.8Pre 85 62 72.9 62.2 82.0 40 47.1 36.1 58.2 11 12.9 6.6 22.0 29.2 18.9 44.9Twinrix/MPost 85 82 96.5 90.0 99.3 81 95.3 88.4 98.7 77 90.6 82.3 95.8 5602.0 3323.7 9442.2Pre 82 52 63.4 52.0 73.8 33 40.2 29.6 51.7 10 12.2 6.0 21.3 28.7 17.9 46.1Eng+HAV/FPost 82 78 95.1 88.0 98.7 74 90.2 81.7 95.7 64 78.0 67.5 86.4 1489.0 820.1 2703.7Pre 86 55 64.0 52.9 74.0 39 45.3 34.6 56.5 9 10.5 4.9 18.9 24.9 16.5 37.7Eng+HAV/MPost 86 84 97.7 91.9 99.7 78 90.7 82.5 95.9 65 75.6 65.1 84.2 1050.3 589.5 1871.2Pre 84 54 64.3 53.1 74.4 34 40.5 29.9 51.7 5 6.0 2.0 13.3 16.6 12.3 22.4HBVX+VAQ/FPost 84 80 95.2 88.3 98.7 78 92.9 85.1 97.3 70 83.3 73.6 90.6 1961.2 1199.2 3207.4Pre 79 36 45.6 34.3 57.2 16 20.3 12.0 30.8 4 5.1 1.4 12.5 13.8 9.4 20.4HBVX+VAQ/MPost 79 65 82.3 72.1 90.0 61 77.2 66.4 85.9 42 53.2 41.6 64.5 513.0 270.9 971.4

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phase/F: Female subjects/M: Male subjectsN: total number of subjects with available resultsn (%): number (percentage) of subjects with anti-HBs antibody concentrations ≥ 3.3 mIU/ml or ≥ 10 mIU/ml or≥100mIU/mlS+ : Seropositivity for anti-HBs antibodies defined as antibody concentrations ≥ 3.3 mIU/mlGMCs: geometric mean concentrations calculated on subjects with anti-HBs antibody concentrations ≥ 3.3 mIU/ml95% CI: 95% confidence intervals; LL: Lower Limit; UL: Upper LimitPre: Blood sampling done prior to administration of challenge dosePost: Blood sampling done one month after administration of challenge dose

CONFIDENTIAL




Final

28 Aug 2009 - 108 -

Supplement 20 Anti-HBs seropositivity rates, proportion of subjects withantibody concentrations greater than or equal to 10 mIU/ml andgreater than or equal to 100 mIU/ml and GMCs (calculated onseropositive subjects) stratified by age (ATP cohort forimmunogenicity)

S+ ≥ 10 mIU/ml ≥100mIU/ml GMC95% CI 95% CI 95%CI 95%CI

Group Timing N

n % LL UL n % LL UL n % LL UL Value LL ULPre 63 52 82.5 70.9 90.9 39 61.9 48.8 73.9 15 23.8 14.0 36.2 41.8 26.1 67.1Twinrix/A1Post 63 61 96.8 89.0 99.6 60 95.2 86.7 99.0 60 95.2 86.7 99.0 13081.1 7271.2 23533.2Pre 59 44 74.6 61.6 85.0 36 61.0 47.4 73.5 13 22.0 12.3 34.7 55.5 33.6 91.4Twinrix/A2Post 59 59 100 93.9 100 58 98.3 90.9 100 53 89.8 79.2 96.2 6127.6 2973.4 12627.6Pre 45 32 71.1 55.7 83.6 18 40.0 25.7 55.7 7 15.6 6.5 29.5 24.4 13.3 45.0Twinrix/A3Post 45 41 91.1 78.8 97.5 41 91.1 78.8 97.5 38 84.4 70.5 93.5 3804.4 1773.2 8162.5Pre 58 34 58.6 44.9 71.4 28 48.3 35.0 61.8 12 20.7 11.2 33.4 56.7 29.9 107.7Eng+HAV/A1Post 58 56 96.6 88.1 99.6 51 87.9 76.7 95.0 44 75.9 62.8 86.1 1861.0 830.5 4170.1Pre 55 38 69.1 55.2 80.9 26 47.3 33.7 61.2 2 3.6 0.4 12.5 18.2 12.9 25.6Eng+HAV/A2Post 55 52 94.5 84.9 98.9 52 94.5 84.9 98.9 45 81.8 69.1 90.9 1467.2 825.3 2608.2Pre 55 35 63.6 49.6 76.2 18 32.7 20.7 46.7 5 9.1 3.0 20.0 19.5 11.0 34.5Eng+HAV/A3Post 55 54 98.2 90.3 100 49 89.1 77.8 95.9 40 72.7 59.0 83.9 696.3 333.4 1454.6Pre 55 31 56.4 42.3 69.7 19 34.5 22.2 48.6 5 9.1 3.0 20.0 23.1 14.2 37.7HBVX+VAQ/A1Post 55 53 96.4 87.5 99.6 52 94.5 84.9 98.9 46 83.6 71.2 92.2 2214.8 1178.1 4163.5Pre 53 32 60.4 46.0 73.5 20 37.7 24.8 52.1 4 7.5 2.1 18.2 15.0 10.3 21.8HBVX+VAQ/A2Post 53 46 86.8 74.7 94.5 45 84.9 72.4 93.3 40 75.5 61.7 86.2 1841.2 961.7 3525.1Pre 55 27 49.1 35.4 62.9 11 20.0 10.4 33.0 0 0.0 0.0 6.5 10.0 7.6 13.3HBVX+VAQ/A3Post 55 46 83.6 71.2 92.2 42 76.4 63.0 86.8 26 47.3 33.7 61.2 273.0 133.7 557.4

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phase/A1: Subjects aged ≤ 50 years of age/A2: Subjects aged between and including, 51 to 60 years of age/A3: Subjects aged ≥ 61 years of ageAge: Age at first vaccine dose in the primary time pointN: number of subjects with available resultsn (%): number (percentage) of subjects with anti-HBs antibody concentration ≥ 3.3 mIU/ml or ≥ 10 mIU/ml or ≥ 100mIU/mlS+ : Seropositivity for anti-HBs antibodies defined as antibody concentrations ≥ 3.3 mIU/mlGMC: Geometric mean concentrations calculated on subjects with anti-HBs antibody concentration ≥ 3.3 mIU/ml95% CI: 95% confidence interval; LL: Lower Limit, UL: Upper LimitPre: Blood sampling done prior to administration of challenge dosePost: Blood sampling done one month after administration of challenge dose�AGE: Stratification based on data collected in the primary study

CONFIDENTIAL




Final

28 Aug 2009 - 109 -

Supplement 21 Anti-HBs seropositivity rates, proportion of subjects withantibody concentrations greater than or equal to 10 mIU/ml andgreater than or equal to 100 mIU/ml and GMCs (calculated onseropositive subjects) stratified by BMI status (ATP cohort forimmunogenicity)


Group Timing N

n % LL UL n % LL UL n % LL UL Value LL ULPre 51 45 88.2 76.1 95.6 37 72.5 58.3 84.1 20 39.2 25.8 53.9 68.2 40.5 114.7Twinrix/B1Post 51 50 98.0 89.6 100 50 98.0 89.6 100 49 96.1 86.5 99.5 17231.1 8968.5 33105.8Pre 62 49 79.0 66.8 88.3 38 61.3 48.1 73.4 10 16.1 8.0 27.7 40.8 26.5 62.8Twinrix/B2Post 62 60 96.8 88.8 99.6 58 93.5 84.3 98.2 56 90.3 80.1 96.4 8314.0 4158.9 16620.4Pre 54 34 63.0 48.7 75.7 18 33.3 21.1 47.5 5 9.3 3.1 20.3 19.7 10.9 35.6Twinrix/B3Post 54 51 94.4 84.6 98.8 51 94.4 84.6 98.8 46 85.2 72.9 93.4 2622.3 1378.0 4990.2Pre 53 43 81.1 68.0 90.6 26 49.1 35.1 63.2 10 18.9 9.4 32.0 32.4 17.9 58.6Eng+HAV/B1Post 53 52 98.1 89.9 100 49 92.5 81.8 97.9 44 83.0 70.2 91.9 1985.4 931.2 4233.0Pre 55 31 56.4 42.3 69.7 27 49.1 35.4 62.9 5 9.1 3.0 20.0 35.7 22.3 57.0Eng+HAV/B2Post 55 53 96.4 87.5 99.6 49 89.1 77.8 95.9 44 80.0 67.0 89.6 1348.2 671.9 2705.3Pre 60 33 55.0 41.6 67.9 19 31.7 20.3 45.0 4 6.7 1.8 16.2 15.9 10.0 25.3Eng+HAV/B3Post 60 57 95.0 86.1 99.0 54 90.0 79.5 96.2 41 68.3 55.0 79.7 751.0 370.7 1521.2Pre 53 39 73.6 59.7 84.7 26 49.1 35.1 63.2 6 11.3 4.3 23.0 20.6 13.9 30.7HBVX+VAQ/B1Post 53 48 90.6 79.3 96.9 46 86.8 74.7 94.5 45 84.9 72.4 93.3 3489.6 1846.7 6594.2Pre 50 25 50.0 35.5 64.5 14 28.0 16.2 42.5 3 6.0 1.3 16.5 15.4 9.3 25.3HBVX+VAQ/B2Post 50 45 90.0 78.2 96.7 43 86.0 73.3 94.2 34 68.0 53.3 80.5 1122.0 539.1 2335.3Pre 60 26 43.3 30.6 56.8 10 16.7 8.3 28.5 0 0.0 0.0 6.0 10.0 7.8 12.9HBVX+VAQ/B3Post 60 52 86.7 75.4 94.1 50 83.3 71.5 91.7 33 55.0 41.6 67.9 349.4 187.4 651.6

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phase/B1: Subjects with BMI < 25 kg/ m2 (Healthy)/B2: Subjects with BMI 25 kg/ m2 to < 30 kg/ m2 (Overweight)/B3: Subjects with BMI ≥ 30 kg/ m2 (Obese)N: number of subjects with available resultsn (%): number (percentage) of subjects with anti-HBs antibody concentration ≥ 3.3 mIU/ml or ≥ 10 mIU/ml or ≥ 100mIU/mlS+ : Seropositivity for anti-HBs antibodies defined as antibody concentrations ≥ 3.3 mIU/mlGMC: Geometric mean concentrations calculated on subjects with anti-HBs antibody concentration ≥ 3.3 mIU/ml95% CI: 95% confidence interval; LL: Lower Limit, UL: Upper LimitBMI: Stratification based on data collected in the primary studyPre: Blood sampling done prior to administration of challenge dosePost: Blood sampling done one month after administration of challenge dose

CONFIDENTIAL




Final

28 Aug 2009 - 110 -

Supplement 22 Anti-HBs seropositivity rates, percentage of subjects withantibody concentrations greater than or equal to 10 mIU/ml andgreater than or equal to 100 mIU/ml and GMCs (calculated onseropositive subjects) stratified by smoking status (ATP cohort forimmunogenicity)

S+ ≥ 10 mIU/ml ≥100 mIU/ml GMC95% CI 95% CI 95%CI 95%CI

Group Timing N

n % LL UL n % LL UL n % LL UL Value LL ULPre 43 33 76.7 61.4 88.2 20 46.5 31.2 62.3 5 11.6 3.9 25.1 22.7 13.3 38.9Twinrix/SYPost 43 41 95.3 84.2 99.4 40 93.0 80.9 98.5 38 88.4 74.9 96.1 4400.2 2173.4 8908.6Pre 124 95 76.6 68.2 83.7 73 58.9 49.7 67.6 30 24.2 17.0 32.7 49.2 34.7 69.7Twinrix/SNPost 124 120 96.8 91.9 99.1 119 96.0 90.8 98.7 113 91.1 84.7 95.5 8572.8 5330.0 13788.4Pre 53 33 62.3 47.9 75.2 21 39.6 26.5 54.0 9 17.0 8.1 29.8 29.7 15.7 56.1Eng+HAV/SYPost 53 51 96.2 87.0 99.5 48 90.6 79.3 96.9 43 81.1 68.0 90.6 1502.3 728.5 3098.1Pre 115 74 64.3 54.9 73.1 51 44.3 35.1 53.9 10 8.7 4.2 15.4 25.5 17.9 36.3Eng+HAV/SNPost 115 111 96.5 91.3 99.0 104 90.4 83.5 95.1 86 74.8 65.8 82.4 1138.7 686.1 1889.8Pre 30 13 43.3 25.5 62.6 4 13.3 3.8 30.7 2 6.7 0.8 22.1 10.2 4.9 21.2HBVX+VAQ/SYPost 30 25 83.3 65.3 94.4 23 76.7 57.7 90.1 20 66.7 47.2 82.7 853.9 313.4 2326.8Pre 133 77 57.9 49.0 66.4 46 34.6 26.6 43.3 7 5.3 2.1 10.5 16.5 12.9 21.2HBVX+VAQ/SNPost 133 120 90.2 83.9 94.7 116 87.2 80.3 92.4 92 69.2 60.6 76.9 1127.9 720.3 1766.1

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phase/SY: Subjects who smoke/SN: Subjects who do not smokeN: number of subjects with available resultsn (%): number (percentage) of subjects with anti-HBs antibody concentration ≥ 3.3 mIU/ml or ≥ 10 mIU/ml or ≥ 100mIU/mlS+ : Seropositivity for anti-HBs antibodies defined as antibody concentrations ≥ 3.3 mIU/mlGMC: Geometric mean concentrations calculated on subjects with anti-HBs antibody concentration ≥ 3.3 mIU/ml95% CI: 95% confidence intervals; LL: Lower Limit, UL: Upper LimitSmoking Status: Stratification based on data collected in the primary studyPre: Blood sampling done prior to administration of challenge dosePost: Blood sampling done one month after administration of challenge dose

CONFIDENTIAL




Final

28 Aug 2009 - 111 -

Supplement 23 Anti-HBs seropositivity rates, proportion of subjects withantibody concentrations greater than or equal to 10mIU/ml andgreater than or equal to 100 mIU/ml and GMCs (calculated onseropositive subjects) stratified by alcohol consumption status (ATPcohort for immunogenicity)

S+ ≥ 10 mIU/ml ≥100 mIU/ml GMC95% CI 95% CI 95%CI 95%CI

Group Timing N

n % LL UL n % LL UL n % LL UL Value LL ULPre 103 72 69.9 60.1 78.5 51 49.5 39.5 59.5 20 19.4 12.3 28.4 40.5 27.0 60.6Twinrix/L1Post 103 99 96.1 90.4 98.9 98 95.1 89.0 98.4 92 89.3 81.7 94.5 5062.4 2954.2 8675.0Pre 54 46 85.2 72.9 93.4 35 64.8 50.6 77.3 13 24.1 13.5 37.6 38.0 23.7 60.9Twinrix/L2Post 54 52 96.3 87.3 99.5 51 94.4 84.6 98.8 49 90.7 79.7 96.9 12767.2 6789.6 24007.5Pre 10 10 100 69.2 100 7 70.0 34.8 93.3 2 20.0 2.5 55.6 51.3 11.4 231.8Twinrix/L3Post 10 10 100 69.2 100 10 100 69.2 100 10 100 69.2 100 12909.6 3819.1 43637.7Pre 100 67 67.0 56.9 76.1 41 41.0 31.3 51.3 12 12.0 6.4 20.0 25.4 17.1 37.6Eng+HAV/L1Post 100 96 96.0 90.1 98.9 89 89.0 81.2 94.4 80 80.0 70.8 87.3 1429.1 840.4 2430.4Pre 62 38 61.3 48.1 73.4 31 50.0 37.0 63.0 7 11.3 4.7 21.9 31.5 18.5 53.6Eng+HAV/L2Post 62 60 96.8 88.8 99.6 57 91.9 82.2 97.3 45 72.6 59.8 83.1 1116.5 548.6 2272.1Pre 6 2 33.3 4.3 77.7 0 0.0 0.0 45.9 0 0.0 0.0 45.9 6.7 2.0 22.9Eng+HAV/L3Post 6 6 100 54.1 100 6 100 54.1 100 4 66.7 22.3 95.7 385.7 42.3 3515.4Pre 93 54 58.1 47.4 68.2 35 37.6 27.8 48.3 8 8.6 3.8 16.2 20.0 14.5 27.7HBVX+VAQ/L1Post 93 85 91.4 83.8 96.2 81 87.1 78.5 93.2 67 72.0 61.8 80.9 1253.9 725.4 2167.2Pre 56 30 53.6 39.7 67.0 13 23.2 13.0 36.4 1 1.8 0.0 9.6 10.7 7.7 14.9HBVX+VAQ/L2Post 56 47 83.9 71.7 92.4 45 80.4 67.6 89.8 35 62.5 48.5 75.1 847.7 416.3 1726.1Pre 14 6 42.9 17.7 71.1 2 14.3 1.8 42.8 0 0.0 0.0 23.2 9.3 4.4 19.7HBVX+VAQ/L3Post 14 13 92.9 66.1 99.8 13 92.9 66.1 99.8 10 71.4 41.9 91.6 928.2 240.3 3585.9

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phase/L1: Subjects who do not consume or mildly consume alcohol (0 - 3)/L2: Subjects who consume alcohol moderately (4 - 21)/L3: Subjects who consume alcohol heavily (> 21)N: number of subjects with available resultsn (%): number (percentage) of subjects with anti-HBs antibody concentration ≥ 3.3 mIU/ml or ≥ 10 mIU/ml or ≥ 100mIU/mlS+ : Seropositivity for anti-HBs antibodies defined as antibody concentrations ≥ 3.3 mIU/mlGMC: Geometric mean concentrations calculated on subjects with anti-HBs antibody concentration ≥ 3.3 mIU/ml95% CI: 95% confidence intervals; LL: Lower Limit, UL: Upper LimitAlcohol Consumption: Stratification based on data collected in the primary studyPre: Blood sampling done prior to administration of challenge dosePost: Blood sampling done one month after administration of challenge dose

CONFIDENTIAL




Final

28 Aug 2009 - 112 -

Supplement 24 Anti-HBs seropositivity rates, percentage of subjects withantibody concentrations greater than or equal to 10mIU/ml andgreater than or equal to 100mIU/ml and GMCs (calculated onseropositive subjects) stratified by concomitant medication intakestatus (ATP cohort for immunogenicity)


Group Timing N

n % LL UL n % LL UL n % LL UL Value LL ULPre 154 116 75.3 67.7 81.9 83 53.9 45.7 61.9 30 19.5 13.5 26.6 38.1 27.8 52.1Twinrix/MYPost 154 148 96.1 91.7 98.6 146 94.8 90.0 97.7 139 90.3 84.4 94.4 7098.3 4747.2 10613.9Pre 13 12 92.3 64.0 99.8 10 76.9 46.2 95.0 5 38.5 13.9 68.4 69.7 26.6 182.4Twinrix/MNPost 13 13 100 75.3 100 13 100 75.3 100 12 92.3 64.0 99.8 8969.7 1193.7 67398.9Pre 154 102 66.2 58.2 73.6 67 43.5 35.5 51.7 16 10.4 6.1 16.3 24.0 17.8 32.4Eng+HAV/MYPost 154 148 96.1 91.7 98.6 141 91.6 86.0 95.4 118 76.6 69.1 83.1 1272.0 835.6 1936.6Pre 14 5 35.7 12.8 64.9 5 35.7 12.8 64.9 3 21.4 4.7 50.8 240.6 27.2 2130.9Eng+HAV/MNPost 14 14 100 76.8 100 11 78.6 49.2 95.3 11 78.6 49.2 95.3 969.1 139.3 6742.6Pre 152 85 55.9 47.6 64.0 46 30.3 23.1 38.2 8 5.3 2.3 10.1 15.1 11.9 19.1HBVX+VAQ/MYPost 152 137 90.1 84.2 94.4 131 86.2 79.7 91.2 105 69.1 61.1 76.3 1059.0 698.1 1606.6Pre 11 5 45.5 16.7 76.6 4 36.4 10.9 69.2 1 9.1 0.2 41.3 22.8 4.4 118.5HBVX+VAQ/MNPost 11 8 72.7 39.0 94.0 8 72.7 39.0 94.0 7 63.6 30.8 89.1 1390.5 158.1 12230.1

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phase/MY: Subjects who took concomitant medication/MN: Subjects who did not take any concomitant medicationN: number of subjects with available resultsn (%): number (percentage) of subjects with anti-HBs antibody concentration ≥ 3.3 mIU/ml or ≥ 10 mIU/ml or ≥ 100mIU/mlS+ : Seropositivity for anti-HBs antibodies defined as antibody concentrations ≥ 3.3 mIU/mlGMC: Geometric mean concentrations calculated on subjects with anti-HBs antibody concentration ≥ 3.3 mIU/ml95% CI: 95% confidence intervals; LL: Lower Limit, UL: Upper LimitConcomitant Medication intake status: Stratification based on data collected in the primary studyPre: Blood sampling done prior to administration of challenge dosePost: Blood sampling done one month after administration of challenge dose

CONFIDENTIAL




Final

28 Aug 2009 - 113 -

Supplement 25 Anti-HBs seropositivity rates, percentage of subjects withantibody concentrations greater than or equal to 10mIU/ml andgreater than or equal to 100mIU/ml and GMCs (calculated onseropositive subjects) stratified by medical condition status (ATPcohort for immunogenicity)

S+ ≥ 10 mIU/ml ≥ 100 mIU/ml GMC95% CI 95% CI 95%CI 95%CI

Group Timing N

n % LL UL n % LL UL n % LL UL Value LL ULPre 12 12 100 73.5 100 7 58.3 27.7 84.8 4 33.3 9.9 65.1 33.7 10.1 112.2Twinrix/PPost 12 12 100 73.5 100 12 100 73.5 100 12 100 73.5 100 13352.6 2934.9 60748.6Pre 134 98 73.1 64.8 80.4 70 52.2 43.4 60.9 25 18.7 12.5 26.3 37.7 26.8 53.1Twinrix/CPost 134 128 95.5 90.5 98.3 126 94.0 88.6 97.4 119 88.8 82.2 93.6 6298.7 4032.4 9838.6Pre 21 18 85.7 63.7 97.0 16 76.2 52.8 91.8 6 28.6 11.3 52.2 65.1 31.5 134.4Twinrix/NPost 21 21 100 83.9 100 21 100 83.9 100 20 95.2 76.2 99.9 11848.1 3621.4 38763.1Pre 21 13 61.9 38.4 81.9 11 52.4 29.8 74.3 2 9.5 1.2 30.4 30.3 15.5 59.2Eng+HAV/PPost 21 20 95.2 76.2 99.9 18 85.7 63.7 97.0 16 76.2 52.8 91.8 1657.5 452.4 6073.0Pre 128 82 64.1 55.1 72.3 51 39.8 31.3 48.9 13 10.2 5.5 16.7 22.8 16.3 31.9Eng+HAV/CPost 128 123 96.1 91.1 98.7 116 90.6 84.2 95.1 96 75.0 66.6 82.2 1081.9 682.5 1715.2Pre 19 12 63.2 38.4 83.7 10 52.6 28.9 75.6 4 21.1 6.1 45.6 68.8 16.3 289.7Eng+HAV/NPost 19 19 100 82.4 100 18 94.7 74.0 99.9 17 89.5 66.9 98.7 2246.8 529.6 9531.9Pre 14 7 50.0 23.0 77.0 5 35.7 12.8 64.9 2 14.3 1.8 42.8 26.4 7.7 90.1HBVX+VAQ/PPost 14 13 92.9 66.1 99.8 12 85.7 57.2 98.2 10 71.4 41.9 91.6 988.0 202.8 4812.8Pre 130 76 58.5 49.5 67.0 41 31.5 23.7 40.3 5 3.8 1.3 8.7 14.1 11.2 17.8HBVX+VAQ/CPost 130 117 90.0 83.5 94.6 113 86.9 79.9 92.2 90 69.2 60.5 77.0 1043.6 666.0 1635.3Pre 19 7 36.8 16.3 61.6 4 21.1 6.1 45.6 2 10.5 1.3 33.1 24.0 5.1 113.3HBVX+VAQ/NPost 19 15 78.9 54.4 93.9 14 73.7 48.8 90.9 12 63.2 38.4 83.7 1457.9 348.0 6107.5

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phase/P: Subjects who had a medical condition in the past/C; Subjects who had a current medical condition/N: Subjects who did not have any medical conditionN: number of subjects with available resultsn (%): number (percentage) of subjects with anti-HBs antibody concentration ≥ 3.3 mIU/ml or ≥ 10 mIU/ml or ≥ 100mIU/mlS+ : Seropositivity for anti-HBs antibodies defined as antibody concentrations ≥ 3.3 mIU/mlGMC: Geometric mean concentrations calculated on subjects with anti-HBs antibody concentration ≥ 3.3 mIU/ml95% CI: 95% confidence intervals; LL: Lower Limit, UL: Upper LimitMedical condition: stratification based on the data collected in the primary studyPre: Blood sampling done prior to administration of challenge dosePost: Blood sampling done one month after administration of challenge dose

CONFIDENTIAL




Final

28 Aug 2009 - 114 -

Supplement 26 Anti-HBs seropositivity rates, percentage of subjects withantibody concentrations greater than or equal to 3.3mIU/ml, greaterthan or equal to 10mIU/ml and greater than or equal to 100mIU/mland GMCs (calculated on seropositive subjects) stratified bydiabetes status (ATP cohort for immunogenicity)

≥ 3.3 mIU/ml ≥ 10 mIU/ml ≥100mIU/ml GMC95% CI 95% CI 95%CI 95%CI

Group Timing N

n % LL UL n % LL UL n % LL UL Value LL ULPre 13 6 46.2 19.2 74.9 2 15.4 1.9 45.4 0 0.0 0.0 24.7 7.9 3.2 19.4Twinrix/DYPost 13 11 84.6 54.6 98.1 11 84.6 54.6 98.1 8 61.5 31.6 86.1 572.4 112.0 2926.2Pre 109 83 76.1 67.0 83.8 63 57.8 48.0 67.2 22 20.2 13.1 28.9 43.0 30.0 61.5Twinrix/DNPost 109 106 97.2 92.2 99.4 105 96.3 90.9 99.0 102 93.6 87.2 97.4 8400.6 5371.0 13139.1Pre 13 10 76.9 46.2 95.0 3 23.1 5.0 53.8 0 0.0 0.0 24.7 11.9 5.6 25.0Eng+HAV/DYPost 13 12 92.3 64.0 99.8 10 76.9 46.2 95.0 6 46.2 19.2 74.9 246.9 41.4 1472.1Pre 107 69 64.5 54.6 73.5 46 43.0 33.5 52.9 12 11.2 5.9 18.8 24.1 16.8 34.8Eng+HAV/DNPost 107 103 96.3 90.7 99.0 98 91.6 84.6 96.1 82 76.6 67.5 84.3 1249.3 753.1 2072.3Pre 17 7 41.2 18.4 67.1 4 23.5 6.8 49.9 0 0.0 0.0 19.5 13.2 6.7 26.3HBVX+VAQ/DYPost 17 16 94.1 71.3 99.9 15 88.2 63.6 98.5 9 52.9 27.8 77.0 182.0 57.7 574.2Pre 103 66 64.1 54.0 73.3 34 33.0 24.1 43.0 5 4.9 1.6 11.0 14.0 10.8 18.2HBVX+VAQ/DNPost 103 92 89.3 81.7 94.5 90 87.4 79.4 93.1 76 73.8 64.2 82.0 1476.0 918.1 2372.9

Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phase/DY = Diabete/Yes/DN = Diabete/NoN: number of subjects with available resultsn (%): number (percentage) of subjects with anti-HAV antibody concentration ≥ 15 mIU/mlGMC: Geometric mean concentrations calculated on subjects with anti-HAV antibody concentrations ≥ 15 mIU/ml95% CI: 95% confidence intervals; LL: Lower Limit, UL: Upper LimitDiabetes: stratification based on the data collected in the primary studyPre: Blood sampling done prior to administration of challenge dosePost: Blood sampling done one month after administration of challenge doseStratification based on primary study

CONFIDENTIAL




Final

28 Aug 2009 - 115 -

Supplement 27 Anamnestic response to the challenge dose with ant-HBs antibody concentrations stratified based on the post-primaryvaccination status (ATP cohort for immunogenicity)

Anamnestic response to the challenge dose95% CI

Group Post-Primary vaccination status N n % LL ULS- 9 3 33.3 7.5 70.1S+(3.3mIU/ml-<10mIU/ml) 2 0 0.0 0.0 84.2S+(10mIU/ml-<100mIU/ml) 17 16 94.1 71.3 99.9S+(≥100mIU/ml) 139 137 98.6 94.9 99.8

Twinrix

Total 167 156 93.4 88.5 96.7S- 30 14 46.7 28.3 65.7S+(3.3mIU/ml-<10mIU/ml) 5 5 100 47.8 100S+(10mIU/ml-<100mIU/ml) 32 29 90.6 75.0 98.0S+(≥100mIU/ml) 101 100 99.0 94.6 100

Eng+HAV

Total 168 148 88.1 82.2 92.6S- 35 13 37.1 21.5 55.1S+(3.3mIU/ml-<10mIU/ml) 11 8 72.7 39.0 94.0S+(10mIU/ml-<100mIU/ml) 37 36 97.3 85.8 99.9S+(≥100mIU/ml) 80 79 98.8 93.2 100

HBVX + VAQ

Total 163 136 83.4 76.8 88.8Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseS- = seronegative subjects (antibody concentration < 3.3mIU/ml for anti-HBs) prior to vaccinationS+ = seropositive subjects (antibody concentration ≥ 3.3mIU/ml for anti-HBs) prior to vaccinationTotal = subjects either seropositive or seronegative at pre-vaccination Challenge Dose response defined as: For initially seronegative subjects, antibody concentration greater than or equal to 10mIU/ml (≥10mIU/ml) For initially seropositive: antibody concentration at least four times the pre-vaccination antibody concentrationN = number of subjects with both pre- and post-vaccination results availablen/% = number/percentage of responders95% CI = exact 95% confidence interval; LL = lower limit, UL = upper limit

CONFIDENTIAL




Final

28 Aug 2009 - 116 -

Supplement 28 Anamnestic response to the challenge dose for anti-HBsantibodies stratified based on the pre-challenge dose (ATP cohortfor immunogenicity)

Immune response to challenge doseresponse

95% CIGroup Pre-vaccination

statusN n % LL UL

S- 39 32 82.1 66.5 92.5S+ (3.3 mIU/ml - <10 mIU/ml) 35 33 94.3 80.8 99.3S+ (≥10 mIU/ml) 93 91 97.8 92.4 99.7

Twinrix

Total 167 156 93.4 88.5 96.7S- 61 50 82.0 70.0 90.6S+ (<10 mIU/ml) 35 29 82.9 66.4 93.4S+ (≥10 mIU/ml) 72 69 95.8 88.3 99.1

Eng+HAV

Total 168 148 88.1 82.2 92.6S- 73 53 72.6 60.9 82.4S+ (<10 mIU/ml) 40 37 92.5 79.6 98.4S+ (≥10 mIU/ml) 50 46 92.0 80.8 97.8

HBVX + VAQ

Total 163 136 83.4 76.8 88.8Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseS- = seronegative subjects (antibody concentration < 3.3 mIU/ml for anti-HBs antibodies) prior to vaccinationS+ = seropositive subjects (antibody concentration ≥ 3.3 mIU/ml for anti-HBs antibodies) prior to vaccinationTotal = subjects either seropositive or seronegative at pre-vaccinationAnamnestic response to challenge dose response defined as : For initially seronegative subjects, antibody concentration greater than or equal to 10mIU/ml(≥10mIU/ml) For initially seropositive: antibody concentration at least four times the pre-vaccination antibody concentrationN = number of subjects with both pre- and post-vaccination results availablen/% = number/percentage of responders95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit

CONFIDENTIAL




Final

28 Aug 2009 - 117 -

Supplement 29 Anti-HBs antibody concentration between pre and postchallenge dose (ATP cohort for immunogenicity)

Ant i -HBs ant i body concent rat i ons (MI U/ ML)

Post Chal l enge

1

10

100

1000

10000

100000

1000000

Pre Chal l enge

1 10 100 1000 10000

Supplement 30 Compliance in returning symptom sheets (Total vaccinatedcohort for the Challenge dose)

Group Number ofdoses

Doses NOTaccording to

protocol

Number ofgeneral SS

Compliance %general SS

Number oflocal SS

Compliance %local SS

Twinrix 172 2 172 100 172 100Eng+HAV 170 1 170 100 170 100HBVX+VAQ 164 1 164 100 164 100Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseSS = Symptom sheets used for the collection of local and general solicited AEsCompliance % = (number of doses with symptom sheet return / number of administered doses) X 100

CONFIDENTIAL




Final

28 Aug 2009 - 118 -

Supplement 31 Incidence and nature of grade 3 symptoms (solicited andunsolicited) reported during the 4-day (Days 0-3) post-vaccinationperiod (Total vaccinated cohort for Challenge dose)


Group N n % LL UL N n % LL UL N n % LL ULTwinrix 172 4 2.3 0.6 5.8 172 3 1.7 0.4 5.0 172 2 1.2 0.1 4.1Eng+HAV 170 0 0.0 0.0 2.1 170 0 0.0 0.0 2.1 170 0 0.0 0.0 2.1HBVX+VAQ 164 4 2.4 0.7 6.1 164 2 1.2 0.1 4.3 164 2 1.2 0.1 4.3Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseN= number of subjects with the administered dosen/%= number/percentage of subjects presenting at least one type of symptom whatever the study vaccine administered95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Supplement 32 Incidence and nature of symptoms (solicited and unsolicited)with causal relationship to vaccination, reported during the 4-day(Days 0-3) post-vaccination period (Total vaccinated cohort forChallenge dose)


Group N n % LL UL N n % LL UL N n % LL ULTwinrix 172 69 40.1 32.7 47.9 172 28 16.3 11.1 22.7 172 58 33.7 26.7 41.3Eng+HAV 170 53 31.2 24.3 38.7 170 26 15.3 10.2 21.6 170 43 25.3 19.0 32.5HBVX+VAQ 164 69 42.1 34.4 50.0 164 29 17.7 12.2 24.4 164 61 37.2 29.8 45.1Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseN= number of subjects with the administered dosen/%= number/percentage of subjects presenting at least one type of symptom whatever the study vaccine administered95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit

CONFIDENTIAL




Final

28 Aug 2009 - 119 -

Supplement 33 Percentage of subjects who reported the occurrence ofunsolicited symptoms classified by MEDDRA Primary SystemOrgan Class and Preferred Term during the 31-day (Days 0-30)post-vaccination period (Total vaccinated cohort for Challenge dose)

Twinrix N = 172

Eng+HAV N = 170

HBVX+VAQ N = 164




At least one symptom 28 16.3 11.1 22.7 10 5.9 2.9 10.6 21 12.8 8.1 18.9Blood and lymphatic systemdisorders (10005329)

Lymphadenitis(10025188)

1 0.6 0.0 3.2 0 0.0 0.0 2.1 1 0.6 0.0 3.4

Cardiac disorders(10007541)

Atrial fibrillation(10003658)

1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2

Ear and labyrinth disorders(10013993)

Vertigo (10047340) 0 0.0 0.0 2.1 0 0.0 0.0 2.1 1 0.6 0.0 3.4

Eye disorders (10015919) Conjunctivitis(10010741)

1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2

Gastrointestinal disorders(10017947)

Abdominal pain upper(10000087)

1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2

Diarrhoea (10012735) 1 0.6 0.0 3.2 0 0.0 0.0 2.1 1 0.6 0.0 3.4Enteritis (10014866) 1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2Toothache (10044055) 0 0.0 0.0 2.1 0 0.0 0.0 2.1 2 1.2 0.1 4.3

General disorders and Chills (10008531) 1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2administration site Fatigue (10016256) 1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2conditions (10018065) Influenza like illness

(10022004)0 0.0 0.0 2.1 1 0.6 0.0 3.2 0 0.0 0.0 2.2

Injection sitehaematoma(10022066)

1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2

Injection sitehaemorrhage(10022067)

1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2

Infections and infestations Bronchitis (10006451) 2 1.2 0.1 4.1 0 0.0 0.0 2.1 1 0.6 0.0 3.4(10021881) Cystitis (10011781) 1 0.6 0.0 3.2 0 0.0 0.0 2.1 1 0.6 0.0 3.4

Gastroenteritis(10017888)

1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2

Influenza (10022000) 2 1.2 0.1 4.1 0 0.0 0.0 2.1 0 0.0 0.0 2.2Nail bed infectionfungal (10067867)

1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2

Nasopharyngitis(10028810)

3 1.7 0.4 5.0 2 1.2 0.1 4.2 0 0.0 0.0 2.2

Pharyngitis(10034835)

0 0.0 0.0 2.1 0 0.0 0.0 2.1 2 1.2 0.1 4.3

Tonsillitis (10044008) 0 0.0 0.0 2.1 0 0.0 0.0 2.1 1 0.6 0.0 3.4Upper respiratory tractinfection (10046306)

1 0.6 0.0 3.2 0 0.0 0.0 2.1 1 0.6 0.0 3.4

Injury, poisoning andprocedural complications

Arthropod bite(10003399)

0 0.0 0.0 2.1 0 0.0 0.0 2.1 1 0.6 0.0 3.4

(10022117) Contusion (10050584) 0 0.0 0.0 2.1 0 0.0 0.0 2.1 1 0.6 0.0 3.4Fracture (10017076) 0 0.0 0.0 2.1 1 0.6 0.0 3.2 1 0.6 0.0 3.4Nerve injury(10052897)

1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2

Wound (10052428) 1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2Investigations (10022891) Blood gonadotrophin 1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2

CONFIDENTIAL




Final

28 Aug 2009 - 120 -

Twinrix N = 172

Eng+HAV N = 170

HBVX+VAQ N = 164




decreased (10005562)Musculoskeletal and Arthralgia (10003239) 1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2connective tissue disorders Back pain (10003988) 3 1.7 0.4 5.0 1 0.6 0.0 3.2 1 0.6 0.0 3.4(10028395) Joint range of motion

decreased (10048706)0 0.0 0.0 2.1 1 0.6 0.0 3.2 0 0.0 0.0 2.2

Myalgia (10028411) 1 0.6 0.0 3.2 0 0.0 0.0 2.1 1 0.6 0.0 3.4Pain in extremity(10033425)

0 0.0 0.0 2.1 1 0.6 0.0 3.2 0 0.0 0.0 2.2

Nervous system disorders Headache (10019211) 2 1.2 0.1 4.1 2 1.2 0.1 4.2 2 1.2 0.1 4.3(10029205) Somnolence

(10041349)0 0.0 0.0 2.1 1 0.6 0.0 3.2 1 0.6 0.0 3.4

Renal and urinary disorders(10038359)


1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2

Nephropathy(10029151)

0 0.0 0.0 2.1 0 0.0 0.0 2.1 1 0.6 0.0 3.4

Reproductive system andbreast disorders (10038604)

Benign prostatichyperplasia(10004446)

0 0.0 0.0 2.1 0 0.0 0.0 2.1 1 0.6 0.0 3.4

Respiratory, thoracic andmediastinal disorders(10038738)

Asthma (10003553) 1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2

Skin and subcutaneoustissue disorders (10040785)

Dermatitis atopic(10012438)

0 0.0 0.0 2.1 0 0.0 0.0 2.1 1 0.6 0.0 3.4

Eczema (10014184) 0 0.0 0.0 2.1 0 0.0 0.0 2.1 1 0.6 0.0 3.4Swelling face(10042682)

1 0.6 0.0 3.2 0 0.0 0.0 2.1 0 0.0 0.0 2.2

Vascular disorders(10047065)

Arterial occlusivedisease (10062599)

0 0.0 0.0 2.1 1 0.6 0.0 3.2 0 0.0 0.0 2.2


CONFIDENTIAL




Final

28 Aug 2009 - 121 -

Supplement 34 Percentage of subjects who started to take the specifiedconcomitant medication at least once during the 31-day (Days 0-30)post-vaccination period (Total vaccinated cohort for the Challengedose)


N n % LL UL N n % LL UL N n % LL ULAny 172 36 20.9 15.1 27.8 170 22 12.9 8.3 18.9 164 36 22.0 15.9 29.1Any antipyretic 172 17 9.9 5.9 15.4 170 12 7.1 3.7 12.0 164 12 7.3 3.8 12.4Prophylactic antipyretic 172 0 0.0 0.0 2.1 170 0 0.0 0.0 2.1 164 0 0.0 0.0 2.2Any antibiotic 172 7 4.1 1.7 8.2 170 2 1.2 0.1 4.2 164 11 6.7 3.4 11.7Prophylactic antibiotic 172 0 0.0 0.0 2.1 170 0 0.0 0.0 2.1 164 0 0.0 0.0 2.2Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseN= number of subjects with the administered dosen/%= number/percentage of subjects who started to take the specified concomitant medication at least once during thementioned period95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Supplement 35 Percentage of subjects who took the specified concomitantmedication at least once during the 4-day (Days 0-3) post-vaccination period (Total vaccinated cohort for the Challenge dose)


N n % LL UL N n % LL UL N n % LL ULAny 172 82 47.7 40.0 55.4 170 64 37.6 30.3 45.4 164 83 50.6 42.7 58.5Any antipyretic 172 21 12.2 7.7 18.1 170 9 5.3 2.4 9.8 164 24 14.6 9.6 21.0Prophylactic antipyretic 172 0 0.0 0.0 2.1 170 0 0.0 0.0 2.1 164 0 0.0 0.0 2.2Any antibiotic 172 4 2.3 0.6 5.8 170 2 1.2 0.1 4.2 164 1 0.6 0.0 3.4Prophylactic antibiotic 172 0 0.0 0.0 2.1 170 0 0.0 0.0 2.1 164 0 0.0 0.0 2.2Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseN= number of subjects with the administered dosen/%= number/percentage of subjects who took the specified concomitant medication at least once during thementioned period95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit

CONFIDENTIAL




Final

28 Aug 2009 - 122 -

Supplement 36 Percentage of subjects who took the specified concomitantmedication at least once during the 31-day (Days 0-30) post-vaccination period (Total vaccinated cohort for the Challenge dose)

Twinrix HAV ENG HBVX VQ95% CI 95% CI 95% CI

N n % LL UL N n % LL UL N n % LL ULAny 172 93 54.1 46.3 61.7 170 73 42.9 35.4 50.7 164 97 59.1 51.2 66.7Any antipyretic 172 31 18.0 12.6 24.6 170 18 10.6 6.4 16.2 164 31 18.9 13.2 25.7Prophylactic antipyretic 172 0 0.0 0.0 2.1 170 0 0.0 0.0 2.1 164 0 0.0 0.0 2.2Any antibiotic 172 10 5.8 2.8 10.4 170 4 2.4 0.6 5.9 164 12 7.3 3.8 12.4Prophylactic antibiotic 172 0 0.0 0.0 2.1 170 0 0.0 0.0 2.1 164 0 0.0 0.0 2.2Twinrix = Subjects received Twinrix in the primary study and in the challenge phaseENG+HAV = Subjects received separate administrations of Engerix-B and Havrix in the primary study and in thechallenge phaseHBVX+VAQ = Subjects received separate administrations of HBVAXPRO and Vaqta in the primary study and in thechallenge phaseN= number of subjects with the administered dosen/%= number/percentage of subjects who took the specified concomitant medication at least once during thementioned period95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit

CONFIDENTIAL




Final

28 Aug 2009 - 123 -

11. REFERENCES

Bauer T, Jilg W. Hepatitis B surface antigen-specific T and B cell memory in individualswho had lost protective antibodies after hepatitis B vaccination. Vaccine 2006;24:572�7.

Centre for Disease Control. Hepatitis B Virus: A Comprehensive Strategy for EliminatingTransmission in the United States Through Universal Childhood Vaccination:Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR.1991; 40(RR-13): 1-19.

GlaxoSmithKline Clinical Report 100382. A phase IV, open, randomized, multicentre,multicountry study to evaluate the effect of several risk factors likely to influence theimmunogenicity of GlaxoSmithKline Biologicals� combined hepatitis A and hepatitis Bvaccine Twinrix� according to a 0, 1 and 6 month schedule, as compared to separatelyadministered monovalent hepatitis A (0, 6 months) and hepatitis B vaccines (0, 1, 6months) from different manufacturers, as well as to demonstrate the non-inferiority ofTwinrix� to the monovalent vaccines, in healthy and non-healthy adults aged 41 yearsor older. Report Date 20 Feb 2006.

GlaxoSmithKline Clinical Report 100383. A phase IV, open, randomized, multicentre,multicountry study to evaluate the effect of several risk factors likely to influence theimmunogenicity of GlaxoSmithKline Biologicals� combined hepatitis A and hepatitis Bvaccine Twinrix� according to a 0, 1 and 6 month schedule, as compared to separatelyadministered monovalent hepatitis A (0, 6 months) and hepatitis B vaccines (0, 1, 6months) from different manufacturers, as well as to demonstrate the non-inferiority ofTwinrix� to the monovalent vaccines, in healthy and non-healthy adults aged 41 yearsor older. Report Date 27 Nov 2006.

GlaxoSmithKline Clinical Report 100384. A phase IV, open, randomized, multicentre,multicountry study to evaluate the effect of several risk factors likely to influence theimmunogenicity of GlaxoSmithKline Biologicals� combined hepatitis A and hepatitis Bvaccine Twinrix� according to a 0, 1 and 6 month schedule, as compared to separatelyadministered monovalent hepatitis A (0, 6 months) and hepatitis B vaccines (0, 1, 6months) from different manufacturers, as well as to demonstrate the non-inferiority ofTwinrix� to the monovalent vaccines, in healthy and non-healthy adults aged 41 yearsor older. Report Date 08 May 2007.

GlaxoSmithKline Clinical Report 100385. A phase IV, open, randomized, multicentre,multicountry study to evaluate the effect of several risk factors likely to influence theimmunogenicity of GlaxoSmithKline Biologicals� combined hepatitis A and hepatitis Bvaccine Twinrix� according to a 0, 1 and 6 month schedule, as compared to separatelyadministered monovalent hepatitis A (0, 6 months) and hepatitis B vaccines (0, 1, 6months) from different manufacturers, as well as to demonstrate the non-inferiority ofTwinrix� to the monovalent vaccines, in healthy and non-healthy adults aged 41 yearsor older. Report Date 20 Oct 2008.

Reutter J, Bart PA, Francioli P, Safary A, Frei PC. Production of antibody to hepatitis Avirus and hepatitis B surface antigen measured after combined hepatitis A/hepatitis B

CONFIDENTIAL




Final

28 Aug 2009 - 124 -

vaccination in 242 adult volunteers. J Viral Hepatitis 1998; 5: 205-211.

White SJ, Freedman LS. Allocation of patients to treatment groups in a controlled clinicalstudy. Br J Cancer 1978; 37: 849-857.

World Health Organisation. Progress in the control of viral hepatitis: Memorandum froma WHO Meeting. Bull WHO 1988; 66(4): 443-445.

CONFIDENTIAL




Final

28 Aug 2009 - 125 -

12. STUDY REPORT AUTHORS /CONTRIBUTING AUTHORS

Scientific Writer:

Statistician:

Project Statistician:

Global Study Manager:

Central Safety Contact:

Clinical Development Manager:

Regulatory Affairs representative:

N + 1 of CDM:

CONFIDENTIAL



CONFIDENTIAL111149 (HAB-160 BST) and 111572 (HAB-168 BST:160)

Final

28 Aug 2009 - 127 -

13.2. CIOMS


Final


13.2.1. Serious Adverse Events CIOMS

CONFIDENTIAL

111149 (HAB-160 BST) and 111572 (HAB-168 BST:160)Final

28 Aug 2009 15cafb56d5c6222e3ff4f04c2cfaa4ac7

CONFIDENTIAL


28 Aug 2009 128d144f960d009e6036a83fac467f934d2

This section contained patient narratives which are textual descriptions of medical history,

treatment and outcome for individual patients who experienced a clinically important adverse

event including serious adverse events during the trial. They have been excluded to protect

patient privacy. This data may be made available subject to an approved research proposal and

a determination of the ability to provide information from the specific narratives whilst protecting

the patient’s privacy. For further information please see the Patient Level Data section of

the GSK Clinical Study Register.


Final

28 Aug 2009 - 1 -

Modular Appendices

List of modular appendices available for the study report and ICH-specificappendices - Study Information equivalent numbering

Modular appendices ICH numbering

Sponsor information -

Protocol and protocol amendments. 16.1.1

Sample Case Report form (unique pages only). 16.1.2

List of IECs or IRBs (plus name of committee chair if required byregulatory authority)

16.1.3

Representative written information for patient and sample consentforms.

16.1.3

List of investigators and other important participants in the study 16.1.4

Investigator CVs or equivalent summaries of training andexperience relevant to the performance of the clinical study

16.1.4

Signatures of principal or coordinating investigator(s) or sponsor�sresponsible medical officer, depending on the regulatoryauthority�s requirement

16.1.5

Listings of patients receiving test drug(s) /investigationalproduct(s) from specific batches, where more than one batch wasused (if applicable).

16.1.6

Randomization list (patient identification and treatment assigned). 16.1.7

Audit certificates (if available). 16.1.8

Documentation of statistical methods 16.1.9

Documentation of inter-laboratory standardization methods andquality assurance procedures, if used

16.1.10

Publications based on the study. 16.1.11

Important publications referenced in the report 16.1.12

Individual listings 16.2

Case report forms (CRFs /eCRFs)CRFs /eCRFs for deaths, other SAEs and withdrawals due toadverse events

16.316.3.1

CONFIDENTIAL


28 Aug 2009 137678ef29f07c3a0bc29aa9b938be2b981

Sponsor Information

CONFIDENTIAL


28 Aug 2009 1be6b7764ba603c7587f6d103ecd6bb8a

CONFIDENTIAL


28 Aug 2009 1384b6856d17501c887bd2a7fcf227c67c3

CONFIDENTIAL

- 1 -

Sponsor Information

e-Track Study Number 100382 (HAB-160)100383 (HAB-161 EXT-160 Y1)100384 (HAB-162 EXT-160 Y2)100385 (HAB-163 EXT-160 Y3)

1. Investigators

Germany:Prof. Dr.

Czech Republic: M.D.

Belgium:Professor M.D.2. �Leiter der klinischen Prüfung� (LKP)Dr. med. habil.

Germany

Telephone: Fax: 3. Medical Monitor

Germany:

GlaxoSmithKline GmbH & Co. KGTheresienhöhe 11, D 80339 München,GermanyTel: Fax:

Czech Republic:

M.D.

GlaxoSmithKline s.r.o.

Na Pankraci 17,19 140 21 Praha 4,

Czech Republic

Tel:

Fax :

Belgium:


Rue de l'Institut, 89B-1330 Rixensart � Belgium

Tel:

Fax:

CONFIDENTIAL


28 Aug 2009 21bd1f8fc62783d3e607388b986557b9a

CONFIDENTIAL


28 Aug 2009 1394b6856d17501c887bd2a7fcf227c67c3

CONFIDENTIAL

- 2 -

4. Study Monitor

Germany:

Sächsisches Serumwerk GmbH

Zirkusstr. 40

01069 Dresden, Germany

Tel:

Fax:

Czech Republic:

GlaxoSmithKline s.r.o.Na Pankraci 17/1685,140 21 Prague 4,Czech Republic

Tel:

Fax:

Belgium: Central Study Coordinator

GlaxoSmithKline BiologicalsRue de L�Institut 89,B-1330 Rixensart, BelgiumTel: : Fax: 5. Study Contact for Reporting of a Serious Adverse EventGermany:

Sächsisches Serumwerk GmbH

Zirkusstr. 40

01069 Dresden, Germany

Tel:

Fax:

Czech Republic:

GlaxoSmithKline s.r.o.Na Pankraci 17/1685,140 21 Prague 4,Czech Republic

Tel:

Fax:

Outside office hours: Mobile phone:

Belgium:

Central Study CoordinatorGlaxoSmithKline BiologicalsRue de L�Institut 89B-1330 Rixensart, Belgium

Tel: : Fax:

CONFIDENTIAL


28 Aug 2009 31bd1f8fc62783d3e607388b986557b9a

CONFIDENTIAL


28 Aug 2009 1404b6856d17501c887bd2a7fcf227c67c3

CONFIDENTIAL

- 3 -

Back-up contact for reporting SAEs:Manager Clinical Safety Vaccines

M.D.GlaxoSmithKline BiologicalsRue de l�Institut 891330 Rixensart, Belgium

Tel:

Fax:

Mobile phone for 7/7 day availability:

6. Study Centres

Germany: Czech Republic:

Czech Republic,Tel:

Fax: e-mail:

Belgium:Professor

Belgium

CONFIDENTIAL


28 Aug 2009 41bd1f8fc62783d3e607388b986557b9a

CONFIDENTIAL


28 Aug 2009 1414b6856d17501c887bd2a7fcf227c67c3

111572

- 1 -

Sponsor Information

eTrack study numberand abbreviated title

111572 (HAB-168 BST:160)

EudraCT number 2008-000526-39

Date of document 25 January 2008

Detailed Title A phase IV, open, multicentre, multicountry study toevaluate the immune response to a challenge dose of GSKBiologicals� Twinrix� vaccine versus monovalenthepatitis A and B vaccines from different manufacturersin healthy and non-healthy adults aged 41 years andolder, approximately 48 months after primary vaccinationin the study 100382 (HAB-160).

1. (Principal) Investigator

Czech Republic

Belgium

2. Medical Monitor

ManagerPediatric and Hepatitis VaccinesGlaxoSmithKline BiologicalsRue de l'Institut, 89B-1330 RixensartTel: 3. Study Monitor

GlaxoSmithKline BiologicalsRue de l'Institut, 89B-1330 RixensartTel: Fax:

CONFIDENTIAL


28 Aug 2009 5e9a0d4a2b992cce93955cd73df5e6a42

CONFIDENTIAL


28 Aug 2009 1424b6856d17501c887bd2a7fcf227c67c3

111572

- 2 -

4. Study Contact for Reporting of a Serious Adverse Event

Czech Republic:Dr. GlaxoSmithKlineNa Pankraci 17/1685140 21, Prague 4Czech RepublicTel: Mobile: Fax:

Belgium:

GlaxoSmithKline BiologicalsGenval, BelgiumTel: Fax :

5. Study Centres

Czech Republic

Belgium

CONFIDENTIAL


28 Aug 2009 6e9a0d4a2b992cce93955cd73df5e6a42

CONFIDENTIAL


28 Aug 2009 1434b6856d17501c887bd2a7fcf227c67c3

Protocol and Protocol Amendments

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 144fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL

28 March 2008 1

GlaxoSmithKline BiologicalsRue de l�Institut 89,

1330 Rixensart, BelgiumConfidential & Proprietary Information

Study vaccines GlaxoSmithKline Biologicals� combined hepatitisA/hepatitis B vaccine Twinrix Adult 720/20,hepatitis B vaccine Engerix-B 20 µg and hepatitisA vaccine Havrix 1440,Aventis Pasteur MSD�s hepatitis B vaccineHB VAX PRO 10 µg and hepatitis A vaccineVaqta 50 U.

eTrack study number 100382 (HAB-160)100383 (HAB-161 EXT-160 Y1)100384 (HAB-162 EXT-160 Y2)100385 (HAB-163 EXT-160 Y3)111149 (HAB-160 BST)

Date of approval 16 September 2003, FinalAmendment 1 28 August 2007 (Final)Amendment 2 25 January 2008 (Final)Administrative Change 1 28 March 2008 (Final)Title A phase IV, open, randomized, multicentre,

multicountry study to evaluate the effect of severalrisk factors likely to influence the immunogenicity ofGlaxoSmithKline Biologicals� combined hepatitis Aand hepatitis B vaccine Twinrix according to a 0, 1and 6 month schedule, as compared to separatelyadministered monovalent hepatitis A (0, 6 months)and hepatitis B vaccines (0, 1, 6 months) fromdifferent manufacturers, as well as to demonstrate thenon-inferiority of Twinrix to the monovalentvaccines, in healthy and non-healthy adults aged41 years or older.

Coordinating author Scientific Writers

Contributing authors • Director, Global ClinicalR&D Vaccines, Paediatrics/Hepatitis vaccines

• Manager, Global ClinicalResearch and Development, Paediatrics/Hepatitisvaccines,

• Central StudyCoordinator

• BiometricianThis protocol was developed based on Version 12 of GlaxoSmithKline Biologicals� Protocol DocumentStandard.

CONFIDENTIAL

111149 (HAB-160 BST)Administrative Change 1

28 March 2008 1c677eafa029f75fc20becd65d7572335

CONFIDENTIAL


28 Aug 2009 2f000975cf40f655d117b2c2b6bada240

CONFIDENTIAL


28 Aug 2009 145fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL 111149 (HAB-160 BST)Administrative Change 1

28 March 2008 2

Investigator Agreement

eTrack study number 100382 (HAB-160)100383 (HAB-161 EXT-160 Y1)100384 (HAB-162 EXT-160 Y2)100385 (HAB-163 EXT-160 Y3)111149 (HAB-160 BST)

Title A phase IV, open, randomized, multicentre, multicountrystudy to evaluate the effect of several risk factors likely toinfluence the immunogenicity of GlaxoSmithKlineBiologicals� combined hepatitis A and hepatitis B vaccineTwinrix according to a 0, 1 and 6 month schedule, ascompared to separately administered monovalent hepatitisA (0, 6 months) and hepatitis B vaccines (0, 1, 6 months)from different manufacturers, as well as to demonstrate thenon-inferiority of Twinrix to the monovalent vaccines, inhealthy and non-healthy adults aged 41 years or older.

I agree:

• To assume responsibility for the proper conduct of the study at this site.

• To conduct the study in compliance with this protocol, any mutually agreed futureprotocol amendments, and with any other study conduct procedures provided byGlaxoSmithKline Biologicals (GSK Biologicals).

• Not to implement any changes to the protocol without agreement from the sponsorand prior review and written approval from the Institutional Review Board (IRB) orIndependent Ethics Committee (IEC), except where necessary to eliminate animmediate hazard to the subjects, or for administrative aspects of the study (wherepermitted by all applicable regulatory requirements).

• That I am thoroughly familiar with the appropriate use of the vaccine, as described inthis protocol, and any other information provided by the sponsor, including, but notlimited to, the following: the current Investigator�s Brochure (IB) or equivalentdocument, IB supplement (if applicable), prescribing information (in the case of amarketed vaccine) and/or Master Data Sheet (if the Master Data Sheet exists andserves as reference document for the vaccine in the case of a marketed vaccine).

• That I am aware of, and will comply with, �Good Clinical Practices� (GCP) and allapplicable regulatory requirements.

• That I have been informed that certain regulatory authorities require the sponsor toobtain and supply, as necessary, details about the investigator�s ownership interest inthe sponsor or the investigational product, and more generally about his/her financialties with the sponsor. GSK Biologicals will use and disclose the information solelyfor the purpose of complying with regulatory requirements.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 146fb0b009324aa43dbd8458969316ad24d


28 March 2008 3

Hence I:

• Agree to supply GSK Biologicals with any necessary information regardingownership interest and financial ties (including those of my spouse and dependentchildren).

• Agree to promptly update this information if any relevant changes occur during thecourse of the study and for 1 year following completion of the study.

• Agree that GSK Biologicals may disclose any information it has about suchownership interests and financial ties to regulatory authorities.

• Agree to provide GSK Biologicals with an updated Curriculum Vitae and other FDArequired documents.

Investigator name:

�Leiter der klinischen Prüfung� (LKP):

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 147fb0b009324aa43dbd8458969316ad24d


28 March 2008 4

Synopsis

Title A phase IV, open, randomized, multicentre, multicountry studyto evaluate the effect of several risk factors likely to influencethe immunogenicity of GlaxoSmithKline Biologicals� combinedhepatitis A and hepatitis B vaccine Twinrix according to a 0, 1and 6 month schedule, as compared to separately administeredmonovalent hepatitis A (0, 6 months) and hepatitis B vaccines(0, 1, 6 months) from different manufacturers, as well as todemonstrate the non-inferiority of Twinrix to the monovalentvaccines, in healthy and non-healthy adults aged 41 years orolder.

Indication/Studypopulation

Healthy and non-healthy (including those taking medications)adults aged 41 years or older, who are seronegative for anti-HAV, anti-HBs and anti-HBc antibodies (Ab) and for HBsAg atthe time of enrollment.

Rationale The immune response after vaccination with GSK Biologicals�combined hepatitis A and B vaccine as well as monovalenthepatitis A and B vaccines from different manufacturers isknown to be influenced by several factors including age, genderand BMI [Reutter J; 1998, White SJ, 1978]. The responses afterimmunization of elderly individuals with hepatitis A andhepatitis B vaccines is a topic that is becoming increasinglyrelevant as the number of aged people travelling to exoticdestinations increases.

In this prospective study, subjects aged 41 years or older, with awide range in body weight and variable general health statuswere enrolled. The influence of risk factors likely to influencethe immune response elicited by Twinrix (e.g. age, gender,body mass index [BMI], smoking, alcohol consumption, diseasesand medications) were assessed. The non-inferiority ofTwinrix to the monovalent vaccines was evaluated in terms ofanti-HBs seroprotection rate and anti-HAV seropositivity rate atMonth 7. Furthermore, the effects of the risk factors on theimmune response elicited by the separately administeredmonovalent hepatitis A and hepatitis B vaccines Engerix�-Band Havrix� as well as HB VAX PRO and Vaqta were alsoassessed. Additionally, the current study will provide dataconcerning the long-term (up to 48 months) anti-HBsseropositivity rates and seroprotection rates and the long-termanti-HAV seropositivity rate in this population.

Finally, to evaluate the immune memory to HBV and HAVantigens in this population, all subjects (irrespective of theirserological status) will receive a challenge dose of the vaccine

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 148fb0b009324aa43dbd8458969316ad24d


28 March 2008 5

that they received in the primary study approximately 48 monthsafter the first dose of the primary vaccination course. A bloodsample will be taken at Day 0, two weeks (Day 14) and onemonth (Day 30) after the administration of the challenge dose toevaluate the anti-HAV and anti-HBs antibody response. At therequest of the Czech authorities the challenge dose study isdescribed in a separate protocol (HAB-168 BST:160 [111572])for the Belgian and Czech centers. The eligibility criteria, studyvisit procedures and data collection will be identical in the twostudies and the data will be combined with this study foranalysis.

Objectives Co-Primary objectives:

Primary vaccination study:

• To evaluate the influence of age, gender and BMI on theimmunogenicity of Twinrix, in terms of individual anti-HAV titers and individual anti-HBs titers, at Month 7.

• To demonstrate the non-inferiority of Twinrix to theseparately administered monovalent vaccines Engerix-B/Havrix or HB VAX PRO /Vaqta in terms of anti-HAV seropositivity rate and anti-HBs seroprotection rate atMonth 7.

Challenge dose study

• To evaluate the anti-HAV and anti-HBs immune memory(in terms of anti-HAV and anti-HBs immune responseelicited by the challenge dose) in a population > 41 years ofage (healthy and non-healthy), approximately 48 monthsafter the first dose of the primary vaccination course.

Secondary:

Primary vaccination study and long term follow-up (up to Month48)

• To evaluate the influence of age, gender and BMI on theimmunogenicity of the separately administered monovalentvaccines Engerix-B /Havrix and HB VAX PRO/Vaqta, in terms of individual anti-HAV and anti-HBstiters at Month 7.

• To describe the immunogenicity of Twinrix, Engerix-B/Havrix and HB VAX PRO /Vaqta in terms of anti-HAV seropositivity rates and GMTs, and anti-HBsseropositivity rates, seroprotection rates and GMTs atMonth 7, by risk factor (age, gender, BMI, smoking habit,

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 149fb0b009324aa43dbd8458969316ad24d


28 March 2008 6

alcohol consumption, diseases and medications) and overall.

• To explore the influence of age, gender and BMI on theimmunogenicity of Twinrix, Engerix-B /Havrix andHB VAX PRO /Vaqta, in terms of anti-HAVseropositivity status and anti-HBs seroprotection status atMonth 7.

• To evaluate the long-term persistence elicited by Twinrix,Engerix-B /Havrix and HB VAX PRO /Vaqta, interms of anti-HAV seropositivity rates and GMTs (atMonths 12, 24, 36 and 48), as well as anti-HBsseropositivity rates, seroprotection rates and GMTs (atMonths 12, 24, 36 and 48).

• To evaluate safety throughout the study period: all seriousadverse events (SAEs) up to Month 7, as well as SAEs withcausal relationship to vaccination or referring to hepatitis Aor B infection, after Month 7 and up to the study end(Month 48).

Challenge dose study:

• To evaluate the immune response to the challenge dose, twoweeks (Day 14) and one month (Day 30) after vaccination.

• To evaluate safety and reactogenicity of the challenge dosein terms of:

− solicited symptoms occurring during the 4-day (Day 0 toDay 3) follow-up period.

− unsolicited symptoms occurring during the 31-day (Day0 to Day 30) follow-up period.

− all serious adverse events (SAE) following the challengedose administration.

Study design Primary vaccination study

• Experimental design: open, randomized, multicentre,multicountry study with 3 parallel groups.

• Treatment Groups: Twinrix (Month 0, 1, 6); Engerix-B(Month 0, 1, 6) co-administered with Havrix (Month 0, 6);HB VAX PRO (Month 0, 1, 6) co-administered withVaqta (Month 0, 6).

• Treatment allocation by SBIR: randomized (ratio 1:1:1).Randomization will be stratified at enrolment based on age(41-50 years; 51-60 years versus ≥61 years), gender andBMI (<25 kg/m2 or lean/healthy BMI, ≥25 kg/m2 and <30kg/m2 or overweight, versus ≥30 kg/m2 or obese; as defined

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 150fb0b009324aa43dbd8458969316ad24d


28 March 2008 7

by the Centres for Disease Control and Prevention [CDC]for the adult population). See Section 6.4 for a detaileddescription of the randomization method.

• Population: a close to �real life� population will be recruitedwith a broad age range, various body weight and generalhealth status.

• The study is self-contained.

• Data collection: RDE.

• Duration of the study: approximately 7 months per subjectfor primary vaccination. Long-term follow-up up to Month48.

• Recruitment method. See Appendix C for details of therecruitment plan.


• Experimental design: open, multicentre study with threeparallel groups.

• Treatment groups for the challenge dose study will be thesame as in the primary study: all subjects will receive onedose of Twinrix ; Engerix-B co-administered withHavrix or HB VAX PRO co-administered with Vaqtaaccording to their randomization in the primary vaccinationstudy.


• Study duration: Approximately one month per subject afterhe/she receives the challenge dose.

• The challenge dose study is described in this protocol for theGerman centers and in a separate protocol (HAB-168BST:160 [111572]) for the Belgian and Czech centers. Theeligibility criteria, study visit procedures and data collectionwill be identical in the two studies and the data will becombined with this study for analysis.

Number ofsubjects

A total of 600 subjects will be enrolled (200 subjects per group)in order to have 540 evaluable subjects (180 subjects per group).

For the challenge dose study

All 590 subjects who have completed the primary vaccinationcourse will be invited to participate in the challenge dose study.A total of 219 subjects are expected to be recruited in theGerman centres (described in this protocol) and 276 subjects areexpected to be recruited in the Belgian and Czech centres

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 151fb0b009324aa43dbd8458969316ad24d


28 March 2008 8

(described in a separate protocol with E- track number 111572).

Co-Primaryendpoints

Primary vaccination study

• Individual anti-HAV and anti-HBs titers after Twinrixvaccination, at Month 7.

• The non-inferiority of Twinrix to the separatelyadministered monovalent vaccines Engerix-B /Havrixand HB VAX PRO /Vaqta in terms of anti-HAVseropositivity rate and anti-HBs seroprotection rate atMonth 7.


• Anti-HAV immune response to the challenge dose isdefined as:

− Anti-HAV antibody titres ≥ 15 mIU/ml at one monthpost-challenge dose in subjects, seronegative at the pre-challenge time point.

− At least a 2-fold increase in anti-HAV antibody titresone month after the challenge dose, in subjects havinganti-HAV antibody titres ≥ 100 mIU/ml at the pre-challenge time point

− or at least a 4-fold increase in anti-HAV antibody titresone month after the challenge dose, in seropositivesubjects having anti-HAV antibody titres < 100 mIU/mlat the pre-challenge time point.

• Anti-HBs antibody response to the challenge dose is definedas

− Anti-HBs antibody titres ≥ 10 mIU/ml at one monthpost-challenge dose in subjects seronegative at the pre-challenge time point.

− At least a 4-fold increase in anti-HBs antibody titres, atone month post-challenge dose in subjects seropositiveat the pre-challenge time point.

Secondaryendpoints

Primary vaccination study and long-term follow up (up to Month48)

• Individual anti-HAV and anti-HBs titers after vaccinationwith Engerix-B / Havrix and HB VAX PRO /Vaqta, atMonth 7.

• Anti-HAV seropositivity rates and GMTs as well as anti-HBs seropositivity rates, seroprotection rates and GMTs atMonth 7 after Twinrix, Engerix-B /Havrix and

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 152fb0b009324aa43dbd8458969316ad24d


28 March 2008 9

HB VAX PRO /Vaqta vaccination, described by age,gender, BMI, smoking habit, alcohol consumption, diseaseand medication, and overall.

• Individual anti-HAV seropositivity status and anti-HBsseroprotection status, at Month 7 after Twinrix, Engerix-B /Havrix and HB VAX PRO /Vaqta vaccination.

• Anti-HAV seropositivity rates and GMTs, as well as anti-HBs seropositivity rates, seroprotection rates and GMTs atMonths 12, 24, 36 and 48.

• Occurrence, intensity and relationship to vaccination of allserious adverse events (SAEs) up to Month 7, as well as ofSAEs with causal relationship to vaccination or referring tohepatitis A or B infection, after Month 7 and up to the studyend (Month 48).


Immunogenicity

• Percentage of subjects with anti-HAV antibody titres ≥ 15mIU/ml and geometric mean titres (GMTs) calculated onseropositive subjects, two weeks and one month after thechallenge dose.

• Percentage of subjects with anti-HBs antibody titres ≥ 3.3mIU/ml, ≥ 10 mIU/ml, ≥ 100 mIU/ml and anti-HBs GMTscalculated on seropositive subjects, two weeks and onemonth after the challenge dose.

Reactogenicity

• Occurrence and intensity of solicited local symptoms in the4-day (Day 0 to 3) follow-up period after the challengedose.

• Occurrence, intensity and relationship of solicited generalsymptoms in the 4-day (Day 0 to 3) follow-up period afterthe challenge dose.

Safety

• Occurrence, intensity and relationship to vaccination ofunsolicited symptoms reported during the 31-day (Day 0 to30) follow-up period after the challenge dose.

• Occurrence of all serious adverse events (SAEs) reportedfollowing the administration of the challenge dose.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 153fb0b009324aa43dbd8458969316ad24d


28 March 2008 10

TABLE OF CONTENTS

PAGE

1. INTRODUCTION....................................................................................................181.1. Background ................................................................................................181.2. Rationale for the study................................................................................18

2. OBJECTIVES.........................................................................................................192.1. Co-Primary objectives.................................................................................192.2. Secondary objectives..................................................................................19

3. STUDY DESIGN OVERVIEW ................................................................................20

4. STUDY COHORT...................................................................................................224.1. Number of subjects / centres ......................................................................224.2. Inclusion criteria..........................................................................................224.3. Exclusion criteria for enrolment...................................................................234.4. Elimination criteria during the study ............................................................234.5. Contraindications to subsequent vaccination ..............................................244.6. Warning and precautions ............................................................................24

5. CONDUCT OF STUDY ..........................................................................................275.1. Ethics and regulatory considerations ..........................................................27

5.1.1. Institutional Review Board/Independent Ethics Committee(IRB/IEC) .....................................................................................27

5.1.2. Informed consent .........................................................................285.2. General study aspects ................................................................................305.3. Subject identification...................................................................................305.4. Outline of study procedures ........................................................................315.5. Detailed description of study stages/visits...................................................375.6. Sample handling and analysis ....................................................................42

5.6.1. Treatment and storage of biological samples...............................435.6.2. Laboratory assays .......................................................................435.6.3. Serology plan...............................................................................44

6. INVESTIGATIONAL PRODUCTS AND ADMINISTRATION...................................456.1. Study vaccines............................................................................................456.2. Dosage and administration .........................................................................466.3. Storage.......................................................................................................476.4. Treatment allocation and randomization .....................................................486.5. Method of blinding and breaking the study blind .........................................496.6. Replacement of unusable vaccine doses....................................................496.7. Packaging...................................................................................................496.8. Vaccine accountability ................................................................................496.9. Concomitant medication/treatment .............................................................49

7. HEALTH ECONOMICS ..........................................................................................50

8. MEDICAL CONDITION AND (SERIOUS) ADVERSE EVENTS..............................508.1. Definition of chronic disease and adverse events .......................................518.2. Definition of a serious adverse event ..........................................................52

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 154fb0b009324aa43dbd8458969316ad24d


28 March 2008 11

8.3. Lack of efficacy...........................................................................................538.4. Clinical laboratory parameters and other abnormal assessments

qualifying as serious adverse events ..........................................................538.5. Time period, frequency, and method of detecting adverse events

and serious adverse events ........................................................................538.5.1. Solicited adverse events ..............................................................56

8.6. Evaluating adverse events and serious adverse events..............................578.6.1. Assessment of intensity ...............................................................578.6.2. Assessment of causality ..............................................................58

8.7. Follow-up of chronic diseases and serious adverse events, andassessment of outcome..............................................................................598.7.1. Chronic diseases .........................................................................598.7.2. Serious adverse events ...............................................................59

8.8. Prompt reporting of serious adverse events to GSK Biologicals..................618.8.1. Time frames for submitting serious adverse event reports

to GSK Biologicals .......................................................................618.8.2. Completion and transmission of serious adverse event

reports to GSK Biologicals ...........................................................618.9. Regulatory reporting requirements for serious adverse events ...................628.10. Post study serious adverse events .............................................................638.11. Pregnancy ..................................................................................................63

9. SUBJECT COMPLETION AND WITHDRAWAL.....................................................649.1. Subject completion .....................................................................................649.2. Subject withdrawal......................................................................................64

9.2.1. Subject withdrawal from the study ...............................................649.2.2. Subject withdrawal from investigational product...........................64

10. DATA EVALUATION: CRITERIA FOR EVALUATION OF OBJECTIVES ...............6510.1. Co-Primary endpoints .................................................................................6510.2. Secondary endpoints ..................................................................................6610.3. Estimated sample size ................................................................................6710.4. Study cohorts to be evaluated.....................................................................6910.5. Derived and transformed data.....................................................................7110.6. Final analyses.............................................................................................72

10.6.1. Analysis of demographics/baseline characteristics ......................7210.6.2. Analysis of immunogenicity..........................................................7210.6.3. Analysis of safety.........................................................................74

10.7. Planned interim analysis .............................................................................75

11. ADMINISTRATIVE MATTERS ...............................................................................75

12. REFERENCES.......................................................................................................76

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 155fb0b009324aa43dbd8458969316ad24d


28 March 2008 12

LIST OF TABLES

PAGE



Table 3 List of study procedures: HB VAX PRO /Vaqta Group............................35

Table 4 Intervals between study visits.................................................................37




Table 8 Stratification by each country per age, gender and BMI .........................48

Table 9 Reporting periods for adverse events and serious adverseevents ....................................................................................................55



Table 12 Intensity scales for solicited symptoms in adults ....................................57

Table 13 Summary table.......................................................................................68


LIST OF FIGURES

PAGE

Figure 1 Power versus R2 (T) with N=180, F-test with alpha=0.05.......................67

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 156fb0b009324aa43dbd8458969316ad24d


28 March 2008 13

APPENDICES

PAGE

Appendix A World Medical Association Declaration of Helsinki .................................77

Appendix B Administrative Matters............................................................................81

Appendix C Overview of the Recruitment Plan ..........................................................86

Appendix D Handling of Biological Samples Collected by the Investigator ................87

Appendix E Shipment of Biological Samples .............................................................90

Appendix F Laboratory Assays .................................................................................91

Appendix G Vaccine supplies, packaging and accountability.....................................92

Appendix H Amendments and Administrative Changes to the Protocol .....................94

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 157fb0b009324aa43dbd8458969316ad24d


28 March 2008 14

List of Abbreviations

Ab Antibody

Anti-HAV Antibodies to hepatitis A virus

Anti-HBc Antibody to hepatitis B core antigen

Anti-HBs Antibody to hepatitis B surface antigen

ATP According-to-protocol analysis

ATP-LT Long term According-To-Protocol cohort

BMI Body Mass Index

CDC Centres for Disease Control and Prevention

CRF Case Report Form

CRA Clinical Research Associate

CSC Central Study Coordinator

EIA Enzyme-immunoassay

EISR Expedited Investigator Safety Report

EL.U. ELISA Units

eTrack Clinical Trial Management System

FDA Food and Drug Administration, United States

GCP Good Clinical Practice

GMT Geometric Mean Titre

GSK GlaxoSmithKline

HAB Combined hepatitis A/ hepatitis B Vaccine

HAV Hepatitis A virus

HBc Hepatitis B core antigen

HbsAg Hepatitis B surface antigen

HBV Hepatitis B virus

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 158fb0b009324aa43dbd8458969316ad24d


28 March 2008 15

ICH International Committee on Harmonization



IU International Units

µg Microgram

mg Milligram

mIU/ml Milli-International Units per milliliter




SBIR Central randomization call-in system on Internet

SOP Standard Operating Procedure

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 159fb0b009324aa43dbd8458969316ad24d


28 March 2008 16

Glossary of Terms

Blinding: A procedure in which one or more parties to the trial arekept unaware of the treatment assignment in order toreduce the risk of biased study outcomes. In a single-blind trial, the investigator and/or his staff are aware ofthe treatment assignment but the subject is not. When theinvestigator and sponsor staff who are involved in thetreatment or clinical evaluation of the subjects andreview/analysis of data are also unaware of the treatmentassignments, the study is double blind. This level ofblinding is maintained throughout the conduct of the trial,and only when the data are cleaned to an acceptable levelof quality will appropriate personnel be unblinded orwhen required in case of a serious adverse event.

Central StudyCoordinator:

An individual assigned by and centrally located at GSKBiologicals at Rixensart who is responsible for assuringproper conduct of a clinical study.

Chronic disease Chronic disease differs from acute disease in that it istreatable yet not curable.

Eligible: Qualified for enrolment into the study based upon strictadherence to inclusion/exclusion criteria.

Evaluable: Meeting all eligibility criteria, complying with theprocedures defined in the protocol, and, therefore,included in the according-to-protocol (ATP) analysis (seeSections 4.4 and 10.4 for details on criteria forevaluability).

Investigational product: A pharmaceutical form of an active ingredient or placebobeing tested or used as a reference in a clinical trial,including a product with a marketing authorization whenused in a way different from the approved form, or whenused for an unapproved indication, or when used to gainfurther information about an approved use.

Medical Monitor: An individual medically qualified to assume theresponsibilities of the sponsor (GSK Biologicals)especially in regards to the ethics, clinical safety of astudy and the assessment of adverse events.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 160fb0b009324aa43dbd8458969316ad24d


28 March 2008 17

Protocol amendment: Any change in a clinical protocol which affects the safetyof subjects, the scope, design, assessments or scientificvalidity of the clinical investigation, e.g., dose change,duration of treatment, number of subjects, controlgroup(s), the assessments.

Protocol modification: Strictly, any change to a clinical protocol that is notconsidered to be a protocol amendment. In essence,changes to clarify (but not alter) existing design featuresof a clinical investigation or to encourage greatercompliance with the intent of the clinical protocol may beissued as modifications rather than amendments. Aprotocol modification addresses logistical oradministrative aspects of the study (e.g., change ofmonitor(s), telephone number(s).

Site Monitor: An individual assigned by the sponsor who is responsiblefor assuring proper conduct of clinical studies at one ormore investigational sites.

Study Monitor: An individual assigned by the sponsor who is responsiblefor assuring proper conduct of a clinical study.

Subject: Term used throughout the protocol to denote anindividual that has been contacted in order to participatein the clinical study, either as a recipient of theinvestigational product(s) or as a control.

Treatment: Term used throughout the clinical study to denote a set ofinvestigational product(s) or marketed product(s) orplacebo intended to be administered to a subject,identified by a unique number, according to the studyrandomization or treatment allocation.

Treatment number: A unique number identifying a treatment to a subject,according to the study randomization or treatmentallocation.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 161fb0b009324aa43dbd8458969316ad24d


28 March 2008 18

1. INTRODUCTION

1.1. Background

Hepatitis A and hepatitis B infections represent the most frequent forms of viralinfections of the liver. These diseases cause serious public health problems and affectcommunities worldwide. Hepatitis A infection caused by the hepatitis A virus (HAV), amember of the Heparnavirus genus in the Picornavirus family, is transmitted via thefaecal oral route. HA infection is symptomatic following a short incubation period of 3 to6 weeks [Lemon SM, 1985]. The hepatitis B virus (HBV) is one of a group of closelyrelated viruses called Hepadnaviridae. HBV requires a longer incubation period, from 6weeks to 6 months, and is spread principally by exposure to contaminated blood andbody fluids [Purcell R H, 1994]. Chronic carriers of HBV have an increased risk ofdeveloping cirrhosis or primary hepatocellular carcinoma of the liver.

It has been recognised that vaccination is the only method conferring long-termprotection against HAV and HBV clinical disease and/or infection. GlaxoSmithKlineBiologicals has developed a combined hepatitis A/hepatitis B vaccine Twinrixadministered according to a 3-dose schedule (0, 1, 6 months). Several studies, conductedin mainly young subjects, have shown that the immunogenicity and safety of Twinrix isat least as good as that of the monovalent vaccines Engerix�-B and Havrix� givenconcomitantly.

Please refer to the Master Data Sheets for a review of the pre-clinical and clinical studiesand information on Twinrix� Adult, Havrix� Adult and Engerix-B.

1.2. Rationale for the study

The immune response after vaccination with GSK Biologicals� combined hepatitis A andB vaccine as well as monovalent hepatitis A and B vaccines from different manufacturersis known to be influenced by several factors including age, gender and BMI [Reutter J;1998, White SJ, 1978]. The responses after immunization of elderly individuals withhepatitis A and hepatitis B vaccines is a topic that is becoming increasingly relevant asthe number of aged people travelling to exotic destinations increases.

In this prospective study, subjects aged 41 years or older, with a wide range in bodyweight and variable general health status were enrolled. The influence of risk factorslikely to influence the immune response elicited by Twinrix (e.g. age, gender, bodymass index [BMI], smoking, alcohol consumption, diseases and medications) wereassessed. The non-inferiority of Twinrix to the monovalent vaccines was evaluated interms of anti-HBs seroprotection rate and anti-HAV seropositivity rate at Month 7.Furthermore, the effects of the risk factors on the immune response elicited by theseparately administered monovalent hepatitis A and hepatitis B vaccines Engerix�-Band Havrix� as well as HB VAX PRO and Vaqta were also assessed. Additionally,the current study will provide data concerning the long-term (up to 48 months) anti-HBsseropositivity rates and seroprotection rates and the long-term anti-HAV seropositivityrate in this population.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 162fb0b009324aa43dbd8458969316ad24d


28 March 2008 19

Finally, to evaluate the immune memory to HBV and HAV antigens in this population,all subjects (irrespective of their serological status) will receive a challenge dose of thevaccine that they received in the primary study, approximately 48 months after the firstdose of the primary vaccination course. A blood sample will be taken at Day 0, twoweeks (Day 14) and one month (Day 30) after the administration of the challenge dose toevaluate the anti-HAV and anti-HBs antibody response. At the request of the Czechauthorities the challenge dose study is described in a separate protocol (HAB-168BST:160 [111572]) for the Belgian and Czech centers. The eligibility criteria, study visitprocedures and data collection will be identical in the two studies and the data will becombined with this study for analysis.

2. OBJECTIVES

2.1. Co-Primary objectives

Primary vaccination study:

• To evaluate the influence of age, gender and BMI on the immunogenicity ofTwinrix, in terms of individual anti-HAV titers and individual anti-HBs titers, atMonth 7.

• To demonstrate the non-inferiority of Twinrix to the separately administeredmonovalent vaccines Engerix-B /Havrix or HB VAX PRO /Vaqta in terms ofanti-HAV seropositivity rate and anti-HBs seroprotection rate at Month 7.


• To evaluate the anti-HAV and anti-HBs immune memory (in terms of anti-HAV andanti-HBs immune response elicited by the challenge dose) in a population > 41 yearsof age (healthy and non-healthy), approximately 48 months after the first dose of theprimary vaccination course.

See Section 10.1 for definition of the primary endpoints.


Primary vaccination study and long term follow-up (up to Month 48)

• To evaluate the influence of age, gender and BMI on the immunogenicity of theseparately administered monovalent vaccines Engerix-B /Havrix andHB VAX PRO /Vaqta, in terms of individual anti-HAV and anti-HBs titers atMonth 7.

• To describe the immunogenicity of Twinrix, Engerix-B /Havrix andHB VAX PRO /Vaqta in terms of anti-HAV seropositivity rates and GMTs, andanti-HBs seropositivity rates, seroprotection rates and GMTs at Month 7, by riskfactor (age, gender, BMI, smoking habit, alcohol consumption, diseases andmedications) and overall.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 163fb0b009324aa43dbd8458969316ad24d


28 March 2008 20

• To explore the influence of age, gender and BMI on the immunogenicity ofTwinrix, Engerix-B /Havrix and HB VAX PRO /Vaqta, in terms of anti-HAV seropositivity status and anti-HBs seroprotection status at Month 7.

• To evaluate the long-term persistence elicited by Twinrix, Engerix-B /Havrixand HB VAX PRO /Vaqta, in terms of anti-HAV seropositivity rates and GMTs(at Months 12, 24, 36 and 48), as well as anti-HBs seropositivity rates, seroprotectionrates and GMTs (at Months 12, 24, 36 and 48).

• To evaluate safety throughout the study period: all serious adverse events (SAEs) upto Month 7, as well as SAEs with causal relationship to vaccination or referring tohepatitis A or B infection, after Month 7 and up to the study end (Month 48)

Challenge dose study:



− solicited symptoms occurring during the 4-day (Day 0 to Day 3) follow-upperiod.

− unsolicited symptoms occurring during the 31-day (Day 0 to Day 30) follow-upperiod.

− all serious adverse events (SAE) following the challenge dose administration.See Section 10.2 for definition of the secondary endpoints.

3. STUDY DESIGN OVERVIEW


• Experimental design: open, randomized, multicentre, multicountry study with 3parallel groups.

• Treatment Groups: Twinrix (Month 0, 1, 6); Engerix-B (Month 0, 1, 6) co-administered with Havrix (Month 0, 6); HB VAX PRO (Month 0, 1, 6) co-administered with Vaqta (Month 0, 6).

• Treatment allocation by SBIR: randomized (ratio 1:1:1). Randomization will bestratified at enrolment based on age (41-50 years; 51-60 years versus ≥61 years),gender and BMI (<25 kg/m2 or lean/healthy BMI, ≥25 kg/m2 and <30 kg/m2 oroverweight, versus ≥30 kg/m2 or obese; as defined by the Centres for DiseaseControl and Prevention [CDC] for the adult population). See Section 6.4 for adetailed description of the randomization method.

• Population: a close to �real life� population will be recruited with a broad age range,various body weight and general health status.



CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 164fb0b009324aa43dbd8458969316ad24d


28 March 2008 21

• Duration of the study: approximately 7 months per subject for primary vaccination.Long-term follow-up up to Month 48.

• Recruitment method. See Appendix C for details of the recruitment plan.



• Treatment groups for the challenge dose study will be the same as in the primarystudy: all subjects will receive one dose of Twinrix ; Engerix-B co-administeredwith Havrix or HB VAX PRO co-administered with Vaqta according to theirrandomization in the primary vaccination study.


• Study duration: Approximately one month per subject after he/she receives thechallenge dose.

• The challenge dose study is described in this protocol for the German centers and ina separate protocol (HAB-168 BST:160 [111572]) for the Belgian and Czechcenters. The eligibility criteria, study visit procedures and data collection will beidentical in the two studies and the data will be combined with this study foranalysis.

Visit 10 One

month after Visit 8

Post-challenge BS






Twinrix (N = 200)



Visit 1 Visit 4

Month 7




Screening










CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 165fb0b009324aa43dbd8458969316ad24d


28 March 2008 22

4. STUDY COHORT

4.1. Number of subjects / centres

A total of 600 subjects will be enrolled (200 subjects per group) in order to have 540evaluable subjects (180 subjects per group). See Section 10.3 for a detailed description ofthe criteria used in the estimation of sample size for the primary vaccination study.

Details of recruitment are discussed in the recruitment plan, which is summarized inAppendix C of this document.

Treatment allocation will be performed using a central randomization call-in system onInternet (SBIR) to achieve balanced enrolment by country. Randomization will bestratified at enrolment based on age, gender and BMI (See Section 6.4).

For the challenge dose study

All 590 subjects who have completed the primary vaccination course will be invited toparticipate in the challenge dose study. A total of 219 subjects are expected to berecruited in the German centres (described in this protocol) and 276 subjects are expectedto be recruited in the Belgian and Czech centres (described in a separate protocol with Etrack number 111572).

See Section 10.3 for a detailed description of the criteria used in the estimation of samplesize for the challenge dose study.

4.2. Inclusion criteria

All subjects must satisfy the following criteria at study entry:


• Subjects who the investigator believes that they can and will comply with therequirements of the protocol (e.g., completion of the diary cards, return for follow-upvisits) should be enrolled in the study.

• A male or female aged 41 years or older at the time of the first vaccination.


• Healthy and non-healthy subjects, including those taking medications, as establishedby medical history and clinical examination before entering into the study.

• Seronegative at screening for anti-HBs, anti-HBc, HBs antigen and anti-HAV.

• If the subject is female, she must be of non-childbearing potential, i.e., eithersurgically sterilized or one year post-menopausal; or, if of childbearing potential, shemust be abstinent or have used adequate contraceptive precautions (i.e., intrauterinecontraceptive device; oral/long term hormonal contraceptives; diaphragm or condomin combination with contraceptive jelly, cream or foam) for 30 days prior to

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 166fb0b009324aa43dbd8458969316ad24d


28 March 2008 23

vaccination, have a negative pregnancy test and must agree to continue suchprecautions for two months after completion of the vaccination series.



• A male or female who completed the primary vaccination phase of the study.


• If the subject is female, she must be of non-childbearing potential, i.e., eithersurgically sterilized or one year post-menopausal; or, if of childbearing potential, shemust be abstinent or have used adequate contraceptive precautions (i.e., intrauterinecontraceptive device; oral/long term hormonal contraceptives; diaphragm or condomin combination with contraceptive jelly, cream or foam) for 30 days prior tovaccination, have a negative pregnancy test and must agree to continue suchprecautions for two months after completion of the vaccination series.

4.3. Exclusion criteria for enrolment

The following criteria should be checked at the time of study entry for the primaryvaccination phase and the challenge dose phase of the study. If any apply, the subjectmust not be included in the study:

• Use of any investigational or non-registered product (drug or vaccine) other than thestudy vaccines within 30 days preceding the first dose of study vaccine, or planneduse during the study period.

• History of any hepatitis A or hepatitis B vaccination or infection, since the primaryvaccination study HAB-160.


Acute disease at the time of enrolment. (Acute disease is defined as the presence of amoderate or severe illness with or without fever. All vaccines can be administered topersons with a minor illness such as diarrhoea, mild upper respiratory infection with orwithout low-grade febrile illness, i.e., Oral/ axillary temperature <37.5°C).• Pregnant or lactating female.

• Female planning to become pregnant or planning to discontinue contraceptiveprecautions during the primary vaccination period (up to Month 7, does not apply tothe challenge dose phase).

4.4. Elimination criteria during the study

The following criteria should be checked at each visit subsequent to the first visit. If anybecome applicable during the study, it will not require withdrawal of the subject from the

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 167fb0b009324aa43dbd8458969316ad24d


28 March 2008 24

study but does determine a subject�s evaluability in the according-to-protocol (ATP)analysis. See Section 10.4 for definition of study cohorts to be evaluated.


4.5. Contraindications to subsequent vaccination

The following events constitute absolute contraindications to further administration ofTwinrix, Engerix-B /Havrix, or HB VAX PRO /Vaqta; if any of these eventsoccur during the study, the subject must not receive additional doses of vaccine but maycontinue other study procedures at the discretion of the investigator (see Section 9). Thesubject must be followed until resolution of the event (see Section 8.7):

• Anaphylactic reaction following the administration of vaccines.

• Pregnancy (see Section 8.11).

The following events constitute contraindications to administration of Twinrix, orEngerix-B /Havrix, or HB VAX PRO /Vaqta at that point in time; if any one ofthese events occurs at the time scheduled for vaccination, the subject may be vaccinatedat a later date, within the time window specified in the protocol (see Section 5.4), orwithdrawn at the discretion of the investigator (see Section 9). The subject must befollowed until resolution of the event (see Section 8.7).

Acute disease at the time of vaccination. (Acute disease is defined as the presence of amoderate or severe illness with or without fever. All vaccines can be administered topersons with a minor illness such as diarrhoea, mild upper respiratory infection with orwithout low-grade febrile illness, i.e., Oral/ axillary temperature <37.5°C. at the time ofvaccination.)The above contraindications are also applicable to the challenge dose phase of the study.

4.6. Warning and precautions

Twinrix�

• As with other vaccines, the administration of Twinrix� should be postponed insubjects suffering from acute severe febrile illness.

• It is possible that subjects may be in the incubation period of a hepatitis A orhepatitis B infection at the time of vaccination. It is not known whether Twinrix�will prevent hepatitis A and hepatitis B in such cases.

• The vaccine will not prevent infection caused by other agents such as hepatitis C andhepatitis E and other pathogens known to infect the liver.

• Twinrix� is not recommended for post-exposure prophylaxis (e.g. needle stickinjury).

• The vaccine has not been tested in patients with impaired immunity. Inhaemodialysis patients and persons with an impaired immune system, adequate anti-

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 168fb0b009324aa43dbd8458969316ad24d


28 March 2008 25

HAV and anti-HBs antibody titers may not be obtained after the primaryimmunisation course and such patients may therefore require administration ofadditional doses of vaccine.

• Twinrix� should under no circumstances be administered intravenously.Engerix�-B


• The vaccine will not prevent infection caused by other pathogens known to infect theliver such as hepatitis A, hepatitis C and hepatitis E virus.


• Engerix�-B should not be administered in the buttock or intradermally since thismay result in a lower immune response.

• Engerix�-B should under no circumstances be administered intravascularly.

• As with all injectable vaccines, appropriate medical treatment and supervision shouldalways be readily available in case of rare anaphylactic reactions following theadministration of the vaccine.

• As with any vaccine, a protective immune response may not be elicited in allvaccines.

Havrix�

• It is possible that subjects may be in the incubation period of a hepatitis A infectionat the time of immunisation. It is not known whether Havrix� (1440 ELISA Units)will prevent hepatitis A in such cases.

• In haemodialysis patients and in subjects with an impaired immune system, adequateanti-HAV antibody titres may not be obtained after a single dose of Havrix� (1440ELISA Units) and such patients may therefore require administration of additionaldoses of vaccine.

• As with all injectable vaccines, appropriate medical treatment should always bereadily available for treatment in case of anaphylactic reactions following theadministration of the vaccine. For this reason, the vaccinee should remain undermedical supervision for 30 minutes after immunisation.

• Havrix� (1440 ELISA Units) should be administered with caution to subjects withthrombocytopenia or a bleeding disorder since bleeding may occur following anintramuscular administration to these subjects.


CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 169fb0b009324aa43dbd8458969316ad24d


28 March 2008 26

• Havrix� (1440 ELISA Units) should under no circumstances be administeredintravenously.

HBVAXPRO�


• Because of the long incubation period for hepatitis B, it is possible for unrecognizedinfection to be present at the time HBvaxPRO is given. HBvaxPRO may not preventhepatitis B in such patients.

• Patients who develop symptoms suggestive of hypersensitivity after an injectionshould not receive further injections of HBvaxPRO.

• As with any parenteral vaccine, epinephrine (adrenaline) should be available forimmediate use should an anaphylactoid reaction occur. Any serious active infectionis reason for delaying use of HBvaxPRO, except when, in the opinion of thephysician, withholding the vaccine entails a greater risk.

• Caution and appropriate care should be exercised in administering HBvaxPRO toindividuals with severely compromised cardiopulmonary status or to others in whoma febrile or systemic reaction could pose a significant risk.

Vaqta�

• As with all injectable vaccines, appropriate medical treatment and supervision shouldalways be readily available in case of a rare anaphylactic event following theadministration of the vaccine.

• Testing for antibodies to hepatitis A prior to a decision on immunisation should beperformed in patients born in areas of high endemicity and/or with a history ofjaundice.

• Vaqta� does not cause immediate protection against hepatitis A, and there may be aperiod of 2 to 4 weeks before antibody induction occurs.


• Vaqta� will not prevent hepatitis caused by infectious agents other than hepatitis Avirus.

• In subjects with an impaired immune system, adequate anti-HAV antibody titres maynot be obtained. If the immunosuppression is due to medical treatment, vaccinationshould be delayed if possible until the completion of therapy and immune systemrecovery.


• As with any vaccine, vaccination with Vaqta may not result in a protective responsein all susceptible vaccines.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 170fb0b009324aa43dbd8458969316ad24d


28 March 2008 27

• As no studies have been performed with Vaqta in subjects with liver disease, cautionis advised if administering the vaccine in these subjects.

5. CONDUCT OF STUDY

5.1. Ethics and regulatory considerations

The study will be conducted according to Good Clinical Practice (GCP), the 1996 versionof the Declaration of Helsinki (Protocol Appendix A), and local rules and regulations ofthe country.

5.1.1. Institutional Review Board/Independent Ethics Committee(IRB/IEC)

The IRB/IEC must be constituted according to the local laws/customs of the participatingcountry. The ICH Harmonized Tripartite Guideline for Good Clinical Practicerecommends that the IRB/IEC should include:

a. At least five members.

b. At least one member whose primary area of interest is in a non-scientific area.

c. At least one member who is independent of the institution/ study site.

Only those IRB/IEC members who are independent of the investigator and the sponsor ofthe study should vote/ provide opinion on a study-related matter.

A list of IRB/IEC members and their qualifications should be obtained by theinvestigator.

This protocol and any other documents that the IRB/IEC may need to fulfil itsresponsibilities, including subject recruitment procedures and information aboutpayments and compensation available to subjects will be submitted to the IRB/IEC by theinvestigator. Written unconditional approval of the IRB/IEC must be in the possession ofthe investigator and GSK Biologicals before commencement of the study. This approvalmust refer to the study by exact protocol title and number, and should identify thedocuments reviewed and state the date of review. Relevant GSK Biologicals� data will besupplied by GSK Biologicals� Study Monitor to the hospital/ university/ independentIRB/IEC for review and approval of the protocol. Verification of IRB/IEC unconditionalapproval of the protocol and the written informed consent statement will be transmittedby the investigator to GSK Biologicals� Study Monitor, i.e., Central Study Coordinator(CSC) using the standard notification form, prior to shipment of vaccine supplies andCRFs to the site.

No deviations from, or changes to, the protocol should be initiated without prior writtensponsor and IRB/IEC approval/ favourable opinion of an appropriate amendment, exceptwhen necessary to eliminate immediate hazards to the subjects or when the change(s)involves only logistical or administrative aspects of the study (e.g., change of monitor[s],

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 171fb0b009324aa43dbd8458969316ad24d


28 March 2008 28

telephone number[s].) Modifications are submitted to the IRB/IEC for information only.However, written verification that the modification was submitted should be obtained.Approvals/ verifications must be transmitted in writing to GSK Biologicals� StudyMonitor, by the investigator.

The IRB/IEC must be informed by the investigator of:

• all subsequent protocol amendments, informed consent changes or revisions of otherdocuments originally submitted for review,

• serious and/or unexpected adverse events occurring during the study, where required,

• all subsequent protocol modifications (for information, except for US studies),

• new information that may affect adversely the safety of the subjects or the conduct ofthe study,

• an annual update and/or request for re-approval, where required,

• when the study has been completed, where required.If a trial is prematurely terminated or suspended for reasons including safety or ethicalissues or severe non-compliance, the sponsor will promptly inform the regulatoryauthorities of the termination or suspension and the reason(s) for the termination orsuspension. If required by applicable regulations, the investigator must inform theIEC/IRB promptly and provide the reason for the suspension or termination (seeAppendix B for further details).

5.1.2. Informed consent

In obtaining and documenting informed consent, the investigator should comply with theapplicable regulatory requirement(s), and should adhere to GCP and to the ethicalprinciples that have their origin in the 1996 edition of the Declaration of Helsinki. Priorto the beginning of the trial, the investigator should have the IRB/IEC�s writtenapproval/favourable opinion of the written informed consent form and any other writteninformation to be provided to the subjects.

Information should be given in both oral and written form whenever possible and asdeemed appropriate by the IRB/IEC.

An investigator or designate will describe the protocol to potential subjects face to face.The Subject Information and Consent Form may be read to the subjects, but, in any event,the investigator or designate shall give the subjects ample opportunity to inquire aboutdetails of the study and ask any questions before dating and signing the Consent Form.

Subject information and consent forms must be in a language fully comprehensible to theprospective subjects. Informed consent shall be documented by the use of a writtenconsent form approved by the IRB/IEC and signed and dated by the subjects and by theperson who conducted the informed consent discussion. The signature confirms theconsent is based on information that has been understood. All illiterate individuals willhave the study, the Subject Information and Consent Form explained to them point by

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 172fb0b009324aa43dbd8458969316ad24d


28 March 2008 29

point by the interviewer in the presence of an impartial witness. The witness willpersonally sign and date the consent form. Oral witnessed consent will replace writtenconsent only in countries where the local custom is contrary or if the subject�s incapacityprecludes this and provided that the local legal obligations are fulfilled.

Each subject�s signed informed consent form must be kept on file by the investigator forpossible inspection by Regulatory Authorities and/or GSK Biologicals� professional andRegulatory Compliance persons. The subjects should receive a copy of the signed anddated written informed consent form and any other written information provided to thesubjects, and should receive copies of any signed and dated consent form updates. Anyamendments to the written information will be provided to subjects.

Both the informed consent discussion and the written informed consent form and anyother written information to be provided to the subjects should include explanations ofthe following:

a. That the trial involves research.

b. The purpose of the trial.

c. The trial treatment(s) and the probability for random assignment to each treatment.

d. The trial procedures to be followed, including all invasive procedures.

e. The subject�s responsibilities.

f. Those aspects of the trial that are experimental.

g. The reasonably foreseeable risks or inconveniences to the subjects and, whenapplicable, to an embryo, fetus or nursing infant.

h. The reasonable expected benefits. When there is no intended clinical benefit tosubjects, the subjects should be made aware of this.

i. The alternative procedure(s) or course(s) of treatment/ methods of prevention thatmay be available to subjects, and their important potential benefits and risks.

j. The compensation and/or treatment available to subjects in the event of trial-relatedinjury.

k. The anticipated prorated payment, if any, to subjects for participating in the trial.

l. The anticipated expenses, if any, to subjects for participating in the trial.

m. That the subjects� participation in the trial is voluntary and subjects may refuse toparticipate or withdraw from the trial, at any time, without penalty or loss of benefitsto which subjects are otherwise entitled.

n. That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies)will be granted direct access to the subject�s original medical records for verificationof clinical trial procedures and/or data, without violating the confidentiality ofsubjects, to the extent permitted by the applicable laws and regulations and that, bysigning a written informed consent, the subject is authorizing such access.

o. That records identifying subjects will be kept confidential and, to the extentpermitted by the applicable laws and/or regulations, will not be made publicly

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 173fb0b009324aa43dbd8458969316ad24d


28 March 2008 30

available. If the results of the trial are published, subjects� identity will remainconfidential.

p. That the subjects will be informed in a timely manner if information becomesavailable that may be relevant to the subjects� willingness for continued participationin the trial.

q. The person(s) to contact for further information regarding the trial and the rights oftrial subjects, and who to contact in the event of trial-related injury.

r. The foreseeable circumstances and/or reasons under which a subject�s participationin the trial may be terminated.

s. The expected duration of a subject�s participation in the trial.

t. The approximate number of subjects involved in the trial.

GSK Biologicals will prepare a representative subject information sheet/informedconsent document which will embody all the elements described above. While it isstrongly recommended that this representative document be followed as closely aspossible, the informed consent requirements given in this document are not intended topre-empt any local regulations which require additional information to be disclosed forinformed consent to be legally effective. Clinical judgement, local regulations andrequirements should guide the final structure and content of the document.

The investigator has the final responsibility for the final presentation of the subjectinformation sheet/informed consent document, respecting the mandatory requirements oflocal regulations. The consent form generated by the investigator with the assistance ofthe local sponsor�s representative, must be approved (along with the protocol, and anyother necessary documentation) by the IRB/IEC and be acceptable to GSK Biologicals.

5.2. General study aspects

Not applicable.

5.3. Subject identification

Subject numbers will be assigned sequentially to subjects contacted by studyinvestigators, according to the range of eTrack subject numbers allocated to each studycentre. The subject participating in the challenge dose study will keep the same subjectnumbers as assigned in the primary phase of the study.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 174fb0b009324aa43dbd8458969316ad24d


28 March 2008 31

5.4. Outline of study proceduresTable 1 List of study procedures: Twinrix Group

Age 41 years or older at the time of first dose of vaccinationVisit SCREEN VISIT

1VISIT 2 VISIT 3 VISIT 4 VISIT 5 VISIT 6 VISIT 7 VISIT 8 VISIT 9 VISIT 10

Timing Day� 21 to

0

Day0

Month1

Month6

Month7

Month12

Month24

Month36

Month48

Day 14after

Month48

Day 30after

Month 48

Sampling timepoint Pre-Vacc

Post-vacc 3

Post-vacc 3

Post-vacc 3

Post-vacc 3

Pre-challe

ngedose

Post-challe

ngedose

Post-challenge

dose

Informed consent • •Check inclusion criteria O • •Check exclusioncriteria

O • •

Check eliminationcriteria

O O O O O O O O

Checkcontraindications

O O •

Check warnings andprecautions

•

Physical examination • O OSmoking habitquestionnaire

•

Alcohol consumptionquestionnaire

•

Medical conditionquestionnaire

• *

Recording ofconcomitantmedication by subjectson diary card

• • • • •

Transcription ofconcomitantmedication

• • • •

Return of medicationdiary card

• •

Pre-vaccination bodytemperature

• • • •

Pregnancy test (urinetest)

• • • •

Randomization •Blood samplingfor screening (10 ml) •for Ab determination(5 ml) • • • • • • •

Vaccination Twinrix • • • •Daily post-vaccinationrecording of solicitedsymptoms (Days 0�3)by subjects

•

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 175fb0b009324aa43dbd8458969316ad24d


28 March 2008 32


1VISIT 2 VISIT 3 VISIT 4 VISIT 5 VISIT 6 VISIT 7 VISIT 8 VISIT 9 VISIT 10

Timing Day� 21 to

0

Day0

Month1

Month6

Month7

Month12

Month24

Month36

Month48

Day 14after

Month48

Day 30after

Month 48


Post-vacc 3

Post-vacc 3

Post-vacc 3

Post-vacc 3

Pre-challe

ngedose

Post-challe

ngedose

Post-challenge

dose


•

Transcription of diarycards by investigator

•

Reporting of SAEs • • • • • • § • § • § • •Study Conclusion • #� •

Post-vacc: Post vaccination• Study procedure that requires documentation in the individual CRF or SAE form, O is used to indicate a studyprocedure that does not require documentation in the individual CRF.Screen: screening.*Including medical history, chronic diseases (chronic disease differs from acute disease in that it is treatable yet notcurable).§ only SAEs related to vaccination or SAEs referring to hepatitis A or B infection (See section 8.2)# including verification of medical condition status: the investigator will compare with the subject�s medical condition atthe beginning of the study (Day 0) and evaluate if the medical condition at Month 7 is the same.� The primary analysis will be performed at Month 7; study conclusion for the primary study. Long-term follow-up visitswill be conducted at Months 12, 24, 36 and 48 to assess persistence of immune response.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 176fb0b009324aa43dbd8458969316ad24d


28 March 2008 33



1VISIT 2 VISIT 3 VISIT 4 VISIT 5 VISIT 6 VISIT 7 VISIT 8 VISIT 9 VISIT

10Timing Day

� 21 to0

Day0

Month1

Month6

Month7

Month12

Month24

Month36

Month48

Day 14after

Month48

Day 30after

Month48


Post-vacc 3

Post-vacc 3

Post-vacc 3

Post-vacc 3

Pre-challen

ge

Post-challe

ngedose

Post-challe

ngedose

Informed consent • •Check inclusion criteria O • •Check exclusion criteria O • •Check elimination criteria O O O O O O O OCheck contraindications O O •Check warnings andprecautions

•

Physical examination • OSmoking habitquestionnaire

•


•


• *

Recording of concomitantmedication by subjects ondiary card

• • • • •

Transcription ofconcomitant medication

• • • •

Return of medication diarycard

• •


• • • •

Pregnancy test (urine test) • • • •Randomization •Blood samplingfor screening (10 ml) •for Ab determination (5 ml) • • • • • • •VaccinationEngerix�-BHavrix�

••

• ••

••

Daily post-vaccinationrecording of solicitedsymptoms (Days 0�3) bysubjects

•

Recording of non-seriousadverse events within 30days post-vaccination, byinvestigator

•

Transcription of diary cardsby investigator

•

Reporting of SAEs • • • • • • § • § • § • •

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 177fb0b009324aa43dbd8458969316ad24d


28 March 2008 34



10Timing Day

� 21 to0

Day0

Month1

Month6

Month7

Month12

Month24

Month36

Month48

Day 14after

Month48

Day 30after

Month48


Post-vacc 3

Post-vacc 3

Post-vacc 3

Post-vacc 3

Pre-challen

ge

Post-challe

ngedose

Post-challe

ngedose

Study Conclusion • #� •Post-vacc: Post vaccination•Study procedure that requires documentation in the individual CRF or SAE form, O is used to indicate a studyprocedure that does not require documentation in the individual CRF.Screen: screening.* Including medical history, chronic diseases (chronic disease differs from acute disease in that it is treatable yet notcurable.§ only SAEs related to vaccination or SAEs referring to hepatitis A or B infection (See section 8.2)# including verification of medical condition status: the investigator will compare with the subject�s medical condition atthe beginning of the study (Day 0) and evaluate if the medical condition at Month 7 is the same.� The primary analysis will be performed at Month 7; study conclusion for the primary study. Long-term follow-up visitswill be conducted at Months 12, 24, 36 and 48 to assess persistence of immune response.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 178fb0b009324aa43dbd8458969316ad24d


28 March 2008 35

Table 3 List of study procedures: HB VAX PRO /Vaqta Group



10Timing Day

� 21 to 0Day

0Month

1Month

6Month

7Month

12Month

24Month

36Month

48Day 14after

Month48

Day30

afterMonth

48Sampling timepoint Pre-

VaccPost-

vacc 3Post-

vacc 3Post-

vacc 3Post-

vacc 3Pre-

challenge

dose

Post-challe

ngedose

Post-challe

ngedose

Informed consent • •Check inclusion criteria O • •Check exclusion criteria O • •Check elimination criteria O O O O O O O OCheck contraindications O O •Check warnings andprecautions

•

Physical examination • OSmoking habitquestionnaire

•


•


• *

Recording of concomitantmedication by subjects ondiary card

• • • • •

Transcription ofconcomitant medication

• • • •

Return of medication diarycard

• •


• • • •

Pregnancy test (urine test) • • • •Randomization •Blood samplingfor screening (10 ml) •for Ab determination (5 ml) • • • • • • •VaccinationHB VAX PROVaqta

••

• ••

••

Daily post-vaccinationrecording of solicitedsymptoms (Days 0�3) bysubjects

•

Recording of non-seriousadverse events within 30days post-vaccination, byinvestigator

•

Transcription of diarycards by investigator

•

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 179fb0b009324aa43dbd8458969316ad24d


28 March 2008 36



10Timing Day

� 21 to 0Day

0Month

1Month

6Month

7Month

12Month

24Month

36Month

48Day 14after

Month48

Day30

afterMonth

48Sampling timepoint Pre-

VaccPost-

vacc 3Post-

vacc 3Post-

vacc 3Post-

vacc 3Pre-

challenge

dose

Post-challe

ngedose

Post-challe

ngedose

Reporting of SAEs • • • • • • § • § • § • •Study Conclusion • #� •

Post-vacc: Post vaccination, Add-vacc: challenge dose•Study procedure that requires documentation in the individual CRF or SAE form, O is used to indicate a studyprocedure that does not require documentation in the individual CRF.Screen: screening.* Including medical history, chronic diseases (chronic disease differs from acute disease in that it is treatable yet notcurable.§ only SAEs related to vaccination or SAEs referring to hepatitis A or B infection (See section 8.2)# including verification of medical condition status: the investigator will compare with the subject�s medical condition atthe beginning of the study (Day 0) and evaluate if the medical condition at Month 7 is the same.� The primary analysis will be performed at Month 7; study conclusion for the primary study. Long-term follow-up visitswill be conducted at Months 12, 24, 36 and 48 to assess persistence of immune response.

It is the investigator�s responsibility to ensure that the intervals between visits/contactsare strictly followed. These intervals determine each subject�s evaluability in theaccording-to-protocol analyses (see Sections 4.4 and 10.4 for details of criteria forevaluability and cohorts to be analyzed).

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 180fb0b009324aa43dbd8458969316ad24d


28 March 2008 37

Table 4 Intervals between study visits

Interval Length of interval1 Screening→Visit 1

(Screening � Day 0) 0 to 21 days

2 Visit 1→Visit 2(Day 0 � Month 1) 30 ± 7 days

3 Visit 1→Visit 3(Month 0 � Month 6) 180 ± 14 days

4 Visit 3→Visit 4(Month 6 � Month 7) 30 � 40 days

5 Visit 1→Visit 5(Day 0 � Month 12) 12 ± 1 month

6 Visit 1→Visit 6(Day 0 � Month 24) 24 ± 2 months

7 Visit 1→Visit 7(Day 0 � Month 36) 36 ± 2 months

8 Visit 1→Visit 8(Day 0 � Month 48) 48-60 months

9 Visit 8→Visit 9(Month 48 � Day 14 after challenge

dose)14 ± 2 days

10 Visit 8→Visit 10(Month 48 � Day 30 after challenge

dose )30- 48 days

5.5. Detailed description of study stages/visits

A description of each stage of the study, as summarized in the outline of study procedures(Section 5.4) is given below.

When materials are provided by GSK Biologicals, it is MANDATORY that all clinicalsamples (including serum samples) will be collected and stored using exclusively thosematerials in the appropriate manner. The use of other materials could result in theexclusion of the subject from the ATP analysis (See Section 10.4 for definition of studycohorts to be evaluated). The investigator must ensure that his/her personnel and thelaboratory (ies) under his/her supervision comply with this requirement. However, whenGSK Biologicals does not provide material for collecting and storing clinical samples,then appropriate materials from the investigator�s site are to be used. Refer to AppendixD and Appendix E.

NOTE: With regard to recruitment/enrolment and follow-up, 3 scenarios are possible:

• Subjects will be recruited/enrolled and followed-up by general practitioners (GP�s),who are referred to as investigator throughout the protocol;

• Subjects will be recruited/enrolled by GP�s and followed-up by the principalinvestigator/investigator;

• Subjects will be recruited/enrolled and followed-up by the principal investigator.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 181fb0b009324aa43dbd8458969316ad24d


28 March 2008 38

Screening: Day �21 to Day 0


• Check inclusion/exclusion criteria.

• Collection of blood for serology (maximum 10 ml of whole blood). The sample willbe centrifuged and separated (see Appendix D). Serum samples will be divided intwo duplicates and stored at − 20 °C. Assessments will be performed at a validatedlaboratory using standardized, validated procedures with adequate controls (SeeSection 5.6.2). The other set of serum duplicates will be transferred toGlaxoSmithKline Biologicals.

• Recording of serious adverse events. In order to fulfil international reportingobligations, SAEs that are related to study participation (e.g. blood sampling) or arerelated to a concurrent medication will be collected and recorded from the time thesubject consents to participate in the study until she/he is discharged.

Visit 1: Day 0 (Vaccination 1)

• Check inclusion/exclusion criteria.

• Assessment of physical examination, including recording of weight (kg) andheight (m).

Calculation of BMI, using the following formula:

Weight in KilogramsBMI =

(Height in Meters) x (Height in Meters)

• Smoking habit questionnaire, to be completed by the investigator

• Alcohol consumption questionnaire, to be completed by the investigator

• Medical condition questionnaire, including medical history and chronic diseases, tobe completed by the investigator. Chronic disease differs from acute disease in that itis treatable yet not curable.

• Diary cards will be distributed to the subjects. Subjects will be instructed to recordduring the period starting from Day 0 up to the Month 7 visit, any medication takenwith start and end date, dosage and with the indication.

• Pre-vaccination assessment of body temperature.

• Pregnancy test (urine) if female subject is of childbearing age and if deemednecessary by the investigator.

• Randomization of subjects to one of the 3 vaccine groups by SBIR.

• Vaccination: Intramuscular administration of:

• Twinrix (left deltoid), or

• Engerix-B (left deltoid) and Havrix (right deltoid), or

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 182fb0b009324aa43dbd8458969316ad24d


28 March 2008 39

• HB VAX PRO (left deltoid) and Vaqta (right deltoid)

Please refer to the guidelines set out in Section 6.2.

The vaccinees will be observed closely for at least 30 minutes, with appropriate medicaltreatment readily available in case of a rare anaphylactic reaction following theadministration of vaccines.• The subjects will be instructed to contact the investigator immediately should they

(the subject) manifest any signs or symptoms they perceive as serious.

• Recording of SAEs. In order to fulfil international reporting obligations, SAEs thatare related to study participation (e.g. blood sampling) or are related to a concurrentmedication will be collected and recorded from the time the subject consents toparticipate in the study until she/he is discharged.

Visit 2: Month 1 (Vaccination 2 for Twinrix, Engerix�-B, HB VAX PRO)

• Check elimination criteria

• Check contraindications to vaccination.

• The subject�s records of medication will be verified and transcribed by theinvestigator to update the concomitant medication section in the CRF.




− Twinrix (left deltoid), or

− Engerix-B (left deltoid), or

− HB VAX PRO (left deltoid)


The vaccinees will be observed closely for at least 30 minutes, with appropriate medicaltreatment readily available in case of a rare anaphylactic reaction following theadministration of vaccines.• Recording of SAEs. The investigator will document the reported SAE(s) in the SAE

forms.

Visit 3: Month 6 (Vaccination 2 for Havrix, Vaqta; Vaccination 3 for Twinrix,Engerix�-B, HB VAX PRO)


• Check contraindications to vaccination.



CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 183fb0b009324aa43dbd8458969316ad24d


28 March 2008 40



• Twinrix (left deltoid), or

• Engerix-B (left deltoid) and Havrix (right deltoid), or

• HB VAX PRO (left deltoid) and Vaqta (right deltoid)


The vaccinees will be observed closely for at least 30 minutes, with appropriate medicaltreatment readily available in case of a rare anaphylactic reaction following theadministration of vaccines.• Recording of SAEs. The investigator will document the reported SAE(s) in the SAE

forms.

Visit 4: Month 7 (Post vaccination 3)


• Return of completed diary cards from subjects.


• Collection of blood for serology (maximum of 5 ml of whole blood). The samplewill be centrifuged and separated (see Appendix D).The serum will be stored at − 20 °C until transfer to GlaxoSmithKline Biologicals(See Section 5.6.2).

• Recording of SAEs. The investigator will document the reported SAE(s) in the SAEforms.

• Study conclusion for primary study (Month 7). This includes verification of themedical condition status: the investigator will compare with the subject�s medicalcondition at the beginning of the study (Day 0) and evaluate if the medical conditionat Month 7 is the same.

Primary analysis will be conducted following this fourth study visit, in order to evaluatethe effect of risk factors on the priming immunogenicity of Twinrix� and themonovalent vaccines.

Visits 5, 6, 7: Months 12, 24 and 36 respectively (Long-term follow-up visits)

The investigator will fill out the �long-term follow-up tracking document� aftercontacting vaccinees to document any subject declining to participate in the study and thereason for refusal.• The investigator must ask each subject in a retrospective manner if the subject has

suffered any unreported serious adverse event(s) or hepatitis A or B infection sincethe last study contact.The investigator will then document in the SAE forms:

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 184fb0b009324aa43dbd8458969316ad24d


28 March 2008 41

• The reported SAE(s) that he/she considers to have a causal relationship tovaccination.

• Hepatitis A or B infection, in this study reported as SAE (as defined per protocol).See Section 8.3 Lack of efficacy.

• Check elimination criteria.

• Collection of blood for serology (maximum of 5 ml of whole blood). The samplewill be centrifuged and separated (see Appendix D).The serum will be stored at − 20 °C until transfer to GlaxoSmithKline Biologicals(See Section 5.6.2).

Visit 8: Month 48 (Challenge dose visit)


• Check inclusion/exclusion criteria

• The investigator must ask each subject in a retrospective manner if the subject hassuffered any unreported serious adverse event(s) or hepatitis A or B infection sincethe last study contact.

• The investigator will then document in the SAE forms:

− The reported SAE(s) that he/she considers to have a causal relationship tovaccination.

− Hepatitis A or B infection, in this study reported as SAE (as defined perprotocol). See Section 8.3 Lack of efficacy.

• Collection of blood for serology (maximum of 5 ml of whole blood). The samplewill be centrifuged and separated (see Appendix D). The serum will be stored at −20 °C until transfer to GlaxoSmithKline Biologicals (See Section 5.6.2).

• Check contraindications for the challenge dose (Twinrix�, Engerix�-B/ Havrix�or HBVAXPRO�/ Vaqta�.


• Check warnings and precautions.

• Physical examination



• Challenge dose of the vaccine that the subjects received in the primary study will beadministered to all subjects at Visit 8 (Month 48). Please refer to the guidelines setout in Section 6.2.

• The vaccinees will be observed closely for at least 30 minutes, with appropriatemedical treatment readily available in case of a rare anaphylactic reaction followingthe administration of vaccine.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 185fb0b009324aa43dbd8458969316ad24d


28 March 2008 42

• Diary cards will be provided to the subject to record the following information:

− Any solicited local or general adverse events on the day of vaccination and onthe 3 subsequent days for a total of 4 days of follow-up (Day 0-3).

− Any other (unsolicited) adverse event on the day of vaccination and thesubsequent 30 days (Days 0-30) after vaccination.

• The subject will be instructed to return their completed diary card to the investigatorat the next study visit.

• The subject will be instructed to contact the investigator immediately should thesubject manifest any signs or symptoms they perceive as serious.

• Recording of concomitant medication/vaccination.

• Recording of all SAEs occurring following vaccination. The investigator willdocument the reported SAE(s) in the SAE forms.

Visit 9: Day 14 after the challenge vaccine dose


Visit 10: One month [Day 30] after the challenge vaccine dose



• The subject will return the completed diary card to the investigator from the previousvisit. The investigator will collect and verify them. He/She will transcribe theinformation into the appropriate sections of the CRF, in English. Any unreturneddiary cards will be sought from the subjects through any convenient procedure.


• Recording of any unsolicited adverse events which may have occurred within onemonth (minimum 30 days) following administration of the challenge dose.

• Transcription of concomitant medication/vaccination in the appropriate sections ofthe CRF.

• Recording of SAEs: The investigator will document the reported SAE(s) in the SAEforms.

• Study conclusion.

5.6. Sample handling and analysis

Samples will not be labelled with information that directly identifies the subjects but willbe coded with the identification number for the subject.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 186fb0b009324aa43dbd8458969316ad24d


28 March 2008 43

Collected samples may be used for purposes related to the quality assurance of thelaboratory tests described in this protocol. This may include the management of thequality of these current tests, the maintenance or improvement of these current tests, thedevelopment of new test methods for the markers described in this protocol, as well asmaking sure that new tests are comparable to previous methods and work reliably.

It may be that any findings in the present or in other studies necessitate furtherinvestigation by GSK Biologicals into the efficacy or immunogenicity of the Twinrix,Engerix-B and Havrix vaccines and its constituents under study or further research in thehepatitis A and hepatitis B diseases under study.Under these circumstances, additionaltesting on the samples may be performed by GSK Biologicals outside the scope of thisprotocol.

A GSK Biologicals Research & Development Position Paper is available which describesthe rationale for and some examples of what these further investigations might include.

Any sample testing will be done in line with the consent of the individual subject.

Any human pharmacogenetic testing will require specific consent from the individualsubjects and the ethics committee approval. Any anti-HIV testing will also requirespecific consent and ethics committee approval.

Refer also to protocol Appendix B, where it is noted that the Investigator cannot performany other biological assays except those described in the protocol or its amendment(s).

If additional testing is performed, the marker priority ranking given in Section 5.6.3 maybe changed.

Collected samples will be stored for up to 15 years (counting from when the last subjectperformed the last study visit), unless local rules, regulations or guidelines requiredifferent timeframes or different procedures, which will then be in line with the subjectconsent. These extra requirements need to be communicated formally to and discussedand agreed with GSK Biologicals.

5.6.1. Treatment and storage of biological samples

See Appendix D of the protocol for details of treatment and storage of biologicalsamples.

See Appendix E for instructions for shipment of biological samples.

5.6.2. Laboratory assays

At screening (Day �21 to Day 0) a maximum of 10 ml of whole venous blood will becollected for anti-HAV, anti-HBs and anti-HBc Ab and for HBs antigen measurement.Serum samples will be divided in two duplicates and stored at − 20 °C. Assessments willbe performed at a validated laboratory using standardized, validated procedures with

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 187fb0b009324aa43dbd8458969316ad24d


28 March 2008 44

adequate controls. The other set of serum duplicates will be transferred toGlaxoSmithKline Biologicals.

At Months 7, 12, 24 and 36, a maximum of 5 ml of whole venous blood will be collectedfor anti-HAV and anti-HBs Ab measurement at GlaxoSmithKline Biologicals� laboratoryor in a validated laboratory designated by GlaxoSmithKline Biologicals, usingstandardized, validated procedures with adequate controls (see Table 5).

At the time of vaccination (Month 48), two weeks and one month after the administrationof the challenge dose (Month 49) approximately 5 ml of whole venous blood will becollected for measurement of anti-HAV and anti-HBs antibody titres.


Marker Assaymethod


Assayunit

Assaycut-off

Laboratory

Anti-HAV EIA Enzygnost ® Anti-HAV*/DADE Behring mIU/ml 15 mIU/ml GSK Bio**

Anti-HBs EIA In-house assay mIU/ml 3.3 mIU/ml GSK Bio**

*: Or equivalent.** 0r in a validated laboratory designated by GSK BiologicalsEIA: Enzyme immunoassay.

5.6.3. Serology plan

In case of insufficient blood sample volume to perform assays for all antibodies, thesamples will be analyzed according to the following priority ranking, detailed in Table 6.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 188fb0b009324aa43dbd8458969316ad24d


28 March 2008 45


Blood sampling timepointTiming Day/ Month Visit no. Marker Laboratory

siteNo.


ranking

Pre-vaccination Day �21 toDay 0 Screening

Anti-HBsAnti-HAVAnti-HBcHBs Ag

Investigator* AllAnti-HBs (1)Anti-HAV (2)Anti-HBc (3)HbsAg (4)

Post-vaccination 3 Month 7 4 Anti-HBsAnti-HAV GSK ** All Anti-HBs (1)

Anti-HAV (2)


Anti-HAV (2)


Anti-HAV (2)


Anti-HAV (2)

Pre-challenge dose Month 48 8 Anti-HBsAnti-HAV GSK ** All Anti-HBs (1)

Anti-HAV (2)

Two weeks post-challenge dose

Day 14after Month

489 Anti-HBs

Anti-HAV GSK ** All Anti-HBs (1)Anti-HAV (2)

One month post-challenge dose

Day 30after Month

4810 Anti-HBs


* In a validated laboratory designated by the investigator**GlaxoSmithKline Biologicals� (Belgium) central laboratory, or in a validated laboratory designated by GlaxoSmithKlineBiologicals.

Any additional serology on antigens contained in the study vaccines will be performed ifdeemed necessary by GlaxoSmithKline Biologicals if any findings in the present study orin other studies necessitate investigation of the immunogenicity of the vaccine. In thiscase, the ranking above may also be changed.

6. INVESTIGATIONAL PRODUCTS AND ADMINISTRATION

6.1. Study vaccines

The vaccines Twinrix, Engerix-B and Havrix to be used have been developed andmanufactured by GSK Biologicals. The Quality Control Standards and Requirements forthese vaccines are described in separate release protocols and the required approvals havebeen obtained.

The vaccines HB VAX PRO and Vaqta used in this study have been developed andmanufactured by Aventis Pasteur MSD. Commercial vaccines are assumed to complywith the specifications given in the manufacturer�s Summary of Product Characteristics.

GlaxoSmithKline Biologicals� combined hepatitis A and hepatitis B vaccine TwinrixAdult will be supplied in pre-filled syringes (PFS) containing a dose volume of 1 ml:

Hepatitis A antigen (strain HM 175 RIT 4380): at least 720 ELISA unitsHbsAg (Recombinant antigen): 20 µg

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 189fb0b009324aa43dbd8458969316ad24d


28 March 2008 46

Aluminium (as salt): 0.45 mgThiomersal: <2 µg2-phenoxyethanol: 5 mg

GlaxoSmithKline Biologicals� recombinant hepatitis B vaccine, Engerix-B will besupplied in PFS containing per 1.0 ml dose:

HbsAg (Recombinant antigen): 20 µgAluminium (as salt): 0.5 mgThiomersal: <2 µg

GlaxoSmithKline Biologicals� inactivated hepatitis A vaccine, Havrix will be suppliedin PFS containing per 1.0 ml dose:

Hepatitis A antigen (strain HM 175): at least 1440 ELISA UnitsAluminium (as salt): 0.5 mg2-phenoxyethanol: 5 mg

Aventis Pasteur MSD�s recombinant hepatitis B vaccine, HB VAX PRO will besupplied as 1.0 ml dose:

Hepatitis B (recombinant HbsAg): 10 µgAluminium (as Al (OH) 3): 0.5 mg

Aventis Pasteur MSD�s inactivated hepatitis A vaccine, Vaqta will be as1.0 ml dose:

Hepatitis A antigen (CR 326F strain): 50 IUAluminium (as Al (OH) 3): 0.45 mg

All subjects will receive a challenge dose of the same vaccine that they received in theprimary study. The composition of the challenge dose will be same as the composition ofthe vaccines administered in the primary study.

Refer to Appendix G for details of vaccine supplies.

6.2. Dosage and administration

All subjects will receive the study vaccines according to their random assignment atDay 0. The vaccines will be administered intramuscularly in the deltoid region.

Subjects included in the Twinrix Group will receive Twinrix at Day 0, Month 1 andMonth 6 as an intramuscular injection in the left deltoid region, using a 23 G, 25 mmneedle.

Subjects included in the Engerix-B + Havrix Group will receive concomitantlyHavrix (right deltoid region) and Engerix-B (left deltoid region) at Day 0 andMonth 6 and a dose of Engerix-B (left deltoid region) at Month 1, using a 23 G, 25 mmneedle.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 190fb0b009324aa43dbd8458969316ad24d


28 March 2008 47

Subjects included in the HB VAX PRO + Vaqta Group will receive concomitantlyVaqta (right deltoid region), and HB VAX PRO (left deltoid region) at Day 0 andMonth 6 and a dose of HB VAX PRO (left deltoid region) at Month 1, administeredaccording to the manufacturer�s recommendations.



Group Visit Month Vaccination Dose Route Site Side1 0 Twinrix 1st IM D L2 1 Twinrix 2nd IM D LTwinrix3 6 Twinrix 3rd IM D L

Engerix-B 1st IM D L1 0Havrix 1st IM D R

2 1 Engerix-B 2nd IM D LEngerix-B 3rd IM D L

Engerix-B+Havrix 3 6

Havrix 2nd IM D RHB VAX PRO 1st IM D L1 0

Vaqta 1st IM D R2 1 HB VAX PRO 2nd IM D L

HB VAX PRO 3rd IM D L

HB VAX PRO+Vaqta 3 6

Vaqta 2nd IM D RIM: Intramuscular; D: Deltoid; L: left; R: Right

Challenge vaccine and dosage:

All subjects (irrespective of their serological status) will be given a challenge dose of thesame vaccine that they received in the primary study at the Month 48 time point.The vaccines will be administered as an intramuscular injection in the deltoid regionusing a 23G, 25 mm needle. The side of injection is as given in Table 7.

The vaccinees will be observed closely for at least 30 minutes following theadministration of vaccines, with appropriate medical treatment readily available in caseof a rare anaphylactic reaction.

6.3. Storage

All vaccines must be stored in a safe and locked place with no access for unauthorizedpersonnel. They must be kept in the refrigerator (+2°C to +8°C/ 36°F to 46°F) and mustnot be frozen. Storage temperature should be monitored and documented at least once perday. It is advisable to have a back-up refrigerator/ freezer in case of power failure/breakdown. Procedures must be in place to ensure that the vaccine is kept at the indicatedtemperature range at all times.

The study monitor must be contacted if the cold chain is broken (e.g. vaccines becomefrozen or refrigeration fails).

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 191fb0b009324aa43dbd8458969316ad24d


28 March 2008 48

Storage conditions for transport of vaccines from country medical department or dispatchcentre to study sites or between sites are described in Appendix G.

6.4. Treatment allocation and randomization

The treatment allocation at the investigator site will be performed using a centralrandomization call-in system on Internet (SBIR). The randomization algorithm will use aminimization procedure [White SJ, 1978] accounting for age, gender and BMI.

The person in charge of the vaccination will access the randomization system on Internet.Upon providing a subject number, the age, gender and BMI of the subject, therandomization system will use the minimization algorithm to determine the treatmentnumber to be used for the subject.

Note that as soon as the target number of subjects in a specific age group, gender group,or BMI group has been reached, the enrolment will be frozen for this group. Additionally,stratification will be blocked per country.

The target sample size is 600 subjects enrolled to reach 540 subjects evaluable for theATP analysis of immunogenicity. The enrolment will be performed to ensure thedistribution of the population for each country as detailed in Table 8.

Table 8 Stratification by each country per age, gender and BMI

Stratum Distribution41-50 years 33%51-60 years 33%Age≥61 years 33%

male 50%Gender female 50 %<25 kg/m2 (lean/healthy) 33%

≥25 and <30 kg/m2 (overweight) 33%BMI*≥30 kg/m2 (obese) 33%

* BMI strata as defined by the CDC for the adult population.

To allow GlaxoSmithKline to take advantage of greater rates of recruitment thananticipated at individual centres in this multicentre study, and thus to reduce the overallstudy recruitment period, each centre will receive enough vaccines to allow an over-enrolment of 5% of the target number of subjects. The vaccine doses will be distributedto the study centres while respecting the randomization block.

Challenge vaccine and dosage:

The vaccines will be numbered sequentially per group. The site has to take the lowesttreatment number available in the fridge of the vaccine group that the subject received inthe primary study. Subjects will be administered the vaccine dose with the lowesttreatment number still available at the study centre. The treatment number must berecorded by the investigator in the eCRF (treatment allocation).

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 192fb0b009324aa43dbd8458969316ad24d


28 March 2008 49

6.5. Method of blinding and breaking the study blind

Due to difference in administration of study vaccines in the 3 groups this will be an openstudy.

6.6. Replacement of unusable vaccine doses

Additional vaccine doses will be provided to replace those that are unusable (seeAppendix G for details of supplies).

In addition to the vaccine doses provided for the planned number of subjects, 5%additional doses will be supplied. In case a vaccine dose is broken or unusable, theinvestigator should replace it with a replacement vaccine dose. Although the sponsorneed not be notified immediately in these cases, documentation of the use of thereplacement vaccine must be recorded by the investigator on the vaccine administrationpage of the CRF and on the vaccine accountability form.


In case a vaccine dose is broken or unusable, the next lowest treatment number availablecan replace the unusable vaccine. Although the sponsor need not be notified immediatelyin these cases (except in the case of cold-chain failure), documentation of the replacementvaccine must be recorded by the investigator on the vaccine accountability form and inthe eCRF.

6.7. Packaging

See Appendix D.

6.8. Vaccine accountability

See Appendix E.

6.9. Concomitant medication/treatment

At each study visit/contact, the investigator should question the subject about anymedication(s) taken.

All concomitant medication, with the exception of vitamins and/or dietary supplements,administered at ANY time during the period starting 7 days before the administration ofthe first vaccine dose and ending at the Month 7 visit, i.e. one month (minimum 30 days)after the last vaccine dose, is to be recorded by the subject.

For the challenge dose of the study, all concomitant medication, with the exception ofvitamins and/ or dietary supplements, administered at any time during the period starting7 days before the administration of the challenge dose and ending at the Month 49 visit,i.e one month (minimum 30 days) after the challenge dose is to be recorded by the

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 193fb0b009324aa43dbd8458969316ad24d


28 March 2008 50

subject. The investigator will verify and complete the subject�s records. The genericname of the medication (trade names are allowed for combination drugs, i.e., multi-component drugs), medical indication, total daily dose, route of administration, start andend dates of treatment, will be transcribed into the medication pages of the CRF for anymedication reported by the subject.

Any vaccine not foreseen in the study protocol administered in the period beginning 30days preceding the first dose and ending at Month 7, i.e. one month (minimum 30 days)after the last vaccine dose, is to be recorded with trade name, route of administration anddate(s) of administration. See Sections 4.3 and 4.4.

Any concomitant medication administered prophylactically in anticipation of reaction tothe vaccination must be recorded in the CRF with generic name of the medication (tradenames are allowed for combination drugs only), total daily dose, route of administration,start and end dates of treatment and coded as �Prophylactic�.

Concomitant medication administered for the treatment of an SAE must be recorded inthe CRF with generic name of the medication (trade names are allowed for combinationdrugs only), medical indication (including which SAE), total daily dose, route ofadministration, start and end dates of treatment. Refer to Section 8.2 for definition ofSAE.

7. HEALTH ECONOMICS

Not applicable.

8. MEDICAL CONDITION AND (SERIOUS) ADVERSEEVENTS

The investigator is responsible for the detection and documentation of medical history,including any chronic disease present in a subject prior to the first study procedure.Medical treatment of any acute or chronic disease (including SAE) and the decision onfurther participation of the subject in the study remains the responsibility of the subject�shabitual treating physician and will be performed according to Good Medical Practicesand local recommendations. Vaccination with registered products, not specified in theprotocol, is allowed.

During the study, the investigator or site staff will be responsible for the detection anddocumentation of events meeting the criteria and definition of an adverse event and aserious adverse event (SAE), as detailed in this section of the protocol.

Each subject will be instructed to contact the investigator immediately should the subjectmanifest any signs or symptoms they perceive as serious.

One month (minimum 30 days) after the challenge dose (Month 49), reports of adverseevents and serious adverse events will be collected.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 194fb0b009324aa43dbd8458969316ad24d


28 March 2008 51

8.1. Definition of chronic disease and adverse events

Pre-existing conditions or signs and/or symptoms present in a subject prior to the start ofthe study (i.e. prior to the first study procedure) should be recorded in the chronicdiseases questionnaire section of the subject�s CRF.

Definition of chronic disease

Chronic disease differs from acute disease in that it is treatable yet not curable.

Definition of an adverse event

An AE is any untoward medical occurrence in a clinical investigation subject, temporallyassociated with the use of a medicinal product, whether or not considered related to themedicinal product.

An AE can therefore be any unfavourable and unintended sign (including an abnormallaboratory finding), symptom, or disease (new or exacerbated) temporally associated withthe use of a medicinal product. For marketed medicinal products, this also includesfailure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.


• Significant or unexpected worsening or exacerbation of the condition/indicationunder study. See Section 8.3 �Lack of Efficacy� for additional information.

• Exacerbation of a chronic or intermittent pre-existing condition including either anincrease in frequency and/or intensity of the condition.

• New conditions detected or diagnosed after investigational product administrationeven though it may have been present prior to the start of the study.


• Signs, symptoms, or the clinical sequelae of a suspected overdose of eitherinvestigational product or a concurrent medication (overdose per se should not bereported as an AE/SAE).

• Significant failure of expected pharmacological or biological action. See Section 8.3,�Lack of Efficacy� for additional information.

• Signs, symptoms temporally associated with vaccine administration.Examples of an AE DO NOT include:

• Medical or surgical procedure (e.g. endoscopy, appendectomy); the condition thatleads to the procedure are an AE.


• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) presentor detected at the start of the study that do not worsen.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 195fb0b009324aa43dbd8458969316ad24d


28 March 2008 52

• The disease/disorder being studied or expected progression, signs, or symptoms ofthe disease/disorder being studied, unless more severe than expected for the subject�scondition.

Aes may include pre- or post-treatment events that occur as a result of protocol-mandatedprocedures (i.e. invasive procedures, modification of subject�s previous therapeuticregimen).

N.B. Aes to be recorded as endpoints (solicited events) are described in Section 8.5.1. Allother Aes will be recorded as UNSOLICITED AES.

Example of events to be recorded in the medical history section of the CRF:

Pre-existing conditions or signs and/or symptoms present in a subject prior to the start ofthe study (i.e. prior to the first study vaccination).

8.2. Definition of a serious adverse event

A serious adverse event (SAE) is any untoward medical occurrence that:

a. results in death,

b. is life-threatening,

NOTE: The term �life-threatening� in the definition of �serious� refers to an event inwhich the subject was at risk of death at the time of the event. It does not refer to anevent, which hypothetically might have caused death, if it were more severe.

c. requires hospitalization or prolongation of existing hospitalization,

NOTE: In general, hospitalization signifies that the subject has been detained (usuallyinvolving at least an overnight stay) at the hospital or emergency ward for observationand/or treatment that would not have been appropriate in the physician�s office or out-patient setting. Complications that occur during hospitalization are no SAEs. If acomplication prolongs hospitalization or fulfils any other serious criteria, the event isserious. When in doubt as to whether �hospitalization� occurred or was necessary, theevent should be considered serious.

d. results in disability/incapacity,

NOTE: The term disability means a substantial disruption of a person�s ability to conductnormal life functions. This definition is not intended to include experiences of relativelyminor medical significance such as uncomplicated headache, nausea, vomiting,diarrhoea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere orprevent everyday life functions but do not constitute a substantial disruption.

e. is a congenital anomaly/birth defect in the offspring of a study subject,

f. medical or scientific judgement should be exercised in deciding whether reporting isappropriate in other situations, such as important medical events that may not beimmediately life-threatening or result in death or hospitalization but may jeopardizethe subject or may require medical or surgical intervention to prevent one of the

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 196fb0b009324aa43dbd8458969316ad24d


28 March 2008 53

other outcomes listed in the above definition. These should also be consideredserious. Examples of such events are invasive or malignant cancers, intensivetreatment in an emergency room or at home for allergic bronchospasm, blooddyscrasias or convulsions that do not result in hospitalization.

g. any signs of suspected or confirmed hepatitis A or hepatitis B. See Section 8.3 Lackof efficacy.

8.3. Lack of efficacy

The signs and symptoms, clinical sequelae resulting from lack of clinical efficacy or bothwill be reported. During the study period (Month 0 � Month 49), any signs of suspectedor confirmed hepatitis A or hepatitis B should be reported as an SAE.

8.4. Clinical laboratory parameters and other abnormalassessments qualifying as serious adverse events

Abnormal laboratory findings (e.g., clinical chemistry, haematology, urinalysis) or otherabnormal assessments (e.g., ECGs, X-rays, vital signs, etc.) that are judged by theinvestigator to be clinically significant will be recorded as SAEs if they meet thedefinition of an SAE, as defined in Section 8.2. Clinically significant abnormal laboratoryfindings or other abnormal assessments that are detected during the study or are present atbaseline and significantly worsen following the start of the study will be reported asSAEs, if they meet the definition of an SAE.

The investigator will exercise his or her medical and scientific judgement in decidingwhether an abnormal laboratory finding or other abnormal assessment is clinicallysignificant.

8.5. Time period, frequency, and method of detecting adverseevents and serious adverse events

All Aes occurring within one month (minimum 30 days) following administration of thechallenge dose must be recorded on the Adverse Event form in the subject�s CRF,irrespective of intensity or whether or not they are considered vaccination-related.

For the primary vaccination study, the standard time period for collecting and recordingSAEs will begin at randomization or the first receipt of vaccine and will end 30 daysfollowing administration of the last dose of study vaccine for each subject.

Additionally, at each follow-up visit (Months 12, 24, 36 and 48) the investigator willdocument in the SAE form any SAE, which the subject may have experienced since thelast study visit:

• that the investigator considers related to vaccination,

• that refers to hepatitis A or B infection (reported as SAE as defined per protocol).See Section 8.3 Lack of efficacy.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 197fb0b009324aa43dbd8458969316ad24d


28 March 2008 54

For the challenge dose study, the time period for collecting and recording SAEs willbegin at the receipt of vaccine and will end 30 days after vaccination.

See Section 8.8 for instructions for reporting and recording SAEs.

Additionally, in order to fulfill international reporting obligations, SAEs that are relatedto study participation (e.g. procedures, invasive tests, a change from existing therapy) orare related to a concurrent medication will be collected and recorded from the time thesubject consents to participate in the study until she/he is discharged.

• The investigator will inquire about the occurrence of SAEs at every visit/contactduring the study and throughout the follow-up phase as appropriate.

An overview of protocol- required reporting periods for adverse events and seriousadverse events after the administration of the challenge dose is given in Table 9.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 198fb0b009324aa43dbd8458969316ad24d


28 March 2008 55

Table 9 Reporting periods for adverse events and serious adverse events

Study activity Pre-vacc.(Consentobtained)

Challenge dose 30 dayspost-challenge dose.

Month 48 Month 49Reporting of Aes

Reporting of SAEs

Pre-vacc.: pre-vaccination

All Aes either observed by the investigator or one of his clinical collaborators or reportedby the subject spontaneously or in response to a direct question will be evaluated by theinvestigator. Aes not previously documented in the study will be recorded in the AdverseEvent form within the subject�s CRF. The nature of each event, date and time (whereappropriate) of onset, outcome, intensity and relationship to vaccination should beestablished. Details of any corrective treatment should be recorded on the appropriatepage of the CRF. Refer to Section 6.9.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 199fb0b009324aa43dbd8458969316ad24d


28 March 2008 56

As a consistent method of soliciting Aes, the subject should be asked a non-leadingquestion such as:

�Have you felt different in any way since receiving the vaccine or since the previousvisit?�

N.B. The investigator should record only those Aes having occurred within the timeframe defined above.

When an AE/SAE occurs, it is the responsibility of the investigator to review alldocumentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relativeto the event. The investigator will then record all relevant information regarding anAE/SAE on the CRF or SAE Report Form as applicable. It is not acceptable for theinvestigator to send photocopies of the subject�s medical records to GSK Biologicals inlieu of the appropriate completed AE/SAE pages/SAE screens in the CRF. However,there may be instances when copies of medical records for certain cases are requested byGSK Biologicals. In this instance, all subject identifiers will be blinded on the copies ofthe medical records prior to submission to GSK Biologicals.

The investigator will attempt to establish a diagnosis of the event based on signs,symptoms, and/or other clinical information. In such cases, the diagnosis should bedocumented as the AE/SAE and not the individual signs/symptoms.

8.5.1. Solicited adverse events

A 4-day (Day 0 to 3) follow-up of solicited local adverse events at the injection site andsolicited general adverse events will be performed after vaccination. Data concerning thefollowing adverse events will be solicited using diary cards provided by the sponsor. SeeTable 10 and Table 11 for details of the local and general adverse events that aresolicited.

Solicited local (injection site) Aes



Solicited general Aes



Headache�Gastrointestinal symptoms include nausea, vomiting, diarrhoea and/or abdominal pain.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 200fb0b009324aa43dbd8458969316ad24d


28 March 2008 57

N.B. Temperature will be recorded in the evening. Should additional temperaturemeasurements be performed at other times of day, the highest temperature will berecorded.

8.6. Evaluating adverse events and serious adverse events

8.6.1. Assessment of intensity

Intensity of the following Aes will be assessed as described:

Table 12 Intensity scales for solicited symptoms in adults

Adverse Event Intensitygrade

Parameter

Pain at injection site 0 Absent1 Painful on touch2 Painful when limb is moved3 Pain that prevents normal activity

Redness at injection site Record greatest surface diameter in mmSwelling at injection site Record greatest surface diameter in mmFever* Record temperature in °C / °FHeadache 0 Absent

1 Headache that is easily tolerated2 Headache that interferes with normal activity3 Headache that prevents normal activity

Fatigue 0 Absent1 Fatigue that is easily tolerated2 Fatigue that interferes with normal activity3 Fatigue that prevents normal activity

Gastrointestinal symptoms 0 Gastrointestinal symptoms absent(nausea, vomiting, diarrhoea 1 Gastrointestinal symptoms that are easily toleratedand/or abdominal pain) 2 Gastrointestinal symptoms that interfere with normal activity

3 Gastrointestinal symptoms that prevent normal activity*Fever is defined as axillary temperature ≥37.5°C / oral temperature ≥ 37.5°C

The maximum intensity of local injection site redness/swelling will be scored at GSKBiologicals as follows:


The intensity of fever will be scored at GSK Biologicals in 0.5°C increments. Oral/axillary temperature > 39.5°C will be scored as fever of grade 3 intensity.

The investigator will make an assessment of intensity for all SAEs reported during thestudy. The assessment will be based on the investigator�s clinical judgement. The

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 201fb0b009324aa43dbd8458969316ad24d


28 March 2008 58

intensity of each SAE, recorded in the SAE Report Form, should be assigned to one ofthe following categories:

1 (mild) = An event which is easily tolerated by the subject, causingminimal discomfort and not interfering with everydayactivities.

2 (moderate) = An event which is sufficiently discomforting to interferewith normal everyday activities.

3 (severe) = An event which prevents normal, everyday activities. (Inadults such an event would, for example, prevent attendanceat work/ school and would necessitate the administration ofcorrective therapy.)

An event that is assessed as Grade 3 (severe) should not be confused with aSAE. Grade 3 is a category utilized for rating the intensity of an event; and bothnon-serious events and SAEs can be assessed as Grade 3. An event is defined as�serious� when it meets one of the pre-defined outcomes as described in Section8.2.

8.6.2. Assessment of causality

The investigator is obligated to assess the relationship between investigational productand the occurrence of each AE/ SAE. The investigator will use clinical judgement todetermine the relationship. Alternative causes, such as natural history of the underlyingdiseases, concomitant therapy, other risk factors and the temporal relationship of theevent to the investigational product will be considered and investigated. The investigatorwill also consult the Investigator Brochure and/or Product Information, for marketedproducts, in the determination of his/her assessment.

There may be situations when a SAE has occurred and the investigator has minimalinformation to include in the initial report to GSK Biologicals. However, it is veryimportant that the investigator always makes an assessment of causality for every eventprior to transmission of the SAE Report Form to GSK Biologicals. The investigator maychange his/her opinion of causality in light of follow-up information, amending the SAEReport Form accordingly. The causality assessment is one of the criteria used whendetermining regulatory reporting requirements.

In case of concomitant administration of multiple vaccines, it may not be possible todetermine the causal relationship of general symptoms to the individual vaccinesadministered. The investigator should, therefore, assess whether the symptom could becausally related to vaccination rather than to the individual vaccines.

Causality of all AE/ SAEs should be assessed by the investigator using the followingquestion:

In your opinion, did the vaccine(s) possibly contribute to the event?

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 202fb0b009324aa43dbd8458969316ad24d


28 March 2008 59

NO : The AE/ SAE is not causally related to administration of the studyvaccine(s). There are other, more likely causes and administrationof the study vaccine(s) is not suspected to have contributed to theSAE.

YES : There is a reasonable possibility that the vaccine contributed to theAE/ SAE.

If an event meets the criteria to be determined �serious� (see Section 8.2 for definition ofserious adverse event), it will be examined by the investigator to the extent to be able todetermine ALL contributing factors applicable to each serious adverse event.

Other possible contributors include:

• Medical history




• Lack of efficacy of the vaccine, if applicable


• Other cause (specify)

8.7. Follow-up of chronic diseases and serious adverse events,and assessment of outcome

8.7.1. Chronic diseases

At Month 7, the investigator will compare with the subject�s medical condition at thebeginning of the study (Day 0) and evaluate if the medical condition at Month 7 is thesame.

8.7.2. Serious adverse events

After the initial SAE report, the investigator is required to proactively follow each subjectand provide further information to GSK Biologicals on the subject�s condition.

All SAEs documented at a previous visit/contact and designated as not recovered/notresolved or recovering/resolving will be reviewed at subsequent visits/contacts.

For the primary study (up to Month 7) and the challenge dose study (up to Month 49).

Investigators will follow-up subjects:

• with SAE, until the event has resolved, subsided, stabilized, disappeared, the event isotherwise explained, or the subject is lost to follow-up;

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 203fb0b009324aa43dbd8458969316ad24d


28 March 2008 60

For the long-term follow-up visits (Month 12 to Month 48)


• with SAEs considered related to vaccination or with confirmed or suspected hepatitisA or B infection (in this study reported as SAE, as defined per protocol), until theevent has resolved, subsided, stabilized, disappeared, the event is otherwiseexplained, or the subject is lost to follow-up;

Clinically significant laboratory abnormalities, related to SAE(s), will be followed upuntil they have returned to normal, or a satisfactory explanation has been provided.Reports relative to the subsequent course of such an abnormality noted for any subjectmust be submitted to the Study Monitor.

GSK Biologicals may request that the investigator perform or arrange for the conduct ofsupplemental measurements and/or evaluations to elucidate as fully as possible the natureand/or causality of the SAE. The investigator is obliged to assist. If a subject dies duringparticipation in the study or during a recognized follow-up period, GSK Biologicals willbe provided with a copy of any available post-mortem findings, including histopathology.

New or updated information will be recorded on the originally completed SAE ReportForm, with all changes signed and dated by the investigator. The updated SAE reportform should be resent to GSK Biologicals within 24 hours of receipt of the follow-upinformation as outlined in Section 8.8.1.

Outcome of any SAE reported during the entire study will be assessed as:





CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 204fb0b009324aa43dbd8458969316ad24d


28 March 2008 61

8.8. Prompt reporting of serious adverse events to GSKBiologicals

8.8.1. Time frames for submitting serious adverse event reports to GSKBiologicals

SAEs will be reported promptly to GSK Biologicals once the investigator determines thatthe event meets the protocol definition of an SAE. The investigator or designate will faxthe SAE reports to GSK Biologicals� Study Contact for Serious Adverse Event Reportingwithin 24 hours of his/her becoming aware of these events. Additional or follow-upinformation relating to the initial SAE report is also to be reported to the GSKBiologicals� Study Contact for Serious Adverse Event Reporting within 24 hours ofreceipt of such information.

8.8.2. Completion and transmission of serious adverse event reports toGSK Biologicals

For the primary study (up to Month 7) and the challenge dose study (up to Month49).

Once an investigator becomes aware that a SAE has occurred in a study subject, she/hewill report the information to GSK Biologicals within 24 hours as outlined in Section8.8.1.

For the long-term follow-up visits (Month 12 to Month 48)

Once an investigator becomes aware that a SAE, considered related to vaccination or anSAE referring to confirmed or suspected hepatitis A or B infection (in this study reportedas SAE, as defined per protocol), has occurred in a study subject, she/he will report theinformation to GSK Biologicals within 24 hours as outlined in Section 8.8.1.

The SAE Report Form will always be completed as thoroughly as possible with allavailable details of the event, signed by the investigator (or designee), and forwarded toGSK Biologicals within the designated time frames. If the investigator does not have allinformation regarding an SAE, he/she will not wait to receive additional informationbefore notifying GSK Biologicals of the event and completing the form. The form will beupdated when additional information is received and forwarded to GSK Biologicalswithin 24 hours as outlined in Section 8.8.1.

The investigator will always provide an assessment of causality at the time of the initialreport as described in Section 8.6.2.

Facsimile (Fax) transmission of the SAE Report Form is the preferred method to transmitthis information to the Study Contact for Reporting SAEs. In rare circumstances and inthe absence of facsimile equipment, notification by telephone is acceptable, with a copyof the SAE Report Form sent by overnight mail. Initial notification via the telephone doesnot replace the need for the investigator to complete and sign the SAE Report Formwithin 24 hours as outlined in Section 8.8.1.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 205fb0b009324aa43dbd8458969316ad24d


28 March 2008 62

In the event of a death determined by the investigator to be related to vaccination,sending of the fax must be accompanied by telephone call to the Study Contact forReporting SAEs.

Study Contact for Reporting SAEs

Germany:

Sächsisches Serumwerk GmbHZirkusstr. 4001069 Dresden, GermanyTel: Fax:

Back-up Study Contact for Reporting SAEsGSK Biologicals Clinical Safety PhysicianTel: Fax: or Mobile phones for 7/7 day availability:

(Head Safety Evaluation and Risk ManagementAdult/Adolescent/Emerging Diseases)Back-up mobile phone contact:

8.9. Regulatory reporting requirements for serious adverseevents

The investigator will promptly report all SAEs to GSK Biologicals in accordance withthe procedures detailed in Section 8.8. GSK Biologicals has a legal responsibility topromptly notify, as appropriate, both the local regulatory authority and other regulatoryagencies about the safety of a product under clinical investigation. Prompt notification ofSAEs by the investigator to the Study Contact for Reporting SAEs is essential so thatlegal obligations and ethical responsibilities towards the safety of other subjects are met.

The investigator, or responsible person according to local requirements, will comply withthe applicable local regulatory requirements related to the reporting of SAEs to regulatoryauthorities and the IRB/IEC.

Expedited Investigator Safety Reports (EISR) are prepared according to GSK Biologicalspolicy and are forwarded to investigators as necessary. An EISR is prepared for a SAEthat is both attributable to the investigational product and unexpected and is a significantnew emerging safety issue. The purpose of the EISR is to fulfill specific regulatory andGood Clinical Practice (GCP) requirements, regarding the product under investigation.

An investigator who receives an EISR describing a SAE or other specific safetyinformation from GSK Biologicals will file it and will notify the IRB/IEC, if appropriateaccording to local requirements.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 206fb0b009324aa43dbd8458969316ad24d


28 March 2008 63

8.10. Post study serious adverse events

A post-study SAE is defined as any event that occurs outside of the SAE detection perioddefined in Section 8.5. Investigators are not obligated to actively seek SAEs in formerstudy participants.

However, if the investigator learns of any SAE, including a death, at any time after asubject has been discharged from the study, and he/she considers the event reasonablyrelated to the investigational product, the investigator will promptly notify the StudyContact for Reporting SAEs.

8.11. Pregnancy

For the primary study and the challenge dose phase of the study:

Subjects who become pregnant during the study (up to and including one month[minimum 30 days] after receiving the study vaccine dose) must not receive additionaldoses of study vaccine but may continue other study procedures at the discretion of theinvestigator.

The investigator, or his/her designee, will collect pregnancy information on any subjectwho becomes pregnant while participating in this study. The investigator, or his/herdesignee, will record pregnancy information on the Pregnancy Report Form and submit itto GSK Biologicals within 24 hours of learning of a subject�s pregnancy. The subject willbe followed to determine the outcome of the pregnancy. At the end of the pregnancy,whether that be full-term or prematurely, information on the status of the mother andchild will be forwarded to GSK Biologicals. Generally, follow-up will be no longer thansix to eight weeks following the estimated delivery date.

While pregnancy itself is not considered an SAE, any pregnancy complication or electivetermination of a pregnancy for medical reasons will be recorded as a SAE, as described inSection 8.2, if the criteria are met, and will be followed as described in Section 8.7.

A spontaneous abortion is always considered to be a SAE and will be reported asdescribed in Section 8.8. Furthermore, any SAE occurring as a result of a post-studypregnancy and considered reasonably related in time to receipt of the investigationalproduct by the investigator, will be reported to GSK Biologicals as described in Section8.10. While the investigator is not obligated to actively seek this information from formerstudy participants, he/she may learn of a pregnancy through spontaneous reporting.

Information on pregnancies identified during the screening phase/prior to vaccineadministration does not need to be collected; this information need not be communicatedto safety.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 207fb0b009324aa43dbd8458969316ad24d


28 March 2008 64

9. SUBJECT COMPLETION AND WITHDRAWAL

9.1. Subject completion

A subject who returns for the concluding visit/is available for the concluding contactforeseen in the protocol is considered to have completed the study.

9.2. Subject withdrawal

Subjects who are withdrawn for SAEs must be clearly distinguished from subjects whoare withdrawn for other reasons. Investigators will follow subjects who are withdrawn asresult of a SAE until resolution of the event (see Section 8.7). Withdrawals will not bereplaced.

9.2.1. Subject withdrawal from the study

From an analysis perspective, a �withdrawal� from the study is any subject who did notcome back for the concluding visit foreseen in the protocol.

A subject qualifies as a �withdrawal� from the study when no study procedure hasoccurred, no follow-up has been performed and no further information has been collectedfor this subject from the date of withdrawal/last contact.

Investigators will make an attempt to contact those subjects who do not return forscheduled visits or follow-up.

Information relative to the withdrawal will be documented on the Study Conclusion pageof the CRF. The investigator will document whether the decision to withdraw from thestudy was made by the subject or the investigator and which of the following possiblereasons was responsible for withdrawal:



• protocol violation (specify)




• other (specify)

9.2.2. Subject withdrawal from investigational product

A �withdrawal� from the investigational product is any subject who does not receive thecomplete treatment, i.e. when no further planned dose is administered from the date ofwithdrawal. A subject withdrawn from the investigational product may not necessarily be

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 208fb0b009324aa43dbd8458969316ad24d


28 March 2008 65

withdrawn from the study as further study procedures or follow-up may be performed(safety or immunogenicity) if planned in the study protocol.

Information relative to premature discontinuation of the investigational product will bedocumented on the Vaccine Administration page of the CRF. The investigator willdocument whether the decision to discontinue further vaccination was made by thesubject or the investigator and which of the following possible reasons was responsiblefor withdrawal:

• serious adverse event,

• non-serious adverse event,

• other (specify).

10. DATA EVALUATION: CRITERIA FOR EVALUATION OFOBJECTIVES

10.1. Co-Primary endpoints


• Individual anti-HAV and anti-HBs titers after Twinrix vaccination, at Month 7.

• The non-inferiority of Twinrix to the separately administered monovalent vaccinesEngerix-B /Havrix and HB VAX PRO /Vaqta in terms of anti-HAVseropositivity rate and anti-HBs seroprotection rate at Month 7.


• Anti-HAV immune response to the challenge dose is defined as:

− Anti-HAV antibody titres ≥ 15 mIU/ml at one month post-challenge dose insubjects, seronegative at the pre-challenge time point.

− At least a 2-fold increase in anti-HAV antibody titres one month after thechallenge dose, in subjects having anti-HAV antibody titres ≥ 100 mIU/ml at thepre-challenge time point

− or at least a 4-fold increase in anti-HAV antibody titres one month after thechallenge dose, in seropositive subjects having anti-HAV antibody titres < 100mIU/ml at the pre-challenge time point.

• Anti-HBs antibody response to the challenge dose is defined as

− Anti-HBs antibody titres ≥ 10 mIU/ml at one month post-challenge dose insubjects seronegative at the pre-challenge time point.

− At least a 4-fold increase in anti-HBs antibody titres, at one month post-challengedose in subjects seropositive at the pre-challenge time point.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 209fb0b009324aa43dbd8458969316ad24d


28 March 2008 66

10.2. Secondary endpoints

Primary vaccination study and long term follow up (up to Month 48)

• Individual anti-HAV and anti-HBs titers after vaccination with Engerix-B /Havrix and HB VAX PRO /Vaqta, at Month 7.

• Anti-HAV seropositivity rates and GMTs as well as anti-HBs seropositivity rates,seroprotection rates and GMTs at Month 7 after Twinrix, Engerix-B /Havrixand HB VAX PRO /Vaqta vaccination, described by age, gender, BMI, smokinghabit, alcohol consumption, disease and medication, and overall.

• Individual anti-HAV seropositivity status and anti-HBs seroprotection status, atMonth 7 after Twinrix, Engerix-B /Havrix and HB VAX PRO /Vaqtavaccination.

• Anti-HAV seropositivity rates and GMTs, as well as anti-HBs seropositivity rates,seroprotection rates and GMTs at Months 12, 24, 36 and 48.

• Occurrence, intensity and relationship to vaccination of all serious adverse events(SAEs) up to Month 7, as well as of SAEs with causal relationship to vaccination orreferring to hepatitis A or B infection, after Month 7 and up to the study end (Month48).


Immunogenicity

• Percentage of subjects with anti-HAV antibody titres ≥ 15 mIU/ml and geometricmean titres (GMTs) calculated on seropositive subjects, two weeks and one monthafter the challenge dose.

• Percentage of subjects with anti-HBs antibody titres ≥ 3.3 mIU/ml, ≥ 10 mIU/ml, ≥100 mIU/ml and anti-HBs GMTs calculated on seropositive subjects, two weeks andone month after the challenge dose.

Reactogenicity

• Occurrence and intensity of solicited local symptoms in the 4-day (Day 0 to 3)follow-up period after the challenge dose.

• Occurrence, intensity and relationship of solicited general symptoms in the 4-day(Day 0 to 3) follow-up period after the challenge dose.

Safety

• Occurrence, intensity and relationship to vaccination of unsolicited symptomsreported during the 31-day (Day 0 to 30) follow-up period after the challenge dose.

• Occurrence of all serious adverse events (SAEs) reported following theadministration of the challenge dose.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 210fb0b009324aa43dbd8458969316ad24d


28 March 2008 67

10.3. Estimated sample size

The first co-primary objective of this study is to evaluate the influence of age, gender andBMI on the immunogenicity of 3 doses (Month 0, 1, 6) of Twinrix, in terms ofindividual anti-HBs titers as well as individual anti-HAV titers, at Month 7.

A multiple regression model with 3 independent variables (age, gender, BMI) on the loganti-HBs and log anti-HAV antibody on 180 evaluable subjects receiving Twinrixgives at least 97% power to conclude on the influence of the independent variables, if the3 independent variables (age, gender, BMI) explain at least 10% of the variability of thelog anti-HBs/anti-HAV response (corresponding to R2 [multiple correlation coefficient]of 10%), using an F-test with 5% significance level (α) (See Figure 1) (software programPass 2000).

Figure 1 Power versus R2 (T) with N=180, F-test with alpha=0.05.

Pow

er

R2(T)

0.70

0.75

0.80

0.85

0.90

0.95

1.00

0.00 0.05 0.10 0.15

The other co-primary objective is to demonstrate that the immunogenicity elicited byTwinrix is non-inferior to that of separately administered Engerix�-B and Havrix�and non-inferior to that of seperately administered HB VAX PRO and Vaqta, in termsof the anti-HAV seropositivity rate and anti-HBs seroprotection rate reached at Month 7,i.e. one month after the full primary vaccination course.The sample size of 540 evaluable subjects (180 subjects per group), calculated for thefirst co-primary objective, will give an overall power of at least 86% to conclude non-inferiority of Twinrix versus the monovalent vaccines Engerix-B /Havrix and versusHB VAX PRO / Vaqta, by comparing a pre-defined non-inferiority limit (�10% for

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 211fb0b009324aa43dbd8458969316ad24d


28 March 2008 68

anti-HAV seropositivity rate and �15% for anti-HBs seroprotection rate) with the lowerlimit of the two-sided standardized asymptotic 95% confidence interval (CI)(corresponding to a 2.5% alpha level) on the difference (Twinrix minus monovalentvaccines) in seroprotection rate (anti-HBs) or seropositivity rate (anti-HAV), whenassuming an anti-HAV seropositivity rate of ≥ 95% at Month 7 and an anti-HBsseroprotection rate of ≥ 80 % at Month 7.

Table 13 Summary table

Comparison Endpoint Referencerate

Non-inferiority

limitPower Type II

error

Effect of risk factors withinTwinrix group

Effect of age, gender, BMIon anti-HAV titers

≥10% ofvariabilityexplained

- 97% 3%

Effect of risk factors withinTwinrix group

Effect of age, gender, BMIon anti-HBs titers

≥10% ofvariabilityexplained

- 97% 3%

Anti-HAV S+ ≥95% -10% 98% 2%Twinrix -Engerix�-B / Havrix� Anti-HBs SP ≥80% -15% 95% 5%

Anti-HAV S+ ≥95% -10% 98% 2%Twinrix -HB VAX PRO /Vaqta Anti-HBs SP ≥80% -15% 95% 5%Overall Power to reach all endpoints(Bonferoni correction) 80% 20%

S+: seropositivity rate, SP: seroprotection rate

Allowing for up to 10% of subjects who may withdraw from the study or who may not beevaluable for analysis, 600 subjects are needed for the analysis of the primary objectives(200 in each group).


The sample size for the challenge dose study is not estimated using any power basedcomputations.

A total of 596 subjects were enrolled in the primary study of which 590 subjectscompleted the study and 583 subjects have participated in the last available long-termfollow up visit at Month 24 (Year 2). Thus, considering a drop-out rate of 15% from theMonth 24 time point, we can expect about 495 subjects to participate in the challengedose study and an evaluable 445 subjects. Of these, 219 subjects are expected to berecruited in the German centers (described in this protocol) and 276 subjects in theBelgian and Czech centers (Challenge phase described in protocol with E-track number111572).


CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 212fb0b009324aa43dbd8458969316ad24d


28 March 2008 69


No. of Subjects expected (N) Subjects with challenge dose response as defined in Primary endpoint

n % Exact 95% CILL UL

356 80.0 76.0 83.6379 85.2 81.5 88.3402 90.3 87.2 92.9

445

424 95.3 92.9 97.1n = No. of subjects (in all centres) with challenge dose response% = (n/N)*100; LL = Lower limit; UL = Upper limit

10.4. Study cohorts to be evaluated

Total cohort

The Total cohort for safety will include all subjects who were enrolled into the study atVisit 1. A summary listing of all SAEs prior to the administration of any dose of studyvaccine(s) (i.e. during the enrolment phase) will be provided, there will be no groupcomparisons.

Total Vaccinated cohort

The Total Vaccinated cohort will include all vaccinated subjects for whom data areavailable. For the Total analysis of immunogenicity, this will include vaccinated subjectsfor whom data concerning immunogenicity endpoint measures are available.

Long-term (LT) total vaccinated cohort

The long-term total vaccinated cohort will include all subjects who received at least onedose of the study vaccine in the primary study and who returned for the Month 48 bloodsampling time point.

Total Vaccinated cohort (Challenge dose)

The Total Vaccinated cohort will include all subjects who received the challenge dose:

• a safety analysis based on the total vaccinated cohort will include all vaccinatedsubjects.

• an immunogenicity analysis based on the total vaccinated cohort will include allvaccinated subjects for whom immunogenicity data are available.

According To Protocol (ATP) cohort for analysis of immunogenicity

The ATP cohort for analysis of immunogenicity will include all evaluable subjectsmeeting all eligibility criteria, complying with the procedures defined in the protocol,with no elimination criteria during the study and for whom data concerningimmunogenicity endpoint measures are available. This will include subjects for whom

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 213fb0b009324aa43dbd8458969316ad24d


28 March 2008 70

assay results are available for Ab against at least one study vaccine antigen componentafter vaccination.

Additionally, subjects should be negative for anti-HBs, anti-HBc, HbsAg and anti-HAV(screening for seronegative status will be performed at the investigators� site and onlyseronegative subjects will be enrolled).

ATP cohort for analysis of safety (Challenge dose)

The ATP cohort for safety will include all eligible subjects

• who have received the complete primary hepatitis B and hepatitis A vaccinationcourse in the primary study.

• who have received the challenge dose.

• who have not received a vaccine not specified or forbidden in the protocol

ATP cohort for analysis of immunogenicity (Challenge dose)

The ATP cohort for analysis of immunogenicity will include all evaluable subjectsincluded in the ATP cohort for analysis of safety ((i.e. those meeting all eligibilitycriteria, complying with the procedures and intervals defined in the protocol, with noelimination criteria during the study) who have received the challenge dose and for whomdata concerning immunogenicity endpoint measures for at least one antigen are availableat the post-challenge dose time point. The interval between Visit 8 (pre-challenge dose)and Visit 10 (post-challenge dose time point) considered for inclusion of a subject in theATP cohort for immunogenicity will be 21 to 48 days.

Long term According-To-Protocol (ATP-LT) cohort for analysis of immunogenicity

For subjects who return at a particular blood sampling time point, the ATP-LT cohort (atthat time point) will include those who were included in the ATP immunogenicityanalysis, who did not receive hepatitis A or hepatitis B vaccine not specified in the studyprotocol and who were not eliminated for abnormal increase� in Ab titre during follow-up period.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 214fb0b009324aa43dbd8458969316ad24d


28 March 2008 71

� Note: the criteria of an Ab (anti-HAV or anti-HBs) titre abnormal increase depends onthe magnitude of Ab level reached at first time point (i.e. the reference value). The caseof an abnormal Ab titre increase was defined as a two-fold increase or more in Ab titers(when the Ab titre at the reference time point was ≥ 100 mIU/ml) or a four-fold increaseor more in Ab titers (when the Ab titre at the reference time point was < 100 mIU/ml).This code will be assigned to eliminate from the analysis subjects who could have beeninfected by the hepatitis A or hepatitis B virus, or who could have received a vaccinedose not specified in the protocol during the study.

10.5. Derived and transformed data

• The cut-off value is defined by the laboratory before the analysis and is described inSection 5.6.2. The cut-off value for the assay for anti-HAV Ab is 15 mIU/ml; thecut-off value for the assay for anti-HBs Ab is 3.3 mIU/ml.

• A seronegative subject is a subject whose titre is below the cut-off value.

• A seropositive subject is a subject whose titre is greater than or equal to the cut-offvalue.

• Seropositivity rate is defined as the percentage of subjects with Ab titre greater thanor equal to the cut-off value.

• Seroprotection rate for anti-HBs is defined as the percentage of subjects with anti-HBs titre ≥ 10 mIU/ml.

• The GMT calculations will be performed by taking the anti-log of the mean of thelog transformation of Ab titers equal to or above the seropositivity level (i.e.15 mIU/ml for anti-HAV and 3.3 mIU/ml for anti-HBs).

After administration of the challenge doseImmunogenicity:

• If GMT has to be calculated on all subjects (as supplement), subjects whose antibodytitres are below the assay cut-off are assigned an arbitrary value of half the cut-off.



− At least a 2-fold increase in anti-HAV antibody titres one month after thechallenge dose, in subjects having anti-HAV antibody titres ≥ 100 mIU/ml at thepre-challenge time point or at least a 4-fold increase in antibody titres one monthafter the challenge dose, in seropositive subjects having anti-HAV antibody titres< 100 mIU/ml at the pre-challenge time point.

• Anti-HBs antibody response to the challenge dose is defined as:


CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 215fb0b009324aa43dbd8458969316ad24d


28 March 2008 72


• For a given subject and a given immunogenicity measurement, missing or non-evaluable measurements will not be replaced. Therefore, an analysis will excludesubjects with missing or non-evaluable measurements.


• For the analysis of solicited symptoms, missing or non-evaluable measurements willnot be replaced. Therefore the analysis of the solicited symptoms based on the totalvaccinated cohort will include only subjects with documented safety data (i.e.symptom screen completed).

• For the analysis of unsolicited adverse events/concomitant medication, all vaccinatedsubjects will be considered and subjects who did not report an event will beconsidered as subjects without an event.

10.6. Final analyses

The challenge dose study is described in this protocol for the German centers and in aseparate protocol (HAB-168 BST:160 [111572]) for the Belgian and Czech centers. Theeligibility criteria, study visit procedures and data collection will be identical in the twostudies and the data will be combined with this study for analysis. One integrated clinicalstudy report will describe this analysis.

10.6.1. Analysis of demographics/baseline characteristics

Demographic characteristics (age, gender, race, weight, height, BMI, smoking habits,alcohol consumption, diseases and medication) of each study cohort will be tabulated.

Challenge dose:

Demographic characteristics (age in years, gender and race), cohort description,withdrawal status will be summarized using descriptive statistics:

• Mean, median, standard deviation will be provided for continuous data such as age.All the demographic analyses would be performed stratified based on the three studygroups in the primary study and overall.

A summary of the tracking log-sheet documenting reasons for non-participation in thechallenge dose study will be provided.


Primary immune response (Month 7)The primary analysis will be based on the ATP cohort for analysis of immunogenicity. Ifthe percent of enrolled subjects excluded from this ATP cohort is more than 5%, a

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 216fb0b009324aa43dbd8458969316ad24d


28 March 2008 73

secondary analysis based on the Total Vaccinated cohort will be performed tocomplement the ATP analysis.

A multiple regression model on the log anti-HAV and a multiple regression model on thelog anti-HBs Ab titers at Month 7, with age, gender and BMI as independent variableswill be constructed for subjects in the Twinrix group (primary endpoint) as well as forsubjects in the Engerix-B/Havrix group and subjects in the HB VAX PRO /Vaqtagroup (secondary endpoints). Significance will be evaluated at a 5% level. Normalityassumptions will be checked for and in case of non-normality, non-parametric evaluationwill be performed (Kruskal-Wallis). Linearity will be checked graphically.

The standardized asymptotic 2-sided 95% Cis on the differences in anti-HBsseroprotection rates and anti-HAV seropositivity rates at Month 7 (Twinrix minusmonovalent vaccines) will be computed. If the lower limit of the Cis for the treatmentdifference is greater than the pre-defined non-inferiority limit (-15% for anti-HBs, -10%for anti-HAV), this will indicate that Twinrix is non-inferior to administration ofEngerix-B and Havrix and administration of HB VAX PRO and Vaqta.

A logistic model on the anti-HAV seropositivity status and a logistic model on the anti-HBs seroprotection status at Month 7, with age, gender and BMI as independent variableswill be constructed for subjects in the Twinrix group, as well as for subjects in theEngerix-B/Havrix group and subjects in the HB VAX PRO /Vaqta group.

For each treatment group, a descriptive analysis will be performed, overall as well as perrisk factor (age, gender, BMI, smoking habits, alcohol consumption, medication intakeand underlying disease status), at Month 7:

• Seropositivity rates, seroprotection rates and GMTs for anti-HBs Ab (with exact95% CI) will be calculated,

• Seropositivity rates and GMTs for anti-HAV Ab (with exact 95% CI) will becalculated.

As chronic administration (defined as more than 14 days) of immunosuppressants orother immune-modifying drugs is no elimination criterion and is no stratification factor, asecond non-inferiority analysis will be performed on subjects without chronicadministration of immunosuppressants or other immune-modifying drugs.

For each Ab, the post-vaccination at Month 7 will be graphically presented by groupusing reverse cumulative curves.

The primary analysis will be based on data obtained up to Month 7 and results will bedescribed in the main study report.

Persistence of Ab responseSeroprotection rates, seropositivity rates and GMTs for anti-HBs Ab with 95%confidence intervals Months 12, 24, 36 and 48.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 217fb0b009324aa43dbd8458969316ad24d


28 March 2008 74

Seropositivity rates and GMTs for anti-HAV Ab with 95% confidence intervals, will betabulated for the ATP-LT immunogenicity cohort at Months 12, 24 36 and 48.

Persistence results of the follow-up at Months 12, 24 36 and 48 will be described inAnnex Reports. Persistence results at Month 48 and the results of the challenge dosestudy will be described in a separate Annex Report.


The primary analysis will be based on the ATP cohort for immunogenicity. If, thepercentage of enrolled subjects excluded from this ATP cohort is 5% or more, a secondanalysis based on the Total Vaccinated cohort will be performed to complement the ATPanalysis.

The following analysis will be performed at the post-challenge dose time point for eachtreatment group:

• Percentage of subjects with anti-HAV response to the challenge dose with exact 95%Cis will be tabulated.

• Percentage of subjects with anti-HBs response to the challenge dose with exact 95%Cis will be tabulated.

• Anti-HAV and anti-HBs GMTs with 95% Cis will be tabulated primarily forseropositive subjects and secondarily for all subjects.

• Percentage of subjects seropositive for anti-HAV antibodies (anti-HAV antibodytitres ≥ 15 mIU/ml), with exact 95% CI will be tabulated (the same will also betabulated stratified based on the baseline characteristics).

• Percentage of subjects with anti-HBs titres ≥ 3.3 mIU/ml, percentage of subjects withanti-HBs titers ≥ 10 mIU/ml and ≥ 100 mIU/ml, with exact 95% Cis will be tabulated(the same will also be tabulated stratified based on the baseline characteristics).

• Distribution of anti-HAV and anti-HBs antibody titres will be presented as reversecumulative distribution curves.

10.6.3. Analysis of safety

SAEs will be described individually for all subjects screened.

Challenge dose

The analysis will be based on the Total Vaccinated cohort. If 5% or more of the enrolledsubjects are eliminated from the ATP cohort for safety analysis, a second analysis will beperformed on the ATP cohort for safety.

• The percentage of subjects with at least one local adverse event (solicited andunsolicited), with at least one general adverse event (solicited and unsolicited) andwith any adverse event (solicited and unsolicited) during the 4-day (Day 0 to Day 3)

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 218fb0b009324aa43dbd8458969316ad24d


28 March 2008 75

follow-up period after the vaccination will be tabulated with exact 95% CI. Similartabulations will be done for grade 3 symptoms.

• The percentage of subjects reporting each individual solicited symptom during the 4-day follow-up period with exact 95% CI, by type of adverse event; by severity (anygrade, grade 3 only); for general symptoms: by relationship to vaccination (anyrelationship, related only) will be tabulated.

• The occurrence of fever will be tabulated per 0.5 °C cumulative increments as well asthe occurrence of fever (> 39.5 °C oral/axillary temperature) with causal relationshipto vaccination.

• The percentage of subjects with at least one report of unsolicited adverse eventclassified by the Medical Dictionary for Regulatory Activities (MedDRA) andreported within the 31-day (Day 0 to Day 30) follow-up period after vaccination willbe tabulated with exact 95% CI. The same tabulation will be performed for grade 3unsolicited adverse events and for unsolicited adverse events with a causalrelationship to vaccination.

• The percentage of subjects who start and report at least one concomitant medication(i.e. any medication, antipyretic medication, prophylactic antipyretics) during the 4-day and 31-day follow-up period after vaccination will be tabulated (with exact 95%CI).

• Serious adverse events reported during the entire study period and withdrawal due toAes/SAEs will be described in detail.

10.7. Planned interim analysis

No interim analysis is planned.

11. ADMINISTRATIVE MATTERS

To comply with Good Clinical Practice important administrative obligations relating toinvestigator responsibilities, monitoring, archiving data, audits, confidentiality andpublications must be fulfilled. See Appendix B for details.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 219fb0b009324aa43dbd8458969316ad24d


28 March 2008 76

12. REFERENCES

Averhoff F, Mahoney F, Coleman P, Schatz G, Hurwitz E, Margolis H. Immunogenicityof hepatitis B vaccines. Implications for persons at occupational risk of hepatitis B virusinfection. Am J Prev Med 1998; 15: 1-8.

Bock HL, Kruppenbacher J, Sänger R, Höbel W, Clemens R and Jilg W. Immunogenicityof a recombinant hepatitis B vaccine in adults. Arch Intern Med 1996; 156: 2226-2231.

Fisman DN, Agrawal D, Leder K. The effect of age on immunologic response torecombinant hepatitis B vaccine: a meta-analysis. Clin Inf Dis 2002; 35: 1368-1375.

Hess G, Hingst V, Cseke J, Boch HL, Clemens R. Influence of vaccination schedules andhost factors on antibody response following hepatitis B vaccination. Eur J Clin Microbiol1992; 11: 334-340.

Honorati C, Mariani E, Dolzani P and Facchini A. Biological parameters in fluencing theimmunological response to plasma derived and recombinant hepatitis B vaccines. Ann IntSuper Sanita 1996; 32: 369-374.

Lemon SM. Type A viral hepatitis: new developments in an old disease. New Engl JMed. 1985; 313: 1059-1067

Purcell R H. Hepatitis viruses: Changing patterns of human diseases. Proc National AcadSci USA. 1994; (91): 2401-2405.

Rendi-Wagner P, Kundi M, Stemberger H et al. Antibody response to three recombinanthepatitis B vaccines: comparative evaluation of multicentre travel-clinic basedexperience. Vaccine 2001; 19: 2055-2060.

Reuman PD Kubilis P, Hurni W, Brown L and Nalin D. The effect of age and weight onthe response to formalin inactivated alum-adjuvanted hepatitis A vaccine in healthyadults. Vaccine 1997; 15: 1157-1161.

Reutter J, Bart PA, Francioli P, Safary A, Frei PC. Production of antibody to hepatitis Avirus and hepatitis B surface antigen measured after combined hepatitis A/hepatitis Bvaccination in 242 adult volunteers. J Viral Hepatitis 1998; 5: 205-211.

Roome AJ, Walsh SJ, Cartter ML, Hadler J. Hepatitis B vaccine responsiveness inConnecticut public safety personnel. JAMA 1993; 270: 2931-2934.

Stoffel M, Lievens M, Dieussaert I, Martin I and André F. Immunogenicity of Twinrix inolder adults: a critical analysis. Expert Review Vaccines 2003; 2 (1), 9-14.


CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 220fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL 111149 (HAB-160 BST) Administrative Change 1

28 March 2008 77

Appendix A World Medical Association Declaration of Helsinki

Recommendations guiding physiciansin biomedical research involving human subjects

Adopted by the 18th World Medical AssemblyHelsinki, Finland, June 1964

and amended by the29th World Medical AssemblyTokyo, Japan, October 1975

35th World Medical AssemblyVenice, Italy, October 1983

41st World Medical AssemblyHong Kong, September 1989

and the48th General Assembly

Somerset West, Republic of South Africa, October 1996

INTRODUCTION

It is the mission of the physician to safeguard the health of the people. His or herknowledge and conscience are dedicated to the fulfilment of this mission.

The Declaration of Geneva of the World Medical Association binds the physician withthe words, �The health of my patient will be my first consideration,� and the InternationalCode of Medical Ethics declares that, �A physician shall act only in the patient�s interestwhen providing medical care which might have the effect of weakening the physical andmental condition of the patient.�

The purpose of biomedical research involving human subjects must be to improvediagnostic, therapeutic and prophylactic procedures and the understanding of the etiologyand pathogenesis of disease.

In current medical practice most diagnostic, therapeutic or prophylactic proceduresinvolve hazards. This applies especially to biomedical research.

Medical progress is based on research which ultimately must rest in part onexperimentation involving human subjects.

In the field of biomedical research a fundamental distinction must be recognized betweenmedical research in which the aim is essentially diagnostic or therapeutic for a patient,and medical research, the essential object of which is purely scientific and withoutimplying direct diagnostic or therapeutic value to the person subjected to the research.

Special caution must be exercised in the conduct of research which may affect theenvironment, and the welfare of animals used for research must be respected.

Because it is essential that the results of laboratory experiments be applied to humanbeings to further scientific knowledge and to help suffering humanity, the World MedicalAssociation has prepared the following recommendations as a guide to every physician in

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 221fb0b009324aa43dbd8458969316ad24d


28 March 2008 78

biomedical research involving human subjects. They should be kept under review in thefuture. It must be stressed that the standards as drafted are only a guide to physicians allover the world. Physicians are not relieved from criminal, civil and ethicalresponsibilities under the laws of their own countries.

I. BASIC PRINCIPLES

Biomedical research involving human subjects must conform to generally acceptedscientific principles and should be based on adequately performed laboratory and animalexperimentation and on a thorough knowledge of the scientific literature.

The design and performance of each experimental procedure involving human subjectsshould be clearly formulated in an experimental protocol which should be transmitted forconsideration, comment and guidance to a specially appointed committee independent ofthe investigator and the sponsor provided that this independent committee is inconformity with the laws and regulations of the country in which the research experimentis performed.

Biomedical research involving human subjects should be conducted only by scientificallyqualified persons and under the supervision of a clinically competent medical person. Theresponsibility for the human subject must always rest with a medically qualified personand never rest on the subject of research, even though the subject has given his or herconsent.

Biomedical research involving human subjects cannot legitimately be carried out unlessthe importance of the objective is in proportion to the inherent risk to the subject.

Every biomedical research project involving human subjects should be preceded bycareful assessment of predictable risks in comparison with foreseeable benefits to thesubject or to others. Concern for the interests of the subject must always prevail over theinterests of science and society.

The right of the research subject to safeguard his or her integrity must always berespected. Every precaution should be taken to respect the privacy of the subject and tominimize the impact of the study on the subject�s physical and mental integrity and onthe personality of the subject.

Physicians should abstain from engaging in research projects involving human subjectsunless they are satisfied that the hazards involved are believed to be predictable.Physicians should cease any investigation if the hazards are found to outweigh thepotential benefits.

In publication of the results of his or her research, the physician is obliged to preserve theaccuracy of the results. Reports of experimentation not in accordance with the principleslaid down in this Declaration should not be accepted for publication.

In any research on human beings, each potential subject must be adequately informed ofthe aims, methods, anticipated benefits and potential hazards of the study and thediscomfort it may entail. He or she should be informed that he or she is at liberty to

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 222fb0b009324aa43dbd8458969316ad24d


28 March 2008 79

abstain from participation in the study and that he or she is free to withdraw his or herconsent to participation at any time. The physician should then obtain the subject�sfreely-given informed consent, preferably in writing.

When obtaining informed consent for the research project the physician should beparticularly cautious if the subject is in a dependent relationship to him or her or mayconsent under duress. In that case the informed consent should be obtained by a physicianwho is not engaged in the investigation and who is completely independent of this officialrelationship.

In case of legal incompetence, informed consent should be obtained from the legalguardian in accordance with national legislation. Where physical or mental incapacitymakes it impossible to obtain informed consent, or when the subject is a minor,permission from the responsible relative replaces that of the subject in accordance withnational legislation.

Whenever the minor child is in fact able to give a consent, the minor�s consent must beobtained in addition to the consent of the minor�s legal guardian.

The research protocol should always contain a statement of the ethical considerationsinvolved and should indicate that the principles enunciated in the present Declaration arecomplied with.

II. MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE(Clinical research)

In the treatment of the sick person, the physician must be free to use a new diagnostic andtherapeutic measure, if in his or her judgement it offers hope of saving life, re-establishing health or alleviating suffering.

The potential benefits, hazards and discomfort of a new method should be weighedagainst the advantages of the best current diagnostic and therapeutic methods.

In any medical study, every patient � including those of a control group, if any � shouldbe assured of the best proven diagnostic and therapeutic method. This does not excludethe use of inert placebo in studies where no proven diagnostic or therapeutic methodexists.

The refusal of the patient to participate in a study must never interfere with thephysician�patient relationship.

If the physician considers it essential not to obtain informed consent, the specific reasonsfor this proposal should be stated in the experimental protocol for transmission to theindependent committee (I, 2).

The Physician can combine medical research with professional care, the objective beingthe acquisition of new medical knowledge, only to the extent that medical research isjustified by its potential diagnostic or therapeutic value for the patient.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 223fb0b009324aa43dbd8458969316ad24d


28 March 2008 80

III. NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMANSUBJECTS(Non-clinical biomedical research)

In the purely scientific application of medical research carried out on a human being, it isthe duty of the physician to remain the protector of the life and health of that person onwhom biomedical research is being carried out.

The subjects should be volunteers � either healthy persons or patients for whom theexperimental design is not related to the patient�s illness.

The investigator or the investigating team should discontinue the research if in his/her ortheir judgement it may, if continued, be harmful to the individual.

In research on man, the interest of science and society should never take precedence overconsiderations related to the well being of the subject.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 224fb0b009324aa43dbd8458969316ad24d


28 March 2008 81

Appendix B Administrative Matters

I. Responsibilities of the Investigator

• To ensure that he/she has sufficient time to conduct and complete the study and hasadequate staff and appropriate facilities and equipment which are available for theduration of the study and to ensure that other studies do not divert essential subjectsor facilities away from the study at hand.

• To submit an up-to-date curriculum vitae and other credentials (e.g., medical licensenumber in the United States) to GSK Biologicals and�where required�to relevantauthorities.

• To acquire the normal ranges for laboratory tests performed locally and, if requiredby local regulations, obtain the Laboratory License or Certification.

• To ensure that no clinical samples (including serum samples) are retained on site orelsewhere without the approval of GSK Biologicals and the express written informedconsent of the subject and/or the subject�s legally authorized representative.

• To perform no other biological assays at the investigator site except those describedin the protocol or its amendment(s).

• To prepare and maintain adequate case histories designed to record observations andother data pertinent to the study.

• To conduct the study in compliance with the protocol and appendices.

• To co-operate with a representative of GSK Biologicals in the monitoring process ofthe study and in resolution of queries about the data.

II. Protocol Amendments and Modifications

No changes to the study protocol will be allowed unless discussed in detail with the GSKBiologicals� Clinical Development Manager/Medical Monitor and filed as anamendment/modification to this protocol.

Any amendment/modification to the protocol will be adhered to by the participatingcentre(s) and will apply to all subjects. Written IRB/IEC approval of protocolamendments is required prior to implementation; modifications are submitted toIRBs/IECs for information only.

III. Sponsor’s Termination of Study

GSK Biologicals reserves the right to temporarily suspend or prematurely discontinuethis study either at a single site or at all sites at any time for safety or ethical issues orsevere non-compliance. Reasons for suspension or early termination will be documentedin the study file at GSK Biologicals.

If GSK Biologicals determines such action is needed, GSK Biologicals will discuss thiswith the Investigator (including the reasons for taking such action). When feasible, GSKBiologicals will provide advance notification to the investigator of the impending actionprior to it taking effect.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 225fb0b009324aa43dbd8458969316ad24d


28 March 2008 82

GSK Biologicals will promptly inform, via written communication, all investigatorsand/or institutions conducting the study, if the study is suspended or terminated for safetyreasons, and will also inform the regulatory authorities of the suspension or terminationof the study and the reason(s) for the action. If required by applicable regulations, theinvestigator must inform the IEC/IRB promptly and provide the reason for the suspensionor termination.

If the study is prematurely discontinued, all study data must be returned to GSK. Inaddition, arrangements will be made for all unused investigational product(s) inaccordance with the applicable GSK procedures for the study. Financial compensation toinvestigators and/or institutions will be in accordance with the agreement establishedbetween the investigator and/or institutions and GSK.

IV. Remote Data Entry Instructions

Remote Data Entry (RDE) will be used as the method for data collection, which meansthat subject information will be entered into a computer at the investigational site. Thesite will be capable of modifying the data to assure accuracy with source documentation.All new/updated information will be reviewed and verified by a GSK Biologicals�representative. This information will finally be stored in a central database maintained byGSK Biologicals. At the conclusion of the study, GSK Biologicals will archive the studydata in accordance with internal procedures. In addition, the investigator will be providedwith a CD-ROM of the final version of the data generated at the investigational site.

Specific instructions for use of RDE will be included in the training material provided tothe investigational site.

V. Monitoring by GSK Biologicals

Monitoring visits by a professional representative of the sponsor will be scheduled to takeplace as close as possible to entry of the first subject, during the study at appropriateintervals and after the last subject has completed the study. It is anticipated thatmonitoring visits will occur at a frequency defined before study start.

These visits are for the purpose of confirming that GSK Biologicals� sponsored studiesare being conducted in compliance with the relevant Good Clinical Practice regulations/guidelines, verifying adherence to the protocol and the completeness and accuracy of dataentered on the CRF pages/RDE screens and Vaccine Inventory Forms. The monitor willverify CRF/RDE entries by comparing them with the source data/documents that will bemade available by the investigator for this purpose. Data to be recorded directly into theCRF pages/RDE screens will be specified in writing preferably in the sourcedocumentation agreement form that is contained in both the monitor�s and investigator�sstudy file. For RDE, the monitor will mark completed and approved screens at each visit.The investigator must ensure provision of reasonable time, space and adequate qualifiedpersonnel for monitoring visits.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 226fb0b009324aa43dbd8458969316ad24d


28 March 2008 83

VI. Archiving of Data

Following closure of the study, the investigator must maintain all site study records in asafe and secure location. The records must be maintained to allow easy and timelyretrieval, when needed (e.g., audit or inspection), and, whenever feasible, to allow anysubsequent review of data in conjunction with assessment of the facility, supportingsystems, and staff. Where permitted by applicable laws/regulations or institutional policy,some or all of these records can be maintained in a validated format other than hard copy(e.g., microfiche, scanned, electronic for studies with an eCRF, for example); however,caution needs to be exercised before such action is taken. The investigator must assurethat all reproductions are legible and are a true and accurate copy of the original, andmeet accessibility and retrieval standards, including re-generating a hard copy, ifrequired. Furthermore, the investigator must ensure there is an acceptable back-up ofthese reproductions and that an acceptable quality control process exists for making thesereproductions.

GSK will inform the investigator/ institution of the time period for retaining these recordsto comply with all applicable regulatory requirements. However, the investigator/institution should seek the written approval of the sponsor before proceeding with thedisposal of these records. The minimum retention time will meet the strictest standardapplicable to that site for the study, as dictated by ICH GCP E6 Section 4.9, anyinstitutional requirements or applicable laws or regulations, or GSKstandards/procedures; otherwise, the minimum retention period will default to 15 years.

The investigator/ institution must notify GSK of any changes in the archivalarrangements, including, but not limited to, the following: archival at an off-site facility,transfer of ownership of the records in the event the investigator leaves the site.

VII. Audits

For the purpose of compliance with Good Clinical Practice and Regulatory AgencyGuidelines it may be necessary for GSK Biologicals or a Drug Regulatory Agency toconduct a site audit. This may occur at any time from start to after conclusion of thestudy.

When an investigator signs the protocol, he agrees to permit drug regulatory agencies andGSK Biologicals audits, providing direct access to source data/ documents. Furthermore,if an investigator refuses an inspection, his data will not be accepted in support of a NewDrug Registration and/or Application, Biologics Licensing Application.

GSK Biologicals has a substantial investment in clinical studies. Having the highestquality data and studies are essential aspects of vaccine development. GSK Biologicalshas a Regulatory Compliance staff who audit investigational sites. RegulatoryCompliance assesses the quality of data with regard to accuracy, adequacy andconsistency. In addition, Regulatory Compliance assures that GSK Biologicals sponsoredstudies are in accordance with GCP and that relevant regulations/guidelines are beingfollowed.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 227fb0b009324aa43dbd8458969316ad24d


28 March 2008 84

To accomplish these functions, Regulatory Compliance selects investigational sites toaudit. These audits usually take 1 to 2 days. The GSK Biologicals� audits entail review ofsource documents supporting the adequacy and accuracy of CRFs, review ofdocumentation required to be maintained, and checks on vaccine accountability. TheGSK Biologicals� audit therefore helps prepare an investigator for a possible regulatoryagency inspection as well as assuring GSK Biologicals of the validity of the databaseacross investigational sites.

The Inspector will be especially interested in the following items:

• Log of visits from the sponsor�s representatives

• IRB/IEC approval

• Vaccine accountability

• Approved study protocol and amendments

• Informed consent of the subjects (written consent [or witnessed oral if applicable] )

• Medical records and other source documents supportive of CRF data

• Reports to the IRB/IEC and the sponsor

• Record retentionGSK Biologicals will gladly help investigators prepare for an inspection.

VIII. Ownership, Confidentiality and Publication

Ownership:All information provided by GSK and all data and information generated by the site aspart of the study (other than a subject�s medical records) are the sole property of GSK.

All rights, title, and interests in any inventions, know-how or other intellectual orindustrial property rights which are conceived or reduced to practice by site staff duringthe course of or as a result of the study are the sole property of GSK, and are herebyassigned to GSK.

If a written contract for the conduct of the study which includes ownership provisionsinconsistent with this statement is executed between GSK and the study site, thatcontract�s ownership provisions shall apply rather than this statement.

Confidentiality:All information provided by GSK and all data and information generated by the site aspart of the study (other than a subject�s medical records) will be kept confidential by theinvestigator and other site staff. This information and data will not be used by theinvestigator or other site personnel for any purpose other than conducting the study.These restrictions do not apply to: (1) information which becomes publicly availablethrough no fault of the investigator or site staff; (2) information which it is necessary todisclose in confidence to an IEC or IRB solely for the evaluation of the study; (3)information which it is necessary to disclose in order to provide appropriate medical careto a study subject; or (4) study results which may be published as described in the next

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 228fb0b009324aa43dbd8458969316ad24d


28 March 2008 85

paragraph. If a written contract for the conduct of the study which includesconfidentiality provisions inconsistent with this statement is executed, that contract�sconfidentiality provisions shall apply rather than this statement.

Publication:For multicentre studies, the first publication or disclosure of study results shall be acomplete, joint multicentre publication or disclosure coordinated by GSK. Thereafter,any secondary publications will reference the original publication(s).

Prior to submitting for publication, presentation, use for instructional purposes, orotherwise disclosing the study results generated by the site (collectively, a �Publication�),the investigator shall provide GSK with a copy of the proposed Publication and allowGSK a period of at least thirty (30) days [or, for abstracts, at least five (5) working days]to review the proposed Publication. Proposed Publications shall not include either GSKconfidential information other than the study results or personal data on any subject, suchas name or initials.

At GSK�s request, the submission or other disclosure of a proposed Publication will bedelayed a sufficient time to allow GSK to seek patent or similar protection of anyinventions, know-how or other intellectual or industrial property rights disclosed in theproposed Publication.

If a written contract for the conduct of the study, which includes publication provisionsinconsistent with this statement is executed, that contract�s publication provisions shallapply rather than this statement.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 229fb0b009324aa43dbd8458969316ad24d


28 March 2008 86

Appendix C Overview of the Recruitment Plan

The study will be conducted in multiple centres in Germany, Belgium and CzechRepublic. Subjects will be enrolled by general practitioners (in collaboration withvaccination centres), travel clinics, vaccination centres and occupational health centres.

Further details will be specified by country in the study file documents.

For each country An equal distribution of subjects over the different age, gender and BMIclasses is needed. Hence, it is possible that eligible subjects can be refused to participatein the study due to this stratification. Competitive enrollment period will be terminated assoon as the required number of subjects has been enrolled (a total of 600 subjects, 200subjects/group). This will be followed up by monitoring and by SBIR.

All 590 subjects who have completed the primary vaccination course will be invited toparticipate in the challenge dose study. A total of 219 subjects are expected to berecruited in the German centres (described in this protocol) and 276 subjects in theBelgian and Czech centres (described in protocol with E track number 111572). If anysubject refuses to participate in the study, the reasons for non-participation will berecorded in the tracking document.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 230fb0b009324aa43dbd8458969316ad24d


28 March 2008 87

Appendix D Handling of Biological Samples Collected by the Investigator

Instructions for Handling of Serum Samples

When materials are provided by GSK Biologicals, it is mandatory that all clinicalsamples (including serum samples) be collected and stored using exclusively thosematerials in the appropriate manner. The use of other materials could result in theexclusion of the subject from analysis. The investigator must ensure that his/herpersonnel and the laboratory(ies) under his/her supervision comply with this requirement.

1. CollectionThe whole blood (by capillary or venous route) should be collected observing appropriateaseptic conditions. It is recommended that Vacutainer tubes WITH integrated serumseparator (e.g. Becton-Dickinson Vacutainer SST or Corvac Sherwood Medical) beused to minimize the risk of haemolysis and to avoid blood cell contamination of theserum when transferring to standard serum tubes.

2. Serum separationThese guidelines aim to ensure high quality serum by minimizing the risk of haemolysis,blood cell contamination of the serum or serum adverse cell toxicity at testing.

• For separation of serum using Vacutainer® tubes, the instructions provided by themanufacturer should be followed. Siliconized tubes should never be used (celltoxicity). Often the manufacturer�s instruction states that the relative centrifugalacceleration known also as �G� must be �between 1000 and 1300 G� with tubesspinning for ten minutes. Error in calculation of centrifuge speed can occur whenlaboratory personnel confuse �G� acceleration with �RPM� (revolutions per minute).The speed of centrifugation must be calculated using the �G� rate provided in themanufacturer�s instructions and the radius of the centrifuge head. After measuringthe radius of the centrifuge machine, a speed/acceleration nomograph must beemployed to determine the centrifuge speed in �RPM�.

• Following separation, the serum should be aseptically transferred to the appropriatestandard tubes using a sterile disposable pipette. The serum should be transferred asgently as possible to avoid blood cell contamination.

• The tube should not be overfilled (max. ¾ of the total volume) to allow room forexpansion upon freezing.

• The tube should be identified by the appropriate label provided by GSK Biologicals(see point 3).

3. Labelling

• The standard labels provided by GSK Biologicals should be used to label each serumsample.

• If necessary, any hand-written additions to the labels should be made using indelibleink.

• The label should be attached to the tube as follows (see diagram):

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 231fb0b009324aa43dbd8458969316ad24d


28 March 2008 88

− first attach the paper part of the label to the tube

− then wrap the label around the tube so that the transparent, plastic part of thelabel overlaps with the label text and bar code and shields them.

This will ensure optimal label attachment.

Plastic, transparent part

Paper, text part

Bar code

Study N°.........

Subject N° ......

POST VACC. I STUDY MTH 1For GlaxoSmithKline

Biologicals

• Labels should not be attached to caps.

4. Sorting and storage

• Tubes should be placed in the GSK Biologicals� carton in numerical order from leftto right, starting from the lower left hand corner, beginning with the pre-vaccinationsamples series, then with the post-vaccination sample series.

• The tubes of serum should be stored in a vertical position at -20°C (alternatively at -70°/80°C is also acceptable) until shipment to GSK Biologicals. Wherever possible,a backup facility for storage of serum samples should be available.

• A standard Serum Listing Form, specifying the samples being shipped for individualsubjects at each timepoint, should be prepared for each shipment. A copy of this listshould be retained at the study site, while the original should be sealed in a plasticenvelope and shipped with the serum samples.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 232fb0b009324aa43dbd8458969316ad24d


28 March 2008 89

• Once flight details are known, a standard Specimen Transfer Form must becompleted and faxed to GSK Biologicals to the number provided below. A copy ofthe Specimen Transfer Form must be in the parcel.1

GLAXOSMITHKLINE BIOLOGICALSAttention Biospecimen Reception

Clinical ImmunologyR & D Department/Building 44

Rue de l�Institut, 89B-1330 Rixensart � Belgium

Telephone:Fax:

E-mail:

GLAXOSMITHKLINE BIOLOGICALSClinical Serology Laval

525 Boulevard Cartier OuestLaval, Québec, Canada H7V 3S8

Telephone: E-mail :

1 The Serum Listing Form and the Specimen Transfer Form are standard documents used in GSKBiologicals� clinical trials. These documents are provided by GSK Biologicals� Clinical Trials� monitorat study initiation.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 233fb0b009324aa43dbd8458969316ad24d


28 March 2008 90

Appendix E Shipment of Biological Samples

Instructions for Shipment of Serum Samples (for centres outside Belgium)

Serum samples should be sent to GSK Biologicals at regular intervals. The frequency ofshipment of samples should be decided upon by the Site Monitor, Central StudyCoordinator and the investigator prior to the study start.

Serum samples should always be sent by air, preferably on a Monday, Tuesday orWednesday, unless otherwise requested by the sponsor.

Serum samples must be placed with dry ice (maximum -20°C) in a container complyingwith International Air Transport Association (IATA) requirements. The completedstandard serum listing form should always accompany the shipment.

The container must be clearly identified with the labels provided by GSK Biologicalsspecifying the shipment address and the storage temperature (-20°C).

The airway bill should contain the instruction for storage of samples at maximum -20°C.

A �proforma� invoice, stating a value for customs purposes only, should be prepared andattached to the container. This document should contain the instruction for storage ofsamples at maximum -20°C.

Details of the shipment, including: * number of samples* airway bill* flight number* flight departure and arrival times

should be sent by fax, two days before shipment, to:




Telephone:Fax:

E-mail:

GLAXOSMITHKLINE BIOLOGICALSClinical Serology Laval

525 Boulevard Cartier OuestLaval, Québec, Canada H7V 3S8

Telephone: E-mail :

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 234fb0b009324aa43dbd8458969316ad24d


28 March 2008 91

Appendix F Laboratory Assays

See Section 5.6.2 Laboratory assays.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 235fb0b009324aa43dbd8458969316ad24d


28 March 2008 92

Appendix G Vaccine supplies, packaging and accountability

It is NOT permitted to use any of the supplies provided by GSK Biologicals for purposesother than those specified in the protocol. Unused supplies will be collected by GSKBiologicals on completion of the study. Used vaccine vials/pre-filled syringes can bedisposed on site according to local biosafety standard for disposal of biological wastematerial.

1. Vaccine suppliesGSK Biologicals will supply the following amounts of numbered doses of studyvaccines, sufficient to administer 3 doses of Twinrix, Engerix-B or HB VAX PROand 2 doses of Havrix or Vaqta, to all subjects of the respective groups (200 subjects/group) as described in the present protocol.

• Approximately 600 doses of Twinrix in pre-filled syringes

• Approximately 600 doses of Engerix-B in pre-filled syringes

• Approximately 400 doses of Havrix in pre-filled syringes

• Approximately 600 doses of HB VAX PRO in monodose vials

• Approximately 400 doses of Vaqta in pre-filled syringes

For the challenge dose study, 200 doses of each of the above vaccines will be supplied.HBVAXPRO� will be supplied in pre-filled syringes for the challenge dose study.

To allow GlaxoSmithKline to take advantage of greater rates of recruitment thananticipated at individual centres in this multicentre study, and thus to reduce the overallstudy recruitment period, each centre will receive enough vaccines to allow an over-enrolment of 5% of the target number of subjects. The vaccine doses will be distributedto the study centres while respecting the randomization block.

An additional 5% of the respective amounts will be supplied for replacement in case ofbreakage, bad storage conditions or any other reason that would make the vaccineunusable (i.e., given by mistake to another subject).

All monodose vials/pre-filled syringes must be accounted for on the form provided.

2. Vaccine packagingThe vaccines will be packed in labelled boxes. The box label will contain, as a minimum,the following information: study number, subject number, lot number (or numbers, whendouble-blind), instructions for vaccine administration.

3. Vaccine accountabilityThe investigator or pharmacist must sign a statement that he/she has received the clinicalsupplies for the study. At all times the figures on supplied, used and remaining vaccinedoses should match. At the end of the study, it must be possible to reconcile deliveryrecords with those of used and unused stocks. An explanation must be given of anydiscrepancies.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 236fb0b009324aa43dbd8458969316ad24d


28 March 2008 93

After approval from GSK Biologicals, used vaccine vials/syringes should be destroyed atthe study site using locally approved biosafety procedures and documentation unlessotherwise described in the protocol. If no adequate biosafety procedures are available atthe study site, the used vaccine vials/syringes are to be returned to an appropriate GSKBiologicals site for destruction in accordance with current GSK SOP NPD-112. Unusedvaccine vials/syringes will be disposed at the local GSK Biologicals site in accordancewith GSK SOP NPD-112. If no processes for destruction of unused vaccines are in placein the local GSK Biologicals site; the unused vials/syringes must be returned to GSKBiologicals in Rixensart, Belgium.

4. Transfers of clinical vaccines or products from country medical department ordispatch centre to study sites or between sites

Storage temperatures must be maintained during transport and deviations must bereported to Logistics and Packaging for guidance. All transfers of clinical vaccines orproducts must be documented using the Clinical Supply Transfer Form. If the duration ofthe transfer is less than four hours, a transportable fridge or any suitable container (e.g.styrofoam container) with a maximum of eight refrigerated cold packs (cooling elements)must be used in order to maintain the vaccines at 2°-8°C during transport. If the durationis more than four hours, a transportable fridge or any suitable container (e.g. styrofoamcontainer) with a minimum of eight cold packs (cooling elements) must be used as wellas a temperature monitoring system that must be placed as close as possible to the dosesand checked upon reception at the final destination. Never place frozen cold packs or dryice inside vaccine/product boxes for vaccine that must be kept at +4°C in order to avoidcold-chain deviation (e.g. frozen vaccines). Exceptions to these instructions are detailedin product-specific transport guidelines.

5. Labels for sample identificationThe investigator will receive labels from GSK Biologicals to identify samples taken fromeach subject at each timepoint. Each label will contain the following information: studynumber, identification number for the subject (e.g. treatment number), samplingtimepoint (e.g., post post vacc 1, post vacc 2), timing (e.g., study Month 7, Month 12).

For the challenge dose study, the subject number will be used for identification of theserum samples.

6. Other supplies provided by GSK BiologicalsIn addition to the vaccines, the study documentation and the sample labels, theinvestigator will receive the following supplies:

• tubes for blood sampling,

• tubes with screw caps for serum samples,

• racks for the tubes of serum.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 237fb0b009324aa43dbd8458969316ad24d


28 March 2008 94

Appendix H Amendments and Administrative Changes to the Protocol

GlaxoSmithKline BiologicalsClinical Research & DevelopmentProtocol Amendment Approval

eTrack study numbersand abbreviated titles

100382 (HAB-160)100383 (HAB-161 EXT-160 Y1)100384 (HAB-162 EXT-160 Y2)100385 (HAB-163 EXT-160 Y3)111149 (HAB-160 BST)

Protocol title: A phase IV, open, randomized, multicentre, multicountrystudy to evaluate the effect of several risk factors likely toinfluence the immunogenicity of GlaxoSmithKlineBiologicals� combined hepatitis A and hepatitis B vaccineTwinrix according to a 0, 1 and 6 month schedule, ascompared to separately administered monovalenthepatitis A (0, 6 months) and hepatitis B vaccines (0, 1, 6months) from different manufacturers, as well as todemonstrate the non-inferiority of Twinrix to themonovalent vaccines, in healthy and non-healthy adultsaged 41 years or older.

Amendment number: Amendment 1Amendment date: 28 August 2007Co-ordinating author: Scientific writerRationale/background for changes:The protocol is being amended to reflect that all subjects will receive a challengedose of the vaccine they received in the primary vaccination, approximately 12months after the Year 3 long-term follow-up time point. A post-dose blood samplewill be taken two weeks and one month (Day 30) later to evaluate the anti-HAV andanti-HBs antibody response.Amended text has been included in bold italics in the following sections:

eTrack studynumber

111149 (HAB-160 BST)

Contributingauthors

• Clinical Development Manager• Manager Biostatistician• Central Study Coordinator• Director, , Global Clinical

R&D Vaccines, Paediatrics/Hepatitis vaccines,Paediatrics/Hepatitis vaccines

• Senior Manager, Global ClinicalDevelopment, Paediatrics/Hepatitis vaccines

• Central Study Coordinator• Biometrician• Project Statistician

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 238fb0b009324aa43dbd8458969316ad24d


28 March 2008 95

Sponsor signatory approval Associate Director AdultVaccines

Senior Manager, Pediatrics/Hepatitis vaccinesGlobal Clinical Development

Section 1.2 Rationale and SynopsisAdditionally, the current study will provide data concerning the long-term (up to 3648 months) anti-HBs seropositivity rates and seroprotection rates and the long-termanti-HAV seropositivity rate in this population.

The protocol is currently being amended to reflect that all subjects (irrespective oftheir seroprotective status) will receive a challenge dose of the vaccine that theyreceived in the primary study, approximately 12 months after the Year 3 long-termfollow-up time point. A blood sample will be taken at the time of vaccination, twoweeks (Day 14) and one month (Day 30) after the administration of the challengedose to evaluate the anti-HAV and anti-HBs anti body response.Section 2.1 Co-primary Objectives and SynopsisChallenge dose study

• To evaluate the anti-HAV and anti-HBs immune memory (in terms of anti-HAV and anti-HBs immune response elicited by the challenge dose) in apopulation > 41 years of age (healthy and non-healthy), approximately 12months after the Year 3 long-term follow-up time point.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 239fb0b009324aa43dbd8458969316ad24d


28 March 2008 96

Section 2.2 Secondary ObjectivesPrimary vaccination study

• To evaluate the long-term persistence elicited by Twinrix, Engerix-B/Havrix and HB VAX PRO /Vaqta, in terms of anti-HAV seropositivityrates and GMTs (at Months 12, 24, 36 and 48), as well as anti-HBsseropositivity rates, seroprotection rates and GMTs (at Months 12, 24, 36 and48).


• To evaluate the immune response to the challenge dose, two weeks (Day 14)and one month (Day 30) after vaccination.

• To evaluate safety and reactogenicity of the challenge dose in terms of:− solicited symptoms occurring during the 4-day (Day 0 to Day 3) follow-up

period.− unsolicited symptoms occurring during the 31-day (Day 0 to Day 30)

follow-up period.− all serious adverse events (SAE) following the challenge dose

administration.Section 3 Study design Overview and SynopsisPrimary vaccination study

• Duration of the study: approximately 7 months per subject for primaryvaccination. Long-term follow-up up to Month 36 48.


• Experimental design: open, randomized, multicentre, multicountry study withthree parallel groups.

• Treatment groups for the challenge dose study will be the same as in theprimary study: all subjects will receive one dose of Twinrix ; Engerix-Bco-administered with Havrix or HB VAX PRO co-administered withVaqta according to their randomization in the primary vaccination study.



The study design was modified to include the challenge dose study.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 240fb0b009324aa43dbd8458969316ad24d


28 March 2008 97

Section 4.1 Number of subjects/ centresA total of 600 subjects will be enrolled (200 subjects per group) in order to have 540evaluable subjects (180 subjects per group). See Section 10.3 for a detaileddescription of the criteria used in the estimation of sample size for the primaryvaccination study.

All subjects who have completed the primary vaccination course will be invited toparticipate in the challenge dose study. See Section 10.3 for a detailed descriptionof the criteria used in the estimation of sample size for the challenge dose study.Section 4.2 Inclusion criteriaThe inclusion criteria were modified to include the challenge dose phase of the study.

Section 4.3 Exclusion criteriaThe following criteria should be checked at the time of study entry for the primaryvaccination phase and the challenge dose phase of the study.History of any hepatitis A or hepatitis B vaccination or infection, since the primaryvaccination study.

Section 4.5 Contraindications to subsequent vaccinationThe above contraindications are also applicable to the challenge dose phase of thestudy.Section 4.6 Warnings and Precautions for the challenge dose was added.Section 5.3 Subject identificationThe subject participating in the challenge dose study will keep the same subjectnumbers as assigned in the primary phase of the study.Section 5.4 Outline of study proceduresThe relevant study procedures for Months 48 and 49 are updated in the followingstudy tables.

• Table 1: List of study procedures: Twinrix Group.• Table 2: List of study procedures: Engerix�-B/Havrix� Group.• Table 3: List of study procedures: HB VAX PRO /Vaqta Group.Table 4 Intervals between study visits has been updated to include the challenge dosevisit (Month 48), the blood sampling visits: two weeks (Day 14 and one month (Day30) after the challenge dose (Month 49).

Interval Length of interval8 Visit 1→→→→Visit 8

(Day 0 � Month 48) 48 ±±±± 2 months

9 Visit 8→→→→Visit 9(Month 48 � Day 14 after challenge dose) 14 ±±±± 2 days

10 Visit 8→→→→Visit 10(Month 48 � Month 49) 30-48 days

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 241fb0b009324aa43dbd8458969316ad24d


28 March 2008 98

Section 5.5 Detailed descriptions of Study Visits:Visit 8: Month 48 (Challenge dose visit)• Written informed consent obtained from the subject.• Check inclusion/ exclusion criteria• The investigator must ask each subject in a retrospective manner if the subject

has suffered any unreported serious adverse event(s) or hepatitis A or Binfection since the last study contact.

• The investigator will then document in the SAE forms:− The reported SAE(s) that he/she considers to have a causal relationship to

vaccination.− Hepatitis A or B infection, in this study reported as SAE (as defined per

protocol). See Section 8.4 Lack of efficacy• Collection of blood for serology (maximum of 5 ml of whole blood). The

sample will be centrifuged and separated (see Appendix D).The serum will be stored at −−−− 20 °C until transfer to GlaxoSmithKlineBiologicals (See Section 5.6.2).

• Check contraindications for the challenge dose (Twinrix�, Engerix�-B/Havrix� or HBVAXPRO�/ Vaqta�.

• Check elimination criteria• Check warnings and precautions.• Physical examination• Pregnancy test (urine) if female subject is of childbearing age and if deemed

necessary by the investigator.• Pre-vaccination assessment of body temperature.• Challenge dose of the vaccine that the subjects received in the primary study

will be administered at Visit 8 (Month 48). Please refer to the guidelines set outin Section 6.2.

• The vaccinees will be observed closely for at least 30 minutes, with appropriatemedical treatment readily available in case of a rare anaphylactic reactionfollowing the administration of vaccine.

• Diary cards will be provided to the subject to record the following informationin the appropriate sections of the diary card:− Any solicited local or general adverse events on the day of vaccination and

on the 3 subsequent days for a total of 4 days of follow-up (Day 0-3).− Any other (unsolicited) adverse event on the day of vaccination and the

subsequent 30 days (Day 0-30) after vaccination.• The subject will be instructed to return their completed diary card to the

investigator at the next study visit.• The subject will be instructed to contact the investigator immediately should

the subject manifest any signs or symptoms they perceive as serious.• Recording of concomitant medication/vaccination.• Recording of SAEs. The investigator will document the reported SAE(s) in the

SAE forms.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 242fb0b009324aa43dbd8458969316ad24d


28 March 2008 99

Visit 9: Day 14 after the challenge vaccine dose• Collection of blood for serology (maximum of 5 ml of whole blood). The

sample will be centrifuged and separated (see Appendix D). The serum will bestored at 20 °C until transfer to GlaxoSmithKline Biologicals (See Section5.6.2).

Visit 10: Month 49 (One month after the challenge dose)• Check elimination criteria


• The subject will return the completed diary card to the investigator from theprevious visit. The investigator will collect and verify them. He/She willtranscribe the information into the appropriate sections of the CRF, inEnglish. Any unreturned diary cards will be sought from the subjects throughany convenient procedure.

• Collection of blood for serology (maximum of 5 ml of whole blood). Thesample will be centrifuged and separated (see Appendix D). The serum will bestored at −−−− 20 °C until transfer to GlaxoSmithKline Biologicals

Visit 10: Month 49 (One month [Day 30] after the challenge vaccine dose)

• Check elimination criteria• Return of completed diary cards from subjects• The subject�s records of medication will be verified and transcribed by the

investigator to update the concomitant medication section in the CRF.• The subject will return the completed diary card to the investigator from the

previous visit. The investigator will collect and verify them. He/She willtranscribe the information into the appropriate sections of the CRF, inEnglish. Any unreturned diary cards will be sought from the subjects throughany convenient procedure.

• Collection of blood for serology (maximum of 5 ml of whole blood). Thesample will be centrifuged and separated (see Appendix D). The serum will bestored at −−−− 20 °C until transfer to GlaxoSmithKline Biologicals.

• Recording of any unsolicited adverse events which may have occurred withinone month (minimum 30 days) following administration of the challenge dose.

• Transcription of concomitant medication/vaccination in the appropriatesections of the CRF.

• Recording of SAEs. The investigator will document the reported SAE(s) in theSAE forms.

• Study conclusion.Section 5.6.2: Laboratory AssayAt the time of vaccination, two weeks and one month after administration of thechallenge dose (Month 49), approximately 5 ml of whole venous blood will becollected for measurement of anti-HAV and anti-HBs antibody titres.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 243fb0b009324aa43dbd8458969316ad24d


28 March 2008 100

Table 5 Laboratory assays

The AUSAB assay kit used for assaying anti-HBs antibodies is replaced with the in-house assay kit.

Table 6 Serology Plan: The following rows have been added

Blood sampling timepoint AntigenPriorityranking

Timing Day/Month

Visit no.Marker Laboratory site No.

subjects

Pre-challenge dose Month 48 8 Anti-HBsAnti-HAV GSK ** All Anti-HBs (1)



Post-challenge dose Month 49 9Anti-HBsAnti-HAV

GSK ** AllAnti-HBs (1)Anti-HAV (2)

Section 6.1 Study Vaccines

Aventis Pasteur MSD�s recombinant hepatitis B vaccine, HB VAX PRO will besupplied inmonodose vials containing per as 1.0 ml dose

All subjects will receive a challenge dose of the same vaccine that they received inthe primary study. The composition of the challenge dose will be same as thecomposition of the vaccines administered in the primary study.Section 6.2 Dosage and administrationChallenge vaccine and dosage:All subjects (irrespective of their serological status) will be given a challenge dose ofthe same vaccine that they received in the primary study at the Month 48 time point.The vaccines will be administered as an intramuscular injection in the deltoidregion using a 23G, 25 mm needle. The side of injection is as given in Table 7.

Section 6.4 Treatment allocation and randomizationChallenge vaccine and dosage:The vaccines will be numbered sequentially per group. The site has to take thelowest treatment number available in the fridge of the vaccine group that the subjectreceived in the primary study. Subjects will be administered the vaccine dose withthe lowest treatment number still available at the study centre. The treatmentnumber must be recorded by the investigator in the eCRF (treatment allocation).

Section 6.9 Concomitant medication/ treatmentFor the challenge dose of the study, all concomitant medication, with the exceptionof vitamins and/ or dietary supplements, administered at any time during the periodstarting 7 days before the administration of the challenge dose and ending at theMonth 49 visit i.e one month (minimum 30 days) after the challenge dose is to berecorded by the subject.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 244fb0b009324aa43dbd8458969316ad24d


28 March 2008 101

Section 8 Medical Condition and (Serious) Adverse EventsThis section was amended to include the information on adverse events and pregnancyreports that will be collected after administration of the challenge dose.

Study Contact for Reporting SAEs (this information has been deleted fromAppendix C)Czech Republic:

Dr. GlaxoSmithKline, s.r.o. GlaxoSmithKlineNa Pankraci 17/1685, Na Pankraci 17/1685140 21 Prague 4, 140 21, Prague 4Czech Republic Czech RepublicTel: Tel: Fax: Mobile: Outside office hours: Mobile phone: Fax: Belgium:

Central Study CoordinatorGlaxoSmithKline BiologicalsRue de L�Institut 89B-1330 Rixensart, BelgiumTel: : Fax:

GlaxoSmithKline BiologicalsRue de L�Institut 89B-1330 Rixensart, BelgiumTel: : Fax:


(Head Safety Evaluation and Risk ManagementAdult/Adolescent/Emerging Diseases)Back-up mobile phone contact:

Section 10.1: Co-Primary Endpoints and SynopsisChallenge dose study


− Anti-HAV antibody titres ≥≥≥≥ 15 mIU/ml at one month post-challenge dosein subjects, seronegative at the pre-challenge time point.

− At least a 2-fold increase in anti-HAV antibody titres one month after the

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 245fb0b009324aa43dbd8458969316ad24d


28 March 2008 102

challenge dose, in subjects having anti-HAV antibody titres ≥≥≥≥ 100 mIU/mlat the pre-challenge time point or

− at least a 4-fold increase in anti-HAV antibody titres one month after thechallenge dose, in seropositive subjects having anti-HAV antibody titres <100 mIU/ml at the pre-challenge time point.


− Anti-HBs antibody titres ≥≥≥≥ 10 mIU/ml at one month post-challenge dose insubjects seronegative at the pre-challenge time point.

− At least a 4-fold increase in anti-HBs antibody titres, at one month post-challenge dose in subjects seropositive at the pre-challenge time point.

Section 10.2: Secondary Endpoints and SynopsisPrimary vaccination study and long term follow up (up to Month 48)

- Anti-HAV seropositivity rates and GMTs, as well as anti-HBs seropositivityrates, seroprotection rates and GMTs at Month 12, 24, 36 and 48.

− Occurrence, intensity and relationship to vaccination of all serious adverseevents (SAEs) up to Month 7, as well as of SAEs with causal relationship tovaccination or referring to hepatitis A or B infection, after Month 7 and upto the study end (Month 49).

Challenge dose studyImmunogenicity

• Percentage of subjects with anti-HAV antibody titres ≥≥≥≥ 15 mIU/ml and GMTscalculated on seropositive subjects, two weeks and one month after thechallenge dose.

• Percentage of subjects with anti-HBs antibody titres ≥≥≥≥ 3.3 mIU/ml, ≥≥≥≥ 10mIU/ml, ≥≥≥≥ 100 mIU/ml and anti-HBs geometric mean titres (GMTs)calculated on seropositive subjects, two weeks and one month after thechallenge dose.

Reactogenicity


• Occurrence, intensity and relationship of solicited general symptoms in the 4-day (Day 0 to 3) follow-up period after the challenge dose.

Safety

• Occurrence, intensity and relationship to vaccination of unsolicited signs andsymptoms reported during the 31-day (Day 0 to 30) follow-up period after thechallenge dose.

• Occurrence of all serious adverse events (SAEs) reported following theadministration of the challenge dose.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 246fb0b009324aa43dbd8458969316ad24d


28 March 2008 103

Section 10.3 Estimation of sample sizeThe sample size for the challenge dose study is not estimated using any powerbased computations. A total of 596 subjects were enrolled in the primary study of which 590 subjectscompleted the study and 583 subjects have participated in the last available long-term follow up visit at Month 24 (Year 2). Thus, considering a drop-out rate of15% from the Month 24 time point, we can expect about 495 subjects to participatein the challenge dose study and an evaluable 445 subjects.Table 14 provides the precision achieved with a sample of 445 subjects, for variouspossible expected values of response (ranging from 80% to 95%) to the challengedose in terms of exact 95% confidence interval.


No. of Subjects expected(N)

Subjects with challenge dose response as defined inPrimary end point


356 80.0 76.0 83.6379 85.2 81.5 88.3402 90.3 87.2 92.9

445


Section 10.4 : Study cohorts to be evaluatedTotal Vaccinated cohort (Challenge dose)The Total Vaccinated cohort will include all subjects who received the challengedose:• a safety analysis based on the total vaccinated cohort will include all vaccinated

subjects.• an immunogenicity analysis based on the total vaccinated cohort will include all

vaccinated subjects for whom immunogenicity data are available

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 247fb0b009324aa43dbd8458969316ad24d


28 March 2008 104

ATP cohort for analysis of safety (Challenge dose)The ATP cohort for safety will include all eligible subjects• who have received the complete primary hepatitis B and hepatitis A vaccination

course in the primary study.• who have received the challenge dose.• who have not received a vaccine not specified or forbidden in the protocol

ATP cohort for analysis of immunogenicity (Challenge dose)The ATP cohort for analysis of immunogenicity will include all evaluable subjectsincluded in the ATP cohort for analysis of safety (i.e. those meeting all eligibilitycriteria, complying with the procedures and intervals defined in the protocol, withno elimination criteria during the study) who have received the challenge dose andfor whom data concerning immunogenicity endpoint measures for at least oneantigen are available at the post- challenge dose time point. The interval betweenVisit 8 (pre-challenge dose) and Visit 10 (post-challenge dose time point)considered for inclusion of a subject in the ATP cohort for immunogenicity will be21 to 48 days.

Section 10.5 : Derived and transformed dataIf GMT has to be calculated on all subjects (as supplement), subjects whoseantibody titres are below the assay cut-off are assigned an arbitrary value of halfthe cut-off.After administration of the challenge doseImmunogenicity:• Anti-HAV immune response to the challenge dose is defined as:

− Anti-HAV antibody titres ≥≥≥≥ 15 mIU/ml at one month post-challenge dose insubjects, seronegative at the pre-challenge time point.

− At least a 2-fold increase in anti-HAV antibody titres one month after thechallenge dose, in seropositive subjects having anti-HAV antibody titres ≥≥≥≥100 mIU/ml at the pre-challenge time point or at least a 4-fold increase inantibody titres one month after the challenge dose, in seropositive subjectshaving anti-HAV antibody titres < 100 mIU/ml at the pre-challenge timepoint.


− At least a 4-fold increase in anti-HBs antibody titres, at one month post-challenge dose in subjects seropositive at the pre-challenge time point.

− Anti-HBs antibody titres ≥≥≥≥ 10 mIU/ml at one month post-challenge dose insubjects seronegative at the pre-challenge time point.

• For a given subject and a given immunogenicity measurement, missing or non-evaluable measurements will not be replaced. Therefore, an analysis willexclude subjects with missing or non-evaluable measurements.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 248fb0b009324aa43dbd8458969316ad24d


28 March 2008 105

Safety/ Reactogenicity

• For the analysis of solicited symptoms, missing or non-evaluable measurementswill not be replaced. Therefore the analysis of the solicited symptoms based onthe total vaccinated cohort will include only subjects with documented safetydata (i.e. symptom screen completed).

• For the analysis of unsolicited adverse events/concomitant medication, allvaccinated subjects will be considered and subjects who did not report an eventwill be considered as subjects without an event.

Section 10.6.1 Analysis of demographicsChallenge dose:Demographic characteristics (age in years, gender and race), cohort description,withdrawal status will be summarized using descriptive statistics:

• Mean, median, standard deviation will be provided for continuous data such asage.

All the demographic analyses would be performed stratified based on the threestudy groups in the primary study and overall.A summary of the tracking log-sheet documenting reasons for non-participation inthe challenge dose study will be provided.Section 10.6.2 Analysis of immunogenicityPersistence of Ab responseSeroprotection rates, seropositivity rates and GMTs for anti-HBs Ab with 95%confidence intervals Months 12, 24, 36 and 48.

Seropositivity rates and GMTs for anti-HAV Ab with 95% confidence intervals, willbe tabulated for the ATP-LT immunogenicity cohort at Months 12, 24 36 and 48.

Persistence results of the follow-up at Months 12, 24 36 and 48 will be described inAnnex Reports. Persistence results at Month 48 and the results of the challengedose study will be described in a separate annex report.Challenge dose responseThe primary analysis will be based on the ATP cohort for immunogenicity. If, thepercentage of enrolled subjects excluded from this ATP cohort is 5% or more, asecond analysis based on the Total Vaccinated cohort will be performed tocomplement the ATP analysis.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 249fb0b009324aa43dbd8458969316ad24d


28 March 2008 106

The following analysis will be performed at the post-challenge dose time point foreach treatment group:

• Percentage of subjects with a anti-HAV response to the challenge dose withexact 95% CI will be tabulated.

• Percentages of subjects with anti-HBs response to the challenge dose with exact95% Cis will be tabulated.

• Anti-HAV and anti-HBs GMTs with 95% Cis will be tabulated primarily forseropositive subjects and secondarily for all subjects.

• Percentage of subjects seropositive for anti-HAV antibodies (anti-HAV antibodytitres ≥≥≥≥ 15 mIU/ml), with exact 95% CI will be tabulated (the same will also betabulated stratified based on the baseline characteristics).

• Percentage of subjects with anti-HBs titres ≥≥≥≥ 3.3 mIU/ml, percentage of subjectswith anti-HBs titres ≥≥≥≥ 10 mIU/ml and ≥≥≥≥ 100 mIU/ml, with exact 95% Cis will betabulated (the same will also be tabulated stratified based on the baselinecharacteristics).

• Distribution of anti-HAV and anti-HBs antibody titres will be presented asreverse cumulative distribution curves.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 250fb0b009324aa43dbd8458969316ad24d


28 March 2008 107

Section 10.6.3 : Analysis of SafetyChallenge doseThe analysis will be based on the Total Vaccinated cohort. If 5% or more of theenrolled subjects are eliminated from the ATP cohort for safety analysis, a secondanalysis will be performed on the ATP cohort for safety.• The percentage of subjects with at least one local adverse event (solicited and

unsolicited), with at least one general adverse event (solicited and unsolicited)and with any adverse event (solicited and unsolicited) during the 4-day (Day 0to Day 3) follow-up period after the vaccination will be tabulated with exact95% CI. Similar tabulations will be done for grade 3 symptoms and symptomsthat will lead to a medically attended visit.

• The percentage of subjects reporting each individual solicited symptom duringthe 4-day follow-up period with exact 95% CI, by type of adverse event; byseverity (any grade, grade 3 only); for general symptoms: by relationship tovaccination (any relationship, related only) and medically attended visit foreach symptom will be tabulated.

• The occurrence of fever will be tabulated per 0.5 °C cumulative increments aswell as the occurrence of fever (> 39.5 °C oral/axillary temperature) with causalrelationship to vaccination and medically attended fever.

• The percentage of subjects with at least one report of unsolicited adverse eventclassified by the Medical Dictionary for Regulatory Activities (MedDRA) andreported within the 31-day (Day 0 to Day 30) follow-up period after vaccinationwill be tabulated with exact 95% CI. The same tabulation will be performed forgrade 3 unsolicited adverse events and for unsolicited adverse events with acausal relationship to vaccination.

• The percentage of subjects who start and report at least one concomitantmedication (i.e. any medication, antipyretic medication, prophylacticantipyretics) during the 4-day and 31-day follow-up period after vaccinationwill be tabulated (with exact 95% CI).

• Serious adverse events reported during the entire study period and withdrawaldue to Aes/SAEs will be described in detail.

Appendix E: The address for shipment of samples has been updated.

Appendix G: The vaccine supplies section has been updated to include the doses ofvaccine that will be supplied for the challenge dose.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 251fb0b009324aa43dbd8458969316ad24d


28 March 2008 108

GlaxoSmithKline BiologicalsClinical Research & Development

Protocol Amendment Approval



Protocol title: A phase IV, open, randomized, multicentre study toevaluate the effect of several risk factors likely toinfluence the immunogenicity of GlaxoSmithKlineBiologicals� combined hepatitis A and hepatitis Bvaccine Twinrix according to a 0, 1 and 6 monthschedule, as compared to separately administeredmonovalent hepatitis A (0, 6 months) and hepatitis Bvaccines (0, 1, 6 months) from different manufacturers,as well as to demonstrate the non-inferiority of Twinrixto the monovalent vaccines, in healthy and non-healthyadults aged 41 years or older.

Amendment number: Amendment 2

Amendment date: 25 January 2008

Coordinating author: Scientific Writers

Rationale/background for changes: The protocol is being amended to reflect thedescription of the challenge dose phase of this study in a separate protocol (HAB-168BST:160 [111572]) for the Czech and Belgian centres that participated in the primarystudy HAB-160 at the request of the Czech authorities. The eligibility criteria, studyvisit procedures and data collection will be identical in the two studies and the data willbe combined with this study for analysis.

To allow sufficient recruitement of eligible subjects for the challenge dose study in allcenters, the timing for administration of the challenge dose is extended to 48-60months.

The protocol also reflected the change in the sponsor signatory from to and the change in LKP from Dr. med. habil.

to Dr. med. Habil.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 252fb0b009324aa43dbd8458969316ad24d


28 March 2008 109

Amended text has been included in bold italics in the following sections:



• Central Study Coordinator• Manager, Global Clinical

Research and Development, Paediatrics/Hepatitisvaccines


• BiometricianSection 1.2 Rationale for the studyFinally, to evaluate the immune memory to HBV and HAV antigens in thispopulation, all All subjects (irrespective of their serological status) will receive achallenge dose of the vaccine that they received in the primary study, approximately 12months after the Year 3 long-term follow-up time point approximately 48 months afterthe first dose of the primary vaccination course. A blood sample will be taken at thetime of vaccination (Day 0), two weeks (Day 14) and one month (Day 30) after theadministration of the challenge dose to evaluate the anti-HAV and anti-HBs antibodyresponse. At the request of the Czech authorities the challenge dose study isdescribed in a separate protocol (HAB-168 BST:160 [111572]) for the Belgian andCzech centers. The eligibility criteria, study visit procedures and data collection willbe identical in the two studies and the data will be combined with this study foranalysis.Section 2.1 Co-Primary objectivesChallenge dose studyTo evaluate the anti-HAV and anti-HBs immune memory (in terms of anti-HAV andanti-HBs immune response elicited by the challenge dose) in a population > 41 years ofage (healthy and non-healthy), approximately 12 48 months after the Year 3 long-termfollow-up time point first dose of the primary vaccination course.Section 3 Study Design OverviewChallenge dose study

• Experimental design: open, randomized, multicentre study with three parallelgroups.

• The challenge dose study is described in this protocol for the German centersand in a separate protocol (HAB-168 BST:160 [111572]) for the Belgian andCzech centers. The eligibility criteria, study visit procedures and data collectionwill be identical in the two studies and the data will be combined with this studyfor analysis.

The study design was updated to clarify the challenge dose phase of the study.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 253fb0b009324aa43dbd8458969316ad24d


28 March 2008 110

Section 4.1 Number of subjects/centresAll subjects who have completed the primary vaccination course will be invited toparticipate in the challenge dose study.For the challenge dose studyAll 590 subjects who have completed the primary vaccination course will be invitedto participate in the challenge dose study. A total of 219 subjects are expected to berecruited in the German centres (described in this protocol) and 276 subjects areexpected to be recruited in the Belgian and Czech centres (described in a separateprotocol with E track number 111572).

4.3 Exclusion criteria for enrolment


• Acute disease at the time of enrolment. (Acute disease is defined as the presence ofa moderate or severe illness with or without fever. All vaccines can beadministered to persons with a minor illness such as diarrhea, mild upperrespiratory infection with or without low-grade febrile illness, i.e., Oral/ axillarytemperature <37.5°C [< 37.0°C for Czech Republic only]).

• Female planning to become pregnant or planning to discontinue contraceptiveprecautions during the primary vaccination period (up to Month 7, does not applyto the challenge dose phase)

4.5 Contraindications to subsequent vaccination

• Acute disease at the time of vaccination. (Acute disease is defined as the presenceof a moderate or severe illness with or without fever. All vaccines can beadministered to persons with a minor illness such as diarrhea, mild upperrespiratory infection with or without low-grade febrile illness, i.e., Oral/ axillarytemperature <37.5°C. at the time of vaccination. [< 37.0°C for Czech Republiconly]).

Section 5.1.1 Institutional Review Board/Independent Ethics Committee(IRB/IEC)The IRB/IEC must be constituted according to the local laws/customs of the eachparticipating country.

Section 5.4 Outline of proceduresTables 1, 2 and 3: List of study proceduresThe tables were modified and Month 49 was replaced with Day 30 after Month 48.

Table 4: The interval between Visit 1 and Visit 8 has been changed from 48 ± 2months to 48-60 months. Month 49 was replaced by Day 30 after challenge dose.

Section 5.5 Detailed description of study stages/ visitsVisit 10: Month 49 (One month [Day 30] after the challenge vaccine dose)

• Return of completed diary cards from subjects

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 254fb0b009324aa43dbd8458969316ad24d


28 March 2008 111

Section 5.6 Sample handling and analysisSamples will not be labelled with information that directly identifies the subjects butwill be coded with the identification number for the subject.Collected samples may be used for purposes related to the quality assurance of thelaboratory tests described in this protocol. This may include the management of thequality of these current tests, the maintenance or improvement of these current tests,the development of new test methods for the markers described in this protocol, aswell as making sure that new tests are comparable to previous methods and workreliably.It may be that any findings in the present or in other studies necessitate furtherinvestigation by GSK Biologicals into the efficacy or immunogenicity of the Twinrix,Engerix-B and Havrix vaccines and its constituents under study or further researchin the hepatitis A and hepatitis B diseases under study.Under these circumstances,additional testing on the samples may be performed by GSK Biologicals outside thescope of this protocol.A GSK Biologicals Research & Development Position Paper is available whichdescribes the rationale for and some examples of what these further investigationsmight include.Any sample testing will be done in line with the consent of the individual subject.Any human pharmacogenetic testing will require specific consent from theindividual subjects and the ethics committee approval. Any anti-HIV testing will alsorequire specific consent and ethics committee approval.Refer also to protocol Appendix B, where it is noted that the Investigator cannotperform any other biological assays except those described in the protocol or itsamendment(s).Collected samples will be stored for up to 15 years (counting from when the lastsubject performed the last study visit), unless local rules, regulations or guidelinesrequire different timeframes or different procedures, which will then be in line withthe subject consent. These extra requirements need to be communicated formally toand discussed and agreed with GSK Biologicals.Section 5.6.3 Serology plan


Day 14after

Month 489 Anti-HBs



Month 49Day 30after

Month 4810 Anti-HBs


Table 12: Footnote changed.*Fever is defined as axillary temperature ≥37.5°C / oral temperature ≥ 37.5°C [< 37.0°C for CzechRepublic only].

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 255fb0b009324aa43dbd8458969316ad24d


28 March 2008 112

Section 6.9 Concomitant medication/ treatmentAll concomitant medication, with the exception of vitamins and/or dietarysupplements, administered at ANY time during the period starting 7 days before theadministration of the first vaccine dose and ending at the Month 7 visit, i.e. one month(minimum 30 days) after the last vaccine dose, is to be recorded by the subject. For thechallenge dose of the study, all concomitant medication, with the exception of vitaminsand/ or dietary supplements, administered at any time during the period starting 7 daysbefore the administration of the challenge dose and ending at the Month 49 visit, i.eone month (minimum 30 days) after the challenge dose is to be recorded by the subject.The investigator will verify and complete the subject�s records. The generic name ofthe medication (trade names are allowed for combination drugs, i.e. multi-componentdrugs), medical indication, total daily dose, route of administration, start and end datesof treatment, will be transcribed into the medication pages of the CRF for anymedication taken up to Month 7 reported by the subject.

Section 8.8.2. Completion and transmission of serious adverse event reports toGSK BiologicalsStudy Contact for Reporting SAEs

Germany:



Belgium:

GlaxoSmithKline BiologicalsRue de L�Institut 89B-1330 Rixensart, BelgiumTel: : Fax: Section 10.2 Secondary endpointsChallenge dose study

Immunogenicity


• Percentage of subjects with anti-HBs antibody titres ≥ 3.3 mIU/ml, ≥ 10 mIU/ml,≥ 100 mIU/ml and anti-HBs geometric mean titres (GMTs) calculated onseropositive subjects, two weeks and one month after the challenge dose.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 256fb0b009324aa43dbd8458969316ad24d


28 March 2008 113

Section 10.3 Estimated sample sizeChallenge dose studyThe sample size for the challenge dose study is not estimated using any power basedcomputations.

A total of 596 subjects were enrolled in the primary study of which 590 subjectscompleted the study and 583 subjects have participated in the last available long-termfollow up visit at Month 24 (Year 2). Thus, considering a drop-out rate of 15% fromthe Month 24 time point, we can expect about 495 subjects to participate in thechallenge dose study and an evaluable 445 subjects. Of these, 219 subjects areexpected to be recruited in the German centers (described in this protocol) and 276subjects in the Belgian and Czech centers (Challenge phase described in protocolwith E-track number 111572).The footnote in Table 14 was modified to clarify that the number of subjects in thesample size included subjects from all centres.

Section 10.4 Study cohorts to be evaluatedLong-term (LT) total vaccinated cohort

The long-term total vaccinated cohort will include all subjects who received at leastone dose of the study vaccine in the primary study and who returned for the Month48 blood sampling time point.

Section 10.6 Final analysesThe challenge dose study is described in this protocol for the German centers and ina separate protocol (HAB-168 BST: 160 [111572]) for the Belgian and Czechcenters. The eligibility criteria, study visit procedures and data collection will beidentical in the two studies and the data will be combined with this study for analysis.One integrated clinical study report will describe this analysis.

Section 10.6.3 Analysis of safety

• The percentage of subjects with at least one local adverse event (solicited andunsolicited), with at least one general adverse event (solicited and unsolicited) andwith any adverse event (solicited and unsolicited) during the 4-day (Day 0 to Day3) follow-up period after the vaccination will be tabulated with exact 95% CI.Similar tabulations will be done for grade 3 symptoms and symptoms that will leadto a medically attended visit.

• The percentage of subjects reporting each individual solicited symptom during the4-day follow-up period with exact 95% CI, by type of adverse event; by severity(any grade, grade 3 only); for general symptoms: by relationship to vaccination(any relationship, related only) and medically attended visit for each symptom willbe tabulated.

• The occurrence of fever will be tabulated per 0.5 °C cumulative increments as wellas the occurrence of fever (> 39.5 °C oral/axillary temperature) with causalrelationship to vaccination and medically attended fever.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 257fb0b009324aa43dbd8458969316ad24d


28 March 2008 114

Appendix C Overview of recruitment plan All 590 subjects who have completed the primary vaccination course will be invitedto participate in the challenge dose study. A total of 219 subjects are expected to berecruited in the German centres (described in this protocol) and 276 subjects in theBelgian and Czech centres (described in protocol with E-track number 111572) Ifany subject refuses to participate in the study, the reasons for non-participation willbe recorded in the tracking document.

Appendix E Shipment of Biological SamplesInstructions for Shipment of Serum Samples (for centres in Belgium)Serum samples should be sent to GSK Biologicals at regular intervals. The frequencyof shipment of samples should be decided upon by the Site Monitor, Central StudyCoordinator and the investigator prior to the study start.Serum samples should always be sent by contract courier designated by the sponsor,unless otherwise requested by the sponsor.Serum samples must be placed with dry ice (maximum -20°C) in a containercomplying with International Air Transport Association (IATA) requirements. Thecompleted standard serum listing form should always accompany the shipment.The container must be clearly identified with the labels provided by GSK Biologicalsspecifying the shipment address and the storage temperature (-20°C).Details of the shipment, including: * number of samples

E date of transfershould be sent by fax, two days before shipment, to:




Telephone: Fax:

E-mail: GLAXOSMITHKLINE BIOLOGICALS

Clinical Serology Laval525 Boulevard Cartier Ouest

Laval, Québec, Canada H7V 3S8Telephone:

E-mail :

Appendix G Vaccine supplies, packaging and accountabilityHBVAXPRO� will be supplied in pre-filled syringes for the challenge dose study.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 258fb0b009324aa43dbd8458969316ad24d


28 March 2008 115


Protocol Amendment ApprovaleTrack study numbersand abbreviated titles





Approved by:Sponsor Signatory title

Manager,Global Clinical Research andDevelopment, Paediatrics/Hepatitisvaccines

dd-mm-yyyy

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 259fb0b009324aa43dbd8458969316ad24d


28 March 2008 116

GlaxoSmithKline BiologicalsClinical Research & DevelopmentProtocol Amendment Approval



Protocol title: A phase IV, open, randomized, multicentre, multicountrystudy to evaluate the effect of several risk factors likely toinfluence the immunogenicity of GlaxoSmithKlineBiologicals� combined hepatitis A and hepatitis B vaccineTwinrix according to a 0, 1 and 6 month schedule, ascompared to separately administered monovalent hepatitisA (0, 6 months) and hepatitis B vaccines (0, 1, 6 months)from different manufacturers, as well as to demonstratethe non-inferiority of Twinrix to the monovalentvaccines, in healthy and non-healthy adults aged 41 yearsor older.

Amendment number: Amendment 2Amendment date: 25 January 2008Agreed by:Investigator:

Investigator signature:

Date:

�Leiter der klinischen Prüfung�(LKP) name:

Dr. med. (Administrative change 128 March 2008)

LKP signature Date

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 260fb0b009324aa43dbd8458969316ad24d


28 March 2008 117


Protocol Administrative Change Approval FormeTrack study numbers andabbreviated titles


Protocol title: A phase IV, open, randomized, multicentre,multicountry study to evaluate the effect of several riskfactors likely to influence the immunogenicity ofGlaxoSmithKline Biologicals’ combined hepatitis Aand hepatitis B vaccine Twinrix according to a 0, 1and 6 month schedule, as compared to separatelyadministered monovalent hepatitis A (0, 6 months) andhepatitis B vaccines (0, 1, 6 months) from differentmanufacturers, as well as to demonstrate the non-inferiority of Twinrix to the monovalent vaccines, inhealthy and non-healthy adults aged 41 years or older.

Administrative changenumber:

Administrative change 1

Administrative change date: 28 March 2008Co-ordinating author: Scientific writerRationale/background for changes:An administrative change is being made to the protocol to reflect the change in LKPfrom Dr. med. Habil. to Dr. med. Amended text has been included in bold italics in the following section:

Page 116 Protocol Amendment Approval

“Leiter der klinischen Prüfung�(LKP) name:

Dr. med. Habil.

Dr. med. Approved by:

Manager, Global ClinicalResearch and Development,Paediatrics/Hepatitis vaccines

For internal use only

------------Checksum------------!Ver.!Created Onc677eafa029f75fc20becd65d7572335 4.9 07/04/2008 ------------------------------------------------

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 261fb0b009324aa43dbd8458969316ad24d


28 March 2008 118


Protocol Administrative Change Approval FormeTrack study numbers andabbreviated titles


Protocol title: A phase IV, open, randomized, multicentre,multicountry study to evaluate the effect of several riskfactors likely to influence the immunogenicity ofGlaxoSmithKline Biologicals’ combined hepatitis Aand hepatitis B vaccine Twinrix according to a 0, 1and 6 month schedule, as compared to separatelyadministered monovalent hepatitis A (0, 6 months) andhepatitis B vaccines (0, 1, 6 months) from differentmanufacturers, as well as to demonstrate the non-inferiority of Twinrix to the monovalent vaccines, inhealthy and non-healthy adults aged 41 years or older.

Administrative changenumber:

Administrative change 1

Administrative change date: 28 March 2008Agreed by:Investigator:

Investigator signature:

Date:

“Leiter der klinischenPrüfung� (LKP) name:

Dr. med.

LKP signature Date

For internal use only ------------Checksum------------!Ver.!Created On

c677eafa029f75fc20becd65d7572335 4.9 07/04/2008 ------------------------------------------------

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 262fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 263fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 264fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 265fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 266fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 267fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 268fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 269fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 270fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 271fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 272fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 273fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 274fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 275fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 276fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 277fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 278fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 279fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 280fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 281fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 282fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 283fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 284fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 285fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL 111149 (HAB-160 BST) Amendment 2

25 January 2008 108


Protocol Amendment Approval






Coordinating author: Scientific Writers

Rationale/background for changes: The protocol is being amended to reflect thedescription of the challenge dose phase of this study in a separate protocol (HAB-168BST:160 [111572]) for the Czech and Belgian centres that participated in the primarystudy HAB-160 at the request of the Czech authorities. The eligibility criteria, studyvisit procedures and data collection will be identical in the two studies and the data willbe combined with this study for analysis.

To allow sufficient recruitement of eligible subjects for the challenge dose study in allcenters, the timing for administration of the challenge dose is extended to 48-60months.

The protocol also reflected the change in the sponsor signatory from to and the change in LKP from Dr. med. habil.

to Dr. med. Habil.

CONFIDENTIAL

111149 (HAB-160 BST)Amendment 2

25 January 2008 108721bbc8e3f9e061c4e6b81f486b78a94

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 286fb0b009324aa43dbd8458969316ad24d


25 January 2008 109

Amended text has been included in bold italics in the following sections:



• Central Study Coordinator• Manager, Global Clinical

Research and Development, Paediatrics/Hepatitisvaccines


• BiometricianSection 1.2 Rationale for the studyFinally, to evaluate the immune memory to HBV and HAV antigens in thispopulation, all All subjects (irrespective of their serological status) will receive achallenge dose of the vaccine that they received in the primary study, approximately 12months after the Year 3 long-term follow-up time point approximately 48 months afterthe first dose of the primary vaccination course. A blood sample will be taken at thetime of vaccination (Day 0), two weeks (Day 14) and one month (Day 30) after theadministration of the challenge dose to evaluate the anti-HAV and anti-HBs antibodyresponse. At the request of the Czech authorities the challenge dose study isdescribed in a separate protocol (HAB-168 BST:160 [111572]) for the Belgian andCzech centers. The eligibility criteria, study visit procedures and data collection willbe identical in the two studies and the data will be combined with this study foranalysis.Section 2.1 Co-Primary objectivesChallenge dose studyTo evaluate the anti-HAV and anti-HBs immune memory (in terms of anti-HAV andanti-HBs immune response elicited by the challenge dose) in a population > 41 years ofage (healthy and non-healthy), approximately 12 48 months after the Year 3 long-termfollow-up time point first dose of the primary vaccination course.Section 3 Study Design OverviewChallenge dose study

• Experimental design: open, randomized, multicentre study with three parallelgroups.

• The challenge dose study is described in this protocol for the German centersand in a separate protocol (HAB-168 BST:160 [111572]) for the Belgian andCzech centers. The eligibility criteria, study visit procedures and data collectionwill be identical in the two studies and the data will be combined with this studyfor analysis.

The study design was updated to clarify the challenge dose phase of the study.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 287fb0b009324aa43dbd8458969316ad24d


25 January 2008 110

Section 4.1 Number of subjects/centresAll subjects who have completed the primary vaccination course will be invited toparticipate in the challenge dose study.For the challenge dose studyAll 590 subjects who have completed the primary vaccination course will be invitedto participate in the challenge dose study. A total of 219 subjects are expected to berecruited in the German centres (described in this protocol) and 276 subjects areexpected to be recruited in the Belgian and Czech centres (described in a separateprotocol with E track number 111572).

4.3 Exclusion criteria for enrolment


• Acute disease at the time of enrolment. (Acute disease is defined as the presence ofa moderate or severe illness with or without fever. All vaccines can beadministered to persons with a minor illness such as diarrhea, mild upperrespiratory infection with or without low-grade febrile illness, i.e., Oral/ axillarytemperature <37.5°C [< 37.0°C for Czech Republic only]).

• Female planning to become pregnant or planning to discontinue contraceptiveprecautions during the primary vaccination period (up to Month 7, does not applyto the challenge dose phase)

4.5 Contraindications to subsequent vaccination

• Acute disease at the time of vaccination. (Acute disease is defined as the presenceof a moderate or severe illness with or without fever. All vaccines can beadministered to persons with a minor illness such as diarrhea, mild upperrespiratory infection with or without low-grade febrile illness, i.e., Oral/ axillarytemperature <37.5°C. at the time of vaccination. [< 37.0°C for Czech Republiconly]).

Section 5.1.1 Institutional Review Board/Independent Ethics Committee(IRB/IEC)The IRB/IEC must be constituted according to the local laws/customs of the eachparticipating country.

Section 5.4 Outline of proceduresTables 1, 2 and 3: List of study proceduresThe tables were modified and Month 49 was replaced with Day 30 after Month 48.

Table 4: The interval between Visit 1 and Visit 8 has been changed from 48 ± 2months to 48-60 months. Month 49 was replaced by Day 30 after challenge dose.

Section 5.5 Detailed description of study stages/ visitsVisit 10: Month 49 (One month [Day 30] after the challenge vaccine dose)

• Return of completed diary cards from subjects

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 288fb0b009324aa43dbd8458969316ad24d


25 January 2008 111

Section 5.6 Sample handling and analysisSamples will not be labelled with information that directly identifies the subjects butwill be coded with the identification number for the subject.Collected samples may be used for purposes related to the quality assurance of thelaboratory tests described in this protocol. This may include the management of thequality of these current tests, the maintenance or improvement of these current tests,the development of new test methods for the markers described in this protocol, aswell as making sure that new tests are comparable to previous methods and workreliably.It may be that any findings in the present or in other studies necessitate furtherinvestigation by GSK Biologicals into the efficacy or immunogenicity of the Twinrix,Engerix-B and Havrix vaccines and its constituents under study or further researchin the hepatitis A and hepatitis B diseases under study.Under these circumstances,additional testing on the samples may be performed by GSK Biologicals outside thescope of this protocol.A GSK Biologicals Research & Development Position Paper is available whichdescribes the rationale for and some examples of what these further investigationsmight include.Any sample testing will be done in line with the consent of the individual subject.Any human pharmacogenetic testing will require specific consent from theindividual subjects and the ethics committee approval. Any anti-HIV testing will alsorequire specific consent and ethics committee approval.Refer also to protocol Appendix B, where it is noted that the Investigator cannotperform any other biological assays except those described in the protocol or itsamendment(s).Collected samples will be stored for up to 15 years (counting from when the lastsubject performed the last study visit), unless local rules, regulations or guidelinesrequire different timeframes or different procedures, which will then be in line withthe subject consent. These extra requirements need to be communicated formally toand discussed and agreed with GSK Biologicals.Section 5.6.3 Serology plan


Day 14after

Month 489 Anti-HBs



Month 49Day 30after

Month 4810 Anti-HBs


Table 12: Footnote changed.*Fever is defined as axillary temperature ≥37.5°C / oral temperature ≥ 37.5°C [< 37.0°C for CzechRepublic only].

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 289fb0b009324aa43dbd8458969316ad24d


25 January 2008 112

Section 6.9 Concomitant medication/ treatmentAll concomitant medication, with the exception of vitamins and/or dietarysupplements, administered at ANY time during the period starting 7 days before theadministration of the first vaccine dose and ending at the Month 7 visit, i.e. one month(minimum 30 days) after the last vaccine dose, is to be recorded by the subject. For thechallenge dose of the study, all concomitant medication, with the exception of vitaminsand/ or dietary supplements, administered at any time during the period starting 7 daysbefore the administration of the challenge dose and ending at the Month 49 visit, i.eone month (minimum 30 days) after the challenge dose is to be recorded by the subject.The investigator will verify and complete the subject�s records. The generic name ofthe medication (trade names are allowed for combination drugs, i.e. multi-componentdrugs), medical indication, total daily dose, route of administration, start and end datesof treatment, will be transcribed into the medication pages of the CRF for anymedication taken up to Month 7 reported by the subject.

Section 8.8.2. Completion and transmission of serious adverse event reports toGSK BiologicalsStudy Contact for Reporting SAEs

Germany:



Belgium:

GlaxoSmithKline BiologicalsRue de L�Institut 89B-1330 Rixensart, BelgiumTel: : Fax: Section 10.2 Secondary endpointsChallenge dose study

Immunogenicity


• Percentage of subjects with anti-HBs antibody titres ≥ 3.3 mIU/ml, ≥ 10 mIU/ml,≥ 100 mIU/ml and anti-HBs geometric mean titres (GMTs) calculated onseropositive subjects, two weeks and one month after the challenge dose.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 290fb0b009324aa43dbd8458969316ad24d


25 January 2008 113

Section 10.3 Estimated sample sizeChallenge dose studyThe sample size for the challenge dose study is not estimated using any power basedcomputations.

A total of 596 subjects were enrolled in the primary study of which 590 subjectscompleted the study and 583 subjects have participated in the last available long-termfollow up visit at Month 24 (Year 2). Thus, considering a drop-out rate of 15% fromthe Month 24 time point, we can expect about 495 subjects to participate in thechallenge dose study and an evaluable 445 subjects. Of these, 219 subjects areexpected to be recruited in the German centers (described in this protocol) and 276subjects in the Belgian and Czech centers (Challenge phase described in protocolwith E-track number 111572).The footnote in Table 14 was modified to clarify that the number of subjects in thesample size included subjects from all centres.

Section 10.4 Study cohorts to be evaluatedLong-term (LT) total vaccinated cohort

The long-term total vaccinated cohort will include all subjects who received at leastone dose of the study vaccine in the primary study and who returned for the Month48 blood sampling time point.

Section 10.6 Final analysesThe challenge dose study is described in this protocol for the German centers and ina separate protocol (HAB-168 BST: 160 [111572]) for the Belgian and Czechcenters. The eligibility criteria, study visit procedures and data collection will beidentical in the two studies and the data will be combined with this study for analysis.One integrated clinical study report will describe this analysis.

Section 10.6.3 Analysis of safety

• The percentage of subjects with at least one local adverse event (solicited andunsolicited), with at least one general adverse event (solicited and unsolicited) andwith any adverse event (solicited and unsolicited) during the 4-day (Day 0 to Day3) follow-up period after the vaccination will be tabulated with exact 95% CI.Similar tabulations will be done for grade 3 symptoms and symptoms that will leadto a medically attended visit.

• The percentage of subjects reporting each individual solicited symptom during the4-day follow-up period with exact 95% CI, by type of adverse event; by severity(any grade, grade 3 only); for general symptoms: by relationship to vaccination(any relationship, related only) and medically attended visit for each symptom willbe tabulated.

• The occurrence of fever will be tabulated per 0.5 °C cumulative increments as wellas the occurrence of fever (> 39.5 °C oral/axillary temperature) with causalrelationship to vaccination and medically attended fever.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 291fb0b009324aa43dbd8458969316ad24d


25 January 2008 114

Appendix C Overview of recruitment plan All 590 subjects who have completed the primary vaccination course will be invitedto participate in the challenge dose study. A total of 219 subjects are expected to berecruited in the German centres (described in this protocol) and 276 subjects in theBelgian and Czech centres (described in protocol with E-track number 111572) Ifany subject refuses to participate in the study, the reasons for non-participation willbe recorded in the tracking document.

Appendix E Shipment of Biological SamplesInstructions for Shipment of Serum Samples (for centres in Belgium)Serum samples should be sent to GSK Biologicals at regular intervals. The frequencyof shipment of samples should be decided upon by the Site Monitor, Central StudyCoordinator and the investigator prior to the study start.Serum samples should always be sent by contract courier designated by the sponsor,unless otherwise requested by the sponsor.Serum samples must be placed with dry ice (maximum -20°C) in a containercomplying with International Air Transport Association (IATA) requirements. Thecompleted standard serum listing form should always accompany the shipment.The container must be clearly identified with the labels provided by GSK Biologicalsspecifying the shipment address and the storage temperature (-20°C).Details of the shipment, including: * number of samples

E date of transfershould be sent by fax, two days before shipment, to:




Telephone: Fax:

E-mail: GLAXOSMITHKLINE BIOLOGICALS

Clinical Serology Laval525 Boulevard Cartier Ouest

Laval, Québec, Canada H7V 3S8Telephone:

E-mail :

Appendix G Vaccine supplies, packaging and accountabilityHBVAXPRO� will be supplied in pre-filled syringes for the challenge dose study.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 292fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 293fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 294fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 295fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 296fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 297fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 298fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 299fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 300fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 301fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 302fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 303fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 304fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 305fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 306fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 307fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 308fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 309fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 310fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 311fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL

25 Jan 2008 1

Sponsor:GlaxoSmithKline Biologicals

Rue de l�Institut 89,1330 Rixensart, Belgium

Study vaccine number 208127 (Bio HAB)103860 (Bio HBV)208109 (Bio HAV)

Study vaccines GlaxoSmithKline (GSK) Biologicals� combinedhepatitis A/hepatitis B vaccine Twinrix� Adult

GSK Biologicals� hepatitis B vaccine Engerix�-B

GSK Biologicals� hepatitis A vaccine Havrix�

Aventis Pasteur MSD�s hepatitis B vaccineHB VAX PRO� and hepatitis A vaccine Vaqta�

eTrack study number andabbreviated title

111572 (HAB-168 BST:160)

EudraCT number 2008-000526-39Date of protocol 25 January 2008 (Final)Title Challenge dose administration of Twinrix� or

comparator 4 years after primary vaccination.

Detailed Title A phase IV, open, multicentre, multicountry study toevaluate the immune response to a challenge dose ofGSK Biologicals� Twinrix� vaccine versusmonovalent hepatitis A and B vaccines from differentmanufacturers in healthy and non-healthy adults aged> 41 years, approximately 48 months after primaryvaccination in study 100382 (HAB-160).

Co-ordinating author Scientific writerContributing authors Manager, Clinical R&D, Hepatitis

Vaccines

Central Study Co-ordinator

BiostatisticianGSK Biologicals� Protocol DS V 12.5

Copyright 2007 the GlaxoSmithKline group of companies. All rights reserved.Unauthorized copying or use of this information is prohibited.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final

25 Jan 2008 16a941b30c86dff13c2e84a0fd3025a64

CONFIDENTIAL


28 Aug 2009 1698a9ea0cd04d3fd7877fbc4172fc0150c

CONFIDENTIAL


28 Aug 2009 312fb0b009324aa43dbd8458969316ad24d

111572 (HAB-168 BST 160)CONFIDENTIAL Final

25 Jan 2008 2

Protocol Sponsor Signatory Approval


111572 (HAB-168 BST:160)


Date of protocol 25 January 2008 (Final)

Detailed Title A phase IV, open, multicentre, multicountry study toevaluate the immune response to a challenge dose ofGSK Biologicals’ Twinrix™ vaccine versusmonovalent hepatitis A and B vaccines from differentmanufacturers in healthy and non-healthy adults aged> 41 years, approximately 48 months after primaryvaccination in study 100382 (HAB-160).

Sponsor signatory: Manager, Clinical R&D, HepatitisVaccines

Signature:

Date:


6a941b30c86dff13c2e84a0fd3025a64 1.2 11/02/2008 ------------------------------------------------

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 313fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 3

Protocol Investigator Agreement

I agree:

• To assume responsibility for the proper conduct of the study at this site.

• To conduct the study in compliance with this protocol, any mutually agreed futureprotocol amendments, and with any other study conduct procedures provided byGlaxoSmithKline Biologicals (GSK Biologicals).

• To ensure that all persons assisting me with the study are adequately informed aboutthe GSK Biologicals investigational product(s) and other study-related duties andfunctions as described in the protocol.

• Not to implement any changes to the protocol without agreement from the sponsorand prior review and written approval from the Institutional Review Board (IRB) orIndependent Ethics Committee (IEC), except where necessary to eliminate animmediate hazard to the subjects, or where permitted by all applicable regulatoryrequirements (for example, for administrative aspects of the study).

• That I am thoroughly familiar with the appropriate use of the vaccine(s), as describedin this protocol, and any other information provided by the sponsor, including, butnot limited to, the following: the current Investigator’s Brochure (IB) or equivalentdocument, IB supplement (if applicable), prescribing information (in the case of amarketed vaccine).

• That I am aware of, and will comply with, “Good Clinical Practice” (GCP) and allapplicable regulatory requirements.

• That I have been informed that certain regulatory authorities require the sponsor toobtain and supply, as necessary, details about the investigator’s ownership interest inthe sponsor or the investigational product, and more generally about his/her financialties with the sponsor. GSK Biologicals will use and disclose the information solelyfor the purpose of complying with regulatory requirements.

Hence I:

• Agree to supply GSK Biologicals with any necessary information regardingownership interest and financial ties (including those of my spouse and dependentchildren).

• Agree to promptly update this information if any relevant changes occur during thecourse of the study and for 1 year following completion of the study.

• Agree that GSK Biologicals may disclose any information it has about suchownership interests and financial ties to regulatory authorities.

• Agree to provide GSK Biologicals with an updated Curriculum Vitae and other FDArequired documents.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 314fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 4


111572 (HAB-168 BST:160)


Date of protocol 25 January 2008 (Final)

Detailed Title A phase IV, open, multicentre, multicountry study toevaluate the immune response to a challenge dose ofGSK Biologicals’ Twinrix™ vaccine versus monovalenthepatitis A and B vaccines from different manufacturersin healthy and non-healthy adults aged > 41 years,approximately 48 months after primary vaccination instudy 100382 (HAB-160).

Investigator name:

Investigator signature Date


6a941b30c86dff13c2e84a0fd3025a64 1.2 11/02/2008 ------------------------------------------------

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 315fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 5

Synopsis

Detailed Title A phase IV, open, multicentre, multicountry study to evaluatethe immune response to a challenge dose of GSK Biologicals’Twinrix™ vaccine versus monovalent hepatitis A and Bvaccines from different manufacturers in healthy and non-healthy adults aged > 41 years, approximately 48 months afterprimary vaccination in study 100382 (HAB-160).

Indication/Studypopulation

Healthy and non-healthy (including those taking medications)adults older than 41 years who participated in the primaryvaccination study HAB-160 approximately 48 months ago.

Rationale In the current study the immune memory to HBV and HAVantigens in this population will be evaluated. All subjects(irrespective of their serological status) will receive achallenge dose, of the vaccine that they received in theprimary study HAB-160 approximately 48 months after thefirst dose of the primary vaccination course. A blood samplewill be taken at Day 0, two weeks (Day 14) and one month(Day 30) after the administration of the challenge dose toevaluate the anti-HAV and anti-HBs antibody response.

The challenge dose study is described in this protocol for theBelgian and the Czech centres. For the German centres it isdescribed in an amendment to the HAB-160 (111149)protocol. The eligibility criteria, study visit procedures anddata collection will be identical in the two studies and the datawill be combined with this study for analysis.

Objectives Primary

To evaluate the anti-HAV and anti-HBs immune memory (interms of anti-HAV and anti-HBs immune response elicited bythe challenge dose) in a population > 41 years of age (healthyand non-healthy), approximately 48 months after the first doseof the primary vaccination course.

Secondary

• To evaluate the long-term persistence elicited by Twinrix,Engerix-B /Havrix and HB VAX PRO /Vaqta, in terms ofanti-HAV seropositivity rates and GMTs as well as anti-HBs seropositivity rates, seroprotection rates and GMTsat Month 48.

• To evaluate the immune response to the challenge dose,two weeks (Day 14) and one month (Day 30) aftervaccination.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 316fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 6

• To retrospectively evaluate all serious adverse events(SAEs) with causal relationship to vaccination orreferring to hepatitis A or B infection from the previousstudy visit up to Month 48.

• To evaluate safety and reactogenicity of the challengedose in terms of:

− solicited symptoms occurring during the 4-day (Day 0to Day 3) follow-up period.

− unsolicited symptoms occurring during the 31-day(Day 0 to Day 30) follow-up period.

− all SAEs following the challenge dose administration.

Study design • Experimental design: open, multicentre study with threeparallel groups.


• Treatment groups for the challenge dose study will be thesame as in the HAB-160 primary study: all subjects willreceive one dose of Twinrix, Engerix-B co-administeredwith Havrix or HBVAXPRO co-administered with Vaqtaaccording to their randomization in the primaryvaccination study.


• Study duration: Approximately one month per subjectafter he/she receives the challenge dose.

• The challenge dose study is described in this protocol forthe Belgian and Czech centres and in an amendment tothe HAB-160 (111149) protocol for the German centres.The eligibility criteria, study visit procedures and datacollection will be identical in the two studies and the datawill be combined with this study for analysis.

Number of subjects All 590 subjects who have completed the primary vaccinationcourse in study HAB-160 will be invited to participate in thechallenge dose study. 276 subjects are expected to berecruited in the Belgian and Czech centres (described in thisprotocol) and 219 subjects in the German centres (described inan amendment to the HAB-160 protocol).

Primary endpoint • Anti-HAV immune response to the challenge dose isdefined as:

− Anti-HAV antibody titres ≥ 15 mIU/ml at one monthpost-challenge dose in subjects, seronegative at thepre-challenge time point.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 317fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 7

− At least a 2-fold increase in anti-HAV antibody titresone month after the challenge dose, in subjects havinganti-HAV antibody titres ≥ 100 mIU/ml at the pre-challenge time point

− or at least a 4-fold increase in anti-HAV antibodytitres one month after the challenge dose, inseropositive subjects having anti-HAV antibody titres< 100 mIU/ml at the pre-challenge time point.

• Anti-HBs antibody response to the challenge dose isdefined as:

− Anti-HBs antibody titres ≥ 10 mIU/ml at one monthpost-challenge dose in subjects seronegative at thepre-challenge time point.

− At least a 4-fold increase in anti-HBs antibody titres,at one month post-challenge dose in subjectsseropositive at the pre-challenge time point.

Secondary endpoints Immunogenicity

• Anti-HAV seropositivity rates and GMTs, as well as anti-HBs seropositivity rates, seroprotection rates and GMTsat Month 48.

• Percentage of subjects with anti-HAV antibody titres ≥ 15mIU/ml and GMTs calculated on seropositive subjects,two weeks and one month after the challenge dose.

• Percentage of subjects with anti-HBs antibody titres ≥ 3.3mIU/ml, ≥ 10 mIU/ml, ≥ 100 mIU/ml and anti-HBsgeometric mean titres (GMTs) calculated on seropositivesubjects, two weeks and one month after the challengedose.

Reactogenicity

• Occurrence and intensity of solicited local symptoms inthe 4-day (Day 0 to 3) follow-up period after thechallenge dose.

• Occurrence, intensity and relationship of solicited generalsymptoms in the 4-day (Day 0 to 3) follow-up periodafter the challenge dose.

Safety

• Retrospective recording of all serious adverse events(SAEs) with causal relationship to vaccination orreferring to hepatitis A or B infection that occurred sincethe last study visit of the HAB-160 long-term follow-upstudy.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 318fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 8

• Occurrence, intensity and relationship to vaccination ofunsolicited symptoms reported during the 31-day (Day 0to 30) follow-up period after the challenge dose.

• Occurrence, intensity and relationship to vaccination ofall SAEs following the administration of the challengedose.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 319fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 9

TABLE OF CONTENTS

PAGE

SYNOPSIS......................................................................................................................5

LIST OF ABBREVIATIONS...........................................................................................14

GLOSSARY OF TERMS ...............................................................................................16

TRADEMARKS .............................................................................................................19

1. INTRODUCTION....................................................................................................201.1. Background ................................................................................................201.2. Rationale for the study................................................................................21

2. OBJECTIVES.........................................................................................................212.1. Primary objective ........................................................................................212.2. Secondary objectives..................................................................................21

3. STUDY DESIGN OVERVIEW ................................................................................22

4. STUDY COHORT...................................................................................................234.1. Number of subjects / centres ......................................................................234.2. Inclusion criteria..........................................................................................234.3. Exclusion criteria for enrolment...................................................................244.4. Elimination criteria during the study ............................................................244.5. Contraindications to subsequent vaccination ..............................................244.6. Warnings and Precautions..........................................................................25

5. CONDUCT OF STUDY ..........................................................................................275.1. Ethics and regulatory considerations ..........................................................27

5.1.1. Institutional Review Board/Independent Ethics Committee(IRB/IEC) .....................................................................................28

5.1.2. Informed consent .........................................................................295.2. General study aspects ................................................................................315.3. Subject identification...................................................................................315.4. Outline of study procedures ........................................................................325.5. Detailed description of study stages/visits...................................................345.6. Sample handling and analysis ....................................................................36

5.6.1. Treatment and storage of biological samples...............................375.6.2. Laboratory assays .......................................................................375.6.3. Serology plan...............................................................................38

6. INVESTIGATIONAL PRODUCTS AND ADMINISTRATION...................................386.1. Study vaccines............................................................................................386.2. Dosage and administration .........................................................................396.3. Storage.......................................................................................................406.4. Treatment allocation and randomisation .....................................................416.5. Method of blinding and breaking the study blind .........................................416.6. Replacement of unusable vaccine doses....................................................416.7. Packaging...................................................................................................41

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 320fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 10

6.8. Vaccine accountability ................................................................................416.9. Concomitant medication/treatment .............................................................41

7. HEALTH ECONOMICS ..........................................................................................42

8. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS.....................................428.1. Definition of an adverse event.....................................................................428.2. Definition of a serious adverse event ..........................................................438.3. Lack of efficacy...........................................................................................448.4. Clinical laboratory parameters and other abnormal assessments

qualifying as adverse events and serious adverse events...........................458.5. Time period, frequency, and method of detecting adverse events

and serious adverse events ........................................................................458.5.1. Solicited adverse events ..............................................................47

8.6. Evaluating adverse events and serious adverse events..............................478.6.1. Assessment of intensity ...............................................................478.6.2. Assessment of causality ..............................................................49

8.7. Follow-up of adverse events and serious adverse events andassessment of outcome..............................................................................50

8.8. Prompt reporting of serious adverse events to GSK Biologicals..................518.8.1. Time frames for submitting serious adverse event reports

to GSK Biologicals .......................................................................528.8.2. Completion and transmission of serious adverse event

reports to GSK Biologicals ...........................................................528.9. Regulatory reporting requirements for serious adverse events ...................548.10. Post-study adverse events and serious adverse events..............................548.11. Pregnancy ..................................................................................................548.12. Treatment of adverse events ......................................................................55

9. SUBJECT COMPLETION AND WITHDRAWAL.....................................................559.1. Subject completion .....................................................................................559.2. Subject withdrawal......................................................................................55

9.2.1. Subject withdrawal from the study ...............................................559.2.2. Subject withdrawal from investigational product...........................56

9.3. Extension study ..........................................................................................56

10. DATA EVALUATION: CRITERIA FOR EVALUATION OF OBJECTIVES ...............5610.1. Primary endpoints.......................................................................................5610.2. Secondary endpoints ..................................................................................5710.3. Estimated sample size ................................................................................5710.4. Study cohorts to be evaluated.....................................................................58

10.4.1. Long-term (LT) total vaccinated cohort ........................................5810.4.2. LT ATP cohort for analysis of immunogenicity .............................5810.4.3. Total Vaccinated cohort (Challenge dose) ...................................5910.4.4. According-To-Protocol (ATP) cohort for analysis of safety

(Challenge dose) .........................................................................5910.4.5. ATP cohort for analysis of immunogenicity (Challenge

dose) ...........................................................................................5910.5. Derived and transformed data.....................................................................5910.6. Final analyses.............................................................................................61

10.6.1. Analysis of demographics/baseline characteristics ......................6110.6.2. Analysis of immunogenicity..........................................................61

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 321fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 11

10.6.3. Analysis of safety (Challenge dose) .............................................6210.7. Planned interim analysis .............................................................................62

11. ADMINISTRATIVE MATTERS ...............................................................................63

12. REFERENCES.......................................................................................................63

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 322fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 12

LIST OF TABLES

PAGE



Table 3 List of study procedures: HB VAX PRO /Vaqta Group............................34




Table 7 Reporting periods for adverse events and serious adverseevents ....................................................................................................46



Table 10 Intensity scales for solicited symptoms...................................................48


CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 323fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 13

APPENDICES

PAGE

Appendix A Administrative Matters............................................................................64

Appendix B Overview of the Recruitment Plan ..........................................................70

Appendix C Handling of Biological Samples Collected by the Investigator ................71

Appendix D Shipment of Biological Samples .............................................................74

Appendix E Laboratory Assays .................................................................................76

Appendix F Vaccine supplies, packaging and accountability.....................................77

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 324fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 14

List of Abbreviations


Anti-HBc Antibody to hepatitis B core antigen



ATP-LT Long term According-To-Protocol cohort

BMI Body Mass Index

CDC Centres for Disease Control and Prevention

CRF Case Report Form

CRA Clinical Research Associate

CSC Central Study Coordinator

EIA Enzyme-immunoassay

EISR Expedited Investigator Safety Report

EL.U. ELISA Units

eTrack Clinical Trial Management System

FDA Food and Drug Administration, United States

GCP Good Clinical Practice

GMT Geometric Mean Titre

GSK GlaxoSmithKline



HBc Hepatitis B core antigen

HBsAg Hepatitis B surface antigen


ICH International Committee on Harmonization

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 325fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 15



IU International Units

µg Microgram

mg Milligram





SBIR Central randomization call-in system on Internet

SOP Standard Operating Procedure

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 326fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 16

Glossary of Terms

Adverse event: Any untoward medical occurrence in a patient or clinicalinvestigation subject, temporally associated with the useof a medicinal product, whether or not considered relatedto the medicinal product.

An AE can therefore be any unfavourable and unintendedsign (including an abnormal laboratory finding),symptom, or disease (new or exacerbated) temporallyassociated with the use of a medicinal product. Formarketed medicinal products, this also includes failure toproduce expected benefits (i.e. lack of efficacy), abuse ormisuse.

Blinding: A procedure in which one or more parties to the trial arekept unaware of the treatment assignment in order toreduce the risk of biased study outcomes. In a single-blind trial, the investigator and/or his staff are aware ofthe treatment assignment but the subject is not. In anobserver-blind study, the subject and the study personnelinvolved in the clinical evaluation of the subjects areblinded while other study personnel may be aware of thetreatment allocation (see Section 6.5 for details onobserver-blinded studies). When the investigator andsponsor staff who are involved in the treatment or clinicalevaluation of the subjects and review/analysis of data arealso unaware of the treatment assignments, the study isdouble blind. Partially-blind is to be used for studydesigns with different blinding levels between differentgroups, e.g. double-blinded consistency lots which areopen with respect to the control group. The level ofblinding is maintained throughout the conduct of the trial,and only when the data are cleaned to an acceptable levelof quality will appropriate personnel be unblinded orwhen required in case of a serious adverse event.

Central StudyCo-ordinator:

An individual assigned by GSK Biologicals Headquarterswho is responsible for assuring the co-ordination of theoperational aspects and proper conduct of a clinical study,including compliance with International Conference onHarmonisation (ICH) Harmonised Tripartite Guidelinefor Good Clinical Practice (GCP) and GSK policies andstandard operating procedures.

Eligible: Qualified for enrolment into the study based upon strictadherence to inclusion/exclusion criteria.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 327fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 17

eTrack: GSK’s clinical trials tracking tool

Evaluable: Meeting all eligibility criteria, complying with theprocedures defined in the protocol, and, therefore,included in the according-to-protocol (ATP) analysis (seeSections 4.4 and 10.4 for details on criteria forevaluability).

Investigational product: A pharmaceutical form of an active ingredient or placebobeing tested or used as a reference in a clinical trial,including a product with a marketing authorisation whenused in a way different from the approved form, or whenused for an unapproved indication, or when used to gainfurther information about an approved use.

Medical Monitor: An individual medically qualified to assume theresponsibilities of the sponsor (GSK Biologicals)especially in regards to the ethics, clinical safety of astudy and the assessment of adverse events.

Protocol amendment: ICH defines a protocol amendment as: “A writtendescription of a change(s) to or formal clarification of aprotocol.” GSK Biologicals further details this to includea change to an approved protocol that affects the safety ofsubjects, scope of the investigation, study design, orscientific integrity of the study.

Protocol administrativechange:

A protocol administrative change addresses changes toonly logistical or administrative aspects of the study.N.B. Any change that falls under the definition of aprotocol amendment (e.g. a change that affects the safetyof subjects, scope of the investigation, study design, orscientific integrity of the study) MUST be prepared as anamendment to the protocol.

Randomisation: Process of random attribution of treatment to subjects inorder to reduce bias of selection

Site Monitor: An individual assigned by the sponsor who is responsiblefor assuring proper conduct of clinical studies at one ormore investigational sites.

Solicited adverse event: Adverse events (AEs) to be recorded as endpoints in theclinical study. The presence/occurrence/intensity of theseevents is actively solicited from the subject or an observerduring a specified post-vaccination follow-up period.

Study Monitor: An individual assigned by the sponsor who is responsible

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 328fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 18

for assuring proper conduct of a clinical study.

Subject: Term used throughout the protocol to denote anindividual that has been contacted in order to participateor participates in the clinical study, either as a recipient ofthe investigational product(s) or as a control.

Subject number: A unique number identifying a subject, assigned to eachsubject consenting to participate in the study.

Treatment: Term used throughout the clinical study to denote a set ofinvestigational product(s) or marketed product(s) orplacebo intended to be administered to a subject,identified by a unique number, according to the studyrandomisation or treatment allocation.

Treatment number: A unique number identifying a treatment to a subject,according to the study randomisation or treatmentallocation.

Unsolicited adverseevent:

Any adverse event (AE) reported in addition to thosesolicited during the clinical study. Also any “solicited”symptom with onset outside the specified period offollow-up for solicited symptoms will be reported as anunsolicited adverse event.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 329fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 19

Trademarks

Twinrix™* GlaxoSmithKline (GSK) Biologicals' combinedhepatitis A/hepatitis B vaccine

Engerix™-B* GSK Biologicals hepatitis B vaccine

Havrix™* GSK Biologicals’ hepatitis A vaccine

HBVAXPRO™ Aventis Pasteur MSD’s hepatitis B vaccine

Vaqta™ Aventis Pasteur MSD’s hepatitis A vaccine

* is the Trademark of the GlaxoSmithKline group of companies

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 330fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 20

1. INTRODUCTION

1.1. Background

Hepatitis A and hepatitis B infections represent the most frequent forms of viralinfections of the liver. These diseases cause serious public health problems and affectcommunities worldwide. Hepatitis A infection caused by the hepatitis A virus (HAV), amember of the Hepatovirus genus in the Picornavirus family, is transmitted via the faecaloral route. HA infection is symptomatic following a short incubation period of 3 to 6weeks [Lemon, 1985]. The hepatitis B virus (HBV) is a member of the Hepadnaviridaefamily. HBV requires a longer incubation period, from 6 weeks to 6 months, and isspread principally by exposure to contaminated blood and body fluids [Purcell, 1994].Chronic carriers of HBV have an increased risk of developing cirrhosis or primaryhepatocellular carcinoma of the liver.

It has been recognised that vaccination is the only method conferring long-termprotection against HAV and HBV clinical disease and/or infection. GlaxoSmithKlineBiologicals has developed a combined hepatitis A/hepatitis B vaccine Twinrixadministered according to a 3-dose schedule (0, 1, 6 months). Several studies, conductedin mainly young subjects, have shown that the immunogenicity and safety of Twinrix isat least as good as that of the monovalent vaccines Engerix�-B and Havrix� givenconcomitantly.

Please refer to the Master Data Sheets for a review of the pre-clinical and clinical studiesand information on Twinrix Adult, Havrix Adult and Engerix-B.

The immune response after vaccination with GSK Biologicals’ combined hepatitis A andB vaccine as well as monovalent hepatitis A and B vaccines from different manufacturersis known to be influenced by several factors including age, gender and BMI [Reutter.1998; White, 1978]. The responses after immunization of elderly individuals withhepatitis A and hepatitis B vaccines is a topic that is becoming increasingly relevant asthe number of aged people travelling to exotic destinations increases.

Approximately 48 months ago, in the primary vaccination study (HAB-160), subjectsaged 41 years or older, with a wide range in body weight and variable general healthstatus were enrolled. The influence of risk factors likely to influence the immuneresponse elicited by Twinrix (e.g. age, gender, body mass index [BMI], smoking, alcoholconsumption, diseases and medications) were assessed. The non-inferiority of Twinrix tothe monovalent vaccines was established in terms of anti-HBs seroprotection rate andanti-HAV seropositivity rate at Month 7. Furthermore, the effects of the risk factors onthe immune response elicited by the separately administered monovalent hepatitis A andhepatitis B vaccines Engerix-B and Havrix as well as HBVAXPRO and Vaqta were alsoassessed.

Additionally, these subjects were followed up for 36 months to determine the evolutionof anti-HBs seropositivity rates and seroprotection rates and the long-term anti-HAVseropositivity rate in this population.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 331fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 21

It was demonstrated in the primary study that the group that received Twinrix showedsignificantly higher anti-HBs seroprotection rates compared to each of the monovalentvaccine groups. The same trend was observed two years after the primary vaccinationcourse. At Year 2, anti-HAV antibody persistence was maintained in all groups andseropositivity rates (> 95%) were similar to those observed at previous time-points (post-primary and at Year 1). However, the percentage of subjects with anti-HBs antibodyconcentrations ≥ 10 mIU/ ml was only 29.9% in the group that received HBVAXPRO andVaqta, 50.0% in the group that received Engerix-B and Havrix and 74.3% in the groupthat received Twinrix. The relatively fast decrease in the percentage of anti-HBsseropositive subjects and percentage of subjects with anti-HBs antibody concentrations ≥10 mIU/ ml could be due to the age of the study population (average age of 57.1 years atYear 2). Recent studies have indicated that immune memory persists beyond the time atwhich anti-HBs antibody levels may no longer be detectable and protects againstclinically relevant disease. In case of exposure to HBV antigen, this immune memoryleads to a rapid and vigorous antibody response [Bauer, 2006].

1.2. Rationale for the study

In the current study the immune memory to HBV and HAV antigens in this populationwill be evaluated. All subjects (irrespective of their serological status) will receive achallenge dose, of the vaccine that they received in the primary study HAB-160approximately 48 months after the first dose of the primary vaccination course. A bloodsample will be taken at Day 0, two weeks (Day 14) and one month (Day 30) after theadministration of the challenge dose to evaluate the anti-HAV and anti-HBs antibodyresponse.

The challenge dose study is described in this protocol for the Belgian and the Czechcentres. For the German centres it is described in an amendment to the HAB-160(111149) protocol. The eligibility criteria, study visit procedures and data collection willbe identical in the two studies and the data will be combined with this study for analysis.

2. OBJECTIVES

2.1. Primary objective

• To evaluate the anti-HAV and anti-HBs immune memory (in terms of anti-HAV andanti-HBs immune response elicited by the challenge dose) in a population > 41 yearsof age (healthy and non-healthy), approximately 48 months after the first dose of theprimary vaccination course.

Refer to Section 10.1 for definition of the primary endpoint.


• To evaluate the long-term persistence elicited by Twinrix, Engerix-B /Havrix andHB VAX PRO /Vaqta, in terms of anti-HAV seropositivity rates and GMTs as well asanti-HBs seropositivity rates, seroprotection rates and GMTs at Month 48.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 332fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 22


• To retrospectively evaluate all serious adverse events (SAEs) with causalrelationship to vaccination or referring to hepatitis A or B infection from theprevious study visit up to Month 48.


− solicited symptoms occurring during the 4-day (Day 0 to Day 3) follow-upperiod.

− unsolicited symptoms occurring during the 31-day (Day 0 to Day 30) follow-upperiod.

− all SAEs following the challenge dose administration.Refer to Section 10.2 for definitions of secondary endpoints.

3. STUDY DESIGN OVERVIEW

Visit 10 One

month after Visit 8

Post-challenge BS






Twinrix (N = 200)



Visit 1 Visit 4

Month 7




Screening












• Treatment groups for the challenge dose study will be the same as in the HAB-160primary study: all subjects will receive one dose of Twinrix, Engerix-B co-administered with Havrix or HBVAXPRO co-administered with Vaqta according totheir randomization in the primary vaccination study.


CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 333fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 23


• The challenge dose study is described in this protocol for the Belgian and Czechcentres and in an amendment to the HAB-160 (111149) protocol for the Germancentres. The eligibility criteria, study visit procedures and data collection will beidentical in the two studies and the data will be combined with this study foranalysis.

4. STUDY COHORT

4.1. Number of subjects / centres

All 590 subjects who have completed the primary vaccination course in study HAB-160will be invited to participate in the challenge dose study. 276 subjects are expected to berecruited in the Belgian and Czech centres (described in this protocol) and 219 subjects inthe German centres (described in an amendment to the HAB-160 protocol).

At the time of initiation of the study, the investigator will contact ALL subjects whocompleted the primary vaccination course in the study 100382 (HAB-160). If at the timeof initiation of the challenge dose study, any subject declines participation, refusal will bedocumented as instructed on the “subject tracking document” provided by GSKBiologicals. The information will be entered in the GSK Biologicals’ clinical database foruse in identification of any safety issue(s) that may have prevented a subject’sparticipation.

See Section 10.3 for a detailed description of the criteria used in the estimation of samplesize for the challenge dose study.

4.2. Inclusion criteria


• A male or female who completed the primary vaccination phase of the HAB-160study.


• If the subject is female, she must be of non-childbearing potential, i.e., eithersurgically sterilized or one year post-menopausal; or, if of childbearing potential, shemust be abstinent or have used adequate contraceptive precautions (i.e., intrauterinecontraceptive device; oral/long term hormonal contraceptives; diaphragm or condomin combination with contraceptive jelly, cream or foam) for 30 days prior tovaccination, have a negative pregnancy test and must agree to continue suchprecautions for two months after the vaccination.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 334fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 24

4.3. Exclusion criteria for enrolment

The following criteria should be checked at the time of study entry. If any apply, thesubject must not be included in the study:

• Use of any investigational or non-registered product (drug or vaccine) other than thestudy vaccines within 30 days preceding the challenge dose, or planned use duringthe study period.

• History of any hepatitis A or hepatitis B vaccination or infection since the primaryvaccination study.


• Acute disease at the time of enrolment. (Acute disease is defined as the presence of amoderate or severe illness with or without fever. All vaccines can be administered topersons with a minor illness such as diarrhoea, mild upper respiratory infection withor without low-grade febrile illness, i.e., Oral/ axillary temperature <37.5°C) [37.0°Cfor Czech Republic only].

• Pregnant or lactating female.

4.4. Elimination criteria during the study

The following criteria should be checked at each visit subsequent to the first visit. If anybecome applicable during the study, it will not require withdrawal of the subject from thestudy but may determine a subject’s evaluability in the according-to-protocol (ATP)analysis. See Section 10.4 for definition of study cohorts to be evaluated.


4.5. Contraindications to subsequent vaccination

The following events constitute absolute contraindications to administration of Twinrix,Engerix-B /Havrix, or HB VAX PRO /Vaqta; if any of these events occurred during theprimary study HAB-160, the subject must not receive the challenge dose of the vaccinesbut may continue other study procedures at the discretion of the investigator (see Section9). The subject must be followed until resolution of the event (see Section 8.7):

• Anaphylactic reaction following the administration of vaccines.The following events constitute contraindications to administration of Twinrix, orEngerix-B /Havrix, or HB VAX PRO /Vaqta at that point in time; if any one of theseevents occurs at the time scheduled for vaccination, the subject may be vaccinated at alater date, within the time window specified in the protocol (see Section 5.3), orwithdrawn at the discretion of the investigator (see Section 9). The subject must befollowed until resolution of the event (see Section 8.7).

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 335fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 25

• Acute disease at the time of vaccination. (Acute disease is defined as the presence ofa moderate or severe illness with or without fever. All vaccines can be administeredto persons with a minor illness such as diarrhoea, mild upper respiratory infectionwith or without low-grade febrile illness, i.e., Oral/ axillary temperature <37.5°C.[< 37.0°C for Czech Republic only] at the time of vaccination.)

4.6. Warnings and Precautions

Twinrix

• As with other vaccines, the administration of Twinrix should be postponed insubjects suffering from acute severe febrile illness.

• It is possible that subjects may be in the incubation period of a hepatitis A orhepatitis B infection at the time of vaccination. It is not known whether Twinrix willprevent hepatitis A and hepatitis B in such cases.

• The vaccine will not prevent infection caused by other agents such as hepatitis C andhepatitis E and other pathogens known to infect the liver.

• Twinrix is not recommended for post-exposure prophylaxis (e.g. needle stick injury).

• The vaccine has not been tested in patients with impaired immunity. Inhaemodialysis patients and persons with an impaired immune system, adequate anti-HAV and anti-HBs antibody concentrations may not be obtained after the primaryimmunisation course and such patients may therefore require administration ofadditional doses of vaccine.

• Twinrix should under no circumstances be administered intravenously.

Engerix-B


• The vaccine will not prevent infection caused by other pathogens known to infect theliver such as hepatitis A, hepatitis C and hepatitis E virus.


• Engerix-B should not be administered in the buttock or intradermally since this mayresult in a lower immune response.

• Engerix-B should under no circumstances be administered intravascularly.

• As with all injectable vaccines, appropriate medical treatment and supervision shouldalways be readily available in case of rare anaphylactic reactions following theadministration of the vaccine.

• As with any vaccine, a protective immune response may not be elicited in allvaccinees.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 336fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 26

Havrix

• It is possible that subjects may be in the incubation period of a hepatitis A infectionat the time of immunisation. It is not known whether Havrix (1440 ELISA Units)will prevent hepatitis A in such cases.

• In haemodialysis patients and in subjects with an impaired immune system, adequateanti-HAV antibody titres may not be obtained after a single dose of Havrix (1440ELISA Units) and such patients may therefore require administration of additionaldoses of vaccine.

• As with all injectable vaccines, appropriate medical treatment should always bereadily available for treatment in case of anaphylactic reactions following theadministration of the vaccine. For this reason, the vaccinee should remain undermedical supervision for 30 minutes after immunisation.

• Havrix (1440 ELISA Units) should be administered with caution to subjects withthrombocytopenia or a bleeding disorder since bleeding may occur following anintramuscular administration to these subjects.


• Havrix (1440 ELISA Units) should under no circumstances be administeredintravenously.

HBVAXPRO


• Because of the long incubation period for hepatitis B, it is possible for unrecognizedinfection to be present at the time HBVAXPRO is given. HBVAXPRO may notprevent hepatitis B in such patients.

• Patients who develop symptoms suggestive of hypersensitivity after an injectionshould not receive further injections of HBVAXPRO.

• As with any parenteral vaccine, epinephrine (adrenaline) should be available forimmediate use should an anaphylactoid reaction occur. Any serious active infectionis reason for delaying use of HBVAXPRO, except when, in the opinion of thephysician, withholding the vaccine entails a greater risk.

• Caution and appropriate care should be exercised in administering v to individualswith severely compromised cardiopulmonary status or to others in whom a febrile orsystemic reaction could pose a significant risk.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 337fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 27

Vaqta

• As with all injectable vaccines, appropriate medical treatment and supervision shouldalways be readily available in case of a rare anaphylactic event following theadministration of the vaccine.

• Testing for antibodies to hepatitis A prior to a decision on immunisation should beperformed in patients born in areas of high endemicity and/or with a history ofjaundice.

• Vaqta does not cause immediate protection against hepatitis A, and there may be aperiod of 2 to 4 weeks before antibody induction occurs.


• Vaqta will not prevent hepatitis caused by infectious agents other than hepatitis Avirus.

• In subjects with an impaired immune system, adequate anti-HAV antibody titres maynot be obtained. If the immunosuppression is due to medical treatment, vaccinationshould be delayed if possible until the completion of therapy and immune systemrecovery.


• As with any vaccine, vaccination with Vaqta may not result in a protective responsein all susceptible vaccinees.

• As no studies have been performed with Vaqta in subjects with liver disease, cautionis advised if administering the vaccine in these subjects.

5. CONDUCT OF STUDY

5.1. Ethics and regulatory considerations

The study will be conducted according to Good Clinical Practice (GCP), the Declarationof Helsinki, and local rules and regulations of the country.

Submission of the protocol and any protocol amendments to regulatory agencies willoccur in accordance with local regulatory requirements. For some countries, submissionto the local regulatory authority may not be required. When submission to the localregulatory authority is required, the timing of the submission relative to IEC/IRBsubmission or approval and whether or not the authority will provide their approval of orfavourable opinion on the protocol or amendment before it can be implemented willdepend on local regulatory requirements.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 338fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 28

5.1.1. Institutional Review Board/Independent Ethics Committee(IRB/IEC)

The IRB/IEC must be constituted according to the local laws/customs of eachparticipating country. The ICH Harmonized Tripartite Guideline for Good ClinicalPractice recommends that the IRB/IEC should include:

(a) At least five members.

(b) At least one member whose primary area of interest is in a non-scientific area.

(c) At least one member who is independent of the institution/ study site.

Only those IRB/IEC members who are independent of the investigator and the sponsor ofthe study should vote/ provide opinion on a study-related matter.

A list of IRB/IEC members and their qualifications should be obtained by theinvestigator.

This protocol and any other documents that the IRB/IEC may need to fulfil itsresponsibilities, including subject recruitment procedures and information aboutpayments and compensation available to subjects will be submitted to the IRB/IEC by theinvestigator. Written unconditional approval of the IRB/IEC must be in the possession ofthe investigator and GSK Biologicals before commencement of the study. This approvalmust refer to the study by exact protocol title and number, and should identify thedocuments reviewed and state the date of review. Relevant GSK Biologicals’ data will besupplied by GSK Biologicals’ Study Monitor to the hospital/ university/ independentIRB/IEC for review and approval of the protocol. Verification of IRB/IEC unconditionalapproval of the protocol and the written informed consent statement will be transmittedby the investigator to GSK Biologicals’ Study Monitor, i.e., Central Study Coordinator(CSC) using the standard notification form, prior to shipment of vaccine supplies to thesite.

No deviations from, or changes to, the protocol should be initiated without prior writtensponsor and IRB/IEC approval/ favourable opinion of an appropriate amendment, exceptwhen necessary to eliminate immediate hazards to the subjects or when the change(s)involves only logistical or administrative aspects of the study (e.g., change of monitor[s],telephone number[s].) Modifications are submitted to the IRB/IEC for information only.However, written verification that the modification was submitted should be obtained.Approvals/ verifications must be transmitted in writing to GSK Biologicals’ StudyMonitor, by the investigator.

The IRB/IEC must be informed by the investigator of:

• all subsequent protocol amendments, informed consent changes or revisions of otherdocuments originally submitted for review,

• serious and/or unexpected adverse events occurring during the study, where required,

• all subsequent protocol modifications (for information, except for US studies),

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 339fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 29

• new information that may affect adversely the safety of the subjects or the conduct ofthe study,

• an annual update and/or request for re-approval, where required,

• when the study has been completed, where required.If a trial is prematurely terminated or suspended for reasons including safety or ethicalissues or severe non-compliance, the sponsor will promptly inform the regulatoryauthorities of the termination or suspension and the reason(s) for the termination orsuspension. If required by applicable regulations, the investigator must inform theIEC/IRB promptly and provide the reason for the suspension or termination (seeAppendix B for further details).

5.1.2. Informed consent

In obtaining and documenting informed consent, the investigator should comply with theapplicable regulatory requirement(s), and should adhere to GCP and to the ethicalprinciples in the Declaration of Helsinki. Prior to the beginning of the trial, theinvestigator should have the IRB/IEC’s written approval/favourable opinion of thewritten informed consent form and any other written information to be provided to thesubjects.

Freely given informed consent should be obtained from every subject prior to clinicaltrial participation.

Information should be given in both oral and written form whenever possible and asdeemed appropriate by the IRB/IEC.

An investigator or designate will describe the protocol to potential subjects face to face.The Informed Consent Form may be read to the subjects, but, in any event, theinvestigator or designate shall give the subjects ample opportunity to inquire about detailsof the study and ask any questions before dating and signing the Informed Consent Form.

While informed consent information can be presented to groups at an initial informationsession, each subject must be given the opportunity to individually pose questions to theinvestigator or designate prior to the subject dating and signing the Informed ConsentForm.

Informed Consent Forms must be in a language fully comprehensible to the prospectivesubjects. Informed consent shall be documented by the use of a written consent formapproved by the IRB/IEC and signed and dated by the subjects and by the person whoconducted the informed consent discussion. The signature confirms the consent is basedon information that has been understood. All illiterate individuals will have the study, theSubject Information and Consent Form explained to them point by point by theinterviewer in the presence of an impartial witness. The witness will personally sign anddate the consent form. Oral witnessed consent will replace written consent only incountries where the local custom is contrary or if the subject’s incapacity precludes thisand provided that the local legal obligations are fulfilled.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 340fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 30

Each subject's signed informed consent form must be kept on file by the investigator forpossible inspection by Regulatory Authorities and/or GSK Biologicals’ professional andRegulatory Compliance persons. The subjects should receive a copy of the signed anddated written informed consent form and any other written information provided to thesubjects, and should receive copies of any signed and dated consent form updates. Anyamendments to the written information will be provided to subjects.

Both the informed consent discussion and the written informed consent form and anyother written information to be provided to the subjects should include explanations ofthe following:

(a) That the trial involves research.

(b) The purpose of the trial.

(c) The trial treatment(s) and the probability for random assignment to each treatment.

(d) The trial procedures to be followed, including all invasive procedures.

(e) The subject’s responsibilities.

(f) Those aspects of the trial that are experimental.

(g) The reasonably foreseeable risks or inconveniences to the subjects and, whenapplicable, to an embryo, fetus or nursing infant.

(h) The reasonable expected benefits. When there is no intended clinical benefit tosubjects, the subjects should be made aware of this.

(i) The alternative procedure(s) or course(s) of treatment/ methods of prevention thatmay be available to subjects, and their important potential benefits and risks.

(j) The compensation and/or treatment available to subjects in the event of trial-relatedinjury.

(k) The anticipated prorated payment, if any, to subjects for participating in the trial.

(l) The anticipated expenses, if any, to subjects for participating in the trial.

(m) That the subjects’ participation in the trial is voluntary and subjects may refuse toparticipate or withdraw from the trial, at any time, without penalty or loss of benefitsto which subjects are otherwise entitled.

(n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) willbe granted direct access to the subject’s original medical records for verification ofclinical trial procedures and/or data, without violating the confidentiality of subjects,to the extent permitted by the applicable laws and regulations and that, by signing awritten informed consent, the subject is authorizing such access.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 341fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 31

(o) That records identifying subjects will be kept confidential and, to the extent permittedby the applicable laws and/or regulations, will not be made publicly available. If theresults of the trial are published, subjects’ identity will remain confidential.

(p) That the subjects will be informed in a timely manner if information becomesavailable that may be relevant to the subjects’ willingness for continued participationin the trial.

(q) The person(s) to contact for further information regarding the trial and the rights oftrial subjects, and who to contact in the event of trial-related injury.

(r) The foreseeable circumstances and/or reasons under which a subject’s participation inthe trial may be terminated.

(s) The expected duration of a subject’s participation in the trial.

(t) The approximate number of subjects involved in the trial.

GSK Biologicals will prepare a representative subject information sheet/informedconsent document which will embody all the elements described above. While it isstrongly recommended that this representative document be followed as closely aspossible, the informed consent requirements given in this document are not intended topre-empt any local regulations which require additional information to be disclosed forinformed consent to be legally effective. Clinical judgement, local regulations andrequirements should guide the final structure and content of the document.

The investigator has the final responsibility for the final presentation of the subjectinformation sheet/informed consent document, respecting the mandatory requirements oflocal regulations. The consent form generated by the investigator with the assistance ofthe local sponsor’s representative, must be approved (along with the protocol, and anyother necessary documentation) by the IRB/IEC and be acceptable to GSK Biologicals.

5.2. General study aspects

Not applicable.

5.3. Subject identification

The subjects participating in the challenge dose study will keep the same subject numbersas assigned in the primary study (HAB-160).

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 342fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 32

5.4. Outline of study procedures

Table 1 List of study procedures: Twinrix Group

Visit VISIT 8 VISIT 9 VISIT 10Timing Month 48 Day 14 after Month 48 Day 30 after Month 48

Sampling timepoint Pre-challenge dose Post-challenge dose Post-challenge doseInformed consent •Check inclusion criteria •Check exclusion criteria •Check elimination criteria ○ ○Check contraindications •Check warnings and precautions •Physical examination ○Recording of concomitant medication bysubjects on diary card

•

Transcription of concomitant medication •Return of medication diary card •Pre-vaccination body temperature •Pregnancy test (urine test) •Blood sampling for Ab determination (5 ml) • • •Vaccination Twinrix •Daily post-vaccination recording of solicitedsymptoms (Days 0�3) by subjects

•


•

Transcription of diary cards by investigator •Reporting of SAEs • •Study Conclusion •• Study procedure that requires documentation in the individual CRF or SAE form, ○ is used to indicate a studyprocedure that does not require documentation in the individual CRF.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 343fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 33


Visit VISIT 8 VISIT 9 VISIT 10

Timing Month 48 Day 14 afterMonth 48

Day 30 afterMonth 48

Sampling timepoint Pre-challengedose

Post-challengedose

Post-challengedose

Informed consent •Check inclusion criteria •Check exclusion criteria •Check elimination criteria ○ ○Check contraindications •Check warnings and precautions •Physical examination ○Recording of concomitant medication by subjects on diarycard

•

Transcription of concomitant medication •Return of medication diary card •Pre-vaccination body temperature •Pregnancy test (urine test) •Blood sampling for Ab determination (5 ml) • • •Vaccination Engerix-B

Havrix••

Daily post-vaccination recording of solicited symptoms(Days 0�3) by subjects

•

Recording of non-serious adverse events within 30 dayspost-vaccination, by investigator

•

Transcription of diary cards by investigator •Reporting of SAEs • •Study Conclusion ••Study procedure that requires documentation in the individual CRF or SAE form, O is used to indicate a studyprocedure that does not require documentation in the individual CRF.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 344fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 34

Table 3 List of study procedures: HB VAX PRO /Vaqta Group

Visit VISIT 8 VISIT 9 VISIT 10Timing Month 48 Day 14 after Month

48Day 30

after Month48

Sampling timepoint Pre-challenge dose Post-challenge dose Post-challenge

doseInformed consent •Check inclusion criteria •Check exclusion criteria •Check elimination criteria ○ ○Check contraindications •Check warnings and precautions •Physical examination ○Recording of concomitant medication bysubjects on diary card

•

Transcription of concomitant medication •Return of medication diary card •Pre-vaccination body temperature •Pregnancy test (urine test) •Blood sampling for Ab determination (5 ml) • • •VaccinationHB VAX PROVaqta

••

Daily post-vaccination recording of solicitedsymptoms (Days 0�3) by subjects

•

Recording of non-serious adverse eventswithin 30 days post-vaccination, by investigator

•

Transcription of diary cards by investigator •Reporting of SAEs • •Study Conclusion ••Study procedure that requires documentation in the individual CRF or SAE form, ○ is used to indicate a studyprocedure that does not require documentation in the individual CRF.

It is the investigator’s responsibility to ensure that the intervals between visits are strictlyfollowed. These intervals determine each subject’s evaluability in the according-to-protocol analyses (see Sections 4.4 and 10.4 for details of criteria for evaluability andcohorts to be analyzed).

The interval between the primary vaccination course (that is the first visit in HAB-160)and Visit 8 is expected to be approximately 48-60 months. The interval between Visit 8and Visit 9 is defined as 14 ± 2 days and that between Visit 8 and Visit 10 is defined as30 to 48 days.

5.5. Detailed description of study stages/visits

When materials are provided by GSK Biologicals, it is MANDATORY that all clinicalsamples (including serum samples) will be collected and stored using exclusively thosematerials in the appropriate manner. The use of other materials could result in theexclusion of the subject from the ATP analysis (See Section 10.4 for definition of study

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 345fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 35

cohorts to be evaluated). The investigator must ensure that his/her personnel and thelaboratory(ies) under his/her supervision comply with this requirement. However, whenGSK Biologicals does not provide material for collecting and storing clinical samples,then appropriate materials from the investigator’s site are to be used. Refer to AppendixC and Appendix D.

Visit 8: Month 48 (Challenge dose visit)


• Check inclusion/exclusion criteria

• The investigator must ask each subject in a retrospective manner if the subject hassuffered any unreported serious adverse event(s) or hepatitis A or B infection sincethe last study contact of the long term follow-up of the primary study HAB-160.

• The investigator will then document in the SAE forms:

− The reported SAE(s) that he/she considers to have a causal relationship tovaccination.

− Hepatitis A or B infection, in this study reported as SAE (as defined perprotocol). See Section 8.3 Lack of efficacy.


• Check contraindications for the challenge dose (Twinrix, Engerix-B/ Havrix orHBVAXPRO/ Vaqta)


• Check warnings and precautions.

• Physical examination



• Challenge dose of the vaccine that the subjects received in the primary study will beadministered to all subjects at Visit 8 (Month 48). Please refer to the guidelines setout in Section 6.2.

• The vaccinees will be observed closely for at least 30 minutes, with appropriatemedical treatment readily available in case of a rare anaphylactic reaction followingthe administration of vaccine.

• Diary cards will be provided to the subject to record the following information:

− Any solicited local or general adverse events on the day of vaccination and onthe 3 subsequent days for a total of 4 days of follow-up (Day 0-3).

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 346fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 36

− Any other (unsolicited) adverse event on the day of vaccination and thesubsequent 30 days (Days 0-30) after vaccination.

• The subject will be instructed to return their completed diary card to the investigatorat the next study visit.

• The subject will be instructed to contact the investigator immediately should thesubject manifest any signs or symptoms they perceive as serious.

• Recording of concomitant medication/vaccination.

• Recording of all SAEs occurring following vaccination. The investigator willdocument the reported SAE(s) in the SAE forms.

Visit 9: Day 14 after the challenge vaccine dose


Visit 10: One month [Day 30] after the challenge vaccine dose


• The subject’s records of medication will be verified and transcribed by theinvestigator to update the concomitant medication section in the CRF.

• The subject will return the completed diary card to the investigator from the previousvisit. The investigator will collect and verify them. He/She will transcribe theinformation into the appropriate sections of the CRF, in English. Any unreturneddiary cards will be sought from the subjects through any convenient procedure.


• Recording of any unsolicited adverse events which may have occurred within onemonth (minimum 30 days) following administration of the challenge dose.

• Transcription of concomitant medication/vaccination in the appropriate sections ofthe CRF.

• Recording of SAEs: The investigator will document the reported SAE(s) in the SAEforms.

• Study conclusion.

5.6. Sample handling and analysis

Samples will not be labelled with information that directly identifies the subjects but willbe coded with the identification number for the subject.

Collected samples may be used for purposes related to the quality assurance of thelaboratory tests described in this protocol. This may include the management of thequality of these current tests, the maintenance or improvement of these current tests, the

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 347fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 37

development of new test methods for the markers described in this protocol, as well asmaking sure that new tests are comparable to previous methods and work reliably.

It may be that any findings in the present or in other studies necessitate furtherinvestigation by GSK Biologicals into the efficacy or immunogenicity of the Twinrix,Engerix-B and Havrix vaccines and its constituents under study or further research in thehepatitis A and hepatitis B diseases under study. Under these circumstances, additionaltesting on the samples may be performed by GSK Biologicals outside the scope of thisprotocol.

A GSK Biologicals Research & Development Position Paper is available which describesthe rationale for and some examples of what these further investigations might include.

Any sample testing will be done in line with the consent of the individual subject.

Any human pharmacogenetic testing will require specific consent from the individualsubjects and the ethics committee approval. Any anti-HIV testing will also requirespecific consent and ethics committee approval.

Refer also to protocol Appendix A, where it is noted that the Investigator cannot performany other biological assays except those described in the protocol or its amendment(s).

If additional testing is performed, the marker priority ranking given in Section 5.6.3 maybe changed.

Collected samples will be stored for up to 15 years (counting from when the last subjectperformed the last study visit), unless local rules, regulations or guidelines requiredifferent timeframes or different procedures, which will then be in line with the subjectconsent. These extra requirements need to be communicated formally to and discussedand agreed with GSK Biologicals.

5.6.1. Treatment and storage of biological samples

See Appendix C of the protocol for details of treatment and storage of biological samples.

See Appendix D for instructions for shipment of biological samples.

5.6.2. Laboratory assays

At the time of vaccination, two weeks and one month after the administration of thechallenge dose, approximately 5 ml of whole venous blood will be collected formeasurement of anti-HAV and anti-HBs antibody concentrations.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 348fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 38


Marker Assaymethod


Assayunit

Assaycut-off

Laboratory

Anti-HAV EIA Enzygnost ® Anti-HAV*/DADE Behring mIU/ml 15 mIU/ml GSK Bio**

Anti-HBs EIA In-house assay mIU/ml 3.3 mIU/ml GSK Bio**

*: Or equivalent.** 0r in a validated laboratory designated by GSK BiologicalsEIA: Enzyme immunoassay.

The GSK Biologicals’ clinical laboratories have established a Quality System supportedby procedures. The activities of GSK Biologicals’ clinical laboratories are auditedregularly for quality assessment by an internal (sponsor-dependent) but laboratory-independent Quality Department.

5.6.3. Serology plan

In case of insufficient blood sample volume to perform assays for all antibodies, thesamples will be analyzed according to the following priority ranking, detailed in Table 5.


Blood sampling timepointTiming Day/ Month Visit no. Marker Laboratory

siteNo.


ranking

Pre-challenge dose Day 0 8 Anti-HBsAnti-HAV GSK ** All Anti-HBs (1)



One MonthPost-challenge dose Day 30 10 Anti-HBs


* In a validated laboratory designated by the investigator**GlaxoSmithKline Biologicals� (Belgium) central laboratory, or in a validated laboratory designated by GlaxoSmithKlineBiologicals.

Any additional serology on antigens contained in the study vaccines will be performed ifdeemed necessary by GlaxoSmithKline Biologicals if any findings in the present study orin other studies necessitate investigation of the immunogenicity of the vaccine. In thiscase, the ranking above may also be changed.

6. INVESTIGATIONAL PRODUCTS AND ADMINISTRATION

6.1. Study vaccines

The vaccines Twinrix, Engerix-B and Havrix to be used have been developed andmanufactured by GSK Biologicals. The Quality Control Standards and Requirements forthese vaccines are described in separate release protocols and the required approvals havebeen obtained.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 349fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 39

The vaccines HB VAX PRO and Vaqta used in this study have been developed andmanufactured by Aventis Pasteur MSD. Commercial vaccines are assumed to complywith the specifications given in the manufacturer's Summary of Product Characteristics.

All subjects will receive a challenge dose of the same vaccine that they received in theprimary study.

GlaxoSmithKline Biologicals’ combined hepatitis A and hepatitis B vaccine TwinrixAdult will be supplied in pre-filled syringes (PFS) containing a dose volume of 1 ml:

Hepatitis A antigen (strain HM 175 RIT 4380): at least 720 ELISA unitsHBsAg (Recombinant antigen): 20 µgAluminium (as salt): 0.45 mgThiomersal: <2 µg2-phenoxyethanol: 5 mg

GlaxoSmithKline Biologicals’ recombinant hepatitis B vaccine, Engerix-B will besupplied in PFS containing per 1.0 ml dose:

HBsAg (Recombinant antigen): 20 µgAluminium (as salt): 0.5 mgThiomersal: <2 µg

GlaxoSmithKline Biologicals’ inactivated hepatitis A vaccine, Havrix will be supplied inPFS containing per 1.0 ml dose:

Hepatitis A antigen (strain HM 175): at least 1440 ELISA UnitsAluminium (as salt): 0.5 mg2-phenoxyethanol: 5 mg

Aventis Pasteur MSD’s recombinant hepatitis B vaccine, HB VAX PRO will be suppliedas 1.0 ml dose:

Hepatitis B (recombinant HBsAg): 10 µgAluminium (as Al (OH) 3): 0.5 mg

Aventis Pasteur MSD’s inactivated hepatitis A vaccine, Vaqta will be supplied as 1.0 mldose:

Hepatitis A antigen (CR 326F strain): 50 IUAluminium (as Al (OH) 3): 0.45 mg

6.2. Dosage and administration

All subjects (irrespective of their serological status) will be given a challenge dose of thesame vaccine that they received in the primary study (HAB-160) at the Month 48 timepoint.The vaccines will be administered as an intramuscular injection in the deltoid region.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 350fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 40

Subjects included in the Twinrix Group will receive Twinrix as an intramuscular injectionin the left deltoid region, using a 23 G, 25 mm needle.

Subjects included in the Engerix-B + Havrix Group will receive concomitantly Havrix(right deltoid region) and Engerix-B (left deltoid region) using a 23 G, 25 mm needle.

Subjects included in the HB VAX PRO+ Vaqta Group will receive concomitantly Vaqta(right deltoid region), and HB VAX PRO (left deltoid region), administered according tothe manufacturer’s recommendations.



Group Visit Day Vaccination Dose Route Site SideTwinrix 8 0 Twinrix 1st IM D L

Engerix-B 1st IM D LEngerix-B +Havrix

8 0Havrix 1st IM D R

HB VAX PRO HB VAX PRO 1st IM D L+Vaqta

8 0Vaqta 1st IM D R

The vaccinees will be observed closely for at least 30 minutes following theadministration of vaccines, with appropriate medical treatment readily available in caseof a rare anaphylactic reaction.

6.3. Storage

All study vaccines to be administered to subjects must be stored in a safe and lockedplace with no access by unauthorised personnel.

A site assessment will be performed during the pre-study activities to ensure that thestudy vaccines will be stored in appropriate conditions during the study.

Study vaccine(s) will be stored at the defined temperature range (i.e. +2 to +8°C).

The storage temperature of study vaccines will be monitored daily while using validatedtemperature monitoring devices and the temperature measurements will be recordedduring working days, preferably at the same time of the day (e.g. at the beginning of theday). Freezing indication will be continuously controlled by an appropriate device placedclose to the study vaccines.

Any temperature deviation, meaning temperature outside the defined range (i.e. +2 to+8°C), must be reported within 2 working days to the Clinical Supplies Unit.

Following exposure to a temperature deviation, the study vaccines will not be used untilwritten approval is given by the sponsor.

Storage conditions for transport of the study vaccine(s) from country medical departmentor dispatch centre to study sites or between sites are described in Appendix F.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 351fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 41

6.4. Treatment allocation and randomisation

The vaccines will be numbered sequentially per group. The site has to take the lowesttreatment number available in the fridge of the vaccine group that the subject received inthe primary study (HAB-160). Subjects will be administered the vaccine dose with thelowest treatment number still available at the study centre. The treatment number must berecorded by the investigator in the eCRF (treatment allocation).

6.5. Method of blinding and breaking the study blind

The study will be conducted in an open manner.

6.6. Replacement of unusable vaccine doses

Additional vaccine doses will be provided to replace those that are unusable (seeAppendix F for details of supplies).

In addition to the vaccine doses provided for the planned number of subjects, 5%additional doses will be supplied. In case a vaccine dose is broken or unusable, theinvestigator should replace it with a replacement vaccine dose. Although the sponsorneed not be notified immediately in these cases, documentation of the use of thereplacement vaccine must be recorded by the investigator on the vaccine administrationscreen of the eCRF and on the vaccine accountability form.

In case a vaccine dose is broken or unusable, the next lowest treatment number availablecan replace the unusable vaccine. Although the sponsor need not be notified immediatelyin these cases (except in the case of cold-chain failure), documentation of the replacementvaccine must be recorded by the investigator on the vaccine accountability form and inthe eCRF.

6.7. Packaging

See Appendix F.

6.8. Vaccine accountability

See Appendix F.

6.9. Concomitant medication/treatment

At each study visit/contact, the investigator should question the subject about anymedication(s) taken.

All concomitant medication, with the exception of vitamins and/ or dietary supplements,administered at any time during the period starting 7 days before the administration of thechallenge dose and ending at one month (minimum 30 days) after the challenge dose is tobe recorded by the subject. The investigator will verify and complete the subject’s

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 352fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 42

records. The generic name of the medication (trade names are allowed for combinationdrugs, i.e., multi-component drugs), medical indication, total daily dose, route ofadministration, start and end dates of treatment, will be transcribed into the medicationscreens of the eCRF for any medication taken up to one month after the challenge dose.

Any vaccine not foreseen in the study protocol administered in the period beginning 30days preceding the challenge dose and ending one month (minimum 30 days) after thechallenge vaccine dose, is to be recorded with trade name, route of administration anddate(s) of administration. See Sections 4.3 and 4.4.

Any concomitant medication administered prophylactically in anticipation of reaction tothe vaccination must be recorded in the eCRF with generic name of the medication (tradenames are allowed for combination drugs only), total daily dose, route of administration,start and end dates of treatment and coded as ‘Prophylactic’.

Concomitant medication administered for the treatment of an SAE must be recorded inthe eCRF with generic name of the medication (trade names are allowed for combinationdrugs only), medical indication (including which SAE), total daily dose, route ofadministration, start and end dates of treatment. Refer to Section 8.2 for definition ofSAE.

7. HEALTH ECONOMICS

Not applicable

8. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS

The investigator is responsible for the detection and documentation of events meeting thecriteria and definition of an adverse event (AE) or serious adverse event (SAE) asprovided in this protocol. During the study, when there is a safety evaluation, theinvestigator or site staff will be responsible for detecting AEs and SAEs, as detailed inthis section of the protocol.

Each subject will be instructed to contact the investigator immediately should theymanifest any signs or symptoms they perceive as serious.

8.1. Definition of an adverse event

An AE is any untoward medical occurrence in a clinical investigation subject, temporallyassociated with the use of a medicinal product, whether or not considered related to themedicinal product.

An AE can therefore be any unfavourable and unintended sign (including an abnormallaboratory finding), symptom, or disease (new or exacerbated) temporally associated withthe use of a medicinal product. For marketed medicinal products, this also includesfailure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 353fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 43


• Significant or unexpected worsening or exacerbation of the condition/indicationunder study. See Section 8.3 ‘Lack of Efficacy’ for additional information.

• Exacerbation of a chronic or intermittent pre-existing condition including eitheran increase in frequency and/or intensity of the condition.

• New conditions detected or diagnosed after investigational productadministration even though it may have been present prior to the start of thestudy.


• Signs, symptoms, or the clinical sequelae of a suspected overdose of eitherinvestigational product or a concurrent medication (overdose per se should notbe reported as an AE/SAE).

• Significant failure of expected pharmacological or biological action. See Section8.3, ‘Lack of Efficacy’ for additional information.

Examples of an AE DO NOT include:

• Medical or surgical procedure (e.g., endoscopy, appendectomy); the conditionthat leads to the procedure is an AE.


• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s)present or detected at the start of the study that do not worsen.

• For therapeutic studies, the disease/disorder being studied, or expectedprogression, signs, or symptoms of the disease/disorder being studied, unlessmore severe than expected for the subject’s condition.

AEs may include pre- or post-treatment events that occur as a result of protocol-mandated procedures (i.e. invasive procedures, modification of subject’s previoustherapeutic regimen).

N.B. AEs to be recorded as endpoints (solicited events) are described in Section 8.5.1.All other AEs will be recorded as UNSOLICITED AES.

Example of events to be recorded in the medical history section of the eCRF:

• Pre-existing conditions or signs and/or symptoms present in a subject prior tothe start of the study (i.e. prior to the first study vaccination).

8.2. Definition of a serious adverse event

A serious adverse event (SAE) is any untoward medical occurrence that:

a. results in death,

b. is life-threatening,

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 354fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 44

NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in whichthe subject was at risk of death at the time of the event. It does not refer to an event,which hypothetically might have caused death, if it were more severe.

c. requires hospitalisation or prolongation of existing hospitalisation,

NOTE: In general, hospitalisation signifies that the subject has been detained (usuallyinvolving at least an overnight stay) at the hospital or emergency ward for observationand/or treatment that would not have been appropriate in the physician�s office or out-patient setting. Complications that occur during hospitalisation are AEs. If acomplication prolongs hospitalisation or fulfils any other serious criteria, the event isserious. When in doubt as to whether �hospitalisation� occurred or was necessary, theAE should be considered serious.

Hospitalisation for elective treatment of a pre-existing condition that did not worsen frombaseline is not considered an AE.

d. results in disability/incapacity, or

NOTE: The term disability means a substantial disruption of a person�s ability to conductnormal life functions. This definition is not intended to include experiences of relativelyminor medical significance such as uncomplicated headache, nausea, vomiting,diarrhoea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere orprevent everyday life functions but do not constitute a substantial disruption.

e. is a congenital anomaly/birth defect in the offspring of a study subject.

f. Medical or scientific judgement should be exercised in deciding whether reporting isappropriate in other situations, such as important medical events that may not beimmediately life-threatening or result in death or hospitalisation but may jeopardizethe subject or may require medical or surgical intervention to prevent one of theother outcomes listed in the above definition. These should also be consideredserious. Examples of such events are invasive or malignant cancers, intensivetreatment in an emergency room or at home for allergic bronchospasm, blooddyscrasias or convulsions that do not result in hospitalisation.

g. Any signs of suspected or confirmed hepatitis A or hepatitis B. See Section 8.3 Lackof efficacy.

8.3. Lack of efficacy

The signs and symptoms, clinical sequelae resulting from lack of clinical efficacy or bothwill be reported. Any signs of suspected or confirmed hepatitis A or hepatitis B since thelast follow up visit (HAB-160 Year 3) till the end of the study (30 days after challengedose) should be reported as an SAE.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 355fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 45

8.4. Clinical laboratory parameters and other abnormalassessments qualifying as adverse events and serious adverseevents

Abnormal laboratory findings (e.g. clinical chemistry, haematology, urinalysis) or otherabnormal assessments (e.g. vital signs) that are judged by the investigator to be clinicallysignificant will be recorded as AEs or SAEs if they meet the definition of an AE, asdefined in Section 8.1 or SAE, as defined in Section 8.2. Clinically significant abnormallaboratory findings or other abnormal assessments that are detected during the study orare present at baseline and significantly worsen following the start of the study will bereported as AEs or SAEs. However, clinically significant abnormal laboratory findings orother abnormal assessments that are associated with the disease being studied, unlessjudged by the investigator as more severe than expected for the subject’s condition, orthat are present or detected at the start of the study and do not worsen, will not bereported as AEs or SAEs.

The investigator will exercise his or her medical and scientific judgement in decidingwhether an abnormal laboratory finding or other abnormal assessment is clinicallysignificant.

8.5. Time period, frequency, and method of detecting adverseevents and serious adverse events

Before administration of the challenge dose, the investigator will document in the SAEform any SAE, which the subject may have experienced since the last study visit of theprimary study HAB-160 (M36 follow-up point)

• That the investigator considers related to vaccination

• That refers to hepatitis A and B infections (reported as SAE as defined per protocol).See Section 8.3 for lack of efficacy.

All AEs occurring within one month (minimum 30 days) following administration of thechallenge dose of vaccine must be recorded onto the Adverse Event screen in thesubject's eCRF, irrespective of intensity or whether or not they are consideredvaccination-related.

The standard time period for collecting and recording SAEs will begin at the receipt ofstudy vaccine and will end one month (minimum 30 days) following administration ofthe challenge dose of study vaccine for each subject. See Section 8.8 for instructions forreporting and recording SAEs.

In addition to the above-mentioned reporting requirements and in order to fulfilinternational reporting obligations, SAEs that are related to study participation (e.g.protocol-mandated procedures, invasive tests, a change from existing therapy) or arerelated to a concurrent GSK medication will be collected and recorded from the time thesubject consents to participate in the study until she/he is discharged.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 356fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 46

An overview of the protocol-required reporting periods for adverse events and seriousadverse events is given in Table 7.

Table 7 Reporting periods for adverse events and serious adverse events

Study activity Pre-vacc.(Consentobtained)

Challenge dose 30 dayspost-challenge dose.

Day 0 Day 30Reporting of AEs

Reporting of SAEs

Pre-vacc.: pre-vaccination

The investigator will inquire about the occurrence of AEs/SAEs at every visit during thestudy.

All AEs either observed by the investigator or one of his clinical collaborators or reportedby the subject spontaneously or in response to a direct question will be evaluated by theinvestigator. AEs not previously documented in the study will be recorded in the AdverseEvent screen within the subject's eCRF. The nature of each event, date and time (whereappropriate) of onset, outcome, intensity and relationship to vaccination should beestablished. Details of any corrective treatment should be recorded on the appropriatescreen of the eCRF. Refer to Section 6.9.

As a consistent method of soliciting AEs, the subject should be asked a non-leadingquestion such as:

"Have you felt different in any way since receiving the vaccine or since the previousvisit?"

N.B. The investigator should record only those AEs having occurred within the timeframe defined above.

AEs already documented in the eCRF, i.e. at a previous assessment, and designated as“not recovered/not resolved” or “recovering/resolving” should be reviewed at subsequentvisits, as necessary. If these have resolved, the documentation in the eCRF should becompleted.

When an AE/SAE occurs, it is the responsibility of the investigator to review alldocumentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relativeto the event. The investigator will then record all relevant information regarding anAE/SAE on the eCRF or SAE Report screens as applicable. It is not acceptable for theinvestigator to send photocopies of the subject’s medical records to GSK Biologicals inlieu of the appropriate completed AE/ SAE screens in the eCRF. However, there may beinstances when copies of medical records for certain cases are requested by GSK

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 357fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 47

Biologicals. In this instance, all subject identifiers will be blinded on the copies of themedical records prior to submission to GSK Biologicals.

The investigator will attempt to establish a diagnosis of the event based on signs,symptoms, and/or other clinical information. In such cases, the diagnosis should bedocumented as the AE/SAE and not the individual signs/symptoms.

The electronic system using SAE screens in the eCRF will be the primary mode forreporting SAEs to GSK Biologicals during the study period. In case this electronicsystem for reporting SAEs does not work or after freezing of the subject's eCRF, paperSAE Report Forms and the facsimile (Fax) system should be used to report SAEs. Referto Section 8.8.2 for details of the back-up reporting system.

8.5.1. Solicited adverse events

A 4-day (Day 0 to 3) follow-up of solicited local adverse events at the injection site andsolicited general adverse events will be performed after vaccination. Data concerning thefollowing adverse events will be solicited using diary cards provided by the sponsor. SeeTable 8 and Table 9 for details of the local and general adverse events that are solicited.

Solicited local (injection site) AEs



Solicited general AEs



Headache�Gastrointestinal symptoms include nausea, vomiting, diarrhoea and/or abdominal pain.

N.B. Temperature will be recorded in the evening. Should additional temperaturemeasurements be performed at other times of day, the highest temperature will berecorded.

8.6. Evaluating adverse events and serious adverse events

8.6.1. Assessment of intensity

Intensity of the following AEs will be assessed as described in Table 10.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 358fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 48

Table 10 Intensity scales for solicited symptoms

Adverse Event Intensity grade ParameterPain at injection site 0 Absent

1 Painful on touch2 Painful when limb is moved3 Pain that prevents normal activity

Redness at injection site Record greatest surface diameter in mmSwelling at injection site Record greatest surface diameter in mmFever* Record temperature in °C / °FHeadache 0 Normal

1 Headache that is easily tolerated2 Headache that interferes with normal activity3 Headache that prevents normal activity

Fatigue 0 Normal1 Fatigue that is easily tolerated2 Fatigue that interferes with normal activity3 Fatigue that prevents normal activity

Gastrointestinal symptoms 0 Gastrointestinal symptoms normal(nausea, vomiting, diarrhoea and/orabdominal pain)

1 Gastrointestinal symptoms that are easily tolerated

2 Gastrointestinal symptoms that interfere with normalactivity

3 Gastrointestinal symptoms that prevent normal activity* Fever is defined as axillary temperature ≥37.5°C / oral temperature ≥ 37.5°C [> 37.0 °C for Czech Republic only]

The maximum intensity of local injection site redness/swelling will be scored at GSKBiologicals as follows:


The intensity of fever will be scored at GSK Biologicals in 0.5°C increments. Oral/axillary temperature > 39.5°C will be scored as fever of grade 3 intensity.

The investigator will make an assessment of the maximum intensity that occurred overthe duration of the event for all other AEs, i.e. unsolicited symptoms, including SAEsreported during the study. The assessment will be based on the investigator’s clinicaljudgement.

The intensity of each AE and SAE recorded in the eCRF or SAE Report screens, asapplicable, should be assigned to one of the following categories:

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 359fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 49

1 (mild) = An AE which is easily tolerated by the subject, causing minimaldiscomfort and not interfering with everyday activities.

2 (moderate) = An AE which is sufficiently discomforting to interfere withnormal everyday activities.

3 (severe) = An AE which prevents normal, everyday activities. (In adults,such an AE would, for example, prevent attendance at work andwould necessitate the administration of corrective therapy.)

An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade3 is a category utilised for rating the intensity of an event; and both AEs and SAEs canbe assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre-defined outcomes as described in Section 8.2.

8.6.2. Assessment of causality

The definitions for “NO” and “YES” have been written in such a way that all events thathave been attributed a “NO” can be pooled with events which in the primary vaccinationstudy were determined to be “not related” or “unlikely to be related” to vaccination.Those events that are attributed a “YES” can be pooled with those events that in the pastwere determined to have a “suspected” or “probable” relationship to vaccination in theprimary vaccination study.

The investigator is obligated to assess the relationship between investigational productand the occurrence of each AE/SAE. The investigator will use clinical judgement todetermine the relationship. Alternative causes, such as natural history of the underlyingdiseases, concomitant therapy, other risk factors and the temporal relationship of theevent to the investigational product will be considered and investigated. The investigatorwill also consult the Investigator Brochure and/or Product Information, for marketedproducts, in the determination of his/her assessment.

There may be situations when a SAE has occurred and the investigator has minimalinformation to include in the initial report to GSK Biologicals. However, it is veryimportant that the investigator always makes an assessment of causality for every eventprior to submission of the SAE to GSK Biologicals. The investigator may change his/heropinion of causality in light of follow-up information, amending the SAE informationaccordingly. The causality assessment is one of the criteria used when determiningregulatory reporting requirements.

In case of concomitant administration of multiple vaccines, it may not be possible todetermine the causal relationship of general AEs to the individual vaccines administered.The investigator should, therefore, assess whether the AE could be causally related tovaccination rather than to the individual vaccines.

All solicited local (injection site) reactions will be considered causally related tovaccination. Causality of all other AEs should be assessed by the investigator using thefollowing question:

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 360fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 50

Is there a reasonable possibility that the AE may have been caused by the investigationalproduct ?

NO : The AE is not causally related to administration of the studyvaccine(s). There are other, more likely causes and administrationof the study vaccine(s) is not suspected to have contributed to theAE.

YES : There is a reasonable possibility that the vaccine(s) contributed tothe AE.

Non-serious and serious AEs will be evaluated as two distinct events. If an event meetsthe criteria to be determined “serious” (see Section 8.2 for definition of serious adverseevent), it will be examined by the investigator to the extent to be able to determine ALLcontributing factors applicable to each serious adverse event.

Other possible contributors include:

• Medical history




• Lack of efficacy of the vaccine(s), if applicable


• Other cause (specify).

8.7. Follow-up of adverse events and serious adverse eventsand assessment of outcome

After the initial AE/SAE report, the investigator is required to proactively follow eachsubject and provide further information to GSK Biologicals on the subject’s condition.

All AEs and SAEs documented at a previous visit/contact and designated as notrecovered/not resolved or recovering/resolving will be reviewed at subsequentvisits/contacts.


• with SAEs or subjects withdrawn from the study as a result of an AE, until theevent has resolved, subsided, stabilised, disappeared, the event is otherwiseexplained, or the subject is lost to follow-up;

• or, in the case of other non-serious AEs, until they complete the study or theyare lost to follow-up.

For the long-term follow-up visit (Month 48)


CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 361fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 51

• with SAEs considered related to vaccination or with confirmed or suspected hepatitisA or B infection (in this study reported as SAE, as defined per protocol), until theevent has resolved, subsided, stabilized, disappeared, the event is otherwiseexplained, or the subject is lost to follow-up.

Clinically significant laboratory abnormalities will be followed up until they havereturned to normal, or a satisfactory explanation has been provided. Additionalinformation (including but not limited to laboratory results) relative to the subsequentcourse of such an abnormality noted for any subject must be made available to the StudyMonitor.

GSK Biologicals may request that the investigator perform or arrange for the conduct ofsupplemental measurements and/or evaluations to elucidate as fully as possible the natureand/or causality of the AE or SAE. The investigator is obliged to assist. If a subject diesduring participation in the study or during a recognised follow-up period, GSKBiologicals will be provided with a copy of any available post-mortem findings,including histopathology.

New or updated information will be recorded on the originally completed screens in theeCRF. The updated SAE Report screens in the eCRF should be resent to GSKBiologicals within 24 hours of receipt of the follow-up information as outlined in Section8.8.1.

In case the electronic SAE reporting system does not work or after freezing of thesubject's eCRF, paper SAE Report Forms and the facsimile (Fax) system should be usedto report SAEs. Refer to Section 8.8.2. for details of the back-up reporting system.Outcome of any non-serious AE occurring within one month (minimum 30 days) dayspost-vaccination (i.e. unsolicited AE) or any SAE reported during the entire study will beassessed as:





• Fatal (SAEs only).

8.8. Prompt reporting of serious adverse events to GSKBiologicals

The SAE screens in the eCRF will be the primary method for reporting SAEs to GSKBiologicals during the study period. In case the electronic SAE reporting system does notwork or after freezing of the subject's eCRF, paper SAE Report Forms and the facsimile(Fax) system should be used to report SAEs.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 362fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 52

8.8.1. Time frames for submitting serious adverse event reports to GSKBiologicals

SAEs will be reported promptly to GSK once the investigator determines that the eventmeets the protocol definition of an SAE. The investigator will complete and submitrelevant information on the SAEs in the SAE screens in eCRF WITHIN 24 HOURS OFHIS/HER BECOMING AWARE OF THESE EVENTS. Additional or follow-up informationrelating to the initial SAE report is also to be completed and submitted in the SAEscreens in eCRF within 24 hours of receipt of such information

When paper SAE Report Form is used as back-up system (if electronic SAE reportingsystem does not work or after freezing of the subject's eCRF), the investigator will faxthe SAE reports to GSK Biologicals’ Central Safety for Serious Adverse EventReporting. During the study, the investigator should update the SAE screens in eCRFonce the electronic system is working again (and not later than 24 hours) and beforeusing it to report additional information.

8.8.2. Completion and transmission of serious adverse event reports toGSK Biologicals

Once an investigator becomes aware that a SAE has occurred in a study subject, theinvestigator will complete and submit the information in the SAE screens in eCRF within24 hours as outlined in Section 8.8.1. The SAE screens in eCRF will always becompleted as thoroughly as possible with all available details of the event and will besubmitted by the investigator. If the investigator does not have all information regardingan SAE, he/she will not wait to receive additional information before notifying GSK ofthe event and completing the SAE screens in eCRF. The SAE screens in eCRF should beupdated when additional information is received WITHIN 24 HOURS as outlined in Section8.8.1.

The investigator will always provide an assessment of causality at the time of the initialreport as described in Section 8.6.2.

When paper SAE Report Form is used as back-up system (if electronic SAE reportingsystem does not work or after freezing of the subject's eCRF), the investigator will reportrelevant information on SAEs to GSK within the 24 hours as outlined in Section 8.8.1.The SAE Report Form will always be completed as thoroughly as possible with allavailable details of the event, signed by the investigator, and forwarded to GSK withinthe designated time frames. If the investigator does not have all information regarding anSAE, he/she will not wait to receive additional information before notifying GSK of theevent and completing the form. When occurring during the study period, the investigatorshould update the SAE screens in eCRF once the electronic system is working again (andnot later than 24 hours). When additional information is received on a SAE reported toGSK using the back-up paper SAE Report Form during the study period, the electronicsystem should be used to report the additional information WITHIN 24 HOURS if theelectronic system is working again and only after updating the SAE screens in eCRF oncethe electronic system was working again.When additional information is received on a SAE after freezing of the subject's eCRF,new or updated information is to be recorded on the paper SAE Report Form, with all

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 363fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 53

changes signed and dated by the investigator. The updated SAE Report Form should beresent to GSK Biologicals WITHIN 24 HOURS of receipt of the follow-up informationas outlined in Section 8.8.1.In rare circumstances, if the electronic system for reporting SAEs does not work and inthe absence of facsimile equipment, notification by telephone is acceptable, with a copyof the SAE Report Form sent by email or by mail. Initial notification via the telephonedoes not replace the need for the investigator to complete and submit SAE screens in theeCRF (or complete and sign the SAE Report Form if back-up system need to be used) asoutlined in Section 8.8.1.

In the event of a death determined by the investigator to be related to vaccination,completion of SAE screens in the eCRF /sending of the fax (if electronic SAE reportingsystem does not work or after freezing of the subject's eCRF) must be accompanied bytelephone call to the Study Contact for Reporting SAEs.

Please see Sponsor Information Sheet for contact details

Study Contact for Reporting SAEsCzech Republic:Dr. GlaxoSmithKlineNa Pankraci 17/1685140 21, Prague 4Czech RepublicTel: Mobile: Fax:

Belgium:

GlaxoSmithKline BiologicalsGenval, BelgiumTel:


(Head Safety Evaluation and Risk Management Adult/Adolescent/Emerging Diseases)Back-up mobile phone contact:

24/24 hour and 7/7 day availability

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 364fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 54

8.9. Regulatory reporting requirements for serious adverseevents

The investigator will promptly report all SAEs to GSK in accordance with the proceduresdetailed in Section 8.8. GSK Biologicals has a legal responsibility to promptly notify, asappropriate, both the local regulatory authority and other regulatory agencies about thesafety of a product under clinical investigation. Prompt notification of SAEs by theinvestigator to the Study Contact for Reporting SAEs is essential so that legal obligationsand ethical responsibilities towards the safety of other subjects are met.

The investigator, or responsible person according to local requirements, will comply withthe applicable local regulatory requirements related to the reporting of SAEs to theIRB/IEC and, if required, to the applicable government authority.

Investigator safety reports are prepared according to the current GSK policy and areforwarded to investigators as necessary. An investigator safety report is prepared for aSAE(s) that is both attributable to investigational product and unexpected. The purpose ofthe report is to fulfil specific regulatory and Good Clinical Practice (GCP) requirements,regarding the product under investigation.

An investigator who receives an investigator safety report describing a SAE(s) or otherspecific safety information (e.g., summary or listing of SAEs) from GSK Biologicals willfile it with the Investigator Brochure or other appropriate study documentation and willnotify the IRB or IEC, if appropriate according to local requirements.

8.10. Post-study adverse events and serious adverse events

A post-study AE/SAE is defined as any event that occurs outside of the AE/SAEdetection period defined in Section 8.5. Investigators are not obligated to actively seekAEs or SAEs in former study participants.

However, if the investigator learns of any SAE, including a death, at any time after asubject has been discharged from the study, and he/she considers the event reasonablyrelated to the investigational product, the investigator will promptly notify the StudyContact for Reporting SAEs.

After freezing of the subject's eCRF, if SAE follow-ups or new SAEs have to be reported,the investigators or designate should use paper SAE Report Forms and the facsimile(Fax) system.

8.11. Pregnancy

Subjects who become pregnant during the study period (up to and including one monthafter receiving the vaccine dose) may continue other study procedures at the discretion ofthe investigator

The investigator, or his/her designee, will collect pregnancy information on any subjectwho becomes pregnant while participating in this study. The investigator, or his/herdesignee, will record pregnancy information on the Pregnancy Report Form and submit it

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 365fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 55

to GSK within 24 hours of learning of a subject's pregnancy. The subject will be followedto determine the outcome of the pregnancy. At the end of the pregnancy, whether that befull-term or prematurely, information on the status of the mother and child will beforwarded to GSK. Generally, follow-up will be no longer than six to eight weeksfollowing the estimated delivery date.

While pregnancy itself is not considered an AE or SAE, any pregnancy complication orelective termination of a pregnancy for medical reasons will be recorded as an AE or aSAE, as described in Section 8.1 and 8.2, and will be followed as described in Section8.7.

A spontaneous abortion is always considered to be a SAE and will be reported asdescribed in Section 8.8. Furthermore, any SAE occurring as a result of a post-studypregnancy AND considered reasonably related in time to receipt of the investigationalproduct by the investigator, will be reported to GSK Biologicals as described in Section8.10. While the investigator is not obligated to actively seek this information from formerstudy participants, he/she may learn of a pregnancy through spontaneous reporting.

Information on pregnancies identified during the screening phase/prior to vaccineadministration does not need to be collected; this information need not be communicatedto safety.

8.12. Treatment of adverse events

Treatment of any adverse event is at the sole discretion of the investigator and accordingto current good medical practice. Any medication administered for the treatment of anAE should be recorded in the subject’s eCRF. Refer to Section 6.9.

9. SUBJECT COMPLETION AND WITHDRAWAL

9.1. Subject completion

A subject who returns for the concluding visit foreseen in the protocol is considered tohave completed the study.

9.2. Subject withdrawal

Subjects who are withdrawn because of AEs must be clearly distinguished from subjectswho are withdrawn for other reasons. Investigators will follow subjects who arewithdrawn as result of a SAE/AE until resolution of the event (see Section 8.7).

9.2.1. Subject withdrawal from the study

From an analysis perspective, a ‘withdrawal’ from the study is any subject who did notcome back for the concluding visit foreseen in the protocol.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 366fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 56

A subject qualifies as a ‘withdrawal’ from the study when no study procedure hasoccurred, no follow-up has been performed and no further information has been collectedfor this subject from the date of withdrawal/last contact.

Investigators will make an attempt to contact those subjects who do not return forscheduled visits or follow-up.

Information relative to the withdrawal will be documented on the Study Conclusionscreen of the eCRF. The investigator will document whether the decision to withdrawfrom the study was made by the subject the investigator and which of the followingpossible reasons was responsible for withdrawal:



• protocol violation (specify)




• other (specify).

9.2.2. Subject withdrawal from investigational product

Not applicable.

9.3. Extension study

Not applicable.

10. DATA EVALUATION: CRITERIA FOR EVALUATION OFOBJECTIVES

10.1. Primary endpoints



− At least a 2-fold increase in anti-HAV antibody titres one month after thechallenge dose, in subjects having anti-HAV antibody titres ≥ 100 mIU/ml at thepre-challenge time point

− or at least a 4-fold increase in anti-HAV antibody titres one month after thechallenge dose, in seropositive subjects having anti-HAV antibody titres < 100mIU/ml at the pre-challenge time point.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 367fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 57




10.2. Secondary endpoints

Immunogenicity

• Anti-HAV seropositivity rates and GMTs, as well as anti-HBs seropositivity rates,seroprotection rates and GMTs at Month 48.

• Percentage of subjects with anti-HAV antibody titres ≥ 15 mIU/ml and GMTscalculated on seropositive subjects, two weeks and one month after the challengedose.

• Percentage of subjects with anti-HBs antibody titres ≥ 3.3 mIU/ml, ≥ 10 mIU/ml, ≥100 mIU/ml and anti-HBs geometric mean titres (GMTs) calculated on seropositivesubjects, two weeks and one month after the challenge dose.

Reactogenicity


• Occurrence, intensity and relationship of solicited general symptoms in the 4-day(Day 0 to 3) follow-up period after the challenge dose.

Safety

• Retrospective recording of all serious adverse events (SAEs) with causal relationshipto vaccination or referring to hepatitis A or B infection that occurred since the laststudy visit of the HAB-160 long-term follow-up study.

• Occurrence, intensity and relationship to vaccination of unsolicited symptomsreported during the 31-day (Day 0 to 30) follow-up period after the challenge dose.

• Occurrence, intensity and relationship to vaccination of all SAEs following theadministration of the challenge dose.

10.3. Estimated sample size

The sample size for the challenge dose study is not estimated using any power basedcomputations.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 368fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 58

A total of 596 subjects were enrolled in the primary study of which 590 subjectscompleted the study and 583 subjects have participated in the last available long-termfollow up visit at Month 24 (Year 2). Thus, considering a drop-out rate of 15% from theMonth 24 time point, we can expect about 495 subjects to participate in the challengedose study and an evaluable 445 subjects. Of these, 276 subjects are expected to berecruited in the Belgian and Czech centres (described in this protocol). 219 subjects areexpected to be recruited in the German centres (described in an amendment to theprimary protocol HAB-160 with e track number 111149).



No. of Subjects expected (N) Subjects with challenge dose response as defined in Primary endpoint


356 80.0 76.0 83.6379 85.2 81.5 88.3402 90.3 87.2 92.9

445



10.4.1. Long-term (LT) total vaccinated cohort

The long-term total vaccinated cohort will include all subjects who received at least onedose of the study vaccine in the primary study and who returned for the Month 48 bloodsampling time point.

10.4.2. LT ATP cohort for analysis of immunogenicity

For subjects who return at the Month 48 time point, the ATP-LT cohort (at that timepoint) will include those who were included in the primary ATP immunogenicityanalysis, who did not receive hepatitis A or hepatitis B vaccine not specified in the studyprotocol and who were not eliminated for abnormal increase† in antibody titre duringfollow-up period.

† Note: the criteria of an antibody (anti-HAV or anti-HBs) titre abnormal increasedepends on the magnitude of antibody level reached at first time point (i.e. the referencevalue). The case of an abnormal antibody titre increase was defined as a two-foldincrease or more in antibody titres (when the antibody titre at the reference time pointwas ≥ 100 mIU/ml) or a four-fold increase or more in antibody titers (when the antibody

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 369fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 59

titre at the reference time point was < 100 mIU/ml). This code will be assigned toeliminate from the analysis subjects who could have been infected by the hepatitis A orhepatitis B virus, or who could have received a vaccine dose not specified in the protocolduring the study.

10.4.3. Total Vaccinated cohort (Challenge dose)

The Total Vaccinated cohort will include all subjects who received the challenge dose:

• a safety analysis based on the total vaccinated cohort will include all vaccinatedsubjects.

• an immunogenicity analysis based on the total vaccinated cohort will include allvaccinated subjects for whom immunogenicity data are available.

10.4.4. According-To-Protocol (ATP) cohort for analysis of safety(Challenge dose)

The ATP cohort for safety will include all eligible subjects:

• who have received the complete primary hepatitis B and hepatitis A vaccinationcourse in the HAB-160 primary study.

• who have received the challenge dose.

• who have not received a vaccine not specified or forbidden in the protocol

10.4.5. ATP cohort for analysis of immunogenicity (Challenge dose)

The ATP cohort for analysis of immunogenicity will include all evaluable subjectsincluded in the ATP cohort for analysis of safety ((i.e. those meeting all eligibilitycriteria, complying with the procedures and intervals defined in the protocol, with noelimination criteria during the study) who have received the challenge dose and for whomdata concerning immunogenicity endpoint measures for at least one antigen are availableat the post-challenge dose time point. The interval between Visit 8 (pre-challenge dose)and Visit 10 (post-challenge dose time point) considered for inclusion of a subject in theATP cohort for immunogenicity will be 21 to 48 days.


Immunogenicity:

• The cut-off value is defined by the laboratory before the analysis and is described inSection 5.6.2. The cut-off value for the assay for anti-HAV antibody is 15 mIU/ml;the cut-off value for the assay for anti-HBs antibody is 3.3 mIU/ml.

• A seronegative subject is a subject whose titre is below the cut-off value.

• A seropositive subject is a subject whose titre is greater than or equal to the cut-offvalue.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 370fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 60

• Seropositivity rate is defined as the percentage of subjects with antibody titre greaterthan or equal to the cut-off value.

• Seroprotection rate for anti-HBs is defined as the percentage of subjects with anti-HBs titre ≥ 10 mIU/ml.

• The GMT calculations will be performed by taking the anti-log of the mean of thelog transformation of antibody titres equal to or above the seropositivity level (i.e.15 mIU/ml for anti-HAV and 3.3 mIU/ml for anti-HBs).

• If GMT has to be calculated on all subjects (as supplement), subjects whose antibodytitres are below the assay cut-off are assigned an arbitrary value of half the cut-off.



− At least a 2-fold increase in anti-HAV antibody titres one month after thechallenge dose, in subjects having anti-HAV antibody titres ≥ 100 mIU/ml at thepre-challenge time point or at least a 4-fold increase in antibody titres one monthafter the challenge dose, in seropositive subjects having anti-HAV antibody titres< 100 mIU/ml at the pre-challenge time point.




• For a given subject and a given immunogenicity measurement, missing or non-evaluable measurements will not be replaced. Therefore, an analysis will excludesubjects with missing or non-evaluable measurements.


• For the analysis of solicited symptoms, missing or non-evaluable measurements willnot be replaced. Therefore the analysis of the solicited symptoms based on the totalvaccinated cohort will include only subjects with documented safety data (i.e.symptom screen completed).

• For the analysis of unsolicited adverse events/concomitant medication, all vaccinatedsubjects will be considered and subjects who did not report an event will beconsidered as subjects without an event.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 371fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 61

10.6. Final analyses

The challenge dose study is described in this protocol for the Belgian and Czech centresand in an amendment to the HAB-160 protocol (E-track: 111149) for the German centres.The eligibility criteria, study visit procedures and data collection will be identical in thetwo studies and the data will be combined with this study for analysis. One integratedclinical study report will describe the results of this analysis.


Demographic characteristics (age in years, gender and race), cohort description,withdrawal status will be summarized using descriptive statistics:

• Mean, median, standard deviation will be provided for continuous data such as age.All the demographic analyses would be performed stratified based on the three studygroups in the primary study and overall.

A summary of the tracking log-sheet documenting reasons for non-participation in thechallenge dose study will be provided.


Persistence of antibody response

Seroprotection rates, seropositivity rates and GMTs for anti-HBs antibodies with 95%confidence intervals will be tabulated for the ATP-LT immunogenicity cohort at Month48.

Seropositivity rates and GMTs for anti-HAV antibodies with 95% confidence intervals,will be tabulated for the ATP-LT immunogenicity cohort at Month 48.


The primary analysis will be based on the ATP cohort for immunogenicity. If thepercentage of enrolled subjects excluded from this ATP cohort is 5% or more, a secondanalysis based on the Total Vaccinated cohort will be performed to complement the ATPanalysis.

The following analysis will be performed at the post-challenge dose time points for eachtreatment group:

• Percentage of subjects with anti-HAV response to the challenge dose with exact 95%CIs will be tabulated.

• Percentage of subjects with anti-HBs response to the challenge dose with exact 95%CIs will be tabulated.

• Anti-HAV and anti-HBs GMTs with 95% CIs will be tabulated primarily forseropositive subjects and secondarily for all subjects.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 372fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 62

• Percentage of subjects seropositive for anti-HAV antibodies (anti-HAV antibodytitres ≥ 15 mIU/ml), with exact 95% CI will be tabulated (the same will also betabulated stratified based on the baseline characteristics).

• Percentage of subjects with anti-HBs titres ≥ 3.3 mIU/ml , percentage of subjects withanti-HBs titers ≥ 10 mIU/ml and ≥ 100 mIU/ml, with exact 95% CIs will betabulated (the same will also be tabulated stratified based on the baselinecharacteristics).

• Distribution of anti-HAV and anti-HBs antibody titres will be presented as reversecumulative distribution curves.

10.6.3. Analysis of safety (Challenge dose)

The analysis will be based on the Total Vaccinated cohort. If 5% or more of the enrolledsubjects are eliminated from the ATP cohort for safety analysis, a second analysis will beperformed on the ATP cohort for safety.

• The percentage of subjects with at least one local adverse event (solicited andunsolicited), with at least one general adverse event (solicited and unsolicited) andwith any adverse event (solicited and unsolicited) during the 4-day (Day 0 to Day 3)follow-up period after the vaccination will be tabulated with exact 95% CI. Similartabulations will be done for grade 3 symptoms.

• The percentage of subjects reporting each individual solicited symptom during the 4-day follow-up period with exact 95% CI, by type of adverse event; by severity (anygrade, grade 3 only); for general symptoms: by relationship to vaccination (anyrelationship, related only) will be tabulated.

• The occurrence of fever will be tabulated per 0.5 °C cumulative increments as well asthe occurrence of fever (> 39.5 °C oral/axillary temperature) with causal relationshipto vaccination.

• The percentage of subjects with at least one report of unsolicited adverse eventclassified by the Medical Dictionary for Regulatory Activities (MedDRA) andreported within the 31-day (Day 0 to Day 30) follow-up period after vaccination willbe tabulated with exact 95% CI. The same tabulation will be performed for grade 3unsolicited adverse events and for unsolicited adverse events with a causalrelationship to vaccination.

• The percentage of subjects who start and report at least one concomitant medication(i.e. any medication, antipyretic medication, prophylactic antipyretics) during the 4-day and 31-day follow-up period after vaccination will be tabulated (with exact 95%CI).

• Serious adverse events reported after the last LTFU visit of the primary study HAB-160 until the end of the study (30 days post-challenge dose) and withdrawal due toAEs/SAEs will be described in detail.

10.7. Planned interim analysis


CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 373fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 63

11. ADMINISTRATIVE MATTERS

To comply with Good Clinical Practice important administrative obligations relating toinvestigator responsibilities, monitoring, archiving data, audits, confidentiality andpublications must be fulfilled. See Appendix A for details.

12. REFERENCES

Lemon SM. Type A viral hepatitis: new developments in an old disease. New Engl JMed. 1985; 313: 1059-1067.

Purcell R H. Hepatitis viruses: Changing patterns of human diseases. Proc National AcadSci USA. 1994; 91: 2401-2405.

Reutter J, Bart PA, Francioli P, Safary A, Frei PC. Production of antibody to hepatitis Avirus and hepatitis B surface antigen measured after combined hepatitis A/hepatitis Bvaccination in 242 adult volunteers. J Viral Hepatitis 1998; 5: 205-211.


Bauer T, Jilg W. Hepatitis B surface antigen-specific T and B cell memory in individualswho had lost protective antibodies after hepatitis B vaccination. Vaccine 2006;24:572–7.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 374fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 64

Appendix A Administrative Matters

I. Responsibilities of the Investigator

• To ensure that he/she has sufficient time to conduct and complete the study andhas adequate staff and appropriate facilities and equipment which are availablefor the duration of the study and to ensure that other studies do not divertessential subjects or facilities away from the study at hand.

• To submit an up-to-date curriculum vitae or Investigator Biography and othercredentials (e.g., medical license number in the United States) to GSK and—where required—to relevant authorities. It is recommended that thisdocumentation indicates any previous clinical research experience and history oftraining in GCP.

• To acquire the reference ranges for laboratory tests performed locally and, ifrequired by local regulations, obtain the laboratory’s current certification orQuality Assurance procedure manual.

• To ensure that no clinical samples (including serum samples) are retained onsiteor elsewhere without the approval of GSK Biologicals and the express writteninformed consent of the subject and/or the subject’s legally authorisedrepresentative.

• To perform no other biological assays on the clinical samples except thosedescribed in the protocol or its amendment(s).

• To prepare and maintain adequate subject source data or raw data designed torecord observations, and other data pertinent to the study.

• To conduct the study in compliance with the protocol any amendment and“Good Clinical Practice” (GCP) and all applicable regulatory requirements.

• To co-operate with a representative of GSK Biologicals in the monitoringprocess of the study and in resolution of queries about the data.

• To permit drug regulatory agencies and GSK audits.

II. Protocol Amendments and Administrative changes

• No changes to the study protocol will be allowed unless discussed in detail withthe GSK Biologicals' Clinical Development Manager/Medical Monitor and filedas an amendment/administrative change to this protocol.

• Any amendment/administrative change to the protocol will be adhered to by theparticipating centre(s) and will apply to all subjects. Written IRB/IEC approvalof protocol amendments is required prior to implementation, except wherepermitted by all applicable regulatory requirements; administrative changes andamendments not submitted for approval are submitted to IRBs/IECs forinformation only.Submission of protocol amendments to regulatory agencieswill occur in accordance with local regulatory requirements. For some countries,submission to the local regulatory authority may not be required. Whensubmission to the local regulatory authority is required, the timing of the

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 375fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 65

submission relative to IEC/IRB submission or approval and whether or not theauthority will provide their approval of or favourable opinion on the amendmentbefore it can be implemented will depend on local regulatory requirements.

III. Sponsor’s Termination of Study

GSK Biologicals reserves the right to temporarily suspend or prematurely discontinuethis study either at a single site or at all sites at any time for reasons including, but notlimited to, safety or ethical issues or severe non-compliance. Reasons for suspension orearly termination will be documented in the study file at GSK Biologicals.

If GSK Biologicals determines that suspension or early termination is needed, GSKBiologicals will discuss this with the Investigator (including the reasons for taking suchaction). When feasible, GSK Biologicals will provide advance notification to theinvestigator of the impending action prior to it taking effect.

GSK Biologicals will promptly inform, via written communication, all investigatorsand/or institutions conducting the study, if the study is suspended or terminated for safetyreasons, and will also inform the regulatory authorities of the suspension or terminationof the study and the reason(s) for the action. If required by applicable regulations, theinvestigator must inform the IEC/IRB promptly and provide the reason for the suspensionor termination.

If the study is prematurely discontinued, all study data must be returned to GSK. Inaddition, arrangements will be made for all unused investigational product(s) inaccordance with the applicable GSK procedures for the study. Financial compensation toinvestigators and/or institutions will be in accordance with the agreement establishedbetween the investigator and/or institutions and GSK.

IV. Case Report Form Instructions / Remote Data Entry Instructions

Remote Data Entry (RDE) will be used as the method for data collection, which meansthat subject information will be entered into a computer at the investigational sitepreferably within 5 working days of becoming available. The site will be capable ofmodifying the data to assure accuracy with source documentation. All new/updatedinformation will be reviewed and verified by a GSK Biologicals' representative. Thisinformation will finally be stored in a central database maintained by GSK Biologicals.At the conclusion of the study, GSK Biologicals will archive the study data in accordancewith internal procedures. In addition, the investigator will be provided with a CD-ROMof the final version of the data generated at the investigational site.

Specific instructions for use of RDE will be included in the training material provided tothe investigational site.

V. Monitoring by GSK Biologicals

To ensure compliance with the protocol, monitoring visits by a professionalrepresentative of the sponsor will be scheduled to take place early in the study, during thestudy at appropriate intervals and after the last subject has completed the study. It is

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 376fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 66

anticipated that monitoring visits will occur at a frequency defined and communicated tothe investigator before study start.

These visits are for the purpose of confirming that GSK Biologicals’ sponsored studiesare being conducted in accordance with the ethical principles that have their origins in theDeclaration of Helsinki and that are consistent with Good Clinical practice (GCP) and theapplicable regulatory requirement(s) (verifying continuing compliance with the protocol,amendment(s), reviewing the investigational product accountability records, verifyingthat the site staff and facilities continue to be adequate to conduct the study. Direct accessto all study-related site and source data/ documents is mandatory for the purpose ofmonitoring review. The monitor will perform a CRF review and a Source Documentverification (verifying RDE entries by comparing them with the source data/documentsthat will be made available by the investigator for this purpose: any data item for whichthe CRF will serve as the source must be identified, agreed and documented. Data to berecorded directly into RDE screens will be specified in writing preferably in the sourcedocumentation agreement form that is contained in both the monitor’s and investigator’sstudy file. For RDE, the monitor will mark completed and approved screens at each visit.The investigator must ensure provision of reasonable time, space and adequate qualifiedpersonnel for monitoring visits. Source data verification (SDV) must be conducted usinga GSK standard SDV sampling strategy (as defined at the study start in the study specificmonitoring guidelines) in which monitors will perform partial SDV for all subjects andfull SDV for selected subjects.

VI. Archiving of Data

Following closure of the study, the investigator must maintain all site study records in asafe and secure location. The records must be maintained to allow easy and timelyretrieval, when needed (e.g., audit or inspection), and, whenever feasible, to allow anysubsequent review of data in conjunction with assessment of the facility, supportingsystems, and staff. Where permitted by applicable laws/regulations or institutionalpolicy, some or all of these records can be maintained in a validated format other thanhard copy (e.g., microfiche, scanned, electronic for studies with an eCRF, for example);however, caution needs to be exercised before such action is taken. The investigator mustassure that all reproductions are legible and are a true and accurate copy of the original,and meet accessibility and retrieval standards, including re-generating a hard copy, ifrequired. Furthermore, the investigator must ensure there is an acceptable back-up ofthese reproductions and that an acceptable quality control process exists for making thesereproductions.

GSK will inform the investigator/ institution of the time period for retaining these recordsto comply with all applicable regulatory requirements. However, the investigator/institution should seek the written approval of the sponsor before proceeding with thedisposal of these records. The minimum retention time will meet the strictest standardapplicable to that site for the study, as dictated by ICH GCP E6 Section 4.9, anyinstitutional requirements or applicable laws or regulations, or GSKstandards/procedures; otherwise, the minimum retention period will default to 15 years.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 377fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 67

The investigator/ institution must notify GSK of any changes in the archivalarrangements, including, but not limited to, the following: archival at an off-site facility,transfer of ownership of the records in the event the investigator leaves the site.

VII. Audits

For the purpose of compliance with Good Clinical Practice and Regulatory AgencyGuidelines it may be necessary for GSK or a Drug Regulatory Agency to conduct a siteaudit. This may occur at any time from start to after conclusion of the study.

When an investigator signs the protocol, he agrees to permit drug regulatory agencies andGSK audits, providing direct access to source data/ documents. Furthermore, if aninvestigator refuses an inspection, his data will not be accepted in support of a New DrugRegistration and/or Application, Biologics Licensing Application.

Having the highest quality data and studies are essential aspects of vaccine development.GSK has a Regulatory Compliance staff who audit investigational sites. RegulatoryCompliance assesses the quality of data with regard to accuracy, adequacy andconsistency. In addition, Regulatory Compliance assures that GSK Biologicals’sponsored studies are in accordance with GCP and that relevant regulations/guidelinesare being followed.

To accomplish these functions, Regulatory Compliance selects investigational sites toaudit. These audits usually take 1 to 2 days. GSK’s audits entail review of sourcedocuments supporting the adequacy and accuracy of eCRFs, review of documentationrequired to be maintained, and checks on vaccine accountability. GSK’s audit thereforehelps prepare an investigator for a possible regulatory agency inspection as well asassuring GSK Biologicals of the validity of the database across investigational sites.

The Inspector will be especially interested in the following items:

• Log of visits from the sponsor’s representatives

• Study personnel

• Study file

• Safety reporting

• IRB/IEC and regulatory authority approvals

• Facilities

• monitoring

• Vaccine accountability

• Approved study protocol and amendments and investigator brochure

• Informed consent of the subjects (written consent [or witnessed oral ifapplicable] )

• Medical records and other source documents supportive of eCRF data

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 378fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 68

• Reports to the IRB/IEC and the sponsor

• Record retention.GSK Biologicals will gladly help investigators prepare for an inspection.

VIII. Ownership, Confidentiality and Publication

Ownership:All information provided by GSK and all data and information generated by the site aspart of the study (other than a subject’s medical records) are the sole property of GSK.

All rights, title, and interests in any inventions, know-how or other intellectual orindustrial property rights which are conceived or reduced to practice by site staff duringthe course of or as a result of the study are the sole property of GSK, and are herebyassigned to GSK.

If a written contract for the conduct of the study which includes ownership provisionsinconsistent with this statement is executed between GSK and the study site, thatcontract’s ownership provisions shall apply rather than this statement.

Confidentiality:Documented evidence that a potential investigator is aware and agrees to the confidentialnature of the information related to the study must be obtained by means of aconfidentiality agreement.

All information provided by GSK and all data and information generated by the site aspart of the study (other than a subject’s medical records) will be kept confidential by theinvestigator and other site staff. This information and data will not be used by theinvestigator or other site personnel for any purpose other than conducting the study.These restrictions do not apply to: (1) information which becomes publicly availablethrough no fault of the investigator or site staff; (2) information which it is necessary todisclose in confidence to an IEC or IRB solely for the evaluation of the study; (3)information which it is necessary to disclose in order to provide appropriate medical careto a study subject; or (4) study results which may be published as described in the nextparagraph. If a written contract for the conduct of the study which includesconfidentiality provisions inconsistent with this statement is executed, that contract’sconfidentiality provisions shall apply rather than this statement.

Publication:For multicentre studies, the first publication or disclosure of study results shall be acomplete, joint multicentre publication or disclosure coordinated by GSK. Thereafter,any secondary publications will reference the original publication(s).

Prior to submitting for publication, presentation, use for instructional purposes, orotherwise disclosing the study results generated by the site (collectively, a “Publication”),the investigator shall provide GSK with a copy of the proposed Publication and allowGSK a period to review the proposed Publication (at least 21 (twenty-one) days [or atleast 15 (fifteen) working days for abstracts/posters/presentations]. Proposed

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 379fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 69

Publications shall not include either GSK confidential information other than the studyresults or personal data on any subject, such as name or initials.

At GSK’s request, the submission or other disclosure of a proposed Publication will bedelayed a sufficient time to allow GSK to seek patent or similar protection of anyinventions, know-how or other intellectual or industrial property rights disclosed in theproposed Publication.

If a written contract for the conduct of the study, which includes publication provisionsinconsistent with this statement is executed, that contract’s publication provisions shallapply rather than this statement.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 380fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 70

Appendix B Overview of the Recruitment Plan

All 590 subjects who have completed the primary vaccination course in study HAB-160will be invited to participate in the challenge dose study. 276 subjects are expected to berecruited in the Belgian and Czech centres (described in this protocol) and 219 subjects inthe German centres (described in an amendment to the HAB-160 protocol).

If any subject refuses to participate in the study, the reasons for non-participation will berecorded in the tracking document.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 381fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 71

Appendix C Handling of Biological Samples Collected by the Investigator

Instructions for Handling of Serum Samples

When materials are provided by GSK Biologicals, it is MANDATORY that all clinicalsamples (including serum samples) will be collected and stored using exclusively thosematerials in the appropriate manner. The use of other materials could result in theexclusion of the subject from the ATP analysis. The investigator must ensure that his/herpersonnel and the laboratory(ies) under his/her supervision comply with this requirement.However, when GSK Biologicals does not provide material for collecting and storingclinical samples, then appropriate materials from the investigator’s site are to be used.

1. CollectionThe whole blood (by capillary or venous route) should be collected observing appropriateaseptic conditions. It is recommended that Vacutainer tubes WITH integrated serumseparator (e.g. Becton-Dickinson Vacutainer SST or Corvac Sherwood Medical) beused to minimise the risk of haemolysis and to avoid blood cell contamination of theserum when transferring to standard serum tubes.

2. Serum separationThese guidelines aim to ensure high quality serum by minimising the risk of haemolysis,blood cell contamination of the serum or serum adverse cell toxicity at testing.

• For separation of serum using Vacutainer® tubes, the instructions provided bythe manufacturer should be followed. Often the manufacturer’s instruction statesthat the relative centrifugal acceleration known also as “G” must be “between1000 and 1300 G” with tubes spinning for ten minutes. Error in calculation ofcentrifuge speed can occur when laboratory personnel confuse “G” accelerationwith “RPM” (revolutions per minute). The speed of centrifugation must becalculated using the “G” rate provided in the manufacturer’s instructions and theradius of the centrifuge head. After measuring the radius of the centrifugemachine, a speed/acceleration nomograph must be employed to determine thecentrifuge speed in “RPM”.

• Following separation, the serum should be aseptically transferred to theappropriate standard tubes using a sterile disposable pipette. The serum shouldbe transferred as gently as possible to avoid blood cell contamination.

• The tube should not be overfilled (max. 3/4 of the total volume) to allow roomfor expansion upon freezing.

• The tube should be identified by the appropriate label provided by GSKBiologicals (see point 3).

3. Labelling

• The standard labels provided by GSK Biologicals should be used to label eachserum sample.

• If necessary, any hand-written additions to the labels should be made usingindelible ink.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 382fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 72

• The label should be attached to the tube as follows (see diagram):

• first attach the paper part of the label to the tube

• then wrap the label around the tube so that the transparent, plastic part of thelabel overlaps with the label text and bar code and shields them.

This will ensure optimal label attachment.

Plastic, transparent part

Paper, text part

Bar code

Study N°.........

Subject N° ......

POST VACC. I STUDY MTH 1For GlaxoSmithKline

Biologicals

• Labels should not be attached to caps.

4. Sorting and storage

• Tubes should be placed in the GSK Biologicals’ cardboard boxes in numericalorder from left to right, starting from the lower left hand corner, beginning withthe pre-vaccination samples series, then with the post-vaccination sample series.

• The tubes of serum should be stored in a vertical position at approximately-20°C (alternatively at approximately -70°/80°C is also acceptable) untilshipment to GSK Biologicals. The storage temperature should be checkedregularly and documented. Wherever possible, a backup facility for storage ofserum samples should be available.

• A standard Biological Specimen Listing Form, specifying the samples beingshipped for individual subjects at each timepoint, should be prepared for eachshipment. A copy of this list should be retained at the study site, while theoriginal should be sealed in a plastic envelope and shipped with the serumsamples.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 383fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 73

• Once shipment details are known, a standard Specimen Transfer Form must becompleted and faxed to GSK Biologicals to the number provided below. A copyof the Specimen Transfer Form must be in the parcel.1



Rue de l'Institut, 89B-1330 Rixensart � Belgium

Telephone: or or or

Fax:E-mail:

1 The Biological Specimen Listing Form and the Specimen Transfer Form are standard documents used inGSK Biologicals’ clinical trials. These documents are provided by GSK Biologicals’ Clinical Trials’monitor at study initiation.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 384fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 74

Appendix D Shipment of Biological Samples

Instructions for Shipment of Serum Samples (for centres outside Belgium)


Serum samples should always be sent by air, preferably on a Monday, Tuesday orWednesday, unless otherwise requested by the sponsor.



The airway bill should contain the instruction for storage of samples at maximum -20°C.

A "proforma" invoice, stating a value for customs purposes only, should be prepared andattached to the container. This document should contain the instruction for storage ofsamples at maximum -20°C.

Details of the shipment, including: * number of samples* airway bill* flight number* flight departure and arrival times




Rue de l'Institut, 89B-1330 Rixensart – Belgium

Telephone:Fax:

E-mail:

Instructions for Shipment of Serum Samples (for centres in Belgium)


Serum samples should always be sent by contract courier designated by the sponsor,unless otherwise requested by the sponsor.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 385fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 75



Details of the shipment, including: * number of samples* date of transfer




Rue de l'Institut, 89B-1330 Rixensart – Belgium

Telephone:Fax:

E-mail:

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 386fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 76

Appendix E Laboratory Assays

See Section 5.6.2 Laboratory assays.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 387fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 77

Appendix F Vaccine supplies, packaging and accountability

1. Vaccine and/or other suppliesGSK Biologicals will supply the following study vaccines, sufficient number of doses toadminister to all subjects as described in the present protocol.

• Approximately 200 doses of Twinrix in pre-filled syringes

• Approximately 200 doses of Engerix-B in pre-filled syringes

• Approximately 200 doses of Havrix in pre-filled syringes

• Approximately 200 doses of HB VAX PRO in pre-filled syringes

• Approximately 200 doses of Vaqta in pre-filled syringes

All pre-filled syringes must be accounted for on the form provided.

Labels for sample identification:The investigator will receive labels from GSK Biologicals to identify samples taken fromeach subject. Each label will contain the following information: study number,identification number for the subject (e.g. Subject number), sampling timepoint (e.g., postvacc 3), timing (e.g., study Month 48).

The subject number will be used for identification of the serum samples.

Other supplies provided by GSK Biologicals:In addition to the vaccines, the study documentation and the sample labels, theinvestigator will receive the following supplies:

• tubes with screw caps for serum samples,

• racks and cardboard boxes for the tubes of serum.The investigator or pharmacist must sign a statement that he/she has received the clinicalsupplies for the study.

It is NOT permitted to use any of the supplies provided by GSK Biologicals for purposesother than those specified in the protocol.

2. Vaccine packagingThe vaccines will be packed in labelled boxes. The box label will contain, as a minimum,the following information: study number, treatment number, lot number (or numbers,when double-blind), instructions for vaccine administration and any other relevantregulatory requirements.

3. Vaccine shipment from GSK Biologicals Rixensart to local country medicaldepartment, dispatching centre or investigational site.

Upon reception of the shipment, its content, quality and maintenance of the cold-chainmust be checked.

The supplies receipt documents must then be returned to:

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 388fb0b009324aa43dbd8458969316ad24d


25 Jan 2008 78

Attention of Clinical Trial Supplies UnitGSK Biologicals RixensartFax : E-mail:

In case of any temperature deviation, the official written approval for the use of vaccinemust be obtained from GSK.

4. Vaccine accountabilityAt all times the figures on supplied, used and remaining vaccine doses should match. Atthe end of the study, it must be possible to reconcile delivery records with those of usedand unused stocks. An explanation must be given of any discrepancies.

After approval from GSK Biologicals and in accordance with GSK SOP WWD-1102,used and unused syringes should be destroyed at the study site using locally approvedbiosafety procedures and documentation unless otherwise described in the protocol. If noadequate biosafety procedures are available at the study site, the used and unusedsyringes are to be returned to an appropriate GSK Biologicals site for destruction, also inaccordance with current GSK SOP WWD-1102.

5. Transfers of clinical vaccines or products from country medical department ordispatch centre to study sites or between sites

Storage temperatures must be maintained during transport and deviations must bereported to GSK for guidance. All transfers of clinical vaccines or products must bedocumented.

All packaging and shipment procedures for transfer of clinical vaccines or products mustfollow procedures approved by the sponsor.

Clinical vaccines or products should always be sent by contract courier designated by thesponsor, unless otherwise requested by the sponsor.

CONFIDENTIAL

111572 (HAB-168 BST 160)Final


CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 389fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 390fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL111572 (HAB-168 BST 160)

Final

Protocol Investigator Agreement

I agree:

o To assume responsibility for the proper conduct of the study at this site.

o To conduct the study in compliance with this protocol, any mutually agreed futureprotocol amendments, and with any other study conduct procedures provided byGlaxoSmithKline Biologicals (GSK Biologicals).

o To ensure that all persons assisting me with the study are adequately informed aboutthe GSK Biologicals investigational product(s) and other study-related duties andfunctions as described in the protocol.

o Not to implement any changes to the protocol without agreement from the sponsor

and prior review and written approval from the Institutional Review Board (IRB) orIndependent Ethics Committee (lEe), except where necessary to eliminate animmediate hazard to the subjects, or where permitted by all applicable regulatoryrequirements (for example, for administrative aspects of the study).

o That I am thoroughly familiar with the appropriate use of the vaccine(s), as describedin this protocol, and any other information provided by the sponsor, including, butnot limited to, the following: the current Investigator's Brochure (IB) or equivalentdocument, IB supplement (if applicable), prescribing information (in the case of amarketed vaccine).

o That I am aware of, and will comply with, "Good Clinical Practice" (GCP) and all

applicable regulatory requirements.

o That I have been informed that certain regulatory authorities require the sponsor toobtain and supply, as necessary, details about the investigator's ownership interest inthe sponsor or the investigational product, and more generally about his/her financialties with the sponsor. GSK Biologicals will use and disclose the information solelyfor the purpose of complying with regulatory requirements.

Hence I:

o Agree to supply GSK Biologicals with any necessary information regardingownership interest and financial ties (including those of my spouse and dependentchildren).

o Agree to promptly update this information if any relevant changes occur during thecourse of the study and for i year following completion of the study.

o Agree that GSK Biologicals may disclose any information it has about suchownership interests and financial ties to regulatory authorities.

o Agree to provide GSK Biologicals with an updated Curriculum Vitae and other FDA

required documents.

25 Jan 20086a941 b30c86dff13c2e84aOfd3025a64

3

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 391fb0b009324aa43dbd8458969316ad24d

07-03-2008 11: 48 P. 02/02

CONFIDENTIAL111572 (HAS-16B eST 160)

Final

eTr3ck study humber andabbreviated title

i I 1572 (HAB-168 BST:160)

EudraCT llUmber 2008-000526-39

Date of protocol

Detailed Title

25 January 2008 (Final)

A phase iv, op~n, multicentr, multicounti' study toevaluate the Í1mune response to a challenge dose ofGSK Biologicals' Twinrixl" vacciòe:versus monovalenthepatitis A and B vaccíne~ from different manufacturersin healthy and non-healthy adults aged;' 4) years,

approximately 48 ,months after primary vaëcination instudy 100382 (HAB-160).

Investigator name:

~ Fêß UolDate

25 J.n 200e 46a941 b30c8GdH1 :lc2a84aOfd3025114

TOTAL P.02

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 392fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 393fb0b009324aa43dbd8458969316ad24d

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 394fb0b009324aa43dbd8458969316ad24d

Sample Case Report Form

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 3959c18a8f42336bf2a269a9749b704a240

nde

GlaxoSmithKline Biologicals Version 12 Date : 20 February 2008 Rue de l’Institut 89, B – 1330 Rixensart, Belgium Tel: Fax:

Center Subject number

|__|__|__|__|__|__| |__|__|__|__|__|

Study Identification: 111149

Abbreviated Title: (HAB-160 BST)

A phase IV, open, randomized, multicentre, multicountry study to evaluate the effect of several risk factors likely to influence the immunogenicity of GlaxoSmithKline Biologicals’ combined hepatitis A and hepatitis B vaccine Twinrix according to a 0, 1 and 6 month schedule, as compared to separately administered monovalent hepatitis A (0, 6 months) and hepatitis B vaccines (0, 1, 6 months) from different manufacturers, as well as to demonstrate the non-inferiority of Twinrix to the monovalent vaccines, in healthy and non-healthy adults aged 41 years or older.

WORKBOOK

CONFIDENTIAL


28 Aug 2009 2e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 3969c18a8f42336bf2a269a9749b704a240

GENERAL INSTRUCTIONS FOR RDE

ABBREVIATIONS: Abbreviations for medical conditions, clinical events or drug names should not be used. Units and route of administration of medication may be abbreviated. NA: not applicable.

DATE

Use the following three-letter abbreviations for each month:

January = JAN February = FEB March = MAR April = APR May = MAY June = JUN July = JUL August = AUG September = SEP October = OCT November = NOV December = DEC

Example : |__|__| |__|__|__| |__|__|__|__|= 1st January 2002

day month year

TIME Unless specified otherwise, use the 24 hour clock : Example: |__|__| : |__|__| hours min

The Medication section, the Concomitant Vaccination section, the Non-Serious Adverse Events section, the Serious Adverse Event (SAE) and the Pregnancy forms must be checked for final assessment at the end of the study. For all subjects enrolled, please complete the Study Conclusion form.

0 1 J A N 2 0 0 2

1 5 3 0 = 3.30 p.m.

CONFIDENTIAL


28 Aug 2009 3e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 3979c18a8f42336bf2a269a9749b704a240

ADVERSE EVENT DEFINITIONS INTENSITY FOR SOLICITED SYMPTOMS

Pain at injection site Fatigue 0 : Absent 0 : Normal 1 : Painful on touch 1 : Fatigue that is easily tolerated 2 : Painful when limb is moved 2 : Fatigue that interferes with normal activity 3 : Prevents normal activity 3 : Fatigue that prevents normal activity Headache Gastrointestinal symptoms 0 : Normal 0 : Normal 1 : Headache that is easily tolerated 1 : Gastrointestinal symptoms that are easily tolerated 2 : Headache that interferes with normal activity 2 : Gastrointestinal symptoms that interfere with normal 3 : Headache that prevents normal activity activity 3 : Gastrointestinal symptoms that prevent normal activity

INTENSITY FOR NON-SOLICITED SYMPTOMS 1 : Mild : An adverse event which is easily tolerated by the subject, causing minimal discomfort and not

interfering with everyday activities. 2 : Moderate : An adverse event which is sufficiently discomforting to interfere with normal everyday activities. 3 : Severe : An adverse event which prevents normal, everyday activities (In adults / adolescents, such an adverse event would, for example, prevent attendance at work / school

and would necessitate the administration of corrective therapy).

CAUSALITY / RELATIONSHIP TO INVESTIGATIONAL PRODUCT S Is there a reasonable possibility that the AE may have been caused by the investigational product ?

NO : The adverse event is not causally related to administration of the study vaccine(s). There are other, more likely causes and administration of the study vaccine(s) is not suspected to have contributed to the adverse event.

YES: There is a reasonable possibility that the vaccine contributed to the adverse event.

OUTCOME 1 : Recovered / Resolved 2 : Recovering / Resolving : If the subject is recovering at the time the subject completes the study or at the time the subject dropped out 3 : Not recovered / Not resolved : This means an AE ongoing at the time the subject completes the study or becomes lost to follow-up; if AE/SAE was ongoing at the time of death, but was not the cause of death. 4 : Recovered with sequelae/ Resolved with sequelae

SERIOUS ADVERSE EVENT A serious adverse event is any untoward medical occurrence that:

• results in death • is life threatening • results in persistent or significant disability / incapacity • requires in-patient hospitalization • prolongation of existing hospitalization • is a congenital anomaly / birth defect in the offspring of a study subject • In addition, important medical events that may jeopardize the subject or may require intervention to

prevent one of the other outcomes listed above should be considered serious. (Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not results in hospitalization; or development of drug dependency or drug abuse).

For each serious adverse event, please fill in the Serious Adverse Event (SAE) form and contact GlaxoSmithKline within 24 hours. Although not considered as ‘serious adverse events’, cancers must be reported in the same way as serious adverse events. Pregnancy must be reported on the specific Pregnancy Report form and this form must be faxed to GlaxoSmithKline within 24 hours.

CONFIDENTIAL


28 Aug 2009 4e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 3989c18a8f42336bf2a269a9749b704a240


111149 (HAB-160 BST)

FLOW SHEET

Twinrix Group

Age 41 years or older at the time of first dose of vaccination

Visit SCREEN VISIT 1

VISIT 2 VISIT 3 VISIT 4 VISIT 5 VISIT 6 VISIT 7 VISIT 8 VISIT 9 VISIT 10

Timing Day – 21 to

0

Day 0

Month 1

Month 6

Month 7

Month 12

Month 24

Month 36

Month 48

Day 14 after Month 48

Month 49

Sampling timepoint Pre- Vacc

Post-vacc 3

Post-vacc 3

Post-vacc 3

Post-vacc 3

Pre-challenge dose

Post-challenge dose

Post-challenge

dose

Informed consent • ••••

Check inclusion criteria O • ••••

Check exclusion criteria O • ••••

Check elimination criteria O O O O O O O O Check contraindications O O ••••

Check warnings and precautions ••••

Physical examination • O O

Smoking habit questionnaire •

Alcohol consumption questionnaire •

Medical condition questionnaire •*

Recording of concomitant medication by subjects on diary card

• • • • ••••

Transcription of concomitant medication • • • •••• Return of medication diary card • •••• Pre-vaccination body temperature • • • ••••

Pregnancy test (urine test) • • • ••••

Randomization •

Blood sampling for screening (10 ml) • for Ab determination (5 ml) • • • • •••• •••• •••• Vaccination Twinrix • • • ••••

Daily post-vaccination recording of solicited symptoms (Days 0–3) by subjects

••••

Recording of non-serious adverse events within 30 days post-vaccination, by investigator

••••

Transcription of diary cards by investigator

••••

Reporting of SAEs • • • • • •§ •§ •§ •••• •••• Study Conclusion •#† ••••

Post-vacc: Post vaccination

• Study procedure that requires documentation in the individual CRF or SAE form, O is used to indicate a study procedure that does not require documentation in the individual CRF. Screen: screening. *Including medical history, chronic diseases (chronic disease differs from acute disease in that it is treatable yet not curable). § only SAEs related to vaccination or SAEs referring to hepatitis A or B infection. # including verification of medical condition status: the investigator will compare with the subject’s medical condition at the beginning of the study (Day 0) and evaluate if the medical condition at Month 7 is the same. † The primary analysis will be performed at Month 7; study conclusion for the primary study. Long-term follow-up visits will be conducted at Months 12, 24, 36 and 48 to assess persistence of immune response.

CONFIDENTIAL


28 Aug 2009 5e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 3999c18a8f42336bf2a269a9749b704a240


111149 (HAB-160 BST)

FLOW SHEET

Engerix™ -B/Havrix™ Group


Visit SCREEN VISIT 1

VISIT 2 VISIT 3 VISIT 4 VISIT 5 VISIT 6 VISIT 7 VISIT 8 VISIT 9 VISIT 10

Timing Day – 21 to

0

Day 0

Month 1

Month 6

Month 7

Month 12

Month 24

Month 36

Month 48


Month 49


Post-vacc 3

Post-vacc 3

Post-vacc 3

Post-vacc 3

Pre-challen

ge

Post-challenge dose

Post-challenge dose




Check elimination criteria O O O O O O O O

Check contraindications O O ••••


Physical examination • O





• • • • ••••

Transcription of concomitant medication

• • • ••••

Return of medication diary card • •••• Pre-vaccination body temperature • • • ••••


Randomization •

Blood sampling

for screening (10 ml) •

for Ab determination (5 ml) • • • • •••• •••• •••• Vaccination Engerix™-B Havrix™

• •

•

• •

•••• ••••


••••


••••


••••

Reporting of SAEs • • • • • •§ •§ •§ • ••••

Study Conclusion •#† ••••

CONFIDENTIAL


28 Aug 2009 6e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4009c18a8f42336bf2a269a9749b704a240


111149 (HAB-160 BST)

FLOW SHEET

Engerix™ -B/Havrix™ Group

Post-vacc: Post vaccination

•Study procedure that requires documentation in the individual CRF or SAE form, O is used to indicate a study procedure that does not require documentation in the individual CRF. Screen: screening.

* Including medical history, chronic diseases (chronic disease differs from acute disease in that it is treatable yet not curable. § only SAEs related to vaccination or SAEs referring to hepatitis A or B infection. # including verification of medical condition status: the investigator will compare with the subject’s medical condition at the beginning of the study (Day 0) and evaluate if the medical condition at Month 7 is the same. † The primary analysis will be performed at Month 7; study conclusion for the primary study. Long-term follow-up visits will be conducted at Months 12, 24, 36 and 48 to assess persistence of immune response.

CONFIDENTIAL


28 Aug 2009 7e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4019c18a8f42336bf2a269a9749b704a240


111149 (HAB-160 BST)

FLOW SHEET

HB VAX PRO /Vaqta Group


Visit SCREEN VISIT 1 VISIT 2 VISIT 3 VISIT 4 VISIT 5 VISIT 6 VISIT 7 VISIT 8 VISIT 9 VISIT 10 Timing Day

– 21 to 0 Day 0 Month 1 Month 6 Month 7 Month

12 Month 24

Month 36

Month 48


Month 49


Post-vacc 3

Post-vacc 3

Post-vacc 3

Post-vacc 3

Pre-challenge dose

Post-challenge dose

Post-challenge dose




Check elimination criteria O O O O O O O O

Check contraindications O O ••••


Physical examination • O





• • • • ••••

Transcription of concomitant medication

• • • ••••

Return of medication diary card • •••• Pre-vaccination body temperature • • • ••••


Randomization •

Blood sampling

for screening (10 ml) • for Ab determination (5 ml) • • • • •••• •••• •••• Vaccination

HB VAX PRO

Vaqta

•

•

•

•

•

•••• ••••


• • • • • • • • ••••


• • • • • • • • ••••


••••

Reporting of SAEs • • • • • •§ •§ •§ •••• •••• Study Conclusion •#† ••••

Post-vacc: Post vaccination, Add-vacc: challenge dose

•Study procedure that requires documentation in the individual CRF or SAE form, O is used to indicate a study procedure that does not require documentation in the individual CRF. Screen: screening. * Including medical history, chronic diseases (chronic disease differs from acute disease in that it is treatable yet not curable. § only SAEs related to vaccination or SAEs referring to hepatitis A or B infection. # including verification of medical condition status: the investigator will compare with the subject’s medical condition at the beginning of the study (Day 0) and evaluate if the medical condition at Month 7 is the same. † The primary analysis will be performed at Month 7; study conclusion for the primary study. Long-term follow-up visits will be conducted at Months 12, 24, 36 and 48 to assess persistence of immune response.

CONFIDENTIAL


28 Aug 2009 8e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4029c18a8f42336bf2a269a9749b704a240


111149 (HAB-160 BST)

FLOW SHEET

Intervals between study visits

Interval Length of interval 1 Screening→Visit 1

(Screening – Day 0) 0 to 21 days

2 Visit 1→Visit 2 (Day 0 – Month 1)

30 ± 7 days

3 Visit 1→Visit 3 (Month 0 – Month 6)

180 ± 14 days

4 Visit 3→Visit 4 (Month 6 – Month 7)

30 - 40 days

5 Visit 1→Visit 5 (Day 0 – Month 12)

12 ± 1 month

6 Visit 1→Visit 6 (Day 0 - Month 24)

24 ± 2 months

7 Visit 1→Visit 7 (Day 0 - Month 36)

36 ± 2 months

8 Visit 1→→→→Visit 8 (Day 0 - Month 48)

48 ±±±± 2 months

9 Visit 8→→→→Visit 9 (Month 48 – Day 14 after challenge

dose) 14 ±±±± 2 days

10 Visit 8→→→→Visit 10 (Month 48 - Month 49)

30- 48 days

CONFIDENTIAL


28 Aug 2009 9e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4039c18a8f42336bf2a269a9749b704a240

VISIT 8

Month 48

Challenge DOSE

Informed Consent has to be obtained prior to any study procedure

CONFIDENTIAL


28 Aug 2009 10e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4049c18a8f42336bf2a269a9749b704a240


Protocol

111149 (HAB-160 BST)

ELIMINATION CRITERIA DURING THE STUDY

The following criteria should be checked at each visit subsequent to the first visit. If any become applicable during the study, it will not require withdrawal of the subject from the study but does determine a subject’s evaluability in the according-to-protocol (ATP) analysis.

• Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine(s)

during the study period

Contraindications and precautions for further doses

The following events constitute absolute contraindications to further administration of Twinrix, Engerix-B /Havrix, or HB VAX PRO /Vaqta; if any of these events occur during the study, the subject must not receive additional doses of vaccine but may continue other study procedures at the discretion of the investigator. The subject must be followed until resolution of the event :

• Anaphylactic reaction following the administration of vaccines. • Pregnancy

The following events constitute contraindications to administration of Twinrix, or Engerix-B /Havrix, or HB VAX PRO /Vaqta at that point in time; if any one of these events occurs at the time scheduled for vaccination, the subject may be vaccinated at a later date, within the time window specified in the protocol, or withdrawn at the discretion of the investigator. The subject must be followed until resolution of the event.

•Acute disease at the time of vaccination. (Acute disease is defined as the presence of a moderate or severe illness with or without fever. All vaccines can be administered to persons with a minor illness such as diarrhoea, mild upper respiratory infection with or without low-grade febrile illness, i.e., Oral/ axillary temperature <37.5°C. [< 37.0°C for Czech R epublic only] at the time of vaccination.)

CONFIDENTIAL


28 Aug 2009 11e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4059c18a8f42336bf2a269a9749b704a240


Protocol

111149 (HAB-160 BST)

Warning and precautions

Twinrix™ � As with other vaccines, the administration of Twinrix™ should be postponed in subjects suffering from

acute severe febrile illness.

� It is possible that subjects may be in the incubation period of a hepatitis A or hepatitis B infection at the time of vaccination. It is not known whether Twinrix™ will prevent hepatitis A and hepatitis B in such cases.

� The vaccine will not prevent infection caused by other agents such as hepatitis C and hepatitis E and other pathogens known to infect the liver.

� Twinrix™ is not recommended for post-exposure prophylaxis (e.g. needle stick injury).

� The vaccine has not been tested in patients with impaired immunity. In haemodialysis patients and persons with an impaired immune system, adequate anti-HAV and anti-HBs antibody titers may not be obtained after the primary immunisation course and such patients may therefore require administration of additional doses of vaccine.

� Twinrix™ should under no circumstances be administered intravenously.

Engerix™ -B � Because of the long incubation period of hepatitis B it is possible for unrecognised infection to be present

at the time of immunisation. The vaccine may not prevent hepatitis B infection in such cases.

� The vaccine will not prevent infection caused by other pathogens known to infect the liver such as hepatitis A, hepatitis C and hepatitis E virus.

� Thiomersal (an organomercuric compound) has been used in the manufacturing process of this medicinal product and residues of it are present in the final product. Therefore, sensitisation reactions may occur.

� Engerix™-B should not be administered in the buttock or intradermally since this may result in a lower immune response.

� Engerix™-B should under no circumstances be administered intravascularly.

� As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of rare anaphylactic reactions following the administration of the vaccine.

� As with any vaccine, a protective immune response may not be elicited in all vaccinees.

CONFIDENTIAL


28 Aug 2009 12e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4069c18a8f42336bf2a269a9749b704a240


Protocol

111149 (HAB-160 BST)

Warning and precautions (Continued)

Havrix™

� It is possible that subjects may be in the incubation period of a hepatitis A infection at the time of immunisation. It is not known whether Havrix™ (1440 ELISA Units) will prevent hepatitis A in such cases.

� In haemodialysis patients and in subjects with an impaired immune system, adequate anti-HAV antibody titres may not be obtained after a single dose of Havrix™ (1440 ELISA Units) and such patients may therefore require administration of additional doses of vaccine.

� As with all injectable vaccines, appropriate medical treatment should always be readily available for treatment in case of anaphylactic reactions following the administration of the vaccine. For this reason, the vaccinee should remain under medical supervision for 30 minutes after immunisation.

� Havrix™ (1440 ELISA Units) should be administered with caution to subjects with thrombocytopenia or a bleeding disorder since bleeding may occur following an intramuscular administration to these subjects.

� The vaccine should not be administered intramuscularly in the gluteal region or subcutaneously/intradermally since administration by these routes may result in a less than optimal anti-HAV antibody response.

� Havrix™ (1440 ELISA Units) should under no circumstances be administered intravenously.

HBVAXPRO™ � Persons with immunodeficiency or those receiving immunosuppressive therapy require larger vaccine

doses and respond less well than healthy individuals.

� Because of the long incubation period for hepatitis B, it is possible for unrecognized infection to be present at the time HBvaxPRO is given. HBvaxPRO may not prevent hepatitis B in such patients.

� Patients who develop symptoms suggestive of hypersensitivity after an injection should not receive further injections of HBvaxPRO.

� As with any parenteral vaccine, epinephrine (adrenaline) should be available for immediate use should an anaphylactoid reaction occur. Any serious active infection is reason for delaying use of HBvaxPRO, except when, in the opinion of the physician, withholding the vaccine entails a greater risk.

� Caution and appropriate care should be exercised in administering HBvaxPRO to individuals with severely compromised cardiopulmonary status or to others in whom a febrile or systemic reaction could pose a significant risk.

CONFIDENTIAL


28 Aug 2009 13e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4079c18a8f42336bf2a269a9749b704a240


Protocol

111149 (HAB-160 BST)

Warning and precautions (Continued)

Vaqta™

� As with all injectable vaccines, appropriate medical treatment and supervision should always be readily

available in case of a rare anaphylactic event following the administration of the vaccine.

� Testing for antibodies to hepatitis A prior to a decision on immunisation should be performed in patients born in areas of high endemicity and/or with a history of jaundice.

� Vaqta™ does not cause immediate protection against hepatitis A, and there may be a period of 2 to 4 weeks before antibody induction occurs.

� Because of the long incubation period (approximately 20 to 50 days) for hepatitis A, it is possible for unrecognised hepatitis A infection to be present at the time the vaccine is given. The vaccine may not prevent hepatitis A in such individuals.

� Vaqta™ will not prevent hepatitis caused by infectious agents other than hepatitis A virus.

� In subjects with an impaired immune system, adequate anti-HAV antibody titres may not be obtained. If the immunosuppression is due to medical treatment, vaccination should be delayed if possible until the completion of therapy and immune system recovery.

� The vaccine has been evaluated in human immunodeficiency virus (HIV) infected adults. There are no data on the use of Vaqta in HIV infected subjects.

� As with any vaccine, vaccination with Vaqta may not result in a protective response in all susceptible vaccines.

� As no studies have been performed with Vaqta in subjects with liver disease, caution is advised if administering the vaccine in these subjects.

CONFIDENTIAL


28 Aug 2009 14e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4089c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)

Protocol CRF Center Visit Date of visit Subject Number

111149

|__|__|__|__|__|__|

VISIT 8 |__|__| |__|__|__| |__|__|__|__| day month year

|__|__|__|__|__|

INFORMED CONSENT

I certify that Informed Consent has been obtained prior to any study procedure.

Informed Consent Date : |__|__| |__|__|__| |__|__|__|__| day month year

DEMOGRAPHICS Date of birth : |__|__| |__|__|__| |__|__|__|__| day month year

Gender : Male

Female

Race : [ 1 ] Black

[ 4 ] Arabic/North African

[ 2 ] White/Caucasian

[ 5 ] East & South East Asian

[ 6 ] South Asian

[ 9 ] Other, please specify: _________________________________

Height : |__|__|__| cm

Weight : |__|__|__| . |__| kg

1.

Previous study (last previous study where the subject has participated) (tick only one):

□ 100382 (HAB-160)

□ 100383 (HAB-161 EXT-160 Y1)

□ 100384 (HAB-162 EXT-160 Y2)

□ 100385 (HAB-163 EXT-160 Y3)

Subject number will be the same as in the previous study

CONFIDENTIAL


28 Aug 2009 15e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4099c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)

Protocol CRF Visit Subject Number

111149

VISIT 8

|__|__|__|__|__|

ELIGIBILITY QUESTION

Did the subject meet all the entry criteria ?

Yes No

If No, please complete below.

INCLUSION CRITERIA

Tick (�) the box next to any of the inclusion criteria the subject failed

[ 1 ] � Subjects who the investigator believes that they can and will comply with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visits) should be enrolled in the study.

[ 2 ] � A male of female who completed the primary vaccination phase of the study.

[ 3 ] � Written informed consent obtained from the subject.

[ 4 ] � If the subject is female, she must be of non-childbearing potential, i.e., either surgically sterilized or one year post-menopausal; or, if of childbearing potential, she must be abstinent or have used adequate contraceptive precautions (i.e., intrauterine contraceptive device; oral/long term hormonal contraceptives; diaphragm or condom in combination with contraceptive jelly, cream or foam) for 30 days prior to vaccination, have a negative pregnancy test and must agree to continue such precautions for two months after completion of the vaccination series.

2.

CONFIDENTIAL


28 Aug 2009 16e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4109c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149

VISIT 8

|__|__|__|__|__|

ELIGIBILITY QUESTION (Continued)

EXCLUSION CRITERIA Tick (�) the box next to any of the exclusion criteria the subject met

[ 5 ] � Use of any investigational or non-registered product (drug or vaccine) other than the study vaccines within 30 days preceding the first dose of study vaccine, or planned use during the study period.

[ 6 ] � History of any hepatitis A or hepatitis B vaccination or infection, since the primary vaccination study.

[ 7 ] � History of allergic disease or reactions likely to be exacerbated by any component of the vaccine.

[ 8 ] � Acute disease at the time of enrolment. (Acute disease is defined as the presence of a moderate or severe illness with or without fever. All vaccines can be administered to persons with a minor illness such as diarrhoea, mild upper respiratory infection with or without low-grade febrile illness, i.e., Oral/ axillary temperature <37.5°C [< 37.0°C for Czech Republic only]).

[ 9 ] � Pregnant or lactating female.

[ 10 ] � Female planning to become pregnant or planning to discontinue contraceptive precautions during the primary vaccination period (up to Month 7).

TREATMENT ALLOCATION Record treatment number: |__|__|__|__|__|

3.

CONFIDENTIAL


28 Aug 2009 17e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4119c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149

VISIT 8

|__|__|__|__|__|

LABORATORY TESTS

BLOOD SAMPLE

Has a blood sample been taken ?

Yes → Please complete only if different from visit date: |__|__| |__|__|__| |__|__|__|__| day month year No

URINE SAMPLE (Pregnancy test – HCG)

Has a urine sample been taken ? Yes → Please complete only if different from visit date: |__|__| |__|__|__| |__|__|__|__| day month year

→ result : Negative

Positive

No NA (for female of non-childbearing potential or for male)

PRE-VACCINATION ASSESSMENT

Temperature : |__|__| . |__| °C � Route : [ A ] Axillary

[ O ] Oral

[ X ] Tympanic (oral conversion)

[ Y ] Tympanic (rectal conversion)

[ R ] Rectal Note : Most tympanic thermometers automatically make conversions from tympanic temperature values to oral or rectal values. Please indicate the appropriate conversion.

4.

CONFIDENTIAL


28 Aug 2009 18e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4129c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149 VISIT 8

Challenge dose Twinrix Group

|__|__|__|__|__|

VACCINE ADMINISTRATION Please complete only if different from visit date : |__|__| |__|__|__| |__|__|__|__| day month year

VACCINE ADMINISTRATION (only one box must be ticked by vaccine)

Side / site route

Has the study vaccine been administered according to the Protocol ?

[ 191] Twinrix

Replacement vial (*)

Wrong vial number (*)

Not administered (**)

(please complete below)

Left

Deltoid

I.M.

Yes

No � please tick all items that apply

Side: Site: Route: Left Deltoid I.M.

Right Thigh S.C.

Buttock

(*) Comments : _______________________________________________________________________

(**) Why not administered ?

Please tick the ONE most appropriate category for non administration :

(SAE) Serious adverse event (complete the Serious Adverse Event form )

Please specify SAE N° : |__|__|

(AEX) Non-Serious adverse event (complete the Non-serious Adverse Event form )

Please specify AE N° (Unsolicited) : |__|__|

(OTH) Other, please specify: __________________________________________________

(e.g. : consent withdrawal, Protocol violation, …) Please tick who took the decision : Investigator Subject

IMMEDIATE POST-VACCINATION OBSERVATION

If any adverse events occurred during the immediate post-vaccination time (protocol specific : 15min – 30min) please fill in the Solicited Adverse Events section, the Non-Serious Adverse Event page or a Serious Adverse Event form.

If any prophylactic medication has been administered in anticipation of study vaccine reaction, please complete the Medication section. Any other vaccines administered during the study period must be recorded in the Concomitant Vaccination section.

5.

CONFIDENTIAL


28 Aug 2009 19e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4139c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149 VISIT 8

Challenge dose HB VAX PRO and Vaqta

group

|__|__|__|__|__|

VACCINE ADMINISTRATION

Please complete only if different from visit date : |__|__| |__|__|__| |__|__|__|__| day month year


Side / site route


[ 173] HB VAX PRO Vaccine





Left

Deltoid

I.M.

Yes


Side Site Route Left Deltoid I.M.

Right Thigh S.C.

Buttock

[ 174] Vaqta Vaccine





Right

Deltoid

I.M.

Yes



Right Thigh S.C.

Buttock

(*) : Comments : ---------------------------------------------------------------------------------------------------------------------

(**) : Please complete next page

6.

CONFIDENTIAL


28 Aug 2009 20e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4149c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149 VISIT 8


group

|__|__|__|__|__|

VACCINE ADMINISTRATION (continued)








(e.g. : consent withdrawal, Protocol violation, …)

Please tick who took the decision : Investigator Subject




7.

CONFIDENTIAL


28 Aug 2009 21e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4159c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149 VISIT 8

Challenge dose Engerix™-B and Havrix™

Group

|__|__|__|__|__|


Please complete only if different from visit date : |__|__| |__|__|__| |__|__|__|__| day month year


Side / site route


[ 5] Engerix™-B Vaccine





Left

Deltoid

I.M.

Yes



Right Thigh S.C.

Buttock

[ 1] Havrix™ Vaccine





Right

Deltoid

I.M.

Yes



Right Thigh S.C.

Buttock

(*) : Comments : ---------------------------------------------------------------------------------------------------------------------

(**) : Please complete next page 8.

CONFIDENTIAL


28 Aug 2009 22e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4169c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149 VISIT 8


Group

|__|__|__|__|__|

VACCINE ADMINISTRATION (continued)









Please tick who took the decision : Investigator Subject




9.

CONFIDENTIAL


28 Aug 2009 23e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4179c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149 VISIT 8

Challenge dose Twinrix Group

|__|__|__|__|__|

SOLICITED ADVERSE EVENTS – LOCAL SYMPTOMS Has the subject experienced any of the following signs/symptoms at the administration site during the solicited period?

[ U ] Information not retrievable

[ N A ] No vaccine administered

[ N ] No

[ Y ] Yes, please tick No/Yes for each symptom. If Yes is ticked, please complete all items.

LOCAL SYMPTOMS Day 0 Day 1 Day 2 Day 3 Ongoing

after day 3? Date of last day of symptoms

day month year

Redness (RE) � No

� Yes � size (mm):

_____

_____

_____

_____

� No � Yes �

|__|__| |__|__|__| |__|__|__|__|

Swelling (SW) � No

� Yes � size (mm):

_____

_____

_____

_____

� No � Yes �

|__|__| |__|__|__| |__|__|__|__|

Pain (PA) � No

� Yes � intensity:

|___|

|___|

|___|

|___|

� No � Yes �

|__|__| |__|__|__| |__|__|__|__|

Intensity : 0 : None

1 : Mild

2 : Moderate

3 : Severe

If any of these adverse events are serious according to Protocol definition, please report event to GSK monitor by telephone or fax within 24 hours (see Protocol) and complete the Serious Adverse Event form .

10.

CONFIDENTIAL


28 Aug 2009 24e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4189c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)

Protocol CRF Subject Number

111149 |___| VISIT 8


group

|__|__|__|__|__|

SOLICITED ADVERSE EVENTS – LOCAL SYMPTOMS For each vaccine, has the subject experienced any of the following signs/symptoms at the administration site during the solicited period?



day month year

HB VAX PRO vaccine [ N ] No [ U ] Information not retrievable [ N A ] No vaccine administered

[ Y ] Yes, please tick No/Yes for each symptom . If Yes is ticked, please complete all items.

Redness (RE) � No

� Yes � size (mm) :

_____

_____

_____

_____

� No � Yes �

|__|__| |__|__|__| |__|__|__|__|



_____

_____

_____

_____

� No � Yes �

|__|__| |__|__|__| |__|__|__|__|

Pain (PA) � No

� Yes � intensity :

|___|

|___|

|___|

|___|

� No � Yes �

|__|__| |__|__|__| |__|__|__|__|

Vaqta vaccine [ N ] No [ U ] Information not retrievable [ N A ] No vaccine administered


Redness (RE) � No


_____

_____

_____

_____

� No � Yes �

|__|__| |__|__|__| |__|__|__|__|



_____

_____

_____

_____

� No � Yes �

|__|__| |__|__|__| |__|__|__|__|

Pain (PA) � No


|___|

|___|

|___|

|___|

� No � Yes �

|__|__| |__|__|__| |__|__|__|__|


1 : Mild

2 : Moderate

3 : Severe


11.

CONFIDENTIAL


28 Aug 2009 25e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4199c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149 |___| VISIT 8


Group

|__|__|__|__|__|

SOLICITED ADVERSE EVENTS – LOCAL SYMPTOMS For each vaccine, has the subject experienced any of the following signs/symptoms at the administration site during the solicited period?



day month year

Engerix™-B vaccine [ N ] No [ U ] Information not retrievable [ N A ] No vaccine administered


Redness (RE) � No


_____

_____

_____

_____

� No � Yes �

|__|__| |__|__|__| |__|__|__|__|



_____

_____

_____

_____

� No � Yes �

|__|__| |__|__|__| |__|__|__|__|

Pain (PA) � No


|___|

|___|

|___|

|___|

� No � Yes �

|__|__| |__|__|__| |__|__|__|__|

Havrix™ vaccine [ N ] No [ U ] Information not retrievable [ N A ] No vaccine administered


Redness (RE) � No


_____

_____

_____

_____

� No � Yes �

|__|__| |__|__|__| |__|__|__|__|



_____

_____

_____

_____

� No � Yes �

|__|__| |__|__|__| |__|__|__|__|

Pain (PA) � No


|___|

|___|

|___|

|___|

� No � Yes �

|__|__| |__|__|__| |__|__|__|__|


1 : Mild

2 : Moderate

3 : Severe


12.

CONFIDENTIAL


28 Aug 2009 26e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4209c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149 VISIT 8

Challenge dose ALL

|__|__|__|__|__|

SOLICITED ADVERSE EVENTS – GENERAL SYMPTOMS

Has the subject experienced any of the following signs/symptoms during the solicited period ? [ U ] Information not retrievable


[ N ] No


GENERAL SYMPTOMS

Day 0 Day 1 Day 2 Day 3 Ongoing after day 3?

Date of last day of symptoms day month year Causality ?

Fever (FE) � No

� Yes � °C :

___.__ � not

taken

___.__ � not

taken

___.__ � not

taken

___.__

� not

taken

� No � Yes �

|__|__| |__|__|__| |__|__|__|__|

� No � Yes

Fatigue (FA) � No


|___|

|___|

|___|

|___|

� No � Yes �

|__|__| |__|__|__| |__|__|__|__|

� No � Yes

Headache (HE) � No


|___|

|___|

|___|

|___|

� No � Yes �

|__|__| |__|__|__| |__|__|__|__|

� No � Yes

Gastrointestinal symptoms (GI) � No


|___|

|___|

|___|

|___|

� No � Yes �

|__|__| |__|__|__| |__|__|__|__|

� No � Yes

Intensity : 0 : None 1 : Mild 2 : Moderate 3 : Severe

Fever : Axillary ≥ 37.5°C (37.0°C for Czech Republic ONLY) Oral ≥ 37.5°C (37.0°C for Czech Republic ONLY)

Tympanic (oral conversion) ≥ 37.5°C (37.0°C for Czech Republic ONLY) Tympanic (rectal conversion) ≥ 38°C (37.5°C for Czech Republic ONLY) Rectal ≥ 38°C (37.5°C for Czech Republic ONLY)


13.

[A] � Axillary [O] � Oral [X] � Tympanic oral [Y] � Tympanic rectal [R] � Rectal

CONFIDENTIAL


28 Aug 2009 27e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4219c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149 VISIT 8

Challenge dose

|__|__|__|__|__|

ADVERSE EVENTS – POST–VACCINATION OBSERVATION

Has the subject experienced any serious or non-serious unsolicited adverse events within one month (minimum 30 days) post-vaccination?

[ U ] Information not retrievable

[ N A ] No Vaccine administered

[ N ] No

[ Y ] Yes, fill in the Non-Serious Adverse Event pages or Serious Adverse Event form.

14.

CONFIDENTIAL


28 Aug 2009 28e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4229c18a8f42336bf2a269a9749b704a240

VISIT 9 2 weeks after Visit 8

at Month 48

Blood sampling

CONFIDENTIAL


28 Aug 2009 29e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4239c18a8f42336bf2a269a9749b704a240

REMINDERS

ELIMINATION CRITERIA

Please check all appropriate criteria before continuing the visit.

ADVERSE EVENTS

Please report adverse events as specified in the Protocol and fill in the Non-Serious Adverse Events pages or the Serious Event (SAE) form, as appropriate. This SAE form must be faxed to GlaxoSmithKline within 24 hours of you becoming aware of these events.

MEDICATION

Please report medication as specified in the Protocol and fill in the Medication section. Please report concomitant vaccination in the Concomitant Vaccination section.

BLOOD SAMPLE

Please don’t forget to proceed to a blood sample

CONFIDENTIAL


28 Aug 2009 30e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4249c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149

VISIT 9

|__|__|__|__|__|

CHECK FOR STUDY CONTINUATION

Did the subject come at visit 9 ? Yes, please complete the next pages.

No

Same reason and decision as previous visit

OR

please tick the ONE most appropriate reason and skip the following pages of this visit.

(SAE) Serious adverse event

(complete the Serious Adverse Event form ) Please specify SAE N° : |__|__|

(AEX) Non-Serious adverse event

(complete the Non-serious Adverse Event page ) Please specify AE N° (Unsol.) : |__|__| or code (Solicited) : |__|__|

(OTH) Other, please specify : _____________________________________


Investigator’s decision Subject’s decision

15.

CONFIDENTIAL


28 Aug 2009 31e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4259c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)

Protocol CRF Visit Date of visit Subject Number

111149


|__|__|__|__|__|

LABORATORY TESTS

BLOOD SAMPLE


Yes → Please complete only if different from visit date: |__|__| |__|__|__| |__|__|__|__| day month year No 16.

CONFIDENTIAL


28 Aug 2009 32e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4269c18a8f42336bf2a269a9749b704a240

VISIT 10 MONTH 49

Post Challenge Dose

CONFIDENTIAL


28 Aug 2009 33e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4279c18a8f42336bf2a269a9749b704a240

REMINDERS



ADVERSE EVENTS

Please report adverse events as specified in the Protocol and fill in the Non-Serious Adverse Events pages or the Serious Event (SAE) form, as appropriate. This SAE form must be faxed to GlaxoSmithKline within 24 hours of you becoming aware of these events.

MEDICATION


CONFIDENTIAL


28 Aug 2009 34e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4289c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149

VISIT 10

|__|__|__|__|__|

CHECK FOR STUDY CONTINUATION

Did the subject come at visit 10 ? Yes, please complete the next pages.

No

Same reason and decision as previous visit

OR

please tick the ONE most appropriate reason and skip the following pages of this visit.


(complete the Serious Adverse Event form ) Please specify SAE N° : |__|__|

(AEX) Non-Serious adverse event

(complete the Non-serious Adverse Event page ) Please specify AE N° (Unsol.) : |__|__| or code (Solicited) : |__|__|

(OTH) Other, please specify : _____________________________________



17.

CONFIDENTIAL


28 Aug 2009 35e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4299c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)

Protocol CRF Visit Date of visit Subject Number

111149


|__|__|__|__|__|

LABORATORY TESTS

BLOOD SAMPLE


Yes → Please complete only if different from visit date: |__|__| |__|__|__| |__|__|__|__| day month year No 18.

CONFIDENTIAL


28 Aug 2009 36e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4309c18a8f42336bf2a269a9749b704a240

CONCOMITANT

VACCINATION

CONFIDENTIAL


28 Aug 2009 37e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4319c18a8f42336bf2a269a9749b704a240


VACCINATION ROUTE

CODE LABEL

ID Intradermal IH Inhalation IM Intramuscular IV Intravenous NA Intranasal OTH Other PE Parenteral PO Oral SC Subcutaneous SL Sublingual TD Transdermal UNK Unknown

CONFIDENTIAL


28 Aug 2009 38e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4329c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149

|__|__|__|__|__|

CONCOMITANT VACCINATION

Has any vaccine other than the study vaccine(s) been administered during the timeframe as specified in the Protocol ? No

Yes, please record concomitant vaccination with trade name, route and / or generic name, and vaccine administration date.

Trade / (Generic) Name Route Administration date

day month year

|__|__| |__|__|__| |__|__|__|__|

For GSK

|__|__| |__|__|__| |__|__|__|__|

For GSK

|__|__| |__|__|__| |__|__|__|__|

For GSK

|__|__| |__|__|__| |__|__|__|__|

For GSK

|__|__| |__|__|__| |__|__|__|__|

For GSK

|__|__| |__|__|__| |__|__|__|__|

For GSK

|__|__| |__|__|__| |__|__|__|__|

For GSK

|__|__| |__|__|__| |__|__|__|__|

19.

CONFIDENTIAL


28 Aug 2009 39e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4339c18a8f42336bf2a269a9749b704a240

MEDICATION

CONFIDENTIAL


28 Aug 2009 40e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4349c18a8f42336bf2a269a9749b704a240


MEDICATION ROUTE

CODE LABEL

EXT External ID Intradermal IH Inhalation IM Intramuscular IR Intraarticular IT Intrathecal IV Intravenous NA Intranasal OTH Other PE Parenteral PO Oral PR Rectal SC Subcutaneous SL Sublingual TD Transdermal TO Topical UNK Unknown VA Vaginal

• All concomitant medication, with the exception of vitamins and/or dietary supplements, administered at ANY time during the period starting with each dose and ending at least one month (minimum 30 days) after each dose are to be recorded with generic name of the medication (trade names are allowed for association drugs only, i.e., multi-component drugs), medical indication, total daily dose, route of administration, start and end dates of treatment.

• Any treatments and/or medications specifically contraindicated, i.e., any immunoglobulins, other blood products and any immune modifying drugs administered within the time frame specified in the Protocol or at any time during the study period are to be recorded with generic name of the medication (trade names are allowed for association drugs only), medical indication, total daily dose, route of administration, start and end dates of treatment.

• Any concomitant medication administered prophylactically in anticipation of reaction to the vaccination must be recorded in the CRF with generic name of the medication (trade names are allowed for association drugs only), total daily dose, route of administration, start and end dates of treatment and coded as “Prophylactic”.

CONFIDENTIAL


28 Aug 2009 41e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4359c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149

|__|__|__|__|__|

MEDICATION

Have any medications/treatments been administered during study period? No Yes, please complete the following table.

Trade / Generic Name Medical Indication Total daily dose Route

Start and end date or tick box if continuing at end of study

day month yea r

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

20.

CONFIDENTIAL


28 Aug 2009 42e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4369c18a8f42336bf2a269a9749b704a240

NON-SERIOUS

ADVERSE

EVENTS

CONFIDENTIAL


28 Aug 2009 43e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4379c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149

Twinrix group

|__|__|__|__|__|

NON-SERIOUS ADVERSE EVENTS

(Please report all serious adverse events only on the Serious Adverse Event (SAE) form). Has any non-serious adverse events occurred within one month (minimum 30 days) post-vaccination, excluding those recorded on the Solicited Adverse Events pages?

No Yes, please complete the following table.

AE No. 1 2 Description _ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

Administration sites

Non-administration site



For GSK

Date Started

|__|__| |__|__|__| |__|__|__|__| day month year

during immediate post-vaccination period (protocol specific: 15 minutes – 30 minutes)

|__|__| |__|__|__| |__|__|__|__| day month year


Date Stopped |__|__| |__|__|__| |__|__|__|__| day month year

|__|__| |__|__|__| |__|__|__|__| day month year

Intensity [ 1 ] Mild

[ 2 ] Moderate

[ 3 ] Severe

[ 1 ] Mild

[ 2 ] Moderate

[ 3 ] Severe

Relationship to investigational products: Is there a reasonable possibility that the AE may have been caused by the investigational product?

No

Yes

No

Yes

Outcome

[ 1 ] Recovered / Resolved

[ 2 ] Recovering / resolving

[ 3 ] Not recovered / not resolved

[ 4 ] Recovered with sequelae / Resolved with sequelae





21.

CONFIDENTIAL


28 Aug 2009 44e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4389c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149

Twinrix group

|__|__|__|__|__|

NON-SERIOUS ADVERSE EVENTS (continued)


_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _





For GSK

Date Started

|__|__| |__|__|__| |__|__|__|__| day month year


|__|__| |__|__|__| |__|__|__|__| day month year



|__|__| |__|__|__| |__|__|__|__| day month year


[ 2 ] Moderate

[ 3 ] Severe

[ 1 ] Mild

[ 2 ] Moderate

[ 3 ] Severe


No

Yes

No

Yes

Outcome









22.

CONFIDENTIAL


28 Aug 2009 45e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4399c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149

Engerix™-B and Havrix™ group

|__|__|__|__|__|

NON-SERIOUS ADVERSE EVENTS (Please report all serious adverse events only on the Serious Adverse Event (SAE) form). Has any non-serious adverse events occurred within one month (minimum 30 days) post-vaccination, excluding those recorded on the Solicited Adverse Events pages?



_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _


[ 5 ] Engerix™-B vaccine

[ 1 ] Havrix™ vaccine


Administration sites [ 5 ] Engerix™-B vaccine



For GSK

Date Started

|__|__| |__|__|__| |__|__|__|__| day month year


|__|__| |__|__|__| |__|__|__|__| day month year



|__|__| |__|__|__| |__|__|__|__| day month year


[ 2 ] Moderate

[ 3 ] Severe

[ 1 ] Mild

[ 2 ] Moderate

[ 3 ] Severe


No

Yes

No

Yes

Outcome









23.

CONFIDENTIAL


28 Aug 2009 46e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4409c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149

Engerix™-B and Havrix™ group

|__|__|__|__|__|



_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _


[ 5] Engerix™-B vaccine

[ 1] Havrix™ vaccine


Administration sites [ 5 ] Engerix™-B vaccine



For GSK

Date Started

|__|__| |__|__|__| |__|__|__|__| day month year


|__|__| |__|__|__| |__|__|__|__| day month year



|__|__| |__|__|__| |__|__|__|__| day month year


[ 2 ] Moderate

[ 3 ] Severe

[ 1 ] Mild

[ 2 ] Moderate

[ 3 ] Severe


No

Yes

No

Yes

Outcome









24.

CONFIDENTIAL


28 Aug 2009 47e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4419c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149

HB VAX PRO and Vaqta group

|__|__|__|__|__|

NON-SERIOUS ADVERSE EVENTS (Please report all serious adverse events only on the Serious Adverse Event (SAE) form). Has any non-serious adverse events occurred within one month (minimum 30 days) post-vaccination, excluding those recorded on the Solicited Adverse Events pages?



_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _


[ 1 7 3 ] HB VAX PRO vaccine

[ 1 7 4 ] Vaqta vaccine






For GSK

Date Started

|__|__| |__|__|__| |__|__|__|__| day month year


|__|__| |__|__|__| |__|__|__|__| day month year



|__|__| |__|__|__| |__|__|__|__| day month year


[ 2 ] Moderate

[ 3 ] Severe

[ 1 ] Mild

[ 2 ] Moderate

[ 3 ] Severe


No

Yes

No

Yes

Outcome









25.

CONFIDENTIAL


28 Aug 2009 48e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4429c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149

HB VAX PRO and Vaqta

|__|__|__|__|__|



_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _

_ _ __ __ __ __ __ __ __ __ __ _ __ _


[ 173] HB VAX PRO vaccine

[ 174] Vaqta vaccine






For GSK

Date Started

|__|__| |__|__|__| |__|__|__|__| day month year


|__|__| |__|__|__| |__|__|__|__| day month year



|__|__| |__|__|__| |__|__|__|__| day month year


[ 2 ] Moderate

[ 3 ] Severe

[ 1 ] Mild

[ 2 ] Moderate

[ 3 ] Severe


No

Yes

No

Yes

Outcome









26.

CONFIDENTIAL


28 Aug 2009 49e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4439c18a8f42336bf2a269a9749b704a240

STUDY

CONCLUSION

CONFIDENTIAL


28 Aug 2009 50e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4449c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149

|__|__|__|__|__|

FOLLOW-UP STUDIES

Would the subject be willing to participate in a follow-up study?

Yes

No, please specify the reason

� Adverse Events, or Serious Adverse Events:

please specify: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

� Other:

please specify: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

27.

CONFIDENTIAL


28 Aug 2009 51e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4459c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149

|__|__|__|__|__|

STUDY CONCLUSION

OCCURRENCE OF SERIOUS ADVERSE EVENT

Did the subject experience any Serious Adverse Event during the study period?

Yes No

If yes, please give the total number of SAE's: |__|__|

PREGNANCY INFORMATION

Did the subject become pregnant during the study?

Yes No Not applicable (not of childbearing potential or male)

If yes, please complete the Pregnancy Notification form.


Did any elimination criteria become applicable during the study?

Yes No

If Yes, please specify: ________________________________________________

28.

CONFIDENTIAL


28 Aug 2009 52e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4469c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST)


111149

|__|__|__|__|__|

STUDY CONCLUSION (continued)

Was the subject withdrawn from study?

No Yes

Please tick the ONE most appropriate category for drop out.


(complete the Serious Adverse Event form )

Please specify SAE N°: |__|__|

(AEX) Non-Serious adverse event (complete the Non-serious Adverse Event page )

Please specify AE N° (Unsol.): |__|__| or code (Solicited): |__|__|

(PTV) Protocol violation, please specify:_________________________________________

(CWS) Consent withdrawal, not due to an adverse event.

(MIG) Migrated / moved from the study area

(LFU) Lost to follow-up.

(OTH) Other, please specify: ____________________________________________


Date of last contact: |__|__| |__|__|__| |__|__|__|__| day month year

Was the subject in good condition at date of last contact?

No, please give details within the Adverse Events section. Yes

INVESTIGATOR'S SIGNATURE

I confirm that I have reviewed the data in this Case Report Form for this subject. All information entered by myself or my colleagues is, to the best of my knowledge, complete and accurate, as of the date below.

Investigator's signature: ___________________________ Date: |__|__| |__|__|__| |__|__|__|__|

Printed Investigator's name: ___________________________

day month year

29.

CONFIDENTIAL


28 Aug 2009 53e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4479c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST) Protocol Previous study Center

111149

100385 (HAB-163 EXT-160 Y3) or 100384 (HAB-163 EXT-160 Y2) or 100383 (HAB-163 EXT-160 Y1) or 100382 (HAB-160)

Tracking Document Reason for non participation

|__|__|__|

Investigator name: (please PRINT name) Signature: Date: (day month year)

|__|__| |__|__|__| |__|__|__|__|

Previous Subject Number

Date of Birth (day month year)

Please document reason for non participation Date of Contact (day month year)

|__|__|__|__|__|


100385 (HAB-163 EXT-160 Y3)

100384 (HAB-162 EXT-160 Y2)

100383 (HAB-161 EXT-160 Y1)

100382 (HAB-160)

|__|__| |__|__|__| |__|__|__|__|

1. Subject not eligible? - please specify criteria that are not fullfilled: ___________________

2. Subject lost to follow-up or not reached

3. Subject eligible but not willing to participate due to:

adverse events, or serious adverse event: please specify: __________________

other: please specify: __________________

4. Subject died on: |__|__| |__|__|__| |__|__|__|__|

|__|__| |__|__|__| |__|__|__|__|

|__|__|__|__|__|


100385 (HAB-163 EXT-160 Y3)

100384 (HAB-162 EXT-160 Y2)

100383 (HAB-161 EXT-160 Y1)

100382 (HAB-160)

|__|__| |__|__|__| |__|__|__|__|






4. Subject died on: |__|__| |__|__|__| |__|__|__|__|

|__|__| |__|__|__| |__|__|__|__|

CONFIDENTIAL


28 Aug 2009 54e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4489c18a8f42336bf2a269a9749b704a240

111149 (HAB-160 BST) Protocol Previous study Center

111149

100385 (HAB-163 EXT-160 Y3) or 100384 (HAB-163 EXT-160 Y2) or 100383 (HAB-163 EXT-160 Y1) or 100382 (HAB-160)

Tracking Document Reason for non participation

|__|__|__|

Investigator name: (please PRINT name) Signature: Date: (day month year)

|__|__| |__|__|__| |__|__|__|__|



Please document reason for non participation Date of Contact (day month year)

|__|__|__|__|__|

Previous studies (last previous study where the subject has participated)

(tick only one):

100385 (HAB-163 EXT-160 Y3)

100384 (HAB-162 EXT-160 Y2)

100383 (HAB-161 EXT-160 Y1)

100382 (HAB-160)

|__|__| |__|__|__| |__|__|__|__|






4. Subject died on: |__|__| |__|__|__| |__|__|__|__|

|__|__| |__|__|__| |__|__|__|__|

|__|__|__|__|__|

Previous studies (last previous study where the subject has participated)

(tick only one):

100385 (HAB-163 EXT-160 Y3)

100384 (HAB-162 EXT-160 Y2)

100383 (HAB-161 EXT-160 Y1)

100382 (HAB-160)

|__|__| |__|__|__| |__|__|__|__|






4. Subject died on: |__|__| |__|__|__| |__|__|__|__|

|__|__| |__|__|__| |__|__|__|__|

CONFIDENTIAL


28 Aug 2009 55e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4499c18a8f42336bf2a269a9749b704a240

Protocol CRF Subject number111149

(HAB-160 BST)DIARY CARD CHALLENGE

DOSE |__|__|__|__|__|

Engerix-B AND Havrix GROUPLOCAL SYMPTOMS (at injection sites)

Please fill in below and assess the occurrence of any of the following signs or symptoms according to the criteria listed hereafter:INTENSITY:Pain (at injection sites): Other local symptoms:0: Absent.1: Painful on touch.2: Painful when limb is moved.3: Spontaneously painful /

prevents normal activity.

1:Mild: An adverse event which is easily tolerated by the subject, causing minimal discomfort and notinterfering with everyday activities.

2:Moderate: An adverse event which is sufficiently discomforting to interfere with normal everyday activities.3:Severe: An adverse event which prevents normal, everyday activities.

(In adults/ adolescents, such an adverse event would, for example, prevent attendance at work/school and would necessitate the administration of corrective therapy).

SIZE: Please measure the greatest diameter (in mm).For investigator only: Could you please check the appropriate box (side / site) for assessment.

for investigator only LOCALSYMPTOMS

Day 0 Day 1Evening

Day 2Evening

Day 3Evening

Ongoingafter Day 3?

Date of last Day of Symptomsday month year

Engerix-B Vaccine

Redness! size (mm): _____ _____ _____ _____

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Swelling! size (mm): _____ _____ _____ _____

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Side Left Right

Site Arm Thigh Buttock

Pain! intensity: |___| |___| |___| |___|

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Havrix Vaccine

Redness! size (mm): _____ _____ _____ _____

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Swelling! size (mm): _____ _____ _____ _____

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Side Left Right


Pain! intensity: |___| |___| |___| |___|

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

OTHER LOCAL SYMPTOMS Please give details belowStart date End date or check box if continuingDescription - please specify side(s) and site(s) Intensity day month year day month year

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

CONFIDENTIAL


28 Aug 2009 56e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4509c18a8f42336bf2a269a9749b704a240



DOSE |__|__|__|__|__|

Engerix-B AND Havrix GROUPGENERAL SYMPTOMS

Please fill in below and assess the occurrence of any of the following signs or symptoms according to the criteria listed hereafter:Temperature:Please record the temperature every day. If temperature has been taken more than once a day, please report the highest value for the day.INTENSITY:Fatigue: Headache: Gastrointestinal symptoms:0: Normal1: Fatigue that is easily tolerated2: Fatigue that interferes with normal

activity3: Fatigue that prevents normal activity

0: Normal1: Headache that is easily tolerated2: Headache that interferes with normal

activity3: Headache that prevents normal activity

0: Normal1: Gastrointestinal symptoms that are easily tolerated2: Gastrointestinal symptoms that interfere with normal

activity3: Gastrointestinal symptoms that prevent normal activity

Other general symptoms:1:Mild: An adverse event which is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities.2:Moderate: An adverse event which is sufficiently discomforting to interfere with normal everyday activities.3:Severe: An adverse event which prevents normal, everyday activities.

(In adults/ adolescents, such an adverse event would, for example, prevent attendance at work/ school and would necessitate theadministration of corrective therapy).

GENERAL SYMPTOMS Day 0 Day 1Evening

Day 2Evening

Day 3Evening

Ongoingafter Day 3?


Temperature!! °F: ! °C! Axillary! Oral! Tympanic (oral setting)! Tympanic (rectal setting)! Rectal

__ . _ __ . _ __ . _ __ . _! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Fatigue! intensity: |___| |___| |___| |___|

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Headache! intensity: |___| |___| |___| |___|

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Gastrointestinal symptoms! intensity: |___| |___| |___| |___|

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

OTHER GENERAL SYMPTOMS Please give details belowStart date End date or check box if continuingDescription - please give details below Intensity day month year day month year

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

MEDICATION Please fill in below if any medication has been taken since the vaccinationStart date End date or check box if continuingTrade/Generic name Reason Total Daily

Dose day month year day month year

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

PLEASE DO NOT FORGET TO BRING BACK THE DIARY CARD ON |__|__| |__|__|__| |__|__|__|__|

IN CASE OF HOSPITALISATION, PLEASE INFORM �..�....�� ": �..�....��..��

CONFIDENTIAL


28 Aug 2009 57e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4519c18a8f42336bf2a269a9749b704a240



DOSE |__|__|__|__|__|

HB VAX PRO And VAQTA GroupLOCAL SYMPTOMS (at injection sites)

Please fill in below and assess the occurrence of any of the following signs or symptoms according to the criteria listed hereafter:INTENSITY:Pain (at injection sites): Other local symptoms:0: Absent.1: Painful on touch.2: Painful when limb is moved.3: Spontaneously painful /





SIZE: Please measure the greatest diameter (in mm).For investigator only: Could you please check the appropriate box (side / site) for assessment.

for investigator only LOCALSYMPTOMS

Day 0 Day 1Evening

Day 2Evening

Day 3Evening

Ongoingafter Day 3?


HB VAX PRO Vaccine

Redness! size (mm): _____ _____ _____ _____

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Swelling! size (mm): _____ _____ _____ _____

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Side Left Right


Pain! intensity: |___| |___| |___| |___|

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

VAQTA Vaccine

Redness! size (mm): _____ _____ _____ _____

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Swelling! size (mm): _____ _____ _____ _____

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Side Left Right


Pain! intensity: |___| |___| |___| |___|

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|


|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

CONFIDENTIAL


28 Aug 2009 58e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4529c18a8f42336bf2a269a9749b704a240



DOSE |__|__|__|__|__|

HB VAX PRO And VAQTA GroupGENERAL SYMPTOMS










Day 2Evening

Day 3Evening

Ongoingafter Day 3?


Temperature!! °C! Axillary! Oral! Tympanic (oral setting)! Tympanic (rectal setting)! Rectal

__ . _ __ . _ __ . _ __ . _! No! Yes ! |__|__| |__|__|__| |__|__|__|__|


! No! Yes ! |__|__| |__|__|__| |__|__|__|__|


! No! Yes ! |__|__| |__|__|__| |__|__|__|__|


! No! Yes ! |__|__| |__|__|__| |__|__|__|__|


|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !



|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !



CONFIDENTIAL


28 Aug 2009 59e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4539c18a8f42336bf2a269a9749b704a240



DOSE |__|__|__|__|__|

TWINRIX GROUPLOCAL SYMPTOMS (at injection site)

Please fill in below and assess the occurrence of any of the following signs or symptoms according to the criteria listed hereafter:INTENSITY:Pain (at injection site): Other local symptoms:0: Absent.1: Painful on touch.2: Painful when limb is moved.3: Spontaneously painful /





SIZE: Please measure the greatest diameter (in mm).

LOCAL SYMPTOMS Day 0 Day 1Evening

Day 2Evening

Day 3Evening

Ongoingafter Day 3?


Redness! size (mm): _____ _____ _____ _____

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Swelling! size (mm): _____ _____ _____ _____

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Pain! intensity: |___| |___| |___| |___|

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|


|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

CONFIDENTIAL


28 Aug 2009 60e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4549c18a8f42336bf2a269a9749b704a240



DOSE |__|__|__|__|__|

TWINRIX GROUPGENERAL SYMPTOMS










Day 2Evening

Day 3Evening

Ongoingafter Day 3?


Temperature! !°F ! °C:! Axillary! Oral! Tympanic (oral setting)! Tympanic (rectal setting)! Rectal

__ . _ __ . _ __ . _ __ . _! No! Yes ! |__|__| |__|__|__| |__|__|__|__|


! No! Yes ! |__|__| |__|__|__| |__|__|__|__|


! No! Yes ! |__|__| |__|__|__| |__|__|__|__|


! No! Yes ! |__|__| |__|__|__| |__|__|__|__|


|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !



|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !



CONFIDENTIAL


28 Aug 2009 61e83b289258e07b40b92a3458bf7c41a4

CONFIDENTIAL


28 Aug 2009 4559c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL

Template CRF version 12.5 – March 05, 2008

GlaxoSmithKline Biologicals Rue de l’Institut 89 B – 1330 Rixensart, Belgium Tel:

Centre number Subject number

|__|__|__|__|__|__| |__|__|__|__|__|__| Treatment number

|__|__|__|__|__|

Protocol 111572 (HAB-168 BST 160)

WORKBOOK

A phase IV, open, multicentre, multicountry study to evaluate the immune response to a challenge dose of GSK Biologicals’ Twinrix™ vaccine versus monovalent hepatitis A and B vaccines from different manufacturers in healthy and non-healthy adults aged > 41 years, approximately 48 months after primary vaccination in study 100382 (HAB-160).

CONFIDENTIAL


28 Aug 2009 6259e06ead43ffa31a53d4c1a44f48cc81

CONFIDENTIAL


28 Aug 2009 4569c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL


GENERAL INSTRUCTIONS

ABBREVIATIONS: Abbreviations for medical conditions, clinical events or drug names should not be used. Units and route of administration of medication may be abbreviated. NA: not applicable.

DATES

Use the following three-letter abbreviations for each month:

January = JAN February = FEB March = MAR April = APR May = MAY June = JUN July = JUL August = AUG September = SEP October = OCT November = NOV December = DEC

Example: | 0 | 1 | | J | A | N | | 2 | 0 | 0 | 6 | = 1st January 2006 day month year

The Medication , the Concomitant Vaccination and the Non-Serious Adverse Events sections as well as possible Serious Adverse Event report(s) must be checked for final assessment at the end of the study. For all subjects enrolled, please complete the Study Conclusion form.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4579c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL


ADVERSE EVENT DEFINITIONS

INTENSITY FOR SOLICITED SYMPTOMS Pain at injection site Fatigue 0: Absent 1: Painful on touch 2: Painful when limb is moved 3: Pain that prevents normal activity

0: Normal 1: Fatigue that is easily tolerated 2: Fatigue that interferes with normal activity 3: Fatigue that prevents normal activity

Headache Gastrointestinal symptoms include nausea, vomiting, diarrhoea and abdominal pain

0: Normal 1: Headache that is easily tolerated 2: Headache that interferes with normal

activity 3: Headache that prevents normal activity

0: Normal 1: Gastrointestinal symptoms that are easily tolerated 2: Gastrointestinal symptoms that interfere with normal

activity 3: Gastrointestinal symptoms that prevent normal activity

INTENSITY FOR NON-SOLICITED SYMPTOMS 1: Mild: An adverse event which is easily tolerated by the subject, causing minimal discomfort and not

interfering with everyday activities. 2: Moderate: An adverse event which is sufficiently discomforting to interfere with normal everyday

activities. 3: Severe: An adverse event which prevents normal, everyday activities (In adults/ adolescents, such an adverse event would, for example, prevent attendance at

work/school and would necessitate the administration of corrective therapy).

CAUSALITY / RELATIONSHIP TO INVESTIGATIONAL PRODUCT S Is there a reasonable possibility that the AE may have been caused by the investigational product?

NO: The adverse event is not causally related to administration of the study vaccine(s). There are other, more likely causes and administration of the study vaccine(s) is not suspected to have contributed to the adverse event.

YES: There is a reasonable possibility that the vaccine contributed to the adverse event.

OUTCOME 1: Recovered / Resolved 2: Recovering / Resolving: Subject is recovering at the time she/he completes the study or at the time she/he

withdraws from study. 3: Not recovered / Not resolved: AE is ongoing at the time the subject completes the study or becomes lost to

follow-up; in case of death AEs that are not the cause of death. 4: Recovered with sequelae / Resolved with sequelae 5: Fatal: AE is the cause of death (only applicable for SAE reports)

SERIOUS ADVERSE EVENT

A serious adverse event is any untoward medical occurrence that:

• results in death. • is life threatening. • results in persistent or significant disability / incapacity. • requires in-patient hospitalization. • prolongation of existing hospitalization. • is a congenital anomaly / birth defect in the offspring of a study subject. • In addition, important medical events that may jeopardize the subject or may require intervention to

prevent one of the other outcomes listed above should be considered serious. (Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization).

For each serious adverse event the investigator becomes aware of, please complete and submit a Serious Adverse Event (SAE) report to GSK Biologicals Study Contact for SAE reporting within 24 hours.

In case of pregnancy the investigator becomes aware of, please complete and submit a Pregnancy Notification form to GSK Biologicals Study Contact for SAE reporting within 24 hours.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4589c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 (HAB-168 BST 160)

FLOW SHEET

Twinrix Group

Visit VISIT 8 VISIT 9 VISIT 10 Timing Month 48 Day 14 after Month 48 Day 30 after Month 48

Sampling timepoint Pre-challenge dose Post-challenge dose Post-challenge dose

Informed consent •

Check inclusion criteria •

Check exclusion criteria •

Check elimination criteria ○ ○

Check contraindications •

Check warnings and precautions •

Physical examination ○

Recording of concomitant medication by

subjects on diary card •

Transcription of concomitant medication • Return of medication diary card • Pre-vaccination body temperature •

Pregnancy test (urine test) •

Blood sampling for Ab determination (5 ml) • • • Vaccination Twinrix •

Daily post-vaccination recording of solicited

symptoms (Days 0–3) by subjects •

Recording of non-serious adverse events

within 30 days post-vaccination, by

investigator

•

Transcription of diary cards by investigator • Reporting of SAEs • • Study Conclusion •

• Study procedure that requires documentation in the individual CRF or SAE form, ○ is used to indicate a study procedure that does not require documentation in the individual CRF.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4599c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 (HAB-168 BST 160)

FLOW SHEET

Engerix-B/Havrix Group


Timing Month 48 Day 14 after Month 48


Sampling timepoint Pre-challenge dose

Post-challenge dose

Post-challenge dose








Recording of concomitant medication by subjects on diary

card •



Blood sampling for Ab determination (5 ml) • • • Vaccination Engerix-B

Havrix • •

Daily post-vaccination recording of solicited symptoms

(Days 0–3) by subjects •

Recording of non-serious adverse events within 30 days

post-vaccination, by investigator

•

Transcription of diary cards by investigator • Reporting of SAEs • • Study Conclusion • •Study procedure that requires documentation in the individual CRF or SAE form, O is used to indicate a study procedure that does not require documentation in the individual CRF.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4609c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 (HAB-168 BST 160)

FLOW SHEET

HB VAX PRO /Vaqta Group


Timing Month 48 Day 14 after Month 48

Day 30 after Month

48 Sampling timepoint Pre-challenge dose Post-challenge dose Post-

challenge dose








Recording of concomitant medication by

subjects on diary card •



Blood sampling for Ab determination (5 ml) • • • Vaccination

HB VAX PRO

Vaqta

• •

Daily post-vaccination recording of solicited

symptoms (Days 0–3) by subjects •

Recording of non-serious adverse events

within 30 days post-vaccination, by investigator

•

Transcription of diary cards by investigator • Reporting of SAEs • • Study Conclusion • •Study procedure that requires documentation in the individual CRF or SAE form, ○ is used to indicate a study procedure that does not require documentation in the individual CRF.

It is the investigator’s responsibility to ensure that the intervals between visits are strictly followed. These intervals determine each subject’s evaluability in the according-to-protocol analyses.

The interval between the primary vaccination course (that is the first visit in HAB-160) and Visit 8 is

expected to be approximately 48-60 months. The interval between Visit 8 and Visit 9 is defined as 14 ± 2 days and that between Visit 8 and Visit 10 is defined as 30 to 48 days.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4619c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL


VISIT 8

MONTH 48 Challenge dose visit

Informed Consent has to be obtained prior to any study procedure

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4629c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 (HAB-168 BST 160)

ELIMINATION CRITERIA DURING THE STUDY The following criteria should be checked at each visit subsequent to the first visit. If any become applicable during the study, it will not require withdrawal of the subject from the study but may determine a subject’s evaluability in the according-to-protocol (ATP) analysis.

[ A ] Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine(s) during the study period.

CONTRAINDICATIONS TO SUBSEQUENT VACCINATION The following events constitute absolute contraindications to administration of Twinrix, Engerix-B /Havrix, or HB VAX PRO /Vaqta; if any of these events occurred during the primary study HAB-160, the subject must not receive the challenge dose of the vaccines but may continue other study procedures at the discretion of the investigator. The subject must be followed until resolution of the event:

[ A ] Anaphylactic reaction following the administration of vaccines.

The following events constitute contraindications to administration of Twinrix, or Engerix-B /Havrix, or HB VAX PRO /Vaqta at that point in time; if any one of these events occurs at the time scheduled for vaccination, the subject may be vaccinated at a later date, within the time window specified in the protocol, or withdrawn at the discretion of the investigator. The subject must be followed until resolution of the event:

[ B ] Acute disease at the time of vaccination. (Acute disease is defined as the presence of a moderate or severe illness with or without fever. All vaccines can be administered to persons with a minor illness such as diarrhoea, mild upper respiratory infection with or without low-grade febrile illness, i.e., Oral/ axillary temperature <37.5°C. [< 37.0°C for Czech R epublic only] at the time of vaccination.)

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4639c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 (HAB-168 BST 160)

WARNINGS AND PRECAUTIONS Twinrix

• As with other vaccines, the administration of Twinrix should be postponed in subjects suffering from acute severe febrile illness.

• It is possible that subjects may be in the incubation period of a hepatitis A or hepatitis B infection at the time of vaccination. It is not known whether Twinrix will prevent hepatitis A and hepatitis B in such cases.

• The vaccine will not prevent infection caused by other agents such as hepatitis C and hepatitis E and other pathogens known to infect the liver.

• Twinrix is not recommended for post-exposure prophylaxis (e.g. needle stick injury). • The vaccine has not been tested in patients with impaired immunity. In haemodialysis patients and

persons with an impaired immune system, adequate anti-HAV and anti-HBs antibody concentrations may not be obtained after the primary immunisation course and such patients may therefore require administration of additional doses of vaccine.

• Twinrix should under no circumstances be administered intravenously.

Engerix-B

• Because of the long incubation period of hepatitis B it is possible for unrecognised infection to be present at the time of immunisation. The vaccine may not prevent hepatitis B infection in such cases.

• The vaccine will not prevent infection caused by other pathogens known to infect the liver such as hepatitis A, hepatitis C and hepatitis E virus.

• Thiomersal (an organomercuric compound) has been used in the manufacturing process of this medicinal product and residues of it are present in the final product. Therefore, sensitisation reactions may occur.

• Engerix-B should not be administered in the buttock or intradermally since this may result in a lower immune response.

• Engerix-B should under no circumstances be administered intravascularly. • As with all injectable vaccines, appropriate medical treatment and supervision should always be readily

available in case of rare anaphylactic reactions following the administration of the vaccine. • As with any vaccine, a protective immune response may not be elicited in all vaccinees.

Havrix

• It is possible that subjects may be in the incubation period of a hepatitis A infection at the time of immunisation. It is not known whether Havrix (1440 ELISA Units) will prevent hepatitis A in such cases.

• In haemodialysis patients and in subjects with an impaired immune system, adequate anti-HAV antibody titres may not be obtained after a single dose of Havrix (1440 ELISA Units) and such patients may therefore require administration of additional doses of vaccine.

• As with all injectable vaccines, appropriate medical treatment should always be readily available for treatment in case of anaphylactic reactions following the administration of the vaccine. For this reason, the vaccinee should remain under medical supervision for 30 minutes after immunization.

• Havrix (1440 ELISA Units) should be administered with caution to subjects with thrombocytopenia or a bleeding disorder since bleeding may occur following an intramuscular administration to these subjects.

• The vaccine should not be administered intramuscularly in the gluteal region or subcutaneously/intradermally since administration by these routes may result in a less than optimal anti-HAV antibody response.

• Havrix (1440 ELISA Units) should under no circumstances be administered intravenously.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4649c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 (HAB-168 BST 160)

WARNINGS AND PRECAUTIONS (continued)

HBVAXPRO

• Persons with immunodeficiency or those receiving immunosuppressive therapy require larger vaccine doses and respond less well than healthy individuals.

• Because of the long incubation period for hepatitis B, it is possible for unrecognized infection to be present at the time HBVAXPRO is given. HBVAXPRO may not prevent hepatitis B in such patients.

• .Patients who develop symptoms suggestive of hypersensitivity after an injection should not receive further injections of HBVAXPRO.

• As with any parenteral vaccine, epinephrine (adrenaline) should be available for immediate use should an anaphylactoid reaction occur. Any serious active infection is reason for delaying use of HBVAXPRO, except when, in the opinion of the physician, withholding the vaccine entails a greater risk.

• Caution and appropriate care should be exercised in administering v to individuals with severely compromised cardiopulmonary status or to others in whom a febrile or systemic reaction could pose a significant risk.

Vaqta

• As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic event following the administration of the vaccine.

• Testing for antibodies to hepatitis A prior to a decision on immunisation should be performed in patients born in areas of high endemicity and/or with a history of jaundice.

• Vaqta does not cause immediate protection against hepatitis A, and there may be a period of 2 to 4 weeks before antibody induction occurs.

• Because of the long incubation period (approximately 20 to 50 days) for hepatitis A, it is possible for unrecognised hepatitis A infection to be present at the time the vaccine is given. The vaccine may not prevent hepatitis A in such individuals.

• Vaqta will not prevent hepatitis caused by infectious agents other than hepatitis A virus. • In subjects with an impaired immune system, adequate anti-HAV antibody titres may not be

obtained. If the immunosuppression is due to medical treatment, vaccination should be delayed if possible until the completion of therapy and immune system recovery.

• The vaccine has been evaluated in human immunodeficiency virus (HIV) infected adults. There are no data on the use of Vaqta in HIV infected subjects.

• As with any vaccine, vaccination with Vaqta may not result in a protective response in all susceptible vaccinees.

• As no studies have been performed with Vaqta in subjects with liver disease, caution is advised if administering the vaccine in these subjects.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4659c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL


111572 (HAB-168 BST 160) Protocol Book Visit Date of visit Subject Number

111572 VISIT 8 |__|__| |__|__|__| |__|__|__|__| day month year

|__|__|__|__|__|__|

INFORMED CONSENT I certify that Informed Consent has been obtained prior to any study procedure.

Informed Consent Date: |__|__| |__|__|__| |__|__|__|__| day month year

Did the subject agree that her/his biological samples(s) may be used by GSK Biologicals for further research that is NOT RELATED to the vaccine(s) or the disease(s) under study?

Yes No NA

DEMOGRAPHICS

Center number: |__|__|__|__|__|__| Date of Birth: |__|__| |__|__|__| |__|__|__|__| day month year Gender: [M] Male

[F] Female

Height: |__|__|__| cm

Weight: |__|__|__| . |__| kg

Subject belongs to : Twinrix Group (Mono-injection)

Engerix-B/Havrix Group OR HB Vax PRO / Vaqta Group

1.


□ 100382 (HAB-160)

□ 100383 (HAB-161 EXT-160 Y1)

□ 100384 (HAB-162 EXT-160 Y2)

□ 100385 (HAB-163 EXT-160 Y3)

Subject number will be the same as in the previous study

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4669c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL


111572 (HAB-168 BST 160) Protocol Book Visit Subject Number

111572

VISIT 8 |__|__|__|__|__|__|

ELIGIBILITY CHECK

Did the subject meet all the entry criteria?

Yes No → If No, tick (�) all boxes corresponding to violations of any inclusion/exclusion criteria.

Do not enter the subject into the study if he/she failed any inclusion or exclusion criteria below.

INCLUSION CRITERIA

Tick (�) the boxes corresponding to any of the inclusion criteria the subject failed

[ 1 ] � Subjects who the investigator believes that they can and will comply with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visits) should be enrolled in the study.

[ 2 ] � A male or female who completed the primary vaccination phase of the HAB-160 study.

[ 3 ] � Written informed consent obtained from the subject.

[ 4 ] � If the subject is female, she must be of non-childbearing potential, i.e., either surgically sterilized or one year post-menopausal; or, if of childbearing potential, she must be abstinent or have used adequate contraceptive precautions (i.e., intrauterine contraceptive device; oral/long term hormonal contraceptives; diaphragm or condom in combination with contraceptive jelly, cream or foam) for 30 days prior to vaccination, have a negative pregnancy test and must agree to continue such precautions for two months after the vaccination.

2.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4679c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572

VISIT 8 |__|__|__|__|__|__|

ELIGIBILITY CHECK (continued)

EXCLUSION CRITERIA Tick (�) the box corresponding to any of the exclusion criteria that disqualified the subject from entry.

[ 5 ] � Use of any investigational or non-registered product (drug or vaccine) other than the study vaccines within 30 days preceding the challenge dose, or planned use during the study period.

[ 6 ] � History of any hepatitis A or hepatitis B vaccination or infection since the primary vaccination study.

[ 7 ] � History of allergic disease or reactions likely to be exacerbated by any component of the vaccine.

[ 8 ] � Acute disease at the time of enrolment. (Acute disease is defined as the presence of a moderate or severe illness with or without fever. All vaccines can be administered to persons with a minor illness such as diarrhoea, mild upper respiratory infection with or without low-grade febrile illness, i.e., Oral/ axillary temperature <37.5°C) [37.0°C for Czech Republic only].

[ 9 ] � Pregnant or lactating female.

RANDOMISATION / TREATMENT ALLOCATION Record treatment number: |__|__|__|__|__|

3.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4689c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 VISIT 8 |__|__|__|__|__|__|

LABORATORY TESTS

BLOOD SAMPLE Has a blood sample been taken?

Yes → Date if different from visit date: |__|__| |__|__|__| |__|__|__|__| day month year

No

HCG URINE PREGNANCY TEST

Has a urine sample been taken?


→ Result: Negative

Positive

No

NA → Not of childbearing potential or male

4.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4699c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 VISIT 8 Twinrix Group |__|__|__|__|__|__|


Date if different from visit date: |__|__| |__|__|__| |__|__|__|__| day month year

Pre-Vaccination temperature: |__|__|. |__| °C → Route: [A] Axillary

[O] Oral

[R] Rectal


Side / Site Route

Has the study vaccine been administered according to the Protocol?

[S] Twinrix TM Vaccine

[R] Replacement vial →|__|__|__|__|__|

[N] Not administered → Please complete below (*)

Left

Deltoid

I.M.

Yes No → Please tick all items that apply

and comment if necessary.

Side: Site: Route: [L] Left [1] Deltoid [IM] I.M. [R] Right [3] Thigh [SC] S.C. [6] Buttock

Comment : ____________________

(*) Why not administered?

→ Please tick (�) the major reason for non administration.

� [SAE] Serious adverse event:

→ Please complete and submit SAE report.

→ Please specify SAE No. |__|__|

� [AEX] Non-Serious adverse event

→ Please complete Non-serious Adverse Event section

→ Please specify AE No. |__|__| � [OTH] Other, please specify: ___________________________________________

(e.g.: consent withdrawal, Protocol violation, …)

→ Please tick (�) who made the decision: [I] � Investigator [S] � Subject

IMMEDIATE POST-VACCINATION OBSERVATION If any adverse events occurred during the immediate post-vaccination time (30 minutes) please fill in the Solicited Adverse Events section, the Non-Serious Adverse Event section or a Serious Adverse Event report.

If any prophylactic medication has been administered in anticipation of study vaccine reaction, please complete the Medication section and tick prophylactic box.

Any other vaccines administered during the study period must be recorded in the Concomitant Vaccination section.

5.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4709c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 VISIT 8 Engerix-B/Havrix Group

OR HB VAX PRO/ Vaqta Group

|__|__|__|__|__|__|


Date if different from visit date: |__|__| |__|__|__| |__|__|__|__| day month year

Pre-Vaccination temperature: |__|__|. |__| °C → Route: [A] Axillary

[O] Oral

[R] Rectal


Side / site route

Has the study vaccine been administered according to the Protocol?

[S] Engerix TM-B/ or HB VAX PRO Vaccine

[R] Replacement vial → |__|__|__|__|__|

[N] Not administered

→ Please complete following page (*)

Left

Deltoid

I.M.


and comment if necessary


Comment : ____________________

[S] Havrix TM / OR Vaqta Vaccine

[R] Replacement vial → |__|__|__|__|__|

[N] Not administered

→ Please complete following page (*)

Right

Deltoid

I.M.


and comment if necessary


Comment : ____________________ 6.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4719c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL


111572 (HAB-168 BST 160)

Protocol Book Visit Subject Number



|__|__|__|__|__|__|

VACCINE ADMINISTRATION (continued) (*) Why not administered?

→ Please tick (�) the major reason for non administration




� [AEX] Non-Serious adverse event:

→ Please complete Non-serious Adverse Event section.

→ Please specify AE No. |__|__|

� [OTH] Other, please specify: ___________________________________________




If any adverse events occurred during the immediate post-vaccination time (30 minutes) please fill in the Solicited Adverse Events section, the Non-Serious Adverse Event section or a Serious Adverse Event report.

If any prophylactic medication has been administered in anticipation of study vaccine reaction, please complete the Medication section and tick prophylactic box.

Any other vaccines administered during the study period must be recorded in the Concomitant Vaccination section. 7.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4729c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL


111572 (HAB-168 BST 160) Protocol Book Subject Number

111572 VISIT 8 Twinrix Group |__|__|__|__|__|__|

SOLICITED ADVERSE EVENTS – LOCAL SYMPTOMS Has the subject experienced any of the following signs/symptoms at the administration site during the solicited period?

[ U ] Information not available


[ N ] No




day month year

Redness [RE] � No

� Yes → size (mm): _____ _____ _____ _____ � No � Yes → |__|__| |__|__|__| |__|__|__|__|

Swelling [SW] � No

� Yes → size (mm): _____ _____ _____ _____ � No � Yes → |__|__| |__|__|__| |__|__|__|__|

Pain [PA] � No

� Yes → intenity: |____| |____| |____| |____| � No � Yes → |__|__| |__|__|__| |__|__|__|__|

Intensity : 0 / 1 / 2 / 3 see Adverse Events definitions

If any of these adverse events meets the protocol definition of serious , please complete and submit Serious Adverse Event report to GSK Biologicals Study Contact for SAE reporting within 24 hours.

8.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4739c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL





|__|__|__|__|__|__|

SOLICITED ADVERSE EVENTS – LOCAL SYMPTOMS For each vaccine, has the subject experienced any of the following signs/symptoms at the administration sites during the solicited period?



day month year

Engerix TM-B OR HB VAX PRO vaccine [N] No [U] Information not available [NA] No vaccine administered [Y] Yes, please tick No/Yes for each symptom. If Yes is ticked, please complete all items.

Redness [RE] � No

� Yes → size (mm): _____ _____ _____ _____ � No � Yes → |__|__| |__|__|__| |__|__|__|__|


� Yes → size (mm): _____ _____ _____ _____ � No � Yes → |__|__| |__|__|__| |__|__|__|__|

Pain [PA] � No


Havrix TM OR Vaqta vaccine [N] No [U] Information not available [NA] No vaccine administered [Y] Yes, please tick No/Yes for each symptom. If Yes is ticked, please complete all items.

Redness [RE] � No

� Yes → size (mm): _____ _____ _____ _____ � No � Yes → |__|__| |__|__|__| |__|__|__|__|


� Yes → size (mm): _____ _____ _____ _____ � No � Yes → |__|__| |__|__|__| |__|__|__|__|

Pain [PA] � No


Intensity : 0 / 1 / 2 / 3 (see Adverse Events definitions)


9.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4749c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 VISIT 8 |__|__|__|__|__|__|

SOLICITED ADVERSE EVENTS - GENERAL SYMPTOMS Has the subject experienced any of the following signs/symptoms during the solicited period? [U] Information not available

[NA] No Vaccine administered

[N] No

[Y] Yes, please tick No/Yes for each symptom. If Yes is ticked, please complete all items.

GENERAL SYMPTOMS

Day 0 Day 1 Day 2 Day 3 Ongoing

after Day 3? Date of last Day of Symptoms

day month year Causality?

Temperature [FE] � No � Yes → ° C:

[A] � Axillary [O] � Oral [R] � Rectal

__ . _

� not

taken

__ . _

� not

taken

__ . _

� not

taken

__ . _

� not

taken

� No � Yes →

|__|__| |__|__|__| |__|__|__|__|

� No

� Yes

Fatigue [ FA ] � No � Yes → intensity: |____| |____| |____| |____|

� No � Yes → |__|__| |__|__|__| |__|__|__|__|

� No

� Yes

Headache [H E ] � No � Yes → intensity: |____| |____| |____| |____|

� No � Yes → |__|__| |__|__|__| |__|__|__|__|

� No

� Yes

Gastrointestinal symptoms [G I ] ( * ) � No � Yes → intensity: |____| |____| |____| |____|

� No � Yes → |__|__| |__|__|__| |__|__|__|__|

� No

� Yes

(*) Gastrointestinal symptoms include nausea, vomiting, diarrhoea and abdominal pain.

Intensity : 0/1/2/3 see AE definitions CRF form C

Temperature : tick Yes from following limits Axillary, Oral, Tympanic (oral conversion) > 37.5 °C > 37.0 °C (for Czech Republic onl y) Rectal and Tympanic (rectal conversion) > 38 °C


10.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4759c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 VISIT 8 |__|__|__|__|__|__|

UNSOLICITED ADVERSE EVENTS Has the subject experienced any serious or non-serious unsolicited adverse events within one month (minimum 30 days) post-vaccination?

[ U ] � Information not available

[ N A ] � No vaccine administered

[ N ] � No

[ Y ] � Yes → Fill in the Non-Serious Adverse Event section or Serious Adverse Event report as necessary.

11.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4769c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL


VISIT 9 DAY 14 AFTER MONTH 48

Post-challenge dose

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4779c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL


REMINDERS



ADVERSE EVENTS

Please report adverse events as specified in the Protocol and fill in the Non-Serious Adverse Events section or a Serious Adverse Event (SAE) report, as appropriate. SAE must be submitted to GSK Biologicals Study Contact for SAE reporting within 24 hours from the time you become aware of the SAE.

MEDICATION


PREGNANCY

In case of pregnancy please fill in the Pregnancy Notification form. This form must be faxed to GlaxoSmithKline within 24 hours of you becoming aware of these events.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4789c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 VISIT 9 |__|__|__|__|__|__|

CHECK FOR STUDY CONTINUATION Did the subject return for visit 9? � Yes → Please complete the next pages

� No → Please complete below and skip the following pages of this visit.

→ Please tick (�) the ONE most appropriate reason and skip the following pages of this visit

� [SAE] Serious adverse event



� [AEX] Non-Serious adverse event


→ Please specify AE No. |__|__| or solicited AE code |__|__|

� [OTH] Other, please specify: _____________________________________



12.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4799c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL




|__|__|__|__|__|__|

LABORATORY TEST

BLOOD SAMPLE

Has a blood sample been taken?


No

13.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4809c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL


VISIT 10 DAY 30 AFTER MONTH 48

Post-challenge dose

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4819c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL


REMINDERS



ADVERSE EVENTS

Please report adverse events as specified in the Protocol and fill in the Non-Serious Adverse Events section or a Serious Adverse Event (SAE) report, as appropriate. SAE must be submitted to GSK Biologicals Study Contact for SAE reporting within 24 hours from the time you become aware of the SAE.

MEDICATION


PREGNANCY

In case of pregnancy please fill in the Pregnancy Notification form. This form must be faxed to GlaxoSmithKline within 24 hours of you becoming aware of these events.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4829c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 VISIT 10 |__|__|__|__|__|__|

CHECK FOR STUDY CONTINUATION Did the subject return for visit 10? � Yes → Please complete the next pages.

� No → Please complete below and skip the following pages of this visit.

� Same reason and decision as previous visit.

OR

→ Please tick (�) the ONE most appropriate reason and skip the following pages of this visit.




� [AEX] Non-Serious adverse event:

→ Please complete Non-serious Adverse Event section.


� [OTH] Other, please specify: _____________________________________



14.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4839c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL




|__|__|__|__|__|__|

LABORATORY TEST

BLOOD SAMPLE

Has a blood sample been taken?


No

15.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4849c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL


CONCOMITANT

VACCINATION

At each study visit/contact, the investigator should question the subject about any vaccination(s) administered.

Any vaccine not foreseen in the study protocol administered in the period beginning 30 days preceding the

challenge dose and ending one month (minimum 30 days) after the challenge vaccine dose, is to be recorded with

trade name, route of administration and date(s) of administration.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4859c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 |__|__|__|__|__|__|

CONCOMITANT VACCINATION

Have any vaccines other than the study vaccine(s) been administered during the timeframe as specified in the Protocol?

No Yes, please record concomitant vaccination with trade name and / or generic name, route and vaccine

administration date.

Trade / (Generic) Name Route Administration date day month year

|__|__| |__|__|__| |__|__|__|__|

For GSK

|__|__| |__|__|__| |__|__|__|__|

For GSK

|__|__| |__|__|__| |__|__|__|__|

For GSK

|__|__| |__|__|__| |__|__|__|__|

For GSK

|__|__| |__|__|__| |__|__|__|__|

For GSK

|__|__| |__|__|__| |__|__|__|__|

For GSK

|__|__| |__|__|__| |__|__|__|__|

For GSK

Route:

ID = Intradermal PE = Parenteral IH = Inhalation PO = Oral IM = Intramuscular SC = Subcutaneous IV = Intravenous SL = Sublingual IN = Intranasal TD = Transdermal

OTH = Other UNK = Unknown 16.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4869c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL


MEDICATION

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4879c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



Medication route. Please use below defined codes.

CODE LABEL

EXT External ID Intradermal IH Inhalation IM Intramuscular IR Intraarticular IT Intrathecal IV Intravenous IN Intranasal OTH Other PE Parenteral PO Oral PR Rectal SC Subcutaneous SL Sublingual TD Transdermal TO Topical UNK Unknown VA Vaginal

At each study visit/contact, the investigator should question the subject about any medication(s) taken.

� All concomitant medication, with the exception of vitamins and/ or dietary supplements, administered at any time during the

period starting 7 days before the administration of the challenge dose and ending at one month (minimum 30 days) after the

challenge dose is to be recorded by the subject. The investigator will verify and complete the subject’s records. The generic

name of the medication (trade names are allowed for combination drugs, i.e., multi-component drugs), medical indication,

total daily dose, route of administration, start and end dates of treatment, will be transcribed into the medication screens of

the eCRF for any medication taken up to one month after the challenge dose.

� Any concomitant medication administered prophylactically in anticipation of reaction to the vaccination must be recorded in

the eCRF with generic name of the medication (trade names are allowed for combination drugs only), total daily dose, route

of administration, start and end dates of treatment and coded as ‘Prophylactic’.

� Concomitant medication administered for the treatment of an SAE must be recorded in the eCRF with generic name of the

medication (trade names are allowed for combination drugs only), medical indication (including which SAE), total daily dose,

route of administration, start and end dates of treatment.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4889c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL


111572 (HAB-168 BST 160)

Protocol Book Subject Number

111572 |__|__|__|__|__|__|

MEDICATION Have any medications/treatments been administered during the time frame as specified in the Protocol?


Trade / Generic Name Medical Indication Total daily

dose Route Start and end date or tick box if continuing at end of study

day month year

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

17.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4899c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4909c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 Twinrix group |__|__|__|__|__|__|

NON-SERIOUS ADVERSE EVENTS (Please report serious adverse events only on the Serious Adverse Event (SAE) reports).

Has any non-serious adverse events occurred within one month (minimum 30 days) post-vaccination, excluding those recorded on the Solicited Adverse Events pages?

No

Yes, please complete the following table.

AE No. 1 2 Description: _______________________

_______________________

_______________________

_______________________

_______________________

_______________________

[L] Administration sites

[G] Non-administration site



For GSK

Date Started: |__|__| |__|__|__| |__|__|__|__| day month year

during immediate post-vaccination period (30 minutes)

|__|__| |__|__|__| |__|__|__|__| day month year


Date Stopped: |__|__| |__|__|__| |__|__|__|__| day month year

|__|__| |__|__|__| |__|__|__|__| day month year

Maximum Intensity: [1] Mild

[2] Moderate

[3] Severe

[1] Mild

[2] Moderate

[3] Severe


[N] No

[Y] Yes

[N] No

[Y] Yes

Outcome: [1] Recovered / resolved

[2] Recovering / resolving

[3] Not recovered / not resolved

[4] Recovered with sequelae / resolved with sequelae

[1] Recovered / resolved




18.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4919c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 Twinrix group |__|__|__|__|__|__|


AE No. 3 4

Description _______________________

_______________________

_______________________

_______________________

_______________________

_______________________





For GSK

Date Started |__|__| |__|__|__| |__|__|__|__| day month year


|__|__| |__|__|__| |__|__|__|__| day month year



|__|__| |__|__|__| |__|__|__|__| day month year

Maximum Intensity [1] Mild

[2] Moderate

[3] Severe

[1] Mild

[2] Moderate

[3] Severe


[N] No

[Y] Yes

[N] No

[Y] Yes

Outcome [1] Recovered / resolved








19.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4929c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4939c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 Engerix-B/Havrix group

OR HB VAX PRO/Vaqta group

|__|__|__|__|__|__|

NON-SERIOUS ADVERSE EVENTS (Please report serious adverse events only on the Serious Adverse Event (SAE) reports).

Has any non-serious adverse events occurred within one month (minimum 30 days) post-vaccination, excluding those recorded on the Solicited Adverse Events pages?

No

Yes, please complete the following table.

AE No. 1 2 Description: _______________________

_______________________

_______________________

_______________________

_______________________

_______________________


[ 9 0 1 ] Engerix TM-B or

HB VAX PROTM vaccine [ 9 0 2 ] Havrix TM or

VaqtaTM vaccine





VaqtaTM vaccine


For GSK



|__|__| |__|__|__| |__|__|__|__| day month year



|__|__| |__|__|__| |__|__|__|__| day month year


[2] Moderate

[3] Severe

[1] Mild

[2] Moderate

[3] Severe


[N] No

[Y] Yes

[N] No

[Y] Yes









20.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4949c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 Engerix-B/Havrix group

OR HB VAX PRO/Vaqta group

|__|__|__|__|__|__|


AE No. 3 4

Description: _______________________

_______________________

_______________________

_______________________

_______________________

_______________________




VaqtaTM vaccine





VaqtaTM vaccine


For GSK



|__|__| |__|__|__| |__|__|__|__| day month year



|__|__| |__|__|__| |__|__|__|__| day month year


[2] Moderate

[3] Severe

[1] Mild

[2] Moderate

[3] Severe


[N] No

[Y] Yes

[N] No

[Y] Yes









21.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4959c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL


STUDY CONCLUSION

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4969c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 |__|__|__|__|__|__|

FOLLOW-UP STUDIES

If a booster study or a follow-up study is offered in the future, would the subject be willing to be contacted and learn more about it?

Yes

No, please specify the most appropriate reason:

→ Adverse Events, or Serious Adverse Events:

please specify: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

→ Other:

please specify: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

22.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4979c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 |__|__|__|__|__|__|

STUDY CONCLUSION

OCCURRENCE OF SERIOUS ADVERSE EVENT

Did the subject experience any Serious Adverse Event during the study?

No Yes → Specify total number of SAE's: |__|__|

PREGNANCY INFORMATION

Did the subject become pregnant during the study?

No Yes → Complete the Pregnancy notification form.

Not Applicable (not of childbearing potential or male).


Did any elimination criteria become applicable during the study?

No Yes → Specify: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

23.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4989c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL



111572 |__|__|__|__|__|__|

STUDY CONCLUSION (continued) Was the subject withdrawn from the study?

No

Yes → Major reason for withdrawal (tick one box only).

[SAE] Serious adverse event:



[AEX] Non-Serious adverse event:



[PTV] Protocol violation, please specify: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

[CWS] Consent withdrawal, not due to an adverse event

[MIG] Migrated / moved from the study area

[LFU] Lost to follow-up.

[OTH] Other, please specify: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

→ Who made the decision: [I] � Investigator [S] � Subject

→ Date of last contact: |__|__| |__|__|__| |__|__|__|__| day month year

→ Was the subject in good condition at date of last contact?

No → Please give details in Adverse Events section

Yes


I confirm that I have reviewed the data in this Case Report Form for this subject. All information entered by myself or my colleagues is, to the best of my knowledge, complete and accurate, as of the date below.

Investigator's signature: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Date: |__|__| |__|__|__| |__|__|__|__|

Printed Investigator's name: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

day month year

24.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 4999c18a8f42336bf2a269a9749b704a240

111572 (HAB-168 BST 160) Protocol Center Number

111572 Tracking Document

Reason for non participation |__|__|__|__|__|__|

Investigator name: (PRINT name) Signature: Date: (day month year)

|__|__| |__|__|__| |__|__|__|__|

Confidential – Template CRF Version 12.5 – February 8, 2008



Reason for non participation Date of Contact (day month year)

|__|__|__|__|__|__|

Previous studies: 100382 (HAB-160) 100383 (HAB-161 EXT 160 Y1) 100384 (HAB-162 EXT 160 Y2) 100385 (HAB-163 EXT 160 Y3

|__|__||__|__|__||__|__|__|__|

[1] Subject not eligible -Please specify criteria that are not fullfilled: ____________________

[2] Subject lost to follow-up or not reached.

[3] Subject eligible but not willing to participate due to:

Adverse event(s), or serious adverse event; Please specify: __________________

Other; Please specify: ____________________

[4] Subject died on : |__|__| |__|__|__| |__|__|__|__|

|__|__||__|__|__||__|__|__|__|

|__|__|__|__|__|__|


|__|__||__|__|__||__|__|__|__|






[4] Subject died on : |__|__| |__|__|__| |__|__|__|__|

|__|__||__|__|__||__|__|__|__|

|__|__|__|__|__|__|


|__|__||__|__|__||__|__|__|__|






[4] Subject died on : |__|__| |__|__|__| |__|__|__|__|

|__|__||__|__|__||__|__|__|__|

|__|__|__|__|__|__|


|__|__||__|__|__||__|__|__|__|






[4] Subject died on : |__|__| |__|__|__| |__|__|__|__|

|__|__||__|__|__||__|__|__|__|

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 5009c18a8f42336bf2a269a9749b704a240

Template CRF version 12.5 – February 8, 2008

111572 (HAB-168 BST 160) Protocol Centre

111572 |__|__|__|__|__|__|

USE OF HUMAN SAMPLES BY GSK In addition to the use of samples for the tests described in the protocol, samples might be used for other research by GSK (see protocol). Please tick what is also covered by the subject Informed Consent form of your center.

[ 2 ] � Quality Assurance of tests described in the protocol

This may include the management of the quality of these current tests, the maintenance or improvement of these current tests, the development of new test methods for the markers described in the protocol as well as making sure that new tests are comparable to previous methods and work reliably.

[ 3 a ] � Further investigation by GSK Biologicals into the ability of TwinrixTM, HavrixTM, EngerixTM-B, HBVAXPROTM and VaqtaTM vaccines to protect people if any findings from related studies require it and further research in hepatitis A and hepatitis B antigens disease under study. These investigations exclude genetics and HIV testing.

[ 3 b ] � Further investigation by GSK Biologicals into the ability of TwinrixTM, HavrixTM, EngerixTM-B, HBVAXPROTM and VaqtaTM vaccines to protect people if any findings from related studies require it and further research in hepatitis A and hepatitis B antigens disease under study. These investigations exclude genetic and HIV testing. Investigator will always ask in advance the permission of the independent Ethics Committee/Institutional Review Board linked to the institution where this research is performed.

[ 4 ] � Further research by GSK Biologicals that is NOT RELATED to TwinrixTM, HavrixTM, EngerixTM-B, HBVAXPROTM and VaqtaTM vaccines or hepatitis A and hepatitis B antigens disease under study done on an anonymous basis (meaning that any identification linking the subject to the sample is destroyed). This research excludes genetic and HIV testing and does not affect subject participation in the study.

Please tick below box if a 15 years GSK storage period is covered by the subject’s Informed Consent form of your center.

� At least 15 years storage period by GSK Biologicals

� Other, specify: _______________________

ICF Effective date: |__|__| |__|__|__| |__|__|__|__| day month year ! Complete and submit a new form for each change during the study.


Investigator's signature: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Date: |__|__| |__|__|__| |__|__|__|__|

Printed Investigator's name: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

day month year

1.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 5019c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL

SAE Report – Template CRF Version 12.5 – February 8, 2008

GlaxoSmithKline Biologicals Rue de l’Institut 89, B – 1330 Rixensart, Belgium Tel:

Protocol (eTrack number)

|_1_|_1_| _1_|_5_|_7_|_2_|

Abbreviated Title

HAB-168 BST 160

Serious Adverse Event Report

Centre number Subject number

|__|__|__|__|__|__| |__|__|__|__|__|__|

Treatment number

|__|__|__|__|__|

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 5029c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL


DEFINITION OF A SERIOUS ADVERSE EVENT (Protocol § 8.2)

A serious adverse event (SAE) is any untoward medical occurrence that: a. results in death, b. is life-threatening,

NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.

c. requires hospitalization or prolongation of existing hospitalization, NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfils any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered serious. Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.

d. results in disability/incapacity, or NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption.

e. is a congenital anomaly/birth defect in the offspring of a study subject. f. Medical or scientific judgement should be exercised in deciding whether reporting is appropriate

in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization.

See also protocol for possible additional specification (possible additional bullets g., h., …)

COLLECTION OF SERIOUS ADVERSE EVENTS Serious Adverse Events (SAEs) related to study participation (e.g. procedures, invasive tests, change from existing therapy) or SAEs related to GSK concurrent medication will be collected and recorded from the time the subject consents to participate in the study For all other SAEs, the standard time period for collecting and recording SAEs will begin from the administration of the first dose of vaccine / placebo / comparator and will end minimum 30 days (see protocol) following administration of the last dose of vaccine / placebo / comparator for each subject.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 5039c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL


INSTRUCTIONS FOR REPORTING SERIOUS ADVERSE EVENT (SAE)

SAE’s MUST BE REPORTED TO GSK STUDY CONTACT WITHIN 24 HOURS (refer to Protocol § 8.8)

1. COMPLETE THE SAE PAGES

Complete these pages as fully and accurately as possible in order to allow safety department to make an assessment of the initially reported information and to minimize the time you spend dealing with data queries. Ensure that all information on SAE pages is consistent with information given on CRF pages :

• Demography • General Medical History / Physical Examination • Vaccine administration page(s) (for administered doses) • Medication • Concomitant Vaccination

2. SIGN AND DATE THE LAST PAGE

3. FAX THE SAE PAGE TO:

• The GSK Biologicals study contact. Refer to protocol for contact name and fax number. • In the event of a death determined by the investigator to be related to the vaccination, sending of

the fax must be accompanied by phone call to the study contact for reporting SAEs.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 5049c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL


GUIDELINES FOR COMPLETING SERIOUS ADVERSE EVENT REPORT

SAE Report N° Mandatory. Attribute a sequential number to each new SAE report, starting from 01 for each subject.

GSK receipt date To be completed by GSK only. The GSK receipt date is the date on which the first GSK employee/designee is notified of the SAE.

SECTION 1 Event A separate form should be used for each SAE however if multiple SAEs which are temporarily or

clinically related are apparent at the time of initial reporting then these may be reported on the same page.

Start date The start date should document the first occurrence of the SAE. This is generally the start date of the signs/symptoms and not necessarily the date that the event met the definition of serious.

Outcome All SAEs must be followed until the events are resolved, the condition stabilises, the events are otherwise explained, or the subject is lost to follow-up. Indicate if the event was “Recovered/Resolved” or Recovered/Resolved with sequelae”. If the SAE is ongoing at the time the subject completed the study or becomes lost to follow-up, the outcome must be recorded as “Recovering/Resolving” or “Not recovered/Not resolved”. Also enter “Not recovered/Nor resolved” if the SAE was ongoing at the time of death, but was not the cause of death, enter fatal for the SAE which was direct cause of death.

End date Record the date of resolution or the date of death as applicable. Leave blank only if the outcome of the event is “Not resolved” – “ Recovering / resolving”.

Intensity Record the maximum intensity that occurred over the duration of the event (see protocol for 1-2-3 definition of intensity). Amend the intensity if it increases. Enter X (not Applicable) if grading can not be applied. For example, intensity for ‘broken leg’.

Relationship to investigational product(s)

This box is mandatory and has to be completed before faxing the form. It is a regulatory requirement for investigators to assess relationship to investigational product(s) based on information available. The assessment should be reviewed on receipt of any new information and amended if necessary. ’A reasonable possibility’ is meant to convey that there are facts/evidence or arguments to suggest a causal relationship. Facts/evidence or arguments that may support ’a reasonable possibility’ include, e.g., a temporal relationship, a pharmacologically-predicted event, or positive dechallenge or rechallenge. Confounding factors, such as concomitant medication, a concurrent illness, or relevant medical history, should also be considered.

Action taken with investigational product(s) as a result of the SAE

If administration of the investigational product was stopped permanently and not restarted enter 1-Investigational product(s) withdrawn and enter the date that investigational product was discontinued in section 9. If administration of the investigational product was not modified and all scheduled doses were given enter 2-Dose not changed. If administration of investigational product was temporarily interrupted but then restarted enter 3-Dose Interrupted. If the subject did not receive investigational product dose at the time of the event or if the subject has received all his doses or if the subject died and there was no prior decision to discontinue investigational product enter X-Not applicable.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 5059c18a8f42336bf2a269a9749b704a240

CONFIDENTIAL


GUIDELINES FOR COMPLETING SERIOUS ADVERSE EVENT REPORT

SECTION 2 Seriousness Requires hospitalisation or prolongation of existing hospitalisation

The following cases are not defined as serious AEs and no SAE report is no to be submitted :

• Hospitalization for elective surgery related to a pre-existing condition which did not increase in severity or frequency following initiation of the study (e.g. : aesthetic surgery or surgery planned before subject enrolled),

• Hospitalisation for routine clinical procedure or for social reason (e.g. : elderly person had an extension of hospitalization because of room is available in a resting home) that are not the result of an adverse event

These latter cases have to be recorded in the CRF only. If the hospitalization arises from a pre-existing condition or was planned prior to the first vaccination, it should be recorded in the Medical History section of the CRF. If the hospitalisation was planned after the first vaccination, it should be recorded in the AE pages. In both cases, it should be recorded as “Hospitalisation” (not an adverse event) or “Hospitalisation for social reason” (not an adverse event) or “Elective surgery” (not an adverse event) and the relationship to vaccination will be checked “No”.

SECTION 4 If investigational product was stopped, did the reported event(s) recur after further investigational product(s) were administered?

If deliberate or inadvertent administration of further dose(s) of investigational product(s) to the subject occurred, did the reported adverse event recur?

SECTION 5 Possible causes of SAE other than investigational product To be completed in any case, whether relationship is Yes or No. Indicate all possible explanations/circumstances which may have contributed to the SAE.

SECTION 8 Relevant Concomitant Medications Give any concomitant medication(s) which may have contributed to the event. There is no need to list medications which are definitely not linked to the event.

SECTION 9 Vaccine name Vaccine should given as described on the CRF vaccination page (or protocol).

In case of multiple vaccinations on the same day, it is important to also mention if the vaccines were administered mixed or separetely.

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 5069c18a8f42336bf2a269a9749b704a240

Protocol (eTrack number) |_1_|_1_|_1_|_5_|_7_|_2_| Country Center Number Subject Number Treatment Number

Abbreviated Title HAB-168 BST 160 __________________ |__|__|__|__|__|__| |__|__|__|__|__|__| |__|__|__|__|__|

SAE Report - Template CRF Version 12.5 – February 8, 2008 Page 1 of 5

SERIOUS ADVERSE EVENT (SAE) SAE Report N° |__|__| GSK receipt date: |__|__||__|__|__||__|__|

� 1. Initial report � 2. First follow-up � 3. Second follow-up � 4. Third follow-up

SECTION 1

Event Start date Outcome End date Maximum intensity

Action taken with investigational product(s) as a

result of the SAE

Withdrawal Relationship to investigational

product(s)

Medically attended visit

Diagnosis only (if known), otherwise sign / symptom

Day Month Year (DD MMM YY)

1: Recovered/ Resolved 2: Recovering / Resolving 3: Not recovered/ Not

resolved 4: Recovered/ Resolved

with sequelae 5: Fatal

If fatal, record date of death


1: Mild 2: Moderate 3: Severe X:Not applicable

1: Investigational product(s) withdrawn

2: Dose not changed 3: Dose Interrupted X: Not applicable

Did the subject withdraw from

study as a result of this SAE?

Y=Yes* N=No

Is there a reasonable possibility that the SAE may have been caused by the investigational

product? Y=Yes N=No

HO: Hospitalisation ER: Emergency

Room MD:Medical Doctor

Refer to protocol for full definition

|__|__||__|__|__||__|__| |__|__||__|__|__||__|__|

|__|__||__|__|__||__|__| |__|__||__|__|__||__|__|

|__|__||__|__|__||__|__| |__|__||__|__|__||__|__|

* Withdrawal : If Yes, please complete the Study Conclusion page in the CRF of the subject and tick SAE as reason for withdrawal

If fatal, was a post-mortem/autopsy performed? � No � Yes � Summarize findings in Section 11 Narrative Remarks of this SAE form.

SECTION 2 - Seriousness specify reason(s) for considering this a SAE, tick all that apply: � Results in death � Results in disability / incapacity � Is life threatening � Congenital anomaly / birth defect in the offspring � Requires hospitalisation or prolongation of existing hospitalisation

� date of admission |__|__||__|__|__||__|__|

� date of discharge |__|__||__|__|__||__|__|

� Other (clinically significant / intervention required) (see definition of SAE)

� specify _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _


Final



Final

28 Aug 2009 5079c18a8f42336bf2a269a9749b704a240




SECTION 3 - Demography Data

Date of birth: (Day Month Year)

|__|__| |__|__|__| |__|__|__|__| Sex: � Male � Female

Weight: |__|__|__|. |__| kg US only Pounds:

|__|__|__| Ounces: |__|__|

SECTION 4 If investigational product was stopped, did the reported event(s) recur after further investigational product(s) were administered?

� No � Yes � Unknown at this time � Not applicable

SECTION 5 – Possible causes of SAE other than investigational product: (tick all that apply)

� Disease under study (not applicable for prophylactic vaccine studies) � Concomitant medication (record in Section 8)

� Medical condition(s) (record in Section 6) � Activity related to study participation (e.g. procedures)

� Lack of efficacy � Other, specify: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

� Withdrawal of investigational product _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

SECTION 6 – Relevant Medical Conditions Specify any RELEVANT past or current medical disorders, allergies, surgeries, etc., that can help explain the SAE

Date of onset Day Month Year (DD MMM YY)

Condition present at time of SAE If No, date of last occurrence Day Month Year (DD MMM YY)

|__|__||__|__|__||__|__|

� Yes � No � |__|__||__|__|__||__|__|

|__|__||__|__|__||__|__|

� Yes � No � |__|__||__|__|__||__|__|

|__|__||__|__|__||__|__|

� Yes � No � |__|__||__|__|__||__|__|


Final



Final

28 Aug 2009 5089c18a8f42336bf2a269a9749b704a240




SECTION 7 – Other relevant risk factors: (specify any family or social history (smoking, diet, drug abuse, occupational hazard) relevant to the SAE):

SECTION 8 – Relevant Concomitant Medications (include details of any concomitant medication(s) which may have contributed to the event)

Drug Name (Trade name preferred) Dose Unit Frequency Route Taken prior

to study? Date started


Date stopped Day Month Year (DD MMM YY)

Ongoing Reason for medication

� No � Yes |__|__||__|__|__||__|__| |__|__||__|__|__||__|__|

� No � Yes

� No � Yes |__|__||__|__|__||__|__| |__|__||__|__|__||__|__|

� No � Yes

� No � Yes |__|__||__|__|__||__|__| |__|__||__|__|__||__|__|

� No � Yes

� No � Yes |__|__||__|__|__||__|__| |__|__||__|__|__||__|__|

� No � Yes

SECTION 9 – Details of investigational product(s)

Vaccine name (in case of multiple vaccination, please specify if vaccines were administered mixed or separately) Dose N° Lot N° Route / site

Date of administration Day Month Year (DD MMM YY)

|__|__||__|__|__||__|__|

|__|__||__|__|__||__|__|

|__|__||__|__|__||__|__|

|__|__||__|__|__||__|__|

Was randomization code broken on investigational site's request? � No � Yes � Not applicable


Final



Final

28 Aug 2009 5099c18a8f42336bf2a269a9749b704a240




SECTION 10 – Details of relevant assessments (provide details of any other tests/procedures which were carried out to diagnose or confirm the SAE, e.g. laboratory data with units and normal range)

SECTION 11 – Narrative remarks (description of signs/symptoms and details of TREATMENT given for SAE)


Final



Final

28 Aug 2009 5109c18a8f42336bf2a269a9749b704a240




SECTION 12 – SAE additional / follow-up information (use this page to provide any additional details on the SAE not already captured on the previous pages)

Investigator's Signature

1. Initial report

2. First follow-up

3. Second follow-up

4. Third follow-up

Date (Day Month Year) |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__|

Investigator's Name (print)


Final



Final

28 Aug 2009 5119c18a8f42336bf2a269a9749b704a240

Template Diary Card version 12.5 � February 8, 2008

Protocol Subject number111572

(HAB-168 BST 160)DIARY CARD Twinrix Group |__|__|__|__|__|__|

LOCAL SYMPTOMS (at injection site)

Please fill in below and assess the occurrence of any of the following signs or symptoms according to the criteria listed hereafter:INTENSITYRedness and Swelling:Measure and record the greatest diameter (in mm).Pain (at injection site): Other local symptoms:0: Absent.1: Painful on touch.2: Painful when limb is moved.3: Pain that prevents normal

activity.



(In adults/ adolescents, such an adverse would, for example, prevent attendance at work/school and would necessitate the administration of corrective therapy).

LOCAL SYMPTOMS Day 0 Day 1 Day 2 Day 3 Ongoingafter Day 3?


Redness→ size (mm): _____ _____ _____ _____

! No! Yes → |__|__| |__|__|__| |__|__|__|__|

Swelling→ size (mm): _____ _____ _____ _____

! No! Yes → |__|__| |__|__|__| |__|__|__|__|

Pain→ intensity: |____| |____| |____| |____|

! No! Yes → |__|__| |__|__|__| |__|__|__|__|

OTHER LOCAL SYMPTOMS Please give details belowStart date End date or tick box if continuingDescription - please specify side(s) and site(s) Intensity day month year day month year

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

Day 0 = date of vaccination : |__|__||__|__|__||__|__|__|__|

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 5129c18a8f42336bf2a269a9749b704a240



(HAB-168 BST 160)DIARY CARD Twinrix Group |__|__|__|__|__|__|

GENERAL SYMPTOMSPlease fill in below and assess the occurrence of any of the following signs or symptoms according to the criteria listed hereafter:Temperature:Please record the temperature every day in the evening. Should additional temperature measurements be performed at other times of the day, thehighest temperature is to be recorded.INTENSITY:Fatigue: Headache: Gastrointestinal symptoms: include nausea, vomiting,

diarrhoea and abdominal pain0: Normal1: Fatigue that is easily tolerated2: Fatigue that interferes with normal







(In adults/ adolescents, such an adverse would, for example, prevent attendance at work/ school and would necessitate theadministration of corrective therapy).


GENERAL SYMPTOMS Day 0 Day 1 Day 2 Day 3 Ongoingafter Day 3?


Temperature→ °C:! Axillary! Oral! Rectal

__ . _ __ . _ __ . _ __ . _! No! Yes → |__|__| |__|__|__| |__|__|__|__|

Fatigue→ intensity: |___| |___| |___| |___|

! No! Yes → |__|__| |__|__|__| |__|__|__|__|

Headache→ intensity: |___| |___| |___| |___|

! No! Yes → |__|__| |__|__|__| |__|__|__|__|

Gastrointestinal symptoms→ intensity: |___| |___| |___| |___|

! No! Yes → |__|__| |__|__|__| |__|__|__|__|

OTHER GENERAL SYMPTOMS Please give details belowStart date End date or tick box if continuingDescription - please give details below Intensity day month year day month year

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

MEDICATION Please fill in below if any medication has been taken since the vaccinationStart date End date or tick box if continuingTrade/Generic name Reason Total Daily


|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !


IN CASE OF HOSPITALISATION, PLEASE INFORM �..�....�� !: �..�....��..��

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 5139c18a8f42336bf2a269a9749b704a240



(HAB-168 BST 160)DIARY CARD Engerix-B / Havrix

Group |__|__|__|__|__|__|

LOCAL SYMPTOMS (at injection sites)


activity.




For investigator only: Could you please tick the appropriate box (side / site) for assessment.


for investigator only LOCALSYMPTOMS Day 0 Day 1 Day 2 Day 3 Ongoing

after Day 3?Date of last Day of Symptomsday month year

EngerixTM-B Vaccine

Redness→ size (mm): _____ _____ _____ _____

! No! Yes → |__|__| |__|__|__| |__|__|__|__|

Swelling→ size (mm): _____ _____ _____ _____

! No! Yes → |__|__| |__|__|__| |__|__|__|__|

Side! Left! Right

Site! Deltoid! Arm! Thigh! Buttock Pain

→ intensity: |___| |___| |___| |___|! No! Yes → |__|__| |__|__|__| |__|__|__|__|

HavrixTM Vaccine

Redness→ size (mm): _____ _____ _____ _____

! No! Yes → |__|__| |__|__|__| |__|__|__|__|

Swelling→ size (mm): _____ _____ _____ _____

! No! Yes → |__|__| |__|__|__| |__|__|__|__|

Side! Left! Right


→ intensity: |___| |___| |___| |___|! No! Yes → |__|__| |__|__|__| |__|__|__|__|


|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 5149c18a8f42336bf2a269a9749b704a240



(HAB-168 BST 160)DIARY CARD Engerix-B / Havrix

Group |__|__|__|__|__|__|














__ . _ __ . _ __ . _ __ . _! No! Yes → |__|__| |__|__|__| |__|__|__|__|


! No! Yes → |__|__| |__|__|__| |__|__|__|__|


! No! Yes → |__|__| |__|__|__| |__|__|__|__|


! No! Yes → |__|__| |__|__|__| |__|__|__|__|


|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !



|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 5159c18a8f42336bf2a269a9749b704a240



(HAB-168 BST 160)DIARY CARD HB VAX PRO / Vaqta

Group |__|__|__|__|__|__|

LOCAL SYMPTOMS (at injection sites)


activity.




For investigator only: Could you please tick the appropriate box (side / site) for assessment.


for investigator only LOCALSYMPTOMS Day 0 Day 1 Day 2 Day 3 Ongoing

after Day 3?Date of last Day of Symptomsday month year

HB VAX PROTM Vaccine

Redness→ size (mm): _____ _____ _____ _____

! No! Yes → |__|__| |__|__|__| |__|__|__|__|

Swelling→ size (mm): _____ _____ _____ _____

! No! Yes → |__|__| |__|__|__| |__|__|__|__|

Side! Left! Right


→ intensity: |___| |___| |___| |___|! No! Yes → |__|__| |__|__|__| |__|__|__|__|

VaqtaTM Vaccine

Redness→ size (mm): _____ _____ _____ _____

! No! Yes → |__|__| |__|__|__| |__|__|__|__|

Swelling→ size (mm): _____ _____ _____ _____

! No! Yes → |__|__| |__|__|__| |__|__|__|__|

Side! Left! Right


→ intensity: |___| |___| |___| |___|! No! Yes → |__|__| |__|__|__| |__|__|__|__|


|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 5169c18a8f42336bf2a269a9749b704a240



(HAB-168 BST 160)DIARY CARD HB VAX PRO / Vaqta

Group |__|__|__|__|__|__|














__ . _ __ . _ __ . _ __ . _! No! Yes → |__|__| |__|__|__| |__|__|__|__|


! No! Yes → |__|__| |__|__|__| |__|__|__|__|


! No! Yes → |__|__| |__|__|__| |__|__|__|__|


! No! Yes → |__|__| |__|__|__| |__|__|__|__|


|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !



|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !



CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 5179c18a8f42336bf2a269a9749b704a240


Final

28-Aug-2009

List of Independent Ethics Committees/Institutional ReviewBoards

Independent Ethics Committees/Institutional Review Boards

InvestigatorLAST + First Name

Centres/sitesNumbers*

Address of Ethics Review Body

Dr.

Dr.

Dr.

Dr.

Dr.

Dr.

Dr:

Prof.

Czech Republic

* GSK Biologicals assigned centre number

CONFIDENTIAL


28 Aug 2009 11a338025db4a4cc481c8944b127deb62

CONFIDENTIAL


28 Aug 2009 5185e8426cdff8f980f584e5167da927f5f

Representative written information for patient and sampleconsent forms

CONFIDENTIAL



CONFIDENTIAL


28 Aug 2009 519d78a3b5b66c63c171db810fab62944ad

Version Number: 1Date: 28 August 2007 1/ 8English version based on Rixensart Model Version 1 dated 28 August 2007

INFORMED CONSENT FORM FOR SUBJECTS WHO WILLRECEIVE ENGERIXTM-B and HAVRIXTM AS THE CHALLENGEDOSE

Study Identification: 111149 (HAB-160 BST)

Study Title: A phase IV, open, randomized, multicentre, multicountry study toevaluate the effect of several risk factors likely to influence the immunogenicity ofGlaxoSmithKline Biologicals� combined hepatitis A and hepatitis B vaccineTwinrixTM according to a 0, 1 and 6 month schedule, as compared to separatelyadministered monovalent hepatitis A (0, 6 months) and hepatitis B vaccines (0, 1,6 months) from different manufacturers, as well as to demonstrate the non-inferiority of TwinrixTM to the monovalent vaccines, in healthy and non-healthyadults aged 41 years or older.

Version Number: 1 Date: 28 August 2007

Company Name: GlaxoSmithKline Biologicals S.A.

Subject Identification: ________________________

This document should be presented to the subject in full; no page(s) or section(s) shouldbe omitted. The document contents should be explained verbally to the subject.

What does giving consent for this study mean?

Consent means agreeing to take part in this clinical research study. You have the right todecide if you want to take part in the study or not. Please take time to read the followinginformation carefully and discuss it if you wish with friends, relatives and your personaldoctor. Ask us if there is anything that is not clear or if you would like more information.

Why is this study being carried out?

You have already been part of the primary study where you received the primaryvaccination course of Engerix�-B administered together with Havrix�. You were alsopart of the follow-up phase of the study up to Year 3. After vaccination, antibody levelstend to decrease over a period of time. However that does not necessarily mean that youare no longer protected. The presence of immune memory can easily be investigated bygiving a vaccine challenge dose and measure the immune response after vaccination. Inthe current study, you will receive an additional dose of the Engerix�-B and Havrix�vaccine (the same vaccines that you received in the primary study). The aim of the studyis to evaluate the immune memory against hepatitis A and hepatitis B antigens byevaluating the immune response elicited after the challenge dose is administered.

Are there alternative products or treatment?

Other licensed vaccines for the prevention of hepatitis A and hepatitis B are available.

CONFIDENTIAL


28 Aug 2009 2486bd8323c0ed18bb5beaf2f641286b4

CONFIDENTIAL



Informed Consent Form for subjects who will receive Engerix�-B and Havrix� as the challengedose CONFIDENTIAL

Study Identification 111149 (HAB-160 BST)


What does this study involve?

In order to be included in the study, the following requirements must be met:

• You have signed this informed consent form.

• You are a male or female adult who completed the primary vaccination course aspart of the HAB-160 primary study.

• If you are of childbearing potential (i.e. able to have children), you must be abstinent(not sexually active) or must be using an effective method of birth control for 30days prior to the vaccination. You must also agree to continue such precautionsduring the study period, ending two months after the vaccination.

• You are not breastfeeding.

• You are not pregnant.

• You should not concurrently participate in another clinical study, or planned to do soat any time during the study period, in which you would be exposed to aninvestigational or a non-investigational product (pharmaceutical product or device).

Based on these assessments, you will be told if you can participate in the vaccination partof the study.

If you take part in the study, you will have the following tests and procedures:

Challenge dose administration visit:

• A pregnancy test (urine) will be performed at this visit if you are a female ofchildbearing age and if deemed necessary by the investigator.

• A blood sample of 5 ml will be taken from you for testing the presence of anti-HAVand anti-HBs antibodies.

• Vaccination: You will receive separate administrations of one dose of the samevaccines (Engerix�-B and Havrix�) that you received in the primary study.

• You will receive a �diary card�. It is a document on which you are requested torecord some information (for e.g. the body temperature and any reactions to thevaccination, any symptoms (solicited symptoms) that you experienced during the 4-day (Day 0-3) follow-up period after vaccination and any symptom that you hadduring the 31-day (Day 0-30) follow-up period after vaccination.

Two weeks later:

• A blood sample of approximately 5 ml will be taken from you for testing thepresence of anti-HAV and anti-HBs antibodies.

One month later


• You have to return the diary card to the investigator

CONFIDENTIAL



CONFIDENTIAL






• Throughout the study, you will be asked to report the use of anymedication/vaccination.

Note: You should contact the study doctor immediately should you have any signs orsymptoms you think may be serious, or if you are hospitalized during the study period.

How many other subjects are there in the study?

A total of 596 subjects participated in the primary vaccination study. All subjects whoparticipated in this primary vaccination study will be invited to participate in thechallenge dose study. A total of 583 subjects came to the Year 2 follow up visit.Considering a drop-out rate of 5% per year from the primary study, the number ofsubjects expected to be enrolled into the study is approximately 495.

Do you have to stay in the study?

Your participation in this study is voluntary. If you do decide to take part, you will begiven this information to keep and be asked to sign this consent form. You may refuse totake part in this study, or once in the study you may decide to discontinue participation atany time. You must inform your study doctor if you decide to do this. Your decision notto take part in the study or to stop participating in the study will not affect your current orfuture medical care, or any benefits to which you may otherwise be entitled. Theinformation and study data collected up to the time of your withdrawal from the studywill be used if it is scientifically appropriate to do so.

Your participation in the study may be stopped for any of the following reasons:

• If you do not follow the study doctor's instructions,

• The study doctor decides it is in the best interest of your health and welfare todiscontinue participation in the study,

• There are either not enough subjects interested in participating in the study or thestudy has reached the required number of subjects,

• GSK Biologicals has decided to stop the study at this site for other reasons notknown at this time,

• GSK Biologicals stops enrolling new subjects into study for any reason and youhaven�t received the study vaccine yet.

What are the foreseeable risks for taking part in the study?

All vaccines may cause side effects in some people although it is possible that you haveno side-effects after vaccination with any of the vaccine you receive in this study.

You may feel pain or discomfort at the injection site and you may see redness or swellingat the injection site. However, these effects usually clear up within a few days.

As with any vaccine, unexpected serious adverse events, including allergic reactions tothe vaccine, may occur. Therefore, it is important that you stay at the study centre at least

CONFIDENTIAL



CONFIDENTIAL






30 minutes after each vaccination, where all the medical equipment to treat any seriousreactions to the study vaccine will be available.

As the possible risks to a pregnant woman and foetus are not known, female subjects ofchildbearing potential will be asked to use a reliable contraceptive method during theperiod starting from 30 days prior to vaccination up to 2 months after vaccination and toundergo a urine pregnancy test before each vaccination.

Blood draws may cause momentary discomfort, minor bruising or bleeding. The amountto be taken will not be harmful to your health.

If you are ill on the day of vaccination, it will be rescheduled.

As a result of the vaccination you may test positive for antibodies in future tests whichmay not necessarily mean that you have contracted the disease. Such positivity testing forthe disease can be distinguished with special tests.

Engerix�-BOther side effects which can rarely occur (less than 1 per 1000 doses of vaccine) are:fever, fatigue, malaise, flu-like symptoms, dizziness, headache, abnormal sensation suchas of burning, prickling, tickling or tingling, nausea, vomiting, diarrhoea, abdominal pain,abnormal liver function tests, pain in the joints and muscles, rash or allergic skinreactions, itching.

Additional side effects that have been reported very rarely (less than 1 per 10,000 dosesof vaccine) include: swelling of the lymph nodes, inflammation of brain or spinal cord ornerves, including inflammation of the optic nerve, infection of the fluid of the spinal cordand the fluid that surrounds the brain, difficulty or impossibility of moving muscles, fits,fainting, low blood pressure, inflammation of the joint causing pain, stiffness or swellingaround a joint, wheezing and difficulty breathing, decrease of blood platelets causing atendency to bleeding or bruising, inflammation of the blood vessels.

Havrix�

Other side effects which can commonly occur (less than 1 per 10 doses of vaccine)include headache, malaise, fever and loss of appetite. Nausea has been uncommonlyreported (less than 1 per 100 doses of vaccine).

Additional side effects that have been reported very rarely (less than 1 per 10,000 dosesof vaccine) include: fatigue, diarrhoea, joint pain, muscle tenderness or weakness and fits.

A cause and effect relationship between these events and vaccination has not beenestablished.

Are there any benefits for taking part in the study?

You will receive vaccination against hepatitis A and hepatitis B disease, with observationand follow-up by the physician and his staff. Also, tests will be done on the blood

CONFIDENTIAL



CONFIDENTIAL






samples taken from you to assess if you have developed immunity. Such tests are notdone during routine vaccination and are therefore a benefit of study participation.

What payments will be made for the study?

You will receive no payment for taking part in this study.

Will you have to meet any cost/expenses for taking part in the study?

You do not have to meet any cost/expenses for taking part in the study.

Who should you contact to answer any questions on the study?

You may ask questions about the study. If you have any questions, please contact:

Name of investigator: _______________________

Address of investigator: _______________________

Telephone number of investigator: _______________________

Fax number of investigator: _______________________

In the event that you are injured in the study what compensation willbe available?

If you are injured by clinical procedures needed only because you are taking part in thisstudy, you will be compensated. Your study doctor can give you a copy of compensationguidelines for this kind of injury.

Who will have access to medical and personal information about youthat is collected in this study?

If you decide to participate in the study, the study doctor and staff will collect medicaland personal information about you as part of doing the study. People who work for orwith GSK, and others like the independent ethics committee or the institutional reviewboard (IEC/IRB) for the study or regulatory authorities responsible for approvingmedicines, will have access to this information at the site in order to check that the studyis done properly. GSK staff who see this information at the site will keep it confidential.

The study site will also transfer to GSK some of the information it collects, in a codedform. The information transferred will not include your name, initials, address, or otherdirect identifiers. It will be assigned a code number that only the site can connect back toyour name.

Your permission to the study doctor and staff to use this information or share it with GSKand others as described below for the study doesn't automatically end at a particular time.

CONFIDENTIAL



CONFIDENTIAL






Medical information about you may be produced as part of the research or studyprocedures. If at the time of the study, this information is known to be relevant to yourmedical care it will be given to the study doctor who will be encouraged to share it withyou or your doctor. While you are in the study, however, the study site will not sharecertain new medical information about you that is created as part of the study (such aswhether or not you are getting study drug, or the results of certain tests) unless the studydoctor decides it is medically important to do so. This is done to stop the study resultsfrom being distorted. Once the study is over, you will be given access to medicalinformation about you that you are entitled to see. You will be told if any of this medicalinformation requires confirmation using a clinical test. This is important because someresearch results are for research purposes and may have only limited relevance forclinical diagnosis or treatment. At any time, you may ask your study doctor to let you seeyour personal information, e.g. name and address and to correct it if necessary.

What will GlaxoSmithKline do with the information it gets?

GSK may use the information that the study doctor gives it (i.e. the coded information):

• By storing and analyzing it electronically to find out what this study is telling us.

• By sharing it with regulatory authorities that approve new medicines, or with groupsthat check that research is done properly

• By publishing the results of the study (this will not include any information thatdirectly identifies you)

• By sharing it as part of research with other companies or universities for the purposeof further understanding or developing this vaccine and with other GlaxoSmithKlineoffices in this country and in other countries. If the information is sent to anothercountry, GSK will apply the same level of protection to your information, to theextent permitted by local law

• By using it to plan new studies or other types of research or other medical purposesrelated to the development of the vaccine.

What will happen to blood samples from this study?

• Samples will not be labelled with information that directly identifies you but will becoded with your study identification number.

• Collected samples may be transferred to GSK Biologicals and other laboratoriesworking for GSK Biologicals.

• By agreeing to take part in this study you will be allowing GSK Biologicals to useyour samples for the following purposes:

• Testing to measure the immune response (e.g. amount of antibodies) to thevaccines you received during the study.

• Testing to assure that the results from your sample are of good quality, forimprovements of those tests or development of new test methods.

CONFIDENTIAL



CONFIDENTIAL






• If any findings from related studies require further investigation into the abilityof the vaccine(s) to protect people or for further research in the hepatitis A andB diseases under study, additional testing on your collected samples may beperformed by GSK Biologicals. This will, however, exclude testing related toyour genes and HIV.

• Collected samples will be stored for up to 15 years.

How is GlaxoSmithKline involved?

The study doctor and the institution are paid to conduct this research study by GSK.

The information and the materials that are given to you in relation to the study areconfidential information belonging to GlaxoSmithKline and should be kept private. Youcan discuss this information in confidence with your doctor or friends and family todecide about taking part in this study and talking about your healthcare.

CONFIDENTIAL



CONFIDENTIAL



Informed consent form for subjects who will receive Engerix�-B and Havrix� as the challengedoses

CONFIDENTIAL Subject ID


Consent statement

I, (Printed name of Subject)

• confirm that I have read the written information (or have had the information read tome) for study 111149 (HAB-160 BST), Version 1, dated 28 August 2007, total of 8pages and the study procedures have been explained to me by study staff during theconsent process for this study.

• confirm that I have had the opportunity to ask questions about this study and I amsatisfied with the answers and explanations that have been provided.

• understand that I grant access to data to authorised persons described in theinformation sheet

• have been given time and opportunity to consider taking part in this study.Tick as appropriate (this decision will not affect your ability to enter the study):I agree that my primary health care physician will be notified of my participation in thisstudy.

Yes No

Tick as appropriateI agree that my biological samples(s) may be used by GSK Biologicals for furtherresearch that is NOT RELATED to the vaccine(s) or the disease(s) under study. Thiswill be done on an anonymous basis (meaning that any identification linking me to thesample is destroyed). Testing on my genes or testing for HIV will not be done. Iunderstand that if I select �No�, it will not affect my participation in the study.

Yes No

I agree to take part in this study.

Subject's Signature _____________________________ Date: _________

DD/ MM/ YY

Signature of Personconducting Consent

_____________________________ Date:

DD/ MM/ YY

Printed Name ofPerson conductingConsent

_____________________________

CONFIDENTIAL



CONFIDENTIAL




INFORMED CONSENT FORM FOR SUBJECTS WHO WILLRECEIVE HBVAXPROTM AND VAQTATM AS THE CHALLENGEDOSE










You have already been part of the primary study where you received the primaryvaccination course of HBVAXPRO� administered together with Vaqta�. You werealso part of the follow-up phase of the study up to Year 3. After vaccination, antibodylevels tend to decrease over a period of time. However that does not necessarily meanthat you are no longer protected. The presence of immune memory can easily beinvestigated by giving a vaccine challenge dose and measure the immune response aftervaccination. In the current study, you will receive an additional dose of theHBVAXPRO� and Vaqta� vaccines (the same vaccines that you received in theprimary study). The aim of the study is to evaluate the immune memory against hepatitisA and hepatitis B antigens by evaluating the immune response elicited after the challengedose is administered.



CONFIDENTIAL



CONFIDENTIAL



Informed Consent Form for subjects who will receive HBVAXPRO� and Vaqta as the challengedose CONFIDENTIAL
















• Vaccination: You will receive one dose of the same vaccines (HBVAXPRO� andVaqta�) that you received in the primary study.


Two weeks later:


One month later



CONFIDENTIAL



CONFIDENTIAL





















As with any vaccine, unexpected serious adverse events, including allergic reactions tothe vaccine, may occur. Therefore, it is important that you stay at the study centre at least

CONFIDENTIAL



CONFIDENTIAL






30 minutes after each vaccination, where all the medical equipment to treat any seriousreactions to the study vaccine will be available.





HBVAXPRO�

Incidence Equal or Greater Than 1% of Injection

Injection site reactions, consisting principally of local pain, soreness and tenderness andincluding pruritis (intense itching sensation), erythema, swelling, warmth and noduleformation, fatigue, malaise, fever (> 100ºF), nausea, diarrhoea, headache, pharyngitis,upper respiratory infection (NOS)

Incidence Less Than 1% of Injections

Sweating, chills, flushing, aching, sensation of warmth, pruritus, rash, urticaria,vomiting, abdominal pains/cramps, diminished appetite, myalgia, arthralgia, back pain,neck pain, shoulder pain, neck stiffness, light headedness, dizziness, tingling or itching orburning sensation of the skin, rhinitis, cough, influenza earache, chronic abnormalincrease of the lymph nodes, sleeplessness/ disturbed sleep, painful or difficult urination,low blood pressure.

Additional Adverse Effects

The following additional adverse effects have been reported with use of the marketedvaccine; however, in many instances a causal relationship to the vaccine has not beenestablished: anaphylaxis and symptoms of immediate hypersensitivity reactionsincluding accumulation of fluid inside tissues, difficult or labored breathing, chestdiscomfort, bronchial spasm, or palpitation have been reported within the first few hoursafter vaccination. An apparent hypersensitivity syndrome (serum-sickness-like) ofdelayed onset has been reported days to weeks after vaccination, including: arthritis(usually transient), and dermatologic reactions such as erythema multiforme (a red rashcaused by hypersensitivity to a drug or disease or other allergen), ecchymoses (purple,black-blue resulting in a bruise) and erythema nodosum (skin condition characterized bytender red nodules on the shins and legs).

CONFIDENTIAL



CONFIDENTIAL






Vasculitis (inflammation of the blood vessel), polyarteritis nodosa (progressive disease ofconnective tissue), loss of hair, eczema (inflammation of the skin), arthritis, pain inextremity, exacerbation of multiple sclerosis, multiple sclerosis, optic neuritis, seizure,febrile seizure, encephalitis, tinnitus and increased erythrocyte sedimentation rate.

Vaqta�

Injection-site complaints, generally mild and transient, were the most frequently reportedcomplaints. The following symptoms irrespective of causality were reported by ≥1% ofsubjects:

Tenderness, pain, warmth, swelling, erythema, ecchymosis, fatigue, fever, abdominalpain, diarrhea, nausea, myalgia, arm pain, back pain, stiffness, headache, pharyngitis,upper respiratory infection, nasal congestion, menstruation disorder. Local and/orsystemic allergic reactions that occurred in <1% of children/adolescents or adults inclinical trials regardless of causality included: Injection site pruritus and/or rash,bronchial constriction; asthma; wheezing; edema/swelling; rash; generalized erythema;urticaria; pruritus, eye irritation/itching; dermatitis.

The following additional adverse reactions have been very rarely reported with use of themarketed vaccine: thrombocytopenia (a blood disease characterised by the low count ofplatelets in the blood, Guillain-Barré syndrome, cerebellar ataxia, encephalitis(inflammation of the brain).


You will receive vaccination against hepatitis A and hepatitis B disease, with observationand follow-up by the physician and his staff. Also, tests will be done on the bloodsamples taken from you to assess if you have developed immunity. Such tests are notdone during routine vaccination and are therefore a benefit of study participation.




You or your child/ ward do not have to meet any cost/expenses for taking part in thestudy.






CONFIDENTIAL



CONFIDENTIAL













Medical information about you may be produced as part of the research or studyprocedures. If at the time of the study, this information is known to be relevant to yourmedical care it will be given to the study doctor who will be encouraged to share it withyou or your doctor. While you are in the study, however, the study site will not sharecertain new medical information about you that is created as part of the study (such aswhether or not you are getting study drug, or the results of certain tests) unless the studydoctor decides it is medically important to do so. This is done to stop the study resultsfrom being distorted. Once the study is over, you will be given access to medicalinformation about you that you are entitled to see. You will be told if any of this medicalinformation requires confirmation using a clinical test. This is important because someresearch results are for research purposes and may have only limited relevance forclinical diagnosis or treatment. At any time, you may ask your study doctor to let you seeyour personal information, e.g. name and address and to correct it if necessary




CONFIDENTIAL



CONFIDENTIAL





















CONFIDENTIAL



CONFIDENTIAL



Informed consent form for subjects who will receive HBVAXPRO� and Vaqta� as the challengedose



Consent statement






Yes No


Yes No



DD/ MM/ YY


_____________________________ Date:

DD/ MM/ YY


_____________________________

CONFIDENTIAL



CONFIDENTIAL




INFORMED CONSENT FORM FOR SUBJECTS WHO WILLRECEIVE TWINRIX AS THE CHALLENGE DOSE










You have already been part of the primary study where you received the primaryvaccination course of Twinrix�. You were also part of the follow-up phase of the studyup to Year 3. After vaccination, antibody levels tend to decrease over a period of time.However that does not necessarily mean that you are no longer protected. The presenceof immune memory can easily be investigated by giving a vaccine challenge dose andmeasure the immune response after vaccination. In the current study, you will receive anadditional dose of the Twinrix� vaccine (the same vaccine that you received in theprimary study). The aim of the study is to evaluate the immune memory against hepatitisA and hepatitis B antigens by evaluating the immune response elicited after the challengedose is administered.



CONFIDENTIAL



CONFIDENTIAL



Informed Consent Form for subjects who will receive Twinrix as the challenge doseCONFIDENTIAL















• A physical examination will be done by the investigator and pre-vaccinationtemperature will be taken.


• Vaccination: You will receive one dose of the same vaccine (Twinrix) that youreceived in the primary study.


Two weeks later:


One month later


CONFIDENTIAL



CONFIDENTIAL






















CONFIDENTIAL



CONFIDENTIAL






Very common (≥ 10%) general reactions that may occur in include fatigue, commonreactions (≥ 1% and < 10%) include headache, malaise and nausea and uncommonreactions (≥ 0.1% and < 1%) include fever and vomiting.

Additional side effects that have been reported very rarely (< 0.01%) include flu-likesymptoms (fever, chills, headache, pain in the muscle or joints), inflammation of brain orspinal cord or nerves, including inflammation of the optic nerve, infection of the fluid ofthe spinal cord and the fluid that surrounds the brain, fits, fainting, low blood pressure,dizziness, abnormal sensation such as of burning, prickling, tickling or tingling, nausea,vomiting, decreased appetite, diarrhoea, abdominal pain, abnormal laboratory liver testresults, inflammation of the joint causing pain, stiffness or swelling around a joint,swelling of the lymph nodes,, decrease of blood platelets causing a tendency to bleedingor bruising, inflammation of the blood vessels, rash or allergic skin reactions, itching.

As with any vaccine, unexpected serious adverse events, including allergic reactions tothe vaccine, may occur. Therefore, it is important that you stay at the study centre at least30 minutes after each vaccination, where all the medical equipment to treat any seriousreactions to the study vaccine will be available.











CONFIDENTIAL



CONFIDENTIAL


















Medical information about you may be produced as part of the research or studyprocedures. If at the time of the study, this information is known to be relevant to yourmedical care it will be given to the study doctor who will be encouraged to share it withyou or your doctor. While you are in the study, however, the study site will not sharecertain new medical information about you that is created as part of the study (such aswhether or not you are getting study drug, or the results of certain tests) unless the studydoctor decides it is medically important to do so. This is done to stop the study resultsfrom being distorted. Once the study is over, you will be given access to medicalinformation about you that you are entitled to see. You will be told if any of this medicalinformation requires confirmation using a clinical test. This is important because someresearch results are for research purposes and may have only limited relevance for

CONFIDENTIAL



CONFIDENTIAL






clinical diagnosis or treatment. At any time, you may ask your study doctor to let you seeyour personal information, e.g. name and address and to correct it if necessary


















CONFIDENTIAL



CONFIDENTIAL







CONFIDENTIAL



CONFIDENTIAL



Informed consent form for subjects who will receive Twinrix as the challenge doseCONFIDENTIAL Subject ID


Consent statement






Yes No


Yes No



DD/ MM/ YY


_____________________________ Date:

DD/ MM/ YY


_____________________________

CONFIDENTIAL



CONFIDENTIAL



Study information letter Study 111149 (HAB-160 BST)CONFIDENTIAL

Version 1 � 31 January 2008 1/1

Study Information letter

[Germany]

Study identification: eTrack study number 111149 (HAB-160 BST)

Study title: A phase IV, open, randomized, multicentre, multicountrystudy to evaluate the effect of several risk factors likely toinfluence the immunogenicity of GlaxoSmithKlineBiologicals� combined hepatitis A and hepatitis B vaccineTwinrix according to a 0, 1 and 6 month schedule, ascompared to separately administered monovalent hepatitis A(0, 6 months) and hepatitis B vaccines (0, 1, 6 months) fromdifferent manufacturers, as well as to demonstrate the non-inferiority of Twinrix to the monovalent vaccines, in healthyand non-healthy adults aged 41 years or older.

Version No. and Date: Version 1 � 31 January 2008

Purpose of this document

By means of this document, we would like to inform you regarding the number ofsubjects in each country who are participating in this trial.

This study is conducted in three study countries. 219 subjects are expected to participatein Germany, 51 subjects in Belgium and 225 subjects in the Czech Republic.

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL

Version Number: 1Date: 28 January 2008 1/ 8English version based on Rixensart Model Version 1 dated 28 January 2008

INFORMED CONSENT FORM FOR SUBJECTS WHO WILLRECEIVE ENGERIX-B and HAVRIX AS THE CHALLENGE DOSE

Study Identification: 111572 (HAB-168 BST 160)

Study Title: A phase IV, open, multicentre, multicountry study to evaluate theimmune response to a challenge dose of GSK Biologicals� Twinrix vaccineversus monovalent hepatitis A and B vaccines from different manufacturers inhealthy and non-healthy adults aged > 41 years, approximately 48 months afterprimary vaccination in the study 100382 (HAB-160).

Version Number: 1 Date: 28 January 2008







You have already been part of the primary study where you received the primaryvaccination course of Engerix�-B administered together with Havrix�. You were alsopart of the follow-up phase of the study up to Year 3. After vaccination, antibody levelstend to decrease over a period of time. However that does not necessarily mean that youare no longer protected. The presence of immune memory can easily be investigated bygiving a vaccine challenge dose and measure the immune response after vaccination. Inthe current study, you will receive an additional dose of the Engerix�-B and Havrix�vaccine (the same vaccines that you received in the primary study). The aim of the studyis to evaluate the immune memory against hepatitis A and hepatitis B antigens byevaluating the immune response elicited after the challenge dose is administered.





CONFIDENTIAL


28 Aug 2009 27260fc35b4fee6c54da7e024f33a11515

CONFIDENTIAL




Study Identification 111572 (HAB-168 BST 160)













• Vaccination: You will receive separate administrations of one dose of the samevaccines (Engerix�-B and Havrix�) that you received in the primary study.


Two weeks later:


One month later





CONFIDENTIAL



CONFIDENTIAL







A total of 596 subjects participated in the primary vaccination study. All subjects whoparticipated in this primary vaccination study will be invited to participate in thechallenge dose study.

This study is conducted in three countries. 51 subjects are expected to participate inBelgium, 225 subjects in the Czech Republic and 219 subjects in Germany.













As the possible risks to a pregnant woman and foetus are not known, female subjects ofchildbearing potential will be asked to use a reliable contraceptive method during the

CONFIDENTIAL



CONFIDENTIAL






period starting from 30 days prior to vaccination up to 2 months after vaccination and toundergo a urine pregnancy test before each vaccination.




Engerix�-BOther side effects which can rarely occur (less than 1 per 1000 doses of vaccine) are:fever, fatigue, malaise, flu-like symptoms, dizziness, headache, abnormal sensation suchas of burning, prickling, tickling or tingling, nausea, vomiting, diarrhoea, abdominal pain,abnormal liver function tests, pain in the joints and muscles, rash or allergic skinreactions, itching.

Additional side effects that have been reported very rarely (less than 1 per 10,000 dosesof vaccine) include: swelling of the lymph nodes, inflammation of brain or spinal cord ornerves, including inflammation of the optic nerve, infection of the fluid of the spinal cordand the fluid that surrounds the brain, difficulty or impossibility of moving muscles, fits,fainting, low blood pressure, inflammation of the joint causing pain, stiffness or swellingaround a joint, wheezing and difficulty breathing, decrease of blood platelets causing atendency to bleeding or bruising, inflammation of the blood vessels.

Havrix�

Other side effects which can commonly occur (less than 1 per 10 doses of vaccine)include headache, malaise, fever and loss of appetite. Nausea has been uncommonlyreported (less than 1 per 100 doses of vaccine).

Additional side effects that have been reported very rarely (less than 1 per 10,000 dosesof vaccine) include: fatigue, diarrhoea, joint pain, muscle tenderness or weakness and fits.

A cause and effect relationship between these events and vaccination has not beenestablished.





CONFIDENTIAL



CONFIDENTIAL




















Medical information about you may be produced as part of the research or studyprocedures. If at the time of the study, this information is known to be relevant to yourmedical care it will be given to the study doctor who will be encouraged to share it withyou or your doctor. While you are in the study, however, the study site will not sharecertain new medical information about you that is created as part of the study (such aswhether or not you are getting study drug, or the results of certain tests) unless the studydoctor decides it is medically important to do so. This is done to stop the study results

CONFIDENTIAL



CONFIDENTIAL






from being distorted. Once the study is over, you will be given access to medicalinformation about you that you are entitled to see. You will be told if any of this medicalinformation requires confirmation using a clinical test. This is important because someresearch results are for research purposes and may have only limited relevance forclinical diagnosis or treatment. At any time, you may ask your study doctor to let you seeyour personal information, e.g. name and address and to correct it if necessary.




• By sharing it with regulatory authorities that approve new medicines, or with groupsthat check that research is done properly.

• By publishing the results of the study (this will not include any information thatdirectly identifies you).

• By sharing it as part of research with other companies or universities for the purposeof further understanding or developing this vaccine and with other GlaxoSmithKlineoffices in this country and in other countries. If the information is sent to anothercountry, GSK will apply the same level of protection to your information, to theextent permitted by local law.










CONFIDENTIAL



CONFIDENTIAL









CONFIDENTIAL



CONFIDENTIAL



Informed consent form for subjects who will receive Engerix�-B and Havrix� as the challengedoses



Consent statement


• confirm that I have read the written information (or have had the information read tome) for study 111572 (HAB-168 BST 160), Version 1, dated 28 January 2008, totalof 8 pages and the study procedures have been explained to me by study staff duringthe consent process for this study.


• understand that I grant access to data to authorised persons described in theinformation sheet.


Yes No


Yes No



DD/ MM/ YY


_____________________________ Date: _________

DD/ MM/ YY


_____________________________

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


INFORMED CONSENT FORM FOR SUBJECTS WHO WILLRECEIVE HBVAXPRO AND VAQTA AS THE CHALLENGE DOSE










You have already been part of the primary study where you received the primaryvaccination course of HBVAXPRO� administered together with Vaqta�. You werealso part of the follow-up phase of the study up to Year 3. After vaccination, antibodylevels tend to decrease over a period of time. However that does not necessarily meanthat you are no longer protected. The presence of immune memory can easily beinvestigated by giving a vaccine challenge dose and measure the immune response aftervaccination. In the current study, you will receive an additional dose of theHBVAXPRO� and Vaqta� vaccines (the same vaccines that you received in theprimary study). The aim of the study is to evaluate the immune memory against hepatitisA and hepatitis B antigens by evaluating the immune response elicited after the challengedose is administered.





CONFIDENTIAL



CONFIDENTIAL

















• Vaccination: You will receive one dose of the same vaccines (HBVAXPRO� andVaqta�) that you received in the primary study.


Two weeks later:


One month later





CONFIDENTIAL



CONFIDENTIAL





















As the possible risks to a pregnant woman and foetus are not known, female subjects ofchildbearing potential will be asked to use a reliable contraceptive method during the

CONFIDENTIAL



CONFIDENTIAL






period starting from 30 days prior to vaccination up to 2 months after vaccination and toundergo a urine pregnancy test before each vaccination.




HBVAXPRO

Incidence Equal or Greater Than 1% of Injection

Injection site reactions, consisting principally of local pain, soreness and tenderness andincluding pruritis (intense itching sensation), erythema, swelling, warmth and noduleformation, fatigue, malaise, fever (> 100ºF), nausea, diarrhoea, headache, pharyngitis,upper respiratory infection (NOS)

Incidence Less Than 1% of Injections

Sweating, chills, flushing, aching, sensation of warmth, pruritus, rash, urticaria,vomiting, abdominal pains/cramps, diminished appetite, myalgia, arthralgia, back pain,neck pain, shoulder pain, neck stiffness, light headedness, dizziness, tingling or itching orburning sensation of the skin, rhinitis, cough, influenza earache, chronic abnormalincrease of the lymph nodes, sleeplessness/ disturbed sleep, painful or difficult urination,low blood pressure.

Additional Adverse Effects

The following additional adverse effects have been reported with use of the marketedvaccine; however, in many instances a causal relationship to the vaccine has not beenestablished: anaphylaxis and symptoms of immediate hypersensitivity reactionsincluding accumulation of fluid inside tissues, difficult or labored breathing, chestdiscomfort, bronchial spasm, or palpitation have been reported within the first few hoursafter vaccination. An apparent hypersensitivity syndrome (serum-sickness-like) ofdelayed onset has been reported days to weeks after vaccination, including: arthritis(usually transient), and dermatologic reactions such as erythema multiforme (a red rashcaused by hypersensitivity to a drug or disease or other allergen), ecchymoses (purple,black-blue resulting in a bruise) and erythema nodosum (skin condition characterized bytender red nodules on the shins and legs).Vasculitis (inflammation of the blood vessel), polyarteritis nodosa (progressive disease ofconnective tissue), loss of hair, eczema (inflammation of the skin), arthritis, pain inextremity, exacerbation of multiple sclerosis, multiple sclerosis, optic neuritis, seizure,febrile seizure, encephalitis, tinnitus and increased erythrocyte sedimentation rate.

CONFIDENTIAL



CONFIDENTIAL






Vaqta

Injection-site complaints, generally mild and transient, were the most frequently reportedcomplaints. The following symptoms irrespective of causality were reported by ≥1% ofsubjects:

Tenderness, pain, warmth, swelling, erythema, ecchymosis, fatigue, fever, abdominalpain, diarrhea, nausea, myalgia, arm pain, back pain, stiffness, headache, pharyngitis,upper respiratory infection, nasal congestion, menstruation disorder. Local and/orsystemic allergic reactions that occurred in <1% of children/adolescents or adults inclinical trials regardless of causality included: Injection site pruritus and/or rash,bronchial constriction; asthma; wheezing; edema/swelling; rash; generalized erythema;urticaria; pruritus, eye irritation/itching; dermatitis.

The following additional adverse reactions have been very rarely reported with use of themarketed vaccine: thrombocytopenia (a blood disease characterised by the low count ofplatelets in the blood, Guillain-Barré syndrome, cerebellar ataxia, encephalitis(inflammation of the brain).













CONFIDENTIAL



CONFIDENTIAL

















CONFIDENTIAL



CONFIDENTIAL



Informed consent form for subjects who will receive HBVAXPRO� and Vaqta� as the challengedose



Consent statement






Yes No


Yes No



DD/ MM/ YY


_____________________________ Date: _________

DD/ MM/ YY


_____________________________

CONFIDENTIAL



CONFIDENTIAL



CONFIDENTIAL


INFORMED CONSENT FORM FOR SUBJECTS WHO WILLRECEIVE TWINRIX AS THE CHALLENGE DOSE










You have already been part of the primary study where you received the primaryvaccination course of Twinrix�. You were also part of the follow-up phase of the studyup to Year 3. After vaccination, antibody levels tend to decrease over a period of time.However that does not necessarily mean that you are no longer protected. The presenceof immune memory can easily be investigated by giving a vaccine challenge dose andmeasure the immune response after vaccination. In the current study, you will receive anadditional dose of the Twinrix� vaccine (the same vaccine that you received in theprimary study). The aim of the study is to evaluate the immune memory against hepatitisA and hepatitis B antigens by evaluating the immune response elicited after the challengedose is administered.





CONFIDENTIAL



CONFIDENTIAL
















• A physical examination will be done by the investigator and pre-vaccinationtemperature will be taken.


• Vaccination: You will receive one dose of the same vaccine (Twinrix) that youreceived in the primary study.


Two weeks later:


One month later




CONFIDENTIAL



CONFIDENTIAL





















Very common (≥ 10%) general reactions that may occur in include fatigue, commonreactions (≥ 1% and < 10%) include headache, malaise and nausea and uncommonreactions (≥ 0.1% and < 1%) include fever and vomiting.

CONFIDENTIAL



CONFIDENTIAL






Additional side effects that have been reported very rarely (< 0.01%) include flu-likesymptoms (fever, chills, headache, pain in the muscle or joints), inflammation of brain orspinal cord or nerves, including inflammation of the optic nerve, infection of the fluid ofthe spinal cord and the fluid that surrounds the brain, fits, fainting, low blood pressure,dizziness, abnormal sensation such as of burning, prickling, tickling or tingling, nausea,vomiting, decreased appetite, diarrhoea, abdominal pain, abnormal laboratory liver testresults, inflammation of the joint causing pain, stiffness or swelling around a joint,swelling of the lymph nodes,, decrease of blood platelets causing a tendency to bleedingor bruising, inflammation of the blood vessels, rash or allergic skin reactions, itching.















CONFIDENTIAL



CONFIDENTIAL


















CONFIDENTIAL



CONFIDENTIAL



Informed consent form for subjects who will receive Twinrix as the challenge doseCONFIDENTIAL Subject ID


Consent statement






Yes No


Yes No



DD/ MM/ YY


_____________________________ Date: _________

DD/ MM/ YY


_____________________________

CONFIDENTIAL



CONFIDENTIAL




Final

28-Aug-2009

List of investigators and other important participants in the study, contact information and numberand distribution of subjects

Investigators Centre number Investigational site Phone number Fax number

Dr. Dr. Dr. Dr. Dr. Dr. Dr: Prof.

Czech Republic


Final

28 Aug 2009 18ac7dd73a271585f6f532bb114855c67


Final

28 Aug 2009 568a316b4266a3581bedbd413f04b9f5b13

This section contained Principal Investigator’s Curriculum Vitae and has been excluded to

protect Principal Investigator privacy.


28-Aug-2009 1

Signature of principal or coordinating investigatorGlaxoSmithKline Biologicals

Global Clinical Research and DevelopmentInvestigator Approval Page

Please note that by signing this page, you take responsibility for the content of the clinicalstudy report, including appendices

STUDY TITLE: A phase IV, open, multicentre, multicountry study to evaluate theimmune response to a challenge dose of GSK Biologicals’ Twinrix™ vaccine versusmonovalent hepatitis A and B vaccines from different manufacturers in healthy and non-healthy adults aged > 41 years, approximately 48 months after primary vaccination instudy 100382 (HAB-160).

Study: 111149 (HAB-160 BST) and 111572 (HAB-168 BST: 160)

Development Phase: IV

I have read this report and confirm that to the best of my knowledge it accuratelydescribes the conduct and results of the study.

Name of Investigator:

Affiliation /investigationalcentre:

Signature of Investigator:

Date:


------------Checksum------------!Ver.!Created Ondee3ccd006b780331b8eb2e76a0a4ca2 1.6 07/09/2009 d144f960d009e6036a83fac467f934d2 1.0 07/09/2009 678ef29f07c3a0bc29aa9b938be2b981 1.0 26/08/2009 4b6856d17501c887bd2a7fcf227c67c3 1.0 27/08/2009 fb0b009324aa43dbd8458969316ad24d 1.0 27/08/2009 9c18a8f42336bf2a269a9749b704a240 1.0 27/08/2009 5e8426cdff8f980f584e5167da927f5f 1.0 04/09/2009 d78a3b5b66c63c171db810fab62944ad 1.1 04/09/2009 a316b4266a3581bedbd413f04b9f5b13 1.0 04/09/2009 4dcef09a745f6101077a0d85b50d1c4b 1.0 27/08/2009 9df7d3ec1b62c26356e3775ceb9d4e44 1.0 04/09/2009 471c8e20f55dd7beab32831e912bc620 1.0 04/09/2009 fb59e7d84608c696735dc89491514f15 1.0 27/08/2009 462a8aa0dc97e9002ef6347e7c7a3d24 1.0 04/09/2009 4016981befe285a68ce87d3d41cbedbf 1.0 04/09/2009 af6b0db9ac864f1977542353b48d586f 1.0 04/09/2009 0fb28de3dc39e2136893f24c7a9f130b 1.0 07/09/2009 ccb5a6fc557c8e06b6b539ff7e5df8fa 1.1 07/09/2009 c7bc8333e138c37efd9969bf2257f5b8 1.0 27/08/2009 1a3fd8e79d9f20be175392b8e07d13ae 1.1 07/09/2009 ------------------------------------------------

CONFIDENTIAL


28 Aug 2009 6119df7d3ec1b62c26356e3775ceb9d4e44


28-Aug-2009 2

GlaxoSmithKline BiologicalsGlobal Clinical Research and Development

Sponsor Signatory Approval PagePlease note that by signing this page, you take responsibility for the content of the clinical

study report, including appendices





Name of Sponsor Signatory: MD

Title of Sponsor Signatory: Senior Manager, Clinical R&D, Paediatric andHepatitis Vaccines, GlaxoSmithKline Biologicals’

Signature:

Date:



CONFIDENTIAL




28-Aug-2009 3

GlaxoSmithKline BiologicalsGlobal Clinical Research and Development

Sponsor Signatory Approval PagePlease note that by signing this page, you take responsibility for the content of the clinical

study report, including appendices





Name of Sponsor Signatory:

Title of Sponsor Signatory: Director, Global Clinical R&D, Paediatric andHepatitis Vaccines,GlaxoSmithKline Biologicals

Signature:

Date:



CONFIDENTIAL




Final

28 Aug 2009 - 1 -

Listings of patients receiving test drug(s) /investigationalproduct(s) from specific batches, where more than one batchwas used

Not applicable

CONFIDENTIAL


28 Aug 2009 1fb1fa9d70247fe7bd4541198e738cd95

CONFIDENTIAL


28 Aug 2009 614471c8e20f55dd7beab32831e912bc620

Randomisation list

CONFIDENTIAL


28 Aug 2009 18c1f96ebcf4488735ef77ae1cf990b0e

CONFIDENTIAL


28 Aug 2009 615fb59e7d84608c696735dc89491514f15

Randomisation list

HAB-160 BST & HAB-168 BST (A.06MAY2009)

Subjects from 111149; Group: Twinrix - Twinrix -------------------------------------------------------------------

Sub. Bl. Sub. Bl. Sub. Bl. Sub. Bl. Sub. Bl. Sub. Bl. No. nb No. nb No. nb No. nb No. nb No. nb -------- -------- -------- -------- -------- --------

. 3 3 3 1 2 2 1 3 3 3 2 2 1 1 3 3 2 2 3 3 3 3 2 2 2 3 3 1 2 2 3 3 3 3 2 2 3 3 2 3 2 2 1 3 1 3 2 2 3 3 3 3 2 2 3 3 3 2 2 3 3 3 2 2 3 3 1 2 2 2 2 3 2 2 1 3 2 2 2 1 3 2 2 2 3 3 2 2 2 3 3 2 2 2 3 1 2 2 2 3 1 3 2 2 1 3 3 2 2 3 2 3 2 2 3 3 3 2 2 1 3 3 2 2 3 3 3 2 2 3 1 3 2 2 2 3 3 2 2 3 1 3 2 2 3 3 3 2 2 3 1 3 2 2 3 3 3 2 2 1 3 1 2 2 3 3 3 2 2 3 3 3 2 2 1 3 3 2 2 3 3 1 2 2 3 3 3 2 2 3 1 3 2 2 3 3 3 2 2


Final



Final

28 Aug 2009 616fb59e7d84608c696735dc89491514f15

Randomisation list


Subjects from 111149; Group: HAV ENG - Havrix+Engerix -------------------------------------------------------------------


. 3 3 3 2 2 2 3 3 3 1 2 2 3 3 3 1 2 2 3 3 3 2 2 2 3 3 3 1 2 2 3 3 3 2 2 2 3 3 3 1 2 2 3 3 3 1 2 2 3 3 3 1 2 2 3 3 3 2 2 2 3 3 2 1 2 3 3 1 2 2 3 3 3 1 2 3 3 2 1 2 3 1 3 1 2 3 3 3 1 2 3 3 3 2 2 3 3 3 2 2 3 3 3 2 2 3 3 3 2 2 3 3 2 2 2 3 3 2 2 2 3 3 1 2 2 3 3 1 2 2 3 3 2 2 2 3 1 1 2 2 3 3 2 2 2 3 3 1 2 2 3 1 1 2 2 3 3 2 2 2 3 3 2 2 2 3 3 2 2 2 3 3 2 2 2 3 3 2 2 2 3 3 1 2 2 3 3 2 2 2 3 3 2 2 2 3 3 2 2 2


Final



Final

28 Aug 2009 617fb59e7d84608c696735dc89491514f15

Randomisation list


Subjects from 111149; Group: HBVX VQ - HB VAX PRO+Vaqta -------------------------------------------------------------------


. 3 3 3 2 2 2 1 1 3 2 2 2 1 2 3 1 2 2 3 2 3 2 2 2 3 3 3 2 2 2 2 3 2 3 2 2 3 3 1 3 2 2 3 3 2 3 2 1 3 2 2 2 3 3 1 1 2 3 1 1 3 2 2 3 3 1 2 2 3 2 3 2 3 3 1 3 2 3 3 1 3 2 3 3 3 2 2 3 1 2 2 2 3 3 3 2 2 3 3 3 2 2 3 1 3 2 2 2 3 3 2 2 3 3 3 2 2 3 3 3 2 2 3 3 3 2 2 3 3 1 2 2 3 3 3 2 2 3 3 3 2 2 3 3 3 2 2 3 3 3 2 2 3 3 2 2 2 1 3 3 2 2 3 3 2 2 2 3 3 3 2 2 3 3 3 2 2 2 3 3 2 2 3 3 3 2 2 3 3 1 2 2 3 1 1 2 2


Final



Final

28 Aug 2009 618fb59e7d84608c696735dc89491514f15

Randomisation list

HAB-168 BST:160 (A.06MAY2009)

Subjects from 111572; Group: Gr 1 - EngerixB-Havrix -------------------------------------------------------------------

Trt. Bl. Trt. Bl. Trt. Bl. No nb No nb No nb -------- -------- --------

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 3 3 3 3


Final



Final

28 Aug 2009 619fb59e7d84608c696735dc89491514f15

Randomisation list

HAB-168 BST:160 (A.06MAY2009)

Subjects from 111572; Group: Gr 2 - Twinrix -------------------------------------------------------------------


3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 3 3


Final



Final

28 Aug 2009 620fb59e7d84608c696735dc89491514f15

Randomisation list

HAB-168 BST:160 (A.06MAY2009)

Subjects from 111572; Group: Gr 3 - HB VAX PRO/Vaqta -------------------------------------------------------------------


3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 1 3 3 3 3 3 3 3 3


Final



Final

28 Aug 2009 621fb59e7d84608c696735dc89491514f15


Final

28 Aug 2009

Audit certificates

None.

CONFIDENTIAL


28 Aug 2009 1996ace430e2cb6d360f2532d958646eb

CONFIDENTIAL


28 Aug 2009 622462a8aa0dc97e9002ef6347e7c7a3d24


Final

28-Aug-2009

Documentation of statistical methods

Refer to Section 5.8 of the study report.

CONFIDENTIAL


28 Aug 2009 19e624663bbd3ca73d4a6dd63924f4313

CONFIDENTIAL


28 Aug 2009 6234016981befe285a68ce87d3d41cbedbf


Final

28-Aug-2009

Documentation of inter-laboratory standardization methods andquality assurance procedures

Not applicable.

CONFIDENTIAL


28 Aug 2009 110ea6f9eb9180c5ef66bab25830515f5

CONFIDENTIAL


28 Aug 2009 624af6b0db9ac864f1977542353b48d586f

This section contained journal publication(s), which are protected by copyright laws and therefore have been excluded.


Final

28 Aug 2009

Publications referenced in the report

There are no key publications referenced in the report.

CONFIDENTIAL


28 Aug 2009 137040a8169fbc908af429632dd927008

CONFIDENTIAL


28 Aug 2009 633ccb5a6fc557c8e06b6b539ff7e5df8fa

Individual Listings

CONFIDENTIAL


28 Aug 2009 159f48a1a5722bff91275c6cc3a45f21d

CONFIDENTIAL


28 Aug 2009 634c7bc8333e138c37efd9969bf2257f5b8

NOTES TO APPENDIX TABLES

The following abbreviations are common throughout the Appendix tables:

Sub. No. : Subject numberEli MA : Eligibility (MA: Main Analysis)

E : Eliminated from reactogenicity and immunogenicity analysesI : Eliminated from immunogenicity analysisMC : Missing ConfirmedN : NoY : YesNA : Not Applicable

Abbreviations which are unique to a particular appendix are presented below.

Appendix Table IA - Individual subject data: Elimination codes

Elim Codes : Elimination codes

Appendix Table I.B - Individual subject data: Demography

SexFM

:::

SexFemaleMale

Center : Study center

Appendix Table ICi - Individual subject data: Dates of Birth - vaccination -sampling - visits

Dates of vaccine administration,Dates of sampling,Dates of visits

VIS ND : Visit Not Done (the subject did not come)VAC ND : Study vaccine administration not doneND : Not Done

Appendix Table ICii - Individual subject data: Reason for visit not done

ReasonAEXSAEOTHSAM

:::::

Reason for visit not doneNon serious adverse eventSerious adverse eventOtherSame reason and decision as previous visit

Appendix Table ID - Individual subject data: General medical history -Physical examination

StatusPAST : Medical history no more present at the physical examinationCURRENT : Medical history present at the physical examinationBoth : Past and current

CONFIDENTIAL



CONFIDENTIAL



Appendix Table IE - Individual subject data: CONCLUSION

Elim CritYN

:::

Did any elimination criteria become applicable during the study?YesNo

Link to AEYesNo

:::

Is the withdrawal of the subject linked to an adverse event ?

Date of lastcontact

Date when last information was collected on subject�s condition

Good Condition? Was the subject in good condition at date of last contact?SAE?

YN

:::

Did the subject experience any Serious Adverse Event during thestudy?YesNo

Nb of SAE : Total number of SAE�s recorded in SAE report.Preg : Did the subject become pregnant during the study / since the end

of the active phase?

Appendix Table IEii - Individual subject data: Subjects whose the code hasbeen broken

Broken date : Unblinding treatment date

Appendix Table IEii - Individual subject data: Extensive safety follow-up

Contact date : Date of study conclusion extended safety follow-up contactSub Cont : Was the subject/subject�s parents/guardian contacted after

the end of the active phase?Reason

Consentwithdrawal /Lost tofollow-up

: Reason for not being contacted:

Non-SeriousAE?

: Did the subject experience any study relevant non-seriousadverse event(s) since the end of the active phase?

Serious AE ?

YESNOSubjectscould not becontacted

: Did the subject experience any serious adverse event(s)since the end of the active phase

Other vaccine : Has the subject received any other investigational and/ornon-registered vaccine and/or drug since the end of theactive phase?

Other vaccinespec

: Specification of the vaccine

Pregnant : Has the subject become pregnant since the end of the activephase?

CONFIDENTIAL



CONFIDENTIAL



YESNONA

:::

YesNoNot applicable

Appendix table IF - Individual subject data : Notes RDE (sticky notes)

Tbl. Note321

:::

Sticky notesNotes dataForce validation

Act : ActivityScr Nb : Screen numberScreen : Screen nameSeq Nb : Sequence numberNote : Description of the note

Appendix Table IG - Individual subject data: Vaccination procedure for eachsubject: list of the administered vaccines and all related information

Trt. No. : Treatment numberAccording toProt?

: Is of the study vaccine be administered according to protocol interms of side/site/route?

Injection? : Vaccine administrationType of vacc.

1

23

:

::

Study vaccine not administered according to protocol: wrongside/site/route or replacement or wrong vial numberStudy vaccine planned but not administered for a given visitAdministration of a study vaccine not planned in the group

Eff VialNumber

: Effective vial number administered

Appendix Table IH - Individual subject data : Smoking history

Smoke now? : Does the subject smoke on a regular basis?What?

CIGARETTESCIGARSPIPECIGARILLOS

: What does the subject smoke?

Daily Average

<= 10 DAILY11-20 DAILY21-40 DAILY> 40 DAILY

: How many cigarettes, cigars,� does the subject smoke onaverage?

Start Date : Specification of the year the subject started smokingSmoke past? : Did the subject smoke on a regular basis in the past?Stop Date : Specification of the year the subject quit smoking

CONFIDENTIAL



CONFIDENTIAL



Appendix Table II - Individual subject data: Reason for vaccine notadministered

Adm? : Study vaccine administrationN : Not administeredR : ReplacementS : Study vaccineW : Wrong vial number

ReasonSAEAEX

:::

Reason why the study vaccine was not administered:Serious adverse eventNon serious adverse event

OTH : Other

Appendix Table IJ - Individual subject data: Reason for non-Eligibility

Eligib.No

::

Did the subject meet all the entry criteria?Some inclusion /exclusion criteria are not met

Study vacc.Yes

No

:

:

The subject received at least one dose of study vaccine (studyvaccine, Replacement or Wrong vial number)No vaccine received

Criterion number : Inclusion OR exclusion criteria number the subject failedReason of inclusionand exclusion criteria

: Description of the criterion number: label from codelist or �Cfr.description in CRF�

Appendix table IK - Individual subject data : Tracking Document Booster orLong Term Follow-up

Prev_sub : Previous PID numberOrigin : Origin of the information

Track.DocDemogErr.TrackPrev.StudyNo Track

:::::

From TRACKDOC of the current studyFrom DEMOG of the current studyInconsistensy between demog and trackdocFrom FU in Previous studySubject from primary without information

DOB : Date of birthCrit_nb

1234

: Criteria number of the reason for nonparticipation into an extension study

Commentfor noneligibility

: If the criteria for non participation into anextension study is �Subject not eligible -Pleasespecify criteria that are not fulfilled�?

CritDescription -Subject not eligible -Please

specify criteria that are notfulfilled-Subject lost to follow-up ornot reached-Subject eligible but not

Label of the criteria number

CONFIDENTIAL



CONFIDENTIAL



willing to participate due to-Subject died

Due to AE?

YN

:

::

If subject is eligible but not willing to participatedue to Adverse events, or Serious adverse eventYesNo

Due toOther?

YN

:

::

If subject is eligible but not willing to participatedue to Other reason that Adverse events, orSerious adverse eventYesNo

Appendix Table IIA - Individual subject data: Solicited local adverse events

L? : Has the subject experienced any local symptoms?U : Information not availableNA : Not Applicable (when the study vaccine was not administered)N : NoY : YesM : Missing

VACC CODE : Vaccine code (corresponding vaccine label presented on the firstpage of Appendix Table IIA)

VA : Vaccine administrationN : Not administeredR : ReplacementS : Study vaccineW : Wrong vial number

PA : Pain (empty or scored from 0 to 3)RE : Redness (greatest diameter)SW : Swelling (greatest diameter)IN : Induration (greatest diameter)EC : Ecchymosis (greatest diameter)EXP

YN

:::

Has the subject experienced some symptoms?YesNo

MA_TYPE : Medical advice sought for the symptomER : Emergency roomHO : HospitalizationMD : Medical doctor

O?YN

:::

Ongoing at the end of the solicited follow-up period?YesNo

Last day : Date of the last day of symptom if it was ongoing after the solicitedfollow-up period

CONFIDENTIAL



CONFIDENTIAL



Appendix table IIB - Individual subject data: Solicited general adverse events

G? : Has the subject experienced any general symptoms?U : Information not availableNA : Not Applicable (when the study vaccine was not administered)N : NoY : YesM : Missing

AC : General aches (empty or scored from 0 to 3)AR : Arthralgia (empty or scored from 0 to 3)DA : Diarrhoea (empty or scored from 0 to 3)DR : Drowsiness (empty or scored from 0 to 3)FA : Fatigue (empty or scored from 0 to 3)FE : Fever = Body temperature in °Cs or °FsFU : Fussiness (empty or scored from 0 to 3)GI : Gastrointestinal symptoms (empty or scored from 0 to 3)HE : Headache (empty or scored from 0 to 3)IR : Irritability/fussiness (empty or scored from 0 to 3)LO : Loss of appetite (empty or scored from 0 to 3)MA : Malaise (empty or scored from 0 to 3)MY : Myalgia (empty or scored from 0 to 3)NA : Nausea (empty or scored from 0 to 3)SL : Sleeping less than usual (empty or scored from 0 to 3)SH : Shivering (empty or scored from 0 to 3)SW : Sweating (empty or scored from 0 to 3)UC : Unusual crying (empty or scored from 0 to 3)VO : Vomiting (empty or scored from 0 to 3)TE : Temperature = Body temperature in °Cs or °Fs

RTE : Route (for body temperature recording)O : OralA : AxillaryR : RectalT : TympanicX : Tympanic oralY : Tympanic rectal

Rte Pre : Route for pre-vaccination temperature recordingPre Vac : Pre-vaccination temperature

EXP : Symptom experiencedCaus : CausalityMA TYPE : Medical advice sought for the symptom

ER : Emergency roomHO : HospitalizationMD : Medical doctor

O?YN

:::

Ongoing at the end of the solicited follow-up period?YesNo

Last day : Date of the last day of symptom if it was ongoing after the solicitedfollow-up period

CONFIDENTIAL



CONFIDENTIAL



Appendix table IIC - Individual subject data: Unsolicited Adverse Event

Verbatim : Description of experience as recorded in the case report formKeyword(MedDRA)

: Specific identification terminology linked to MedDRA classificationcodes

LLT MedDRAcode

: Lower Level Term Code for MedDRA, Lowest level of theterminology, related to a single PT as a synonym, lexical variant,or quasi-synonym. (All PTs have an identical LLT).

Preferred term : Medical term assigned to the keyword/verbatim, Represents asingle medical concept

SOC code : Primary System Organ Class code: Highest level of theterminology, and distinguished by anatomical or physiologicalsystem, etiology, or purpose

Chro : Chronic illnessPr Do : Study vaccine dose given prior to the adverse eventM? : Medical advice sought for the symptomType

ER::

Type of medical adviceEmergency room

HO : HospitalizationMD : Medical doctor

Caus : Reasonable possibility that the AE have been caused by theinvestigational product?

Start date : Date of onset of adverse eventImm Pst Vac : Adverse event starting during immediate post-vaccination periodDay onset : Number of days since last study vaccine doseEnd date : Date of end of adverse eventDur (d) : Duration (days) of adverse eventInt : Maximum intensity

1 : Mild2 : Moderate3 : Severe

L/G : Local or general symptomOut : Outcome

1 : Recovered/Resolved2 : Recovering/Resolving3 : Not recovered/Not resolved45

::

Recovered with sequelae/Resolved with sequelaeDied

Vacc Code : Vaccine code (corresponding vaccine label presented on the firstpage of Appendix Tables IIC)

Ser : Serious adverse event

Appendix tables IIDi - Individual subject data: Medication

Prev dose : Previous study vaccine doseRel. day of onset : Day of onset of medication, relative to previous study vaccine doseStart date : Start date of medicationEnd date : End date of medicationDur (day) : Duration (days) of medicationTrade-Generic name : Trade and/or generic name of medicationMedical indication : Medical indication for which medication was usedGSK Antibiot

Y::

AntibioticYes

CONFIDENTIAL



CONFIDENTIAL



GSK AntipyrY

::

AntipyreticYes

ProphY

::

Prophylactic medicationYes

Appendix table IIDii - Individual subject data: Concomitant Vaccination

Trade name : Trade name of concomitant vaccine administeredAdmin. date : Date of administration of concomitant vaccinePrevious vaccinationdate

: Date of administration of previous study vaccine dose

Prev dose : Previous study vaccine doseRel. day of onset : Day of onset of concomitant vaccination, relative to date of

previous study vaccine dose

Appendix Tables IIE - Individual subject data: Extensive swelling limbs

Vac : Vaccine administered for which the large swelling reaction isreported

Physexam : Date of physical examinationExam

YN

:

::

Was the examination performed by a member of studypersonnel during the large swelling reaction period?YesNo

Ext. Swell Start : Date when the swelling was first considered to be a largeswelling reaction

H. advc : Number of hours between last vaccination and large swellingreaction, if the swelling occured within 24 hours after vaccination

Pr Do : Previous dose of vaccinationDay onset : Number of days between the previous vaccination date and the

onset date of large swelling reactionSw. size : Measurement of the greatest diameter of swelling (mm)Swe Typ : Type of swelling

LOC : local swelling around injection site, not involving adjacent jointDIF : diffuse swelling, not involving adjacent jointADJ : swelling, involving adjacent joint

Circum swo : Circumference of swollen limb (at the site of max swelling) (mm)Circum opp : Circumference of the opposite limb (at the same level) (mm)Val temp : Temperature (maximum temperature if temperature has been

taken more than once a day)Rout : Temperature measurement route

A : axilllaryO : oralRX

:: Rectaltympanic

Red : Symptom of redness occurring during the large swelling reactionRed Dia : Largest diameter of redness (mm)Ind : Symptom of induration occurring during the large swelling

reactionInd Dia : Largest diameter of induration (mm)Pain : Symptom of pain occurring during the large swelling reaction

CONFIDENTIAL



CONFIDENTIAL



Pain Int123

::::

Pain intensity (at administration site)Minor reaction to touchcries/ protests on touchcries when limb is moved / spontaneously painful

Func Imp : Symptom of functional impairment occurring during the largeswelling reaction

Imp Int1

23

::

::

Functional impairment intensityeasily tolerated, causing minimal discomfort and not interferingwith everyday activitiessufficiently discomforting to interfere with normal everydayactivitiesprevents normal everyday activities

Ext. Swell. end : Last date when the swelling was still considered to be largeswelling reaction

H. dura : Duration in hours, if the large swelling reaction lasted for lessthan 24 hours.

Out1234

:::::

Outcome of the large swelling reactionrecovered/resolvedrecovering/resolvingnot recoverd / not resolvedrecovered with sequelae / resolved with sequelae

Alt ExplYN

:::

Is there an alternative explanation for the swelling?YesNo

Explanat : Explanation of an alternative for the swelling

Appendix table IIIA - Individual subject data: IMMUNOGENICITY

cut : Cut-off of the laboratory assayGSKBIO : GlaxoSmithKline BiologicalsAP : Absence of parallelismBS ND : Blood sampling not doneIR : Invalid resultQNS : Quantity of serum not sufficientBlank : Blood sample not available or test not requestedPRE : Pre-vaccinationPI : Post-vaccination 1PII : Post-vaccination 2PIII : Post-vaccination 3

Appendix table IIIB - Individual subject data: CMI

QCNF : Quality Criteria Not FulfilledTP : Technical ProblemNM : No MaterialND : Not DoneNR : Not recordedIR : Invalid resultsBSNA : Blood Sample Not Available

CONFIDENTIAL



CONFIDENTIAL



Appendix table IVA - Individual subject data: Haematology

cut : Cut-off of the laboratory assayINVESTIG : InvestigatorVIS ND : Visit not doneND : Not doneBlank : Blood sample not available or test not requestedPRE : Pre-vaccinationPI : Post-vaccination 1PII : Post-vaccination 2PIII : Post-vaccination 3

Appendix table IVB - Individual subject data: Biochemistry

cut : Cut-off of the laboratory assayINVESTIG InvestigatorVIS ND : Visit not doneND : Not doneBlank : Blood sample not available or test not requestedPRE : Pre-vaccinationPI : Post-vaccination 1PII : Post-vaccination 2PIII : Post-vaccination 3

Appendix table IVC - Individual subject data: Urinology

cut : Cut-off of the laboratory assayINVESTIG : InvestigatorSBCODE/RES : SmithKline Beecham code/ResultVIS ND : Visit not doneND : Not donePRE : Pre-vaccinationPI : Post-vaccination 1PII : Post-vaccination 2PIII : Post-vaccination 3

CONFIDENTIAL



CONFIDENTIAL



This section contained data from each individual patient, rather than in aggregate. They have

been excluded to protect patient privacy. Anonymized data from each patient may be made

available subject to an approved research proposal. For further information please see the

Patient Level Data section of the GSK Clinical Study Register.

CRF /eCRFs for deaths, other SAEs and withdrawals due toadverse events

CONFIDENTIAL


28 Aug 2009 17c399fd660b8a8786db65db27758c154

CONFIDENTIAL


28 Aug 2009 10091a3fd8e79d9f20be175392b8e07d13ae

This section contained data from each individual patient, rather than in aggregate. They have

been excluded to protect patient privacy. Anonymized data from each patient may be made

available subject to an approved research proposal. For further information please see the

Patient Level Data section of the GSK Clinical Study Register.

111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009

Study Reporting and Analysis Plan Approval

Title: A phase IV, open, multicentre, multicountry study to evaluate the immune response to a challenge dose of GSK Biologicals. Twinrix. vaccine versus monovalent hepatitis A and B vaccines from different manufacturers in healthy and non-healthy adults aged > 41 years, approximately 48 months after primary vaccination in study 100382 (HAB-160).

eTrack study number 111572,111149

eTrack abbreviated title

111572(HAB-168 BST 160) 111149(HAB-160 BST)

Scope: All data pertaining to the above studies mentioned

Date: 12-Mar-09

Co-ordinating author:

Other author(s):

Approved by:

Clinical Development Manager/Epidemiologist

Signature dd-mmm-yyyy Project Statistician Signature dd-mmm-yyyy Franchise Stat Signature dd-mmm-yyyy

FORM-WWCD-BIO-8003-01 GSK SOP Reference: SOP-BIO-WWCD-8003

Version: Aug 2007 Page 1 of 66


TABLE OF CONTENTS

PAGE

1. LIST OF AMENDMENTS TO THE RAP ................................................................... 9

2. INTRODUCTION ...................................................................................................... 9

3. DATA EVALUATION: CRITERIA FOR EVALUATION OF OBJECTIVES ............... 10 3.1. Primary Endpoints ...................................................................................... 10 3.2. Secondary Endpoints .................................................................................. 10 3.3. Study cohorts to be evaluated ..................................................................... 11

3.3.1. Long-term (LT) total vaccinated cohort ........................................ 11 3.3.2. LT ATP cohort for analysis of immunogenicity ............................. 11 3.3.3. Total Vaccinated cohort (Challenge dose) ................................... 11 3.3.4. According-To-Protocol (ATP) cohort for analysis of safety

(Challenge dose) ......................................................................... 12 3.3.5. ATP cohort for analysis of immunogenicity (Challenge

dose) ........................................................................................... 12 3.4. Derived and transformed data ..................................................................... 12 3.5. Data presentation description ..................................................................... 14 3.6. Group description ....................................................................................... 14 3.7. Final analyses ............................................................................................. 14

3.7.1. Analysis of demographics/baseline characteristics ...................... 14 3.7.2. Analysis of immunogenicity .......................................................... 15 3.7.3. Analysis of safety (Challenge dose) ............................................. 16 3.7.4. Methodology for computing CI ..................................................... 17

3.8. Interim analysis ........................................................................................... 17

4. CHANGE FROM PROTOCOL................................................................................ 18

5. ANNEX 1: INDIVIDUAL LISTINGS AND TEMPLATE OF TABLES ........................ 18 5.1. Individual listings for the final analysis ........................................................ 18 5.2. List of tables for the final analysis ............................................................... 19

5.2.1. For Demographics Analysis ......................................................... 19 5.2.2. For Safety Analysis ...................................................................... 20 5.2.3. For Persistence Analysis ............................................................. 22 5.2.4. For Immunogenicity Analysis ....................................................... 23

5.3. Template of tables ...................................................................................... 26

6. ANNEX 2: CRITERIA FOR ELIMINATING SUBJECTS FROM STAT ANALYSES ............................................................................................................ 66




LIST OF TABLES AND FIGURES

PAGE

Table D 1 Number of subjects enrolled into the study as well as the number of subjects excluded from ATP analyses with reasons for exclusion. ............................................................................................... 26

Table D 2 Number of subjects by centre (Total vaccinated cohort) ......................... 27

Table D 3 Number of subjects at each visit and list of withdrawn subjects (Total vaccinated cohort) ........................................................................ 27

Table D 4 Number of subjects entered, completed and withdrawn with reason for withdrawal (Total vaccinated cohort) ..................................... 28

Table D 5 Summary of tracking log-sheets for all subjects initially enrolled in the primary study (Total Vaccinated Cohort) ....................................... 28

Table D 6 Deviation from specifications for age and intervals between study visits (Total vaccinated cohort) ............................................................... 29

Table D 7 Deviation from specifications for age and intervals between study visits (ATP cohort for immunogenicity) ................................................... 29

Table D 8 Minimum and maximum activity dates (Total vaccinated cohort) ............ 29

Table D 9 Summary of demographic characteristics (Total vaccinated cohort) .................................................................................................... 30

Table D 10 Summary of demographic characteristics (ATP cohort for Immunogenicity) ..................................................................................... 30

Table D 11 Summary of demographic characteristics (ATP cohort for safety) .......... 30

Table R 1 Number and percentage of subjects who received a vaccine dose (Total vaccinated cohort) ............................................................... 31

Table R 2 Compliance (Total Vaccinated Cohort) ................................................... 31

Table R 3 Incidence and nature of symptoms (solicited and unsolicited) reported during the 4-day (Days 0-3) post-vaccination period following vaccination (Total vaccinated cohort) ...................................... 32

Table R 4 Incidence and nature of grade 3 symptoms (solicited and unsolicited) reported during the 4-day (Days 0-3) post-vaccination period following vaccination (Total vaccinated cohort) ......... 32

Table R 5 Incidence and nature of symptoms (solicited and unsolicited) reported during the 4-day (Days 0-3) post-vaccination period




following vaccination with causal relationship to vaccination (Total vaccinated cohort) ........................................................................ 32

Table R 6 Incidence of solicited local symptoms reported during the 4-day (Days 0-3) post-vaccination period (Total vaccinated cohort) ................. 32

Table R 7 Incidence of solicited general symptoms reported during the 4-day (Days 0-3) post-vaccination period (Total vaccinated cohort) .......... 33

Table R 8 Percentage of subjects reporting the occurrence of unsolicited symptoms classified by MEDDRA Primary System Organ Class and Preferred Term within the 31-day (Days 0-30) post-vaccination period (Total vaccinated cohort) .......................................... 34

Table R 9 Percentage of subjects reporting the occurrence of grade 3 unsolicited symptoms classified by MEDDRA Primary System Organ Class and Preferred Term within the 31-day (Days 0-30) post-vaccination period (Total vaccinated cohort) ................................... 34

Table R 10 Percentage of subjects reporting the occurrence of unsolicited symptoms classified by MEDDRA Primary System Organ Class and Preferred Term that are causally related to vaccination, within the 31-day (Days 0-30) post-vaccination period (Total vaccinated cohort) .................................................................................. 34

Table R 11 Incidence of concomitant medication within the 4-day (Day 0-4) post vaccination period (Total vaccinated cohort) ................................... 34

Table R 12 Incidence of concomitant medication within the 31-day (Day 0-30) post vaccination period (Total vaccinated cohort) ............................ 35

Table R 13 Incidence of concomitant medication within the 4-day (Day 0-4) post vaccination period (Total vaccinated cohort) ................................... 36

Table R 14 Incidence of concomitant medication within the 31-day (Day 0-30) post vaccination period (Total vaccinated cohort) ............................. 36

Table R 15 Listing of SAEs ....................................................................................... 36

Table I 1 Anti-HBs seropositivity rates, percentage of subjects with anti-HBs antibody concentrations >=10mIU/ml and geometric mean concentrations (GMC) calculated on seropositive subjects at month 48 (LT-ATP immunogenicity cohort) ............................................ 37

Table I 2 Seropositivity rates and geometric mean concentrations (GMC) for Anti-HAV antibodies at month 48 (LT-ATP immunogenicity cohort) .................................................................................................... 37

Table I 3 Seroprotection and seropositivity rates and geometric mean concentrations (GMC) calculated on seropositive subjects for Anti-HBs antibodies (ATP immunogenicity cohort) before and after the challenge dose ......................................................................... 38



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Table I 4 Seropositivity rates and geometric mean concentrations (GMC)

calculated on seropositive subjects for Anti-HAV antibodies (ATP immunogenicity cohort) before and after the challenge dose .................. 38

Table I 5 Geometric Mean Concentrations (GMC) calculated on all subjects for Anti-HBs antibodies (ATP immunogenicity cohort) before and after the challenge dose ....................................................... 39

Table I 6 Geometric mean concentrations (GMC) calculated on all subjects for Anti-HAV antibodies (ATP immunogenicity cohort) before and after the challenge dose ......................................................................... 39

Table I 7 Percentage of subjects with anti-HBs antibody concentrations ≥ 3.3 mIU/ml, ≥ 10 mIU/ml, ≥ 100 mIU/ml after the challenge dose according to their post primary vaccination status (ATP Cohort for immunogenicity) ................................................................................ 40

Table I 8 Percentage of subjects with anti-HBs antibody concentrations ≥ 3.3 mIU/ml, ≥ 10 mIU/ml, ≥ 100 mIU/ml after the challenge dose according to their pre challenge dose status (ATP Cohort for immunogenicity) ..................................................................................... 40

Table I 9 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified by GENDER (LT ATP cohort for immunogenicity) ............................................................. 42

Table I 10 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by GENDER (LT ATP cohort for immunogenicity) ....................................... 43

Table I 11 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified by AGE† (LT ATP cohort for immunogenicity) ..................................................................... 44

Table I 12 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by AGE† (LT ATP cohort for immunogenicity) .............................................. 45

Table I 13 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified by BMI† status (LT ATP cohort for immunogenicity) ............................................................. 45

Table I 14 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by BMI† status (LT ATP cohort for immunogenicity) .................................... 46

Table I 15 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified by Smoking status† (LT ATP cohort for immunogenicity) ....................................................... 47



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Table I 16 ANTI-HBs Seropositivity rates, proportion of subjects with

antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by Smoking Status† (LT ATP cohort for immunogenicity) ............................ 48

Table I 17 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified by Alcohol consumption† status (LT ATP cohort for immunogenicity) ...................... 48

Table I 18 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by Alcohol consumption† status(LT ATP cohort for immunogenicity) ........... 49

Table I 19 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified by Concomitant Medication intake status† (LT ATP cohort for immunogenicity) ............... 49

Table I 20 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by Concomitant Medication intake status† (LT ATP cohort for immunogenicity) ..................................................................................... 50

Table I 21 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified by Medical condition† status(ATP cohort for immunogenicity) ................................... 50

Table I 22 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by Medical condition† status (ATP cohort for immunogenicity) .................... 51

Table I 23 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified by diabetes† status (ATP cohort for immunogenicity) ............................................................ 51

Table I 24 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by Diabetes† status (ATP cohort for immunogenicity).................................. 52

Table I 25 Immune response to the challenge dose for Anti-HAV antibodies (ATP cohort for immunogenicity) ............................................................ 53

Table I 26 Immune response to the challenge dose for Anti-HBs antibodies (ATP cohort for immunogenicity) ............................................................ 54

Table I 27 Immune response to the challenge dose for Anti-HBs antibodies stratified based on the pre-challenge dose (ATP cohort for immunogenicity) ..................................................................................... 54



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Table I 28 Immune response to the challenge dose for Anti-HBs antibodies

with antibody concentrations stratified based on the post primary vaccination status (ATP cohort for immunogenicity) ............................... 55

Figure I 1 Reverse cumulative curves for <antibody> <concentrations> at <pre challenge dose> (<ATP Immunogenicity Cohort>) ......................... 57

Figure I 2 Reverse cumulative curves for <antibody> <concentrations> at <14 days after the challenge dose> (<ATP Immunogenicity Cohort>) ................................................................................................. 58

Figure I 3 Reverse cumulative curves for <antibody> <concentrations> at <one month after the challenge dose> (<ATP Immunogenicity Cohort>) ................................................................................................. 59

Figure I 4 Reverse cumulative curves for <antibody> <concentrations> at <pre time point> (<LT ATP Immunogenicity Cohort>) ............................ 60

Figure I 5 Anti- HBs antibody concentrations between the pre and post challenge dose (ATP cohort for immunogenicity) ................................... 61

Figure I 6 Anti-HAV antibody concentrations between the pre and post challenge dose (ATP cohort for immunogenicity) ................................... 61

Figure I 7 GMC evolution curve of anti-HAV antibodies concentrations from primary to month 48 time point(<LT ATP Immunogenicity Cohort>) ................................................................................................. 62

Figure I 8 GMC evolution curve of anti-HBs antibodies concentrations from primary to month 48 time point (<LT ATP Immunogenicity Cohort>) ................................................................................................. 63

Table CTRS 1 Demography for CTRS .......................................................................... 64

Table CTRS 2 Number (%) of subjects with solicited local symptom during the 4-day (Days 0-3) post-vaccination period (Total Vaccinated Cohort) ................................................................................................... 64

Table CTRS 3 Number (%) of subjects with solicited general symptom during the 4-Day (Day 0- 3) post-vaccination period (Total Vaccinated Cohort) ................................................................................................... 65

Table CTRS 4 Number (%) of subjects with adverse events (Total Vaccinated cohort) .................................................................................................... 65

Table CTRS 5 Number (%) of subjects with serious adverse events (Total Vaccinated cohort) ................................................................................. 65




LIST OF ABBREVIATIONS




CI Confidence Interval

GMC Geometric Mean Concentrations

GSK GlaxoSmithKline









1. LIST OF AMENDMENTS TO THE RAP

Date Description

12-Mar-09 Final version

2. INTRODUCTION

In the primary vaccination study (HAB-160), subjects aged 41 years or older, with a wide range in body weight and variable general health status were enrolled. The influence of risk factors likely to influence the immune response elicited by Twinrix (e.g. age, gender, body mass index [BMI], smoking, alcohol consumption, diseases and medications) were assessed. The non-inferiority of Twinrix to the monovalent vaccines was evaluated in terms of anti-HBs seroprotection rate and anti-HAV seropositivity rate at Month 7. Furthermore, the effects of the risk factors on the immune response elicited by the separately administered monovalent hepatitis A and hepatitis B vaccines Engerix™-B and Havrix™ as well as HB VAX PRO and Vaqta were assessed.

It was demonstrated in the primary study that the group which received Twinrix showed significantly higher anti-HBs seroprotection rates compared to each of the monovalent vaccine groups. In the present study, the immune response to a challenge dose of GSK Biologicals’ Twinrix™ vaccine versus monovalent hepatitis A and B vaccines from different manufacturers in healthy and non-healthy adults aged> 41 years, approximately 48 months after primary vaccination in study 100382 (HAB-160) will be evaluated. All subjects (irrespective of their serological status) will receive a challenge dose, of the vaccine that they received in the primary study HAB-160. The challenge dose study is described in the (111572) protocol for the Belgian and the Czech centres. For the German centres it is described in an amendment to the HAB-160 (111149) protocol. The eligibility criteria, study visit procedures and data collection will be identical in the two studies and the data will be combined for analysis. This document summarizes the planned statistical analyses (Section 3) based on the study features as per protocol dated 25JAN2008 for 111572 and the protocol dated 28MAR2008 for 111149.The changes in the analyses as compared to the protocol are provided in section 4.The list of tables/listings to be produced in the statistical report is available in section 5.



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 3. DATA EVALUATION: CRITERIA FOR EVALUATION OF

OBJECTIVES

3.1. Primary Endpoints

•Anti-HAV immune response to the challenge dose is defined as: - Anti-HAV antibody concentrations ≥ 15 mIU/ml at one month post-challenge

dose in subjects, seronegative at the pre-challenge time point. - At least a 2-fold increase in anti-HAV antibody concentrations one month after

the challenge dose, in subjects having anti-HAV antibody concentrations ≥ 100 mIU/ml at the prechallenge time point.

- Or at least a 4-fold increase in anti-HAV antibody concentrations one month

after the challenge dose, in seropositive subjects having anti-HAV antibody concentrations< 100 mIU/ml at the pre-challenge time point.

•Anti-HBs antibody response to the challenge dose is defined as:

- Anti-HBs antibody concentrations ≥ 10 mIU/ml at one month post-challenge dose in subjects seronegative at the pre-challenge time point.

- At least a 4-fold increase in anti-HBs antibody concentrations, at one month post-

challenge dose in subjects seropositive at the pre-challenge time point.

3.2. Secondary Endpoints

Immunogenicity • Anti-HAV seropositivity rates and GMCs, as well as anti-HBs seropositivity rates, seroprotection rates and GMCs at Month 48. • Percentage of subjects with anti-HAV antibody concentrations ≥ 15mIU/ml and GMCs calculated on seropositive subjects, two weeks and one month after the challenge dose. • Percentage of subjects with anti-HBs antibody concentrations ≥ 3.3mIU/ml, ≥10mIU/ml, ≥ 100 mIU/ml and anti-HBs geometric mean concentrations (GMCs) calculated on seropositive subjects, two weeks and one month after the challenge dose. Reactogenicity • Occurrence and intensity of solicited local symptoms in the 4-day (Day 0 to 3) follow-up period after the challenge dose. • Occurrence, intensity and relationship of solicited general symptoms in the 4-day (Day 0 to 3) follow-up period after the challenge dose.



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Safety • Retrospective recording of all serious adverse events (SAEs) with causal relationship to vaccination or referring to hepatitis A or B infection that occurred since the last study visit of the HAB-160 long-term follow-up study. • Occurrence, intensity and relationship to vaccination of unsolicited symptoms reported during the 31-day (Day 0 to 30) follow-up period after the challenge dose. • Occurrence, intensity and relationship to vaccination of all SAEs following the administration of the challenge dose.


3.3.1. Long-term (LT) total vaccinated cohort

The long-term total vaccinated cohort will include all subjects who received at least one dose of the study vaccine in the primary study and who returned for the Month 48 blood sampling time point.

3.3.2. LT ATP cohort for analysis of immunogenicity

For subjects who return at the Month 48 time point, the LT-ATP cohort (at that time point) will include those who were included in the primary ATP immunogenicity analysis, who did not receive hepatitis A or hepatitis B vaccine not specified in the study protocol and who were not eliminated for abnormal increase† in antibody concentrations during follow-up period. † Note: the criteria of an antibody (anti-HAV or anti-HBs) concentrations abnormal increase depends on the magnitude of antibody level reached at first time point (i.e. the reference value). The case of an abnormal antibody concentrations increase was defined as a two-fold increase or more in antibody concentrations (when the antibody concentrations at the reference time point was ≥ 100 mIU/ml) or a four-fold increase or more in antibody concentrations (when the antibody concentrations at the reference time point was < 100 mIU/ml). This code will be assigned to eliminate from the analysis subjects who could have been infected by the hepatitis A or hepatitis B virus, or who could have received a vaccine dose not specified in the protocol during the study.

3.3.3. Total Vaccinated cohort (Challenge dose)

The Total Vaccinated cohort will include all subjects who received the challenge dose: • A safety analysis based on the total vaccinated cohort will include all vaccinated subjects.

• An immunogenicity analysis based on the total vaccinated cohort will include all vaccinated subjects for whom immunogenicity data are available. FORM-WWCD-BIO-8003-01 GSK SOP Reference: SOP-BIO-WWCD-8003


111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 3.3.4. According-To-Protocol (ATP) cohort for analysis of safety

(Challenge dose)

The ATP cohort for safety will include all eligible subjects: • Who have received the complete primary hepatitis B and hepatitis A vaccination course in the HAB-160 primary study. •Who have received the challenge dose. •Who have not received a vaccine not specified or forbidden in the protocol.

3.3.5. ATP cohort for analysis of immunogenicity (Challenge dose)

The ATP cohort for analysis of immunogenicity will include all evaluable subjects included in the ATP cohort for analysis of safety ((i.e. those meeting all eligibility criteria, complying with the procedures and intervals defined in the protocol, with no elimination criteria during the study) who have received the challenge dose and for whom data concerning immunogenicity endpoint measures for at least one antigen are available at the post-challenge dose time point. The interval between Visit 8 (pre-challenge dose) and Visit 10 (post-challenge dose time point) considered for inclusion of a subject in the ATP cohort for immunogenicity will be 21 to 48 days.

The list of applicable elimination codes for each cohort can be found in section 6.

Cohort Elimination codes Eli Type

ATP cohort for analysis for safety 1010-1500 MA

ATP cohort for analysis for immunogenicity 1010-2500 MA

ATP cohort for long term (LT) Persistence 3040-3120 MA


Immunogenicity • The cut-off value is defined by the laboratory before the analysis. The cut-off value for the assay for anti-HAV antibody is 15 mIU/ml.The cut-off value for the assay for anti-HBs antibody is 3.3 mIU/ml. • A seronegative subject is a subject whose antibody concentration is below the cut-off value.



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 • A seropositive subject is a subject whose antibody concentration is greater than or equal to the cut-off value. • Seropositivity rate is defined as the percentage of subjects with antibody concentrations greater than or equal to the cut-off value. • Seroprotection rate for anti-HBs is defined as the percentage of subjects with anti- HBs concentrations ≥ 10 mIU/ml. • The GMC calculations will be performed by taking the anti-log of the mean of the log transformation of antibody concentrations equal to or above the seropositivity level (i.e.15 mIU/ml for anti-HAV and 3.3 mIU/ml for anti-HBs). • If GMC has to be calculated on all subjects (as supplement), subjects whose antibody concentrations are below the assay cut-off are assigned an arbitrary value of half the cut-off. • Anti-HAV immune response to the challenge dose is defined as: Anti-HAV antibody concentrations ≥ 15 mIU/ml at one month post-challenge

dose in subjects, seronegative at the pre-challenge time point.

At least a 2-fold increase in anti-HAV antibody concentrations one month after the challenge dose, in subjects having anti-HAV antibody concentrations ≥ 100 mIU/ml at the pre-challenge time point or at least a 4-fold increase in antibody concentrations one month after the challenge dose, in seropositive subjects having anti-HAV antibody concentrations < 100 mIU/ml at the pre-challenge time point.


At least a 4-fold increase in anti-HBs antibody concentrations, at one month post-challenge dose in subjects seropositive at the pre-challenge time point.

Anti-HBs antibody concentrations ≥10 mIU/ml at one month post-challenge dose in subjects seronegative at the pre-challenge time point.

For a given subject and a given immunogenicity measurement, missing or non-evaluable measurements will not be replaced. Therefore, an analysis will exclude subjects with missing or non-evaluable measurements.

Safety/ Reactogenicity • For the analysis of solicited symptoms, missing or non-evaluable measurements will not be replaced. Therefore the analysis of the solicited symptoms based on the total vaccinated cohort will include only subjects with documented safety data (i.e. symptom screen completed). FORM-WWCD-BIO-8003-01 GSK SOP Reference: SOP-BIO-WWCD-8003


111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 • For the analysis of unsolicited adverse events/concomitant medication, all vaccinated subjects will be considered and subjects who did not report an event will be considered as subjects without an event.

3.5. Data presentation description

The following decimal description will be used for the demography, reactogenicity and immunogenicity analyses.

Display Table Parameters Number of decimal digits All summaries % of count, including

LL & UL of CI 1

Demographic characteristics Mean, median age 1 Demographic characteristics SD (age)

2

anti-HBs GMC 1 anti-HAV GMC 1

3.6. Group description

The following groups will be used for the statistical analyses.

Study Group order in tables

Group label in tables

Group definition for footnote

111572/111149

1 Twinrix Subjects who received the Twinrix vaccine

111572/111149

2 Eng + HAV Subjects who received the Engerix and Havrix vaccines

111572/111149

3 HBVX + VAQ Subjects who received the HB VAX PRO and Vaqta vaccines

3.7. Final analyses

The challenge dose study is described in the protocol (E-track: 111572) for the Belgian and Czech centres and in an amendment to the HAB-160 protocol (E-track: 111149) for the German centres.The eligibility criteria, study visit procedures and data collection will be identical in the two studies and the data will be combined for analysis. One integrated clinical study report will describe the results of this analysis.


Demographic characteristics (age in years, gender and race), cohort description and withdrawal status will be summarized using descriptive statistics:



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Mean, median and standard deviation will be provided for continuous data such as age. All the demographic analyses will be performed stratified based on the three study groups in the primary study and overall. A summary of the tracking log-sheet documenting reasons for non-participation in the challenge dose study will be provided.


Persistence of antibody response Seroprotection rates, seropositivity rates and GMCs for anti-HBs antibodies with 95% confidence intervals will be tabulated for the LT-ATP immunogenicity cohort at Month 48. Seropositivity rates and GMCs for anti-HAV antibodies with 95% confidence intervals, will be tabulated for the LT-ATP immunogenicity cohort at Month 48. GMC evolution for anti-HAV and anti-HBs antibodies will be graphically presented for the LT-ATP immunogenicity cohort.

The distribution of anti-HAV and anti-HBs antibody concentrations will be graphically presented by the RCC for the LT-ATP immunogenicity cohort.

Response to challenge dose The primary analysis will be based on the ATP cohort for immunogenicity. If the percentage of enrolled subjects excluded from this ATP cohort is 5% or more, a second analysis based on the Total Vaccinated cohort will be performed to complement the ATP analysis. The following analysis will be performed for each treatment group: • Percentage of subjects with anti-HAV response to the challenge dose with exact 95% CIs will be tabulated. • Percentage of subjects with anti-HBs response to the challenge dose with exact 95% CIs will be tabulated. The following tabulations will be done at the pre and post challenge time points for each treatment group: • Anti-HAV and anti-HBs GMCs with 95% CIs will be tabulated primarily for seropositive subjects and secondarily for all subjects (the same will also be tabulated stratified based on the baseline characteristics).



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 • Percentage of subjects seropositive for anti-HAV antibodies (anti-HAV antibody concentrations ≥ 15 mIU/ml), with exact 95% CI will be tabulated (the same will also be tabulated stratified based on the baseline characteristics). • Percentage of subjects with anti-HBs concentrations ≥ 3.3 mIU/ml, percentage of subjects with anti-HBs concentrations ≥ 10 mIU/ml and ≥ 100 mIU/ml, with exact 95% CIs will be tabulated (the same will also be tabulated stratified based on the baseline characteristics). The following tabulations will be done for each treatment group: •Percentage of subjects with anti-HBs antibody concentrations ≥ 3.3mIU/ml, ≥ 10 mIU/ml, ≥ 100 mIU/ml ≥ 100 mIU/ml 30 days after the challenge dose according to their pre-challenge dose status will be tabulated (seronegative (<3.3mIU/ml), 3.3- <10mIU/ml, >=10mIU/ml). • Percentage of subjects with anti-HBs antibody concentrations ≥ 3.3 mIU/ml, ≥ 10 mIU/ml, ≥ 100 mIU/ml after the challenge dose according to their post-primary vaccination status (at month 7: <3.3mIU/ml, 3.3- <10mIU/ml, 10- <100mIU/ml and >=100mIU/ml).will be tabulated. • Percentage of subjects with anti-HBs response to the challenge dose with exact 95% CIs stratified based on the pre-challenge and post primary vaccination status will be tabulated. • Distribution of anti-HAV and anti-HBs antibody concentrations will be presented as reverse cumulative distribution curves at pre, 14 days and 30 days after the challenge dose. • A graphical representation of the relationship between anti-HBs/anti-HAV antibody concentrations observed after the challenge dose and at the pre-challenge time point will be presented. 3.7.3. Analysis of safety (Challenge dose)

The analysis will be based on the Total Vaccinated cohort. If 5% or more of the enrolled subjects are eliminated from the ATP cohort for safety analysis, a second analysis will be performed on the ATP cohort for safety. • The percentage of subjects with at least one local adverse event (solicited and unsolicited), with at least one general adverse event (solicited and unsolicited) and with any adverse event (solicited and unsolicited) during the 4-day (Day 0 to Day 3) follow-up period after the vaccination will be tabulated with exact 95% CI. Similar tabulations will be done for grade 3 symptoms.



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 • The percentage of subjects reporting each individual solicited symptom during the 4-day follow-up period with exact 95% CI, by type of adverse event; by severity (any grade, grade 3 only); for general symptoms: by relationship to vaccination (any relationship, related only) will be tabulated. • The occurrence of fever will be tabulated per 0.5 °C cumulative increments as well as the occurrence of fever (> 39.5 °C oral/axillary temperature) with causal relationship to vaccination. • The percentage of subjects with at least one report of unsolicited adverse event classified by the Medical Dictionary for Regulatory Activities (MedDRA) and reported within the 31-day (Day 0 to Day 30) follow-up period after vaccination will be tabulated with exact 95% CI. The same tabulation will be performed for grade 3 unsolicited adverse events and for unsolicited adverse events with a causal relationship to vaccination. • The percentage of subjects who start and report at least one concomitant medication (i.e. any medication, antipyretic medication, prophylactic antipyretics) during the 4-day and 31-day follow-up period after vaccination will be tabulated (with exact 95%CI). • Serious adverse events reported during the entire study period and withdrawal due to AEs/SAEs will be described in detail. • SAEs causally related to vaccination or hepA/B infection reported since the last visit of the HAB160 LTFU phase will be described in detail.

3.7.4. Methodology for computing CI

All CI will be 2 sided 95% CI.

• The exact 95% CIs for a proportion within a group will be calculated from Proc StatXact.

• The 95% CI for geometric mean concentrations (GMCs) will be obtained within each group separately. The 95% CI for the mean of log- transformed concentration will be first obtained assuming that log-transformed values were normally distributed with unknown variance. The 95% CI for the GMCs will be then obtained by exponential-transformation of the 95% CI for the mean of log-transformed concentration.

3.8. Interim analysis




111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 4. CHANGE FROM PROTOCOL

The following analysis has been included.

• Percentage of subjects with anti-HBs antibody concentrations ≥ 3.3 mIU/ml, ≥ 10 mIU/ml, ≥ 100 mIU/ml after the challenge dose according to their pre-challenge dose status and post primary status has been included in the analysis.

• Immune response to the challenge dose for anti-HBs antibody concentrations stratified based on the pre-challenge and post primary vaccination status has been included in the analysis.

• The distribution of anti-HAV and anti-HBs antibody concentrations graphically presented by the RCC for the LT-ATP immunogenicity cohort.has been included

• GMC evolution curves for anti-HAV and anti-HBs antibodies for the LT-ATP immunogenicity cohort.has been included.

5. ANNEX 1: INDIVIDUAL LISTINGS AND TEMPLATE OF TABLES

5.1. Individual listings for the final analysis

Appendix Table I.A - Elimination codes

Appendix Table I.B - Demography

Appendix Table I.Ci - Dates of birth, Informed consent, Vaccination and blood sampling, Contact

Appendix Table I.Cii - Reason for visit not done

Appendix Table I.D - General medical history - Physical examination

Appendix Table I.Ei - Conclusion of active phase Appendix Table I.G / I.H - Vaccination procedure

Appendix Table I.I - Reason for not administration of vaccine

Appendix Table I.J - Tracking document

Appendix Table II.Ai - Solicited local symptoms

Appendix Table II.B - Solicited general symptoms

Appendix Table II.Ci - Unsolicited adverse events within (31) days post-vaccination

Appendix Table II.Cii - Unsolicited adverse events after (31) days post-vaccination

Appendix Table II.Di - Concomitant medications

Appendix Table II.Dii - Concomitant vaccinations



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Appendix Table III.A – Immunogenicity

Appendix Table IV.C – Urinology

5.2. List of tables for the final analysis

5.2.1. For Demographics Analysis

TABLE # Table Title

Final Analysis

Macro

Table D 1 Number of subjects enrolled into the study as well as the number of subjects excluded from ATP analyses with reasons for exclusion.

CR %ELIMLIST

Table D 2 Number of subjects by centre (Total vaccinated cohort) ST %CENTER

Table D 3 Number of subjects at each visit and list of withdrawn subjects (Total vaccinated cohort)

ST %DROPOUT

Table D 4 Number of subjects entered, completed and withdrawn with reason for withdrawal (Total vaccinated cohort)

CR %DROP_SUM

Table D 5 Summary of tracking log-sheets for all subjects initially enrolled in the primary study (Total Vaccinated Cohort)

ST %TRACKING

Table D 6 Deviation from specifications for age and intervals between study visits (Total vaccinated cohort)

ST %INT_VAL

Table D 7 Deviation from specifications for age and intervals between study visits (ATP cohort for immunogenicity)

WT %INT_VAL

Table D 8 Minimum and maximum activity dates (Total vaccinated cohort)

WT %DATE

Table D 9 Summary of demographic characteristics (Total vaccinated cohort)

ST %DEMOGRA

Table D 10 Summary of demographic characteristics (ATP cohort for Immunogenicity)

CR %DEMOGRA

Table D 11 Summary of demographic characteristics (ATP cohort for safety)

ST %DEMOGRA

Table CTRS 1

Demography for CTRS CTRS %CTR_DEMOG

CR = Within the clinical report ST = As a supplementary table or figure WT = As a working or CTRS table or figure TBD = To be done



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 5.2.2. For Safety Analysis

TABLE # in reference of annex 1

Table Title

Final Analysis

Macro

Table R 1 Number and percentage of subjects who received a vaccine dose (Total vaccinated cohort)

CR * %EXPO

Table R 2 Compliance (Total Vaccinated Cohort) ST %COMPLI Table R 3 Incidence and nature of symptoms

(solicited and unsolicited) reported during the 4-day (Days 0-3) post-vaccination period following vaccination (Total vaccinated cohort)

CR * %LOCGEN

Table R 4 Incidence and nature of grade 3 symptoms (solicited and unsolicited) reported during the 4-day (Days 0-3) post-vaccination period following vaccination (Total vaccinated cohort)

CR * %LOCGEN

Table R 5 Incidence and nature of symptoms (solicited and unsolicited) reported during the 4-day (Days 0-3) post-vaccination period following vaccination with causal relationship to vaccination (Total vaccinated cohort)

ST* %LOCGEN

Table R 6 Incidence of solicited local symptoms reported during the 4-day (Days 0-3) post-vaccination period (Total vaccinated cohort)

CR* %FREQ

Table R 7 Incidence of solicited general symptoms reported during the 4-day (Days 0-3) post-vaccination period (Total vaccinated cohort)

CR* %FREQ

Table R 8 Percentage of subjects reporting the occurrence of unsolicited symptoms classified by MEDDRA Primary System Organ Class and Preferred Term within the 31-day (Days 0-30) post-vaccination period (Total vaccinated cohort)

CR* %UNSOL

Table R 9 Percentage of subjects reporting the occurrence of grade 3 unsolicited symptoms classified by MEDDRA Primary System Organ Class and Preferred Term within the 31-day (Days 0-30) post-vaccination period (Total vaccinated cohort)

CR* %UNSOL

Percentage of subjects reporting the occurrence of unsolicited symptoms

CR* %UNSOL



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Table R 10 classified by MEDDRA Primary System

Organ Class and Preferred Term that are causally related to vaccination, within the 31-day (Days 0-30) post-vaccination period (Total vaccinated cohort)

Table R 11 Incidence of concomitant medication within the 4-day (Day 0-4) post vaccination period (Total vaccinated cohort)

CR* %CMED_INC


ST* %CMED_INC


CR* %CMED_INC


ST* %CMED_INC

Table R 15 Listing of SAEs CR %SAE Table CTRS 2 Number (%) of subjects with solicited local

symptom during the 4-day (Days 0-3) post-vaccination period (Total Vaccinated Cohort)

CTRS %FREQ

Table CTRS 3 Number (%) of subjects with solicited general symptom during the 4-Day (Day 0- 3) post-vaccination period (Total Vaccinated Cohort)

CTRS %FREQ

Table CTRS 4 Number (%) of subjects with adverse events (Total Vaccinated cohort)

CTRS %CTR_AE

Table CTRS 5 Number (%) of subjects with serious adverse events (Total Vaccinated cohort)

CTRS %CTR_SAE

CR = Within the clinical report ST = As a supplementary table or figure WT = As a working table or CTRS Table *: a complementary analysis based on the ATP cohort for safety will be provided if more than 5% of the vaccinated subjects are excluded from that cohort. The resulting tables will appear as supplemental tables.



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 5.2.3. For Persistence Analysis

TABLE # Abbreviated Title (see annex 1 for the proposed wording in the stat report)

Final Analysis

Macro

Table I 1 Anti-HBs seropositivity rates, percentage of subjects with anti-HBs antibody concentrations >=10mIU/ml and geometric mean concentrations (GMC) calculated on seropositive subjects at month 48 (LT-ATP immunogenicity cohort)

CR* %GMT

Table I 2

Seropositivity rates and geometric mean concentrations (GMC) for Anti-HAV antibodies at month 48 (LT-ATP immunogenicity cohort)

CR* %GMT

CR = Within the clinical report ST = As a supplementary table or figure WT = As a working or CTRS table or figure *: a complementary analysis based on the LT Total Vaccinated cohort will be provided. The resulting tables will appear as supplemental tables.



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 5.2.4. For Immunogenicity Analysis

TABLE # Abbreviated Title (see annex 1 for the proposed wording in the stat report)

Final Analysis

Macro

Table I 3 Seroprotection and seropositivity rates and geometric mean concentrations (GMC) calculated on seropositive subjects for Anti-HBs antibodies (ATP immunogenicity cohort) before and after the challenge dose

CR* %GMT

Table I 4 Seropositivity rates and geometric mean concentrations (GMC) calculated on seropositive subjects for Anti-HAV antibodies (ATP immunogenicity cohort) before and after the challenge dose

CR* %GMT

Table I 5 Geometric Mean Concentrations (GMC) calculated on all subjects for Anti-HBs antibodies (ATP immunogenicity cohort) before and after the challenge dose

CR* %GMT

Table I 6 Geometric mean concentrations (GMC) calculated on all subjects for Anti-HAV antibodies (ATP immunogenicity cohort) before and after the challenge dose

CR* %GMT

Table I 7 Percentage of subjects with anti-HBs antibody concentrations ≥ 3.3 mIU/ml, ≥ 10 mIU/ml, ≥ 100 mIU/ml after the challenge dose according to their post primary vaccination status (ATP Cohort for immunogenicity)

CR* %GMT

Table I 8 Percentage of subjects with anti-HBs antibody concentrations ≥ 3.3 mIU/ml, ≥ 10 mIU/ml, ≥ 100 mIU/ml after the challenge dose according to their pre challenge dose status (ATP Cohort for immunogenicity)

CR* %GMT

Table I 9 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified by GENDER (LT ATP cohort for immunogenicity)

ST* %GMT

Table I 10 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by GENDER (LT ATP cohort for immunogenicity)

ST* %GMT

Table I 11 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified by AGE† (LT ATP cohort for immunogenicity)

ST* %GMT

Table I 12 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by AGE† (LT ATP cohort for immunogenicity)

ST* %GMT

Table I 13 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified

ST* %GMT




by BMI† status(LT ATP cohort for immunogenicity) Table I 14 ANTI-HBs Seropositivity rates, proportion of subjects

with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by BMI† status (LT ATP cohort for immunogenicity)

ST* %GMT

Table I 15 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified by Smoking status† (LT ATP cohort for immunogenicity)

ST* %GMT

Table I 16 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by Smoking Status† (LT ATP cohort for immunogenicity)

ST* %GMT

Table I 17 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified by Alcohol consumption† status(LT ATP cohort for immunogenicity)

ST* %GMT

Table I 18 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by Alcohol consumption† status(LT ATP cohort for immunogenicity)

ST* %GMT

Table I 19 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified by Concomitant Medication intake status† (LT ATP cohort for immunogenicity)

ST* %GMT

Table I 20 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by Concomitant Medication intake status† (LT ATP cohort for immunogenicity)

ST* %GMT

Table I 21 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified by Medical condition† status(ATP cohort for immunogenicity)

ST* %GMT

Table I 22 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by Medical condition† status(ATP cohort for immunogenicity)

ST* %GMT

Table I 23 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified by diabetes† status (ATP cohort for immunogenicity)

ST* %GMT

Table I 24 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive

ST* %GMT




subjects) stratified by Diabetes† status (ATP cohort for immunogenicity)

Table I 25 Immune response to the challenge dose for Anti-HAV antibodies (ATP cohort for immunogenicity)

CR* %RESPONSE

Table I 26 Immune response to the challenge dose for Anti-HBs antibodies (ATP cohort for immunogenicity)

CR* %RESPONSE

Table I 27 Immune response to the challenge dose for Anti-HBs antibodies stratified based on the pre-challenge dose (ATP cohort for immunogenicity)

ST* %RESPONSE

Table I 28 Immune response to the challenge dose for Anti-HBs antibodies with antibody concentrations stratified based on the post primary vaccination status (ATP cohort for immunogenicity)

ST* %RESPONSE

Figure I 1 Reverse cumulative curves for <antibody> <concentrations> at <pre challenge dose> (<ATP Immunogenicity Cohort>)

ST* %REVCUM

Figure I 2 Reverse cumulative curves for <antibody> <concentrations> at <14 days after the challenge dose> (<ATP Immunogenicity Cohort>)

ST* %REVCUM

Figure I 3 Reverse cumulative curves for <antibody> <concentrations> at <one month after the challenge dose> (<ATP Immunogenicity Cohort>)

ST* %REVCUM

Figure I 4 Reverse cumulative curves for <antibody> <concentrations> at <pre time point> (<LT ATP Immunogenicity Cohort>)

ST* %REVCUM

Figure I 5 Anti- HBs antibody concentrations between the pre and post challenge dose (ATP cohort for immunogenicity)

ST* %REVCUM

Figure I 6 Anti-HAV antibody concentrations between the pre and post challenge dose (ATP cohort for immunogenicity)

ST* %REVCUM

Figure I 7 GMC evolution curve of anti-HAV antibodies concentrations from primary to month 48 time point(<LT ATP Immunogenicity Cohort>)

CR TBD

Figure I 8 GMC evolution curve of anti-HBs antibodies concentrations from primary to month 48 time point (<LT ATP Immunogenicity Cohort>)

CR TBD

CR = Within the clinical report ST = As a supplementary table or figure WT = As a working or CTRS table or figure *: a complementary analysis based on the Total Vaccinated cohort will be provided if more than 5% of the vaccinated subjects are excluded from that cohort. The resulting tables will appear as supplemental table




5.3. Template of tables

Table D 1 Number of subjects enrolled into the study as well as the number of subjects excluded from ATP analyses with reasons for exclusion.

Title Total Percent Twinrix Eng + Hav HBVX + VAQ

Subjects or vaccine number not allocated (code 1010 )

Total enrolled cohort Total vaccinated cohort Administration of vaccine(s) forbidden in the protocol (code 1040 )

Study vaccine dose not administered according to protocol (code 1070 )

ATP safety cohort Non compliance with blood sampling schedule (including wrong and unknown dates)(code 2090 )

Essential serological data missing (code 2100 ) Obvious incoherence or abnormality or error in data (code 2120 )

ATP immunogenicity cohort LT ATP Persistence Cohort Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines Percent = percentage of subjects in the considered ATP cohort relative to the Total vaccinated cohort. Subjects may have more than one elimination code assigned therefore for each elimination reason n (s) is provided where: n= number of subjects with the elimination code assigned excluding subjects who have been assigned a lower elimination code number s= number of subjects with the elimination code assigned



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Table D 2 Number of subjects by centre (Total vaccinated cohort)

Centre Twinrix Eng + Hav HBVX + VAQ Total n n n n % Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines n = number of subjects included in each group or in total for a given centre or for all centres. All= sum of all subjects in each group or in total (sum of all groups). % = n/All*100 Centre = GSK assigned centre number. Table D 3 Number of subjects at each visit and list of withdrawn subjects

(Total vaccinated cohort)

Group Visit N Withdrawn

Subject(N°) Reasons for withdraw

Twinrix Visit 8 Visit 9 Visit 10 Eng + Hav Visit 8 Visit 9 Visit 10 HBVX + VAQ Visit 8 Visit 9 Visit 10 Overall Visit 8 Visit 9 Visit 10 Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines N = number of subjects in each vaccine group N° = subject identification of withdraw



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Table D 4 Number of subjects entered, completed and withdrawn with reason

for withdrawal (Total vaccinated cohort)

Twinrix Eng + Hav HBVX + VAQ Total

Number of subjects enrolled Number of subjects completed Number of subjects withdrawn Reasons for withdraw: Serious Adverse Event Non-serious adverse event Protocol violation Consent withdrawal (not due to an adverse event) Migrated/moved from study area Lost to follow-up (subjects with incomplete vaccination course)

Lost to follow-up (subjects with complete vaccination course)

Others Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines Enrolled= number of subjects who were enrolled in the study Completed = number of subjects who completed visit 10 Withdrawn = number of subjects who did not come for the visit 10

Table D 5 Summary of tracking log-sheets for all subjects initially enrolled in the primary study (Total Vaccinated Cohort)

Twinrix N =

Eng + Hav N =

HBVX + VAQ N =

Total N =

n % n % n % n % Not participating in booster study Not eligible Lost to follow-up Not willing to participate due to AE or SAE Not willing to participate for other reason Died Missing Enrolled in booster study Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines N = number of subjects enrolled in the initial study n/% = number/percentage of subjects in a given category



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Table D 6 Deviation from specifications for age and intervals between study

visits (Total vaccinated cohort)

Group

Age VIS_8-VIS_9 VIS_8-VIS_10 Protocol Protocol Protocol Adapted >41 Y from 12 From 30 from 21 to 48 D to 16 D to 48 D

Twinrix N / / n % range Eng + Hav N n % range HBVX + VAQ N n % range Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines VIS = Visit Y = Years D = Days N = Total number of subjects in the considered cohort n = number of subjects out of the specified interval. % = proportion of subjects out of the specified interval among with subjects present at the considered visits. % (for age) = proportion of subjects out of the specified interval using as denominator the number of subjects enrolled.

Table D 7 Deviation from specifications for age and intervals between study visits (ATP cohort for immunogenicity)

See template Table D 6

Table D 8 Minimum and maximum activity dates (Total vaccinated cohort)

Activity Minimum Maximum number date date 80 Visit 8 month 48 90 Visit 9 month 48 + 14d 100 Visit 10 month 48 + 30d



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Table D 9 Summary of demographic characteristics (Total vaccinated cohort)

Twinrix Eng + Hav HBVX + VAQ Total Parameters or N= XXX N= XXX N= XXX N= XXX

Characteristics Categories Value or n % Value or

n % Value or

n % Value or n %

Age(Y) Mean SD Median Minimum Maximum Gender Female Male Race Black White/Caucasian Oriental Arabic/north East/south east

asian

South asian American

hispanic

Japanese Other Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines N = total number of subjects n = number of subjects in a given category Value = value of the considered parameter % = n / Number of subjects with available results x 100 SD= standard deviation Age(Y) = age expressed in years

Table D 10 Summary of demographic characteristics (ATP cohort for Immunogenicity)


Table D 11 Summary of demographic characteristics (ATP cohort for safety)





Table R 1 Number and percentage of subjects who received a vaccine dose (Total vaccinated cohort)

Total number

Twinrix N= XXX

Eng + Hav N= XXX

HBVX + VAQ N= XXX

Total (N = XXX)

Of doses received n % n % n % n %

0 1 Any Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines N = number of subjects in each group or in total included in the considered cohort n/% = number/percentage of subjects receiving the specified total number of doses in each group or in total Any = number and percentage of subjects receiving at least one dose Table R 2 Compliance (Total Vaccinated Cohort)

Doses Number NOT Number Compliance Number Compliance of according of % of % Group Doses to protocol general SS General local SS Local Twinrix Eng + Hav

HBVX + VAQ

Overall Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines SS = Symptom sheets used for the collection of local and general solicited AEs Compliance % = (number of subjects returning a symptom sheet (SS)/number of doses) x 100



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Table R 3 Incidence and nature of symptoms (solicited and unsolicited)

reported during the 4-day (Days 0-3) post-vaccination period following vaccination (Total vaccinated cohort)

Any symptom General symptoms Local symptoms 95% CI 95% CI 95% CI 95% CI Group N n % LL UL N n % LL UL N n % LL UL Twinrix Eng + Hav

HBVX + VAQ

Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines N= number of subjects with at least one administered dose n/%= number/percentage of subjects presenting at least one type of symptom at the study vaccine site 95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Table R 4 Incidence and nature of grade 3 symptoms (solicited and unsolicited) reported during the 4-day (Days 0-3) post-vaccination period following vaccination (Total vaccinated cohort)

See template Table R 3

Table R 5 Incidence and nature of symptoms (solicited and unsolicited) reported during the 4-day (Days 0-3) post-vaccination period following vaccination with causal relationship to vaccination (Total vaccinated cohort)


Table R 6 Incidence of solicited local symptoms reported during the 4-day (Days 0-3) post-vaccination period (Total vaccinated cohort)

Each Group 95 % CI

Symptom Type N n % LL UL Pain Any Grade 3 Redness (mm) Any ≥50.0mm Swelling (mm) Any ≥50.0mm N= number of subjects with at least one documented dose n/%= number/percentage of subjects reporting at least once the symptom 95%CI= Exact 95% confidence interval; LL =lower limit, UL = upper limit



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Table R 7 Incidence of solicited general symptoms reported during the 4-day

(Days 0-3) post-vaccination period (Total vaccinated cohort)

Each Group 95 % CI

Symptom Type N n % LL UL Fatigue Any Grade 3 Related Grade 3 * Related Fever/(Axillary) (°C) Any >37.5°C >38.0°C >38.5°C >39.0°C >39.5°C Related >39.5°C * Related Gastrointestinal symptoms Any Grade 3 Related Grade 3 * Related Headache Any Grade 3 Related Grade 3 * Related N= number of subjects with at least one documented dose n/%= number/percentage of subjects reporting at least once the symptom 95%CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit




Table R 8 Percentage of subjects reporting the occurrence of unsolicited symptoms classified by MEDDRA Primary System Organ Class and Preferred Term within the 31-day (Days 0-30) post-vaccination period (Total vaccinated cohort)

Primary System Organ Class (CODE)

Preferred Term (CODE)

Twinrix N= XXX

Eng + Hav N= XXX

HBVX + VAQ N= XXX

n % 95% CI n % 95% CI n % 95% CI LL UL LL UL LL UL At least one symptom

(Each body system category + 4 digit code)

Each preferred term + 4 digit code)

Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines At least one symptom = At least one symptom experienced regardless of the System Organ Class N = Number of subjects having received at least one dose n/% = Number / percentage of subjects reporting at least once a specified symptom within 31 days after vaccination day 0 to day 30 95% CI = Exact 95% confidence interval

Table R 9 Percentage of subjects reporting the occurrence of grade 3 unsolicited symptoms classified by MEDDRA Primary System Organ Class and Preferred Term within the 31-day (Days 0-30) post-vaccination period (Total vaccinated cohort)


Table R 10 Percentage of subjects reporting the occurrence of unsolicited symptoms classified by MEDDRA Primary System Organ Class and Preferred Term that are causally related to vaccination, within the 31-day (Days 0-30) post-vaccination period (Total vaccinated cohort)



Each Group 95% CI N n % LL UL



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Each Group 95% CI N n % LL UL Any Any antipyretic Prophylactic antipyretic N= number of subjects with at least one administered dose n/%= number/percentage of subjects who started to take the specified concomitant medication at least once during the

mentioned period 95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit Table R 12 Incidence of concomitant medication within the 31-day (Day 0-30) post vaccination period (Total vaccinated cohort)






Each Group 95% CI N n % LL UL Any Any antipyretic Prophylactic antipyretic N= number of subjects with at least one administered dose n/%= number/percentage of subjects who reported at least one concomitant medication during the mentioned period 95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit



Table R 15 Listing of SAEs

Group Pid Case Id

Age (Years)

Sex Verbatim

Preferred term

System Organ Class

MA type

Dose Day of onset

Duration Causality

Outcome

Twinrix Eng + Hav

HBVX + VAQ

Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines Age (Year) = Age (year) at SAE onset



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Table I 1 Anti-HBs seropositivity rates, percentage of subjects with anti-HBs

antibody concentrations >=10mIU/ml and geometric mean concentrations (GMC) calculated on seropositive subjects at month 48 (LT-ATP immunogenicity cohort)

Each Group Timing N S+ ≥ 10 mIU/ml GMC n % 95% CI n % 95% CI value 95% CI

LL UL LL UL LL UL PIII(M7)

PIII(M12) PIII(M24) PIII(M24)* PIII(M36) PIII(M48)

GMC=geometric mean antibody concentration, calculated for seropositive subjects. N = number of subjects with available results n/% = number/percentage of subjects with antibody concentrations above the specified cut-off 95% CI; LL, UL = exact 95% confidence interval; lower and upper limits PIII (M7) to PIII (M24): anti-HBs antibody concentrations tested with AUSAB ® EIA /Abbott assay with cut-off 3.3mIU/ml PIII (M24)* onwards: anti-HBs antibody concentrations tested with the validated in-house elisa assay with cut-off 3.3mIU/ml PIII (M36): Blood sampling after the third dose; 36 months after the first dose of primary vaccination course PIII (M48): Blood sampling after the third dose; (48-60) months after the first dose of primary vaccination course

Table I 2 Seropositivity rates and geometric mean concentrations (GMC) for Anti-HAV antibodies at month 48 (LT-ATP immunogenicity cohort)

Each Group Timing N S+ GMC n % 95% CI value 95% CI

LL UL LL UL PIII(M7)

PIII(M12) PIII(M24) PIII(M36) PIII(M48)

GMC=geometric mean antibody concentration, calculated for seropositive subjects. N = number of subjects with available results n/% = number/percentage of subjects with antibody concentrations above the specified cut-off 95% CI; LL, UL = exact 95% confidence interval; lower and upper limits PIII (M48): Blood sampling after the third dose;(48-60) months after the first dose of primary vaccination course




Table I 3 Seroprotection and seropositivity rates and geometric mean concentrations (GMC) calculated on seropositive subjects for Anti-HBs antibodies (ATP immunogenicity cohort) before and after the challenge dose

≥ 3.3mIU/ml ≥ 10 mIU/ML ≥ 100 mIU/ML GMC 95% CI 95% CI 95% CI

Group Timing N n % LL UL n % LL UL n % LL UL value LL UL

(Each group)

Pre

Post (Day14)

Post (Day30)

GMC=geometric mean antibody concentration, calculated for seropositive subjects. N = number of subjects with available results n/% = number/percentage of subjects with antibody concentrations above the specified cut-off 95% CI; LL, UL = exact 95% confidence interval; lower and upper limits Pre= Prior to administration of challenge dose Post (Day14) =Two weeks after the administration of challenge dose Post (Day30) =One month after the administration of challenge dose

Table I 4 Seropositivity rates and geometric mean concentrations (GMC) calculated on seropositive subjects for Anti-HAV antibodies (ATP immunogenicity cohort) before and after the challenge dose

Group Timing N ≥ 15mIU/ml GMC

n % 95%CI value 95%CI (Each group)

Pre

Post (Day14)

Post (Day30)

GMC = geometric mean antibody concentration, calculated for seropositive subjects. N = number of subjects with available results n/% = number/percentage of subjects with antibody concentrations above the specified cut-off 95% CI; LL, UL = exact 95% confidence interval; lower and upper limits Pre= Prior to administration of challenge dose Post (Day14) =Two weeks after the administration of challenge dose Post (Day30) =One month after the administration of challenge dose




Table I 5 Geometric Mean Concentrations (GMC) calculated on all subjects for Anti-HBs antibodies (ATP immunogenicity cohort) before and after the challenge dose

GMC 95% CI

Group Timing N value LL UL

(Each group) Pre

Post (Day14)

Post (Day30)

GMC=geometric mean antibody concentration, calculated for all subjects. N = number of subjects with available results 95% CI; LL, UL = exact 95% confidence interval; lower and upper limits Pre= Prior to administration of challenge dose Post (Day14) =Two weeks after the administration of challenge dose Post (Day30) =One month after the administration of challenge dose

Table I 6 Geometric mean concentrations (GMC) calculated on all subjects for Anti-HAV antibodies (ATP immunogenicity cohort) before and after the challenge dose

GMC 95%CI

Group Timing N value LL UL (Each group)

Pre

Post (Day14)

Post (Day30)

GMC = geometric mean antibody concentration, calculated for all subjects. N = number of subjects with available results n/% = number/percentage of subjects with antibody concentrations above the specified cut-off 95% CI; LL, UL = exact 95% confidence interval; lower and upper limits Pre= Prior to administration of challenge dose Post (Day14) =Two weeks after the administration of challenge dose Post (Day30) =One month after the administration of challenge dose




Table I 7 Percentage of subjects with anti-HBs antibody concentrations ≥ 3.3 mIU/ml, ≥ 10 mIU/ml, ≥ 100 mIU/ml after the challenge dose according to their post primary vaccination status (ATP Cohort for immunogenicity)

Post challenge dose (Day 30) ≥ 3.3 MIU/ML ≥ 10 MIU/ML ≥100 MIU/ML GMC 95% CI 95% CI 95% CI

Antibody Group Post primary vaccination status


Anti-HBs Twinrix <3.3 mIU/ml 3.3 - <10 mIU/ml 10 - <100 mIU/ml >=100 mIU/ml Eng +

Hav

<3.3 mIU/ml

3.3 - <10 mIU/ml 10 - <100 mIU/ml >=100 mIU/ml HBVX +

VAQ

<3.3 mIU/ml

3.3 - <10 mIU/ml 10 - <100 mIU/ml >=100 mIU/ml Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines GMC = geometric mean antibody concentration, calculated for all subjects. Antibody concentrations below the cut-off of the assays were given an arbitrary value of one half the cut-off for the purpose of calculating the GMC N = number of subjects with available results n/% = number/percentage of subjects with antibody concentrations above the specified cut-off 95% CI; LL, UL = exact 95% confidence interval; lower and upper limits Table I 8 Percentage of subjects with anti-HBs antibody concentrations ≥ 3.3

mIU/ml, ≥ 10 mIU/ml, ≥ 100 mIU/ml after the challenge dose according to their pre challenge dose status (ATP Cohort for immunogenicity)

≥ 3.3 MIU/ML ≥ 10 MIU/ML ≥ 100 MIU/ML GMC 95% CI 95% CI 95% CI

Antibody Group Pre Challenge dose status


Anti-HBs Twinrix <3.3 mIU/ml 3.3 - <10 mIU/ml >=10mIU/ml Eng +

Hav

<3.3 mIU/ml




≥ 3.3 MIU/ML ≥ 10 MIU/ML ≥ 100 MIU/ML GMC 95% CI 95% CI 95% CI

Antibody Group Pre Challenge dose status


3.3 - <10 mIU/ml >=10mIU/ml HBVX +

VAQ

<3.3 mIU/ml

3.3 - <10 mIU/ml >=10mIU/ml Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines GMC = geometric mean antibody concentration, calculated for all subjects. Antibody concentrations below the cut-off of the assays were given an arbitrary value of one half the cut-off for the purpose of calculating the GMC. N = number of subjects with available results n/% = number/percentage of subjects with antibody concentrations above the specified cut-off 95% CI; LL, UL = exact 95% confidence interval; lower and upper limits



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Table I 9 Seropositivity rates and GMCs (calculated on seropositive subjects)

for ANTI-HAV antibodies stratified by GENDER (LT ATP cohort for immunogenicity)

Group Timing N >= 15 mIU/ml GMC 95% CI 95%CI

n % LL UL Value LL UL Twinrix/F Pre

Post

Twinrix/M Pre

Post

Eng+HAV/F Pre

Post

Eng+HAV/M Pre

Post

HBVX+VAQ/F Pre

Post

HBVX+VAQ/M Pre

Post

Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines /F: Female subjects /M: Male subjects N: total number of subjects n (%): number (percentage) of subjects with anti-HAV antibody concentrations ≥15 mIU/ml GMCs: geometric mean concentrations calculated on subjects with anti-HAV antibody concentrations ≥ 15 mIU/ml 95% CI: 95% confidence intervals; LL: Lower Limit; UL: Upper Limit Pre: Blood sampling done prior to administration of challenge dose Post: Blood sampling done one month after administration of challenge dose



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Table I 10 ANTI-HBs Seropositivity rates, proportion of subjects with antibody

concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by GENDER (LT ATP cohort for immunogenicity)

Group Timing N >= 3.3 mIU/ml >= 10 mIU/ml >=100mIU/ml GMC 95% CI 95% CI 95%CI 95%CI

n % LL UL n % LL UL n % LL UL Value LL UL Twinrix/F Pre

Post

Twinrix/M Pre

Post

Eng+HAV/F Pre

Post

Eng+HAV/M Pre

Post

HBVX+VAQ/F Pre

Post

HBVX+VAQ/M Pre

Post

Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines /F: Female subjects /M: Male subjects N: total number of subjects n (%): number (percentage) of subjects with anti-HBs antibody concentrations ≥ 3.3 mIU/ml or ≥ 10 mIU/ml or ≥100mIU/ml GMCs: geometric mean concentrations calculated on seropositive subjects 95% CI: 95% confidence intervals; LL: Lower Limit; UL: Upper Limit Pre: Blood sampling done prior to administration of challenge dose Post: Blood sampling done one month after administration of challenge dose



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Table I 11 Seropositivity rates and GMCs (calculated on seropositive subjects)

for ANTI-HAV antibodies stratified by AGE† (LT ATP cohort for immunogenicity)


n % LL UL Value LL UL Twinrix/A1 Pre

Post

Twinrix/A2 Pre

Post

Twinrix/A3 Pre

Post

Eng+HAV/A1 Pre

Post

Eng+HAV/A2 Pre

Post

Eng+HAV/A3 Pre

Post

HBVX+VAQ/A1 Pre

Post

HBVX+VAQ/A2 Pre

Post

HBVX+VAQ/A3 Pre

Post

Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines /A1: Subjects aged ≤ 50 years of age /A2: Subjects aged between and including, 51 to 60 years of age /A3: Subjects aged ≥ 61 years of age †Age: Age at first vaccine dose in the primary time point N: number of subjects with available results n (%): number (percentage) of subjects with anti-HAV antibody concentration ≥ 15 mIU/ml GMC: Geometric mean concentrations calculated on subjects with anti-HAV antibody concentrations ≥ 15 mIU/ml 95% CI: 95% confidence interval; LL: Lower Limit, UL: Upper Limit Pre: Blood sampling done prior to administration of challenge dose Post: Blood sampling done one month after administration of challenge dose




Table I 12 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by AGE† (LT ATP cohort for immunogenicity)

See template Table I 11

Table I 13 Seropositivity rates and GMCs (calculated on seropositive subjects)

for ANTI-HAV antibodies stratified by BMI† status (LT ATP cohort for immunogenicity)


n % LL UL Value LL UL Twinrix/B1 Pre

Post

Twinrix/B2 Pre

Post

Twinrix/B3 Pre

Post

Eng+HAV/B1 Pre

Post

Eng+HAV/B2 Pre

Post

Eng+HAV/B3 Pre

Post

HBVX+VAQ/B1 Pre

Post

HBVX+VAQ/B2 Pre

Post

HBVX+VAQ/B3 Pre

Post



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines /B1: Subjects with BMI < 25 kg/m2 (Healthy) /B2: Subjects with BMI 25 kg/ m2 to < 30 kg/ m2 (Overweight) /B3: Subjects with BMI ≥ 30 kg/ m2 (Obese) N: number of subjects with available results n (%): number (percentage) of subjects with anti-HAV antibody concentration ≥ 15 mIU/ml GMC: Geometric mean concentrations calculated on subjects with anti-HAV antibody concentrations ≥ 15 mIU/ml 95% CI: 95% confidence interval; LL: Lower Limit, UL: Upper Limit †BMI: Stratification based on data collected in the primary study Pre: Blood sampling done prior to administration of challenge dose Post: Blood sampling done one month after administration of challenge dose

Table I 14 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by BMI† status (LT ATP cohort for immunogenicity)

See template Table I 13




Table I 15 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified by Smoking status† (LT ATP cohort for immunogenicity)


n % LL UL Value LL UL Twinrix/SY Pre

Post

Twinrix/SN Pre

Post

Eng+HAV/SY Pre

Post

Eng+HAV/SN Pre

Post

HBVX+VAQ/SY Pre

Post

HBVX+VAQ/SN Pre

Post

Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines /SY: Subjects who smoke /SN: Subjects who do not smoke N: number of subjects with available results n (%): number (percentage) of subjects with anti-HAV antibody concentration ≥ 15 mIU/ml GMC: Geometric mean concentrations calculated on subjects with anti-HBs antibody concentrations ≥ 15 mIU/ml 95% CI: 95% confidence intervals; LL: Lower Limit, UL: Upper Limit †Smoking Status: Stratification based on data collected in the primary study Pre: Blood sampling done prior to administration of challenge dose Post: Blood sampling done one month after administration of challenge dose




Table I 16 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by Smoking Status† (LT ATP cohort for immunogenicity)

See Template Table I 15

Table I 17 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified by Alcohol consumption† status (LT ATP cohort for immunogenicity)


n % LL UL Value LL UL Twinrix/L1 Pre

Post

Twinrix/L2 Pre

Post

Twinrix/L3 Pre

Post

Eng+HAV/L1 Pre

Post

Eng+HAV/L2 Pre

Post

Eng+HAV/L3 Pre

Post

HBVX+VAQ/L1 Pre

Post

HBVX+VAQ/L2 Pre

Post

HBVX+VAQ/L3 Pre

Post



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines /L1: Subjects who do not consume or mildly consume alcohol (0 - 3) /L2: Subjects who consume alcohol moderately (4 - 21) /L3: Subjects who consume alcohol heavily (> 21) N: number of subjects with available results n (%): number (percentage) of subjects with anti-HAV antibody concentration ≥ 15 mIU/ml GMC: Geometric mean concentrations calculated on subjects with anti-HAV antibody concentrations ≥ 15 mIU/ml 95% CI: 95% confidence intervals; LL: Lower Limit, UL: Upper Limit †Alcohol Consumption: Stratification based on data collected in the primary study Pre: Blood sampling done prior to administration of challenge dose Post: Blood sampling done one month after administration of challenge dose

Table I 18 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by Alcohol consumption† status(LT ATP cohort for immunogenicity)


Table I 19 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified by Concomitant Medication intake status† (LT ATP cohort for immunogenicity)


n % LL UL Value LL UL Twinrix/MY Pre

Post

Twinrix/MN Pre

Post

Eng+HAV/MY Pre

Post

Eng+HAV/MN Pre

Post

HBVX+VAQ/MY Pre Post

HBVX+VAQ/MN Pre

Post



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines /MY: Subjects who took concomitant medication /MN: Subjects who did not take any concomitant medication N: number of subjects with available results n (%): number (percentage) of subjects with anti-HAV antibody concentration ≥ 15 mIU/ml GMC: Geometric mean concentrations calculated on subjects with anti-HAV antibody concentrations ≥ 15 mIU/ml 95% CI: 95% confidence intervals; LL: Lower Limit, UL: Upper Limit † Concomitant Medication intake status: Stratification based on data collected in the primary study Pre: Blood sampling done prior to administration of challenge dose Post: Blood sampling done one month after administration of challenge dose

Table I 20 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by Concomitant Medication intake status† (LT ATP cohort for immunogenicity)


Table I 21 Seropositivity rates and GMCs (calculated on seropositive subjects)

for ANTI-HAV antibodies stratified by Medical condition† status(ATP cohort for immunogenicity)


n % LL UL Value LL UL Twinrix/P Pre

Post

Twinrix/C Pre

Post

Twinrix/N Pre

Post

Eng+HAV/P Pre

Post

Eng+HAV/C Pre

Post

Eng+HAV/N Pre





n % LL UL Value LL UL Post

HBVX+VAQ/P Pre

Post

HBVX+VAQ/C Pre

Post

HBVX+VAQ/N Pre

Post

Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines /P: Subjects who had a medical condition in the past /C; Subjects who had a current medical condition /N: Subjects who did not have any medical condition N: number of subjects with available results n (%): number (percentage) of subjects with anti-HAV antibody concentration ≥ 15 mIU/ml GMC: Geometric mean concentrations calculated on subjects with anti-HAV antibody concentrations ≥ 15 mIU/ml 95% CI: 95% confidence intervals; LL: Lower Limit, UL: Upper Limit †Medical condition: stratification based on the data collected in the primary study Pre: Blood sampling done prior to administration of challenge dose Post: Blood sampling done one month after administration of challenge dose

Table I 22 ANTI-HBs Seropositivity rates, proportion of subjects with antibody

concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by Medical condition† status (ATP cohort for immunogenicity)


Table I 23 Seropositivity rates and GMCs (calculated on seropositive subjects) for ANTI-HAV antibodies stratified by diabetes† status (ATP cohort for immunogenicity)


n % LL UL Value LL UL Twinrix/DY Pre

Post





n % LL UL Value LL UL Twinrix/DN Pre

Post

Eng+HAV/DY Pre

Post

Eng+HAV/DN Pre

Post

HBVX+VAQ/DY Pre

Post

HBVX+VAQ/DN Pre

Post

Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines /DY = Diabete/Yes /DN = Diabete/No N: number of subjects with available results n (%): number (percentage) of subjects with anti-HAV antibody concentration ≥ 15 mIU/ml GMC: Geometric mean concentrations calculated on subjects with anti-HAV antibody concentrations ≥ 15 mIU/ml 95% CI: 95% confidence intervals; LL: Lower Limit, UL: Upper Limit †Diabetes: stratification based on the data collected in the primary study Pre: Blood sampling done prior to administration of challenge dose Post: Blood sampling done one month after administration of challenge dose

Table I 24 ANTI-HBs Seropositivity rates, proportion of subjects with antibody concentrations ≥3.3mIU/ml,≥10mIU/ml and ≥100mIU/ml and GMCs (calculated on seropositive subjects) stratified by Diabetes† status (ATP cohort for immunogenicity)




111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Table I 25 Immune response to the challenge dose for Anti-HAV antibodies

(ATP cohort for immunogenicity)

Immune response to the challenge dose

95% CI Group Pre-vaccination

status N n % LL UL

Twinrix S- S+ (<100mIU/ml) S+ (>=100mIU/ml) Total Eng + Hav

S-

S+ (<100mIU/ml) S+ (>=100mIU/ml) Total HBVX + VAQ

S-

S+ (<100mIU/ml) S+ (>=100mIU/ml) Total Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines S- = seronegative subjects (antibody concentration < 15mIU/ml for anti-HAV) prior to vaccination S+ = seropositive subjects (antibody concentration >= 15mIU/ml for anti-HAV) prior to vaccination Total = subjects either seropositive or seronegative at pre-vaccination Challenge Dose response defined as: For initially seronegative subjects, antibody concentration greater than or equal the cut-off (>=15mIU/ml) For initially seropositive subjects with pre-vaccination antibody concentration < 100mIU/ml: antibody concentration at least four times the pre-vaccination antibody concentration For initially seropositive subjects with pre-vaccination antibody concentration >=100mIU/ml: antibody concentration at least two times the pre-vaccination antibody concentration N = number of subjects with both pre- and post-vaccination results available n/% = number/percentage of responders 95% CI = exact 95% confidence interval; LL = lower limit, UL = upper limit




Table I 26 Immune response to the challenge dose for Anti-HBs antibodies (ATP cohort for immunogenicity)



status N n % LL UL

Twinrix S- S+ Total Eng + Hav

S-

S+ Total HBVX + VAQ

S-

S+ Total Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines S- = seronegative subjects (antibody concentration < 3.3mIU/ml for anti-HBs) prior to vaccination S+ = seropositive subjects (antibody concentration >= 3.3mIU/ml for anti-HBs) prior to vaccination Total = subjects either seropositive or seronegative at pre-vaccination Challenge Dose response defined as: For initially seronegative subjects, antibody concentration greater than or equal 10mIU/ml(>=10mIU/ml) For initially seropositive: antibody concentration at least four times the pre-vaccination antibody concentration N = number of subjects with both pre- and post-vaccination results available n/% = number/percentage of responders 95% CI = exact 95% confidence interval; LL = lower limit, UL = upper limit Table I 27 Immune response to the challenge dose for Anti-HBs antibodies stratified based on the pre-challenge dose (ATP cohort for immunogenicity)



status N n % LL UL

Twinrix S- S+(3.3mIU/ml - <10mIU/ml) S+(≥10mIU/ml) Total Eng + Hav

S-

S+(3.3mIU/ml - <10mIU/ml) S+(≥10mIU/ml) Total






status N n % LL UL

HBVX + VAQ

S-

S+(3.3mIU/ml - <10mIU/ml) S+(≥10mIU/ml) Total Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines S- = seronegative subjects (antibody concentration < 3.3mIU/ml for anti-HBs) prior to vaccination S+ = seropositive subjects (antibody concentration >= 3.3mIU/ml for anti-HBs) prior to vaccination Total = subjects either seropositive or seronegative at pre-vaccination Challenge Dose response defined as: For initially seronegative subjects, antibody concentration greater than or equal to 10mIU/ml(>=10mIU/ml) For initially seropositive: antibody concentration at least four times the pre-vaccination antibody concentration N = number of subjects with both pre- and post-vaccination results available n/% = number/percentage of responders 95% CI = exact 95% confidence interval; LL = lower limit, UL = upper limit Table I 28 Immune response to the challenge dose for Anti-HBs antibodies with antibody concentrations stratified based on the post primary vaccination status (ATP cohort for immunogenicity)


95% CI Group Post-Primary vaccination

status N n % LL UL

Twinrix S- S+(3.3mIU/ml-<10mIU/ml) S+(10mIU/ml-<100mIU/ml) S+(≥100mIU/ml) Total Eng + Hav

S-

S+(3.3mIU/ml-<10mIU/ml) S+(10mIU/ml-<100mIU/ml) S+(≥100mIU/ml) Total HBVX + VAQ

S-

S+(3.3mIU/ml-<10mIU/ml) S+(10mIU/ml-<100mIU/ml) S+(≥100mIU/ml) Total



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines S- = seronegative subjects (antibody concentration < 3.3mIU/ml for anti-HBs) prior to vaccination S+ = seropositive subjects (antibody concentration >= 3.3mIU/ml for anti-HBs) prior to vaccination Total = subjects either seropositive or seronegative at pre-vaccination Challenge Dose response defined as: For initially seronegative subjects, antibody concentration greater than or equal to 10mIU/ml (>=10mIU/ml) For initially seropositive: antibody concentration at least four times the pre-vaccination antibody concentration N = number of subjects with both pre- and post-vaccination results available n/% = number/percentage of responders 95% CI = exact 95% confidence interval; LL = lower limit, UL = upper limit



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Figure I 1 Reverse cumulative curves for <antibody> <concentrations> at <pre

challenge dose> (<ATP Immunogenicity Cohort>)



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Figure I 2 Reverse cumulative curves for <antibody> <concentrations> at <14

days after the challenge dose> (<ATP Immunogenicity Cohort>)



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Figure I 3 Reverse cumulative curves for <antibody> <concentrations> at <one

month after the challenge dose> (<ATP Immunogenicity Cohort>)



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Figure I 4 Reverse cumulative curves for <antibody> <concentrations> at <pre

time point> (<LT ATP Immunogenicity Cohort>)



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Figure I 5 Anti- HBs antibody concentrations between the pre and post

challenge dose (ATP cohort for immunogenicity)

Anti-HBs antibody concentrations (MIU/ML)

Post Challenge

1

10

100

1000

10000

100000

1000000

Pre Challenge

1 10 100 1000 10000

Figure I 6 Anti-HAV antibody concentrations between the pre and post

challenge dose (ATP cohort for immunogenicity)

See Template Figure I 5



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Figure I 7 GMC evolution curve of anti-HAV antibodies concentrations from primary to month 48 time point(<LT ATP Immunogenicity Cohort>)

Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Figure I 8 GMC evolution curve of anti-HBs antibodies concentrations from primary to month 48 time point (<LT ATP Immunogenicity Cohort>)

Twinrix = Subjects who received the Twinrix vaccine Eng + Hav = Subjects who received the Engerix and Havrix vaccines HBVX + VAQ = Subjects who received the HB VAX PRO and Vaqta vaccines PIII(M7) to PIII(M24) : anti-HBs antibody concentrations tested with AUSAB ® EIA /Abbott assay with cut-off 3.3mIU/ml PIII(M24): anti-HBs antibody concentrations retested with the validated in-house assay with cut-off 3.3mIU/ml PIII(M36) to PIII(M48) : anti-HBs antibody concentrations tested with the validated in-house assay with cut-off 3.3mIU/ml



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 Table CTRS 1 Demography for CTRS

Number of subjects Twinrix Eng + Hav HBVX + VAQ Planned, N Randomised, N (Total Vaccinated Cohort) Completed, n (%) Total Number Subjects Withdrawn, n (%) Withdrawn due to Adverse Events, n (%) Withdrawn due to Lack of Efficacy, n (%) Withdrawn for other reasons, n (%) Demographics Twinrix Eng + Hav HBVX + VAQ N (Total Vaccinated Cohort) Females: Males Mean Age, years (SD) White/Caucasian, n (%)

Table CTRS 2 Number (%) of subjects with solicited local symptom during the 4-day (Days 0-3) post-vaccination period (Total Vaccinated Cohort)

Event Intensity Each Group(N=XXX) n % 95% CI LL UL PAIN Any Grade 3 REDNESS Any ≥ 50 mm SWELLING Any ≥ 50 mm N = number of subjects with local Symptom Sheets completed n/% = number/percentage of subjects reporting a specified symptom 95%CI, LL and UL = Exact 95% confidence interval, lower and upper limit Any = all reports of the specified symptom irrespective of intensity grade and relationship to vaccination




Table CTRS 3 Number (%) of subjects with solicited general symptom during the 4-Day (Day 0- 3) post-vaccination period (Total Vaccinated Cohort)

Event Intensity Each Group(N=XXX) n % 95% CI LL UL FATIGUE Any Grade 3 Related FEVER Any (≥ 37.5°C) (Oral or Axillary) > 39.5°C Related GASTROINTESTINAL Any SYMPTOMS Grade 3 Related HEADACHE Any Grade 3 Related N = number of subjects with general Symptom Sheets completed n/% = number/percentage of subjects reporting a specified symptom 95%CI, LL and UL = Exact 95% confidence interval, lower and upper limit Any = all reports of the specified symptom irrespective of intensity grade and relationship to vaccination

Table CTRS 4 Number (%) of subjects with adverse events (Total Vaccinated cohort)

Most frequent adverse events - On-Therapy (occuring within day 0-30 following vaccination)

Twinrix N = XXX

Eng + Hav N = XXX

HBVX + VAQ N = XXX

Subjects with any AE(s), n (%) Each AE

Table CTRS 5 Number (%) of subjects with serious adverse events (Total Vaccinated cohort)

All SAEs Twinrix N = XXX

Eng + Hav N = XXX

HBVX + VAQ N = XXX

Subjects with any SAE(s), n (%) [n related] Each SAE All fatal SAEs Twinrix

N = XXX Eng + Hav N = XXX

HBVX + VAQ N = XXX

Subjects with any SAE(s), n(%) [n related]



111572 (HAB-168 BST 160) 111149 (HAB-160 BST) CONFIDENTIAL Date: 12 Mar 2009 6. ANNEX 2: CRITERIA FOR ELIMINATING SUBJECTS

FROM STAT ANALYSES

Refer Elim code specifications document.



This section contained Principal Investigator’s Curriculum Vitae and has been excluded to

protect Principal Investigator privacy.

In February 2013, GlaxoSmithKline (GSK) announced a ... › ctr-gsk-7381 › 111149 › e... ·...

Documents

Transcript of In February 2013, GlaxoSmithKline (GSK) announced a ... › ctr-gsk-7381 › 111149 › e... ·...