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

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Patience Burke
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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: /049 (-049) Title: An open randomized study to evaluate the immunogenicity and reactogenicity of SmithKline Beecham Biologicals' combined hepatitis A / hepatitis B vaccine compared to separate vaccinations with commercially available hepatitis A and hepatitis B vaccines of SmithKline Beecham Biologicals, when injected according to a 0, 7, 21 day schedule in healthy adult volunteers. Rationale: The immune response after administration of three vaccine doses of a combined Hepatitis A and B () vaccine within three weeks was evaluated and compared to the respective monovalent hepatitis A (HAV) and hepatitis B (HBV) vaccines. Phase: IIIb Study Period: 28 April 1997 to 3 February 1999 Study Design: Open, randomised (1:1), controlled, multi-centre study with two groups. Centres: Four centres in Germany and four centres in United Kingdom. Indication: To protect healthy adult volunteers against hepatitis A and hepatitis B infections. Treatment: The study groups were: group: received vaccine at days 0, 7, 21, 365. HAV+HBV group: received HAV (1440 EL.U) and HBV vaccines at day 0, HBV vaccine at day 7 and 21, and a booster dose of HBV and HAV vaccines at day 365. The vaccines were administered intramuscularly in the deltoid region. Objectives: To evaluate the immunogenicity of combined hepatitis A and hepatitis B vaccine administered according the 0, 7, 21 day vaccination schedule and booster at month 12, by measuring the anti-hepatitis A virus (anti-hav) and anti-hepatitis B surface antigen (anti-hbs) antibody levels at month 0, 1, 2, 3, 12 and 13. Primary Outcome/Efficacy Variable: Proportion of subjects with anti-hav antibody concentrations 33 miu/ml (seroconversion rate) and with anti-hbs antibody concentrations 10 miu/ml (seroprotection rate) observed at month 1, i.e. one week after last vaccination of the primary course. Secondary Outcome/Efficacy Variable(s): Seroconversion and seroprotection rates at any other visit, i.e. after month 2, 3, 12, and 13 Geometric Mean Concentrations (GMCs) at any visit. Number of withdrawals, The incidence rates of local and general symptoms after each injection and overall, The frequency, intensity and relationship of each individual solicited symptom. The combined response was defined as the proportion of subjects with anti-hav antibody concentrations 33 miu/ml and with anti- HBs antibody concentrations 10 miu/ml. Statistical Methods: The analyses were performed on the According-To-Protocol (ATP) cohort for immunogenicity and the ATP cohort for safety. The Intent-To-Treat (ITT) cohort included all subjects vaccinated in the study for whom data were available. The ATP cohort for immunogenicity included all subjects who met all eligibility criteria, complying with the procedures defined in the protocol for whom assay results were available for antibodies against at least one study vaccine antigen component for at least one blood-sampling time point and who were initially seronegative for both anti-hav and anti-hbs antibodies. As a consequence, seropositivity and seroconversion rates are equivalents. The ATP cohort for safety included all subjects, who had received at least one dose of study vaccine according to their random assignment for whom at least one symptom sheet has been received, for whom vaccine has been administered according to the protocol, who had not received a vaccine not specified or forbidden in the protocol. Analysis of immunogenicity: The analysis of immunogenicity was performed on the ATP cohort for immunogenicity. The seroconversion rates for anti-hav, seroprotection rates for anti-hbs and GMCs for anti-hbs and anti-hav antibodies were calculated with their 95% Confidence Intervals (CIs) for all time points for which blood samples were taken. For anti-hav seroconversion, antibody concentrations below the cut-offs were given an arbitrary value of half the cut off for analysis purposes. In addition to the above analysis, combined response (i.e. the number of subjects who were seropositive for anti-hav and seroprotected for anti-hbs antibodies) of the two groups were also compared. For anti-hav seroconversion, the primary objective (equivalence between group 1 and group 2) will be met if the lower limit of the 95 CI of the difference between (group 1 group 2) seroconversions is above 5%. 1

2 For anti-hbs seroprotection, the primary objective (equivalence between group 1 and group 2) will be met if the lower limit of the 95 CI of the difference between (group 1 group 2) seroconversions is above 10%. For the combined anti-hav anti-hbs response, the primary objective will be met if the lower limit of the 95% CI of (group 1 group 2) combined response is above 10%. Analysis of safety: The analysis of safety was performed on the ATP cohort for safety. For the ATP cohort for safety, the safety response variables were analysed with percentages, exact 95% CIs. The incidence of symptoms was calculated on the number of subjects reporting symptoms (i.e. across doses) over the entire follow-up period after each vaccine dose (4 days). For each group, the incidence of solicited local symptoms over the entire follow-up period (4 days) was calculated in addition to intensity. For each group, the incidence of solicited general symptoms over the entire follow-up period (4 days) was calculated in addition to intensity and relationship. The occurrence of unsolicited adverse within 30 days after vaccination were calculated per group by WHO Body systems. The number of subjects who reported at least one serious adverse event was reported. Study Population: Healthy male and female volunteers between the ages of years at first vaccination and who had negative concentrations for anti-hav, anti-hbs and/or anti-hepatitis B core antigen (anti-hbc) antibodies at screening. HAV+HBV Number of Subjects: Planned, N Randomised, N (ITT cohort) Completed, n (%) 211 (88.3) 223 (92.9) Total Number Subjects Withdrawn, n (%) 28 (11.7) 17 (7.1) Withdrawn due to Adverse Events n (%) 2 (0.8) 1 (0.4) Withdrawn due to Lack of Efficacy n (%) Not applicable Not applicable Withdrawn for other reasons n (%) 26 (10.9) 16 (6.7) Demographics HAV+HBV N (ITT cohort) Females: Males 132: :129 Mean Age, years (SD) 25.7 (6.45) 27.0 (7.31) White, n (%) 234 (97.9) 233 (97.1) Differences of the anti-hav seroconversion and anti-hbs seroprotection rates between the study groups at Month 1 (ATP cohort for immunogenicity) Antibody Difference (%) LL (%) UL (%) Anti-HAV * 2.74 Anti-HBs * 5.76 Difference (%): Difference of Rates between groups "" and "HAV+HBV" in % LL (%): Lower Limit of the 95%-CI Difference of Rates between groups UL (%): Upper Limit of the 95%-CI Difference of Rates between groups *equivalence criteria met Anti-HAV antibody concentrations and seropositivity rates at Month 1 (ATP cohort for immunogenicity) Group N S+ 95% CI GMC (miu/ml) 95% CI n % HAV+HBV n (%)= number (percentage) of subjects with Anti-HAV antibody concentrations 33 miu/ml Anti-HBs antibody concentrations and seroprotection (SP) rates at Month 1 (ATP cohort for immunogenicity) Group N SP 95% CI GMC (miu/ml) 95% CI n % HAV+HBV

3 n (%)= number (percentage) of subjects with Anti-HBs antibody concentrations 10 MIU/ml Comparison between the two groups for combined response (for anti-hav and anti-hbs antibodies) at month 1 (ATP cohort for immunogenicity) group HAV+HBV group Difference of combined response 95% CI N = 211 N = 192 ( group HAV+HBV group) % 83.33% -1,34% -9.02* % CI LL, UL = 95% confidence interval of lower and upper limits *equivalence criteria met Combined response for anti-hav and anti-hbs antibodies at Month 1 (ATP cohort for immunogenicity) Group N Combined response n % 95 % CI LL UL HAV+HBV n (%) = number (percentage) of responders for both antigens (i.e. number of subjects with anti-hav antibody concentrations 33 miu/ml and with anti-hbs antibody concentrations 10 miu/ml) 95% CI = exact 95% confidence intervals; LL, UL: lower and upper limits Seropositivity rates and GMCs of anti-hav antibodies (ATP cohort for immunogenicity) Group Timing N S+ 95% CI GMC 95% CI n % (miu/ml) SCREENING* POST III(M1) POST III(M2)* POST III(M3)* POST III(M12)* POST IV(M13)* HAV + HBV SCREENING* POST III(M1) POST III(M2)* POST III(M3)* POST III(M12)* POST IV(M13)* *:Secondary endpoints n (%)= number (percentage) of subjects with anti-hav antibody concentrations 33 miu/ml Post III (Mx) = Blood sampling timepoint after third vaccination; at Month x Post IV (Mx) = Blood sampling timepoint after booster vaccination; at Month x Month 12 and Month 13 results were not available in the clinical study report Seroprotection (SP) rates and GMCs of anti-hbs antibodies (ATP cohort for immunogenicity) Group Timing N SP 95% CI GMC 95% CI n % (miu/ml) SCREENING* POST III(M1) POST III(M2)* POST III(M3)* POST III(M12)* POST IV(M13)*

4 HAV+HBV SCREENING* POST III(M1) POST III(M2)* POST III(M3)* POST III(M12)* POST IV(M13)* *:Secondary endpoints n (%)= number (percentage) of subjects with Anti-HBs antibody concentrations 10 miu/ml) Post III (Mx): Blood sampling timepoint after third vaccination, at Month x Post IV (Mx) = Blood sampling timepoint after booster vaccination; at Month x Secondary Outcome Variable(s): Incidence of solicited local symptoms for the 4 day (days 0-3) follow-up period after vaccination (ATP cohort for safety) Dose Group Intensity N Redness Soreness Swelling n % 95% CI n % 95% CI n % 95% CI 1 Any HAV+HBV Any Any HAV+HBV Any Any HAV+HBV Any Across Any doses Grade HAV+HBV Any Grade N = Number of subjects with at least one local symptom sheet completed n (%)= Number (percentage) of subjects with at least one specific solicited local symptom reported 95% CI = 95% Confidence Interval; LL, UL: lower and upper limits Grade 3 pain = spontaneously painful Grade 3 redness and swelling = > 50 mm Number of documented doses reporting at least one local symptom regardless of the number of injections (a symptom will be counted once even if reported on multiple sites) Secondary Outcome Variable(s): Incidence of solicited general symptoms for the 4-day (days 0-3) follow-up period after vaccination (ATP cohort for safety) Dose Group Intensity N Fatigue Fever (axillary) Headache n % 95% CI n % 95% CI n % 95% CI 1 Any HAV+HBV Any Any HAV+HBV Any Any HAV+HBV Any Across doses HAV+HBV Any Grade Related Any Grade Related Dose Group Intensity N Malaise Nausea Vomiting n % 95% CI 95% CI 95% CI 1 Any

5 HAV+HBV Any Any HAV+HBV Any Any HAV+HBV Any Across doses HAV+HBV Any Grade Related Any Grade Related N = Number of subjects with at least one general symptom sheet completed n (%)= Number (percentage) of subjects with at least one specific solicited general symptom reported 95% CI = 95% Confidence Interval; LL, UL: lower and upper limits Fever (axillary route) = temperature 37.5 C Grade 3 fever = temperature > 39.0 C Grade 3 fatigue/ headache/ malaise/ vomiting/ nausea = specific symptom that prevented normal activity Related = Related = the investigator determined that there was a reasonable possibility that the study vaccine contributed to the solicited general event Safety Results: Number (%) of subjects with unsolicited adverse events (classified by WHO Body systems) (ATP cohort for safety) Most frequent adverse events On Therapy- (occurring within 30 days following vaccination group N = 221 Subjects with any AE(s), n (%) 69 (31.2) 58 (27.6) Resistance mechanism 17 (7.7 ) 13 (6.2 ) Gastrointestinal system 13 (5.9 ) 12 (5.7) Respiratory system 17 (7.7 ) 6 (2.9 ) Central and peripheral nervous system 11 (5.0 ) 6 (2.9 ) Body as a whole general 10 (4.5 ) 6 (2.9 ) Platelet bleeding and clotting 7 (3.2 ) 9 (4.3 ) Application site 6 (2.7 ) 9 (4.3 ) Musculoskeletal system 3 (1.4 ) 4 (1.9 ) Skin and appendages 2 (0.9 ) 5 (2.4 ) Vision 4 (1.8 ) 1 (0.5 ) Reproductive female 3 (1.4 ) 0 (0.0 ) Safety results: Number (%) of subjects with serious adverse events (SAEs) (Total vaccinated cohort) n (%) [n considered by the investigator to be related to study medication] HAV+HBV group N = 210 All SAEs group N = 239 Subjects with any SAE(s), n (%) [related] 3 (1.3) [1] 2 (0.8) [0] Fracture distal radius (left) 0 (0.0) [0] 1 (0.4) [0] Headache 1 (0.4) [1] 0 (0.0) [0] Malleolar fracture 1 (0.4) [0] 0 (0.0) [0] Numbness of face (left) 1 (0.4) [1] 0 (0.0) [0] Pelvic infection 0 (0.0) [0] 1 (0.4) [0] Pregnancy terminated by miscarriage 1 (0.4) [0] 0 (0.0) [0] Raptured ligament 1 (0.4) [0] 0 (0.0) [0] Vomiting 1 (0.4) [1] 0 (0.0) [0] HAV+HBV group N = 240 Fatal SAEs group N = 239 Subjects with fatal SAE(s), n (%) [related] 0 (0.0) [0] 0 (0.0) [0] HAV+HBV group N = 240 5

6 Conclusion: See publications below Publications: Nothdurft HD et al. Accelerated vaccination schedules provide protection against hepatitis A and B in last-minute travelers. J Travel Med; 2004; 11(4): Nothdurft HS et al. Rapid protection against hepatitis A and B using an accelerated vaccination schedule. Comparison of a combined vaccine, Twinrix with separate vaccines. Biodrugs; 2003; 17(Suppl.1): Date Updated: 09-Aug

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

Study No.: Title: Rationale: Phase: Study Period: Study Design: Center: Indication: Treatment: Objective: Primary Outcome/Efficacy Variable: The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product.