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

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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.: /007 (DTPw-HBV=Hib-MenAC-TT-007) Title: A phase III, open, randomized, controlled primary vaccination study to demonstrate the non-inferiority of GlaxoSmithKline (GSK) Biologicals Hib-MenAC vaccine when mixed extemporaneously and given as a single injection with GSK Biologicals Tritanrix -HepB vaccine as compared to Tritanrix -HepB/Hiberix with respect to the immunogenicity of the hepatitis B antigen, when administered to healthy infants at 6, 10 and 14 weeks of age after a birth dose of hepatitis B vaccine. Hib-MenAC: GSK Biologicals combined Haemophilus influenzae type b and N. meningitidis serogroup A and C vaccine. DTPw-HBV (Tritanrix -HepB): GSK Biologicals combined diphtheria, tetanus, whole cell pertussis and hepatitis B vaccine. Hib (Hiberix ): GSK Biologicals Haemophilus influenzae type b vaccine. Engerix -B: GSK Biologicals hepatitis B vaccine. Rationale: The aim of this study was to evaluate the immunogenicity and safety of a combined DTPw-HBV/Hib-MenAC vaccine administered according to a 6, 10, 14 weeks vaccination schedule in healthy infants who had received hepatitis B vaccine at birth. Phase: III. Study Period: 13 October 2004 to 25 July 2005 Study Design: Open label, randomized controlled with 2 balanced groups (1:1). Centers: Four study sites in South Africa. Indication: Primary immunization against diphtheria, tetanus, pertussis, hepatitis B and Hib diseases of healthy infants at 6, 10 and 14 weeks of age after a birth dose of hepatitis B vaccine. Treatment: The study groups were as follows: Group : subjects received DTPw-HBV extemporaneously mixed with Hib-MenAC vaccine, Group : subjects received DTPw-HBV extemporaneously mixed with Hib vaccine. The vaccines were administered by intramuscular injection into the anterolateral quadrant of the left thigh. A birth dose of hepatitis B vaccine was provided to all subjects. Objectives: To demonstrate non-inferiority of a Hib-MenAC vaccine extemporaneously mixed with DTPw-HBV vaccine and administered as a single injection, as compared to the control group receiving a combined DTPw-HBV/Hib vaccine with respect to the immunogenicity of the hepatitis B antigen (HBs), when administered as a 3-dose primary vaccination at 6, 10, 14 weeks of age to infants who received a birth dose of hepatitis B vaccine. Non-inferiority objective was demonstrated if the lower limit of the standardized asymptotic for the difference was above -10%. Primary Outcome/Efficacy Variable: One month after Dose 3 of the combined vaccine: seroprotection against HBs (defined as anti-hbs antibody concentrations 10 miu/ml). Secondary Outcome/Efficacy Variable(s): One month after Dose 3: Immunogenicity Seroprotection or seropositivity defined as: Anti-diphtheria antibody concentrations 0.1 IU/mL by ELISA or IU/mL by VERO-cell neutralization test, Anti-tetanus antibody concentrations 0.1 IU/mL, Anti-polyribosylribitol phosphate (anti-prp) antibody concentrations 0.15 μg/ml, Serum bactericidal antibody titers against N. meningitidis serogroup C and A (rsba*-menc and rsba-mena) 1:8**, Anti-polysaccharide C and A (anti-psc and anti-psa) antibody concentrations 0.3 μg/ml*. Vaccine response to the Bordetella pertussis (BPT) antigen defined as the appearance of antibodies (anti-bpt antibody concentrations 15 EL.U/mL) in initially seronegative subjects or post-vaccination anti-bpt antibody concentrations the pre-vaccination anti-bpt concentrations in initially seropositive subjects. *Serum bactericidal assay using baby rabbit complement ** In a random sub-sample of 25% of subjects in the control vaccine group receiving DTPw-HBV/Hib () and in all

2 subjects in the study vaccine group receiving DTPw-HBV/Hib-MenAC (SN+AC). Safety Occurrence of solicited symptoms (local and general) during the 4-day (Day 0-3) follow-up period after each dose (fever only after hepatitis B vaccine at birth), Occurrence of unsolicited adverse events (AEs) during the 31-day (Day 0-30) follow-up period after each dose, Occurrence of serious adverse events (SAEs) during the entire study period. Statistical Methods: The analyses were performed on the Total Vaccinated Cohort, the According-To-Protocol (ATP) cohort for immunogenicity and the Hepatitis B Cohort. - The Total Vaccinated Cohort included all subjects who received at least one dose of combined vaccine. - The ATP cohort for immunogenicity included all vaccinated subjects who complied with the procedures defined in the protocol and for whom immunogenicity data were available. - The Hepatitis B cohort included all subjects who received Hepatitis B vaccine at birth. Analysis of immunogenicity: The analysis of immunogenicity was performed on the ATP cohort for immunogenicity. The standardized asymptotic 95% CI was calculated for the difference in the percentage of subjects with anti-hbs antibody concentrations 10 miu/ml one month after the last vaccine dose between DTPw-HBV/Hib-MenAC () group and DTPw-HBV/Hib () group. Non-inferiority objective was demonstrated if the lower limit of the standardized asymptotic for the difference was above -10%. For each group, Geometric Mean Concentrations (GMCs) or Geometric Mean titers (GMTs) and Seroprotection/ Seropositivity rates with 95% confidence interval (CIs) were summarized at post-vaccination for antidiphtheria and anti-tetanus and at pre and post-vaccination course for all the other antibodies. For rsba-menc, rsba- MenA, anti-psc and anti-psa antibodies, GMCs or GMTs and seropositivity rates were summarized for the control group in a random sub-sample of 25% of subjects. For each group, vaccine response to BPT was calculated with exact 95%CI at post-vaccination. Analysis of safety: The analysis of safety was performed on the Total Vaccinated Cohort. For each solicited symptom, the percentage of subjects with the symptom reported during the 4-day (Day 0-3) follow-up period was summarized for each group after each dose and across doses of the combined vaccine dose with exact. The percentage of subjects with fever reported during the 4-day (Day 0-3) follow-up period after the administration of the hepatitis B vaccine at birth was also summarized for each group (Hepatitis B Cohort). The percentage of subjects with unsolicited AEs within 31 days (Day 0-30) following the administration of the Hepatitis B vaccine dose at birth (Hepatitis B Cohort) and after the combined vaccine dose (Total Vaccinated Cohort) was tabulated according to the Medical Dictionary for Regulatory Activities (MedDRA) preferred term for each group. The occurrence of SAEs was tabulated according to the MedDRA preferred term for each group after the administration of the hepatitis B vaccine at birth (Hepatitis B Cohort) and after the combined vaccine dose. Study Population: Male or female subjects aged 7 days ± 3 days, born after a gestation period of 36 to 42 weeks born to mothers proven to be seronegative for human immunodeficiency virus (HIV) and HBsAg. Subjects were free of obvious health problems as established by medical history of the pregnancy and clinical examination before entering into the study. Written informed consent was obtained from the parent(s) or guardian(s) of the subject before study entry. Number of subjects Planned, N Hepatitis B cohort, N Randomized, N (Total Vaccinated Cohort) Completed, n (%) 93 (98.9) 94 (98.9) Total Number Subjects Withdrawn, n (%) 1 (1.1) 1 (1.1) Withdrawn due to Adverse Events, n (%) 0 (0.0) 0 (0.0) Withdrawn due to Lack of Efficacy, n (%) Not applicable Not applicable Withdrawn for other reasons, n (%) 1 (1.1) 1 (1.1) Demographics N (Total Vaccinated Cohort) Females:Males 42:52 50:45 Mean Age, weeks (SD)* 6.2 (0.45) 6.1 (0.43) Black, n (%) 71 (75.5) 67 (70.5) *Age at the time of the first combined vaccine dose. Primary Efficacy Results: Difference between and groups in terms of percentages of subjects with anti-hbs antibody

3 concentrations 10 miu/ml, one month after Dose 3 (ATP cohort for immunogenicity). Difference in seroprotection rate ( group minus group) Group N % Group N % Difference % 95 % CI LL UL * 6.09 % = percentage of subjects with specified antibody concentrations = 95% Standardized asymptotic confidence interval; LL = lower limit, UL = upper limit *Non-inferiority objective was met as the lower limit (LL) of the standardized asymptotic was above -10% Primary Efficacy Results: Seroprotection rates and GMCs for anti-hbs antibodies (ATP cohort for immunogenicity). 10 miu/ml GMC (miu/ml) n % Pre PIII (M 3.5) * Pre PIII (M 3.5) * = 95% confidence interval; LL = lower limit, UL = upper limit *Primary efficacy variable Seroprotection rates and GMCs for anti-prp antibodies (ATP cohort for immunogenicity) μg/ml 1 μg/ml GMC (μg/ml) LL UL Pre PIII (M 3.5) Pre PIII (M 3.5) = 95% confidence interval; LL = lower limit, UL = upper limit Seropositivity rates and GMTs for rsba-mena antibodies (ATP cohort for immunogenicity). 1:8 GMT Pre PIII (M 3.5) Pre PIII (M 3.5) n (%) = number (percentage) of subjects with specified antibody titers = 95% confidence interval; LL = lower limit, UL = upper limit Seropositivity rates and GMTs for rsba-menc antibodies (ATP cohort for immunogenicity). 1:8 GMT

4 Pre PIII (M 3.5) Pre PIII (M 3.5) n (%) = number (percentage) of subjects with specified antibody titers = 95% confidence interval; LL = lower limit, UL = upper limit Seropositivity rates and GMCs for anti-psa antibodies (ATP cohort for immunogenicity). 0.3 μg/ml GMC (μg/ml) Pre PIII (M 3.5) Pre PIII (M 3.5) = 95% confidence interval; LL = lower limit, UL = upper limit Seropositivity rates and GMCs for anti-psc antibodies (ATP cohort for immunogenicity). 0.3 μg/ml GMC (μg/ml) Pre PIII (M 3.5) Pre PIII (M 3.5) = 95% confidence interval; LL = lower limit, UL = upper limit Seroprotection rates (defined as anti-diphtheria antibody concentrations 0.1 IU/ml by ELISA) and GMCs for antidiphtheria antibodies at Post Dose 3 - Month 3.5 (ATP cohort for immunogenicity). 0.1 IU/mL GMC (IU/mL) Group N = 95% confidence interval; LL = lower limit, UL = upper limit Anti-diphtheria seroprotection status defined as anti-diphtheria antibody concentration 0.1 IU/ml by ELISA or antidiphtheria antibody concentration IU/ml by Vero-cell neutralization test if ELISA result < 0.1 IU/ml one month after the third dose (ATP cohort for immunogenicity) Seronegativity assessed by Seronegativity assessed by the Overall seronegativity for Estimated proportion of subjects seroprotected

5 ELISA Vero-cell neutralization test for subjects seronegative by ELISA Anti-Diphtheria antibodies (SP) and its Group N n/n % n /N % n/n x n /N % SP LL UL 88 5/ / /88 x 3/ / * N = number of subjects tested by ELISA n/n = number of subjects with concentrations < 0.1 IU/mL / number of subjects tested by ELISA n /N = number of subjects with concentrations < IU/mL / number of subjects tested by Vero cell Neutralisation test % = proportion of subjects with concentrations < considered cut-off (0.1 IU/mL for ELISA and IU/mL for Neutralisation) n/n x n /N = the multiplication of the two proportions = overall seronegativity for anti-diphtheria Overall = based on both the ELISA and the Vero cell Neutralisation testing = exact 95% confidence interval; LL = lower limit, UL = upper limit *No subject in the group was seronegative for anti-diphtheria by ELISA. Seroprotection rates and GMCs for anti-tetanus antibodies at Post Dose 3 - Month 3.5 (ATP cohort for immunogenicity). 0.1 IU/mL GMC (IU/mL) Group N = 95% confidence interval; LL = lower limit, UL = upper limit Seropositivity rates and GMCs for anti-bpt antibodies (ATP cohort for immunogenicity). 15 EL.U/mL GMC (EL.U/mL) Pre PIII (M 3.5) Pre PIII (M 3.5) = 95% confidence interval; LL = lower limit, UL = upper limit Vaccine response to BPT at Post Dose 3 (Month 3.5) (ATP cohort for immunogenicity). Group Pre-vaccination N status LL UL S S Total S S Total N = number of subjects with both pre- and post-vaccination results available n (%) = number (percentage) of responders. Vaccine response was defined as the appearance of antibodies (anti-bpt antibody concentrations 15 EL.U/mL) in initially seronegative subjects or post-vaccination anti-bpt antibody concentrations the pre-vaccination anti-bpt concentrations in initially seropositive subjects S-/S+ = seronegative/seropositive subjects at pre-vaccination Total = subjects either seropositive or seronegative at pre-vaccination 95%CI = exact 95% confidence interval; LL = lower limit; UL = upper limit

6 Number and percentage of subjects with fever during the 4-day (Day 0-3) post-hepatitis B vaccination period (Hepatitis B Cohort). Symptom Intensity Fever (Rectal) N = C >40.0 C Related N = number of subjects with a symptom sheet completed n (%) = number (percentage) of subjects for whom fever was reported Related = fever considered by the investigator to be causally related to the study vaccination = exact 95% confidence interval; LL = lower limit, UL = upper limit Number and percentage of subjects with solicited local symptoms during the 4-day (Day 0-3) follow-up period (Total Vaccinated Cohort). Symptom Intensity Dose 1 N = 91 N = 93 Pain Any Grade Redness Any > 30 mm Swelling Any > 30 mm Dose 2 N = 93 N = 94 Pain Any Grade Redness Any > 30 mm Swelling Any > 30 mm Dose 3 N = 93 N = 94 Pain Any Grade Redness Any > 30 mm Swelling Any > 30 mm Across Doses N = 93 Pain Any Grade Redness Any > 30 mm Swelling Any > 30 mm N = number of subjects with a symptom sheet completed n (%) = number (percentage) of subjects for whom the specified symptom was reported Any = incidence of a particular symptom regardless of grade

7 Grade 3 pain = cried when limb was moved/spontaneously painful = exact 95% confidence interval; LL = lower limit, UL = upper limit Number and percentage of subjects with solicited general symptoms during the 4-day (Day 0-3) follow-up period (Total Vaccinated Cohort). Symptom Intensity/ Relationship Dose 1 N = 91 N = 93 Drowsiness Any Grade Related Fever (Rectal) 38.0 C > 40.0 C Related Irritability Any Grade Related Loss of appetite Any Grade Related Dose 2 N = 93 N = 94 Drowsiness Any Grade Related Fever (Rectal) 38.0 C > 40.0 C Related Irritability Any Grade Related Loss of appetite Any Grade Related Dose 3 N = 93 N = 94 Drowsiness Any Grade Related Fever (Rectal) 38.0 C > 40.0 C Related Irritability Any Grade Related Loss of appetite Any Grade Related Across Doses N = 93 Drowsiness Any Grade Related

8 Fever (Rectal) 38.0 C > 40.0 C Related Irritability Any Grade Related Loss of appetite Any Grade Related N = number of subjects with at a symptom sheet completed n (%) = number (percentage) of subjects for whom the specified symptom was reported Any = incidence of a particular symptom regardless of grade or relationship to study vaccination Grade 3 drowsiness = drowsiness which prevented normal everyday activities Grade 3 irritability = crying that could not be comforted Grade 3 loss of appetite = not eating at all Related = symptom considered by the investigator to be causally related to the study vaccination = exact 95% confidence interval; LL = lower limit, UL = upper limit Safety Results: Number (%) of subjects with unsolicited adverse events after the administration of the Hepatitis B vaccine dose (Hepatitis B Cohort). Most Frequent AEs - On-Therapy (occurring within Day 0-30 following vaccination) N = 96 Subjects with any AE(s), n (%) 16 (16.7) 24 (25.3) Upper respiratory tract infection 3 (3.1) 5 (5.3) Dermatitis 1 (1.0) 5 (5.3) Abdominal pain 5 (5.2) 0 (0.0) Irritability 0 (0.0) 4 (4.2) Rash 1 (1.0) 3 (3.2) Constipation 1 (1.0) 2 (2.1) Influenza 2 (2.1) 1 (1.1) Cough 1 (1.0) 1 (1.1) Eczema 1 (1.0) 1 (1.1) Heat rash 1 (1.0) 1 (1.1) Pyrexia 0 (0.0) 2 (2.1) Rash generalized 2 (2.1) 0 (0.0) Rhinitis 0 (0.0) 2 (2.1) Abdominal pain upper 1 (1.0) 0 (0.0) Crying 0 (0.0) 1 (1.1) Diarrhea 1 (1.0) 0 (0.0) Eye discharge 1 (1.0) 0 (0.0) Eye swelling 1 (1.0) 0 (0.0) Fungal infection 0 (0.0) 1 (1.1) Localized infection 1 (1.0) 0 (0.0) Nasal congestion 0 (0.0) 1 (1.1) Ocular hyperaemia 1 (1.0) 0 (0.0) Pneumonia 1 (1.0) 0 (0.0) Rash papular 0 (0.0) 1 (1.1) Respiratory tract infection 0 (0.0) 1 (1.1) Rhinitis allergic 0 (0.0) 1 (1.1) Urticaria 0 (0.0) 1 (1.1) Vomiting 1 (1.0) 0 (0.0) Safety Results: Number (%) of subjects with unsolicited adverse events after the administration of the combined vaccine doses (Total Vaccinated Cohort). Most frequent adverse events - On-Therapy (occurring within Day 0-30 following vaccination) N = 94 Subjects with any AE(s), n (%) 65 (69.1) 67 (70.5)

9 Upper respiratory tract infection 26 (27.7) 25 (26.3) Rhinitis 7 (7.4) 9 (9.5) Influenza 11 (11.7) 3 (3.2) Diarrhea 9 (9.6) 4 (4.2) Gastroenteritis 5 (5.3) 7 (7.4) Cough 5 (5.3) 6 (6.3) Lymphadenopathy 5 (5.3) 3 (3.2) Rash 2 (2.1) 4 (4.2) Bronchitis 1 (1.1) 4 (4.2) Constipation 2 (2.1) 3 (3.2) Vomiting 2 (2.1) 3 (3.2) Abscess 2 (2.1) 2 (2.1) Bronchiolitis 1 (1.1) 3 (3.2) Dermatitis 1 (1.1) 3 (3.2) Oral candidiasis 2 (2.1) 2 (2.1) Pyrexia 2 (2.1) 2 (2.1) Conjunctivitis 2 (2.1) 1 (1.1) Otitis media 2 (2.1) 1 (1.1) Safety Results: Number (%) of subjects with serious adverse events (SAEs) after the administration of the Hepatitis B vaccine dose (Hepatitis B Cohort). Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs N = 96 Subjects with any SAE(s), n (%) [n related] 1 (1.0) [0] 0 (0.0) [0] Pneumonia 1 (1.0) [0] 0 (0.0) [0] Fatal SAEs N = 96 Subjects with fatal SAE(s) 0 (0.0) [0] 0 (0.0) [0] Safety Results: Number (%) of subjects with serious adverse events (SAEs) after the administration of the combined vaccine doses (Total Vaccinated Cohort). Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs N = 94 Subjects with any SAE(s), n (%) [n related] 2 (2.1) [1] 1 (1.1) [0] Gastroenteritis 1 (1.1) [0] 1 (1.1) [0] Dehydration 1 (1.1) [0] 0 (0.0) [0] Pyrexia 1 (1.1) [1] 0 (0.0) [0] Upper respiratory tract infection 0 (0.0) [0] 1 (1.1) [0] Fatal SAEs N = 94 Subjects with fatal SAE(s) 0 (0.0) [0] 0 (0.0) [0] Conclusion: One month after Dose 3, at least 94.3% of all subjects had anti-hbs antibody concentrations 10 miu/ml. At the same time point, 98.9% & 96.4% of the subjects of the group had rsba-menc and rsba-mena titers the cut-off value, respectively. After the combined vaccine doses, pain and irritability were the most frequently reported solicited local and general symptoms, respectively, across doses and groups. After the administration of the hepatitis B birth dose, at least one unsolicited AE was reported in 16 (16.7%) and 24 (25.3%) subjects in the and groups, respectively; after the combined vaccine dose, at least one unsolicited AE was reported for 65 (69.1%) and 67 (70.5%) subjects in the and groups, respectively. One SAE was reported for 1 subject in the group after administration of the hepatitis B birth dose; 3 SAEs were reported after the administration of the combined vaccines, 2 in the group and 1 in the group. One SAE reported in the group after administration of the combined vaccine was considered by the investigator to be related to study vaccination. No fatal SAEs were reported during the course of the study. Date updated: 23-April-2015