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.: (10PN-PD-DIT-005) Title: A phase II, randomized, controlled study to assess the reactogenicity and immunogenicity of GlaxoSmithKline (GSK) Biologicals 10-valent pneumococcal conjugate vaccine, when administered concomitantly with GSK Biologicals combined diphtheria-tetanus- acellular pertussis-hepatitis B-inactivated polio virus/haemophilus influenzae type b vaccine (Infanrix hexa ) as a 3-dose primary immunization course at 2, 4 and 6 months of age. 10Pn-PD-DiT: GlaxoSmithKline (GSK) Biologicals 10-valent pneumococcal conjugate vaccine. Infanrix hexa (DTPa-HBV-IPV/Hib): GSK Biologicals combined diphtheria tetanus acellular pertussis hepatitis B- inactivated polio virus vaccine to be mixed with a lyophilized Haemophilus influenzae type b tetanus conjugate vaccine. Rationale: The aim of this study was to evaluate the safety and immunogenicity of the 10Pn-PD-DiT vaccine, coadministered with DTPa-HBV-IPV/Hib vaccine. Havrix served as control. Havrix (HAV): GSK Biologicals inactivated hepatitis A vaccine. Phase: II Study Period: 04 April 2006 to 30 October 2006 Study Design: Observer-blind, randomized (1:1), controlled study with 2 parallel groups. Centers: 10 study centers in Chile. Indication: Three-dose primary vaccination of healthy infants against Streptococcus pneumonia, diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, Haemophilus influenzae type b and hepatitis A. Treatment: The study groups were as follows: 10Pn Group received 10Pn-PD-DiT according to a 3-dose vaccination schedule. HAV Group received HAV vaccine according to a 3-dose vaccination schedule. Both vaccines were administered intramuscularly into the right thigh according to a 3-dose vaccination schedule at months of age. DTPa-HBV-IPV/Hib vaccine was given concomitantly to both study groups through an intramuscular injection in the left thigh according to the same 3-dose vaccination schedule. To comply with local immunization recommendations licensed oral polio vaccine (OPV) was administered to all subjects at 7 months of age. Objectives: To assess the safety of the 10Pn-PD-DiT vaccine when co-administered with DTPa-HBV-IPV/Hib vaccine in infants at months of age in terms of the occurrence of adverse events (AEs) with intensity grade 3. Primary Outcome/Efficacy Variable: Occurrence of grade 3 AEs (solicited and/or unsolicited) within 4 days (Day 0-3) after each vaccination. Secondary Outcome/Efficacy Variable(s): Safety Occurrence of solicited local symptoms (any and grade 3) within 4 days (Day 0-3) after each vaccination. Occurrence of solicited general symptoms (any and grade 3) within 4 days (Day 0-3) after each vaccination. Occurrence of unsolicited AEs within 31 days (Day 0-30) after each vaccination. Occurrence of serious adverse events (SAEs) during the whole study period. Immunogenicity Prior to and 1 month after the administration of the 3rd dose of the primary vaccination course with 10Pn-PD-DiT in all subjects: Antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F Antibody concentrations against protein D. Anti-pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F antibody concentrations 0.20 g/ml. Seropositivity status, defined as: - Anti-pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F antibody concentrations 0.05 g/ml - Anti-protein D (anti-pd) antibody concentrations 100 EL.U/mL. 1 month after the administration of the 3rd dose of the primary vaccination course with 10Pn-PD-DiT or HAV vaccine, in 50% of subjects in each group: Opsonophagocytic activity against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. Anti-hepatitis A (anti-hav) antibody concentrations. Seropositivity status, defined as: - Opsonophagocytic activity against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F 8. - Anti-HAV antibody concentrations 15 miu/ml.

2 Prior to and 1 month after the administration of the 3rd dose of the primary vaccination course with DTPa-HBV-IPV/Hib vaccine in 50% of subjects in each group: Anti-polyribosyl ribitol phosphate (anti-prp), anti-diphtheria and anti-tetanus toxoids, anti-pertussis toxoid (anti-pt), anti-filamentous haemagglutinin (anti-fha), anti-pertactin (anti-prn) antibody concentrations. Seropositivity status, defined as: - Anti-PT antibody concentrations 5 EL.U/mL. - Anti-FHA antibody concentrations 5 EL.U/mL. - Anti-PRN antibody concentrations 5 EL.U/mL. Seroprotection status, defined as: - Anti-diphtheria toxoid antibody concentrations 0.1 IU/mL. - Anti-tetanus toxoid antibody concentrations 0.1 IU/mL. - Anti-PRP antibody concentrations 0.15 g/ml & 1.0 g/ml. 1 month after the administration of the 3rd dose of the primary vaccination course with DTPa-HBV-IPV/Hib vaccine in 50% of subjects in each group: Anti-hepatitis B surface antigen (anti-hbs) antibody concentrations and anti-polio type 1, 2 and 3 titers. Seroprotection status, defined as: - Anti-HBs antibody concentrations 10 miu/ml. - Anti-polio type 1 titers 8. - Anti-polio type 2 titers 8. - Anti-polio type 3 titers 8. Primary vaccine response to PT, FHA and PRN; defined as appearance of antibodies in subjects who were initially seronegative (i.e., with antibody concentrations < 5 EL.U/mL), or at least maintenance of pre-vaccination antibody concentrations in those who were initially seropositive (i.e., with antibody concentrations 5 EL.U/mL). Statistical Methods: The analyses were performed on the Total vaccinated cohort and the according-to-protocol (ATP) cohort for immunogenicity. The Total vaccinated cohort included all subjects who received at least one dose of vaccine. The according-to-protocol (ATP) cohort for immunogenicity included all evaluable subjects with available immunogenicity data. Statistical analyses were performed per treatment actually administered. Analysis of safety The analysis of safety was performed on the Total vaccinated cohort. Standardized asymptotic 95% CIs for the difference between groups (10Pn minus HAV), in terms of percentage of subjects with grade 3 AEs (solicited and/or unsolicited) within 4 days (Day 0-3) after at least one vaccination dose, were computed. The percentage of subjects with solicited local or general AEs within the 4-day follow-up period was summarized per dose and across doses with exact 95% confidence interval (CI). The number (percentage) of subjects with unsolicited AEs within the 31-day follow-up period was tabulated according to the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms. SAEs occurring during the study period were reported according to the MedDRA preferred terms. Analysis of immunogenicity The analysis of immunogenicity was performed on the ATP cohort for immunogenicity Geometric mean antibody concentrations/titers (GMCs/GMTs), seropositivity, seroprotection and vaccine response rates (as applicable) were calculated with their 95% CI for each group, each antigen/serotype and at each applicable blood sampling time point. Study Population: Male or female subjects between, and including, 6 and 12 weeks (42-90 days) of age at the time of the first vaccination, born after a gestation period of 36 to 42 weeks and free of obvious health problems as established by medical history and clinical examination before entering into the study. Subjects with a previous vaccination against, a history of or intercurrent diphtheria, tetanus, pertussis, polio, hepatitis B, Haemophilus influenzae type b, hepatitis A and/or Streptococcus pneumoniae diseases were excluded. Written informed consent was obtained from the parent or guardian of the subject prior to study enrolment. Number of subjects 10Pn Group HAV Group Planned, N Randomized, N (Total Vaccinated Cohort) Completed, n (%) 117 (98.3) 120 (99.2) Total Number Subjects Withdrawn, n (%) 2 (1.7) 1 (0.8) Withdrawn due to Adverse Events n (%) 0 (0) 0 (0)

3 Withdrawn due to Lack of Efficacy n (%) Not applicable Not applicable Withdrawn for other reasons n (%) 2 (1.7) 1 (0.8) Demographics 10Pn Group HAV Group N (Total Vaccinated Cohort) Females:Males 60:59 62:59 Mean Age, weeks (SD) 8.4 (1.25) 8.4 (1.22) White - Caucasian, n (%) 119 (100) 120 (99.2) Primary Efficacy Results: Difference between groups in percentage of subjects reporting a grade 3* solicited /or unsolicited symptom during the 4-day (Day 0-3) post-vaccination period (Total vaccinated cohort) Dose 10Pn Group HAV Group Difference in percentage (10Pn minus HAV) N n % 95% CI N n % 95% CI % 95% CI LL UL Dose Dose Dose Across doses N = number of subjects with at least one documented dose n (%) = number (percentage) of subjects with a specified symptom 95% CI = standardized asymptotic 95% confidence interval, LL = Lower Limit, UL = Upper Limit * Grade 3 unsolicited AEs were defined as unsolicited AEs which prevented normal, everyday activities; for definitions of grade 3 solicited local and general symptoms, please refer to the next 2 tables below. Number (percentage) of subjects with solicited local symptoms reported during the 4-day (Day 0-3) post-vaccination period following each dose and overall (Total vaccinated cohort) Symptom Intensity 10Pn Group HAV Group N n % 95% CI N n % 95% CI Dose 1 Pain Any Grade Redness Any > 30 mm Swelling Any > 30 mm Dose 2 Pain Any Grade Redness Any > 30 mm Swelling Any > 30 mm Dose 3 Pain Any Grade Redness Any > 30 mm Swelling Any > 30 mm Across doses Pain Any Grade Redness Any

4 > 30 mm Swelling Any > 30 mm N= number of subjects with at least one documented dose n (%) = number (percentage) of subjects with at least once the symptom whatever the number of injections 95% CI= exact 95% confidence interval; LL = lower limit, UL = upper limit Grade 3 pain= Cried when limb was moved / spontaneously painful Number (percentage) of subjects with solicited general symptoms reported during the 4-day (Day 0-3) post-vaccination period following each dose and overall (Total vaccinated cohort) Symptom Intensity / 10Pn Group HAV Group relationship N n % 95 % CI N n % 95 % CI Dose 1 Drowsiness Any Grade Related Fever* 38 C > 40 C Related Irritability Any Grade Related Loss of appetite Any Grade Related Dose 2 Drowsiness Any Grade Related Fever* 38 C > 40 C Related Irritability Any Grade Related Loss of appetite Any Grade Related Dose 3 Drowsiness Any Grade Related Fever* 38 C > 40 C Related Irritability Any Grade Related Loss of appetite Any Grade Related Across doses Drowsiness Any

5 Grade Related Fever* 38 C > 40 C Related Irritability Any Grade Related Loss of appetite Any Grade Related N= number of subjects with at least one documented dose n (%) = number (percentage) of subjects with at least once the symptom whatever the number of injections 95% CI= exact 95% confidence interval; LL = lower limit, UL = upper limit * Rectal temperature measurements Grade 3 drowsiness = drowsiness that 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 have a causal relationship to study vaccination Seropositivity rates and GMCs for pneumococcal antibodies (22F-ELISA) against serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (ATP cohort for immunogenicity) Antibody Group Timing N 0.05 g/ml 0.2 g/ml GMC (g/ml) n % 95% CI LL UL Anti-1 10Pn PRE PIII(M5) HAV PRE PIII(M5) Anti-4 10Pn PRE PIII(M5) HAV PRE PIII(M5) Anti-5 10Pn PRE PIII(M5) HAV PRE PIII(M5) Anti-6B 10Pn PRE PIII(M5) HAV PRE PIII(M5) Anti-7F 10Pn PRE PIII(M5) HAV PRE PIII(M5) Anti-9V 10Pn PRE PIII(M5) HAV PRE PIII(M5) Anti-14 10Pn PRE PIII(M5) HAV PRE PIII(M5) Anti-18C 10Pn PRE

6 PIII(M5) HAV PRE PIII(M5) Anti-19F 10Pn PRE PIII(M5) HAV PRE PIII(M5) Anti-23F 10Pn PRE PIII(M5) HAV PRE PIII(M5) PRE = before first dose Seropositivity rates and GMCs for anti-pd antibodies (ATP cohort for immunogenicity) Antibody Group Timing N 100 EL.U/mL GMC (EL.U/mL) Anti-PD 10Pn PRE PIII(M5) HAV PRE PIII(M5) PRE = before first dose Seropositivity rates and GMTs for opsonophagocytic activity against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F, one month after Dose 3 (ATP cohort for immunogenicity) Antibody Group Timing N 8 GMT Opsono-1 10Pn PIII(M5) HAV PIII(M5) Opsono-4 10Pn PIII(M5) HAV PIII(M5) Opsono-5 10Pn PIII(M5) HAV PIII(M5) Opsono-6B 10Pn PIII(M5) HAV PIII(M5) Opsono-7F 10Pn PIII(M5) HAV PIII(M5) Opsono-9V 10Pn PIII(M5) HAV PIII(M5) Opsono-14 10Pn PIII(M5) HAV PIII(M5) Opsono- 10Pn PIII(M5) C HAV PIII(M5) Opsono-19F 10Pn PIII(M5) HAV PIII(M5)

7 Opsono-23F 10Pn PIII(M5) HAV PIII(M5) n (%) = number (percentage) of subjects with antibody titer within the specified range Seropositivity rates and GMCs for anti-hav antibodies, one month after Dose 3 (ATP cohort for immunogenicity) Group Timing N 15 miu/ml GMC (miu/ml) 10Pn PIII(M5) HAV PIII(M5) Seropositivity rates and GMCs for anti-diphtheria and anti-tetanus antibodies (ATP cohort for immunogenicity) Antibody Group Timing N 0.1 IU/mL GMC (IU/mL) Anti-diphtheria 10Pn PRE PIII(M5) HAV PRE PIII(M5) Anti-tetanus 10Pn PRE PIII(M5) HAV PRE PIII(M5) PRE = before first dose Seropositivity rates and GMCs for anti-pt, anti-fha and anti-prn antibodies (ATP cohort for immunogenicity) Antibody Group Timing N 5 EL.U/mL GMC (EL.U/mL) Anti-PT 10Pn PRE PIII(M5) HAV PRE PIII(M5) Anti-FHA 10Pn PRE PIII(M5) HAV PRE PIII(M5) Anti-PRN 10Pn PRE PIII(M5) HAV PRE PIII(M5)

8 PRE = before first dose Seropositivity rates and GMCs for anti-hbs antibodies, one month after Dose 3 (ATP cohort for immunogenicity) Antibody Group Timing N 10 miu/ml GMC (miu/ml) Anti-HBs 10Pn PIII(M5) HAV PIII(M5) Seropositivity rates and GMTs for anti-polio 1, anti-polio 2 and anti-polio 3 antibodies, one month after Dose 3 (ATP cohort for immunogenicity) Antibody Group Timing N 8 GMT Anti-polio 1 10Pn PIII(M5) HAV PIII(M5) Anti-polio 2 10Pn PIII(M5) HAV PIII(M5) Anti-polio 3 10Pn PIII(M5) HAV PIII(M5) n (%) = number (percentage) of subjects with antibody titer within the specified range Seropositivity rates and GMCs for anti-prp antibodies (ATP cohort for immunogenicity) Antibody Anti- PRP Group Timing N 0.15 g/ml 1 g/ml GMC (g/ml) n % 95% CI LL UL 10Pn PRE PIII(M5) HAV PRE PIII(M5) PRE = before first dose Vaccine response to PT, FHA and PRN, one month after Dose 3 (ATP cohort for immunogenicity) Antibody Group Pre-vaccination status N Vaccine Response n % 95% CI LL UL Anti-PT 10Pn S S Total HAV S S Total Anti-FHA 10Pn S S

9 Total HAV S S Total Anti-PRN 10Pn S S Total HAV S S Total S- = seronegative subjects (antibody concentration < 5 EL.U/mL) prior to vaccination S+ = seropositive subjects (antibody concentration 5 EL.U/mL) prior to vaccination Total = subjects either seropositive or seronegative at pre-vaccination N = number of subjects with both pre- and post-vaccination results available n (%) = number (percentage) of responders Vaccine response defined as: For initially seronegative subjects, antibody concentration 5 EL.U/mL at PIII(M5) For initially seropositive subjects, antibody concentration at PIII(M5) pre-vaccination antibody concentration 95% CI = exact 95% confidence interval; LL = lower limit, UL = upper limit Safety Results: Number (%) of subjects with adverse events (Total vaccinated cohort) Most frequent adverse events - On-Therapy (occurring within Day 0-30 following vaccination) 10Pn Group N = 119 HAV Group N = 121 Subjects with any AE(s), n (%) 104 (87.4) 101 (83.5) Bronchitis 46 (38.7) 49 (40.5) Nasopharyngitis 30 (25.2) 27 (22.3) Upper respiratory tract infection 21 (17.6) 20 (16.5) Injection site induration 18 (15.1) 16 (13.2) Abdominal pain 13 (10.9) 4 (3.3) Pharyngitis 5 (4.2) 11 (9.1) Conjunctivitis 5 (4.2) 10 (8.3) Diarrhoea 4 (3.4) 8 (6.6) Nasal congestion 6 (5.0) 6 (5.0) Gastrooesophageal reflux disease 2 (1.7) 9 (7.4) Cough 6 (5.0) 4 (3.3) Pyrexia 3 (2.5) 7 (5.8) Vomiting 3 (2.5) 6 (5.0) Unsolicited AEs counting rule: > 30 subjects per treatment group and <= 3 groups, display the most frequent 10 events in each group Safety Results: Number (%) of subjects with serious adverse events (Total vaccinated cohort) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs 10Pn Group N = 119 HAV Group N = 121 Subjects with any SAE(s), n (%) [n related] 8 (6.7) [0] 8 (6.6) [0] Bronchiolitis 2 (1.7) [0] 3 (2.5) [0] Pneumonia 1 (0.8) [0] 3 (2.5) [0] Pneumonia respiratory syncytial viral 1 (0.8) [0] 3 (2.5) [0] Bronchitis 0 (0.0) [0] 1 (0.8) [0] Bronchopneumonia 1 (0.8) [0] 0 (0.0) [0] Gastroenteritis rotavirus 1 (0.8) [0] 0 (0.0) [0] Interstitial lung disease 0 (0.0) [0] 1 (0.8) [0] Otitis media acute 0 (0.0) [0] 1 (0.8) [0] Pertussis 1 (0.8) [0] 0 (0.0) [0] Pneumonia parainfluenzae viral 0 (0.0) [0] 1 (0.8) [0] Pyelonephritis acute 1 (0.8) [0] 0 (0.0) [0]

10 Respiratory failure 1 (0.8) [0] 0 (0.0) [0] Respiratory syncytial virus infection 1 (0.8) [0] 0 (0.0) [0] Fatal SAEs 10Pn Group N = 119 HAV Group N = 121 Subjects with fatal SAE(s), n (%) [n related] 0 (0.0) [0] 0 (0.0) [0] Conclusion: Across doses, at least one grade 3 solicited or unsolicited symptom was reported during the 4-day follow-up period after vaccination for 41 (34.5%) and 30 (24.8%) subjects in the 10Pn Group and the HAV Group, respectively. At least one unsolicited AE was reported for 104 (87.4%) and 101 (83.5%) subjects in the 10Pn Group and the HAV Group, respectively. SAEs were reported for 8 subjects in each group. None of these SAEs were considered by the investigators to be related to the study vaccination. No fatal SAEs were reported. Please also refer to the publications below. Date updated: 05 August 2013