Study Number: Title: Rationale: Phase: Study Period Study Design: Centres: 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 Number: (DTPa-HBV-IPV-116) Title: A phase II, observer-blind, randomized study to evaluate the immunogenicity, safety and reactogenicity of GlaxoSmithKline (GSK) Biologicals combined DSSITGDPa-HBV-IPV/Hib vaccine containing diphtheria toxoid from the Statens Serum Institute (SSI) of Denmark and tetanus toxoid from GSK Biologicals Kft [GD], compared to the currently licensed GSK Biologicals DTPa-HBV-IPV/Hib vaccine (Infanrix hexa ) when administered to healthy infants at 2, 3 and 4 months of age. Infanrix hexa (DTPa-HBV-IPV/Hib): GSK Biologicals combined diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus and Haemophilus influenzae type b vaccine. DSSITGDPa-HBV-IPV/Hib (PF): Preservative-free formulation of the combined DSSITGDPa-HBV-IPV/Hib vaccine. DSSITGDPa-HBV-IPV/Hib (PC): Preservative-containing formulation of the combined DSSITGDPa-HBV-IPV/Hib vaccine. Rationale: The aim of this study was to evaluate the immunogenicity of the hexavalent DSSITGDPa-HBV-IPV/Hib vaccine containing diphtheria toxoid provided by the Statens Serum Institute of Denmark (DSSI) and tetanus toxoid provided by GSK Biologicals Kft in Gödöllö (TGD) was non-inferior to the immunogenicity of the currently licensed formulation of the vaccine. Phase: II Study Period: From 12 October 2006 to 31 May 2007 Study Design: Observer-blind study, randomized (1:1:1), multicentre study with 3 groups. Centres: 6 centres in Finland Indication: Diphtheria-Tetanus-aPertussis-Hepatitis B-Poliomyelitis Treatment: The study groups were as follows: PF Group: Subjects received the preservative-free (PF) formulation of DSSITGDPa-HBV-IPV/Hib; PC Group: Subjects received the preservative-containing (PC) formulation of DSSITGDPa-HBV-IPV/Hib; Control Group: Subjects received the licensed formulation of DTPa-HBV-IPV/Hib. Vaccines were administered intramuscularly into the anterolateral quadrant of the right thigh according to a 3-dose vaccination schedule at 2, 3 and 4 months of age. Objectives: To demonstrate that the immunogenicity of the DSSITGDPa-HBV-IPV/Hib vaccine (preservative-free formulation) in terms of antibody response to all vaccine antigens is non-inferior to that of the DTPa-HBV-IPV/Hib vaccine, one month after a three-dose primary vaccination course. Criteria for non-inferiority (one month after the third vaccine dose): For diphtheria (Vero-cell neutralization assay), tetanus, hepatitis B, poliovirus types 1, 2 and 3 and polyribosylribitol phosphate (PRP): the upper limit of the standardized asymptotic 95% confidence interval (CI) on the group difference [Control Group minus PC Group] in the percentage of seroprotected subjects is 10%. For the pertussis antigens [pertussis toxoid (PT), filamentous haemagglutinin (FHA) and pertactin (PRN)] the upper limit of the 95% CI on the ratio of geometric mean concentrations (GMCs) of antibodies [Control Group divided by PF Group] is 1.5 Primary Outcome/Efficacy Variable: Immunogenicity one month after the third dose of study vaccines: Seroprotection status - Anti-diphtheria antibody concentrations IU/ml (based on Vero-cell neutralization assay); - Anti-tetanus toxoid antibody concentrations 0.1 IU/ml; - Anti-hepatitis B surface antigen (HBs) antibody concentrations 10 miu/ml; - Anti-poliovirus type 1 antibody titres 8; - Anti-poliovirus type 2 antibody titres 8; - Anti-poliovirus type 3 antibody titres 8; - Anti-polyribosyl-ribitol-phosphate (anti-prp) antibody concentrations 0.15 µg/ml. Anti-pertussis toxoids (anti-pt), anti-filamentous hemagglutinin (anti-fha) and anti-pertactin (anti-prn) antibody concentrations. Secondary Outcome/Efficacy Variable(s): Immunogenicity one month after the third dose of study vaccines: Vaccine response to PT, FHA and PRN, defined as appearance of antibodies in subjects who were initially seronegative (i.e. with concentrations < cut-off value) or at least maintenance of pre-vaccination antibody concentrations in subjects

2 who were initially seropositive (i.e. with concentrations cut-off value), taking into consideration the decreasing maternal antibodies. Anti-diphtheria antibody concentration 0.1 IU/ml (based on ELISA). Antibody concentrations/titres for anti-diphtheria, anti-tetanus, anti-hbs, anti-poliovirus types 1, 2, 3 and anti-prp. Immunogenicity before the first dose of the study vaccine: Antibody concentrations for anti-diphtheria, anti-tetanus, anti-pt, anti-fha and anti-prn. Safety: Occurrence of solicited local symptoms within 8 days (Day 0-Day 7) after each vaccine dose. Occurrence of solicited general symptoms within 8 days (Day 0-Day 7) after each vaccine dose. Occurrence of unsolicited symptoms within 31 days (Day 0-Day 30) after each vaccine dose. Occurrence of serious adverse events (SAEs) during the entire study period. 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 the study vaccine. The ATP cohort for immunogenicity included all subjects who received at least one dose of the study vaccine, for whom administration site was known, who did not receive a vaccine not specified or forbidden in the protocol and for whom assay results were available for antibodies against at least one study vaccine antigen component after vaccination and who complied with the protocol vaccination schedule and blood sampling schedule.. Analysis of Immunogenicity: The analysis of immunogenicity was performed on the ATP cohort for immunogenicity. The immunogenicity of the PF Group was compared to that of the Control Group by computing: The standardized asymptotic 95% CI for the difference between groups [Control Group minus PF Group] in terms of seroprotection rates to anti-diphtheria, anti-tetanus, anti-hbs, anti-polio 1, 2 and 3 and anti-prp, one month after the third vaccine dose. The 95%CI for the groups GMC ratio [Control Group divided by PF Group] for anti-pt, anti-fha and anti-prn antibodies, using an analysis of covariance (ANCOVA) model on the logarithm10 transformation of the concentrations. In addition, for each group, at each time point that a serological result was available, Seroprotection/seropositivity/vaccines response rates with 95% CI were calculated. Geometric Mean Titres (GMTs)/GMCs with 95% CI were tabulated for each antigen Analysis of Safety (solicited and unsolicited adverse events) The analysis of safety was performed on the Total vaccinated cohort. The percentages of subjects reporting each individual local and general solicited symptom within the 8-day (Days 0-7) post vaccination period following each dose and across doses were tabulated, with exact 95% CI. The same tabulation was performed for grade 3 solicited symptoms and for general solicited symptoms assessed by the investigator as causally related to the study vaccine. The percentage of subjects with unsolicited AEs, classified by the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms, within the 31-day (Days 0-30) following vaccination was tabulated. The percentage of subjects with SAEs, classified by MedDRA preferred terms, was tabulated for the entire study period. Study Population: Healthy male or female subjects between, and including, 8 and 12 weeks of age at the time of the first vaccination, born after a gestation period of 36 to 42 weeks. Subjects with evidence of previous or intercurrent diphtheria, tetanus, pertussis, polio, hepatitis B and/or Haemophilus influenzae type b vaccination or disease were excluded. Written informed consent was obtained from the parents/guardians of the subjects. Number of Subjects: PF Group PC Group Control Group Planned, N Randomised, N (Total Vaccinated Cohort) Completed, n (%) 151 (98.7) 148 (98.7) 152 (100) Total Number Subjects Withdrawn, n (%) 2 (1.3) 2 (1.3) 0 (0.0) Withdrawn due to Adverse Events, n (%) 1 (0.7) 1 (0.7) 0 (0.0) Withdrawn due to Lack of Efficacy, n (%) Not applicable Not applicable Not applicable Withdrawn for other reasons, n (%) 1 (0.7) 1 (0.7) 0 (0.0) Demographics PF Group PC Group Control Group N (Total Vaccinated Cohort) Females: Males 68:85 75:75 64:88

3 Mean Age, weeks (SD) 9.9 (1.51) 10.0 (1.45) 10.1 (1.35) White - Caucasian, n (%) 152 (99.3) 147 (98.0) 148 (97.4) Primary Efficacy Results: Difference between groups in seroprotection rates to anti-diptheria (both tests), anti-tetanus, anti- HBs, anti-poliovirus types 1, 2 and 3; and anti-prp with standardized asymptotic 95% CIs, one month after third vaccine dose (ATP cohort for immunogenicity) Difference in seroprotection rate (Group 2 minus Group 1) 95 % CI Antibody Cut-off Group 1 N % Group 2 N % Difference % LL UL anti-diphtheria (Vero) IU/mL PF Control Control - PF * anti-diphtheria (ELISA) 0.1 IU/mL PF Control Control - PF Anti-Tetanus 0.1 IU/mL PF Control Control - PF * anti-hbs 10 MIU/mL PF Control Control - PF * Anti-PRP 0.15 UG/mL PF Control Control - PF * anti-polio1 8ED50 PF Control Control - PF * anti-polio2 8ED50 PF Control Control - PF * anti-polio3 8ED50 PF Control Control - PF * % = percentage of subjects with anti-<each antibody> concentration >= cut-off 95% CI = 95% Standardized asymptotic confidence interval; LL = lower limit, UL = upper limit *Criterion for non-inferiority: Upper limit of the standardized asymptotic 95%CI 10%. Primary Efficacy Results: Ratio of GMCs in terms of the 3 pertussis antigens with 95% CIs one month after third vaccine dose using ANCOVA model (ATP cohort for immunogenicity) Adjusted GMC ratio 95% CI Antibody Group N Adjusted Group N Adjusted Ratio order Value LL UL* description GMC description GMC anti-pt Control PF Control /PF anti-fha Control PF Control /PF anti-prn Control PF Control /PF Adjusted GMC = geometric mean antibody concentration adjusted for baseline concentration N = Number of subjects with both pre- and post-vaccination results available 95% CI = 95% confidence interval for the adjusted GMC ratio (Ancova model: adjustment for baseline concentration - pooled variance); LL = lower limit, UL = upper limit *Criterion for non-inferiority: Upper limit of the 95%CI 1.5 Primary Efficacy Results: Seroprotection rates and GMCs for anti-diphtheria (Vero-cell neutralization assay) antibodies one month after third dose (ATP cohort for immunogenicity) IU/mL GMC(IU/mL ) 95% CI 95% CI Antibody Group Timing N n % LL UL value LL UL anti-diphtheria (Vero) PF POST PC POST Control POST Primary Efficacy Results: Seroprotection rates and GMCs for anti-tetanus antibodies (ATP cohort for immunogenicity) 0.1 IU/mL 1 IU/mL GMC (IU/mL) 95% CI 95% CI 95% CI Antibody Group Timing N n % LL UL n % LL UL value LL UL Anti-Tetanus PF PRE POST PC PRE

4 POST Control PRE POST seroprotection = Anti-Tetanus antibody concentration >= 0.1 IU/ML PRE = blood sample taken before the first dose at the first study visit Primary Efficacy Results: Seroprotection rates and GMCs for anti-hbs antibodies one month after third dose (ATP cohort for immunogenicity) 10 miu/ml 100 miu/ml GMC (miu/ml) 95% CI 95% CI 95% CI Antibody Group Timing N n % LL UL n % LL UL value LL UL anti-hbs PF POST PC POST Control POST seroprotection = anti-hbs antibody concentration >= 10 MIU/ML Primary Efficacy Results: Seroprotection rates and GMTs for anti-polio1, anti-polio 2 and anti-polio 3 antibodies one month after third dose (ATP cohort for immunogenicity) 8 ED50 GMT 95% CI 95% CI Antibody Group Timing N n % LL UL value LL UL anti-polio1 PF POST PC POST Control POST anti-polio2 PF POST PC POST Control POST anti-polio3 PF POST PC POST Control POST GMT = geometric mean antibody titre calculated on all subjects n/% = number/percentage of subjects with titre above the specified cut-off Primary Efficacy Results: Seroprotection rates and GMCs for anti-prp antibodies one month after third dose (ATP cohort for immunogenicity) 0.15 UG/mL 1 UG/mL GMC (UG/mL) 95% CI 95% CI 95% CI Antibody Group Timing N n % LL UL n % LL UL value LL UL anti-prp PF POST PC POST Control POST Seroprotection = HIB.PRP AB antibody concentration 0.15 UG/ML

5 Primary Efficacy Results: Seropositivity rates and GMCs for anti-pt, anti-fha and anti-prn antibodies (ATP cohort for immunogenicity) 5 ELU/mL GMC (ELU/mL) 95% CI 95% CI Antibody Group Timing N n % LL UL value LL UL anti-pt PF PRE POST PC PRE POST Control PRE POST anti-fha PF PRE POST PC PRE POST Control PRE POST anti-prn PF PRE POST PC PRE POST Control PRE POST PRE = blood sample taken before the first dose at the first study visit Secondary Outcome Results: Vaccine response for anti-pt, anti-fha and anti-prn antibodies one month after third dose (ATP cohort for immunogenicity) Vaccine Response 95% CI Antibody Group Pre-vaccination N n % LL UL status anti-pt PF S S Total PC S S Total Control S S Total anti-fha PF S S Total PC S S Total Control S S Total anti-prn PF S S

6 Total PC S S Total Control S S Total S- = seronegative subjects (antibody concentration < 5 ELU/mL for anti-pt, anti-fha and anti-prn prior to vaccination S+ = seropositive subjects (antibody concentration >= 5 ELU/mL for anti-pt, anti-fha and anti-prn prior to vaccination Total = subjects either seropositive or seronegative at pre-vaccination Vaccine response defined as: For initially seronegative subjects, antibody concentration >= 5 ELU/ML one month after third dose For initially seropositive subjects: antibody concentration one month after third dose >= 1 fold 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 Secondary Outcome Results: Seroprotection rates and GMCs for anti-diphtheria (ELISA) antibodies (ATP cohort for immunogenicity) 0.1 IU/mL 1 IU/mL GMC (IU/mL) 95% CI 95% CI 95% CI Antibody Group Timing N n % LL UL n % LL UL value LL UL Anti- Diphtheria (ELISA) PF PRE POST PC PRE POST Control PRE POST ) seroprotection = anti-diphtheria (ELISA) antibody concentration >= 0.1 IU/ML PRE = blood sample taken before the first dose at the first study visit Secondary Outcome Results: Number(%) of subjects reporting solicited local symptoms during the 8-day (Days 0-7) postvaccination period following each dose and across doses (Total vaccinated cohort) PF Group PC Group Control Group 95 % CI 95 % CI 95 % CI Symptom Type N n % LL UL N n % LL UL N n % LL UL Dose 1 Pain Any Grade Redness Any >20 mm Swelling Any >20 mm

7 Dose 2 Pain Any Grade Redness Any >20 mm Swelling Any >20 mm Dose 3 Pain Any Grade Redness Any >20 mm Swelling Any >20 mm Across Doses Pain Any Grade Redness Any >20 mm Swelling Any >20 mm N= number of subjects with at least one administered dose n/%= number/percentage of subjects reporting at least once the symptom 95%CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit Grade 3 Pain = Cried when limb was moved/spontaneously painful Secondary Outcome Results: Number(%) of subjects reporting solicited general symptoms during the 8-day (Days 0-7) post-vaccination period following each dose and across doses (Total vaccinated cohort) PF Group PC Group Control Group 95 % CI 95 % CI 95 % CI Symptom Type N n % LL UL N n % LL UL N n % LL UL Dose 1 Drowsiness Any Grade Related Fever/(Rectally) 38.0 C >39.5 C Related Irritability Any Grade Related Loss of appetite Any Grade Related Dose 2 Drowsiness Any Grade Related Fever/(Rectally) 38.0 C >39.5 C Related Irritability Any Grade Related Loss of appetite Any Grade Related

8 Dose 3 Drowsiness Any Grade Related Fever/(Rectally) 38.0 C >39.5 C Related Irritability Any Grade Related Loss of appetite Any Grade Related Across Doses Drowsiness Any Grade Related Fever/(Rectally) 38.0 C >39.5 C Related Irritability Any Grade Related Loss of appetite Any Grade Related N= number of subjects with at least one administered dose n/%= number/percentage of subjects reporting at least once the symptom 95% CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit Grade 3 Drowsiness = Drowsiness that prevented normal activity Grade 3 Irritability = Crying that cannot be comforted/prevented normal activity Grade 3 Loss of appetite = Not eating at all Safety Results: Number (%) of subjects with adverse events (Total vaccinated cohort) Most frequent 10 adverse events - On-Therapy (occurring within day 0-30 following vaccination) PF GroupN = 153 PC Group N = 150 Control Group N = 152 Subjects with any AE(s), n (%) 111 (72.5) 110 (73.3) 117 (77.0) Rhinitis 28 (18.3) 23 (15.3) 22 (14.5) Upper respiratory tract infection 35 (22.9) 16 (10.7) 22 (14.5) Injection site induration 10 (6.5) 18 (12.0) 19 (12.5) Pyrexia 15 (9.8) 18 (12.0) 11 (7.2) Conjunctivitis 15 (9.8) 16 (10.7) 9 (5.9) Diarrhoea 12 (7.8) 6 (4.0) 21 (13.8) Otitis media 6 (3.9) 12 (8.0) 13 (8.6) Cough 8 (5.2) 13 (8.7) 9 (5.9) Rash 5 (3.3) 9 (6.0) 10 (6.6) Constipation 5 (3.3) 11 (7.3) 4 (2.6) Nasal congestion 7 (4.6) 6 (4.0) 6 (3.9) Flatulence 4 (2.6) 5 (3.3) 6 (3.9) Vomiting 3 (2.0) 7 (4.7) 5 (3.3) Safety Results: Number (%) of subjects with serious adverse events during the entire study period (Total vaccinated cohort) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs PF Group N = 153 PC Group N = 150 Control Group N = 152 Subjects with any SAE(s), n (%) [n related] 2 (1.3) [0] 5 (3.3) [1] 5 (3.3) [0] Laryngitis 1 (0.7) [0] 0 (0.0) [0] 1 (0.7) [0]

9 Anal abscess 0 (0.0) [0] 0 (0.0) [0] 1 (0.7) [0] Decreased appetite 0 (0.0) [0] 1 (0.7) [1] 0 (0.0) [0] Dermatitis atopic 0 (0.0) [0] 0 (0.0) [0] 1 (0.7) [0] Gastroenteritis 1 (0.7) [0] 0 (0.0) [0] 0 (0.0) [0] Haematemesis 0 (0.0) [0] 1 (0.7) [0] 0 (0.0) [0] Listless 0 (0.0) [0] 1 (0.7) [0] 0 (0.0) [0] Overdose 0 (0.0) [0] 1 (0.7) [0] 0 (0.0) [0] Pneumonia 0 (0.0) [0] 0 (0.0) [0] 1 (0.7) [0] Pyelonephritis 0 (0.0) [0] 0 (0.0) [0] 1 (0.7) [0] Pyelonephritis acute 0 (0.0) [0] 1 (0.7) [0] 0 (0.0) [0] Pyrexia 0 (0.0) [0] 1 (0.7) [0] 0 (0.0) [0] Upper respiratory tract infection 0 (0.0) [0] 1 (0.7) [0] 0 (0.0) [0] Fatal SAEs PF Group PC Group Control Group Subjects with fatal SAE(s), n (%) [n related] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] Conclusion: One month after the third dose, the upper limits of the standardized asymptotic 95% CIs of the difference between the groups, Control Group minus PF Group, in term of seroprotection rates against diphtheria (Vero), tetanus, Polio 1 and 3 and PRP were all below the pre-defined 10% limit for non-inferiority. The upper limits of the standardized asymptotic 95% CIs of the difference between the groups, Control Group minus PF Group, in term of seroprotection rates against HBs and Polio 2 was above 10%. The upper limit of the 95% CI of the groups GMC ratio, Control Group divided by PF Group, was below the pre-defined 1.5 non-inferiority limit for anti-pt and above 1.5 for anti-fha and anti-prn. At this timepoint, at least 97.8% of subjects had seroprotective anti-diphtheria antibody concentration above IU/mL, and all subjects had seroprotective concentrations of anti-tetanus antibodies in the three groups. Seroprotection rates against hepatitis B, Polio 1, 2 and 3 and PRP were at least 74.4% in each group. GMCs values for anti-pt were 59.2, 49.6 and 67.4 for PF Group, PC Group and Control Group respectively. Considering anti-fha, the values were 135.0, and for PF Group, PC Group and Control Group respectively. For anti-prn, the GMCs values were 68.6, 75.3 and for PF Group, PC Group and Control Group respectively. During the 31-Days follow period after vaccination, unsolicited AEs were reported for 111 (72.5%) subjects in the PF Group, 110 (73.3%) subjects in the PC Group and 117 (77.0%) subjects.in the Control Group During the entire study period, SAEs were reported for 2 (1.3%) subjects in the PF Group, 5 (3.3%) subjects in the PC Group and 5 (3.3%) subjects in the Control Group. One SAE reported in the PC Group was assessed by the investigators as causally related to vaccination. No fatal SAEs were reported during the course of the study. Date updated: 18-May-2015