The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not

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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. GSK Medicine:GSK A Study Number: (SPNG-008) Title: Study to determine protective efficacy against otitis media and assess safety of an investigational protein-based pneumococcal vaccine A in healthy infants. GSK A vaccine (dply-phtd) : GlaxoSmithKline (GSK) Biologicals Streptococcus pneumoniae (S. pneumoniae) protein vaccine Rationale: The purpose of this study was to demonstrate the incremental efficacy of pneumococcal proteins pneumolysin toxoid (dply) and histidine triad protein D (PhtD) over the effect of Prevnar 13 in preventing acute otitis media (AOM) in Native American infants aged less than 24 months, living in the southwestern United States (US) in and around the Navajo and White Mountain Apache reservations as well as to evaluate the impact on acute lower respiratory tract infection (ALRI) and on nasopharyngeal carriage up to the second year of life. Pneumococcal protein vaccine was administered as a three-dose primary vaccination at 2, 4, 6 months of age and as a booster dose at months of age, and co-administered with Prevnar 13. Surveillance for occurrence of AOM and ALRI started from administration of dose 1 of the study vaccine and was conducted over a study period of approximately 22 months to capture the seasonal fluctuations in S. pneumoniae burden and to allow sufficient follow-up for AOM efficacy. The hypothesis was that investigational vaccine would reduce the incidence of clinical AOM compared to control group because pneumococcal proteins have the potential to reduce the pneumococcal non-conjugate vaccine type (NCVT) colonization and disease; these proteins may also enhance the impact on any residual vaccine serotype colonization and disease. Accordingly the study also investigated reduction in ALRI and nasopharyngeal colonization of pneumococcal NCVT. In addition the study also assessed the immunogenicity, reactogenicity and safety of pneumococcal dply and PhtD protein vaccine During the follow-up period, persistence of immune response was evaluated. Similarly, immunogenicity of Prevnar 13 and PedvaxHIB was assessed in order to document potential impact of pneumococcal protein vaccine on Prevnar 13 serotype-specific immune responses and immune response against polyribosylribitol phosphate (PRP) antigen. Placebo containing AlPO4, was selected as control vaccine and allowed the assessment of efficacy, safety and immunogenicity of the pneumococcal dply and PhtD proteins vaccine in a double-blinded manner. Three sub-cohorts of subjects were foreseen: (1) Immuno/reacto sub-cohort for assessment of immunogenicity (400 subjects), (2) Carriage sub-cohort for assessment of impact on carriage of S. pneumoniae ( 800 subjects) and (3) No additional procedures sub-cohort comprising subjects not included in any of the above sub-cohorts ( 600). For each subject the study duration was approximately 22 months: primary epoch starting at Day 0 and ending at Month 5 and booster epoch starting at Month 10 and ending at Month 22; data pertinent to period between Month 5 and Month 10 were collected and reported at the time of booster epoch. Prevnar 13 (Prev13): Pfizer s 13-valent pneumococcal conjugate vaccine PedvaxHIB: Haemophilus influenzae b conjugate vaccine (Meningococcal Protein Conjugate) Placebo: Alum (AlPO4) placebo Phase: II Study Period: From 21 May 2012 to 26 July Study Design: Double-blind, randomized, placebo-controlled, multi-centric, single-country study Centers: 5 centers in the US Indication: Three-dose primary vaccination against S. pneumoniae of healthy infants between 6-12 weeks (42-90 days) of age at the time of the first vaccination, followed by a booster dose at months of age. Treatment: The study groups were as follows: -: subjects who received investigational dply-phtd vaccine co-administered with Prev13, as primary vaccination at 2, 4, 6 months of age and as booster vaccination at months of age. -: subjects who received Placebo co-administered with Prev13, as primary vaccination at 2, 4, 6 months of age and as booster vaccination at months of age. Notes: -Prev13 was given as study vaccine to all subjects at 2, 4, 6 and months of age. Immunogenicity was assessed only in the Immuno/reacto sub-cohort. No reactogenicity was assessed at Prevnar 13 injection site. -PedvaxHIB was given as study vaccine to subjects in the Immuno/reacto sub-cohort at 2, 4 and months.

2 Immunogenicity was assessed post-primary, pre-booster and one and twelve months post-booster vaccination with no assessment of reactogenicity. For the Carriage and No additional procedure sub-cohorts, a Hib vaccine was given as part of the routine vaccination schedule. -All subjects were allowed to receive licensed inactivated influenza vaccines at any time even if concomitantly administered with the study vaccines, and/or recommended pediatric vaccines (for example Diphtheria-tetanus-acellular pertussis vaccine (DTaP), Inactivated poliovirus (IPV), Hepatitis B virus vaccine (HepB), rotavirus, Measles Mumps and Rubella vaccine (MMR), Hepatitis A virus (vaccine) (HepA), varicella vaccines) which might be administered either concomitantly or at least 7 days before or after each dose of study vaccines. The dply-phtd and Placebo vaccines were administered intramuscularly into the right anterolateral thigh at the primary epoch and, into the right deltoid or anterolateral thigh (if the deltoid muscle size was not adequate) at the booster epoch. The co-administered Prev13 and PedvaxHIB vaccines were administered intramuscularly into the left anterolateral thigh at the primary epoch and into the left deltoid or anterolateral thigh (if the deltoid muscle size was not adequate) at the booster epoch. Objectives: To demonstrate the efficacy of a 3-dose primary course at 2, 4 and 6 months of age followed by a booster dose at months of age with dply-phtd vaccine co-administered with Prev13 in preventing clinical AOM diagnosed and verified against American Academy of Pediatrics (AAP) criteria. Criteria: Efficacy (VE) in preventing clinical AOM diagnosed and verified against AAP criteria was to be demonstrated if the one-sided p-value calculated for the null hypothesis H0 = (clinical AOM VE 0%) was lower than the one-sided alpha level of 17.8%. Primary Outcome Variable(s): Efficacy (in all subjects) Occurrence of any clinical AOM episodes diagnosed and verified against AAP criteria. Secondary Outcome Variable(s): Efficacy (in all subjects) Occurrence of any healthcare-provider-diagnosed clinical AOM. Occurrence of any clinical AOM episodes diagnosed and verified against modified AAP criteria. Occurrence of any recurrent AOM (at least 3 episodes in 6 months or at least 4 episodes in 12 months). Occurrence of any draining AOM. Occurrence of any draining pneumococcal AOM. Occurrence of AOM with temporally related carriage. Occurrence of any medically attended ALRI. Occurrence of medically attended ALRI with fever documented at the visit or history of fever within 3 days preceding a given episode. Occurrence of any medically attended healthcare-provider-diagnosed ALRI with fever documented at the visit or history of fever within 3 days preceding a given episode. Carriage (in Carriage sub-cohort) One month post-dose 3 [PIII(M5)], prior to booster dose [PIII(M10)] and six and twelve months post-booster dose [Postbooster(M16) and Post-booster(M22), respectively] Occurrence of S. pneumoniae (any and serotype specific) in the nasopharynx. Immunogenicity (in Immuno/reacto sub-cohort) One month post-dose 3 [PIII(M5)], prior to booster dose [Pre-booster (M10), one and twelve months post-booster dose [Post-booster(M11) and Post-booster(M22), respectively] Immune responses to components of the investigational vaccine. Concentrations of antibodies against pneumococcal dply and PhtD proteins. Level of anti-ply antibodies inhibiting Ply haemolysis activity* Immune responses to components of the co-administered PedvaxHIB vaccine. Concentrations of antibodies against Polyribosylribitol phosphate (PRP)**. One month post-dose 3 [PIII(M5)], prior to booster dose [Pre-booster(M10)] and one month post-booster dose [Post-booster (M11)] Immune responses to components of the co-administered Prevnar 13 vaccine.

3 Concentrations of antibodies against vaccine pneumococcal serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F #. Concentrations of antibodies against cross-reactive pneumococcal serotype 6C***. One month post-dose 3 [PIII(M5)] and one month post-booster dose [Post-booster(M11)] Immune responses to components of the co-administered Prevnar 13 vaccine for additional parameters # Opsonophagocytic activity against vaccine pneumococcal serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. Opsonophagocytic activity against cross-reactive pneumococcal serotype 6C. Safety and reactogenicity: Occurrence of solicited local and general Adverse events (AEs) (in Immuno/reacto sub-cohort) Occurrence of each solicited local AE (any, grade 3) within 4 days (Day 0 - Day 3) after each pneumococcal protein vaccine dose. Occurrence of each solicited general AE (any, grade 3, related) within 4 days (Day 0 - Day 3) after each vaccine dose. Occurrence of unsolicited AEs (in Immuno/reacto sub-cohort) Occurrence of unsolicited AEs within 31 days (Day 0 - Day 30) after any vaccination, according to the Medical Dictionary for Regulatory Activities (MedDRA) classification. Occurrence of Serious adverse events (SAEs) (in all subjects) - Occurrence of SAEs during the entire study period (from Day 0 to Month 22). - *Inhibition of Ply hemolysis activity was not evaluated due to assay stability issues. **Antibody concentrations against PRP at Month 22 will be presented when available. ***Assay linked to antibody concentrations against serotype 6C was not performed. # Antibody concentrations and OPA titers against vaccine pneumococcal serotypes will be presented when available. Statistical Methods: Analyses were performed on the Total Vaccinated cohort, the Modified According To Protocol (ATP) cohort for efficacy and the ATP cohort for immunogenicity. The Total Vaccinated cohort included all vaccinated subjects who received at least one vaccination dose. The Modified ATP cohort for efficacy included all evaluable subjects from the ATP cohort for efficacy (i.e. those meeting all eligibility criteria, complying with the procedures and intervals between primary doses as defined in the protocol, with no applicable elimination criteria during the study for this cohort and for whom data concerning efficacy outcome measures were available), for whom non-compliance with the vaccination intervals during primary vaccination constituted the only elimination criterion from ATP cohort for efficacy. The ATP cohort for immunogenicity included all evaluable subjects from the Immuno/reacto* sub-cohort (who were included in the Total Vaccinated cohort), i.e. those meeting all eligibility criteria, complying with the procedures and intervals defined in the protocol for study vaccine and investigational vaccine Prevnar13 (note that non-compliance with PedvaxHib vaccination schedule did not constitute an elimination criteria) and between defined vaccination and blood sampling, with no applicable elimination criteria during the study for this cohort, and for whom data concerning immunogenicity outcome measures were available. Analysis of efficacy The analysis was performed on the Modified ATP cohort and the Total Vaccinated cohort. The confirmatory analysis of efficacy with the associated vaccine efficacy (VE) was based on the occurrence of all episodes of clinical AOM diagnosed and verified against AAP criteria (AAP AOM) anytime from two weeks after the administration of the third primary dose of the study vaccine up to Month 22 or up to the time of censoring or up to the time of withdrawal (whichever came first). Time to occurrence of AAP AOM during the defined efficacy follow-up period was compared between both groups to estimate VE and its 95% confidence interval (CI) using the Anderson & Gill model, with a robust sandwich estimator for variance matrix considered as a generalization of the Cox proportional hazard model, taking into account recurrent events [Kelly, 2000].The VE was defined as 1 minus the hazard ratio: VE = (1 hazard ratio) x 100. In order to check the statistical significance, the 1-sided p-value for the Wald-Test obtained from the generalized Cox proportional hazard model was calculated. The objective was to be met if the one-sided p-value calculated for the null hypothesis H0 = [clinical AOM VE 0%] was lower than defined 1-sided alpha level (17.8%) at the end of study. The number of episodes, follow-up days and associated rate, in addition to the VE with 95% CI based on generalized Cox

4 model was tabulated for each outcome: AOM diagnosed and verified against modified AAP criteria, AOM diagnosed by healthcare provider, draining AOM including draining pneumococcal AOM and draining non-pneumococcal AOM, medically attended ALRI, ALRI with defined fever or history of fever and ALRI diagnosed by Healthcare provider with defined fever or history of fever. The number and associated rate of recurrent AOM was computed per group with 95% CI. Occurrence of AOM with temporally related carriage taken within 3 days of diagnosis was computed for both groups. Analysis of immunogenicity The analysis was performed on the ATP cohort for immunogenicity. For each group, at each appropriate time point that a blood sample result was available, geometric mean concentrations (GMCs) with their 95% CIs were tabulated and seropositivity rates with exact 95%CIs were calculated for each appropriate antigen. Analysis of carriage The analysis was performed on the Total Vaccinated cohort. Number of subjects with positive nasopharyngeal sample were calculated per group at each swab time point and VE with 95% CI, were calculated for carriage of S.pneumoniae. Analysis of safety The analysis was performed on the Total Vaccinated cohort For each group, in the Immuno/reacto sub-cohort, the incidence of each individual solicited local and general symptom reported during the 4-day (Days 0-3) after primary and booster vaccination period was calculated with exact 95% CIs after each vaccine dose and across doses. The same tabulation was performed for Grade 3 solicited symptoms and for general solicited symptoms with causal relationship to vaccination. For both groups in the Immuno/reacto sub-cohort, the percentage of subjects with at least 1 unsolicited AE within the 31-Day (Days 0-30) after primary and booster vaccination was tabulated. Solicited and unsolicited symptoms experienced by at least 5 % of subjects, classified by MedDRA Primary System Organ Class and Preferred Term within the 31-day post-primary and booster vaccination period, including number of events reported and excluding SAEs, were tabulated. For all subjects in both groups, the number and percentage of subjects with at least 1 SAE occurring during entire study period (Day-0 to Month-22) as well as the number of SAEs were tabulated according to MedDRA Primary System Organ Class and Preferred Term, for both groups. The table includes SAEs with causal relationship to vaccination and fatal SAEs. Study Population: Healthy, as established by medical history and clinical examination before entering the study, male and female American Indian infants born after a gestation period of more than 35 6/7 weeks, between and including, 6 and 12 weeks (42-90 days) of age at the time of the first vaccination, without use of any investigational or non-registered product (drug or vaccine) other than the study vaccine within 30 days preceding the first dose of study vaccine, or planned use during the study period; without chronic administration of immuno-suppressants or other immune-modifying drugs since birth and with no previous vaccination against S. pneumoniae were included in the study. Written inform consent was obtained from the parent(s)/legally Authorized Representative(s) (LAR) of the subject before study entry. Where parent(s)/lar(s) were illiterate, the consent form was countersigned by a witness. Number of subjects vaccinated, completed and withdrawn with reason for withdrawal (Total Vaccinated cohort) Number of subjects vaccinated Number of subjects completed Number of subjects withdrawn Reasons for withdrawal: Serious Adverse Event 0 0 Non-Serious Adverse Event 2 1 Protocol violation 3 3 Consent withdrawal (not due to an adverse event) Migrated/moved from study area Lost to follow-up (subjects with incomplete 8 0 vaccination course) Lost to follow-up (subjects with complete vaccination 3 4 course) Sponsor study termination 0 0

5 Other Vaccinated = number of subjects who were vaccinated in the study Completed = number of subjects who completed last study visit Withdrawn = number of subjects who did not come back for the last visit Summary of demographic characteristics (Total Vaccinated cohort) Demographics N = 900 N = 903 Characteristics Parameters or Value or n % Value or n % Age (Weeks) at vaccination dose 1 Categories Mean SD Median Minimum Maximum Sex Female Male Geographic Ancestry American Indian or Alaskan Native N = Total number of subjects n/% = number / percentage of subjects in a given category Value = value of the considered parameter SD = standard deviation Primary Outcome Results: Vaccine Efficacy (with p-value) for time to occurrence of any episodes of AOM diagnosed and verified against AAP criteria (AAP AOM) anytime from 2 weeks after the administration of dose 3 (Modified ATP cohort for efficacy) Person-year rate VE Event Type Group N n T (year) n/t LL UL % LL UL 1-SIDED P-VALUE* AAP AOM dply/phtd Control N = number of subjects n = number of episodes T(year) = sum of follow-up expressed in years n/t = person-year rate n/t LL-UL = lower and upper limits of the exact 95% confidence interval around n/t VE (%) = vaccine efficacy (generalized Cox regression model) VE LL-UL = lower and upper limits of the 95% confidence interval around VE derived from generalized Cox regression model *Criterion: VE in preventing clinical AAP AOM was to be demonstrated if the 1-sided p-value calculated for the null hypothesis H0 = (clinical AOM VE 0%) was lower than the 1-sided alpha level of 17.8%. Note: Censoring variables were taken into account to compute the occurrence of cases Secondary Outcome Results: Vaccine Efficacy for time to occurrence of any episodes of AOM diagnosed and verified against modified AAP criteria (AAP-MOD AOM) and AOM diagnosed by healthcare provider (HCP AOM) anytime from 2 weeks after the administration of dose 3 (Modified ATP cohort for efficacy) Person-year rate VE Event Type Group N n T (year) n/t LL UL % LL UL AAP-MOD AOM dply/phtd Control HCP AOM dply/phtd Control

6 N = number of subjects n = number of episodes T(year) = sum of follow-up expressed in years n/t = person-year rate n/t LL-UL = lower and upper limits of the exact 95% confidence interval around n/t VE (%) = vaccine efficacy (generalised Cox regression model) VE LL-UL = lower and upper limits of the 95% confidence interval around VE derived from generalised Cox regression model Note: Censoring variables were taken into account to compute the occurrence of cases Secondary Outcome Results: Vaccine Efficacy for time to occurrence of any episodes of draining AOM, draining pneumococcal AOM and draining non-pneumococcal AOM anytime from 2 weeks after the administration of dose 3 (Modified ATP cohort for efficacy) Person-year rate VE Event Type Group N n T (year) n/t LL UL % LL UL Draining AOM dply/phtd Control Draining pneumococcal AOM dply/phtd Control Draining non-pneumococcal dply/phtd AOM Control N = number of subjects n = number of episodes T(year) = sum of follow-up expressed in years n/t = person-year rate n/t LL-UL = lower and upper limits of the exact 95% confidence interval around n/t VE (%) = vaccine efficacy (generalised Cox regression model) VE LL-UL = lower and upper limits of the 95% confidence interval around VE derived from generalised Cox regression model Note: Censoring variables were taken into account to compute the occurrence of cases Secondary Outcome Results: Vaccine Efficacy for time to occurrence of any episodes of medically attended ALRI (MA- ALRI), ALRI with defined fever or history of fever (ALRI with fever) and ALRI diagnosed by Health-Care Provider with defined fever or history of fever (HCP-ALRI with fever) anytime from 2 weeks after the administration of dose 3 (Modified ATP cohort for efficacy) Person-year rate VE Event Type Group N n T (year) n/t LL UL % LL UL MA-ALRI dply/phtd Control ALRI with fever dply/phtd Control HCP-ALRI with fever dply/phtd Control N = number of subjects n = number of episodes T(year) = sum of follow-up expressed in years n/t = person-year rate n/t LL-UL = lower and upper limits of the exact 95% confidence interval around n/t VE (%) = vaccine efficacy (generalised Cox regression model) VE LL-UL = lower and upper limits of the 95% confidence interval around VE derived from generalised Cox regression model Note: Censoring variables were taken into account to compute the occurrence of cases Secondary Outcome Results: Occurrence of recurrent healthcare provider diagnosed AOM anytime from the administration of dose 1 (Total Vaccinated cohort) N = 900 N = 903

7 Event Type n % LL UL n % LL UL Recurrent HCP-AOM Recurrent AOM defined as at least 3 AOM episodes diagnosed by a physician or equivalent licensed medical professional and occurring within 6 months or at least 4 episodes within one year, regardless of the etiology. N = number of subjects n/% = number/percentage of subjects reporting at least one event LL, UL for percentage = Exact 95% Lower and Upper confidence limits Secondary Outcome Results: Occurrence of AOM with temporally related carriage anytime from the administration of dose 1 (Total Vaccinated cohort) N = 900 N = 903 Event Type n % LL UL n % LL UL AOM with temporally related carriage N = number of subjects n/% = number/percentage of subjects reporting at least one event LL, UL for percentage = Exact 95% Lower and Upper confidence limit Secondary Outcome Results: Occurrence of any S.pneumoniae in nasopharyngeal swabs and Vaccine Efficacy- Carriage sub-cohort (Total Vaccinated cohort) VE 95% CI Age Timing N n % LL UL N n % LL UL % LL UL 6-12 weeks Day 0* months Month months Month months Month months Month Across all post-vaccination time points N = number of subjects with swab cultured at the considered time point n/% = number/percentage of subjects with swab positive for the specified bacteria at the considered time point Across all post-vaccination time points: N = number of subjects with swab cultured after at least Month 5, and 22 n/% = number/percentage of subjects with swab positive for the specified bacteria after at least one post-vaccination time point VE [%] = vaccine efficacy estimated as 1-Relative Risk LL = lower limit, UL = upper limit of the 95% confidence interval [CI] [conditional exact method] *Vaccine efficacy computed at Day 0 reflects difference in incidences before any vaccine dose administration Secondary Outcome Results: Number(%) of subjects with anti-ply antibody concentration greater than or equal to 12 EL.U/mL and GMCs - Immuno/reacto sub-cohort (ATP cohort for immunogenicity) 12 EL.U/mL GMC (EL.U/mL) Antibody Group Timing N n % LL UL value LL UL anti-ply dply/phtd PRE(D0) PIII(M5) Pre-Booster(M10) Post-Booster(M11) Post-Booster(M22) Control PRE(D0) PIII(M5) Pre-Booster(M10) Post-Booster(M11) Post-Booster(M22)

8 N= number of subjects with available results n/% = number/percentage of subjects with concentration within the specified range GMC = geometric mean antibody concentration 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE(D0) = pre-vaccination blood sample PIII(M5) = one month post-dose 3 Pre-Booster(M10) = prior to booster dose Post-Booster(M11) = one month post-booster dose Post-Booster(M22) = twelve months post-booster dose Secondary Outcome Results: Number (%) of subjects with anti-phtd antibody concentration greater than or equal to 17 EL.U/mL and GMCs - Immuno/reacto sub-cohort (ATP cohort for immunogenicity) 17 EL.U/mL GMC (EL.U/mL) Antibody Group Timing N n % LL UL value LL UL anti-phtd dply/phtd PRE(D0) PIII(M5) Pre-Booster(M10) Post-Booster(M11) Post-Booster(M22) Control PRE(D0) PIII(M5) Pre-Booster(M10) Post-Booster(M11) Post-Booster(M22) N= number of subjects with available results n/% = number/percentage of subjects with concentration within the specified range GMC = geometric mean antibody concentration 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE(D0) = pre-vaccination blood sample PIII(M5) = one month post-dose 3 Pre-Booster(M10) = prior to booster dose Post-Booster(M11) = one month post-booster dose Post-Booster(M22) = twelve months post-booster dose Secondary Outcome Results: Number (%) of subjects with anti-prp antibody concentration greater than or equal to 0.15 µg/ml or 1 µg/ml and GMCs - Immuno/reacto sub-cohort (ATP cohort for immunogenicity) 0.15 µg/ml 1 µg/ml GMC (µg/ml) 95% CI Antibody Group Timing N n % LL UL n % LL UL value LL UL anti-prp dply/phtd PIII(M5) Pre-Booster(M10) Post-Booster(M11) Control PIII(M5) Pre-Booster(M10) Post-Booster(M11) N= number of subjects with available results n/% = number/percentage of subjects with concentration within the specified range GMC = geometric mean antibody concentration 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PIII(M5) = one month post-dose 3 Pre-Booster(M10) = prior to booster dose Post-Booster(M11) = one month post-booster dose Secondary Outcome Results: Number (%) of subjects with solicited local symptoms during the 4-day (Days 0-3) postprimary vaccination period following each dose and across doses Immuno/reacto sub-cohort (Total Vaccinated cohort)

9 Symptom Intensity N n % LL UL N n % LL UL 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 >30 mm Swelling Any >30 mm N = number of subjects with at least one documented dose 95%CI = Exact 95% CI; LL = Lower Limit, UL = Upper Limit Any = Occurrence of any local symptom regardless of its intensity grade Grade 3 Pain = Cried when limb was moved/spontaneously painful Secondary Outcome Results: Number (%) of subjects with solicited general symptoms during the 4-day (Days 0-3) postprimary vaccination period following each dose and across doses Immuno/reacto sub-cohort (Total Vaccinated cohort) Symptom Intensity/Relationship N n % LL UL N n % LL UL Dose 1 Drowsiness Any Grade Related Irritability / fussiness Any Grade Related Loss of appetite Any Grade Related Temperature (Axillary) 38.0 C >40.0 C Related Dose 2 Drowsiness Any Grade

10 Related Irritability / fussiness Any Grade Related Loss of appetite Any Grade Related Temperature (Axillary) 38.0 C >40.0 C Related Dose 3 Drowsiness Any Grade Related Irritability / fussiness Any Grade Related Loss of appetite Any Grade Related Temperature (Axillary) 38.0 C >40.0 C Related Across doses Drowsiness Any Grade Related Irritability / fussiness Any Grade Related Loss of appetite Any Grade Related Temperature (Axillary) 38.0 C >40.0 C Related N = number of subjects with at least one documented dose 95%CI = Exact 95% CI; LL = Lower Limit, UL = Upper Limit Any = Occurrence of any general symptom regardless of intensity grade or relationship to vaccination Grade 3 Drowsiness = Symptom that prevented normal activity Grade 3 Irritability/fussiness =Crying that could not be comforted/symptom that prevented normal activity Grade 3 Loss of appetite =Did not eat at all Related = Symptom assessed by the investigator as causally related to study vaccination Secondary Outcome Results: Number (%) of subjects with solicited local symptoms during the 4-day (Days 0-3) postbooster vaccination period Immuno/reacto sub-cohort (Total Vaccinated cohort) 95 % CI 95 % CI Symptom Intensity N n % LL UL N n % LL UL Pain Any Grade Redness Any >30 mm Swelling Any >30 mm

11 N = number of subjects with the documented dose 95%CI = Exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit Any = Occurrence of any local symptom regardless of its intensity grade Grade 3 Pain = Cried when limb was moved/spontaneously painful Secondary Outcome Results: Number (%) of subjects with solicited general symptoms during the 4-day (Days 0-3) postbooster vaccination period Immuno/reacto sub-cohort (Total Vaccinated cohort) Symptom Intensity/Relationship N n % LL UL N n % LL UL Drowsiness Any Grade Related Irritability / fussiness Any Grade Related Loss of appetite Any Grade Related Temperature (Axillary) 38.0 C >40.0 C Related N = number of subjects with the documented dose 95%CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit Any = Occurrence of any general symptom regardless of intensity grade or relationship to vaccination Grade 3 Drowsiness = Symptom that prevented normal activity Grade 3 Irritability/fussiness =Crying that could not be comforted/symptom that prevented normal activity Grade 3 Loss of appetite =Did not eat at all Related = Symptom assessed by the investigator as causally related to study vaccination Secondary Outcome Results: Number (%) of subjects reporting unsolicited AEs within the 31-day (Days 0-30) post-primary vaccination period Immuno/reacto sub-cohort (Total Vaccinated cohort) N = 200 N = 200 n % LL UL n % LL UL At least one symptom At least one symptom = at least one symptom experienced (regardless of the MedDRA Preferred Term) N = number of subjects with at least one administered dose 95% CI = exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit Secondary Outcome Results: Number (%) of subjects reporting unsolicited AEs within the 31-day (Days 0-30) post-booster vaccination period Immuno/reacto sub-cohort (Total Vaccinated cohort) N = 178 N = 174 n % LL UL n % LL UL At least one symptom At least one symptom = at least one symptom experienced (regardless of the MedDRA Preferred Term) N = number of subjects with the administered dose 95% CI = exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit Secondary Outcome Results: Number (%) of subjects reporting the occurrence of SAEs during the whole study period (Total Vaccinated cohort): Please refer to the safety section.

12 Safety Results: Solicited and unsolicited symptoms experienced by at least 5 % of subjects, classified by MedDRA Primary System Organ Class and Preferred Term within the 31-day (Days 0-30) post vaccination period, including number of events reported - SAE excluded Immuno/reacto sub-cohort (Total Vaccinated cohort) N = 200 N = 200 Primary System Organ Class (CODE) Preferred Term (CODE) n* n % LL UL n* n % LL UL At least one symptom Gastrointestinal disorders ( ) Diarrhoea ( ) Teething ( ) General disorders and administration site Pain ( ) conditions ( ) Pyrexia ( ) Swelling ( ) Infections and infestations ( ) Conjunctivitis ( ) Upper respiratory tract infection ( ) Viral infection ( ) Metabolism and nutrition disorders Decreased appetite ( ) ( ) Nervous system disorders ( ) Somnolence ( ) Psychiatric disorders ( ) Irritability ( ) Respiratory, thoracic and mediastinal Cough ( ) disorders ( ) Rhinorrhoea ( ) Skin and subcutaneous tissue disorders Dermatitis diaper ( ) ( ) Erythema ( ) At least one symptom = at least one symptom experienced (regardless of the MedDRA Preferred Term) N = number of subjects with the administered dose n* = number of events reported 95% CI = Exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit Safety Results: Number (%) of subjects with SAEs during the whole study period (Day-0 to Month-22) including number of events reported (Total Vaccinated cohort) dply/phtd Group N = 900 Control Group N = 903 Type of Event Primary System Organ Class Preferred Term (CODE) n* n % n* n % SAE At least one symptom Cardiac disorders ( ) Cardiac failure congestive ( ) Congenital, familial and genetic disorders Benign familial neonatal convulsions ( ) ( ) Haemangioma congenital ( ) Ear and labyrinth disorders ( ) Tympanic membrane perforation ( ) Gastrointestinal disorders ( ) Diarrhoea ( ) Gastrooesophageal reflux disease ( ) Sandifer s syndrome ( ) Stomatitis ( ) Vomiting ( ) General disorders and administration site conditions ( ) Developmental delay ( ) Fever neonatal ( ) Influenza like illness ( ) Pyrexia ( )

13 Hepatobiliary disorders ( ) Acute hepatic failure ( ) Immune system disorders ( ) Anaphylactic reaction ( ) Drug hypersensitivity ( ) Infections and infestations ( ) Abscess neck ( ) Adenovirus infection ( ) Arthritis bacterial ( ) Bacterial pyelonephritis ( ) Bacteriuria ( ) Bronchiolitis ( ) Campylobacter gastroenteritis ( ) Cellulitis ( ) Cellulitis staphylococcal ( ) Coxsackie viral infection ( ) Croup infectious ( ) Dacryocystitis ( ) Eczema herpeticum ( ) Escherichia bacteraemia ( ) Escherichia pyelonephritis ( ) Escherichia urinary tract infection ( ) Gastroenteritis ( ) Gastroenteritis salmonella ( ) Gastroenteritis viral ( ) Groin abscess ( ) Haemophilus bacteraemia ( ) Impetigo ( ) Influenza ( ) Lower respiratory tract infection viral ( ) Mastoiditis ( ) Meningitis ( ) Otitis media ( ) Otitis media acute ( ) Parainfluenzae virus infection ( ) Parotitis ( ) Periorbital cellulitis ( ) Periumbilical abscess ( ) Pertussis ( ) Pneumococcal bacteraemia ( ) Pneumococcal sepsis ( ) Pneumonia ( ) Pneumonia bacterial ( ) Pneumonia influenzal ( ) Pneumonia pneumococcal ( ) Pneumonia respiratory syncytial viral ( ) Pneumonia viral ( ) Pseudomonal sepsis ( ) Pyelonephritis ( )

14 Respiratory syncytial virus bronchiolitis ( ) Sepsis ( ) Septic shock ( ) Sinusitis ( ) Staphylococcal abscess ( ) Staphylococcal sepsis ( ) Tonsillitis ( ) Upper respiratory tract infection ( ) Urinary tract infection ( ) Urinary tract infection enterococcal ( ) Viral infection ( ) Viral rash ( ) Injury, poisoning and procedural Accidental exposure to product complications ( ) ( ) Animal bite ( ) Burns second degree ( ) Craniocerebral injury ( ) Femur fracture ( ) Foreign body ( ) Head injury ( ) Injury ( ) Pulmonary contusion ( ) Road traffic accident ( ) Skull fracture ( ) Subarachnoid haemorrhage ( ) Thermal burn ( ) Investigations ( ) Blood culture positive ( ) Metabolism and nutrition disorders Dehydration ( ) ( ) Failure to thrive ( ) Hypernatraemia ( ) Hypocalcaemia ( ) Hypochloraemia ( ) Hyponatraemia ( ) Metabolic acidosis ( ) Musculoskeletal and connective tissue Juvenile idiopathic arthritis disorders ( ) ( ) Neoplasms benign, malignant and Clear cell sarcoma of the kidney unspecified (incl cysts and polyps) ( ) ( ) Neuroblastoma ( ) Nervous system disorders ( ) Epilepsy ( ) Febrile convulsion ( ) Haemorrhage intracranial ( ) Partial seizures ( ) Seizure ( ) Tremor ( ) Psychiatric disorders ( ) Mental status changes ( ) Reproductive system and breast Balanoposthitis ( ) disorders ( ) Respiratory, thoracic and mediastinal disorders ( ) Apnoeic attack ( ) Apparent life threatening event ( )

15 Related SAE Asthma ( ) Bronchial hyperreactivity ( ) Choking ( ) Cough ( ) Hypoxia ( ) Pneumonia aspiration ( ) Pneumonitis ( ) Respiratory disorder ( ) Respiratory distress ( ) Status asthmaticus ( ) Wheezing ( ) Skin and subcutaneous tissue disorders Dermatitis atopic ( ) ( ) Vascular disorders ( ) Haematoma ( ) Kawasaki s disease ( ) At least one symptom Gastrointestinal disorders ( ) Diarrhoea ( ) General disorders and administration site Pyrexia ( ) conditions ( ) Nervous system disorders ( ) Febrile convulsion ( ) At least one symptom Fatal SAE Related At least one symptom fatal SAE At least one symptom = at least one symptom experienced (regardless of the MedDRA Preferred Term) N = number of subjects with the administered dose n* = number of events reported Conclusion: The confirmatory objective to demonstrate the efficacy of GSK Biologicals pneumococcal protein vaccine in young children when given as a 3+1 infant schedule co-administered with Prevnar 13 in preventing clinical AOM diagnosed and verified against AAP criteria was not reached as the one-sided p-value calculated for the null hypothesis H0 = (clinical AAP-AOM VE 0%) was 30.2%, which is higher than the pre-defined level of 17.8%. During the 31-day post-primary vaccination period in the Immuno/reacto sub cohort, at least one unsolicited symptom was reported for 114 (57.0%) subjects in both dply/phtd and Control groups. During the 31-day post-booster vaccination period, at least one unsolicited symptom was reported for 53 (29.8%) and 47 (27.0%) subjects in the dply/phtd and Control groups, respectively During the entire study period, at least one SAE was reported for 461 out of 1803 subjects: 229 (25.4%) subjects in the dply/phtd group and 232 (25.7%) in the Control group. Among these, for 3 subjects, 4 SAEs were assessed by the investigator as causally related to vaccination: one subject was reported with diarrhea and pyrexia, one subject was reported with pyrexia (both from the dply/phtd group) and one subject from the was reported with febrile convulsion. No fatal SAEs were reported during the study period. Date updated: 10-July-2017