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    Clinical Trial Results:
    Study to compare immunogenicity of GSK Biologicals' 10Pn-PD-DiT 4-dose presentation to the licensed Synflorix (10Pn-PD-DiT) vaccine when co-administered with DTPw-combination vaccine in healthy infants

    Summary
    EudraCT number
    		 2014-000750-11
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    22 May 2016

    Results information
    Results version number
    		 v3(current)
    This version publication date
    04 Nov 2022
    First version publication date
    20 Nov 2016
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    Correction of full data set and alignment between registries.

    Trial information

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    Trial identification
    Sponsor protocol code
    200799
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02447432
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l’Institut 89, Rixensart, Belgium, B-1330
    Public contact
    Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    22 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the non-inferiority of 10Pn-PD-DiT vaccine (4-dose presentation) as compared to 10Pn-PD-DiT vaccine (Synflorix 1-dose presentation) in terms of the immune response to the 10 vaccine pneumococcal serotypes one month after dose 3. Criterion: Non-inferiority was demonstrated if the upper limit (UL) of the 2-sided 95% confidence interval (CI) of the geometric mean antibody concentration (GMC) ratios (Synflorix/10Pn_4d) was below a limit of 2-fold for each of the 10 vaccine pneumococcal serotypes.
    Protection of trial subjects
    All subjects were supervised for 30 min after vaccination with appropriate medical treatment readily available. Vaccines were administered by qualified and trained personnel. Only eligible subjects that had no contraindications to any components of the vaccines were vaccinated. Subjects were followed-up for 30 days after each/last vaccination.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Jun 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bangladesh: 320
    Worldwide total number of subjects
    320
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    320
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Two epochs were defined in the study. The duration of the study was for Epoch 001: Primary starting at Month 0 and ending at Month 4 and for Epoch 002: Booster starting at Month 8 and ending at Month 9. 5 subjects did not participate to the Epoch 002 (none due to an serious adverse event).

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 320
    Number of subjects completed
    		 320

    Period 1
    Period 1 title
    Epoch 001
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Observer-blind: during the course of the study, the vaccine recipient and those responsible for the evaluation of any study outcome were all unaware of which vaccine was administered. Vaccine preparation and administration was done by authorised medical personnel who didn’t participate in any of the study clinical evaluation. The laboratory in charge of the laboratory testing was blinded to the treatment, and codes were used to link the subject and study to each sample.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 10Pn_4d Group
    Arm description
    		 Healthy male or female subjects, between and including 6 to 10 weeks (42-76 days) of age at the time of first vaccination, received 3 doses of the investigational 4-dose presentation 10Pn-PD-DiT vaccine given approximatively at 6, 10 and 18 weeks of age (primary vaccination – Epoch 001) and 3 doses of DTPw-HBV/Hib vaccine given approximatively at 6, 10 and 14 weeks of age (according to the EPI schedule). They also received a booster dose of the 4-dose presentation 10Pn-PD-DiT vaccine at approximatively 9 months of age (Epoch-002).
    Arm type
    		 Experimental

    Investigational medicinal product name
    10Pn-PD-DiT 4-dose presentation
    Investigational medicinal product code
    GSK1024850A
    Other name
    10Pn-PD-DiT-4-dose presentation
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    3 doses were given approximatively at 6, 10 and 18 weeks of age (primary vaccination) and a booster dose at approximatively 9 months of age. The vaccine was administered by intramuscular injection into the right anterolateral thigh.

    Investigational medicinal product name
    Tritanrix HB
    Investigational medicinal product code
    DTPw-HBV
    Other name
    DTPw-HBV
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Tritanrix HB and Hiberix were used for the preparation of the DTPw-HBV/Hib vaccine: DTPw-HBV component: suspension in monodose vial to be reconstituted with Hib component. 3 doses were given approximatively at 6, 10 and 14 weeks of age (primary vaccination). The vaccine was administered by intramuscular injection into the left anterolateral thigh.

    Investigational medicinal product name
    Hiberix
    Investigational medicinal product code
    Hib
    Other name
    Hib
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Tritanrix HB and Hiberix were used for the preparation of the DTPw-HBV/Hib vaccine: DTPw-HBV component: suspension in monodose vial to be reconstituted with Hib component. 3 doses were given approximatively at 6, 10 and 14 weeks of age (primary vaccination). The vaccine was administered by intramuscular injection into the left anterolateral thigh.

    Arm title
    		 Synflorix Group
    Arm description
    		 Healthy male or female subjects, between and including 6 to 10 weeks (42-76 days) of age at the time of first vaccination, received 3 doses of the licensed 1-dose presentation 10Pn-PD-DiT (Synflorix) vaccine given approximatively at 6, 10 and 18 weeks of age (primary vaccination – Epoch 001) and 3 doses of DTPw-HBV/Hib vaccine given approximatively at 6, 10 and 14 weeks of age (according to the EPI schedule). They also received a booster dose of the 1-dose presentation 10Pn-PD-DiT vaccine at approximatively 9 months of age (Epoch-002).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tritanrix HB
    Investigational medicinal product code
    DTPw-HBV
    Other name
    DTPw-HBV
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Tritanrix HB and Hiberix were used for the preparation of the DTPw-HBV/Hib vaccine: DTPw-HBV component: suspension in monodose vial to be reconstituted with Hib component. 3 doses were given approximatively at 6, 10 and 14 weeks of age (primary vaccination). The vaccine was administered by intramuscular injection into the left anterolateral thigh.

    Investigational medicinal product name
    Hiberix
    Investigational medicinal product code
    Hib
    Other name
    Hib
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Tritanrix HB and Hiberix were used for the preparation of the DTPw-HBV/Hib vaccine: DTPw-HBV component: suspension in monodose vial to be reconstituted with Hib component. 3 doses were given approximatively at 6, 10 and 14 weeks of age (primary vaccination). The vaccine was administered by intramuscular injection into the left anterolateral thigh.

    Investigational medicinal product name
    Synflorix
    Investigational medicinal product code
    GSK1024850A
    Other name
    10Pn-PD-DiT-1-dose presentation
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    3 doses were given approximatively at 6, 10 and 18 weeks of age (primary vaccination) and a booster dose at approximatively 9 months of age. The vaccine was administered by intramuscular injection into the right anterolateral thigh.

    Number of subjects in period 1
    		10Pn_4d Group Synflorix Group
    Started
    160
    160
    Completed
    155
    147
    Not completed
    5
    13
         Consent withdrawn by subject
    -
    4
         Adverse event
    1
    1
         Migrated/moved from study area
    3
    5
         Lost to follow-up
    1
    3
    Period 2
    Period 2 title
    Epoch 002
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Observer-blind: during the course of the study, the vaccine recipient and those responsible for the evaluation of any study outcome were all unaware of which vaccine was administered. Vaccine preparation and administration was done by authorised medical personnel who didn’t participate in any of the study clinical evaluation. The laboratory in charge of the laboratory testing was blinded to the treatment, and codes were used to link the subject and study to each sample.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 10Pn_4d Group
    Arm description
    		 Healthy male or female subjects, between and including 6 to 10 weeks (42-76 days) of age at the time of first vaccination, received 3 doses of the investigational 4-dose presentation 10Pn-PD-DiT vaccine given approximatively at 6, 10 and 18 weeks of age (primary vaccination – Epoch 001) and 3 doses of DTPw-HBV/Hib vaccine given approximatively at 6, 10 and 14 weeks of age (according to the EPI schedule). They also received a booster dose of the 4-dose presentation 10Pn-PD-DiT vaccine at approximatively 9 months of age (Epoch-002).
    Arm type
    		 Experimental

    Investigational medicinal product name
    10Pn-PD-DiT 4-dose presentation
    Investigational medicinal product code
    GSK1024850A
    Other name
    10Pn-PD-DiT-4-dose presentation
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    3 doses were given approximatively at 6, 10 and 18 weeks of age (primary vaccination) and a booster dose at approximatively 9 months of age. The vaccine was administered by intramuscular injection into the right anterolateral thigh.

    Investigational medicinal product name
    Tritanrix HB
    Investigational medicinal product code
    DTPw-HBV
    Other name
    DTPw-HBV
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Tritanrix HB and Hiberix were used for the preparation of the DTPw-HBV/Hib vaccine: DTPw-HBV component: suspension in monodose vial to be reconstituted with Hib component. 3 doses were given approximatively at 6, 10 and 14 weeks of age (primary vaccination). The vaccine was administered by intramuscular injection into the left anterolateral thigh.

    Investigational medicinal product name
    Hiberix
    Investigational medicinal product code
    Hib
    Other name
    Hib
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Tritanrix HB and Hiberix were used for the preparation of the DTPw-HBV/Hib vaccine: DTPw-HBV component: suspension in monodose vial to be reconstituted with Hib component. 3 doses were given approximatively at 6, 10 and 14 weeks of age (primary vaccination). The vaccine was administered by intramuscular injection into the left anterolateral thigh.

    Arm title
    		 Synflorix Group
    Arm description
    		 Healthy male or female subjects, between and including 6 to 10 weeks (42-76 days) of age at the time of first vaccination, received 3 doses of the licensed 1-dose presentation 10Pn-PD-DiT (Synflorix) vaccine given approximatively at 6, 10 and 18 weeks of age (primary vaccination – Epoch 001) and 3 doses of DTPw-HBV/Hib vaccine given approximatively at 6, 10 and 14 weeks of age (according to the EPI schedule). They also received a booster dose of the 1-dose presentation 10Pn-PD-DiT vaccine at approximatively 9 months of age (Epoch-002).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tritanrix HB
    Investigational medicinal product code
    DTPw-HBV
    Other name
    DTPw-HBV
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Tritanrix HB and Hiberix were used for the preparation of the DTPw-HBV/Hib vaccine: DTPw-HBV component: suspension in monodose vial to be reconstituted with Hib component. 3 doses were given approximatively at 6, 10 and 14 weeks of age (primary vaccination). The vaccine was administered by intramuscular injection into the left anterolateral thigh.

    Investigational medicinal product name
    Hiberix
    Investigational medicinal product code
    Hib
    Other name
    Hib
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Tritanrix HB and Hiberix were used for the preparation of the DTPw-HBV/Hib vaccine: DTPw-HBV component: suspension in monodose vial to be reconstituted with Hib component. 3 doses were given approximatively at 6, 10 and 14 weeks of age (primary vaccination). The vaccine was administered by intramuscular injection into the left anterolateral thigh.

    Investigational medicinal product name
    Synflorix
    Investigational medicinal product code
    GSK1024850A
    Other name
    10Pn-PD-DiT-1-dose presentation
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    3 doses were given approximatively at 6, 10 and 18 weeks of age (primary vaccination) and a booster dose at approximatively 9 months of age. The vaccine was administered by intramuscular injection into the right anterolateral thigh.

    Number of subjects in period 2 [1]
    		10Pn_4d Group Synflorix Group
    Started
    152
    145
    Completed
    152
    145
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The number of participants who started each study period depends on the actual rate of return of the subjects.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    10Pn_4d Group
    Reporting group description
    		 Healthy male or female subjects, between and including 6 to 10 weeks (42-76 days) of age at the time of first vaccination, received 3 doses of the investigational 4-dose presentation 10Pn-PD-DiT vaccine given approximatively at 6, 10 and 18 weeks of age (primary vaccination – Epoch 001) and 3 doses of DTPw-HBV/Hib vaccine given approximatively at 6, 10 and 14 weeks of age (according to the EPI schedule). They also received a booster dose of the 4-dose presentation 10Pn-PD-DiT vaccine at approximatively 9 months of age (Epoch-002).

    Reporting group title
    Synflorix Group
    Reporting group description
    		 Healthy male or female subjects, between and including 6 to 10 weeks (42-76 days) of age at the time of first vaccination, received 3 doses of the licensed 1-dose presentation 10Pn-PD-DiT (Synflorix) vaccine given approximatively at 6, 10 and 18 weeks of age (primary vaccination – Epoch 001) and 3 doses of DTPw-HBV/Hib vaccine given approximatively at 6, 10 and 14 weeks of age (according to the EPI schedule). They also received a booster dose of the 1-dose presentation 10Pn-PD-DiT vaccine at approximatively 9 months of age (Epoch-002).

    Reporting group values
    		 10Pn_4d Group Synflorix Group Total
    Number of subjects
    		 160 160
    Age categorical
    Units: Subjects
    Age continuous
    Age continuous description
    Units: weeks
        arithmetic mean (standard deviation)
    		 6.9 ± 1.3 6.8 ± 1.2 -
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    		 80 73 153
        Male
    		 80 87 167

    End points

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    End points reporting groups
    Reporting group title
    10Pn_4d Group
    Reporting group description
    		 Healthy male or female subjects, between and including 6 to 10 weeks (42-76 days) of age at the time of first vaccination, received 3 doses of the investigational 4-dose presentation 10Pn-PD-DiT vaccine given approximatively at 6, 10 and 18 weeks of age (primary vaccination – Epoch 001) and 3 doses of DTPw-HBV/Hib vaccine given approximatively at 6, 10 and 14 weeks of age (according to the EPI schedule). They also received a booster dose of the 4-dose presentation 10Pn-PD-DiT vaccine at approximatively 9 months of age (Epoch-002).

    Reporting group title
    Synflorix Group
    Reporting group description
    		 Healthy male or female subjects, between and including 6 to 10 weeks (42-76 days) of age at the time of first vaccination, received 3 doses of the licensed 1-dose presentation 10Pn-PD-DiT (Synflorix) vaccine given approximatively at 6, 10 and 18 weeks of age (primary vaccination – Epoch 001) and 3 doses of DTPw-HBV/Hib vaccine given approximatively at 6, 10 and 14 weeks of age (according to the EPI schedule). They also received a booster dose of the 1-dose presentation 10Pn-PD-DiT vaccine at approximatively 9 months of age (Epoch-002).
    Reporting group title
    10Pn_4d Group
    Reporting group description
    		 Healthy male or female subjects, between and including 6 to 10 weeks (42-76 days) of age at the time of first vaccination, received 3 doses of the investigational 4-dose presentation 10Pn-PD-DiT vaccine given approximatively at 6, 10 and 18 weeks of age (primary vaccination – Epoch 001) and 3 doses of DTPw-HBV/Hib vaccine given approximatively at 6, 10 and 14 weeks of age (according to the EPI schedule). They also received a booster dose of the 4-dose presentation 10Pn-PD-DiT vaccine at approximatively 9 months of age (Epoch-002).

    Reporting group title
    Synflorix Group
    Reporting group description
    		 Healthy male or female subjects, between and including 6 to 10 weeks (42-76 days) of age at the time of first vaccination, received 3 doses of the licensed 1-dose presentation 10Pn-PD-DiT (Synflorix) vaccine given approximatively at 6, 10 and 18 weeks of age (primary vaccination – Epoch 001) and 3 doses of DTPw-HBV/Hib vaccine given approximatively at 6, 10 and 14 weeks of age (according to the EPI schedule). They also received a booster dose of the 1-dose presentation 10Pn-PD-DiT vaccine at approximatively 9 months of age (Epoch-002).

    Primary: Antibody concentrations against pneumococcal serotypes (Epoch 001)

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    End point title
    		 Antibody concentrations against pneumococcal serotypes (Epoch 001)
    End point description
    Antibodies assessed for this outcome measure were those against the vaccine/cross-reactive pneumococcal serotypes 1, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F (ANTI-1, -4, -5, -6A, -6B, -7F, -9V, -14, -18C, -19A, -19F and -23F). Antibody concentrations were measured by 22F-inhibition enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). The cut-off of the assay was an antibody concentration higher than or equal to (≥) 0.05 µg/mL. Primary outcome results correspond to antibody concentrations for the 10 vaccine serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F.
    End point type
    Primary
    End point timeframe
    At study Month 4, e. g. at one month post-Dose 3 of pneumococcal vaccine
    End point values
    		 10Pn_4d Group Synflorix Group
    Number of subjects analysed
    154
    146
    Units: µg/mL
    geometric mean (confidence interval 95%)
        ANTI-1 (N=154,146)
    2.78 (2.43 to 3.18)
    3.03 (2.6 to 3.54)
        ANTI-4 (N=154,146)
    4.23 (3.69 to 4.84)
    3.87 (3.33 to 4.51)
        ANTI-5 (N=154,146)
    5.12 (4.46 to 5.88)
    5.3 (4.59 to 6.12)
        ANTI-6B (N=154,146)
    1.23 (0.95 to 1.57)
    1.37 (1.05 to 1.79)
        ANTI-7F (N=154,146)
    5.52 (4.9 to 6.22)
    5.79 (5.06 to 6.62)
        ANTI-9V (N=154,146)
    4.6 (3.98 to 5.32)
    4.07 (3.34 to 4.95)
        ANTI-14 (N=154,146)
    4.97 (4.05 to 6.1)
    4.84 (3.91 to 5.99)
        ANTI-18C (N=154,146)
    19.58 (16.65 to 23.03)
    21.18 (17.9 to 25.06)
        ANTI-19F (N=154,146)
    13.24 (11.17 to 15.68)
    13.11 (11.16 to 15.41)
        ANTI-23F (N=154,146)
    1.59 (1.25 to 2.01)
    2.04 (1.61 to 2.58)
        ANTI-6A (N=154,146)
    0.31 (0.25 to 0.38)
    0.29 (0.23 to 0.36)
        ANTI-19A (N=154,146)
    0.76 (0.6 to 0.96)
    0.68 (0.54 to 0.86)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    (Synflorix/10Pn_4d) antibody GMCs ratio for ANTI-1 serotype: to demonstrate non-inferiority of 10Pn-PD-DiT vaccine (4-dose presentation) as compared to 10Pn-PD-DiT vaccine (1-dose presentation) in terms of immune response, 1 month after dose 3. Criterion: the upper limit (UL) of the 2-sided 95% confidence interval (CI) of the geometric mean antibody concentration (GMC) ratios (Synflorix/10Pn_4d) should be below a limit of 2-fold for each of the 10 serotypes.
    Comparison groups
    Synflorix Group v 10Pn_4d Group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 GMCs ratio
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.33
    Notes
    [1] - GMCs ratio and its 95 % CI were obtained using an ANOVA model on the logarithm-10 transformed concentrations-pooled variance.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    (Synflorix/10Pn_4d) antibody GMCs ratio for ANTI-4 serotype: to demonstrate non-inferiority of 10Pn-PD-DiT vaccine (4-dose presentation) as compared to 10Pn-PD-DiT vaccine (1-dose presentation) in terms of immune response, 1 month after dose 3. Criterion: the upper limit (UL) of the 2-sided 95% confidence interval (CI) of the geometric mean antibody concentration (GMC) ratios (Synflorix/10Pn_4d) should be below a limit of 2-fold for each of the 10 serotypes.
    Comparison groups
    Synflorix Group v 10Pn_4d Group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 GMCs ratio
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.12
    Notes
    [2] - GMCs ratio and its 95 % CI were obtained using an ANOVA model on the logarithm-10 transformed concentrations-pooled variance.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    (Synflorix/10Pn_4d) antibody GMCs ratio for ANTI-5 serotype: to demonstrate non-inferiority of 10Pn-PD-DiT vaccine (4-dose presentation) as compared to 10Pn-PD-DiT vaccine (1-dose presentation) in terms of immune response, 1 month after dose 3. Criterion: the upper limit (UL) of the 2-sided 95% confidence interval (CI) of the geometric mean antibody concentration (GMC) ratios (Synflorix/10Pn_4d) should be below a limit of 2-fold for each of the 10 serotypes.
    Comparison groups
    Synflorix Group v 10Pn_4d Group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 GMCs ratio
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.26
    Notes
    [3] - GMCs ratio and its 95 % CI were obtained using an ANOVA model on the logarithm-10 transformed concentrations-pooled variance.
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    (Synflorix/10Pn_4d) antibody GMCs ratio for ANTI-6B serotype: to demonstrate non-inferiority of 10Pn-PD-DiT vaccine (4-dose presentation) as compared to 10Pn-PD-DiT vaccine (1-dose presentation) in terms of immune response, 1 month after dose 3. Criterion: the upper limit (UL) of the 2-sided 95% confidence interval (CI) of the geometric mean antibody concentration (GMC) ratios (Synflorix/10Pn_4d) should be below a limit of 2-fold for each of the 10 serotypes.
    Comparison groups
    Synflorix Group v 10Pn_4d Group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 GMCs ratio
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.61
    Notes
    [4] - GMCs ratio and its 95 % CI were obtained using an ANOVA model on the logarithm-10 transformed concentrations-pooled variance.
    Statistical analysis title
    		 Statistical analysis 5
    Statistical analysis description
    (Synflorix/10Pn_4d) antibody GMCs ratio for ANTI-7F serotype: to demonstrate non-inferiority of 10Pn-PD-DiT vaccine (4-dose presentation) as compared to 10Pn-PD-DiT vaccine (1-dose presentation) in terms of immune response, 1 month after dose 3. Criterion: the upper limit (UL) of the 2-sided 95% confidence interval (CI) of the geometric mean antibody concentration (GMC) ratios (Synflorix/10Pn_4d) should be below a limit of 2-fold for each of the 10 serotypes.
    Comparison groups
    Synflorix Group v 10Pn_4d Group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 GMCs ratio
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.25
    Notes
    [5] - GMCs ratio and its 95 % CI were obtained using an ANOVA model on the logarithm-10 transformed concentrations-pooled variance.
    Statistical analysis title
    		 Statistical analysis 6
    Statistical analysis description
    (Synflorix/10Pn_4d) antibody GMCs ratio for ANTI-9V serotype: to demonstrate non-inferiority of 10Pn-PD-DiT vaccine (4-dose presentation) as compared to 10Pn-PD-DiT vaccine (1-dose presentation) in terms of immune response, 1 month after dose 3. Criterion: the upper limit (UL) of the 2-sided 95% confidence interval (CI) of the geometric mean antibody concentration (GMC) ratios (Synflorix/10Pn_4d) should be below a limit of 2-fold for each of the 10 serotypes.
    Comparison groups
    Synflorix Group v 10Pn_4d Group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 GMCs ratio
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.13
    Notes
    [6] - GMCs ratio and its 95 % CI were obtained using an ANOVA model on the logarithm-10 transformed concentrations-pooled variance.
    Statistical analysis title
    		 Statistical analysis 7
    Statistical analysis description
    (Synflorix/10Pn_4d) antibody GMCs ratio for ANTI-14 serotype: to demonstrate non-inferiority of 10Pn-PD-DiT vaccine (4-dose presentation) as compared to 10Pn-PD-DiT vaccine (1-dose presentation) in terms of immune response, 1 month after dose 3. Criterion: the upper limit (UL) of the 2-sided 95% confidence interval (CI) of the geometric mean antibody concentration (GMC) ratios (Synflorix/10Pn_4d) should be below a limit of 2-fold for each of the 10 serotypes.
    Comparison groups
    Synflorix Group v 10Pn_4d Group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 GMCs ratio
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.31
    Notes
    [7] - GMCs ratio and its 95 % CI were obtained using an ANOVA model on the logarithm-10 transformed concentrations-pooled variance.
    Statistical analysis title
    		 Statistical analysis 8
    Statistical analysis description
    (Synflorix/10Pn_4d) antibody GMCs ratio for ANTI-18C serotype: to demonstrate non-inferiority of 10Pn-PD-DiT vaccine (4-dose presentation) as compared to 10Pn-PD-DiT vaccine (1-dose presentation) in terms of immune response, 1 month after dose 3. Criterion: the upper limit (UL) of the 2-sided 95% confidence interval (CI) of the geometric mean antibody concentration (GMC) ratios (Synflorix/10Pn_4d) should be below a limit of 2-fold for each of the 10 serotypes.
    Comparison groups
    Synflorix Group v 10Pn_4d Group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 GMCs ratio
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.37
    Notes
    [8] - GMCs ratio and its 95 % CI were obtained using an ANOVA model on the logarithm-10 transformed concentrations-pooled variance.
    Statistical analysis title
    		 Statistical analysis 9
    Statistical analysis description
    (Synflorix/10Pn_4d) antibody GMCs ratio for ANTI-19F serotype: to demonstrate non-inferiority of 10Pn-PD-DiT vaccine (4-dose presentation) as compared to 10Pn-PD-DiT vaccine (1-dose presentation) in terms of immune response, 1 month after dose 3. Criterion: the upper limit (UL) of the 2-sided 95% confidence interval (CI) of the geometric mean antibody concentration (GMC) ratios (Synflorix/10Pn_4d) should be below a limit of 2-fold for each of the 10 serotypes.
    Comparison groups
    Synflorix Group v 10Pn_4d Group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    Method
    Parameter type
    		 GMCs ratio
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.25
    Notes
    [9] - GMCs ratio and its 95 % CI were obtained using an ANOVA model on the logarithm-10 transformed concentrations-pooled variance.
    Statistical analysis title
    		 Statistical analysis 10
    Statistical analysis description
    (Synflorix/10Pn_4d) antibody GMCs ratio for ANTI-23F serotype: to demonstrate non-inferiority of 10Pn-PD-DiT vaccine (4-dose presentation) as compared to 10Pn-PD-DiT vaccine (1-dose presentation) in terms of immune response, 1 month after dose 3. Criterion: the upper limit (UL) of the 2-sided 95% confidence interval (CI) of the geometric mean antibody concentration (GMC) ratios (Synflorix/10Pn_4d) should be below a limit of 2-fold for each of the 10 serotypes.
    Comparison groups
    Synflorix Group v 10Pn_4d Group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [10]
    Method
    Parameter type
    		 GMCs ratio
    Point estimate
    1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.8
    Notes
    [10] - GMCs ratio and its 95 % CI were obtained using an ANOVA model on the logarithm-10 transformed concentrations-pooled variance.

    Secondary: Titers for opsonophagocytic activity against pneumococcal serotypes (Epoch 001)

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    End point title
    		 Titers for opsonophagocytic activity against pneumococcal serotypes (Epoch 001)
    End point description
    Titers for opsonophagocytic activity assessed for this outcome measure were those for opsonophagocytic activity against the vaccine/cross-reactive pneumococcal serotypes 1, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F (OPA-1, -4, -5, -6A, -6B, -7F, -9V, -14, -18C, 19 A ,-19F and -23F). The cut-off of the assay was a titer for opsonophagocytic activity higher than or equal to (≥) 8.
    End point type
    Secondary
    End point timeframe
    At study Month 4, e. g. at one month post-Dose 3 of pneumococcal vaccine
    End point values
    		 10Pn_4d Group Synflorix Group
    Number of subjects analysed
    75
    74
    Units: Titers
    geometric mean (confidence interval 95%)
        OPA-1 (N=74,74)
    48.3 (34.9 to 67)
    52.8 (36 to 77.5)
        OPA-4 (N=75,74)
    823.1 (670.9 to 1009.8)
    836.8 (644.5 to 1086.6)
        OPA-5 (N=73,74)
    179 (140.7 to 227.8)
    211 (162.9 to 273.2)
        OPA-6B (N=73,73)
    560.6 (336.9 to 932.8)
    759.6 (470.2 to 1227.3)
        OPA-7F (N=74,73)
    2044 (1669.3 to 2502.9)
    2076.8 (1627 to 2650.9)
        OPA-9V (N=75,74)
    613.3 (444.9 to 845.4)
    821.1 (602.5 to 1119.2)
        OPA-14 (N=73,74)
    1563.9 (1105.1 to 2213.2)
    1655.8 (1141.1 to 2402.7)
        OPA-18C (N=75,74)
    3965.4 (3288.6 to 4781.5)
    3809.7 (3067 to 4732.3)
        OPA-19F (N=75,74)
    2151.3 (1573.5 to 2941.4)
    2879.2 (2348.4 to 3529.9)
        OPA-23F (N=75,74)
    524.8 (338.5 to 813.9)
    730.2 (495.6 to 1075.7)
        OPA-6A (N=66,69)
    50.3 (26.9 to 94)
    68.5 (36.8 to 127.7)
        OPA-19A (N=72,71)
    98.6 (60.9 to 159.6)
    117.1 (71.9 to 190.6)
    No statistical analyses for this end point

    Secondary: Concentrations of antibodies against protein D (Anti-PD) (Epoch 001)

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    End point title
    		 Concentrations of antibodies against protein D (Anti-PD) (Epoch 001)
    End point description
    Anti-PD antibody concentrations were measured by enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs), in ELISA Units per milliliter (EL.U/mL). The cut-off of the assay was an anti-PD antibody concentration higher than or equal to (≥) 153 EL.U/mL.
    End point type
    Secondary
    End point timeframe
    At study Month 4, e. g. at one month post-Dose 3 of pneumococcal vaccine
    End point values
    		 10Pn_4d Group Synflorix Group
    Number of subjects analysed
    78
    75
    Units: EL.U/mL
        geometric mean (confidence interval 95%)
    2410.5 (2029.2 to 2863.5)
    2495.4 (2055.7 to 3029.1)
    No statistical analyses for this end point

    Secondary: Number of subjects with any and Grade 3 solicited local symptoms (Epoch 001)

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    End point title
    		 Number of subjects with any and Grade 3 solicited local symptoms (Epoch 001)
    End point description
    Assessed local symptoms were pain, redness and swelling. Any = Occurrence of the specified solicited local symptom, regardless of intensity. Grade 3 Pain = Crying when limb was moved/spontaneously painful. Grade 3 Redness/Swelling = Redness/swelling at injection site larger than (>) 30 millimeters (mm). Dose 1 = 10Pn-PD-DIT+DTPw-HBV/Hib at 6 weeks of age. Dose 2 = 10Pn-PD-DIT+DTPw-HBV/Hib at 10 weeks of age. Dose 4 = 10Pn-PD-DIT at 18 weeks of age.
    End point type
    Secondary
    End point timeframe
    Within the 4-day (Days 0-3) post-vaccination period following each primary dose (D) of 10Pn-PD-DiT vaccine
    End point values
    		 10Pn_4d Group Synflorix Group
    Number of subjects analysed
    159
    156
    Units: Subjects
        Any Pain, post D1 (N=159;156)
    82
    90
        Grade 3 Pain, post D1 (N=159;156)
    4
    5
        Any Redness, post D1 (N=159;156)
    24
    26
        Grade 3 Redness, post D1 (N=159;156)
    0
    0
        Any Swelling, post D1 (N=159;156)
    63
    64
        Grade 3 Swelling, post D1 (N=159;156)
    0
    0
        Any Pain, post D2 (N=158,152)
    56
    56
        Grade 3 Pain, post D2 (N=158,152)
    1
    0
        Any Redness, post D2 (N=158,152)
    22
    26
        Grade 3 Redness, post D2 (N=158,152)
    0
    0
        Any Swelling, post D2 (N=158,152)
    31
    37
        Grade 3 Swelling, post D2 (N=158,152)
    0
    0
        Any Pain, post D4 (N=155,147)
    13
    15
        Grade 3 Pain, post D4 (N=155,147)
    0
    0
        Any Redness, post D4 (N=155,147)
    9
    8
        Grade 3 Redness, post D4 (N=155,147)
    0
    0
        Any Swelling, post D4 (N=155,147)
    11
    9
        Grade 3 Swelling, post D4 (N=155,147)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with any and Grade 3 solicited general symptoms and with solicited general symptoms with relationship to vaccination (Epoch 001)

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    End point title
    		 Number of subjects with any and Grade 3 solicited general symptoms and with solicited general symptoms with relationship to vaccination (Epoch 001)
    End point description
    Assessed solicited general symptoms were Drowsiness, Irritability/Fussiness (Irr./Fuss.), Loss of appetite (Loss Appet.) and Fever (axillary route - temperature equal or higher than [≥] 37.5 degrees Celsius [°C]). Any = Occurrence of the specified solicited general symptom, regardless of intensity or relationship to vaccination. Grade 3 Drowsiness = Drowsiness that prevented normal activity. Grade 3 Irr./Fuss. = Crying that could not be comforted/prevented normal activity. Grade 3 Loss of appetite = Subject did not eat at all. Grade 3 Fever = (axillary) temperature higher than (>) 39.5°C. Related = Occurrence of the specified symptom assessed by the investigator as causally related to vaccination. Dose 1 = 10Pn-PD-DIT+DTPw-HBV/Hib at 6 weeks of age. Dose 2 = 10Pn-PD-DIT+DTPw-HBV/Hib at 10 weeks of age. Dose 4 = 10Pn-PD-DIT at 18 weeks of age.
    End point type
    Secondary
    End point timeframe
    Within the 4-day (Days 0-3) post-vaccination period following each primary dose (D) of 10Pn-PD-DiT vaccine
    End point values
    		 10Pn_4d Group Synflorix Group
    Number of subjects analysed
    159
    156
    Units: Subjects
        Any Drowsiness, post D1 (N=159,156)
    26
    31
        Grade 3 Drowsiness, post D1 (N=159,156)
    1
    5
        Any Irr./Fuss., post D1 (N=159,156)
    61
    62
        Grade 3 Irr./Fuss., post D1 (N=159,156)
    14
    8
        Any Loss Appet., post D1 (N=159,156)
    43
    46
        Grade 3 Loss Appet., post D1 (N=159,156)
    4
    3
        Any Fever, post D1 (N=159,156)
    28
    30
        Grade 3 Fever, post D1 (N=159,156)
    0
    0
        Any Drowsiness, post D2 (N=158,152)
    15
    23
        Grade 3 Drowsiness, post D2 (N=158,152)
    1
    1
        Any Irr./Fuss., post D2 (N=158,152)
    39
    47
        Grade 3 Irr./Fuss., post D2 (N=158,152)
    4
    5
        Any Loss Appet., post D2 (N=158,152)
    24
    20
        Grade 3 Loss Appet., post D2 (N=158,152)
    3
    2
        Any Fever, post D2 (N=158,152)
    23
    18
        Grade 3 Fever, post D2 (N=158,152)
    0
    0
        Any Drowsiness, post D4 (N=155,147)
    6
    8
        Grade 3 Drowsiness, post D4 (N=155,147)
    0
    1
        Any Irr./Fuss., post D4 (N=155,147)
    10
    12
        Grade 3 Irr./Fuss., post D4 (N=155,147)
    0
    1
        Any Loss Appet., post D4 (N=155,147)
    5
    5
        Grade 3 Loss Appet., post D4 (N=155,147)
    0
    0
        Any Fever, post D4 (N=155,147)
    2
    6
        Grade 3 Fever, post D4 (N=155,147)
    0
    0
        Related Drowsiness, post D1 (N=159,156)
    26
    29
        Related Irr./Fuss., post D1 (N=159,156)
    61
    62
        Related Loss Appet., post D1 (N=159,156)
    43
    46
        Related Fever, post D1 (N=159,156)
    28
    30
        Related Drowsiness, post D2 (N=158,152)
    15
    23
        Related Irr./Fuss., post D2 (N=158,152)
    39
    47
        Related Loss Appet., post D2 (N=158,152)
    23
    20
        Related Fever, post D2 (N=158,152)
    22
    18
        Related Drowsiness, post D4 (N=155,147)
    6
    8
        Related Irr./Fuss., post D4 (N=155,147)
    10
    12
        Related Loss Appet., post D4 (N=155,147)
    5
    5
        Related Fever, post D4 (N=155,147)
    2
    6
    No statistical analyses for this end point

    Secondary: Number of subjects with any unsolicited adverse events (AEs) (Epoch 001)

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    End point title
    		 Number of subjects with any unsolicited adverse events (AEs) (Epoch 001)
    End point description
    An unsolicited AE was defined as any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For the marketed products administered in the study, this also included failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse of the product. Any = Occurrence of an unsolicited AE, regardless of intensity or relationship to vaccination.
    End point type
    Secondary
    End point timeframe
    Within the 31-day (Days 0-30) period post primary vaccination, across doses
    End point values
    		 10Pn_4d Group Synflorix Group
    Number of subjects analysed
    160
    160
    Units: Subjects
    10
    16
    No statistical analyses for this end point

    Secondary: Number of subjects with any serious adverse events (SAEs) (Epoch 001)

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    End point title
    		 Number of subjects with any serious adverse events (SAEs) (Epoch 001)
    End point description
    An SAE was defined as any medical occurrence that resulted in death, was life-threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity in a subject. AE(s) considered as SAE(s) also included invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that did not result in hospitalization, as per the medical or scientific judgement of the physician. Any = Occurrence of an SAE, regardless of relationship to vaccination.
    End point type
    Secondary
    End point timeframe
    From Month 0 to Month 4
    End point values
    		 10Pn_4d Group Synflorix Group
    Number of subjects analysed
    160
    160
    Units: Subjects
    4
    9
    No statistical analyses for this end point

    Secondary: Antibody concentrations against pneumococcal serotypes (Epoch 002)

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    End point title
    		 Antibody concentrations against pneumococcal serotypes (Epoch 002)
    End point description
    Antibodies assessed for this outcome measure were those against the vaccine/cross-reactive pneumococcal serotypes 1, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F (ANTI-1, -4, -5, -6A, -6B, -7F, -9V, -14, -18C, -19A, -19F and -23F). Antibody concentrations were measured by 22F-inhibition enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). The cut-off of the assay was an antibody concentration higher than or equal to (≥) 0.05 µg/mL.
    End point type
    Secondary
    End point timeframe
    At Month 8 (M8) and Month 9 (M9), e.g.: prior to and at one month post booster vaccination with pneumococcal vaccine
    End point values
    		 10Pn_4d Group Synflorix Group
    Number of subjects analysed
    151
    144
    Units: µg/mL
    geometric mean (confidence interval 95%)
        ANTI-1 M8 (N=151,144)
    0.93 (0.79 to 1.1)
    0.99 (0.81 to 1.19)
        ANTI-1 M9 (N=151,144)
    6.37 (5.48 to 7.41)
    7.5 (6.28 to 8.97)
        ANTI-4 M8 (N=151,144)
    1.9 (1.65 to 2.19)
    1.71 (1.45 to 2.01)
        ANTI-4 M9 (N=151,143)
    9.68 (8.47 to 11.06)
    9.41 (8.16 to 10.86)
        ANTI-5 M8 (N=151,144)
    1.75 (1.5 to 2.05)
    1.75 (1.48 to 2.08)
        ANTI-5 M9 (N=151,144)
    11.53 (10.14 to 13.12)
    12.24 (10.65 to 14.05)
        ANTI-6B M8 (N=151,144)
    1.14 (0.93 to 1.4)
    1.06 (0.84 to 1.32)
        ANTI-6B M9 (N=151,144)
    3.76 (3.01 to 4.69)
    4.11 (3.21 to 5.25)
        ANTI-7F M8 (N=151,144)
    2.86 (2.5 to 3.27)
    2.75 (2.4 to 3.16)
        ANTI-7F M9 (N=151,144)
    12.84 (11.38 to 14.48)
    13.71 (12.01 to 15.65)
        ANTI-9V M8 (N=151,144)
    2.32 (1.96 to 2.75)
    2.25 (1.83 to 2.76)
        ANTI-9V M9 (N=151,144)
    12.07 (10.42 to 13.98)
    12.43 (10.22 to 15.13)
        ANTI-14 M8 (N=151,144)
    2.98 (2.39 to 3.72)
    2.4 (1.9 to 3.04)
        ANTI-14 M9 (N=151,143)
    9.84 (8.02 to 12.08)
    9.72 (7.92 to 11.93)
        ANTI-18C M8 (N=151,144)
    8.37 (7.14 to 9.82)
    9.23 (7.82 to 10.9)
        ANTI-18C M9 (N=151,144)
    41.64 (36.87 to 47.02)
    47.06 (41.88 to 52.88)
        ANTI-19F M8 (N=151,144)
    6.36 (5.36 to 7.55)
    6.45 (5.5 to 7.57)
        ANTI-19F M9 (N=151,144)
    23.43 (19.48 to 28.19)
    24.96 (21.07 to 29.57)
        ANTI-23F M8 (N=151,144)
    1.09 (0.89 to 1.33)
    1.21 (0.96 to 1.53)
        ANTI-23F M9 (N=151,144)
    6.69 (5.66 to 7.9)
    6.69 (5.33 to 8.41)
        ANTI-6A M8 (N=151,144)
    0.31 (0.24 to 0.39)
    0.3 (0.24 to 0.38)
        ANTI-6A M9 (N=151,144)
    0.97 (0.74 to 1.26)
    1.11 (0.83 to 1.49)
        ANTI-19A M8 (N=151,144)
    0.7 (0.55 to 0.89)
    0.69 (0.54 to 0.88)
        ANTI-19A M9 (N=151,144)
    3.03 (2.26 to 4.05)
    3.63 (2.73 to 4.82)
    No statistical analyses for this end point

    Secondary: Titers for opsonophagocytic activity against pneumococcal serotypes (Epoch 002)

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    End point title
    		 Titers for opsonophagocytic activity against pneumococcal serotypes (Epoch 002)
    End point description
    Titers for opsonophagocytic activity assessed for this outcome measure were those for opsonophagocytic activity against the vaccine/cross-reactive pneumococcal serotypes 1, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F (OPA-1, -4, -5, -6A, -6B, -7F, -9V, -14, -18C, -19A, -19F and -23F). The cut-off of the assay was a titer for opsonophagocytic activity higher than or equal to (≥) 8.
    End point type
    Secondary
    End point timeframe
    At study Month 8 (M8) and Month 9 (M9), e.g.: prior to and at one month post booster vaccination with pneumococcal vaccine
    End point values
    		 10Pn_4d Group Synflorix Group
    Number of subjects analysed
    76
    73
    Units: Titers
    geometric mean (confidence interval 95%)
        OPA-1 M8 (N=72,70)
    11.5 (8.2 to 16.1)
    12.8 (9.1 to 17.9)
        OPA-1 M9 (N=73,71)
    227.7 (170.6 to 303.9)
    326.7 (238.7 to 447)
        OPA-4 M8 (N=72,70)
    248.1 (178.6 to 344.7)
    280.5 (193.4 to 406.6)
        OPA-4 M9 (N=76,73)
    2025.4 (1641.6 to 2498.8)
    2888.7 (2221.6 to 3756.1)
        OPA-5 M8 (N=73,71)
    51.3 (37 to 71.3)
    62.7 (44.4 to 88.7)
        OPA-5 M9 (N=76,73)
    550.6 (437.8 to 692.4)
    801.2 (633.2 to 1013.6)
        OPA-6B M8 (N=73,70)
    290.3 (177.1 to 475.7)
    286.8 (183.5 to 448)
        OPA-6B M9 (N=74,72)
    851.3 (533.4 to 1358.6)
    1352 (913.9 to 1999.9)
        OPA-7F M8 (N=74,73)
    1112.8 (864.8 to 1431.8)
    1181.7 (933.4 to 1495.9)
        OPA-7F M9 (N=76,73)
    4574.7 (3756.1 to 5571.6)
    5635.8 (4561.7 to 6962.9)
        OPA-9V M8 (N=69,72)
    415.8 (280.6 to 616.3)
    570.6 (408.4 to 797.3)
        OPA-9V M9 (N=76,73)
    2308.4 (1903.3 to 2799.7)
    3181.9 (2376.9 to 4259.6)
        OPA-14 M8 (N=73,72)
    660.1 (432.4 to 1007.6)
    745 (513.9 to 1080)
        OPA-14 M9 (N=76,73)
    3345.6 (2585 to 4330.1)
    3649.1 (2808.6 to 4741.2)
        OPA-18C M8 (N=74,73)
    1505.4 (1196.4 to 1894.1)
    1735.2 (1373.8 to 2191.7)
        OPA-18C M9 (N=76,73)
    7316.1 (6137.6 to 8720.8)
    7181.6 (6003.6 to 8590.7)
        OPA-19F M8 (N=74,72)
    770.1 (536.6 to 1105.3)
    1254.3 (990.8 to 1587.9)
        OPA-19F M9 (N=76,73)
    3197.3 (2271.1 to 4501.2)
    4757.7 (3772.3 to 6000.4)
        OPA-23F M8 (N=70,69)
    267.7 (168.7 to 424.9)
    252.7 (154.8 to 412.4)
        OPA-23F M9 (N=76,73)
    1250.8 (931.3 to 1679.8)
    1465.6 (1002.9 to 2141.7)
        OPA-6A M8 (N=72,68)
    52.4 (27.4 to 100.1)
    45.5 (24 to 86.5)
        OPA-6A M9 (N=71,68)
    192 (102.9 to 358.4)
    284.4 (158.4 to 510.6)
        OPA-19A M8 (N=73,71)
    42.7 (25.1 to 72.7)
    43.6 (26.6 to 71.3)
        OPA-19A M9 (N=76,72)
    410.4 (246.7 to 682.8)
    591.7 (356.9 to 980.9)
    No statistical analyses for this end point

    Secondary: Concentrations of antibodies against protein D (Anti-PD) (Epoch 002)

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    End point title
    		 Concentrations of antibodies against protein D (Anti-PD) (Epoch 002)
    End point description
    Anti-PD antibody concentrations were measured by enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs), in ELISA Units per milliliter (EL.U/mL). The cut-off of the assay was an anti-PD antibody concentration higher than or equal to (≥) 153 EL.U/mL.
    End point type
    Secondary
    End point timeframe
    At study Month 9 (M9), e.g.: at one month post booster vaccination with pneumococcal vaccine
    End point values
    		 10Pn_4d Group Synflorix Group
    Number of subjects analysed
    76
    73
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-PD
    2672.4 (2285.5 to 3124.8)
    2944 (2486.2 to 3486)
    No statistical analyses for this end point

    Secondary: Number of subjects with any and Grade 3 solicited local symptoms (Epoch 002)

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    End point title
    		 Number of subjects with any and Grade 3 solicited local symptoms (Epoch 002)
    End point description
    Assessed local symptoms were pain, redness and swelling. Any = Occurrence of the specified solicited local symptom, regardless of intensity. Grade 3 Pain = Crying when limb was moved/spontaneously painful. Grade 3 Redness/Swelling = Redness/swelling at injection site larger than (>) 30 millimeters (mm).
    End point type
    Secondary
    End point timeframe
    Within the 4-day (Days 0-3) period after booster vaccination
    End point values
    		 10Pn_4d Group Synflorix Group
    Number of subjects analysed
    152
    145
    Units: Subjects
        Any Pain
    9
    2
        Grade 3 Pain
    1
    0
        Any Redness
    14
    5
        Grade 3 Redness
    0
    0
        Any Swelling
    16
    8
        Grade 3 Swelling
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with any and Grade 3 solicited general symptoms and with solicited general symptoms with relationship to vaccination (Epoch 002)

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    End point title
    		 Number of subjects with any and Grade 3 solicited general symptoms and with solicited general symptoms with relationship to vaccination (Epoch 002)
    End point description
    Assessed solicited general symptoms were Drowsiness, Irritability/Fussiness (Irr./Fuss.), Loss of appetite (Loss Appet.) and Fever (axillary route - temperature equal or higher than [≥] 37.5 degrees Celsius [°C]). Any = Occurrence of the specified solicited general symptom, regardless of intensity or relationship to vaccination. Related = Occurrence of the specified symptom assessed by the investigators as causally related to vaccination. Grade 3 Drowsiness = Drowsiness that prevented normal activity. Grade 3 Irr./Fuss. = Crying that could not be comforted/prevented normal activity. Grade 3 Loss of appetite = Subject did not eat at all. Grade 3 Fever = (Axillary) temperature higher than (>) 39.5°C.
    End point type
    Secondary
    End point timeframe
    Within the 4-day (Days 0-3) period after booster vaccination
    End point values
    		 10Pn_4d Group Synflorix Group
    Number of subjects analysed
    152
    145
    Units: Subjects
        Any Drowsiness
    8
    4
        Grade 3 Drowsiness
    0
    0
        Related Drowsiness
    8
    4
        Any Irr./Fuss.
    11
    5
        Grade 3 Irr./Fuss.
    1
    0
        Related Irr./Fuss.
    11
    5
        Any Loss Appet.
    8
    4
        Grade 3 Loss Appet.
    0
    0
        Related Loss Appet.
    8
    4
        Any Fever
    4
    3
        Grade 3 Fever
    0
    0
        Related Fever
    4
    3
    No statistical analyses for this end point

    Secondary: Number of subjects with any unsolicited AEs (Epoch 002)

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    End point title
    		 Number of subjects with any unsolicited AEs (Epoch 002)
    End point description
    An unsolicited AE was defined as any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For the marketed products administered in the study, this also included failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse of the product. Any = Occurrence of an unsolicited AE, regardless of intensity or relationship to vaccination.
    End point type
    Secondary
    End point timeframe
    Within the 31-day (Days 0-30) period post booster vaccination
    End point values
    		 10Pn_4d Group Synflorix Group
    Number of subjects analysed
    152
    145
    Units: Subjects
        Any AE(s)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with any SAEs during the entire duration of the study

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    End point title
    		 Number of subjects with any SAEs during the entire duration of the study
    End point description
    An SAE was defined as any medical occurrence that resulted in death, was life-threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity in a subject. AE(s) considered as SAE(s) also included invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that did not result in hospitalization, as per the medical or scientific judgement of the physician. Any = Occurrence of an SAE, regardless of relationship to vaccination.
    End point type
    Secondary
    End point timeframe
    From Day 0 to Month 9
    End point values
    		 10Pn_4d Group Synflorix Group
    Number of subjects analysed
    160
    160
    Units: Subjects
        Any SAE(s)
    4
    9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited symptoms and Unsolicited AEs: during 31 days post vaccination period; SAEs: during the whole study period (from Day 0 to Month 9).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Synflorix Group
    Reporting group description
    		 Healthy male or female subjects, between and including 6 to 10 weeks (42-76 days) of age at the time of first vaccination, received 3 doses of the licensed 1-dose presentation 10Pn-PD-DiT (Synflorix) vaccine given approximatively at 6, 10 and 18 weeks of age (primary vaccination – Epoch 001) and 3 doses of DTPw-HBV/Hib vaccine given approximatively at 6, 10 and 14 weeks of age (according to the EPI schedule). They also received a booster dose of the 1-dose presentation 10Pn-PD-DiT vaccine at approximatively 9 months of age (Epoch-002).

    Reporting group title
    10Pn_4d Group
    Reporting group description
    		 Healthy male or female subjects, between and including 6 to 10 weeks (42-76 days) of age at the time of first vaccination, received 3 doses of the investigational 4-dose presentation 10Pn-PD-DiT vaccine given approximatively at 6, 10 and 18 weeks of age (primary vaccination – Epoch 001) and 3 doses of DTPw-HBV/Hib vaccine given approximatively at 6, 10 and 14 weeks of age (according to the EPI schedule). They also received a booster dose of the 4-dose presentation 10Pn-PD-DiT vaccine at approximatively 9 months of age (Epoch-002).

    Serious adverse events
    		 Synflorix Group 10Pn_4d Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 160 (5.63%)
    4 / 160 (2.50%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Chemical poisoning
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cerebral palsy
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngomalacia
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Febrile convulsion
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 160 (1.25%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    2 / 160 (1.25%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 160 (2.50%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Synflorix Group 10Pn_4d Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    126 / 160 (78.75%)
    120 / 160 (75.00%)
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    42 / 160 (26.25%)
    38 / 160 (23.75%)
         occurrences all number
    66
    55
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    102 / 160 (63.75%)
    101 / 160 (63.13%)
         occurrences all number
    163
    160
    Pyrexia
         subjects affected / exposed
    47 / 160 (29.38%)
    51 / 160 (31.88%)
         occurrences all number
    57
    59
    Swelling
         subjects affected / exposed
    81 / 160 (50.63%)
    83 / 160 (51.88%)
         occurrences all number
    118
    121
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    40 / 160 (25.00%)
    37 / 160 (23.13%)
         occurrences all number
    65
    69
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    84 / 160 (52.50%)
    77 / 160 (48.13%)
         occurrences all number
    126
    121
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    53 / 160 (33.13%)
    58 / 160 (36.25%)
         occurrences all number
    75
    80

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Apr 2015
    Amendment 1 The protocol amendment has been issued to implement the following guidance from the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B):  Following post-study approval discussion with the Ethical Review Committee (ERC) of the ICDDR,B regarding the strengthening of the informed consent process, the presence of one witness has been requested for the informed consent of each subject’s parent/legally acceptable representative, irrespective of literacy status.  In line with local ICDDR,B guidelines, the ERC required the implementation of a Data and Safety Monitoring Board (DSMB) which will be established by the ERC. The safety monitoring section has been updated accordingly.
    21 Oct 2015
    Amendment 2 Recently Synflorix effectiveness against vaccine-related serotype 19A has been added to the product information and Synflorix can be recommended for active immunization against 19A pneumococcal disease in addition to the vaccine serotypes. The purpose of this amendment is to add demonstration of the non-inferiority of the 10Pn-PD-DiT vaccine (4-dose presentation) as compared to 10Pn-PD-DiT vaccine (1-dose presentation) in terms of the immune response to the vaccine-related serotype 19A as a first secondary objective. Following review of the validation package of the anti-protein D (PD) IgG ELISA, the Company decided to fully redevelop and revalidate this assay in order to comply with the latest validation requirements of the Regulatory Authorities. In consequence, the anti-PD ELISA assay cut-off has been changed.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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