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    Clinical Trial Results:
    A phase III, open study in children previously enrolled in study 10PN-PD-DIT-037 (111188) to assess the immunogenicity, safety and reactogenicity of GlaxoSmithKline (GSK) Biologicals’ 10-valent pneumococcal conjugate vaccine when administered as a booster dose at either 9-18 or 15-18 months of age in primed children or when administered as a catch-up vaccination (2+1 schedule) in unprimed children during the second year of life.

    Summary
    EudraCT number
    		 2011-002140-27
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    19 Aug 2011

    Results information
    Results version number
    		 v3(current)
    This version publication date
    15 Dec 2022
    First version publication date
    24 May 2015
    Other versions
    		 v1 (removed from public view) , v2
    Version creation reason
    • Correction of full data set
    Correction of full data set and alingment between registries.

    Trial information

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    Trial identification
    Sponsor protocol code
    112909
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01030822
    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 Trials Call Center, GlaxoSmithKline Biologicals, 044 2089904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089904466, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000673-PIP01-09
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Mar 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Aug 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the immune responses following vaccination with a booster dose of the 10Pn-PD-DiT vaccine administered at either 9-12 or 15-18 months of age in children previously vaccinated with the 10Pn-PD-DiT vaccine in study 10PN-PD-DIT-037 (111188) according to a 3-dose primary vaccination at 6, 10 and 14 weeks of age.
    Protection of trial subjects
    All subjects were supervised closely for at least 30 minutes following vaccination with appropriate medical treatment readily available. Vaccines were administered by qualified and trained personnel. Vaccines were administered only to eligible subjects that had no contraindications to any components of the vaccines. Subjects were followed-up for one month (minimum 30 days) following administration of the last dose of study vaccines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Apr 2010
    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
    India: 287
    Worldwide total number of subjects
    287
    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)
    287
    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
    		 -

    Pre-assignment
    Screening details
    		 A total of 287 participants were randomized, but 2 participants withdrew their consent and 3 participants moved away from the study area, therefore only 282 received a study vaccine.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Synflorix 1 Group
    Arm description
    		 Subjects who were previously primed with a 3-dose primary vaccination of Synflorix vaccine in the 10PN-PD-DIT-037 (111188) study, received a booster dose of Synflorix vaccine, administered intramuscularly in the right or left thigh, at 9-18 months of age.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Synflorix
    Investigational medicinal product code
    Other name
    10Pn-PD-DiT
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 booster dose at 9-18 months of age, administered in in the right or left thigh.

    Arm title
    		 Synflorix 2 Group
    Arm description
    		 Subjects who were previously primed with a 3-dose primary vaccination of Synflorix vaccine in the 10PN-PD-DIT-037 (111188) study, received a booster dose of Synflorix vaccine, administered intramuscularly in the right or left thigh, at 15-18 months of age.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Synflorix
    Investigational medicinal product code
    Other name
    10Pn-PD-DiT
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 booster dose at 15-18 months of age, administered in in the right or left thigh.

    Arm title
    		 Tritanrix-HepB+Hiberix Group
    Arm description
    		 Unprimed subjects who were previously vaccinated with Tritanrix-HepB and Hiberix vaccines in the Control Group of the 10PN-PD-DIT-037 (111188) study, received a catch-up vaccination with Synflorix vaccine (2 primary doses +1 booster dose), administered intramuscularly in the right or left thigh, during their second year of life: 2+1 catch-up vaccination starting at 12-18 months of age with an interval of at least 8 weeks (56-118 days) between primary doses; the booster dose was administered at 18-24 months of age.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Synflorix
    Investigational medicinal product code
    Other name
    10Pn-PD-DiT
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 booster dose at 15-18 months of age, administered in in the right or left thigh.

    Investigational medicinal product name
    Tritanrix-HepB
    Investigational medicinal product code
    Other name
    DTPw-HBV
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Unprimed subjects previously vaccinated with 3 doses of TritanrixTM-HepB vaccines in the Control Group of study 10PN-PD-DIT-037.

    Investigational medicinal product name
    Hiberix
    Investigational medicinal product code
    Other name
    Hib
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Unprimed subjects previously vaccinated with 3 doses of Hiberix vaccines in the Control Group of study 10PN-PD-DIT-037.

    Number of subjects in period 1 [1]
    		Synflorix 1 Group Synflorix 2 Group Tritanrix-HepB+Hiberix Group
    Started
    100
    95
    87
    Completed
    69
    71
    61
    Not completed
    31
    24
    26
         Consent withdrawn by subject
    16
    13
    16
         Lost to follow-up
    9
    4
    7
         Moved/migrated from study area
    6
    7
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 287 participants were randomized, but 2 participants withdrew their consent and 3 participants moved away from the study area, therefore only 282 received a study vaccine.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Synflorix 1 Group
    Reporting group description
    		 Subjects who were previously primed with a 3-dose primary vaccination of Synflorix vaccine in the 10PN-PD-DIT-037 (111188) study, received a booster dose of Synflorix vaccine, administered intramuscularly in the right or left thigh, at 9-18 months of age.

    Reporting group title
    Synflorix 2 Group
    Reporting group description
    		 Subjects who were previously primed with a 3-dose primary vaccination of Synflorix vaccine in the 10PN-PD-DIT-037 (111188) study, received a booster dose of Synflorix vaccine, administered intramuscularly in the right or left thigh, at 15-18 months of age.

    Reporting group title
    Tritanrix-HepB+Hiberix Group
    Reporting group description
    		 Unprimed subjects who were previously vaccinated with Tritanrix-HepB and Hiberix vaccines in the Control Group of the 10PN-PD-DIT-037 (111188) study, received a catch-up vaccination with Synflorix vaccine (2 primary doses +1 booster dose), administered intramuscularly in the right or left thigh, during their second year of life: 2+1 catch-up vaccination starting at 12-18 months of age with an interval of at least 8 weeks (56-118 days) between primary doses; the booster dose was administered at 18-24 months of age.

    Reporting group values
    		 Synflorix 1 Group Synflorix 2 Group Tritanrix-HepB+Hiberix Group Total
    Number of subjects
    		 100 95 87 282
    Age categorical
    Units: Subjects
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 12.5 ( 2.74 ) 15.6 ( 1.27 ) 16.1 ( 1.18 ) -
    Gender categorical
    Units: Subjects
        Female
    		 39 50 48 137
        Male
    		 61 45 39 145

    End points

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    End points reporting groups
    Reporting group title
    Synflorix 1 Group
    Reporting group description
    		 Subjects who were previously primed with a 3-dose primary vaccination of Synflorix vaccine in the 10PN-PD-DIT-037 (111188) study, received a booster dose of Synflorix vaccine, administered intramuscularly in the right or left thigh, at 9-18 months of age.

    Reporting group title
    Synflorix 2 Group
    Reporting group description
    		 Subjects who were previously primed with a 3-dose primary vaccination of Synflorix vaccine in the 10PN-PD-DIT-037 (111188) study, received a booster dose of Synflorix vaccine, administered intramuscularly in the right or left thigh, at 15-18 months of age.

    Reporting group title
    Tritanrix-HepB+Hiberix Group
    Reporting group description
    		 Unprimed subjects who were previously vaccinated with Tritanrix-HepB and Hiberix vaccines in the Control Group of the 10PN-PD-DIT-037 (111188) study, received a catch-up vaccination with Synflorix vaccine (2 primary doses +1 booster dose), administered intramuscularly in the right or left thigh, during their second year of life: 2+1 catch-up vaccination starting at 12-18 months of age with an interval of at least 8 weeks (56-118 days) between primary doses; the booster dose was administered at 18-24 months of age.

    Primary: Concentrations of antibodies against vaccine pneumococcal serotypes

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    End point title
    		 Concentrations of antibodies against vaccine pneumococcal serotypes [1] [2]
    End point description
    Antibodies assessed for this outcome measure were those against the vaccine pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (ANTI-1, -4, -5, -6B, -7F, -9V, -14, -18C, -19F and -23F). Antibody concentrations were measured by 22F enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). The seropositivity cut-off of the assay was an antibody concentration greater than or equal to (≥) 0.05 µg/mL. Antibody concentrations lower than (<) 0.05 μg/mL, were given an arbitrary value of half the cut-off for the purpose of GMC calculation.
    End point type
    Primary
    End point timeframe
    Prior to booster vaccination (PRE), one month after booster vaccination (Month 1) and at approximately 24 months of age: at Month 15 for the Synflorix 1 Group and at Month 9 for Synflorix 2 Group [24 months (mths) of age]
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting values for the Synflorix 1 Group and the Synflorix 2 Group.
    End point values
    		 Synflorix 1 Group Synflorix 2 Group
    Number of subjects analysed
    89
    71
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-1 PRE (N=88;69)
    0.37 (0.29 to 0.48)
    0.31 (0.23 to 0.41)
        Anti-1 Month 1 (N=80;61)
    4.78 (3.87 to 5.91)
    5.98 (4.54 to 7.9)
        Anti-1 24 mths of age (N=59;55)
    0.96 (0.68 to 1.37)
    1.37 (1 to 1.87)
        Anti-4 PRE (N=88;68)
    0.76 (0.58 to 1)
    0.58 (0.44 to 0.75)
        Anti-4 Month 1 (N=81;63)
    7.28 (5.41 to 9.79)
    11.56 (7.96 to 16.79)
        Anti-4 24 mths of age (N=59;55)
    1.24 (0.9 to 1.7)
    2.29 (1.53 to 3.42)
        Anti-5 PRE (N=88;69)
    0.5 (0.4 to 0.63)
    0.38 (0.29 to 0.48)
        Anti-5 Month 1 (N=81;62)
    5.86 (4.69 to 7.32)
    7.2 (5.25 to 9.86)
        Anti-5 24 mths of age (N=59;55)
    1.19 (0.86 to 1.65)
    2.03 (1.43 to 2.86)
        Anti-6B PRE (N=88;71)
    0.65 (0.5 to 0.85)
    0.49 (0.37 to 0.64)
        Anti-6B Month 1 (N=81;64)
    2.82 (2.16 to 3.68)
    2.98 (2.05 to 4.32)
        Anti-6B 24 mths of age (N=59;55)
    0.78 (0.54 to 1.11)
    0.9 (0.61 to 1.32)
        Anti-7F PRE (N=88;70)
    1.12 (0.92 to 1.38)
    0.93 (0.73 to 1.19)
        Anti-7F Month 1 (N=81;63)
    6.3 (4.8 to 8.25)
    7.89 (5.91 to 10.54)
        Anti-7F 24 mths of age (N=59;55)
    1.3 (0.96 to 1.76)
    1.98 (1.43 to 2.75)
        Anti-9V PRE (N=88;71)
    1.2 (0.94 to 1.52)
    0.96 (0.74 to 1.25)
        Anti-9V Month 1 (N=81;64)
    8.03 (6.03 to 10.69)
    9.76 (7.08 to 13.44)
        Anti-9V 24 mths of age (N=58;55)
    1.7 (1.2 to 2.41)
    2.27 (1.64 to 3.14)
        Anti-14 PRE (N=89;70)
    1.76 (1.22 to 2.53)
    1.52 (1.08 to 2.15)
        Anti-14 Month 1 (N=81;64)
    10.18 (7.6 to 13.65)
    11.85 (8.15 to 17.22)
        Anti-14 24 mths of age (N=59;55)
    3.02 (2.09 to 4.37)
    4.11 (2.98 to 5.67)
        Anti-18C PRE (N=89;71)
    2.51 (1.94 to 3.23)
    1.55 (1.19 to 2.03)
        Anti-18C Month 1 (N=81;63)
    33.39 (24.73 to 45.08)
    42.43 (31.48 to 57.2)
        Anti-18C 24 mths of age (N=59;55)
    5.56 (3.84 to 8.05)
    10.04 (6.55 to 15.37)
        Anti-19F PRE (N=89;70)
    1.78 (1.34 to 2.36)
    1.23 (0.97 to 1.57)
        Anti-19F Month 1 (N=81;64)
    13.68 (9.86 to 18.97)
    13.64 (9.42 to 19.76)
        Anti-19F 24 mths of age (N=59;55)
    2.57 (1.81 to 3.65)
    4.15 (2.88 to 5.98)
        Anti-23F PRE (N=88;70)
    0.73 (0.55 to 0.97)
    0.65 (0.48 to 0.89)
        Anti-23F Month 1 (N=81;63)
    5.54 (4.02 to 7.63)
    6.48 (4.69 to 8.96)
        Anti-23F 24 mths of age (N=59;55)
    1.3 (0.88 to 1.91)
    1.38 (0.96 to 1.98)
    No statistical analyses for this end point

    Secondary: Concentrations of antibodies against vaccine pneumococcal serotypes

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    End point title
    		 Concentrations of antibodies against vaccine pneumococcal serotypes [3]
    End point description
    Antibodies assessed for this outcome measure were those against the vaccine pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (ANTI-1, -4, -5, -6B, -7F, -9V, -14, -18C, -19F and -23F). Antibody concentrations were measured by 22F enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). The seropositivity cut-off of the assay was an antibody concentration ≥ 0.05 µg/mL. Antibody concentrations < 0.05 μg/mL were given an arbitrary value of half the cut-off for the purpose of GMC calculation.
    End point type
    Secondary
    End point timeframe
    Prior to vaccination (PRE), one month post-Dose 2 (Month 3), prior to (Month 6) and one month after the third (booster) vaccine dose (Month 7)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting values for the Tritanrix-HepB+Hiberix Group.
    End point values
    		 Tritanrix-HepB+Hiberix Group
    Number of subjects analysed
    81
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-1 PRE (N=81)
    0.04 (0.03 to 0.04)
        Anti-1 Month 3 (N=69)
    2.5 (1.93 to 3.24)
        Anti-1 Month 6 (N=65)
    1.03 (0.82 to 1.29)
        Anti-1 Month 7 (N=54)
    3.32 (2.69 to 4.1)
        Anti-4 PRE (N=80)
    0.04 (0.03 to 0.05)
        Anti-4 Month 3 (N=71)
    5.89 (4.23 to 8.22)
        Anti-4 Month 6 (N=65)
    2.23 (1.85 to 2.69)
        Anti-4 Month 7 (N=54)
    8.22 (5.92 to 11.42)
        Anti-5 PRE (N=80)
    0.05 (0.04 to 0.06)
        Anti-5 Month 3 (N=71)
    2.81 (2.2 to 3.58)
        Anti-5 Month 6 (N=65)
    1.39 (1.13 to 1.7)
        Anti-5 Month 7 (N=54)
    5.32 (4.21 to 6.72)
        Anti-6B PRE (N=80)
    0.03 (0.03 to 0.04)
        Anti-6B Month 3 (N=70)
    0.71 (0.53 to 0.95)
        Anti-6B Month 6 (N=65)
    0.61 (0.47 to 0.78)
        Anti-6B Month 7 (N=54)
    1.4 (1.04 to 1.88)
        Anti-7F PRE (N=81)
    0.06 (0.05 to 0.08)
        Anti-7F Month 3 (N=71)
    4.63 (3.38 to 6.34)
        Anti-7F Month 6 (N=65)
    2.72 (2.28 to 3.24)
        Anti-7F Month 7 (N=54)
    7.41 (5.87 to 9.34)
        Anti-9V PRE (N=80)
    0.04 (0.03 to 0.05)
        Anti-9V Month 3 (N=71)
    2.09 (1.53 to 2.87)
        Anti-9V Month 6 (N=65)
    1.74 (1.4 to 2.17)
        Anti-9V Month 7 (N=54)
    4.88 (3.73 to 6.37)
        Anti-14 PRE (N=80)
    0.06 (0.05 to 0.08)
        Anti-14 Month 3 (N=71)
    5.01 (3.75 to 6.69)
        Anti-14 Month 6 (N=65)
    2.84 (2.25 to 3.57)
        Anti-14 Month 7 (N=54)
    7.59 (5.87 to 9.8)
        Anti-18C PRE (N=80)
    0.04 (0.03 to 0.05)
        Anti-18C Month 3 (N=70)
    29.1 (19.86 to 42.64)
        Anti-18C Month 6 (N=65)
    12.44 (9.16 to 16.91)
        Anti-18C Month 7 (N=54)
    75.19 (57.69 to 98.01)
        Anti-19F PRE (N=80)
    0.07 (0.05 to 0.1)
        Anti-19F Month 3 (N=71)
    16.39 (11.15 to 24.1)
        Anti-19F Month 6 (N=65)
    7.74 (5.85 to 10.24)
        Anti-19F Month 7 (N=54)
    30.71 (23.76 to 39.68)
        Anti-23F PRE (N=80)
    0.04 (0.03 to 0.05)
        Anti-23F Month 3 (N=71)
    1.13 (0.82 to 1.57)
        Anti-23F Month 6 (N=65)
    0.85 (0.67 to 1.09)
        Anti-23F Month 7 (N=54)
    2.15 (1.69 to 2.75)
    No statistical analyses for this end point

    Secondary: Concentrations of antibodies against vaccine pneumococcal serotypes (Persistence)

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    End point title
    		 Concentrations of antibodies against vaccine pneumococcal serotypes (Persistence)
    End point description
    Antibodies assessed for this outcome measure were those against the vaccine pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (ANTI-1, -4, -5, -6B, -7F, -9V, -14, -18C, -19F and -23F). Antibody concentrations were measured by 22F enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). The seropositivity cut-off of the assay was an antibody concentration ≥ 0.05 µg/mL. Antibody concentrations < 0.05 μg/mL were given an arbitrary value of half the cut-off for the purpose of GMC calculation.
    End point type
    Secondary
    End point timeframe
    Prior to booster vaccination (PRE) for the Synflorix 1 and Synflorix 2 Groups and prior to catch-up vaccination (PRE) for the Tritanrix-HepB+Hiberix Group
    End point values
    		 Synflorix 1 Group Synflorix 2 Group Tritanrix-HepB+Hiberix Group
    Number of subjects analysed
    89
    90
    84
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-1 (N=88;87;84)
    0.37 (0.29 to 0.48)
    0.3 (0.24 to 0.39)
    0.04 (0.03 to 0.04)
        Anti-4 (N=88;85;83)
    0.76 (0.58 to 1)
    0.57 (0.45 to 0.72)
    0.04 (0.03 to 0.05)
        Anti-5 (N=88;87;83)
    0.5 (0.4 to 0.63)
    0.38 (0.31 to 0.47)
    0.05 (0.04 to 0.06)
        Anti-6B (N=88;90;83)
    0.65 (0.5 to 0.85)
    0.51 (0.4 to 0.65)
    0.03 (0.03 to 0.04)
        Anti-7F (N=88;89;84)
    1.12 (0.92 to 1.38)
    0.98 (0.79 to 1.23)
    0.06 (0.04 to 0.08)
        Anti-9V (N=88;90;83)
    1.2 (0.94 to 1.52)
    0.98 (0.78 to 1.23)
    0.04 (0.03 to 0.05)
        Anti-14 (N=89;89;83)
    1.76 (1.22 to 2.53)
    1.37 (1 to 1.87)
    0.06 (0.05 to 0.08)
        Anti-18C (N=89;90;83)
    2.51 (1.94 to 3.23)
    1.61 (1.26 to 2.05)
    0.04 (0.03 to 0.05)
        Anti-19F (N=89;88;83)
    1.78 (1.34 to 2.36)
    1.36 (1.1 to 1.68)
    0.07 (0.05 to 0.09)
        Anti-23F (N=88;88;83)
    0.73 (0.55 to 0.97)
    0.64 (0.49 to 0.85)
    0.04 (0.03 to 0.05)
    No statistical analyses for this end point

    Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Persistence)

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    End point title
    		 Opsonophagocytic activity (OPA) titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Persistence)
    End point description
    OPA titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Opsono-1, -4, -5, -6B, -7F, -9V, -14, -18C, -19F and -23F) were calculated, expressed as geometric mean titers (GMTs) and tabulated. The seropositivity cut-off for the assay was ≥ 8. Antibody titers < 8 were given an arbitrary value of half the cut-off for the purpose of GMT calculation.
    End point type
    Secondary
    End point timeframe
    Prior to booster vaccination (PRE) for the Synflorix 1 and Synflorix 2 Groups and prior to catch-up vaccination (PRE) for the Tritanrix-HepB+Hiberix Group
    End point values
    		 Synflorix 1 Group Synflorix 2 Group Tritanrix-HepB+Hiberix Group
    Number of subjects analysed
    87
    84
    78
    Units: Titer
    geometric mean (confidence interval 95%)
        Opsono-1 (N=87;84;77)
    16.5 (11.2 to 24.3)
    15.6 (10.5 to 23)
    4.4 (3.9 to 5)
        Opsono-4 (N=85;81;67)
    70.3 (43.9 to 112.5)
    102.8 (66.4 to 159.1)
    6.2 (4.2 to 9.3)
        Opsono-5 (N=87;81;78)
    11.9 (8.9 to 15.9)
    10.4 (7.8 to 13.7)
    4.2 (3.8 to 4.7)
        Opsono-6B (N=87;82;71)
    50.2 (30.7 to 82.1)
    62 (36.5 to 105.5)
    5.3 (3.9 to 7)
        Opsono-7F (N=87;84;65)
    1162.5 (910 to 1485)
    1551.1 (1269.4 to 1895.3)
    1186.4 (588.8 to 2390.7)
        Opsono-9V (N=83;82;60)
    430.4 (310.7 to 596.1)
    617.6 (477.6 to 798.6)
    192.6 (93.6 to 396.5)
        Opsono-14 (N=85;79;69)
    206.4 (134.2 to 317.5)
    166.3 (105.7 to 261.6)
    13.5 (7.8 to 23.5)
        Opsono-18C (N=85;81;74)
    30.4 (20.7 to 44.6)
    23 (15.6 to 34)
    4.8 (3.8 to 6)
        Opsono-19F (N=86;82;76)
    43 (29.9 to 61.7)
    42.4 (29.5 to 60.8)
    4.2 (3.9 to 4.6)
        Opsono-23F (N=86;80;72)
    157 (83.2 to 296.3)
    531.1 (280.3 to 1006.4)
    41.9 (18.8 to 93.2)
    No statistical analyses for this end point

    Secondary: OPA titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F

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    End point title
    		 OPA titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F [4]
    End point description
    OPA titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Opsono-1, -4, -5, -6B, -7F, -9V, -14, -18C, -19F and -23F) were calculated, expressed as geometric mean titers (GMTs) and tabulated. The seropositivity cut-off for the assay was ≥ 8. Antibody titers < 8 were given an arbitrary value of half the cut-off for the purpose of GMT calculation.
    End point type
    Secondary
    End point timeframe
    Prior to booster vaccination (PRE), one month after booster vaccination (Month 1) and at approximately 24 months of age: at Month 15 for the Synflorix 1 Group and at Month 9 for Synflorix 2 Group (24 mths of age)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting values for the Synflorix 1 Group and the Synflorix 2 Group.
    End point values
    		 Synflorix 1 Group Synflorix 2 Group
    Number of subjects analysed
    87
    65
    Units: Titer
    geometric mean (confidence interval 95%)
        Opsono-1 PRE (N=87;65)
    16.5 (11.2 to 24.3)
    14.3 (9.3 to 22.1)
        Opsono-1 Month 1 (N=79;58)
    1138.3 (828.6 to 1563.7)
    2096.7 (1464.8 to 3001.1)
        Opsono-1 24 mths of age (N=57;54)
    69.6 (40.1 to 121)
    173.8 (105.5 to 286.5)
        Opsono-4 PRE (N=85;63)
    70.3 (43.9 to 112.5)
    101.6 (62.6 to 164.9)
        Opsono-4 Month 1 (N=79;58)
    3368.8 (2618 to 4334.9)
    7202.1 (5336.1 to 9720.6)
        Opsono-4 24 mths of age (N=57;54)
    557.4 (284 to 1093.9)
    2525.6 (1474.5 to 4325.9)
        Opsono-5 PRE (N=87;62)
    11.9 (8.9 to 15.9)
    9.7 (7.2 to 13.1)
        Opsono-5 Month 1 (N=79;58)
    452.7 (353 to 580.6)
    834.6 (610.9 to 1140.2)
        Opsono-5 24 mths of age (N=56;55)
    45.7 (29.6 to 70.7)
    90.6 (54.8 to 149.8)
        Opsono-6B PRE (N=87;63)
    50.2 (30.7 to 82.1)
    60 (32.9 to 109.3)
        Opsono-6B Month 1 (N=79;57)
    1556.6 (1090 to 2223)
    1781.2 (1042.5 to 3043.6)
        Opsono-6B 24 mths of age (N=51;52)
    241.4 (127.7 to 456.4)
    287.5 (149 to 555)
        Opsono-7F PRE (N=87;65)
    1162.5 (910 to 1485)
    1539.1 (1262.9 to 1875.6)
        Opsono-7F Month 1 (N=79;57)
    7814.8 (5984.8 to 10204.3)
    11064.4 (8182.9 to 14960.5)
        Opsono-7F 24 mths of age (N=55;52)
    2891.2 (1954.4 to 4276.9)
    5371.9 (3712.4 to 7773.4)
        Opsono-9V PRE (N=83;63)
    430.4 (310.7 to 596.1)
    704.9 (533.7 to 931.1)
        Opsono-9V Month 1 (N=79;58)
    4440 (3305.4 to 5964.2)
    7870.3 (5634.4 to 10993.4)
        Opsono-9V 24 mths of age (N=49;52)
    1926.1 (1316.6 to 2817.9)
    3504.5 (2501 to 4910.6)
        Opsono-14 PRE (N=85;62)
    206.4 (134.2 to 317.5)
    184 (109.8 to 308.2)
        Opsono-14 Month 1 (N=79;57)
    2057.1 (1569.6 to 2696.1)
    4407.5 (3193.2 to 6083.5)
        Opsono-14 24 mths of age (N=56;53)
    668.5 (403.1 to 1108.6)
    1641.2 (944.2 to 2852.9)
        Opsono-18C PRE (N=85;62)
    30.4 (20.7 to 44.6)
    22.2 (14.1 to 35)
        Opsono-18C Month 1 (N=79;58)
    1889.7 (1429.4 to 2498.1)
    3643.2 (2572.2 to 5160.2)
        Opsono-18C 24 mths of age (N=52;53)
    233.6 (142.2 to 383.8)
    1155 (662 to 2015)
        Opsono-19F PRE (N=86;63)
    43 (29.9 to 61.7)
    34.7 (23.4 to 51.6)
        Opsono-19F Month 1 (N=78;58)
    1672.9 (1096.3 to 2552.7)
    2404.4 (1583.1 to 3651.6)
        Opsono-19F 24 mths of age (N=51;53)
    107.3 (61.4 to 187.6)
    357.9 (218.9 to 585)
        Opsono-23F PRE (N=86;61)
    157 (83.2 to 296.3)
    498.2 (231.4 to 1072.9)
        Opsono-23F Month 1 (N=79;58)
    3812.3 (2630.8 to 5524.5)
    5937.2 (3587.6 to 9825.5)
        Opsono-23F 24 mths of age (N=54;55)
    1994.1 (959.7 to 4143.4)
    3018.5 (1389 to 6559.6)
    No statistical analyses for this end point

    Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F

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    End point title
    		 Opsonophagocytic activity (OPA) titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F [5]
    End point description
    OPA titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Opsono-1, -4, -5, -6B, -7F, -9V, -14, -18C, -19F and -23F) were calculated, expressed as geometric mean titers (GMTs) and tabulated. The seropositivity cut-off for the assay was ≥ 8. Antibody titers < 8 were given an arbitrary value of half the cut-off for the purpose of GMT calculation.
    End point type
    Secondary
    End point timeframe
    Prior to vaccination (PRE), one month post-Dose 2 (Month 3), prior to (Month 6) and one month after the third (booster) vaccine dose (Month 7)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting values for the Tritanrix-HepB+Hiberix Group.
    End point values
    		 Tritanrix-HepB+Hiberix Group
    Number of subjects analysed
    75
    Units: Titer
    geometric mean (confidence interval 95%)
        Opsono-1 PRE (N=74)
    4.3 (3.9 to 4.8)
        Opsono-1 Month 3 (N=68)
    76.1 (49 to 118.2)
        Opsono-1 Month 6 (N=64)
    18.1 (11.5 to 28.4)
        Opsono-1 Month 7 (N=54)
    309.8 (203 to 472.9)
        Opsono-4 PRE (N=64)
    5.8 (4 to 8.6)
        Opsono-4 Month 3 (N=66)
    2256.3 (1840 to 2766.8)
        Opsono-4 Month 6 (N=63)
    959.7 (727.2 to 1266.6)
        Opsono-4 Month 7 (N=54)
    2946.2 (2097.9 to 4137.4)
        Opsono-5 PRE (N=75)
    4.2 (3.8 to 4.7)
        Opsono-5 Month 3 (N=64)
    76.3 (53.3 to 109.3)
        Opsono-5 Month 6 (N=63)
    24.6 (17 to 35.6)
        Opsono-5 Month 7 (N=54)
    212 (148.9 to 301.7)
        Opsono-6B PRE (N=68)
    5.3 (3.9 to 7.2)
        Opsono-6B Month 3 (N=63)
    348.2 (165.7 to 731.6)
        Opsono-6B Month 6 (N=61)
    201.5 (98.2 to 413.5)
        Opsono-6B Month 7 (N=53)
    740.5 (419.6 to 1306.8)
        Opsono-7F PRE (N=63)
    1106.8 (540.7 to 2265.9)
        Opsono-7F Month 3 (N=67)
    7462.5 (5653.9 to 9849.6)
        Opsono-7F Month 6 (N=63)
    6295.9 (4545 to 8721.4)
        Opsono-7F Month 7 (N=54)
    10104 (7377.8 to 13837.4)
        Opsono-9V PRE (N=58)
    205.9 (98.7 to 429.4)
        Opsono-9V Month 3 (N=61)
    5792.5 (4586.3 to 7315.9)
        Opsono-9V Month 6 (N=62)
    3463.4 (2716.3 to 4416.1)
        Opsono-9V Month 7 (N=53)
    7000 (5265.1 to 9306.6)
        Opsono-14 PRE (N=67)
    12.4 (7.1 to 21.6)
        Opsono-14 Month 3 (N=65)
    2359.8 (1576.1 to 3533.2)
        Opsono-14 Month 6 (N=63)
    1293.6 (886.8 to 1887.2)
        Opsono-14 Month 7 (N=54)
    3709.4 (2463.5 to 5585.2)
        Opsono-18C PRE (N=71)
    4.8 (3.8 to 6.1)
        Opsono-18C Month 3 (N=66)
    2487.5 (1541.2 to 4014.8)
        Opsono-18C Month 6 (N=62)
    2546.4 (1755 to 3694.7)
        Opsono-18C Month 7 (N=54)
    8814.6 (6810.9 to 11407.7)
        Opsono-19F PRE (N=73)
    4.2 (3.9 to 4.6)
        Opsono-19F Month 3 (N=65)
    1768.6 (1120.3 to 2792)
        Opsono-19F Month 6 (N=62)
    753.8 (497.3 to 1142.5)
        Opsono-19F Month 7 (N=51)
    3808.8 (2689.5 to 5393.9)
        Opsono-23F PRE (N=69)
    38.7 (17.1 to 87.5)
        Opsono-23F Month 3 (N=67)
    3378.1 (2014.8 to 5664)
        Opsono-23F Month 6 (N=62)
    1868.2 (956.9 to 3647.5)
        Opsono-23F Month 7 (N=53)
    4357.3 (2246.9 to 8449.8)
    No statistical analyses for this end point

    Secondary: Concentrations of antibodies against cross-reactive pneumococcal serotypes 6A and 19A (Persistence)

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    End point title
    		 Concentrations of antibodies against cross-reactive pneumococcal serotypes 6A and 19A (Persistence)
    End point description
    Antibodies assessed for this outcome measure were those against cross-reactive pneumococcal serotypes 6A and 19A (ANTI-6A and -19A). Antibody concentrations were measured by 22F ELISA, expressed as geometric mean concentrations (GMCs), in µg/mL. The seropositivity cut-off of the assay was an antibody concentration ≥ 0.05 µg/mL. Antibody concentrations < 0.05 μg/mL were given an arbitrary value of half the cut-off for the purpose of GMC calculation.
    End point type
    Secondary
    End point timeframe
    Prior to booster vaccination (PRE) for the Synflorix 1 and Synflorix 2 Groups and prior to catch-up vaccination (PRE) for the Tritanrix-HepB + Hiberix Group
    End point values
    		 Synflorix 1 Group Synflorix 2 Group Tritanrix-HepB+Hiberix Group
    Number of subjects analysed
    89
    89
    84
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-6A (N=89;87;83)
    0.19 (0.14 to 0.26)
    0.22 (0.16 to 0.29)
    0.03 (0.03 to 0.04)
        Anti-19A (N=88;89;84)
    0.31 (0.21 to 0.45)
    0.33 (0.25 to 0.45)
    0.06 (0.04 to 0.08)
    No statistical analyses for this end point

    Secondary: Concentrations of antibodies against cross-reactive pneumococcal serotypes 6A and 19A

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    End point title
    		 Concentrations of antibodies against cross-reactive pneumococcal serotypes 6A and 19A [6]
    End point description
    Antibodies assessed for this outcome measure were those against the cross-reactive pneumococcal serotypes 6A and 19A (ANTI-6A and -19A). Antibody concentrations were measured by 22F enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). The seropositivity cut-off of the assay was an antibody concentration ≥ 0.05 µg/mL. Antibody concentrations < 0.05 μg/mL were given an arbitrary value of half the cut-off for the purpose of GMC calculation.
    End point type
    Secondary
    End point timeframe
    Prior to booster vaccination (PRE), one month after booster vaccination (Month 1) and at approximately 24 months of age: at Month 15 for the Synflorix 1 Group and at Month 9 for Synflorix 2 Group (24 mths of age)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting values for the Synflorix 1 Group and the Synflorix 2 Group.
    End point values
    		 Synflorix 1 Group Synflorix 2 Group
    Number of subjects analysed
    89
    70
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-6A PRE (N=89;70)
    0.19 (0.14 to 0.26)
    0.19 (0.14 to 0.27)
        Anti-6A Month 1 (N=81;62)
    0.82 (0.59 to 1.14)
    0.95 (0.63 to 1.44)
        Anti-6A 24 mths of age (N=59;55)
    0.32 (0.22 to 0.48)
    0.36 (0.22 to 0.59)
        Anti-19A PRE (N=88;70)
    0.31 (0.21 to 0.45)
    0.3 (0.22 to 0.41)
        Anti-19A Month 1 (N=81;64)
    2.54 (1.61 to 4.03)
    2.87 (1.78 to 4.61)
        Anti-19A 24 mths of age (N=59;55)
    0.71 (0.45 to 1.14)
    1.33 (0.85 to 2.08)
    No statistical analyses for this end point

    Secondary: Concentrations of antibodies against cross-reactive pneumococcal serotypes 6A and 19A

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    End point title
    		 Concentrations of antibodies against cross-reactive pneumococcal serotypes 6A and 19A [7]
    End point description
    Antibodies assessed for this outcome measure were those against cross-reactive pneumococcal serotypes 6A and 19A (ANTI-6A and -19A). Antibody concentrations were measured by 22F enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). The seropositivity cut-off of the assay was an antibody concentration ≥ 0.05 µg/mL. Antibody concentrations < 0.05 μg/mL were given an arbitrary value of half the cut-off for the purpose of GMC calculation.
    End point type
    Secondary
    End point timeframe
    Prior to vaccination (PRE), one month post-Dose 2 (Month 3), prior to (Month 6) and one month after the third (booster) vaccine dose (Month 7)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting values for the Tritanrix-HepB+Hiberix Group.
    End point values
    		 Tritanrix-HepB+Hiberix Group
    Number of subjects analysed
    81
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-6A PRE (N=80)
    0.03 (0.03 to 0.04)
        Anti-6A Month 3 (N=70)
    0.35 (0.25 to 0.5)
        Anti-6A Month 6 (N=65)
    0.33 (0.24 to 0.45)
        Anti-6A Month 7 (N=54)
    0.76 (0.53 to 1.09)
        Anti-19A PRE (N=81)
    0.06 (0.04 to 0.08)
        Anti-19A Month 3 (N=71)
    2.49 (1.77 to 3.51)
        Anti-19A Month 6 (N=65)
    1.94 (1.44 to 2.61)
        Anti-19A Month 7 (N=54)
    7.91 (5.62 to 11.13)
    No statistical analyses for this end point

    Secondary: Opsonophagocytic activity (OPA) titers against cross-reactive pneumococcal serotypes 6A and 19A (Persistence)

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    End point title
    		 Opsonophagocytic activity (OPA) titers against cross-reactive pneumococcal serotypes 6A and 19A (Persistence)
    End point description
    OPA titers against cross-reactive pneumococcal serotypes 6A and 19A (Opsono-6A and -19A) were calculated, expressed as geometric mean titers (GMTs) and tabulated. The seropositivity cut-off for the assay was ≥ 8. Antibody titers < 8 were given an arbitrary value of half the cut-off for the purpose of GMT calculation.
    End point type
    Secondary
    End point timeframe
    Prior to booster vaccination (PRE) for the Synflorix 1 and Synflorix 2 Groups and prior to catch-up vaccination (PRE) for the Tritanrix-HepB + Hiberix Group
    End point values
    		 Synflorix 1 Group Synflorix 2 Group Tritanrix-HepB+Hiberix Group
    Number of subjects analysed
    86
    82
    78
    Units: Titer
    geometric mean (confidence interval 95%)
        Opsono-6A (N=86;82;72)
    21.1 (13.2 to 33.6)
    30.1 (18.4 to 49.3)
    10.3 (6.3 to 17)
        Opsono-19A (N=86;82;78)
    9.7 (6.8 to 13.7)
    7.4 (5.7 to 9.7)
    4.8 (4 to 5.7)
    No statistical analyses for this end point

    Secondary: Opsonophagocytic activity (OPA) titers against cross-reactive pneumococcal serotypes 6A and 19A

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    End point title
    		 Opsonophagocytic activity (OPA) titers against cross-reactive pneumococcal serotypes 6A and 19A [8]
    End point description
    OPA titers against cross-reactive pneumococcal serotypes 6A and 19A (Opsono-6A and -19A) were calculated, expressed as geometric mean titers (GMTs) and tabulated. The seropositivity cut-off for the assay was ≥ 8. Antibody titers < 8 were given an arbitrary value of half the cut-off for the purpose of GMT calculation.
    End point type
    Secondary
    End point timeframe
    Prior to booster vaccination (PRE), one month after booster vaccination (Month 1) and at approximately 24 months of age: at Month 15 for the Synflorix 1 Group and at Month 9 for Synflorix 2 Group (24 mths of age)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting values for the Synflorix 1 Group and the Synflorix 2 Group.
    End point values
    		 Synflorix 1 Group Synflorix 2 Group
    Number of subjects analysed
    86
    63
    Units: Titer
    geometric mean (confidence interval 95%)
        Opsono-6A PRE (N=86;63)
    21.1 (13.2 to 33.6)
    27.1 (15.7 to 47)
        Opsono-6A Month 1 (N=79;57)
    168.7 (96.3 to 295.5)
    262.5 (135.4 to 509)
        Opsono-6A 24 mths of age (N=54;53)
    62.2 (33.7 to 114.8)
    96.6 (45.4 to 205.6)
        Opsono-19A PRE (N=86;63)
    9.7 (6.8 to 13.7)
    7 (5.3 to 9.3)
        Opsono-19A Month 1 (N=78;57)
    161.6 (93.7 to 278.5)
    385.6 (223.4 to 665.5)
        Opsono-19A 24 mths of age (N=53;51)
    17.8 (9.8 to 32.1)
    60 (33 to 109.2)
    No statistical analyses for this end point

    Secondary: Opsonophagocytic activity (OPA) titers against cross-reactive pneumococcal serotypes 6A and 19A

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    End point title
    		 Opsonophagocytic activity (OPA) titers against cross-reactive pneumococcal serotypes 6A and 19A [9]
    End point description
    OPA titers against cross-reactive pneumococcal serotypes 6A and 19A (Opsono-6A and -19A) were calculated, expressed as geometric mean titers (GMTs) and tabulated. The seropositivity cut-off for the assay was ≥ 8. Antibody titers < 8 were given an arbitrary value of half the cut-off for the purpose of GMT calculation.
    End point type
    Secondary
    End point timeframe
    Prior to vaccination (PRE), one month post-Dose 2 (Month 3), prior to (Month 6) and one month after the third (booster) vaccine dose (Month 7)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting values for the Tritanrix-HepB+Hiberix Group.
    End point values
    		 Tritanrix-HepB+Hiberix Group
    Number of subjects analysed
    75
    Units: Titer
    geometric mean (confidence interval 95%)
        Opsono-6A PRE (N=69)
    10.2 (6.1 to 17.1)
        Opsono-6A Month 3 (N=65)
    324.9 (176.1 to 599.5)
        Opsono-6A Month 6 (N=63)
    329 (181 to 598.2)
        Opsono-6A Month 7 (N=52)
    616.2 (369.2 to 1028.5)
        Opsono-19A PRE (N=75)
    4.8 (4 to 5.8)
        Opsono-19A Month 3 (N=64)
    506.6 (305.5 to 840.1)
        Opsono-19A Month 6 (N=61)
    402.1 (248.9 to 649.5)
        Opsono-19A Month 7 (N=54)
    1770.9 (1190.6 to 2634)
    No statistical analyses for this end point

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

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    End point title
    		 Concentrations of antibodies against protein D (Anti-PD) (Persistence)
    End point description
    Anti-protein D (Anti-PD) antibody concentrations by Enzyme-Linked Immunosorbent Assay (ELISA) were calculated, expressed as geometric mean concentrations (GMCs) in ELISA unit per milliliter (EL.U/mL) and tabulated. The seropositivity cut-off for the assay was ≥ 100 EL.U/mL. Antibody concentrations < 100 EL.U/mL were given an arbitrary value of half the cut-off for the purpose of GMC calculation.
    End point type
    Secondary
    End point timeframe
    Prior to booster vaccination (PRE) for the Synflorix 1 and Synflorix 2 Groups and prior to catch-up vaccination (PRE) for the Tritanrix-HepB + Hiberix Group
    End point values
    		 Synflorix 1 Group Synflorix 2 Group Tritanrix-HepB+Hiberix Group
    Number of subjects analysed
    89
    90
    82
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-PD
    776.3 (629 to 958.2)
    618.6 (488.2 to 783.9)
    71.6 (62.3 to 82.2)
    No statistical analyses for this end point

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

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    End point title
    		 Concentrations of antibodies against protein D (Anti-PD) [10]
    End point description
    Anti-protein D (Anti-PD) antibody concentrations by Enzyme-Linked Immunosorbent Assay (ELISA) were calculated, expressed as geometric mean concentrations (GMCs) in ELISA unit per milliliter (EL.U/mL) and tabulated. The seropositivity cut-off for the assay was ≥ 100 EL.U/mL. Antibody concentrations < 100 EL.U/mL were given an arbitrary value of half the cut-off for the purpose of GMC calculation.
    End point type
    Secondary
    End point timeframe
    Prior to booster vaccination (PRE), one month after booster vaccination (Month 1) and at approximately 24 months of age: at Month 15 for the Synflorix 1 Group and at Month 9 for Synflorix 2 Group (24 mths of age)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting values for the Synflorix 1 Group and the Synflorix 2 Group.
    End point values
    		 Synflorix 1 Group Synflorix 2 Group
    Number of subjects analysed
    89
    71
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-PD PRE (N=89;71)
    776.3 (629 to 958.2)
    654.7 (497.9 to 860.9)
        Anti-PD Month 1 (N=81;61)
    3704.2 (2825.6 to 4856)
    5297.6 (3934 to 7133.8)
        Anti-PD 24 mths of age (N=59;54)
    1337.3 (953.8 to 1875)
    2191.9 (1582.5 to 3036)
    No statistical analyses for this end point

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

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    End point title
    		 Concentrations of antibodies against protein D (Anti-PD) [11]
    End point description
    Anti-protein D (Anti-PD) antibody concentrations by Enzyme-Linked Immunosorbent Assay (ELISA) were calculated, expressed as geometric mean concentrations (GMCs) in ELISA unit per milliliter (EL.U/mL) and tabulated. The seropositivity cut-off for the assay was ≥ 100 EL.U/mL. Antibody concentrations < 100 EL.U/mL were given an arbitrary value of half the cut-off for the purpose of GMC calculation.
    End point type
    Secondary
    End point timeframe
    Prior to vaccination (PRE), one month post-Dose 2 (Month 3), prior to (Month 6) and one month after the third (booster) vaccine dose (Month 7)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting values for the Tritanrix-HepB+Hiberix Group.
    End point values
    		 Tritanrix-HepB+Hiberix Group
    Number of subjects analysed
    79
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-PD PRE (N=79)
    72.5 (62.9 to 83.7)
        Anti-PD Month 3 (N=70)
    527.7 (397.4 to 700.9)
        Anti-PD Month 6 (N=65)
    443.2 (333.1 to 589.6)
        Anti-PD Month 7 (N=54)
    1727.2 (1306.6 to 2283.3)
    No statistical analyses for this end point

    Secondary: Number of subjects with any and Grade 3 solicited local symptoms

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    End point title
    		 Number of subjects with any and Grade 3 solicited local symptoms
    End point description
    Solicited local symptoms assessed include pain, redness and swelling. Grade 3 pain was defined as crying when limb was moved/spontaneously painful. Grade 3 swelling/redness was defined as swelling/redness larger than (>) 30 millimeters (mm). “Any” is defined as incidence of the specified symptom regardless of intensity.
    End point type
    Secondary
    End point timeframe
    Within the 4-day follow-up period (Days 0-3) after the booster dose for the Synflorix 1 and Synflorix 2 Groups and across doses for the Tritanrix-HepB + Hiberix Group
    End point values
    		 Synflorix 1 Group Synflorix 2 Group Tritanrix-HepB+Hiberix Group
    Number of subjects analysed
    93
    85
    82
    Units: Subjects
        Any Pain
    31
    25
    26
        Grade 3 Pain
    2
    4
    5
        Any Redness
    16
    12
    11
        Grade 3 Redness
    2
    0
    1
        Any Swelling
    14
    14
    16
        Grade 3 Swelling
    4
    1
    2
    No statistical analyses for this end point

    Secondary: Number of subjects with any, Grade 3 and related solicited general symptoms

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    End point title
    		 Number of subjects with any, Grade 3 and related solicited general symptoms
    End point description
    Assessed solicited general symptoms were Drowsiness, Irritability/Fussiness (Irr./Fuss.), Loss of appetite (Loss Appet.) and Fever (rectal temperature greater than or equal to [≥] 38.0 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 everyday activities. Grade 3 Irr./Fuss. = Crying that could not be comforted/prevented normal everyday activities. Grade 3 Loss of appetite = Subject did not eat at all. Grade 3 Fever = Rectal temperature higher than (>) 40.0°C.
    End point type
    Secondary
    End point timeframe
    Within the 4-day follow-up period (Days 0-3) after the booster dose for the Synflorix 1 and Synflorix 2 Groups and across doses for the Tritanrix-HepB + Hiberix Group
    End point values
    		 Synflorix 1 Group Synflorix 2 Group Tritanrix-HepB+Hiberix Group
    Number of subjects analysed
    92
    85
    82
    Units: Subjects
        Any Drowsiness
    5
    4
    5
        Grade 3 Drowsiness
    0
    0
    2
        Related Drowsiness
    4
    4
    3
        Any Fever
    20
    13
    22
        Grade 3 Fever
    0
    1
    0
        Related Fever
    19
    13
    21
        Any Irr./Fuss
    19
    9
    12
        Grade 3 Irr./Fuss.
    1
    1
    1
        Related Irr./Fuss.
    15
    9
    9
        Any Loss Appet.
    14
    9
    10
        Grade 3 Loss Appet.
    0
    2
    0
        Related Loss Appet.
    9
    8
    9
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects with unsolicited adverse events (AEs)
    End point description
    An AE is 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. Unsolicited AE covers any AE reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms.
    End point type
    Secondary
    End point timeframe
    Within 31-day follow-up period (Days 0-30) after vaccination
    End point values
    		 Synflorix 1 Group Synflorix 2 Group Tritanrix-HepB+Hiberix Group
    Number of subjects analysed
    100
    95
    87
    Units: Subjects
        Any AE
    7
    1
    5
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects with serious adverse events (SAEs)
    End point description
    SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity.
    End point type
    Secondary
    End point timeframe
    After the first vaccination up to study end (from Month 0 to Month 15)
    End point values
    		 Synflorix 1 Group Synflorix 2 Group Tritanrix-HepB+Hiberix Group
    Number of subjects analysed
    100
    95
    87
    Units: Subjects
        Any SAE
    2
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited AEs: during the 4 days post vaccination; Unsolicited AEs: during the 31 days post vaccination after booster dose in the Synflorix 1 and Synflorix 2 Groups and across doses in the Tritanrix-HepB+Hiberix Group; SAEs: from Month 0 to Month 15
    Adverse event reporting additional description
    The occurrence of reported AEs (all/related) was not available and is encoded as equal to the number of subjects affected.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Synflorix 1 Group
    Reporting group description
    		 Subjects who were previously primed with a 3-dose primary vaccination of Synflorix vaccine in the 10PN-PD-DIT-037 (111188) study, received a booster dose of Synflorix vaccine, administered intramuscularly in the right or left thigh, at 9-18 months of age.

    Reporting group title
    Tritanrix-HepB+Hiberix Group
    Reporting group description
    		 Unprimed subjects who were previously vaccinated with Tritanrix-HepB and Hiberix vaccines in the Control Group of the 10PN-PD-DIT-037 (111188) study, received a catch-up vaccination with Synflorix vaccine (2 primary doses +1 booster dose), administered intramuscularly in the right or left thigh, during their second year of life: 2+1 catch-up vaccination starting at 12-18 months of age with an interval of at least 8 weeks (56-118 days) between primary doses; the booster dose was administered at 18-24 months of age.

    Reporting group title
    Synflorix 2 Group
    Reporting group description
    		 Subjects who were previously primed with a 3-dose primary vaccination of Synflorix vaccine in the 10PN-PD-DIT-037 (111188) study, received a booster dose of Synflorix vaccine, administered intramuscularly in the right or left thigh, at 15-18 months of age.

    Serious adverse events
    		 Synflorix 1 Group Tritanrix-HepB+Hiberix Group Synflorix 2 Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 87 (1.15%)
    0 / 95 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Nervous system disorders
    Febrile convulsion
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 87 (1.15%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Skin infection
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 87 (1.15%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Synflorix 1 Group Tritanrix-HepB+Hiberix Group Synflorix 2 Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 100 (48.00%)
    38 / 87 (43.68%)
    29 / 95 (30.53%)
    General disorders and administration site conditions
    Pain
    alternative assessment type: Systematic
         subjects affected / exposed [1]
    31 / 93 (33.33%)
    26 / 82 (31.71%)
    25 / 85 (29.41%)
         occurrences all number
    31
    26
    25
    Redness
    alternative assessment type: Systematic
         subjects affected / exposed [2]
    16 / 93 (17.20%)
    11 / 82 (13.41%)
    12 / 85 (14.12%)
         occurrences all number
    16
    11
    12
    Swelling
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    14 / 93 (15.05%)
    16 / 82 (19.51%)
    14 / 85 (16.47%)
         occurrences all number
    14
    16
    14
    Drowsiness
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    5 / 92 (5.43%)
    5 / 82 (6.10%)
    4 / 85 (4.71%)
         occurrences all number
    5
    5
    4
    Fever (≥38°C)
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    20 / 92 (21.74%)
    22 / 82 (26.83%)
    13 / 85 (15.29%)
         occurrences all number
    20
    22
    13
    Irritability
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    19 / 92 (20.65%)
    12 / 82 (14.63%)
    9 / 85 (10.59%)
         occurrences all number
    19
    12
    9
    Loss of appetite
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    14 / 92 (15.22%)
    10 / 82 (12.20%)
    9 / 85 (10.59%)
         occurrences all number
    14
    10
    9
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment for this event, for this phase was performed solely on subjects with available results.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment for this event, for this phase was performed solely on subjects with available results.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment for this event, for this phase was performed solely on subjects with available results.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment for this event, for this phase was performed solely on subjects with available results.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment for this event, for this phase was performed solely on subjects with available results.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment for this event, for this phase was performed solely on subjects with available results.
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment for this event, for this phase was performed solely on subjects with available results.

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Apr 2010
    The inclusion criteria for enrolment in the Pn-Pn (booster dose) groups has been modified to 9-18 months of age at the time of randomisation instead of 9-12 months due to a delay in the study start. This amendment extended the age range at the time of randomization of subjects who were primed in the primary vaccination study 10PN-PD-DIT-037 and thereby optimized the number of primed subjects to be included in the booster dose groups in this study. This amendment also extended the age at the time of booster vaccination in the Pn-Pn9 Group (early booster group) to 9-18 months instead of 9-12 months in order to keep the study fully randomized; giving the opportunity to any primed subject to be randomly allocated to one of the two booster groups. For the purpose of analysis, this group was splited to 9-12 months and 13-18 months in order to have an analysis on the early booster subset for the primary objective.

    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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