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    Clinical Trial Results:
    A phase III long-term follow-up study to assess immunological memory induced following primary and booster vaccination with GSK Biologicals’ 10-valent pneumococcal conjugate vaccine (10Pn-PD-DiT), through evaluation of early antibody responses after an additional dose of 10Pn-PD-DiT at 40-48 months of age, to evaluate in the fourth year of life, the immunogenicity and safety of a 2-dose catch-up immunization course with the 10Pn-PD-DiT vaccine and the impact of pneumococcal vaccination on nasopharyngeal carriage.

    Summary
    EudraCT number
    		 2008-008104-41
    Trial protocol
    		 CZ  
    Global end of trial date
    29 Jul 2011

    Results information
    Results version number
    		 v1
    This version publication date
    20 Jun 2016
    First version publication date
    02 Aug 2015
    Other versions
    		 v2 , v3

    Trial information

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    Trial identification
    Sponsor protocol code
    112801
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00950833
    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 2089-904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089-904466, 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Aug 2011
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Sep 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    •To demonstrate the immunological memory induced following primary vaccination in study 10PN-PD-DIT-010 (107017) and booster vaccination in study 10PN-PD-DIT-014 (107137) with the 10Pn-PD-DiT vaccine, through evaluation of early antibody responses after an additional dose of 10Pn-PD-DiT at 40-48 months of age, compared to the unprimed group. Criteria for immune memory: The immune memory will be demonstrated if the lower limit of the 95% CI around the GMC ratios (pooled primed groups over unprimed group) is higher than 1 for all 10 vaccine serotypes.
    Protection of trial subjects
    The vaccines were observed closely for at least 30 minutes following the administration of vaccine(s), with appropriate medical treatment readily available in case of a rare anaphylactic reaction.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Aug 2009
    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
    Czech Republic: 466
    Worldwide total number of subjects
    466
    EEA total number of subjects
    466
    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)
    0
    Children (2-11 years)
    466
    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
    		 During the screening the following steps occurred: check for inclusion/exclusion criteria, contraindications/precautions, medical history of the subjects and signing informed consent forms.

    Pre-assignment period milestones
    Number of subjects started
    		 466
    Number of subjects completed
    		 443

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Vaccine not administered: 5
    Reason: Number of subjects
    		 Consent withdrawn by subject: 18
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 10Pn-PD-DiT/Paracetamol Group
    Arm description
    		 Subjects were vaccinated with three primary vaccination doses with prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), and a booster dose of GSK Biologicals’ Synflorix™ vaccine, co-administered with Infanrix™ hexa and with prophylactic antipyretic treatment (rectal paracetamol) in study 10PN-PD-DIT-014 BST-010 and who received in this study one dose of Synflorix™ vaccine at month 9 (40-48 months of age).
    Arm type
    		 Experimental

    Investigational medicinal product name
    10-valent pneumococcal conjugate vaccine
    Investigational medicinal product code
    Other name
    10Pn, 10Pn-PD-DiT, GlaxoSmithKline (GSK) Biologicals’ 10-valent pneumococcal conjugate vaccine, Synflorix™, GlaxoSmithKline (GSK) Biologicals’ 1024850A vaccine
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose administered intramuscularly in the deltoid muscle at Month 9 (40-48 month of age).

    Arm title
    		 10Pn-PD-DiT Group
    Arm description
    		 Subjects were vaccinated with three primary vaccination doses with prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), at 12-15 months of age a booster dose of GSK Biologicals’ Synflorix™ vaccine, co-administered with Infanrix™ hexa without prophylactic antipyretic treatment (rectal paracetamol) in study 10PN-PD-DIT-014 BST-010 (107137) and one dose of Synflorix™ vaccine in this study at Month 9 (month 40-48 of age).
    Arm type
    		 Experimental

    Investigational medicinal product name
    10-valent Streptococcus pneumoniae conjugate vaccine
    Investigational medicinal product code
    Other name
    10Pn, 10Pn-PD-DiT, GlaxoSmithKline (GSK) Biologicals’ 10-valent pneumococcal conjugate vaccine, Synflorix™, GlaxoSmithKline (GSK) Biologicals’ 1024850A vaccine
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose administered intramuscularly in the deltoid region at Month 9 (month 40-48 of age).

    Arm title
    		 Unprimed Group
    Arm description
    		 Subjects were vaccinated with three primary vaccination doses without prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), at 12-15 months of age a booster dose of GSK Biologicals’ 10Pn-PD-DiT vaccine, co-administered with Infanrix™ hexa without prophylactic antipyretic treatment (rectal) in study 10PN-PD-DIT-014 BST-010 (107137) and two doses, one of the 10Pn-PD-DiT vaccine at Month 9 (40-48 months of age) and one at Month 11 (42-50 months of age).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    10-valent Streptococcus pneumoniae conjugate vaccine
    Investigational medicinal product code
    Other name
    10Pn, 10Pn-PD-DiT, GlaxoSmithKline (GSK) Biologicals’ 10-valent pneumococcal conjugate vaccine, Synflorix™, GlaxoSmithKline (GSK) Biologicals’ 1024850A vaccine
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Two doses administered intramuscularly in the deltoid muscle at Month 9 (40-48 months of age) and Month 11 (42-50 months of age).

    Number of subjects in period 1 [1]
    		10Pn-PD-DiT/Paracetamol Group 10Pn-PD-DiT Group Unprimed Group
    Started
    112
    108
    223
    Completed
    112
    108
    223
    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: 5 of the enrolled subjects were allocated subject numbers but did not receive vaccination, hence they were excluded from the study. Also, 18 subjects dropped out of the study prior to start and were eliminated from the Total vaccinated cohort.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    10Pn-PD-DiT/Paracetamol Group
    Reporting group description
    		 Subjects were vaccinated with three primary vaccination doses with prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), and a booster dose of GSK Biologicals’ Synflorix™ vaccine, co-administered with Infanrix™ hexa and with prophylactic antipyretic treatment (rectal paracetamol) in study 10PN-PD-DIT-014 BST-010 and who received in this study one dose of Synflorix™ vaccine at month 9 (40-48 months of age).

    Reporting group title
    10Pn-PD-DiT Group
    Reporting group description
    		 Subjects were vaccinated with three primary vaccination doses with prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), at 12-15 months of age a booster dose of GSK Biologicals’ Synflorix™ vaccine, co-administered with Infanrix™ hexa without prophylactic antipyretic treatment (rectal paracetamol) in study 10PN-PD-DIT-014 BST-010 (107137) and one dose of Synflorix™ vaccine in this study at Month 9 (month 40-48 of age).

    Reporting group title
    Unprimed Group
    Reporting group description
    		 Subjects were vaccinated with three primary vaccination doses without prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), at 12-15 months of age a booster dose of GSK Biologicals’ 10Pn-PD-DiT vaccine, co-administered with Infanrix™ hexa without prophylactic antipyretic treatment (rectal) in study 10PN-PD-DIT-014 BST-010 (107137) and two doses, one of the 10Pn-PD-DiT vaccine at Month 9 (40-48 months of age) and one at Month 11 (42-50 months of age).

    Reporting group values
    		 10Pn-PD-DiT/Paracetamol Group 10Pn-PD-DiT Group Unprimed Group Total
    Number of subjects
    		 112 108 223 443
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 39.2 ( 1.53 ) 39.1 ( 1.54 ) 37.7 ( 3.36 ) -
    Gender categorical
    Units: Subjects
        Female
    		 60 48 99 207
        Male
    		 52 60 124 236
    Subject analysis sets

    Subject analysis set title
    Poled primed Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    AP-AP and NAP-pre Groups were pooled into Primed Group.

    Subject analysis sets values
    		 Poled primed Group
    Number of subjects
    220
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    39.15 ( 1.53 )
    Gender categorical
    Units: Subjects
        Female
    108
        Male
    112

    End points

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    End points reporting groups
    Reporting group title
    10Pn-PD-DiT/Paracetamol Group
    Reporting group description
    		 Subjects were vaccinated with three primary vaccination doses with prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), and a booster dose of GSK Biologicals’ Synflorix™ vaccine, co-administered with Infanrix™ hexa and with prophylactic antipyretic treatment (rectal paracetamol) in study 10PN-PD-DIT-014 BST-010 and who received in this study one dose of Synflorix™ vaccine at month 9 (40-48 months of age).

    Reporting group title
    10Pn-PD-DiT Group
    Reporting group description
    		 Subjects were vaccinated with three primary vaccination doses with prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), at 12-15 months of age a booster dose of GSK Biologicals’ Synflorix™ vaccine, co-administered with Infanrix™ hexa without prophylactic antipyretic treatment (rectal paracetamol) in study 10PN-PD-DIT-014 BST-010 (107137) and one dose of Synflorix™ vaccine in this study at Month 9 (month 40-48 of age).

    Reporting group title
    Unprimed Group
    Reporting group description
    		 Subjects were vaccinated with three primary vaccination doses without prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), at 12-15 months of age a booster dose of GSK Biologicals’ 10Pn-PD-DiT vaccine, co-administered with Infanrix™ hexa without prophylactic antipyretic treatment (rectal) in study 10PN-PD-DIT-014 BST-010 (107137) and two doses, one of the 10Pn-PD-DiT vaccine at Month 9 (40-48 months of age) and one at Month 11 (42-50 months of age).

    Subject analysis set title
    Poled primed Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    AP-AP and NAP-pre Groups were pooled into Primed Group.

    Primary: Antibody concentrations against 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).

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    End point title
    		 Antibody concentrations against 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). [1]
    End point description
    End point type
    Primary
    End point timeframe
    At 7-10 days after the single/first dose of 10-valent pneumococcal conjugate vaccine.
    Notes
    [1] - 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 analysis was based on the pooled primed group that included the subjects in the remaining baseline groups.
    End point values
    		 Unprimed Group Poled primed Group
    Number of subjects analysed
    204
    215
    Units: μg/mL
    geometric mean (confidence interval 95%)
        Anti-1 (N=215; 204)
    1.24 (1.07 to 1.42)
    7.63 (6.57 to 8.86)
        Anti-4 (N=215; 204)
    4.52 (3.96 to 5.17)
    12.95 (11.37 to 14.75)
        Anti-5 (N=215; 202)
    0.72 (0.63 to 0.84)
    9.76 (8.44 to 11.29)
        Anti-6B (N=215; 203)
    0.27 (0.22 to 0.33)
    7.67 (6.7 to 8.78)
        Anti-7F (N=215; 204)
    1.37 (1.19 to 1.58)
    6.51 (5.69 to 7.46)
        Anti-9V (N=213; 202)
    0.69 (0.58 to 0.83)
    9.75 (8.46 to 11.24)
        Anti-14 (N=214; 204)
    1.01 (0.8 to 1.27)
    23.07 (20.03 to 26.57)
        Anti-18C (N=214; 204)
    3.25 (2.71 to 3.9)
    32.54 (28.15 to 37.61)
        Anti-19F (N=214;204)
    4.31 (3.59 to 5.17)
    39.84 (34.12 to 46.51)
        Anti-23F (N=215; 204)
    0.25 (0.2 to 0.32)
    9.24 (7.86 to 10.86)
    Statistical analysis title
    		 Immune response non-inferiority - Anti-1
    Statistical analysis description
    To demonstrate the immunological memory induced following primary vaccination in study 10PN-PD-DIT-010 (107017) and booster vaccination in study 10PN-PD-DIT-014 (107137) with the 10Pn-PD-DiT vaccine, through evaluation of early antibody responses after an additional dose of 10Pn-PD-DiT vaccine at 40-48 months of age, compared to the Unprimed Group.
    Comparison groups
    Unprimed Group v Poled primed Group
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 GMC ratio
    Point estimate
    6.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.03
         upper limit
    		 7.58
    Notes
    [2] - The immune memory would be demonstrated if the lower limit of the 95% confidence interval (CI) around the geometric mean concentration (GMC) ratios (Pooled Primed Group over Unprimed Group) was higher than 1 for all 10 vaccine serotypes.
    Statistical analysis title
    		 Immune response non-inferiority - Anti-4
    Statistical analysis description
    To demonstrate the immunological memory induced following primary vaccination in study 10PN-PD-DIT-010 (107017) and booster vaccination in study 10PN-PD-DIT-014 (107137) with the 10Pn-PD-DiT vaccine, through evaluation of early antibody responses after an additional dose of 10Pn-PD-DiT vaccine at 40-48 months of age, compared to the Unprimed Group.
    Comparison groups
    Unprimed Group v Poled primed Group
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 GMC ratio
    Point estimate
    2.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.38
         upper limit
    		 3.45
    Notes
    [3] - The immune memory would be demonstrated if the lower limit of the 95% confidence interval (CI) around the geometric mean concentration (GMC) ratios (Pooled Primed Group over Unprimed Group) was higher than 1 for all 10 vaccine serotypes.
    Statistical analysis title
    		 Immune response non-inferiority - Anti-5
    Statistical analysis description
    To demonstrate the immunological memory induced following primary vaccination in study 10PN-PD-DIT-010 (107017) and booster vaccination in study 10PN-PD-DIT-014 (107137) with the 10Pn-PD-DiT vaccine, through evaluation of early antibody responses after an additional dose of 10Pn-PD-DiT vaccine at 40-48 months of age, compared to the Unprimed Group.
    Comparison groups
    Unprimed Group v Poled primed Group
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 GMC ratio
    Point estimate
    13.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.96
         upper limit
    		 16.55
    Notes
    [4] - The immune memory would be demonstrated if the lower limit of the 95% confidence interval (CI) around the geometric mean concentration (GMC) ratios (Pooled Primed Group over Unprimed Group) was higher than 1 for all 10 vaccine serotypes.
    Statistical analysis title
    		 Immune response non-inferiority - Anti-6B
    Statistical analysis description
    To demonstrate the immunological memory induced following primary vaccination in study 10PN-PD-DIT-010 (107017) and booster vaccination in study 10PN-PD-DIT-014 (107137) with the 10Pn-PD-DiT vaccine, through evaluation of early antibody responses after an additional dose of 10Pn-PD-DiT vaccine at 40-48 months of age, compared to the Unprimed Group.
    Comparison groups
    Unprimed Group v Poled primed Group
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 GMC ratio
    Point estimate
    28.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 22.54
         upper limit
    		 36.81
    Notes
    [5] - The immune memory would be demonstrated if the lower limit of the 95% confidence interval (CI) around the geometric mean concentration (GMC) ratios (Pooled Primed Group over Unprimed Group) was higher than 1 for all 10 vaccine serotypes.
    Statistical analysis title
    		 Immune response non-inferiority - Anti-7F
    Statistical analysis description
    To demonstrate the immunological memory induced following primary vaccination in study 10PN-PD-DIT-010 (107017) and booster vaccination in study 10PN-PD-DIT-014 (107137) with the 10Pn-PD-DiT vaccine, through evaluation of early antibody responses after an additional dose of 10Pn-PD-DiT vaccine at 40-48 months of age, compared to the Unprimed Group.
    Comparison groups
    Unprimed Group v Poled primed Group
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 GMC ratio
    Point estimate
    4.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.9
         upper limit
    		 5.78
    Notes
    [6] - The immune memory would be demonstrated if the lower limit of the 95% confidence interval (CI) around the geometric mean concentration (GMC) ratios (Pooled Primed Group over Unprimed Group) was higher than 1 for all 10 vaccine serotypes.
    Statistical analysis title
    		 Immune response non-inferiority - Anti-9V
    Statistical analysis description
    To demonstrate the immunological memory induced following primary vaccination in study 10PN-PD-DIT-010 (107017) and booster vaccination in study 10PN-PD-DIT-014 (107137) with the 10Pn-PD-DiT vaccine, through evaluation of early antibody responses after an additional dose of 10Pn-PD-DiT vaccine at 40-48 months of age, compared to the Unprimed Group.
    Comparison groups
    Unprimed Group v Poled primed Group
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 GMC ratio
    Point estimate
    14.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.21
         upper limit
    		 17.75
    Notes
    [7] - The immune memory would be demonstrated if the lower limit of the 95% confidence interval (CI) around the geometric mean concentration (GMC) ratios (Pooled Primed Group over Unprimed Group) was higher than 1 for all 10 vaccine serotypes.
    Statistical analysis title
    		 Immune response non-inferiority - Anti-14
    Statistical analysis description
    To demonstrate the immunological memory induced following primary vaccination in study 10PN-PD-DIT-010 (107017) and booster vaccination in study 10PN-PD-DIT-014 (107137) with the 10Pn-PD-DiT vaccine, through evaluation of early antibody responses after an additional dose of 10Pn-PD-DiT vaccine at 40-48 months of age, compared to the Unprimed Group.
    Comparison groups
    Unprimed Group v Poled primed Group
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 GMC ratio
    Point estimate
    22.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 17.51
         upper limit
    		 30
    Notes
    [8] - The immune memory would be demonstrated if the lower limit of the 95% confidence interval (CI) around the geometric mean concentration (GMC) ratios (Pooled Primed Group over Unprimed Group) was higher than 1 for all 10 vaccine serotypes.
    Statistical analysis title
    		 Immune response non-inferiority - Anti-18C
    Statistical analysis description
    To demonstrate the immunological memory induced following primary vaccination in study 10PN-PD-DIT-010 (107017) and booster vaccination in study 10PN-PD-DIT-014 (107137) with the 10Pn-PD-DiT vaccine, through evaluation of early antibody responses after an additional dose of 10Pn-PD-DiT vaccine at 40-48 months of age, compared to the Unprimed Group.
    Comparison groups
    Unprimed Group v Poled primed Group
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    Method
    Parameter type
    		 GMC ratio
    Point estimate
    10.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.95
         upper limit
    		 12.61
    Notes
    [9] - The immune memory would be demonstrated if the lower limit of the 95% confidence interval (CI) around the geometric mean concentration (GMC) ratios (Pooled Primed Group over Unprimed Group) was higher than 1 for all 10 vaccine serotypes.
    Statistical analysis title
    		 Immune response non-inferiority - Anti-19F
    Statistical analysis description
    To demonstrate the immunological memory induced following primary vaccination in study 10PN-PD-DIT-010 (107017) and booster vaccination in study 10PN-PD-DIT-014 (107137) with the 10Pn-PD-DiT vaccine, through evaluation of early antibody responses after an additional dose of 10Pn-PD-DiT vaccine at 40-48 months of age, compared to the Unprimed Group.
    Comparison groups
    Unprimed Group v Poled primed Group
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [10]
    Method
    Parameter type
    		 GMC ratio
    Point estimate
    9.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.29
         upper limit
    		 11.74
    Notes
    [10] - The immune memory would be demonstrated if the lower limit of the 95% confidence interval (CI) around the geometric mean concentration (GMC) ratios (Pooled Primed Group over Unprimed Group) was higher than 1 for all 10 vaccine serotypes.
    Statistical analysis title
    		 Immune response non-inferiority - Anti-23F
    Statistical analysis description
    To demonstrate the immunological memory induced following primary vaccination in study 10PN-PD-DIT-010 (107017) and booster vaccination in study 10PN-PD-DIT-014 (107137) with the 10Pn-PD-DiT vaccine, through evaluation of early antibody responses after an additional dose of 10Pn-PD-DiT vaccine at 40-48 months of age, compared to the Unprimed Group.
    Comparison groups
    Unprimed Group v Poled primed Group
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    Method
    Parameter type
    		 GMC ratio
    Point estimate
    36.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 27.59
         upper limit
    		 48.34
    Notes
    [11] - The immune memory would be demonstrated if the lower limit of the 95% confidence interval (CI) around the geometric mean concentration (GMC) ratios (Pooled Primed Group over Unprimed Group) was higher than 1 for all 10 vaccine serotypes.

    Secondary: Anti-1, anti-4, anti-5, anti-6B, anti-7F, anti-9V, anti-14, anti-18C, anti 19F and anti23-F antibody concentrations.

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    End point title
    		 Anti-1, anti-4, anti-5, anti-6B, anti-7F, anti-9V, anti-14, anti-18C, anti 19F and anti23-F antibody concentrations. [12]
    End point description
    End point type
    Secondary
    End point timeframe
    Prior to the single/first dose of 10-valent pneumococcal conjugate vaccine.
    Notes
    [12] - 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 analysis was based on the pooled primed group that included the subjects in the remaining baseline groups.
    End point values
    		 Unprimed Group Poled primed Group
    Number of subjects analysed
    209
    215
    Units: μg/mL
    geometric mean (confidence interval 95%)
        Anti-1 (N=215; 208)
    0.09 (0.08 to 0.11)
    0.27 (0.23 to 0.33)
        Anti-4 (N=213; 206)
    0.05 (0.04 to 0.06)
    0.2 (0.17 to 0.23)
        Anti-5 (N=212; 208)
    0.1 (0.09 to 0.11)
    0.41 (0.36 to 0.47)
        Anti-6B (N=212; 202)
    0.1 (0.08 to 0.12)
    0.8 (0.61 to 1.05)
        Anti-7F (N=215; 209)
    0.06 (0.05 to 0.07)
    0.48 (0.41 to 0.56)
        Anti-9V (N=211; 203)
    0.07 (0.06 to 0.09)
    0.5 (0.41 to 0.61)
        Anti-14 (N=213; 203)
    0.28 (0.22 to 0.36)
    1.21 (0.97 to 1.5)
        Anti-18C (N=215; 205)
    0.09 (0.07 to 0.11)
    0.65 (0.54 to 0.79)
        Anti-19F (N=215; 208)
    0.44 (0.32 to 0.59)
    2.35 (1.75 to 3.15)
        Anti-23F (N=215; 207)
    0.08 (0.07 to 0.1)
    0.96 (0.72 to 1.29)
    No statistical analyses for this end point

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

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    End point title
    		 Opsonophagocytic activity (OPA) titres against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. [13]
    End point description
    End point type
    Secondary
    End point timeframe
    Prior to (PRE) and 7-10 days after (POST) the single/first dose of 10-valent pneumococcal conjugate vaccine.
    Notes
    [13] - 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 analysis was based on the pooled primed group that included the subjects in the remaining baseline groups.
    End point values
    		 Unprimed Group Poled primed Group
    Number of subjects analysed
    191
    199
    Units: Titres
    geometric mean (confidence interval 95%)
        Opsono-1, PRE (N=199; 191)
    5.4 (4.7 to 6.2)
    10.2 (8 to 12.9)
        Opsono-1, POST (N=194; 182)
    632 (524.4 to 761.7)
    3106.5 (2670 to 3614.5)
        Opsono-4, PRE (N=189; 174)
    9.1 (6.8 to 12.1)
    18.1 (13.1 to 24.9)
        Opsono-4, POST (N=195; 187)
    13109.9 (11080.6 to 15510.7)
    27273.3 (22682.9 to 32792.6)
        Opsono-5, PRE (N=199; 185)
    4 (4 to 4.1)
    8.9 (7.6 to 10.5)
        Opsono-5, POST (N=194; 182)
    145.8 (111.7 to 190.3)
    1020 (874 to 1190.2)
        Opsono-6B, PRE (N=183; 173)
    46.7 (29.8 to 73.3)
    163.5 (108.5 to 246.4)
        Opsono-6B, POST (N=192; 184)
    1472.2 (1053.2 to 2057.8)
    5789.5 (4637.3 to 7227.9)
        Opsono-7F, PRE (N=187; 167)
    973.4 (798.5 to 1186.6)
    1112.3 (951.4 to 1300.4)
        Opsono-7F, POST (N=191; 186)
    13647.4 (11801.9 to 15781.3)
    19988.9 (16834.5 to 23734.2)
        Opsono-9V, PRE (N=171; 156)
    268.2 (192.2 to 374.3)
    481.8 (394.6 to 588.1)
        Opsono-9V, POST (N=194; 186)
    14668.8 (12476.1 to 17247)
    17952.5 (14699.2 to 21925.7)
        Opsono-14, PRE (N=184; 166)
    145.3 (97.5 to 216.6)
    267.6 (196.9 to 363.8)
        Opsono-14, POST (N=195; 187)
    4454.3 (3921.1 to 5059.9)
    16256.8 (13573 to 19471.4)
        Opsono-18C, PRE (N=186; 169)
    5.7 (4.7 to 7)
    14.2 (10.6 to 19.2)
        Opsono-18C, POST (N=188; 180)
    9092.2 (7381.2 to 11199.9)
    7413.8 (6072.3 to 9051.6)
        Opsono-19F, PRE (N=192; 186)
    12.9 (9.6 to 17.2)
    79.5 (55.4 to 113.9)
        Opsono-19F, POST (N=192; 190)
    902.5 (659.2 to 1235.6)
    6271.1 (4814.8 to 8168)
        Opsono-23F, PRE (N=189; 166)
    220.6 (132 to 368.7)
    462.7 (292.9 to 730.9)
        Opsono-23F, POST (N=197; 189)
    5776.5 (4686.8 to 7119.5)
    15613.5 (12386.9 to 19680.6)
    No statistical analyses for this end point

    Secondary: Antibody concentrations against pneumococcal serotypes 6A and 19A (anti-6A and 19A).

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    End point title
    		 Antibody concentrations against pneumococcal serotypes 6A and 19A (anti-6A and 19A). [14]
    End point description
    End point type
    Secondary
    End point timeframe
    Prior to and 7-10 days after the single/first dose of 10-valent pneumococcal conjugate vaccine.
    Notes
    [14] - 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 analysis was based on the pooled primed group that included the subjects in the remaining baseline groups.
    End point values
    		 Unprimed Group Poled primed Group
    Number of subjects analysed
    207
    215
    Units: μg/mL
    geometric mean (confidence interval 95%)
        Anti-6A, PRE (N=214; 207)
    0.11 (0.09 to 0.13)
    0.39 (0.3 to 0.5)
        Anti-6A, PI (N=215; 203)
    0.2 (0.17 to 0.25)
    2.4 (2.01 to 2.85)
        Anti-19A, PRE (N=215; 207)
    0.22 (0.18 to 0.28)
    0.52 (0.41 to 0.67)
        Anti-19A, PI (N=214; 203)
    0.65 (0.52 to 0.82)
    6.75 (5.41 to 8.41)
    No statistical analyses for this end point

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

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    End point title
    		 Opsonophagocytic activity (OPA) titres against pneumococcal cross-reactive serotypes 6A and 19A. [15]
    End point description
    End point type
    Secondary
    End point timeframe
    Prior to and 7-10 days after the single/first dose of 10-valent pneumococcal conjugate vaccine.
    Notes
    [15] - 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 analysis was based on the pooled primed group that included the subjects in the remaining baseline groups.
    End point values
    		 Unprimed Group Poled primed Group
    Number of subjects analysed
    183
    191
    Units: Titres
    geometric mean (confidence interval 95%)
        Opsono-6A, PRE (N=178; 167)
    49 (32.4 to 74)
    95.2 (65.3 to 138.7)
        Opsono-6A, PI (N=191; 180)
    863.3 (619.3 to 1203.4)
    2408.4 (1815.7 to 3194.5)
        Opsono-19A, PRE (N=190; 183)
    880.5 (622.7 to 1245)
    15.9 (11.7 to 21.6)
        Opsono-19A, PI (N=191; 175)
    597.6 (467.2 to 764.4)
    2104.9 (1560.9 to 2838.7)
    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). [16]
    End point description
    End point type
    Secondary
    End point timeframe
    Prior to and 7-10 days after the single/first dose of 10-valent pneumococcal conjugate vaccine.
    Notes
    [16] - 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 analysis was based on the pooled primed group that included the subjects in the remaining baseline groups.
    End point values
    		 Unprimed Group Poled primed Group
    Number of subjects analysed
    204
    215
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-PD, PRE (N=210; 198)
    105.6 (93.8 to 119)
    464.2 (401.6 to 536.5)
        Anti-PD, PI (N=215; 204)
    374.3 (315.1 to 444.6)
    2673.7 (2359.1 to 3030.2)
    No statistical analyses for this end point

    Secondary: Memory B-cell detection for serotype specific polysaccharides (PS) (polysaccharides 1, 5, 6B, 18C, 19F, 23F and C).

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    End point title
    		 Memory B-cell detection for serotype specific polysaccharides (PS) (polysaccharides 1, 5, 6B, 18C, 19F, 23F and C).
    End point description
    End point type
    Secondary
    End point timeframe
    Prior to (PRE) and 7-10 days (POST) after the single/first dose of 10-valent pneumococcal conjugate vaccine.
    End point values
    		 10Pn-PD-DiT/Paracetamol Group 10Pn-PD-DiT Group Unprimed Group
    Number of subjects analysed
    112
    107
    210
    Units: mIU/ml
    arithmetic mean (standard deviation)
        1 PS, PRE
    288.6 ( 352.5 )
    269.5 ( 432.2 )
    254.8 ( 368.4 )
        5 PS, PRE
    139.4 ( 214.7 )
    141.9 ( 232.4 )
    81.5 ( 109.2 )
        6 PS, PRE
    372 ( 545.5 )
    327.2 ( 554.4 )
    639.9 ( 846.5 )
        18C PS, PRE
    537.7 ( 641.8 )
    530.9 ( 693.8 )
    135.2 ( 200.6 )
        19F PS, PRE
    169.7 ( 415.3 )
    149.1 ( 194.4 )
    164.5 ( 343.4 )
        23F PS, PRE
    112.6 ( 176.1 )
    285 ( 484.3 )
    185.6 ( 270.1 )
        C-PS, PRE
    475.9 ( 682.3 )
    462.5 ( 704.5 )
    469.9 ( 639.2 )
        1 PS, POST
    1488.8 ( 1584.2 )
    1017.4 ( 1309.9 )
    755.9 ( 1017.4 )
        5 PS, POST
    233.5 ( 235.7 )
    406.6 ( 447.8 )
    152.6 ( 231 )
        6 PS, POST
    629.1 ( 773.2 )
    1265.8 ( 1738.6 )
    526 ( 648.6 )
        18C PS, POST
    3839 ( 5960.5 )
    8308.4 ( 7166.9 )
    2053.8 ( 2122.2 )
        19F PS, POST
    1056.7 ( 1334 )
    1092.4 ( 1724.3 )
    708.2 ( 1609.4 )
        23F PS, POST
    579.8 ( 632.5 )
    1123.7 ( 2095.4 )
    327.9 ( 470.5 )
        C-PS, POST
    679.2 ( 885.8 )
    915.5 ( 1191.3 )
    762.6 ( 1039.4 )
    No statistical analyses for this end point

    Secondary: Anti-1, anti-4, anti-5, anti-6B, anti-7F, anti-9V, anti-14, anti-18C, anti 19F and anti23-F antibody concentrations.

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    End point title
    		 Anti-1, anti-4, anti-5, anti-6B, anti-7F, anti-9V, anti-14, anti-18C, anti 19F and anti23-F antibody concentrations. [17]
    End point description
    End point type
    Secondary
    End point timeframe
    1 month after vaccination with the second dose of 10-valent pneumococcal conjugate vaccine (Month 12).
    Notes
    [17] - 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 analysis was based on the unprimed group only.
    End point values
    		 Unprimed Group
    Number of subjects analysed
    209
    Units: μg/mL
    geometric mean (confidence interval 95%)
        Anti-1 (N=209)
    2.33 (2.13 to 2.54)
        Anti-4 (N=209)
    6.26 (5.73 to 6.84)
        Anti-5 (N=209)
    2.69 (2.44 to 2.96)
        Anti-6B (N=209)
    0.84 (0.73 to 0.97)
        Anti-7F (N=208)
    3.63 (3.33 to 3.95)
        Anti-9V (N=209)
    1.73 (1.56 to 1.93)
        Anti-14 (N=209)
    5.21 (4.6 to 5.89)
        Anti-18C (N=209)
    13.59 (11.91 to 15.51)
        Anti-19F (N=209)
    11.83 (10.35 to 13.52)
        Anti-23F (N=209)
    0.99 (0.86 to 1.15)
    No statistical analyses for this end point

    Secondary: Opsono-1, opsono-4, opsono-5, opsono-6B, opsono-7F, opsono-9V, opsoo-14, opsono-18C, opsono-19F and opsono-23F titres.

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    End point title
    		 Opsono-1, opsono-4, opsono-5, opsono-6B, opsono-7F, opsono-9V, opsoo-14, opsono-18C, opsono-19F and opsono-23F titres. [18]
    End point description
    End point type
    Secondary
    End point timeframe
    1 month after vaccination with the second dose of 10-valent pneumococcal conjugate vaccine (Month 12).
    Notes
    [18] - 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 analysis was based on the unprimed group only.
    End point values
    		 Unprimed Group
    Number of subjects analysed
    201
    Units: Tires
    geometric mean (confidence interval 95%)
        Opsono-1 (N=201)
    125.6 (105 to 150.1)
        Opsono-4 (N=200)
    2451.2 (2203.6 to 2726.8)
        Opsono-5 (N=198)
    57.2 (47.3 to 69.1)
        Opsono-6B (N=196)
    1345 (1066.8 to 1695.7)
        Opsono-7F (N=198)
    6527.2 (5836.5 to 7299.6)
        Opsono-9V (N=197)
    6091.6 (5328.7 to 6963.8)
        Opsono-14 (N=197)
    4544.9 (4030.2 to 5125.4)
        Opsono-18C (N=196)
    3827.5 (3367.5 to 4350.4)
        Opsono-19F (N=201)
    1251 (1045.6 to 1496.8)
        Opsono-23F (N=198)
    4629.1 (3890.6 to 5507.8)
    No statistical analyses for this end point

    Secondary: Anti-6A and anti-19A antibody concentrations.

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    End point title
    		 Anti-6A and anti-19A antibody concentrations. [19]
    End point description
    End point type
    Secondary
    End point timeframe
    1 month after vaccination with the second dose of 10-valent pneumococcal conjugate vaccine (Month 12).
    Notes
    [19] - 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 analysis was based on the unprimed group only.
    End point values
    		 Unprimed Group
    Number of subjects analysed
    209
    Units: μg/mL
    geometric mean (confidence interval 95%)
        Anti-6A
    0.51 (0.43 to 0.6)
        Anti-19A
    1.99 (1.68 to 2.36)
    No statistical analyses for this end point

    Secondary: Opsono-6A and opsono-19A titres.

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    End point title
    		 Opsono-6A and opsono-19A titres. [20]
    End point description
    End point type
    Secondary
    End point timeframe
    1 month after vaccination with the second dose of 10-valent pneumococcal conjugate vaccine (Month 12).
    Notes
    [20] - 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 analysis was based on the unprimed group only
    End point values
    		 Unprimed Group
    Number of subjects analysed
    196
    Units: Titres
    geometric mean (confidence interval 95%)
        Opsono-6A (N=193)
    918.6 (742.7 to 1136.1)
        Opsono-19A (N=196)
    597.6 (467.2 to 764.4)
    No statistical analyses for this end point

    Secondary: Anti-PD antibody concentrations.

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    End point title
    		 Anti-PD antibody concentrations. [21]
    End point description
    End point type
    Secondary
    End point timeframe
    1 month after vaccination with the second dose of 10-valent pneumococcal conjugate vaccine (Month 12).
    Notes
    [21] - 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 analysis was based on the unprimed group only.
    End point values
    		 Unprimed Group
    Number of subjects analysed
    209
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-PD
    785.9 (695.7 to 887.7)
    No statistical analyses for this end point

    Secondary: Rabbit complement-mediated Serum Bactericidal Activity assay against Neisseria meningitidis serogroup A (rSBAMenA), rSBA-MenC, rSBA-MenW-135 and rSBA-MenY titres.

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    End point title
    		 Rabbit complement-mediated Serum Bactericidal Activity assay against Neisseria meningitidis serogroup A (rSBAMenA), rSBA-MenC, rSBA-MenW-135 and rSBA-MenY titres. [22]
    End point description
    End point type
    Secondary
    End point timeframe
    25-36 months post-vaccination in previous study
    Notes
    [22] - 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 analysis was based on the unprimed group only.
    End point values
    		 Unprimed Group
    Number of subjects analysed
    83
    Units: Titres
    geometric mean (confidence interval 95%)
        rSBA-MenA (N=66)
    325.5 (243.9 to 434.5)
        rSBA-MenC (N=80)
    63.6 (41.2 to 98)
        rSBA-MenY (N=83)
    372.2 (270 to 513)
        rSBA-MenW-135 (N=83)
    247.6 (190.7 to 321.5)
    No statistical analyses for this end point

    Secondary: Number of subjects reported with any and grade 3 solicited local symptoms.

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    End point title
    		 Number of subjects reported with any and grade 3 solicited local symptoms. [23]
    End point description
    End point type
    Secondary
    End point timeframe
    During the 4-day (Days 0-3) post-vaccination period.
    Notes
    [23] - 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 analysis was based on the primed baseline groups.
    End point values
    		 10Pn-PD-DiT/Paracetamol Group 10Pn-PD-DiT Group
    Number of subjects analysed
    112
    108
    Units: Subjects
        Any pain
    75
    67
        Grade 3 pain
    7
    5
        Any redness
    58
    60
        Grade 3 redness
    13
    12
        Any swelling
    43
    41
        Grade 3 swelling
    11
    11
    No statistical analyses for this end point

    Secondary: Number of subjects reported with any and grade 3 solicited local symptoms.

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    End point title
    		 Number of subjects reported with any and grade 3 solicited local symptoms. [24]
    End point description
    End point type
    Secondary
    End point timeframe
    During the 4-day (Days 0-3) post-vaccination period.
    Notes
    [24] - 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 analysis was based on the unprimed group only
    End point values
    		 Unprimed Group
    Number of subjects analysed
    223
    Units: Subjects
        Any pain, D1 (N=223)
    150
        Grade 3 pain, D1 (N=223)
    13
        Any redness, D1 (N=223)
    102
        Grade 3 redness, D1 (N=223)
    23
        Any swelling, D1 (N=223)
    78
        Grade 3 swelling, D1 (N=223)
    14
        Any pain, D2 (N=222)
    121
        Grade 3 pain, D2 (N=222)
    12
        Any redness, D2 (N=222)
    93
        Grade 3 redness, D2 (N=222)
    12
        Any swelling, D2 (N=222)
    65
        Grade 3 swelling, D2 (N=222)
    3
        Any pain, Across (N=223)
    167
        Grade 3 pain, Across (N=223)
    23
        Any redness, Across (N=223)
    127
        Grade 3 redness, Across (N=223)
    29
        Any swelling, Across (N=223)
    101
        Grade 3 swelling, Across (N=223)
    16
    No statistical analyses for this end point

    Secondary: Number of subjects reported with any, grade 3 and related solicited general symptoms.

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    End point title
    		 Number of subjects reported with any, grade 3 and related solicited general symptoms. [25]
    End point description
    End point type
    Secondary
    End point timeframe
    During the 4-day (Days 0-3) post-vaccination period.
    Notes
    [25] - 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 analysis was based on the primed baseline groups.
    End point values
    		 10Pn-PD-DiT/Paracetamol Group 10Pn-PD-DiT Group
    Number of subjects analysed
    112
    108
    Units: Subjects
        Any drowsiness
    41
    34
        Related drowsiness
    0
    0
        Grade 3 drowsiness
    26
    26
        Any Irritability
    33
    26
        Related Irritability
    1
    0
        Grade 3 Irritability
    21
    16
        Any loss of appetite
    23
    15
        Related loss of appetite
    1
    1
        Grade 3 loss of appetite
    13
    10
        Any fever (Axillary/37.5°C)
    12
    8
        Grade 3 fever (Axillary/39.5°C)
    0
    1
        Related fever
    10
    5
    No statistical analyses for this end point

    Secondary: Number of subjects reported with any, grade 3 and related solicited general symptoms.

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    End point title
    		 Number of subjects reported with any, grade 3 and related solicited general symptoms. [26]
    End point description
    End point type
    Secondary
    End point timeframe
    During the 4-day (Days 0-3) post-vaccination period.
    Notes
    [26] - 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 analysis was based on the unprimed group only
    End point values
    		 Unprimed Group
    Number of subjects analysed
    223
    Units: Subjects
        Any drowsiness, D1 (N=223)
    79
        Grade 3 drowsiness, D1 (N=223)
    1
        Related drowsiness, D1 (N=223)
    56
        Any Irritability, D1 (N=223)
    69
        Grade 3 Irritability, D1 (N=223)
    2
        Related irritability, D1 (N=223)
    49
        Any loss of appetite, D1 (N=223)
    47
        Grade 3 loss of appetite, D1 (N=223)
    5
        Related loss of appetite, D1 (N=223)
    32
        Any fever (Axillary/37.5°C), D1 (N=223)
    23
        Grade 3 fever (Axillary/39.5°C), D1 (N=223)
    1
        Related fever, D1 (N=223)
    15
        Any drowsiness, D2 (N=222)
    60
        Grade 3 drowsiness, D2 (N=222)
    1
        Related drowsiness, D2 (N=222)
    43
        Any Irritability, D2 (N=222)
    59
        Grade 3 Irritability, D2 (N=222)
    1
        Related irritability, D2 (N=222)
    44
        Any loss of appetite, D2 (N=222)
    26
        Grade 3 loss of appetite, D2 (N=222)
    1
        Related loss of appetite, D2 (N=222)
    16
        Any fever (Axillary/37.5°C), D2 (N=222)
    9
        Grade 3 fever (Axillary/39.5°C), D2 (N=222)
    1
        Related fever, D2 (N=222)
    5
        Any drowsiness, Across (N=223)
    102
        Grade 3 drowsiness, Across (N=223)
    2
        Related drowsiness, Across (N=223)
    73
        Any Irritability, Across (N=223)
    98
        Grade 3 Irritability, Across (N=223)
    3
        Related irritability, Across (N=223)
    74
        Any loss of appetite, Across (N=223)
    61
        Grade 3 loss of appetite, Across (N=223)
    6
        Related loss of appetite, Across (N=223)
    42
        Any fever (Axillary/37.5°C), Across (N=223)
    30
        Grade 3 fever (Axillary/39.5°C), Across (N=223)
    2
        Related fever, Across (N=223)
    19
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects reported with unsolicited adverse events (AEs).
    End point description
    End point type
    Secondary
    End point timeframe
    Within 31 days after each vaccination.
    End point values
    		 10Pn-PD-DiT/Paracetamol Group 10Pn-PD-DiT Group Unprimed Group
    Number of subjects analysed
    112
    108
    223
    Units: Subjects
        Any AE(s)
    24
    29
    73
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects reported with serious adverse events (SAEs).
    End point description
    End point type
    Secondary
    End point timeframe
    During the entire study period.
    End point values
    		 10Pn-PD-DiT/Paracetamol Group 10Pn-PD-DiT Group Unprimed Group
    Number of subjects analysed
    112
    108
    223
    Units: Subjects
        Any SAE(s)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with S.pneumoniae (vaccine serotypes) in nasopharyngeal swabs.

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    End point title
    		 Number of subjects with S.pneumoniae (vaccine serotypes) in nasopharyngeal swabs. [27]
    End point description
    End point type
    Secondary
    End point timeframe
    At 31-44 months of age and prior to the single/first dose of 10-valent pneumococcal conjugate vaccine and 40-48 months of age.
    Notes
    [27] - 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 analysis was based on the pooled primed group that included the subjects in the remaining baseline groups.
    End point values
    		 Unprimed Group Poled primed Group
    Number of subjects analysed
    210
    216
    Units: Subjects
        31-44 months (N=216; 210)
    40
    21
        40-48 months (N=212; 208)
    46
    20
    No statistical analyses for this end point

    Secondary: Number of subjects with S.pneumoniae (cross-reactive serotypes) in nasopharyngeal swabs.

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    End point title
    		 Number of subjects with S.pneumoniae (cross-reactive serotypes) in nasopharyngeal swabs. [28]
    End point description
    End point type
    Secondary
    End point timeframe
    At 31-44 months of age and prior to the single/first dose of 10-valent pneumococcal conjugate vaccine and 40-48 months of age.
    Notes
    [28] - 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 analysis was based on the pooled primed group that included the subjects in the remaining baseline groups.
    End point values
    		 Unprimed Group Poled primed Group
    Number of subjects analysed
    210
    216
    Units: Subjects
        31-44 months (N=216; 210)
    9
    13
        40-48 months (N=212; 208)
    19
    18
    No statistical analyses for this end point

    Secondary: Number of subjects with S.pneumoniae (non-vaccine and non-cross-reactive serotypes) in nasopharyngeal swabs.

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    End point title
    		 Number of subjects with S.pneumoniae (non-vaccine and non-cross-reactive serotypes) in nasopharyngeal swabs. [29]
    End point description
    End point type
    Secondary
    End point timeframe
    At 31-44 months of age and prior to the single/first dose of 10-valent pneumococcal conjugate vaccine and 40-48 months of age.
    Notes
    [29] - 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 analysis was based on the pooled primed group that included the subjects in the remaining baseline groups.
    End point values
    		 Unprimed Group Poled primed Group
    Number of subjects analysed
    210
    216
    Units: Subjects
        31-44 months (N=216; 210)
    25
    34
        40-48 months (N=212; 208)
    27
    35
    No statistical analyses for this end point

    Secondary: Number of subjects with H. influenzae in nasopharyngeal swabs.

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    End point title
    		 Number of subjects with H. influenzae in nasopharyngeal swabs. [30]
    End point description
    End point type
    Secondary
    End point timeframe
    At 31-44 months of age and prior to the single/first dose of 10-valent pneumococcal conjugate vaccine and 40-48 months of age.
    Notes
    [30] - 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 analysis was based on the pooled primed group that included the subjects in the remaining baseline groups.
    End point values
    		 Unprimed Group Poled primed Group
    Number of subjects analysed
    210
    216
    Units: Subjects
        31-44 months (N=216; 210)
    43
    54
        40-48 months (N=212; 208)
    89
    74
    No statistical analyses for this end point

    Secondary: Number of subjects with S. pneumonia (vaccine serotypes) in nasopharyngeal swabs.

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    End point title
    		 Number of subjects with S. pneumonia (vaccine serotypes) in nasopharyngeal swabs. [31]
    End point description
    End point type
    Secondary
    End point timeframe
    At 31-44 months of age and prior to the single/first dose of 10-valent pneumococcal conjugate vaccine and 40-48 months of age.
    Notes
    [31] - 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 analysis was based on the pooled primed group that included the subjects in the remaining baseline groups.
    End point values
    		 Unprimed Group Poled primed Group
    Number of subjects analysed
    210
    216
    Units: Subjects
        31-44 months (N=216; 210)
    39
    20
        40-48 months (N=212; 208)
    41
    18
    No statistical analyses for this end point

    Secondary: Number of subjects with S. pneumonia (cross-reactive serotypes) in nasopharyngeal swabs.

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    End point title
    		 Number of subjects with S. pneumonia (cross-reactive serotypes) in nasopharyngeal swabs. [32]
    End point description
    End point type
    Secondary
    End point timeframe
    At 31-44 months of age and prior to the single/first dose of 10-valent pneumococcal conjugate vaccine and 40-48 months of age.
    Notes
    [32] - 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 analysis was based on the pooled primed group that included the subjects in the remaining baseline groups.
    End point values
    		 Unprimed Group Poled primed Group
    Number of subjects analysed
    210
    216
    Units: Subjects
        31-44 months (N=216; 210)
    9
    13
        40-48 months (N=212; 208)
    18
    18
    No statistical analyses for this end point

    Secondary: Number of subjects with S. pneumonia (non-vaccine and non-cross-reactive serotypes) in nasopharyngeal swabs.

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    End point title
    		 Number of subjects with S. pneumonia (non-vaccine and non-cross-reactive serotypes) in nasopharyngeal swabs. [33]
    End point description
    End point type
    Secondary
    End point timeframe
    At 31-44 months of age and prior to the single/first dose of 10-valent pneumococcal conjugate vaccine and 40-48 months of age.
    Notes
    [33] - 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 analysis was based on the pooled primed group that included the subjects in the remaining baseline groups.
    End point values
    		 Unprimed Group Poled primed Group
    Number of subjects analysed
    210
    216
    Units: Subjects
        31-44 months (N=216; 210)
    24
    32
        40-48 months (N=212; 208)
    25
    33
    No statistical analyses for this end point

    Secondary: Number of subjects with H. influenzae in nasopharyngeal swabs.

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    End point title
    		 Number of subjects with H. influenzae in nasopharyngeal swabs. [34]
    End point description
    End point type
    Secondary
    End point timeframe
    At 31-44 months of age and prior to the single/first dose of 10-valent pneumococcal conjugate vaccine and 40-48 months of age.
    Notes
    [34] - 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 analysis was based on the pooled primed group that included the subjects in the remaining baseline groups.
    End point values
    		 Unprimed Group Poled primed Group
    Number of subjects analysed
    210
    216
    Units: Subjects
        31-44 months (N=216; 210)
    35
    49
        40-48 months (N=212; 208)
    70
    50
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited symptoms: 4-day follow-up periods after vaccination (Days 0- 3), across doses; Unsolicited AEs: 31-day follow-up periods after vaccination (Days 0-30), across doses; SAEs: during the entire study period.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    10Pn-PD-DiT/ Paracetamol Group
    Reporting group description
    		 Subjects were vaccinated with three primary vaccination doses with prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), and a booster dose of GSK Biologicals’ Synflorix™ vaccine, co-administered with Infanrix™ hexa and with prophylactic antipyretic treatment (rectal paracetamol) in study 10PN-PD-DIT-014 BST-010 and who received in this study one dose of Synflorix™ vaccine at month 9 (40-48 months of age).

    Reporting group title
    10Pn-PD-DiT Group
    Reporting group description
    		 Subjects were vaccinated with three primary vaccination doses with prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), at 12-15 months of age a booster dose of GSK Biologicals’ Synflorix™ vaccine, co-administered with Infanrix™ hexa without prophylactic antipyretic treatment (rectal paracetamol) in study 10PN-PD-DIT-014 BST-010 (107137) and one dose of Synflorix™ vaccine in this study at Month 9 (month 40-48 of age).

    Reporting group title
    Unprimed Group
    Reporting group description
    		 Subjects were vaccinated with three primary vaccination doses without prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), at 12-15 months of age a booster dose of GSK Biologicals’ 10Pn-PD-DiT vaccine, co-administered with Infanrix™ hexa without prophylactic antipyretic treatment (rectal) in study 10PN-PD-DIT-014 BST-010 (107137) and two doses, one of the 10Pn-PD-DiT vaccine at Month 9 (40-48 months of age) and one at Month 11 (42-50 months of age).

    Serious adverse events
    		 10Pn-PD-DiT/ Paracetamol Group 10Pn-PD-DiT Group Unprimed Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 108 (0.00%)
    0 / 223 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 10Pn-PD-DiT/ Paracetamol Group 10Pn-PD-DiT Group Unprimed Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    75 / 112 (66.96%)
    67 / 108 (62.04%)
    167 / 223 (74.89%)
    General disorders and administration site conditions
    Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    75 / 112 (66.96%)
    67 / 108 (62.04%)
    167 / 223 (74.89%)
         occurrences all number
    75
    67
    167
    Redness
    alternative assessment type: Systematic
         subjects affected / exposed
    58 / 112 (51.79%)
    60 / 108 (55.56%)
    127 / 223 (56.95%)
         occurrences all number
    58
    60
    127
    Swelling
    alternative assessment type: Systematic
         subjects affected / exposed
    43 / 112 (38.39%)
    41 / 108 (37.96%)
    101 / 223 (45.29%)
         occurrences all number
    43
    41
    101
    Drowsiness
    alternative assessment type: Systematic
         subjects affected / exposed
    41 / 112 (36.61%)
    34 / 108 (31.48%)
    102 / 223 (45.74%)
         occurrences all number
    41
    34
    102
    Irritability
    alternative assessment type: Systematic
         subjects affected / exposed
    33 / 112 (29.46%)
    26 / 108 (24.07%)
    98 / 223 (43.95%)
         occurrences all number
    33
    26
    98
    Loss of appetite
    alternative assessment type: Systematic
         subjects affected / exposed
    23 / 112 (20.54%)
    15 / 108 (13.89%)
    61 / 223 (27.35%)
         occurrences all number
    23
    15
    61
    Fever/(Axillary ≥ 37.5°C)
    alternative assessment type: Systematic
         subjects affected / exposed
    12 / 112 (10.71%)
    8 / 108 (7.41%)
    30 / 223 (13.45%)
         occurrences all number
    12
    8
    30

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Mar 2011
    The primary objective of the current study is to demonstrate the immunological memory induced following primary vaccination in study 10PN-PD-DIT-010 (107017) and booster vaccination in study 10PN-PD-DIT-014 (107137) with the 10Pn-PD-DiT vaccine, through evaluation of early antibody responses after an additional dose of 10Pn-PD-DiT at 40-48 months of age. In addition, as secondary objective, the antibody persistence 25-36 months following vaccination with GSK Biologicals’ MenACWYTT conjugate vaccine in study 10PN-PD-DIT-014 (107137) will be evaluated in terms of the percentage of subjects with N. meningitidis serogroup A, C, W-135 and Y titers ≥ 8 as measured by a serum bactericidal assay using rabbit complement (rSBA). In addition, to support the data obtained by rSBA testing, antibody concentrations against meningococcal polysaccharides are planned to be assessed by ELISA. However, the sponsor has decided not to perform the ELISA testing against meningococcal polysaccharides for this study for the following reasons: ● the World Health Organization (WHO) considers SBA the primary means of assessing immune response to meningococcal conjugate vaccines [WHO, 2006; WHO, 1999] ● circulating bactericidal antibodies are more critical for persistent protection against meningococcal disease than antibodies against meningococcal polysaccharides [CDC, 2011; WHO, 2006]. Although antibody concentrations will not be determined by ELISA, all subjects will be informed of their antibody titers measured by rSBA when statistical analyses has been completed.

    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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