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    Clinical Trial Results:
    A phase III, single group, open study to assess the immunogenicity, safety and reactogenicity of GlaxoSmithKline (GSK) Biologicals’ 10-valent pneumococcal conjugate vaccine in Mexico when co-administered with GSK Biologicals’ Infanrix hexa (DTPa-HBV-IPV/Hib) vaccine as a 3-dose primary immunization course at 2, 4 and 6 months of age and GSK Biologicals’ Rotarix vaccine (HRV) as a 2-dose primary immunization course at 2 and 4 months of age.

    Summary
    EudraCT number
    		 2015-001510-10
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    31 Mar 2008

    Results information
    Results version number
    		 v1
    This version publication date
    22 Mar 2016
    First version publication date
    31 Jul 2015
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    109661
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00489554
    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, 44 2089904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Aug 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the immunogenicity of GSK Biologicals’ 10-valent pneumococcal conjugate vaccine in Mexico, one month post dose III, when co-administered with GSK Biologicals’ Infanrix hexa and GSK Biologicals’ Rotarix vaccines, to the immune responses as observed in the pivotal non-inferiority, lot-to-lot consistency study 10PN-PD-DIT-001 in Europe.
    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. The subject’s parents/guardians were instructed to contact the investigator immediately should their child manifest any signs or symptoms they perceived as serious. Subjects were followed up for any safety event from the time the subject consented to participate in the study until she/he was discharged.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Jul 2007
    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
    Mexico: 230
    Worldwide total number of subjects
    230
    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)
    230
    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
    		 230 subjects were enrolled in the study, all of whom were vaccinated. Study duration was of approximately 5 months (from Day 0, day of 1st vaccination, up to Month 5).

    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.

    Period 1
    Period 1 title
    Overall Study (Day 0 to Month 5) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Synflorix Vaccine Group
    Arm description
    		 Subjects receiving 3 doses of 10Pn-PD-DiT (Synflorix) vaccine co-administered with 3 doses of DTPa-HBV-IPV/Hib (Infanrix hexa) vaccine at 2, 4 and 6 months of age, and co-administered with 2 doses of HRV (Rotarix) vaccine at 2 and 4 months of age. 10Pn-PD-DIT and DTPa-HBV-IPV/Hib vaccines were administered intramuscularly in the thigh, on the right and left side, respectively. HRV vaccine was administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    10-valent pneumococcal and non-typeable H. influenzae protein D conjugate vaccine
    Investigational medicinal product code
    10Pn-PD-DiT
    Other name
    Pneumococcal conjugate vaccine GSK1024850A; 10Pn
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular injection, 3 doses administered in the right thigh.

    Investigational medicinal product name
    Infanrix hexa
    Investigational medicinal product code
    DTPa-HBV-IPV/Hib
    Other name
    Pharmaceutical forms
    Powder and suspension for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular injection, 3 doses administered in the left thigh.

    Investigational medicinal product name
    Rotarix
    Investigational medicinal product code
    Other name
    HRV
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Oral, 2 doses.

    Number of subjects in period 1
    		Synflorix Vaccine Group
    Started
    230
    Completed
    226
    Not completed
    4
         Consent withdrawn by subject
    1
         Adverse event, non-fatal
    2
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Synflorix Vaccine Group
    Reporting group description
    		 Subjects receiving 3 doses of 10Pn-PD-DiT (Synflorix) vaccine co-administered with 3 doses of DTPa-HBV-IPV/Hib (Infanrix hexa) vaccine at 2, 4 and 6 months of age, and co-administered with 2 doses of HRV (Rotarix) vaccine at 2 and 4 months of age. 10Pn-PD-DIT and DTPa-HBV-IPV/Hib vaccines were administered intramuscularly in the thigh, on the right and left side, respectively. HRV vaccine was administered orally.

    Reporting group values
    		 Synflorix Vaccine Group Total
    Number of subjects
    		 230 230
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 230 230
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: weeks
        arithmetic mean (standard deviation)
    		 8.2 ( 1.63 ) -
    Gender categorical
    Units: Subjects
        Female
    		 123 123
        Male
    		 107 107

    End points

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    End points reporting groups
    Reporting group title
    Synflorix Vaccine Group
    Reporting group description
    		 Subjects receiving 3 doses of 10Pn-PD-DiT (Synflorix) vaccine co-administered with 3 doses of DTPa-HBV-IPV/Hib (Infanrix hexa) vaccine at 2, 4 and 6 months of age, and co-administered with 2 doses of HRV (Rotarix) vaccine at 2 and 4 months of age. 10Pn-PD-DIT and DTPa-HBV-IPV/Hib vaccines were administered intramuscularly in the thigh, on the right and left side, respectively. HRV vaccine was administered orally.

    Subject analysis set title
    10Pn-001 Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This group consisted in a pooling of the subjects receiving the 10Pn vaccine in study 10PN-PD-DIT-001 (105553) (EuDRA CT number: 2005-003300-11). These subjects received in this 10PN-PD-DIT-001 study a 3-dose primary vaccination course of 10Pn vaccine at 2, 3 and 4 months of age (3 different lots)co-administered with DTPa-HBV-IPV/Hib (Infanrix hexa), except for the second dose in France which was co-administered with Infanrix-IPV/Hib™ vaccine. The number of subjects in this subject analysis set is in total 1107 subjects, 230 being a placeholder value.

    Primary: Antibody concentrations against pneumococcal vaccine serotypes

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    End point title
    		 Antibody concentrations against pneumococcal vaccine serotypes [1]
    End point description
    Concentrations were expressed as geometric mean concentration (GMC). The vaccine pneumococcal serotypes assessed include 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F.
    End point type
    Primary
    End point timeframe
    One month after the administration of the 3rd vaccine dose i.e. Month 5
    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.
    End point values
    		 Synflorix Vaccine Group
    Number of subjects analysed
    219
    Units: microgram per milliliter
    geometric mean (confidence interval 95%)
        Anti-1 antibody (N=219)
    2.13 (1.94 to 2.34)
        Anti-4 antibody (N=218)
    3.04 (2.77 to 3.34)
        Anti-5 antibody (N=218)
    3.24 (2.97 to 3.53)
        Anti-6B antibody (N=218)
    1.32 (1.14 to 1.54)
        Anti-7F antibody (N=218)
    3.72 (3.4 to 4.07)
        Anti-9V antibody (N=218)
    3.71 (3.37 to 4.09)
        Anti-14 antibody (N=218)
    5.27 (4.66 to 5.96)
        Anti-18C antibody (N=219)
    6.05 (5.3 to 6.89)
        Anti-19F antibody (N=219)
    5.49 (4.88 to 6.17)
        Anti-23F antibody (N=218)
    2 (1.7 to 2.35)
    No statistical analyses for this end point

    Primary: Antibody concentrations against Protein D

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    End point title
    		 Antibody concentrations against Protein D [2]
    End point description
    Concentrations were given as geometric mean concentration (GMC) expressed as enzyme-linked immuno-sorbent assay (ELISA) units per milliliter.
    End point type
    Primary
    End point timeframe
    One month after the administration of the 3rd vaccine dose i.e. Month 5
    Notes
    [2] - 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.
    End point values
    		 Synflorix Vaccine Group
    Number of subjects analysed
    219
    Units: ELISA units per milliliter
    geometric mean (confidence interval 95%)
        Anti-Protein D antibody
    2923.2 (2588.6 to 3301.1)
    No statistical analyses for this end point

    Primary: Comparison of 10PN-PD-DIT-001 study vs 10PN-PD-DIT-029 study as regards Anti-Pneumococcal Vaccine Serotype Antibody Concentrations

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    End point title
    		 Comparison of 10PN-PD-DIT-001 study vs 10PN-PD-DIT-029 study as regards Anti-Pneumococcal Vaccine Serotype Antibody Concentrations
    End point description
    Antibodies assessed for this comparison endpoint were antibodies 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). The seropositivity cut-off of the assay was an antibody concentration ≥ 0.05 µg/mL. Studies compared as regards results for antibody concentrations against 10Pn pneumococcal vaccine serotypes were studies 10PN-PD-DIT-029 (this study) and 10PN-PD-DIT-001 (105553) (EuDRA CT number: 2005-003300-11) via a comparison of 10Pn-001 Group over Synflorix Vaccine Group.
    End point type
    Primary
    End point timeframe
    One month after the administration of the 3rd vaccine dose, i.e. at Month 5
    End point values
    		 Synflorix Vaccine Group 10Pn-001 Group
    Number of subjects analysed
    219
    1107
    Units: µg/mL
    number (not applicable)
        Anti-1 (N=219;1100)
    2.13
    1.05
        Anti-4 (N=218;1106)
    3.04
    1.45
        Anti-5 (N=218;1104)
    3.24
    1.7
        Anti-6B (N=218;1100)
    1.32
    0.33
        Anti-7F (N=218;1107)
    3.72
    1.72
        Anti-9V (N=218,1103)
    3.71
    1.32
        Anti-14 (N=218,1100)
    5.27
    2.9
        Anti-18C (N=219,1102)
    6.05
    1.66
        Anti-19F (N=219,1104)
    5.49
    1.84
        Anti-23F (N=218,1102)
    2
    0.53
    Statistical analysis title
    		 10PN-PD-DIT-001 over -029 Anti-1 GMC ratio
    Statistical analysis description
    One month after the administration of the 3rd vaccine dose, i.e. at Month 5, ratios of geometric mean concentrations (GMCs), by enzyme-linked immunosorbent assay (ELISA), of 10Pn-001 Group over Synflorix Vaccine Group were calculated for each of the 10 pneumococcal serotypes and for protein D (PD), using an ANOVA model. This statistical analysis section concerns Anti-1 pneumococcal antibodies.
    Comparison groups
    Synflorix Vaccine Group v 10Pn-001 Group
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 GMC ratio (see above)
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 0.55
    Notes
    [3] - Comparability to the 10PN-PD-DIT-001 study in terms of non-inferiority was demonstrated if the upper limit of the 2-sided 95% confidence interval (CI) on the GMC ratios (GMCs from study 10PN-PD-DIT-001 over GMCs of current 10PN-PD-DIT-029 study) was below a limit of 2-fold for all of the 10 vaccine pneumococcal serotypes and for protein D (PD).
    Statistical analysis title
    		 10PN-PD-DIT-001 over -029 Anti-4 GMC ratio
    Statistical analysis description
    One month after the administration of the 3rd vaccine dose, i.e. at Month 5, ratios of geometric mean concentrations (GMCs), by enzyme-linked immunosorbent assay (ELISA), of 10Pn-001 Group over Synflorix Vaccine Group were calculated for each of the 10 pneumococcal serotypes and for protein D (PD), using an ANOVA model. This statistical analysis section concerns Anti-4 pneumococcal antibodies.
    Comparison groups
    Synflorix Vaccine Group v 10Pn-001 Group
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 GMC ratio (see above)
    Point estimate
    0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.54
    Notes
    [4] - Comparability to the 10PN-PD-DIT-001 study in terms of non-inferiority was demonstrated if the upper limit of the 2-sided 95% confidence interval (CI) on the GMC ratios (GMCs from study 10PN-PD-DIT-001 over GMCs of current 10PN-PD-DIT-029 study) was below a limit of 2-fold for all of the 10 vaccine pneumococcal serotypes and for protein D (PD).
    Statistical analysis title
    		 10PN-PD-DIT-001 over -029 Anti-5 GMC ratio
    Statistical analysis description
    One month after the administration of the 3rd vaccine dose, i.e. at Month 5, ratios of geometric mean concentrations (GMCs), by enzyme-linked immunosorbent assay (ELISA), of 10Pn-001 Group over Synflorix Vaccine Group were calculated for each of the 10 pneumococcal serotypes and for protein D (PD), using an ANOVA model. This statistical analysis section concerns Anti-5 pneumococcal antibodies.
    Comparison groups
    Synflorix Vaccine Group v 10Pn-001 Group
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 GMC ratio (see above)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 0.59
    Notes
    [5] - Comparability to the 10PN-PD-DIT-001 study in terms of non-inferiority was demonstrated if the upper limit of the 2-sided 95% confidence interval (CI) on the GMC ratios (GMCs from study 10PN-PD-DIT-001 over GMCs of current 10PN-PD-DIT-029 study) was below a limit of 2-fold for all of the 10 vaccine pneumococcal serotypes and for protein D (PD).
    Statistical analysis title
    		 10PN-PD-DIT-001 over -029 Anti-6B GMC ratio
    Statistical analysis description
    One month after the administration of the 3rd vaccine dose, i.e. at Month 5, ratios of geometric mean concentrations (GMCs), by enzyme-linked immunosorbent assay (ELISA), of 10Pn-001 Group over Synflorix Vaccine Group were calculated for each of the 10 pneumococcal serotypes and for protein D (PD), using an ANOVA model. This statistical analysis section concerns Anti-6B pneumococcal antibodies.
    Comparison groups
    Synflorix Vaccine Group v 10Pn-001 Group
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 GMC ratio (see above)
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 0.3
    Notes
    [6] - Comparability to the 10PN-PD-DIT-001 study in terms of non-inferiority was demonstrated if the upper limit of the 2-sided 95% confidence interval (CI) on the GMC ratios (GMCs from study 10PN-PD-DIT-001 over GMCs of current 10PN-PD-DIT-029 study) was below a limit of 2-fold for all of the 10 vaccine pneumococcal serotypes and for protein D (PD).
    Statistical analysis title
    		 10PN-PD-DIT-001 over -029 Anti-7F GMC ratio
    Statistical analysis description
    One month after the administration of the 3rd vaccine dose, i.e. at Month 5, ratios of geometric mean concentrations (GMCs), by enzyme-linked immunosorbent assay (ELISA), of 10Pn-001 Group over Synflorix Vaccine Group were calculated for each of the 10 pneumococcal serotypes and for protein D (PD), using an ANOVA model. This statistical analysis section concerns Anti-7F pneumococcal antibodies.
    Comparison groups
    Synflorix Vaccine Group v 10Pn-001 Group
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 GMC ratio (see above)
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 0.52
    Notes
    [7] - Comparability to the 10PN-PD-DIT-001 study in terms of non-inferiority was demonstrated if the upper limit of the 2-sided 95% confidence interval (CI) on the GMC ratios (GMCs from study 10PN-PD-DIT-001 over GMCs of current 10PN-PD-DIT-029 study) was below a limit of 2-fold for all of the 10 vaccine pneumococcal serotypes and for protein D (PD).
    Statistical analysis title
    		 10PN-PD-DIT-001 over -029 Anti-9V GMC ratio
    Statistical analysis description
    One month after the administration of the 3rd vaccine dose, i.e. at Month 5, ratios of geometric mean concentrations (GMCs), by enzyme-linked immunosorbent assay (ELISA), of 10Pn-001 Group over Synflorix Vaccine Group were calculated for each of the 10 pneumococcal serotypes and for protein D (PD), using an ANOVA model. This statistical analysis section concerns Anti-9V pneumococcal antibodies.
    Comparison groups
    Synflorix Vaccine Group v 10Pn-001 Group
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 GMC ratio (see above)
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 0.4
    Notes
    [8] - Comparability to the 10PN-PD-DIT-001 study in terms of non-inferiority was demonstrated if the upper limit of the 2-sided 95% confidence interval (CI) on the GMC ratios (GMCs from study 10PN-PD-DIT-001 over GMCs of current 10PN-PD-DIT-029 study) was below a limit of 2-fold for all of the 10 vaccine pneumococcal serotypes and for protein D (PD).
    Statistical analysis title
    		 10PN-PD-DIT-001 over -029 Anti-14 GMC ratio
    Statistical analysis description
    One month after the administration of the 3rd vaccine dose, i.e. at Month 5, ratios of geometric mean concentrations (GMCs), by enzyme-linked immunosorbent assay (ELISA), of 10Pn-001 Group over Synflorix Vaccine Group were calculated for each of the 10 pneumococcal serotypes and for protein D (PD), using an ANOVA model. This statistical analysis section concerns Anti-14 pneumococcal antibodies.
    Comparison groups
    Synflorix Vaccine Group v 10Pn-001 Group
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    Method
    Parameter type
    		 GMC ratio (see above)
    Point estimate
    0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 0.63
    Notes
    [9] - Comparability to the 10PN-PD-DIT-001 study in terms of non-inferiority was demonstrated if the upper limit of the 2-sided 95% confidence interval (CI) on the GMC ratios (GMCs from study 10PN-PD-DIT-001 over GMCs of current 10PN-PD-DIT-029 study) was below a limit of 2-fold for all of the 10 vaccine pneumococcal serotypes and for protein D (PD).
    Statistical analysis title
    		 10PN-PD-DIT-001 over -029 Anti-18C GMC ratio
    Statistical analysis description
    One month after the administration of the 3rd vaccine dose, i.e. at Month 5, ratios of geometric mean concentrations (GMCs), by enzyme-linked immunosorbent assay (ELISA), of 10Pn-001 Group over Synflorix Vaccine Group were calculated for each of the 10 pneumococcal serotypes and for protein D (PD), using an ANOVA model. This statistical analysis section concerns Anti-18C pneumococcal antibodies.
    Comparison groups
    Synflorix Vaccine Group v 10Pn-001 Group
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [10]
    Method
    Parameter type
    		 GMC ratio (see above)
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 0.32
    Notes
    [10] - Comparability to the 10PN-PD-DIT-001 study in terms of non-inferiority was demonstrated if the upper limit of the 2-sided 95% confidence interval (CI) on the GMC ratios (GMCs from study 10PN-PD-DIT-001 over GMCs of current 10PN-PD-DIT-029 study) was below a limit of 2-fold for all of the 10 vaccine pneumococcal serotypes and for protein D (PD).
    Statistical analysis title
    		 10PN-PD-DIT-001 over -029 Anti-19F GMC ratio
    Statistical analysis description
    One month after the administration of the 3rd vaccine dose, i.e. at Month 5, ratios of geometric mean concentrations (GMCs), by enzyme-linked immunosorbent assay (ELISA), of 10Pn-001 Group over Synflorix Vaccine Group were calculated for each of the 10 pneumococcal serotypes and for protein D (PD), using an ANOVA model. This statistical analysis section concerns Anti-19F pneumococcal antibodies.
    Comparison groups
    Synflorix Vaccine Group v 10Pn-001 Group
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    Method
    Parameter type
    		 GMC ratio (see above)
    Point estimate
    0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 0.4
    Notes
    [11] - Comparability to the 10PN-PD-DIT-001 study in terms of non-inferiority was demonstrated if the upper limit of the 2-sided 95% confidence interval (CI) on the GMC ratios (GMCs from study 10PN-PD-DIT-001 over GMCs of current 10PN-PD-DIT-029 study) was below a limit of 2-fold for all of the 10 vaccine pneumococcal serotypes and for protein D (PD).
    Statistical analysis title
    		 10PN-PD-DIT-001 over -029 Anti-23F GMC ratio
    Statistical analysis description
    One month after the administration of the 3rd vaccine dose, i.e. at Month 5, ratios of geometric mean concentrations (GMCs), by enzyme-linked immunosorbent assay (ELISA), of 10Pn-001 Group over Synflorix Vaccine Group were calculated for each of the 10 pneumococcal serotypes and for protein D (PD), using an ANOVA model. This statistical analysis section concerns Anti-23F pneumococcal antibodies.
    Comparison groups
    Synflorix Vaccine Group v 10Pn-001 Group
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [12]
    Method
    Parameter type
    		 GMC ratio (see above)
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 0.32
    Notes
    [12] - Comparability to the 10PN-PD-DIT-001 study in terms of non-inferiority was demonstrated if the upper limit of the 2-sided 95% confidence interval (CI) on the GMC ratios (GMCs from study 10PN-PD-DIT-001 over GMCs of current 10PN-PD-DIT-029 study) was below a limit of 2-fold for all of the 10 vaccine pneumococcal serotypes and for protein D (PD).

    Primary: Comparison of 10PN-PD-DIT-001 study vs 10PN-PD-DIT-029 study as regards Anti-protein D (anti-PD) antibody concentrations

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    End point title
    		 Comparison of 10PN-PD-DIT-001 study vs 10PN-PD-DIT-029 study as regards Anti-protein D (anti-PD) antibody concentrations
    End point description
    Antibodies assessed for this comparison endpoint were antibodies against protein D (anti-PD). The seropositivity cut-off of the assay was an antibody concentration ≥ 100 enzyme-linked immunosorbent assay (ELISA) units per millilitre (EL.U/mL). Studies compared as regards results for Anti-PD antibody concentrations were studies 10PN-PD-DIT-029 (this study) and 10PN-PD-DIT-001 (105553) (EuDRA CT number: 2005-003300-11) via a comparison of 10Pn-001 Group over Synflorix Vaccine Group.
    End point type
    Primary
    End point timeframe
    One month after the administration of the 3rd vaccine dose, i.e. at Month 5
    End point values
    		 Synflorix Vaccine Group 10Pn-001 Group
    Number of subjects analysed
    219
    1095
    Units: EL.U/mL
    number (not applicable)
        Anti-PD
    2923.2
    1529.9
    Statistical analysis title
    		 10PN-PD-DIT-001 over -029 Anti-PD GMC ratio
    Statistical analysis description
    One month after the administration of the 3rd vaccine dose, i.e. at Month 5, ratios of geometric mean concentrations (GMCs), by enzyme-linked immunosorbent assay (ELISA), of 10Pn-001 Group over Synflorix Vaccine Group were calculated for each of the 10 pneumococcal serotypes and for protein D (PD), using an ANOVA model. This statistical analysis section concerns Anti-PD antibodies.
    Comparison groups
    Synflorix Vaccine Group v 10Pn-001 Group
    Number of subjects included in analysis
    1314
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [13]
    Method
    Parameter type
    		 GMC ratio (see above)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.6
    Notes
    [13] - Comparability to the 10PN-PD-DIT-001 study in terms of non-inferiority was demonstrated if the upper limit of the 2-sided 95% confidence interval (CI) on the GMC ratios (GMCs from study 10PN-PD-DIT-001 over GMCs of current 10PN-PD-DIT-029 study) was below a limit of 2-fold for all of the 10 vaccine pneumococcal serotypes and for protein D (PD).

    Secondary: Opsonophagocytic titer against pneumococcal vaccine serotypes

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    End point title
    		 Opsonophagocytic titer against pneumococcal vaccine serotypes
    End point description
    The results were presented as the geometric mean dilution of serum (opsonic titer) able to sustain 50% killing of live pneumococci under the assay conditions. The vaccine pneumococcal serotypes assessed include 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F.
    End point type
    Secondary
    End point timeframe
    One month after the administration of the 3rd vaccine dose i.e. Month 5
    End point values
    		 Synflorix Vaccine Group
    Number of subjects analysed
    97
    Units: titer
    geometric mean (confidence interval 95%)
        Opsono-1 titer (N=97)
    94.1 (68.2 to 130)
        Opsono-4 titer (N=97)
    670.8 (516.1 to 871.7)
        Opsono-5 titer (N=94)
    148.8 (120.6 to 183.6)
        Opsono-6B titer (N=96)
    345.4 (205.5 to 580.4)
        Opsono-7F titer (N=96)
    4435.4 (3635.9 to 5410.7)
        Opsono-9V titer (N=96)
    1186.1 (955.9 to 1471.7)
        Opsono-14 titer (N=94)
    1168.3 (907.4 to 1504.2)
        Opsono-18C titer (N=94)
    222.9 (157.9 to 314.9)
        Opsono-19F titer (N=92)
    589.2 (441.9 to 785.5)
        Opsono-23F titer (N=95)
    1876.3 (1325.4 to 2656)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-pneumococcal vaccine serotypes antibody concentrations greater than or equal to 0.2 microgram per milliliter

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    End point title
    		 Number of subjects with anti-pneumococcal vaccine serotypes antibody concentrations greater than or equal to 0.2 microgram per milliliter
    End point description
    The vaccine pneumococcal serotypes assessed include 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F.
    End point type
    Secondary
    End point timeframe
    One month after the administration of the 3rd vaccine dose i.e. Month 5
    End point values
    		 Synflorix Vaccine Group
    Number of subjects analysed
    219
    Units: Subjects
        Anti-1 antibody (N=219)
    219
        Anti-4 antibody (N=218)
    218
        Anti-5 antibody (N=218)
    218
        Anti-6B antibody (N=218)
    203
        Anti-7F antibody (N=218)
    218
        Anti-9V antibody (N=218)
    218
        Anti-14 antibody (N=218)
    216
        Anti-18C antibody (N=219)
    218
        Anti-19F antibody (N=219)
    217
        Anti-23F antibody (N=218)
    207
    No statistical analyses for this end point

    Secondary: Antibody concentrations against pneumococcal cross-reactive serotypes

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    End point title
    		 Antibody concentrations against pneumococcal cross-reactive serotypes
    End point description
    Antibody concentrations were expressed as Geometric Mean Concentrations against pneumococcal cross-reactive serotypes 6A and 19A.
    End point type
    Secondary
    End point timeframe
    One month after the administration of the 3rd vaccine dose i.e. Month 5
    End point values
    		 Synflorix Vaccine Group
    Number of subjects analysed
    219
    Units: microgram per milliliter
    geometric mean (confidence interval 95%)
        Anti-6A antibody
    0.28 (0.24 to 0.34)
        Anti-19A antibody
    0.26 (0.22 to 0.31)
    No statistical analyses for this end point

    Secondary: Opsonophagocytic titer against pneumococcal cross-reactive serotypes

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    End point title
    		 Opsonophagocytic titer against pneumococcal cross-reactive serotypes
    End point description
    The results were presented as the geometric mean dilution of serum (opsonic titer) able to sustain 50% killing of live pneumococci under the assay conditions. The cross-reactive pneumococcal serotypes assessed include 6A and 19A.
    End point type
    Secondary
    End point timeframe
    One month after the administration of the 3rd vaccine dose i.e. Month 5
    End point values
    		 Synflorix Vaccine Group
    Number of subjects analysed
    91
    Units: titer
    geometric mean (confidence interval 95%)
        Opsono-6A titer (N=91)
    159.2 (98.8 to 256.4)
        Opsono-19A titer (N=81)
    11.6 (7.3 to 18.4)
    No statistical analyses for this end point

    Secondary: Number of subjects seropositive against vaccine pneumococcal serotypes

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    End point title
    		 Number of subjects seropositive against vaccine pneumococcal serotypes
    End point description
    Seropositivity was defined as anti-pneumococcal antibody concentration greater than or equal to 0.05 microgram per milliliter. The vaccine pneumococcal serotypes assessed include 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F.
    End point type
    Secondary
    End point timeframe
    One month after the administration of the 3rd vaccine dose i.e. Month 5
    End point values
    		 Synflorix Vaccine Group
    Number of subjects analysed
    219
    Units: Subjects
        Anti-1 antibody (N=219)
    219
        Anti-4 antibody (N=218)
    218
        Anti-5 antibody (N=218)
    218
        Anti-6B antibody (N=218)
    212
        Anti-7F antibody (N=218)
    218
        Anti-9V antibody (N=218)
    218
        Anti-14 antibody (N=218)
    218
        Anti-18C antibody (N=219)
    218
        Anti-19F antibody (N=219)
    219
        Anti-23F antibody (N=218)
    212
    No statistical analyses for this end point

    Secondary: Number of subjects seropositive for opsonic titer against vaccine pneumococcal serotypes

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    End point title
    		 Number of subjects seropositive for opsonic titer against vaccine pneumococcal serotypes
    End point description
    Seropositivity was defined as an opsonic titer greater than or equal to 8. The vaccine pneumococcal serotypes assessed include 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F.
    End point type
    Secondary
    End point timeframe
    One month after the administration of the 3rd vaccine dose i.e. Month 5
    End point values
    		 Synflorix Vaccine Group
    Number of subjects analysed
    97
    Units: Subjects
        Opsono-1 titer (N=97)
    83
        Opsono-4 titer (N=97)
    93
        Opsono-5 titer (N=94)
    93
        Opsono-6B titer (N=96)
    76
        Opsono-7F titer (N=96)
    96
        Opsono-9V titer (N=96)
    96
        Opsono-14 titer (N=94)
    93
        Opsono-18C titer (N=94)
    91
        Opsono-19F titer (N=92)
    90
        Opsono-23F titer (N=95)
    90
    No statistical analyses for this end point

    Secondary: Number of subjects seropositive against cross-reactive pneumococcal serotypes

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    End point title
    		 Number of subjects seropositive against cross-reactive pneumococcal serotypes
    End point description
    Seropositivity was defined as anti-pneumococcal antibody concentration greater than or equal to 0.05 microgram per milliliter. The cross-reactive pneumococcal serotypes assessed include 6A and 19A.
    End point type
    Secondary
    End point timeframe
    One month after the administration of the 3rd vaccine dose i.e. Month 5
    End point values
    		 Synflorix Vaccine Group
    Number of subjects analysed
    219
    Units: Subjects
        Anti-6A antibody
    203
        Anti-19A antibody
    198
    No statistical analyses for this end point

    Secondary: Number of subjects seropositive for opsonic titer against cross-reactive pneumococcal serotypes

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    End point title
    		 Number of subjects seropositive for opsonic titer against cross-reactive pneumococcal serotypes
    End point description
    Seropositivity was defined as anti-pneumococcal antibody opsonic titer greater than or equal to 8. The vaccine pneumococcal cross-reactive serotypes assessed include 6A and 19A.
    End point type
    Secondary
    End point timeframe
    One month after the administration of the 3rd vaccine dose i.e. Month 5
    End point values
    		 Synflorix Vaccine Group
    Number of subjects analysed
    91
    Units: Subjects
        Opsono-6A titer (N=91)
    69
        Opsono-19A titer (N=81)
    19
    No statistical analyses for this end point

    Secondary: Number of subjects seropositive for anti-Protein D antibodies

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    End point title
    		 Number of subjects seropositive for anti-Protein D antibodies
    End point description
    Seropositivity was defined as antibody concentration greater than or equal to 100 Enzyme-Linked Immuno Sorbent Assay (ELISA) units per milliliter.
    End point type
    Secondary
    End point timeframe
    One month after the administration of the 3rd vaccine dose i.e. Month 5
    End point values
    		 Synflorix Vaccine Group
    Number of subjects analysed
    219
    Units: Subjects
        Anti-PD antibody
    219
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any and grade 3 solicited local Adverse Events (AEs)

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    End point title
    		 Number of subjects reporting any and grade 3 solicited local Adverse Events (AEs)
    End point description
    Grade 3 redness and swelling was > 30 millimeter (mm) and grade 3 pain was subjects crying when limb was moved/spontaneously painful. Any was occurrence of any local symptom regardless of grade and whatever the number of injections.
    End point type
    Secondary
    End point timeframe
    Within 4 days following any vaccine dose
    End point values
    		 Synflorix Vaccine Group
    Number of subjects analysed
    230
    Units: Subjects
        Any pain
    196
        Grade 3 pain
    80
        Any redness
    91
        Grade 3 redness
    0
        Any swelling
    178
        Grade 3 swelling
    10
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any, grade 3 and related solicited general AEs

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    End point title
    		 Number of subjects reporting any, grade 3 and related solicited general AEs
    End point description
    Any fever was defined as axillary temperature ≥ 37.5 degree centigrade (°C), grade 3 fever was axillary temperature > 39.5°C. Grade 3 drowsiness, irritability, and loss of appetite was general symptom which prevented normal everyday activities. Grade 3 diarrhea was ≥ 6 looser than normal stools/day and Grade 3 vomiting was ≥ 3 episodes of vomiting/day. Related was solicited general symptom considered by the investigator to have a causal relationship to study vaccination.
    End point type
    Secondary
    End point timeframe
    Within 4 days following any vaccine dose
    End point values
    		 Synflorix Vaccine Group
    Number of subjects analysed
    230
    Units: Subjects
        Any diarrhea
    55
        Grade 3 diarrhea
    5
        Related diarrhea
    55
        Any drowsiness
    156
        Grade 3 drowsiness
    7
        Related drowsiness
    153
        Any fever
    147
        Grade 3 fever
    0
        Related fever
    147
        Any irritability
    198
        Grade 3 irritability
    21
        Related irritability
    196
        Any loss of appetite
    113
        Grade 3 loss of appetite
    1
        Related loss of appetite
    111
        Any vomiting
    56
        Grade 3 vomiting
    7
        Related vomiting
    56
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any unsolicited AEs

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    End point title
    		 Number of subjects reporting any unsolicited AEs
    End point description
    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 days after any vaccine dose
    End point values
    		 Synflorix Vaccine Group
    Number of subjects analysed
    230
    Units: Subjects
        Any AE(s)
    174
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any serious adverse events (SAEs)

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    End point title
    		 Number of subjects reporting any 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 or are a congenital anomaly/birth defect in the offspring of a study subject.
    End point type
    Secondary
    End point timeframe
    Entire study period, from Day 0 up to Month 5
    End point values
    		 Synflorix Vaccine Group
    Number of subjects analysed
    230
    Units: Subjects
        Any SAE(s)
    15
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events: Entire study period, from Day 0 up to Month 5. Systematically assessed frequent adverse events (AEs) and non-systematically assessed frequent AEs: During the 4- (Days 0-3) and 31-day (Days0-30) follow-up periods post vaccination,
    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
    11.0
    Reporting groups
    Reporting group title
    Synflorix vaccine Group
    Reporting group description
    		 Subjects receiving 10Pn-PD-DiT (Synflorix) vaccine co-administered with DTPa-HBV-IPV/Hib (Infanrix hexa) vaccine at 2-4-6 months of age, and co-administered with HRV (Rotarix) vaccine at 2-4 months of age. 10Pn-PD-DIT and DTPa-HBV-IPV/Hib vaccines were administered intramuscularly in the thigh, on the right and left side, respectively. HRV vaccine was administered orally.

    Serious adverse events
    		 Synflorix vaccine Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 230 (6.52%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial hyperreactivity
         subjects affected / exposed
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    6 / 230 (2.61%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    Bronchiolitis
         subjects affected / exposed
    4 / 230 (1.74%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 230 (0.87%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    2 / 230 (0.87%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Herpangina
         subjects affected / exposed
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 230 (0.87%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Synflorix vaccine Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    198 / 230 (86.09%)
    General disorders and administration site conditions
    Pain (solicited AE)
    alternative assessment type: Systematic
         subjects affected / exposed
    196 / 230 (85.22%)
         occurrences all number
    196
    Redness (solicited AE)
    alternative assessment type: Systematic
         subjects affected / exposed
    91 / 230 (39.57%)
         occurrences all number
    91
    Swelling (solicited AE)
    alternative assessment type: Systematic
         subjects affected / exposed
    178 / 230 (77.39%)
         occurrences all number
    178
    Diarrhea (solicited AE)
    alternative assessment type: Systematic
         subjects affected / exposed
    55 / 230 (23.91%)
         occurrences all number
    55
    Drowsiness (solicited AE)
    alternative assessment type: Systematic
         subjects affected / exposed
    156 / 230 (67.83%)
         occurrences all number
    156
    Fever (solicited AE)
    alternative assessment type: Systematic
         subjects affected / exposed
    147 / 230 (63.91%)
         occurrences all number
    147
    Irritability (solicited AE)
    alternative assessment type: Systematic
         subjects affected / exposed
    198 / 230 (86.09%)
         occurrences all number
    198
    Loss of appetite (solicited AE)
    alternative assessment type: Systematic
         subjects affected / exposed
    113 / 230 (49.13%)
         occurrences all number
    113
    Vomiting (solicited AE)
    alternative assessment type: Systematic
         subjects affected / exposed
    56 / 230 (24.35%)
         occurrences all number
    56
    Eye disorders
    Conjunctivitis (unsolicited AE)
         subjects affected / exposed
    21 / 230 (9.13%)
         occurrences all number
    21
    Gastrointestinal disorders
    Diarrhea (unsolicited AE)
         subjects affected / exposed
    14 / 230 (6.09%)
         occurrences all number
    14
    Respiratory, thoracic and mediastinal disorders
    Cough (unsolicited AE)
         subjects affected / exposed
    17 / 230 (7.39%)
         occurrences all number
    17
    Infections and infestations
    Nasopharyngitis (unsolicited AE)
         subjects affected / exposed
    123 / 230 (53.48%)
         occurrences all number
    123
    Pharyngitis (unsolicited AE)
         subjects affected / exposed
    37 / 230 (16.09%)
         occurrences all number
    37
    Gastroenteritis (unsolicited AE)
         subjects affected / exposed
    16 / 230 (6.96%)
         occurrences all number
    16
    Laryngitis (unsolicited AE)
         subjects affected / exposed
    13 / 230 (5.65%)
         occurrences all number
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Mar 2007
    This amendment is made in order to update specific study information; because of an updated protocol template (version 12.4); and in general to facilitate reading of the protocol.

    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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