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    Clinical Trial Results:
    A Phase 3, Open Label, Randomized, Controlled, Multi-Center Study to Evaluate the Safety and Immunogenicity of Novartis Meningococcal B Recombinant Vaccine When Administered Concomitantly With Routine Vaccines to Healthy Infants in Taiwan.

    Summary
    EudraCT number
    		 2014-005568-14
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    17 Jun 2016

    Results information
    Results version number
    		 v1
    This version publication date
    08 Mar 2017
    First version publication date
    08 Mar 2017
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    205249
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02173704
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l'Institut 89, Rixensart, Belgium, B-1330
    Public contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089904466, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    09 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To demonstrate the sufficiency of the immune response to Bexsero® vaccine, when administered concomitantly with routine vaccines (i.e. Infanrix- IPV+Hib®, Engerix-B® and Prevenar-13®) to healthy infants at 2, 4, 6 months of age as measured by percentage of subjects with human serum bactericidal activity (h-SBA) titer ≥ 1:5 against the indicator strains H44/76, 5/99 and NZ98/254 at 1 month after the third vaccination (at 7 months of age); 2. To assess the safety of a 3-dose schedule (at 2, 4, 6 months) of Novartis Meningococcal B recombinant vaccine followed by a booster dose at 12 months when concomitantly administered with routine vaccines in healthy infants; 3. To assess serious adverse events (SAEs), medically attended adverse events (AEs), AEs leading to withdrawal throughout the entire study.
    Protection of trial subjects
    This clinical study was designed and shall be implemented and reported in accordance with the International Conference of harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations, Novartis codes on protection of human rights, and with the ethical principles laid down in the Declaration of Helsinki (European Council 2001, US Code of Federal Regulations, ICH 1997).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Sep 2014
    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
    Taiwan: 225
    Worldwide total number of subjects
    225
    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)
    225
    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
    		 Subjects were recruited from 2 sites in Taiwan.

    Pre-assignment
    Screening details
    		 All subjects were enrolled.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The study was an open-label study. Therefore, no blinding procedures were utilized.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bexsero + Routine Group
    Arm description
    		 Subjects received three doses of Bexsero® vaccine at 2, 4, 6 months followed by a booster dose at 12 months, concomitantly administered with routine vaccines (i.e. combined Infanrix-IPV+Hib® and Prevenar-13® at 2, 4, 6 months of age; Engerix-B® at 6 months of age; Priorix® and Varilrix® at 12 months of age.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bexsero®
    Investigational medicinal product code
    rMenB+OMV NZ
    Other name
    Novartis Meningococcal Recombinant B with Outer Membrane Vesicles (OMV) Vaccine
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL dose, administered in the anterolateral area of the right or left thigh.

    Investigational medicinal product name
    Prevenar-13®
    Investigational medicinal product code
    Other name
    Pfizer 13-valent pneumococcal conjugate vaccine
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL dose, administered in the anterolateral area of the right or left thigh.

    Investigational medicinal product name
    Infanrix-IPV+Hib®
    Investigational medicinal product code
    Other name
    GSK 5-in-1 DTPa-IPV-Hib vaccine
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL dose, administered in the anterolateral area of the right or left thigh.

    Investigational medicinal product name
    Engerix-B®
    Investigational medicinal product code
    Other name
    GSK Hepatitis B vaccine
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL dose, administered in the anterolateral area of the right or left thigh.

    Investigational medicinal product name
    Priorix®
    Investigational medicinal product code
    Other name
    GSK Measles, Mumps and Rubella vaccine
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL dose, administered in the anterolateral area of the right or left thigh.

    Investigational medicinal product name
    Varilrix®
    Investigational medicinal product code
    Other name
    GSK Varicella vaccine
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL dose, administered in the anterolateral area of the right or left thigh.

    Arm title
    		 Routine Group
    Arm description
    		 Subjects received routine vaccines Infanrix-IPV+Hib® and Prevenar-13® at 2, 4, 6 months of age; Engerix-B® vaccine at 6 months; Priorix® and Varilrix® vaccines at 12 months of age.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Prevenar-13®
    Investigational medicinal product code
    Other name
    Pfizer 13-valent pneumococcal conjugate vaccine
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL dose, administered in the anterolateral area of the right or left thigh.

    Investigational medicinal product name
    Infanrix-IPV+Hib®
    Investigational medicinal product code
    Other name
    GSK 5-in-1 DTPa-IPV-Hib vaccine
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL dose, administered in the anterolateral area of the right or left thigh.

    Investigational medicinal product name
    Engerix-B®
    Investigational medicinal product code
    Other name
    GSK Hepatitis B vaccine
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL dose, administered in the anterolateral area of the right or left thigh.

    Investigational medicinal product name
    Priorix®
    Investigational medicinal product code
    Other name
    GSK Measles, Mumps and Rubella vaccine
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL dose, administered in the anterolateral area of the right or left thigh.

    Investigational medicinal product name
    Varilrix®
    Investigational medicinal product code
    Other name
    GSK Varicella vaccine
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL dose, administered in the anterolateral area of the right or left thigh.

    Number of subjects in period 1
    		Bexsero + Routine Group Routine Group
    Started
    150
    75
    Completed
    137
    71
    Not completed
    13
    4
         Consent withdrawn by subject
    9
    4
         Adverse event, non-fatal
    1
    -
         Unspecified
    1
    -
         Lost to follow-up
    1
    -
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bexsero + Routine Group
    Reporting group description
    		 Subjects received three doses of Bexsero® vaccine at 2, 4, 6 months followed by a booster dose at 12 months, concomitantly administered with routine vaccines (i.e. combined Infanrix-IPV+Hib® and Prevenar-13® at 2, 4, 6 months of age; Engerix-B® at 6 months of age; Priorix® and Varilrix® at 12 months of age.

    Reporting group title
    Routine Group
    Reporting group description
    		 Subjects received routine vaccines Infanrix-IPV+Hib® and Prevenar-13® at 2, 4, 6 months of age; Engerix-B® vaccine at 6 months; Priorix® and Varilrix® vaccines at 12 months of age.

    Reporting group values
    		 Bexsero + Routine Group Routine Group Total
    Number of subjects
    		 150 75 225
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 150 75 225
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    		 67.9 ± 6.46 68.9 ± 6.86 -
    Gender categorical
    Units: Subjects
        Female
    		 82 27 109
        Male
    		 68 48 116

    End points

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    End points reporting groups
    Reporting group title
    Bexsero + Routine Group
    Reporting group description
    		 Subjects received three doses of Bexsero® vaccine at 2, 4, 6 months followed by a booster dose at 12 months, concomitantly administered with routine vaccines (i.e. combined Infanrix-IPV+Hib® and Prevenar-13® at 2, 4, 6 months of age; Engerix-B® at 6 months of age; Priorix® and Varilrix® at 12 months of age.

    Reporting group title
    Routine Group
    Reporting group description
    		 Subjects received routine vaccines Infanrix-IPV+Hib® and Prevenar-13® at 2, 4, 6 months of age; Engerix-B® vaccine at 6 months; Priorix® and Varilrix® vaccines at 12 months of age.

    Primary: Percentage of subjects with Serum Bactericidal Activity (SBA) titer ≥ 1:5 against Neisseria meningitidis serogroup B strains

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    End point title
    		 Percentage of subjects with Serum Bactericidal Activity (SBA) titer ≥ 1:5 against Neisseria meningitidis serogroup B strains
    End point description
    Percentage of subjects with Serum Bactericidal Activity (SBA) titer ≥ 1:5 at one month following the third vaccination (at 7 months of age) against the indicator strains H44/76, 5/99, NZ98/254 and strain M10713 when Bexsero® was administered concomitantly with routine vaccines (Infanrix-IPV+Hib®, Prevenar-13® and Engerix®). The analysis was performed on the Full Analysis Set (FAS) population Day 152, which included all subjects in the Exposed set who received at least one dose of a study vaccination and provided immunogenicity data at relevant time points.
    End point type
    Primary
    End point timeframe
    At Day 1 and one month after the third vaccination (Day 152)
    End point values
    		 Bexsero + Routine Group Routine Group
    Number of subjects analysed
    135
    71
    Units: Percentage
    number (confidence interval 95%)
        H44/76 (Day 1) (N=116;59)
    0 (0 to 3.1)
    0 (0 to 6.1)
        H44/76 (Day 152) (N=130;66)
    100 (97.2 to 100)
    0 (0 to 5.4)
        5/99 (Day 1) (N=124;69)
    1 (0.02 to 4.4)
    1 (0.04 to 7.8)
        5/99 (Day 152) (N=129;70)
    100 (97.2 to 100)
    0 (0 to 5.1)
        M10713 (Day 1) (N=100;57)
    10 (4.9 to 17.6)
    19 (10 to 31.9)
        M10713 (Day 152) (N=123;65)
    59 (50.1 to 68.1)
    8 (2.5 to 17)
        NZ98/254 (Day 1) (N=134;71)
    0 (0 to 2.7)
    0 (0 to 5.1)
        NZ98/254 (Day 152) (N=135;71)
    79 (71.4 to 85.8)
    0 (0 to 5.1)
    Statistical analysis title
    		 Statistical analysis H44/76 strain
    Statistical analysis description
    The null hypothesis associated with the primary objective is that the proportion of subjects with SBA titers ≥ 1:5 one month after the third dose of the Bexsero® vaccine was ≤ 0.70. Assuming the results for the three strains are independent, the power to reject the null hypothesis associated with the primary objectives to demonstrate sufficiency of response (for all three strains was 92 %).
    Comparison groups
    Bexsero + Routine Group v Routine Group
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    		 Exact test of binomial proportion
    Parameter type
    		 Single binomial proportion
    Point estimate
    100
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 97.2
         upper limit
    		 100
    Notes
    [1] - The criterion for a sufficient immune response was that the lower limit of the two-sided 95% CI for the percentage of subjects with SBA titer ≥ 1:5 should be ≥ 70%.
    Statistical analysis title
    		 Statistical analysis 5/99 strain
    Statistical analysis description
    The power to reject the null hypothesis associated with the primary objective for the 5/99 strain was 99 %.
    Comparison groups
    Bexsero + Routine Group v Routine Group
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    		 Exact test of binomial proportion
    Parameter type
    		 Single binomial proportion
    Point estimate
    100
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 97.2
         upper limit
    		 100
    Notes
    [2] - The criterion for a sufficient immune response was that the lower limit of the two-sided 95 % CI for the percentage of subjects with SBA titer ≥ 1:5 should be ≥ 70 %.
    Statistical analysis title
    		 Statistical analysis NZ98/254 strain
    Statistical analysis description
    The power to reject the null hypothesis associated with the primary objective for the NZ98/254 strain was 94 %.
    Comparison groups
    Bexsero + Routine Group v Routine Group
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    		 Exact test of binomial proportion
    Parameter type
    		 Single binomial proportion
    Point estimate
    79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 71.4
         upper limit
    		 85.8
    Notes
    [3] - The criterion for a sufficient immune response was that the lower limit of the two-sided 95% CI for the percentage of subjects with SBA titer ≥ 1:5 should be ≥ 70 %.

    Secondary: Percentage of subjects with SBA titer ≥ 1:5 against Neisseria meningitidis serogroup B strains, when Bexsero® booster dose was administered with routine vaccines (Priorix® + Varilrix® vaccines)

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    End point title
    		 Percentage of subjects with SBA titer ≥ 1:5 against Neisseria meningitidis serogroup B strains, when Bexsero® booster dose was administered with routine vaccines (Priorix® + Varilrix® vaccines)
    End point description
    Percentage of subjects with SBA titer ≥ 1:5 before booster vaccination and after booster vaccination when Bexsero® booster dose was administered with routine vaccines (Priorix® + Varilrix® vaccines) as compared to when only routine vaccines were administered. The analysis was performed on the FAS population Day 335, which included all subjects in the Exposed set who received at least one dose of a study vaccination and provided immunogenicity data at relevant time points.
    End point type
    Secondary
    End point timeframe
    Day 305 and Day 335
    End point values
    		 Bexsero + Routine Group Routine Group
    Number of subjects analysed
    136
    71
    Units: Percentage
    geometric mean (confidence interval 95%)
        H44/76 (Day 305) (N=123;64)
    81 (73.3 to 87.8)
    2 (0.04 to 8.4)
        H44/76 (Day 335) (N=127;64)
    99 (95.7 to 99.98)
    2 (0.04 to 8.4)
        5/99 (Day 305) (N=135;70)
    99 (94.8 to 99.82)
    1 (0.04 to 7.7)
        5/99 (Day 335) (N=134;71)
    99 (94.7 to 99.82)
    0 (0 to 5.1)
        M10713 (Day 305) (N=130;65)
    22 (14.8 to 29.6)
    11 (4.4 to 20.9)
        M10713 (Day 335) (N=130;69)
    92 (86.3 to 96.2)
    13 (6.1 to 23.3)
        NZ98/254 (Day 305) (N=136;70)
    17 (11 to 24.3)
    1 (0.04 to 7.7)
        NZ98/254 (Day 335) (N=136;71)
    94 (88.7 to 97.4)
    0 (0 to 5.1)
    Statistical analysis title
    		 Statistical analysis H44/76 strain
    Statistical analysis description
    The null hypothesis associated with the primary objective is that the proportion of subjects with SBA titers ≥ 1:5 one month after the third dose of the Bexsero® vaccine was ≤ 0.70. Assuming the results for the three strains are independent, the power to reject the null hypothesis associated with the primary objectives to demonstrate sufficiency of response (for all three strains was 92%).
    Comparison groups
    Bexsero + Routine Group v Routine Group
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    		 Exact test of binomial proportion
    Parameter type
    		 Single binomial proportion
    Point estimate
    99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 95.7
         upper limit
    		 99.98
    Notes
    [4] - The criterion for a sufficient immune response was that the lower limit of the two-sided 95% CI for the percentage of subjects with SBA titer ≥ 1:5 should be ≥ 70%.
    Statistical analysis title
    		 Statistical analysis 5/99 strain
    Statistical analysis description
    The power to reject the null hypothesis associated with the secondary objective for the 5/99 strain was 99%.
    Comparison groups
    Bexsero + Routine Group v Routine Group
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    Method
    		 Exact test for binomial proportion
    Parameter type
    		 Single binomial proportion
    Point estimate
    99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 94.7
         upper limit
    		 99.82
    Notes
    [5] - The criterion for a sufficient immune response was that the lower limit of the two-sided 95% CI for the percentage of subjects with SBA titer ≥ 1:5 should be ≥ 75%.
    Statistical analysis title
    		 Statistical analysis NZ98/254 strain
    Statistical analysis description
    The power to reject the null hypothesis associated with the secondary objective for the NZ98/254 strain was 99%.
    Comparison groups
    Bexsero + Routine Group v Routine Group
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    		 Exact test for binomial proportions
    Parameter type
    		 Single binomial proportion
    Point estimate
    94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 88.7
         upper limit
    		 97.4
    Notes
    [6] - The criterion for a sufficient immune response was that the lower limit of the two-sided 95% CI for the percentage of subjects with SBA titer ≥ 1:5 should be ≥ 75%.

    Secondary: SBA Geometric Mean Titers (GMTs) against Neisseria meningitidis serogroup B indicator strains, when Bexsero® vaccine was administered with routine vaccines

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    End point title
    		 SBA Geometric Mean Titers (GMTs) against Neisseria meningitidis serogroup B indicator strains, when Bexsero® vaccine was administered with routine vaccines
    End point description
    SBA GMTs against the indicator strains H44/76, 5/99, NZ98/254 and strain M10713 were evaluated at baseline (2 months of age, Day 1), 1 month after the third vaccination with Bexsero® with concomitant routine vaccines (Infanrix-IPV+Hib®, Prevenar-13®, Engerix®) (7 months of age, Day 152) or prior to the booster dose of Bexsero® with routine vaccines (Priorix®, Varilrix®) (12 months of age, Day 305) and 1 month after the booster dose (13 months of age, Day 335), as compared to when only routine vaccines were administered. The analysis was performed on the FAS population, which included all subjects in the Exposed set who received at least one dose of a study vaccination and provided immunogenicity data at relevant time points.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 152, Day 305 and Day 335
    End point values
    		 Bexsero + Routine Group Routine Group
    Number of subjects analysed
    145
    73
    Units: Titers
    geometric mean (confidence interval 95%)
        H44/76 (Day 1) (N=132;65)
    1.01 (0.99 to 1.02)
    1.02 (0.98 to 1.05)
        H44/76 (Day 152) (N=130;66)
    72 (64 to 81)
    1.01 (0.99 to 1.03)
        H44/76 (Day 305) (N=123;64)
    11 (9.27 to 13)
    1.26 (1.06 to 1.5)
        H44/76 (Day 335) (N=127;64)
    157 (131 to 188)
    1.1 (1.01 to 1.19)
        5/99 (Day 1) (N=141;72)
    1.08 (0.98 to 1.18)
    1.03 (0.98 to 1.08)
        5/99 (Day 152) (N=129;70)
    963 (864 to 1073)
    1 (1 to 1)
        5/99 (Day 305) (N=135;70)
    205 (174 to 242)
    1.1 (0.91 to 1.33)
        5/99 (Day 335) (N=134;71)
    2315 (1893 to 2832)
    1 (1 to 1)
        M10713 (Day 1) (N=121;64)
    1.36 (1.2 to 1.54)
    1.75 (1.37 to 2.24)
        M10713 (Day 152) (N=123;65)
    8.41 (6.63 to 11)
    1.25 (1.08 to 1.46)
        M10713 (Day 305) (N=130;65)
    2.18 (1.81 to 2.63)
    1.6 (1.34 to 1.91)
        M10713 (Day 335) (N=130;69)
    17 (14 to 20)
    1.58 (1.33 to 1.89)
        NZ98/254 (Day 1) (N=145;73)
    1.01 (0.99 to 1.02)
    1 (1 to 1)
        NZ98/254 (Day 152) (N=135;71)
    9.2 (7.82 to 11)
    1.02 (0.98 to 1.05)
        NZ98/254 (Day 305) (N=136;70)
    1.91 (1.63 to 2.25)
    1.04 (0.98 to 1.1)
        NZ98/254 (Day 335) (N=136;71)
    26 (21 to 31)
    1 (1 to 1)
    No statistical analyses for this end point

    Secondary: SBA Geometric Mean Ratios (GMRs) against Neisseria meningitidis serogroup B strains

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    End point title
    		 SBA Geometric Mean Ratios (GMRs) against Neisseria meningitidis serogroup B strains
    End point description
    GMRs of post-vaccination versus pre-vaccination of SBA titer against the indicator strains H44/76, 5/99, NZ98/254 and strain M10713 were evaluated at one month after the third vaccination with Bexsero® vaccine and concomitant routine vaccines (Infanrix-IPV+Hib®, Prevenar-13® and Engerix®) (Day 152), as compared to baseline (Day 1) or at one month after the administration of the booster dose of Bexsero® vaccine and routine vaccines (Priorix® and Varilrix®) (Day 335), as compared to prior to the booster dose (Day 305). The analysis was performed on the FAS population, which included all subjects in the Exposed set who received at least one dose of a study vaccination and provided immunogenicity data at relevant time points.
    End point type
    Secondary
    End point timeframe
    Day 152 and Day 335
    End point values
    		 Bexsero + Routine Group Routine Group
    Number of subjects analysed
    135
    71
    Units: Ratio
    number (confidence interval 95%)
        H44/76 (Day 152/Day 1) (N=116;59)
    71 (63 to 80)
    0.99 (0.95 to 1.04)
        H44/76 (Day 335/Day 305) (N=113;56)
    155 (127 to 188)
    1.07 (0.97 to 1.19)
        5/99 (Day 152/Day 1) (N=124;69)
    875 (752 to 1019)
    0.97 (0.93 to 1.03)
        5/99 (Day 335/Day 305) (N=129;70)
    2110 (1674 to 2659)
    0.97 (0.93 to 1.03)
        M10713 (Day 152/Day 1) (N=100;57)
    5.69 (4.25 to 7.61)
    0.68 (0.54 to 0.85)
        M10713 (Day 335/Day 305) (N=105;60)
    12 (8.99 to 15)
    0.91 (0.68 to 1.21)
        NZ98/254 (Day 152/Day 1) (N=134;71)
    9.18 (7.79 to 11)
    1.02 (0.98 to 1.05)
        NZ98/254 (Day 335/Day 305) (N=135;71)
    25 (21 to 31)
    1 (1 to 1)
    No statistical analyses for this end point

    Secondary: Percentages of subjects with SBA titers ≥ 1:8 against Neisseria meningitidis serogroup B, when Bexsero® vaccine was administered with routine vaccines

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    End point title
    		 Percentages of subjects with SBA titers ≥ 1:8 against Neisseria meningitidis serogroup B, when Bexsero® vaccine was administered with routine vaccines
    End point description
    Percentages of subjects with SBA titers ≥1:8 against N.meningitidis serogroup B strains, at one month after concomitant administration of third primary dose of Bexsero® with routine vaccines (Infanrix-IPV+Hib® + Prevenar-13® + Engerix®) and at one month after concomitant administration of Bexsero® booster dose with routine vaccines (Priorix® + Varilrix®), as compared to when only routine vaccines were administered. The analysis was performed on the FAS-3 population, which included all subjects in the Exposed set who received at least one dose of a study vaccination and who provided immunogenicity data at relevant time points.
    End point type
    Secondary
    End point timeframe
    At Day 1, Day 152, Day 305 and Day 335
    End point values
    		 Bexsero + Routine Group Routine Group
    Number of subjects analysed
    145
    73
    Units: Percentage
    number (confidence interval 95%)
        H44/76 (Day 1) (N=132;65)
    0 (0 to 2.8)
    0 (0 to 5.5)
        H44/76 (Day 152) (N=130;66)
    100 (97.2 to 100)
    0 (0 to 5.4)
        H44/76 (Day 305) (N=123;64)
    66 (56.8 to 74.2)
    2 (0.04 to 8.4)
        H44/76 (Day 335) (N=127;64)
    99 (95.7 to 99.98)
    0 (0 to 5.6)
        5/99 (Day 1) (N=141;72)
    1 (0.02 to 3.9)
    0 (0 to 5)
        5/99 (Day 152) (N=129;70)
    100 (97.2 to 100)
    0 (0 to 5.1)
        5/99 (Day 305) (N=135;70)
    99 (94.8 to 99.82)
    1 (0.04 to 7.7)
        5/99 (Day 335) (N=134;71)
    99 (94.7 to 99.82)
    0 (0 to 5.1)
        M10713 (Day 1) (N=121;64)
    3 (0.9 to 8.2)
    8 (2.6 to 17.3)
        M10713 (Day 152) (N=123;65)
    49 (39.7 to 58)
    5 (1 to 12.9)
        M10713 (Day 305) (N=130;65)
    15 (9.7 to 22.8)
    3 (0.37 to 10.7)
        M10713 (Day 335) (N=130;69)
    77 (68.7 to 83.9)
    6 (1.6 to 14.2)
        NZ98/254 (Day 1) (N=145;73)
    0 (0 to 2.5)
    0 (0 to 4.9)
        NZ98/254 (Day 152) (N=135;71)
    59 (49.7 to 66.9)
    0 (0 to 5.1)
        NZ98/254 (Day 305) (N=136;70)
    9 (4.6 to 14.9)
    0 (0 to 5.1)
        NZ98/254 (Day 335) (N=136;71)
    86 (79 to 91.4)
    0 (0 to 5.1)
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any solicited local adverse events (AEs) after receiving Bexsero® vaccine with routine vaccines, at 2, 4 and 6 months of age

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    End point title
    		 Number of subjects reporting any solicited local adverse events (AEs) after receiving Bexsero® vaccine with routine vaccines, at 2, 4 and 6 months of age
    End point description
    The number of subjects who reported any solicited local symptoms following concomitant administration of Bexsero® vaccine with routine vaccines (Infanrix-IPV+Hib®, Prevenar-13® and Engerix-B®), as compared to when only routine vaccines were administered alone at 2, 4 and 6 months of age. Assessed solicited local symptoms were: Erythema, Induration, Swelling and Tenderness. Any = occurrence of the symptom regardless of intensity grade. The analysis was performed on the Solicited Safety Set, which included all subjects in the Exposed population who provided post-vaccination reactogenicity data.
    End point type
    Secondary
    End point timeframe
    From Day 1 (6 hours) to Day 7 after each vaccination
    End point values
    		 Bexsero + Routine Group Routine Group
    Number of subjects analysed
    148
    73
    Units: Subjects
        Erythema (1st Bexsero® vacc.) (N=148;0)
    54
    0
        Induration (1st Bexsero® vacc.) (N=147;0)
    63
    0
        Swelling (1st Bexsero® vacc.) (N=146;0)
    34
    0
        Tenderness (1st Bexsero® vacc.) (N=147;0)
    75
    0
        Erythema (1st Infanrix-IPV+Hib® vacc.) (N=148;73)
    26
    3
        Induration (1st Infanrix-IPV+Hib® vacc.)(N=148;73)
    23
    11
        Swelling (1st Infanrix-IPV+Hib® vacc.) (N=148;73)
    15
    3
        Tenderness (1st Infanrix-IPV+Hib® vacc.)(N=146;73)
    45
    12
        Erythema (1st Prevenar-13® vacc.) (N=148;73)
    26
    9
        Induration (1st Prevenar-13® vacc.) (N=148;73)
    29
    15
        Swelling (1st Prevenar-13® vacc.) (N=148;73)
    11
    4
        Tenderness (1st Prevenar-13® vacc.) (N=147;73)
    50
    12
        Erythema (2nd Bexsero® vacc.) (N=140;0)
    59
    0
        Induration (2nd Bexsero® vacc.) (N=140;0)
    51
    0
        Swelling (2nd Bexsero® vacc.) (N=140;0)
    35
    0
        Tenderness (2nd Bexsero® vacc.) (N=140;0)
    67
    0
        Erythema (2nd Infanrix-IPV+Hib® vacc.) (N=140;72)
    39
    12
        Induration (2nd Infanrix-IPV+Hib® vacc.)(N=140;72)
    23
    16
        Swelling (2nd Infanrix-IPV+Hib® vacc.) (N=140;72)
    18
    6
        Tenderness (2nd Infanrix-IPV+Hib® vacc.)(N=140;72)
    45
    10
        Erythema (2nd Prevenar-13® vacc.) (N=140;72)
    35
    12
        Induration (2nd Prevenar-13® vacc.) (N=140;72)
    18
    8
        Swelling (2nd Prevenar-13® vacc.) (N=140;72)
    12
    6
        Tenderness (2nd Prevenar-13® vacc.) (N=140;72)
    44
    9
        Erythema (3rd Bexsero® vacc.) (N=138;0)
    55
    0
        Induration (3rd Bexsero® vacc.) (N=138;0)
    57
    0
        Swelling (3rd Bexsero® vacc.) (N=138;0)
    49
    0
        Tenderness (3rd Bexsero® vacc.) (N=138;0)
    68
    0
        Erythema (3rd Infanrix-IPV+Hib® vacc.) (N=137;72)
    28
    15
        Induration (3rd Infanrix-IPV+Hib® vacc.)(N=138;72)
    25
    16
        Swelling (3rd Infanrix-IPV+Hib® vacc.) (N=138;72)
    20
    10
        Tenderness (3rd Infanrix-IPV+Hib® vacc.)(N=138;72)
    42
    8
        Erythema (3rd Prevenar-13® vacc.) (N=138;72)
    27
    12
        Induration (3rd Prevenar-13® vacc.) (N=138;72)
    21
    11
        Swelling (3rd Prevenar-13® vacc.) (N=138;72)
    17
    4
        Tenderness (3rd Prevenar-13® vacc.) (N=138;72)
    45
    9
        Erythema (Engerix-B® vacc.) (N=138;72)
    33
    12
        Induration (Engerix-B® vacc.) (N=137;72)
    33
    17
        Swelling (Engerix-B® vacc.) (N=138;71)
    25
    6
        Tenderness (Engerix-B® vacc.) (N=138;72)
    45
    7
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any solicited systemic AEs and other solicited data after receiving Bexsero® vaccine with routine vaccines or routine vaccines alone, at 2, 4 and 6 months of age

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    End point title
    		 Number of subjects reporting any solicited systemic AEs and other solicited data after receiving Bexsero® vaccine with routine vaccines or routine vaccines alone, at 2, 4 and 6 months of age
    End point description
    The number of subjects who reported any solicited systemic AEs and other solicited data following concomitant administration of Bexsero® vaccine with routine vaccines (Infanrix-IPV+Hib®, Prevenar-13® and Engerix-B®), as compared to when only routine vaccines were administered alone at 2, 4 and 6 months of age. Assessed solicited systemic symptoms were: Change in Eating Habits, Diarrhea, Irritability, Persistent Crying, Rash, Sleepiness, Vomiting and Fever (defined as body temperature ≥ 38.0 °C). Other solicited data included: Prevention of Pain and/or Fever and Treatment of Pain and/or Fever. Any = occurrence of the symptom regardless of intensity grade. The analysis was performed on the Solicited Safety Set, which included all subjects in the Exposed population who provided post-vaccination reactogenicity data.
    End point type
    Secondary
    End point timeframe
    From Day 1 (6 hours) to Day 7 after each vaccination
    End point values
    		 Bexsero + Routine Group Routine Group
    Number of subjects analysed
    148
    73
    Units: Subjects
        Change in Eating Habits (1st vacc.) (N=148;73)
    92
    26
        Diarrhea (1st vacc.) (N=148;73)
    28
    8
        Irritability (1st vacc.) (N=148;73)
    111
    32
        Persistent Crying (1st vacc.) (N=148;73)
    96
    30
        Rash (1st vacc.) (N=148;73)
    18
    4
        Sleepiness (1st vacc.) (N=148;73)
    79
    33
        Vomiting (1st vacc.) (N=148;73)
    21
    6
        Fever (1st vacc.) (N=148;73)
    71
    11
        Change in Eating Habits (2nd vacc.) (N=140;72)
    72
    21
        Diarrhea (2nd vacc.) (N=140;72)
    30
    9
        Irritability (2nd vacc.) (N=140;72)
    90
    31
        Persistent Crying (2nd vacc.) (N=140;72)
    82
    23
        Rash (2nd vacc.) (N=140;72)
    18
    8
        Sleepiness (2nd vacc.) (N=140;72)
    66
    21
        Vomiting (2nd vacc.) (N=140;72)
    16
    9
        Fever (2nd vacc.) (N=140;71)
    72
    11
        Change in Eating Habits (3rd vacc.) (N=138;72)
    72
    17
        Diarrhea (3rd vacc.) (N=138;72)
    19
    4
        Irritability (3rd vacc.) (N=138;72)
    94
    28
        Persistent Crying (3rd vacc.) (N=138;72)
    72
    28
        Rash (3rd vacc.) (N=138;72)
    16
    4
        Sleepiness (3rd vacc.) (N=138;72)
    49
    13
        Vomiting (3rd vacc.) (N=138;72)
    15
    7
        Fever (3rd vacc.) (N=138;72)
    68
    12
        Prevention of Pain/Fever (1st vacc.) (N=147;73)
    4
    0
        Treatment of Pain/Fever (1st vacc.) (N=147;73)
    35
    1
        Prevention of Pain/Fever (2nd vacc.) (N=140;71)
    4
    0
        Treatment of Pain/Fever (2nd vacc.) (N=140;71)
    38
    2
        Prevention of Pain/Fever (3rd vacc.) (N=138;72)
    6
    1
        Treatment of Pain/Fever (3rd vacc.) (N=138;72)
    30
    5
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any solicited local AEs after receiving Bexsero® booster dose with routine vaccines, at 12 months of age

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    End point title
    		 Number of subjects reporting any solicited local AEs after receiving Bexsero® booster dose with routine vaccines, at 12 months of age
    End point description
    The number of subjects who reported any solicited local AEs following concomitant administration of Bexsero® dose with routine vaccines (Priorix® and Varilrix®), as compared to when only routine vaccines were administered alone, at 12 months of age. Assessed solicited local symptoms were: Erythema, Induration, Swelling and Tenderness. Any = occurrence of the symptom regardless of intensity grade. The analysis was performed on the Solicited Safety Set, which included all subjects in the Exposed population who provided post-vaccination reactogenicity data.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 7 after booster vaccination
    End point values
    		 Bexsero + Routine Group Routine Group
    Number of subjects analysed
    137
    72
    Units: Subjects
        Erythema (Bexsero® booster vacc.) (N=136;0)
    53
    0
        Induration (Bexsero® booster vacc.) (N=136;0)
    56
    0
        Swelling (Bexsero® booster vacc.) (N=135;0)
    44
    0
        Tenderness (Bexsero® booster vacc.) (N=136;0)
    66
    0
        Erythema (Priorix® vacc.) (N=137;72)
    24
    13
        Induration (Priorix® vacc.) (N=137;72)
    15
    6
        Swelling (Priorix® vacc.) (N=137;72)
    19
    4
        Tenderness (Priorix® vacc.) (N=137;72)
    37
    6
        Erythema (Varilrix® vacc.) (N=137;72)
    32
    14
        Induration (Varilrix® vacc.) (N=137;72)
    14
    7
        Swelling (Varilrix® vacc.) (N=137;72)
    21
    6
        Tenderness (Varilrix® vacc.) (N=137;72)
    41
    5
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any solicited systemic AEs and other solicited data after receiving Bexsero® booster dose with routine vaccines, at 12 months of age

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    End point title
    		 Number of subjects reporting any solicited systemic AEs and other solicited data after receiving Bexsero® booster dose with routine vaccines, at 12 months of age
    End point description
    The number of subjects who reported any solicited systemic AEs and other solicited data following concomitant administration of Bexsero® booster dose with routine vaccines (Priorix® and Varilrix®), as compared to when only routine vaccines were administered alone at 12 months of age. Assessed solicited systemic AEs were: Change in Eating Habits, Diarrhea, Irritability, Persistent Crying, Rash, Sleepiness, Vomiting, Fever (defined as body temperature ≥ 38.0 °C) and Lymphadenopathy. Other solicited data included: Prevention of Pain and/or Fever and Treatment of Pain and/or Fever. Any = occurrence of the symptom regardless of intensity grade. The analysis was performed on the Solicited Safety Set, which included all subjects in the Exposed population who provided post-vaccination reactogenicity data.
    End point type
    Secondary
    End point timeframe
    From Day 1 (6 hours) to Day 7 after vaccination
    End point values
    		 Bexsero + Routine Group Routine Group
    Number of subjects analysed
    137
    72
    Units: Subjects
        Change in Eating Habits (N=137;72)
    58
    19
        Diarrhea (N=137;72)
    27
    10
        Irritability (N=137;72)
    71
    16
        Persistent Crying (N=137;72)
    58
    15
        Rash (N=137;72)
    25
    9
        Sleepiness (N=137;72)
    36
    9
        Vomiting (N=137;72)
    10
    6
        Fever (N=137;72)
    60
    6
        Lymphadenopathy (N=136;72)
    1
    1
        Prevention of Pain/Fever (N=137;72)
    1
    0
        Treatment of Pain/Fever (N=137;72)
    20
    3
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any and Grade 3 solicited systemic AEs after receiving Priorix® and Varilrix® routine vaccines at 12 months of age

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    End point title
    		 Number of subjects reporting any and Grade 3 solicited systemic AEs after receiving Priorix® and Varilrix® routine vaccines at 12 months of age
    End point description
    The number of subjects who reported any and Grade 3 solicited systemic AEs after the administration of Varilrix® and Priorix® vaccines (with and without Bexsero® vaccine) at 12 months of age. Solicited systemic AEs assessed were Rash and Lymphadenopathy. The symptoms were collected for an extended period of 28 days following Varilrix® and Priorix® vaccinations. Any = occurrence of the symptom regardless of intensity grade. Grade 3 symptom = symptom that prevented normal activity. The analysis was performed on the Safety Set (solicited AEs), which included all subjects in the Exposed population who provided post-vaccination reactogenicity data.
    End point type
    Secondary
    End point timeframe
    From Day 1 through Day 28 after Priorix® and Varilrix® vaccinations
    End point values
    		 Bexsero + Routine Group Routine Group
    Number of subjects analysed
    137
    72
    Units: Subjects
        Any Rash
    50
    24
        Grade 3 Rash
    5
    5
        Lymphadenopathy
    34
    21
    No statistical analyses for this end point

    Secondary: Number of subjects reporting unsolicited AEs after receiving Bexsero® vaccination with routine vaccines

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    End point title
    		 Number of subjects reporting unsolicited AEs after receiving Bexsero® vaccination with routine vaccines
    End point description
    The number of subjects who reported any unsolicited AEs following concomitant administration of Bexsero® vaccine with routine vaccines (Infanrix-IPV + Hib®, Prevenar-13®, Engerix-B®, Priorix® and Varilrix®), as compared to when only routine vaccines were administered alone. An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and 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. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. Possibly or probably related AE = AE assessed by the investigator as related to the vaccination. The analysis was performed on the Safety Set (Unsolicited AEs).
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 7 after each vaccination
    End point values
    		 Bexsero + Routine Group Routine Group
    Number of subjects analysed
    145
    72
    Units: Subjects
        Any AEs (1st vacc.) (N=145;72)
    46
    8
        Possibly/Probably Related AEs(1st vacc.)(N=145;72)
    35
    6
        Any AEs (2nd vacc.) (N=141;72)
    30
    7
        Possibly/Probably Related AEs(2nd vacc.)(N=141;72)
    22
    5
        Any AEs (3rd vacc.) (N=138;72)
    51
    18
        Possibly/Probably Related AEs(3rd vacc.)(N=138;72)
    45
    7
        Any AEs (booster) (N=137;72)
    43
    9
        Possibly/Probably Related AEs (booster) (N=137;72)
    37
    4
    No statistical analyses for this end point

    Secondary: Number of subjects reporting serious adverse events (SAEs), medically attended AEs (MAEs), AEs leading to withdrawal, hospitalization and death

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    End point title
    		 Number of subjects reporting serious adverse events (SAEs), medically attended AEs (MAEs), AEs leading to withdrawal, hospitalization and death
    End point description
    Number of subjects who reported SAEs, medically attended AEs, AEs leading to withdrawal from the study, AEs leading to hospitalization and AEs leading to death, following concomitant administration of Bexsero® vaccine with routine vaccines (Infanrix-IPV + Hib®, Prevenar-13®, Engerix-B®, Priorix® and Varilrix®), as compared to when only routine vaccines were administered alone. SAEs assessed include medical occurrences that result in death, are life-threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. Possibly or probably related SAE = SAE assessed by the investigator as related to the vaccination. Medically attended AEs were defined as events for which the subject received medical attention defined as hospitalization, an emergency room visit, or a visit to or from medical personnel (medical doctor) for any reason. The analysis was performed on the Safety Set (Unsolicited AEs).
    End point type
    Secondary
    End point timeframe
    Throughout the whole study period (from Day 1 to Day 335)
    End point values
    		 Bexsero + Routine Group Routine Group
    Number of subjects analysed
    145
    72
    Units: Subjects
        Any SAEs
    13
    8
        Possibly or Probably Related SAEs
    0
    0
        Medically attended AEs
    131
    66
        AEs leading to withdrawal
    4
    0
        AEs leading to hospitalization
    13
    8
        AEs leading to death
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects reporting Grade 3 solicited local AEs after receiving Bexsero® vaccine with routine vaccines, at 2, 4 and 6 months of age

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    End point title
    		 Number of subjects reporting Grade 3 solicited local AEs after receiving Bexsero® vaccine with routine vaccines, at 2, 4 and 6 months of age
    End point description
    The number of subjects who reported Grade 3 solicited local symptoms following concomitant administration of Bexsero® vaccine with routine vaccines (Infanrix-IPV+Hib®, Prevenar-13® and Engerix-B®), as compared to when only routine vaccines were administered alone at 2, 4 and 6 months of age. Assessed solicited local symptoms were: Erythema, Induration, Swelling and Tenderness. Grade 3 symptom = symptom that prevented normal activity. The analysis was performed on the Solicited Safety Set, which included all subjects in the Exposed population who provided post-vaccination reactogenicity data.
    End point type
    Secondary
    End point timeframe
    From Day 1 (6 hours) to Day 7 after each vaccination
    End point values
    		 Bexsero + Routine Group Routine Group
    Number of subjects analysed
    148
    73
    Units: Subjects
        Grade 3 Erythema (1st Bexsero®) (N=148;0)
    0
    0
        Grade 3 Induration (1st Bexsero®) (N=147;0)
    0
    0
        Grade 3 Swelling (1st Bexsero®) (N=146;0)
    0
    0
        Grade 3 Tenderness (1st Bexsero®) (N=147;0)
    8
    0
        Grade 3 Erythema (1st Infanrix-IPV+Hib®)(N=148;73)
    0
    0
        Grade3 Induration(1st Infanrix-IPV+Hib®)(N=148;73)
    0
    0
        Grade 3 Swelling (1st Infanrix-IPV+Hib®)(N=148;73)
    0
    0
        Grade3 Tenderness(1st Infanrix-IPV+Hib®)(N=146;73)
    2
    0
        Grade 3 Erythema (1st Prevenar-13®) (N=148;73)
    0
    0
        Grade 3 Induration (1st Prevenar-13®) (N=148;73)
    0
    0
        Grade 3 Swelling (1st Prevenar-13®) (N=148;73)
    0
    0
        Grade 3 Tenderness (1st Prevenar-13®) (N=147;73)
    3
    0
        Grade 3 Erythema (2nd Bexsero®) (N=140;0)
    0
    0
        Grade 3 Induration (2nd Bexsero®) (N=140;0)
    0
    0
        Grade 3 Swelling (2nd Bexsero®) (N=140;0)
    0
    0
        Grade 3 Tenderness (2nd Bexsero®) (N=140;0)
    5
    0
        Grade 3 Erythema (2nd Infanrix-IPV+Hib®)(N=140;72)
    0
    0
        Grade3 Induration(2nd Infanrix-IPV+Hib®)(N=140;72)
    0
    0
        Grade 3 Swelling (2nd Infanrix-IPV+Hib®)(N=140;72)
    0
    0
        Grade3 Tenderness(2nd Infanrix-IPV+Hib®)(N=140;72)
    3
    0
        Grade 3 Erythema (2nd Prevenar-13®) (N=140;72)
    0
    0
        Grade 3 Induration (2nd Prevenar-13®) (N=140;72)
    0
    0
        Grade 3 Swelling (2nd Prevenar-13®) (N=140;72)
    0
    0
        Grade 3 Tenderness (2nd Prevenar-13®) (N=140;72)
    3
    0
        Grade 3 Erythema (3rd Bexsero®) (N=138;0)
    0
    0
        Grade 3 Induration (3rd Bexsero®) (N=138;0)
    0
    0
        Grade 3 Swelling (3rd Bexsero®) (N=138;0)
    0
    0
        Grade 3 Tenderness (3rd Bexsero®) (N=138;0)
    6
    0
        Grade 3 Erythema (3rd Infanrix-IPV+Hib®)(N=137;72)
    0
    0
        Grade3 Induration(3rd Infanrix-IPV+Hib®)(N=138;72)
    0
    0
        Grade 3 Swelling (3rd Infanrix-IPV+Hib®)(N=138;72)
    0
    0
        Grade3 Tenderness(3rd Infanrix-IPV+Hib®)(N=138;72)
    2
    0
        Grade 3 Erythema (3rd Prevenar-13®) (N=138;72)
    0
    0
        Grade 3 Induration (3rd Prevenar-13®) (N=138;72)
    0
    0
        Grade 3 Swelling (3rd Prevenar-13®) (N=138;72)
    0
    0
        Grade 3 Tenderness (3rd Prevenar-13®) (N=138;72)
    3
    0
        Grade 3 Erythema (Engerix-B®) (N=138;72)
    0
    0
        Grade 3 Induration (Engerix-B®) (N=137;72)
    0
    0
        Grade 3 Swelling (Engerix-B®) (N=138;71)
    0
    0
        Grade 3 Tenderness (Engerix-B®) (N=138;72)
    3
    0
    No statistical analyses for this end point

    Secondary: Number of subjects reporting Grade 3 solicited systemic AEs after receiving Bexsero® vaccine with routine vaccines or routine vaccines alone, at 2, 4 and 6 months of age

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    End point title
    		 Number of subjects reporting Grade 3 solicited systemic AEs after receiving Bexsero® vaccine with routine vaccines or routine vaccines alone, at 2, 4 and 6 months of age
    End point description
    The number of subjects who reported Grade 3 solicited systemic AEs following concomitant administration of Bexsero® vaccine with routine vaccines (Infanrix-IPV+Hib®, Prevenar-13® and Engerix-B®), as compared to when only routine vaccines were administered alone at 2, 4 and 6 months of age. Assessed solicited systemic symptoms were: Change in Eating Habits, Diarrhea, Irritability, Persistent Crying, Rash, Sleepiness and Vomiting. Grade 3 symptom = symptom that prevented normal activity. The analysis was performed on the Solicited Safety Set, which included all subjects in the Exposed population who provided post-vaccination reactogenicity data.
    End point type
    Secondary
    End point timeframe
    From Day 1 (6 hours) to Day 7 after each vaccination
    End point values
    		 Bexsero + Routine Group Routine Group
    Number of subjects analysed
    148
    73
    Units: Subjects
        Grade3 Change in Eating Habits(1st vacc)(N=148;73)
    0
    0
        Grade 3 Diarrhea (1st vacc.) (N=148;73)
    2
    1
        Grade 3 Irritability (1st vacc.) (N=148;73)
    3
    0
        Grade 3 Persistent Crying (1st vacc.) (N=148;73)
    5
    0
        Grade 3 Rash (1st vacc.) (N=148;73)
    0
    0
        Grade 3 Sleepiness (1st vacc.) (N=148;73)
    0
    1
        Grade 3 Vomiting (1st vacc.) (N=148;73)
    0
    0
        Grade3 Change in Eating Habits(2nd vacc)(N=140;72)
    2
    0
        Grade 3 Diarrhea (2nd vacc.) (N=140;72)
    1
    0
        Grade 3 Irritability (2nd vacc.) (N=140;72)
    3
    1
        Grade 3 Persistent Crying (2nd vacc.) (N=140;72)
    5
    0
        Grade 3 Rash (2nd vacc.) (N=140;72)
    0
    1
        Grade 3 Sleepiness (2nd vacc.) (N=140;72)
    0
    0
        Grade 3 Vomiting (2nd vacc.) (N=140;72)
    0
    0
        Grade3 Change in Eating Habits(3rd vacc)(N=138;72)
    1
    0
        Grade 3 Diarrhea (3rd vacc.) (N=138;72)
    0
    0
        Grade 3 Irritability (3rd vacc.) (N=138;72)
    3
    1
        Grade 3 Persistent Crying (3rd vacc.) (N=138;72)
    3
    0
        Grade 3 Rash (3rd vacc.) (N=138;72)
    1
    0
        Grade 3 Sleepiness (3rd vacc.) (N=138;72)
    0
    0
        Grade 3 Vomiting (3rd vacc.) (N=138;72)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects reporting Grade 3 solicited local AEs after receiving Bexsero® booster dose with routine vaccines, at 12 months of age

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    End point title
    		 Number of subjects reporting Grade 3 solicited local AEs after receiving Bexsero® booster dose with routine vaccines, at 12 months of age
    End point description
    The number of subjects who reported solicited local AEs following concomitant administration of Bexsero® dose with routine vaccines (Priorix® and Varilrix®), as compared to when only routine vaccines were administered alone, at 12 months of age. Assessed solicited local symptoms were: Erythema, Induration, Swelling and Tenderness. Grade 3 symptom = symptom that prevented normal activity. The analysis was performed on the Solicited Safety Set, which included all subjects in the Exposed population who provided post-vaccination reactogenicity data.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 7 after booster vaccination
    End point values
    		 Bexsero + Routine Group Routine Group
    Number of subjects analysed
    137
    72
    Units: Subjects
        Grade 3 Erythema (Bexsero® booster vacc.)(N=136;0)
    0
    0
        Grade3 Induration(Bexsero® booster vacc.)(N=136;0)
    0
    0
        Grade 3 Swelling (Bexsero® booster vacc.)(N=135;0)
    0
    0
        Grade3 Tenderness(Bexsero® booster vacc.)(N=136;0)
    6
    0
        Grade 3 Erythema (Priorix® vacc.) (N=137;72)
    0
    0
        Grade 3 Induration (Priorix® vacc.) (N=137;72)
    0
    0
        Grade 3 Swelling (Priorix® vacc.) (N=137;72)
    0
    0
        Grade 3 Tenderness (Priorix® vacc.) (N=137;72)
    3
    0
        Grade 3 Erythema (Varilrix® vacc.) (N=137;72)
    0
    0
        Grade 3 Induration (Varilrix® vacc.) (N=137;72)
    0
    0
        Grade 3 Swelling (Varilrix® vacc.) (N=137;72)
    0
    0
        Grade 3 Tenderness (Varilrix® vacc.) (N=137;72)
    3
    0
    No statistical analyses for this end point

    Secondary: Number of subjects reporting Grade 3 solicited systemic AEs after receiving Bexsero® booster dose with routine vaccines, at 12 months of age

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    End point title
    		 Number of subjects reporting Grade 3 solicited systemic AEs after receiving Bexsero® booster dose with routine vaccines, at 12 months of age
    End point description
    The number of subjects who reported Grade 3 solicited systemic AEs following concomitant administration of Bexsero® booster dose with routine vaccines (Priorix® and Varilrix®), as compared to when only routine vaccines were administered alone at 12 months of age. Assessed solicited systemic AEs were: Change in Eating Habits, Diarrhea, Irritability, Persistent Crying, Rash, Sleepiness and Vomiting. Grade 3 symptom = symptom that prevented normal activity. The analysis was performed on the Solicited Safety Set, which included all subjects in the Exposed population who provided post-vaccination reactogenicity data.
    End point type
    Secondary
    End point timeframe
    From Day 1 (6 hours) to Day 7 after booster vaccination
    End point values
    		 Bexsero + Routine Group Routine Group
    Number of subjects analysed
    137
    72
    Units: Subjects
        Grade 3 Change in Eating Habits (N=137;72)
    2
    1
        Grade 3 Diarrhea (N=137;72)
    1
    0
        Grade 3 Irritability (N=137;72)
    2
    0
        Grade 3 Persistent Crying (N=137;72)
    0
    1
        Grade 3 Rash (N=137;72)
    1
    0
        Grade 3 Sleepiness (N=137;72)
    0
    0
        Grade 3 Vomiting (N=137;72)
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited local and systemic symptoms: from Day 1 to Day 7 after each vaccination; Unsolicited AEs and SAEs: throughout the study period (from Day 1 to Day 335).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Bexsero + Routine Group
    Reporting group description
    		 Subjects received three doses of Bexsero® vaccine at 2, 4, 6 months followed by a booster dose at 12 months, concomitantly administered with routine vaccines (i.e. combined Infanrix-IPV+Hib® and Prevenar-13® at 2, 4, 6 months of age; Engerix-B® at 6 months of age; Priorix® and Varilrix® at 12 months of age.

    Reporting group title
    Routine Group
    Reporting group description
    		 Subjects received routine vaccines Infanrix-IPV+Hib® and Prevenar-13® at 2, 4, 6 months of age; Engerix-B® vaccine at 6 months; Priorix® and Varilrix® vaccines at 12 months of age.

    Serious adverse events
    		 Bexsero + Routine Group Routine Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 148 (8.78%)
    8 / 73 (10.96%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed [1]
    1 / 145 (0.69%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Kawasaki's disease
         subjects affected / exposed [2]
    0 / 145 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed [3]
    0 / 145 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed [4]
    1 / 145 (0.69%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed [5]
    0 / 145 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed [6]
    0 / 145 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed [7]
    3 / 145 (2.07%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed [8]
    4 / 145 (2.76%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed [9]
    1 / 145 (0.69%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand-foot-and-mouth disease
         subjects affected / exposed [10]
    2 / 145 (1.38%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed [11]
    1 / 145 (0.69%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed [12]
    1 / 145 (0.69%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed [13]
    1 / 145 (0.69%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed [14]
    1 / 145 (0.69%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Croup infectious
         subjects affected / exposed [15]
    0 / 145 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exanthema subitum
         subjects affected / exposed [16]
    1 / 145 (0.69%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed [17]
    1 / 145 (0.69%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed [18]
    1 / 145 (0.69%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed [19]
    0 / 145 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed [20]
    1 / 145 (0.69%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed [21]
    1 / 145 (0.69%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyuria
         subjects affected / exposed [22]
    1 / 145 (0.69%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed [23]
    0 / 145 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonella bacteraemia
         subjects affected / exposed [24]
    1 / 145 (0.69%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed [25]
    1 / 145 (0.69%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed [26]
    2 / 145 (1.38%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [11] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [12] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [13] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [14] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [15] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [16] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [17] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [18] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [19] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [20] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [21] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [22] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [23] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [24] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [25] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    [26] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed on the Exposed population, only on subjects with their symptom sheets completed.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bexsero + Routine Group Routine Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    148 / 148 (100.00%)
    72 / 73 (98.63%)
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    111 / 148 (75.00%)
    45 / 73 (61.64%)
         occurrences all number
    246
    84
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    134 / 148 (90.54%)
    52 / 73 (71.23%)
         occurrences all number
    357
    85
    Crying
         subjects affected / exposed
    124 / 148 (83.78%)
    50 / 73 (68.49%)
         occurrences all number
    337
    109
    Injection site erythema
         subjects affected / exposed
    113 / 148 (76.35%)
    35 / 73 (47.95%)
         occurrences all number
    285
    66
    Injection site pain
         subjects affected / exposed
    121 / 148 (81.76%)
    27 / 73 (36.99%)
         occurrences all number
    300
    47
    Injection site induration
         subjects affected / exposed
    105 / 148 (70.95%)
    39 / 73 (53.42%)
         occurrences all number
    370
    86
    Injection site swelling
         subjects affected / exposed
    89 / 148 (60.14%)
    24 / 73 (32.88%)
         occurrences all number
    238
    41
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    34 / 148 (22.97%)
    21 / 73 (28.77%)
         occurrences all number
    34
    21
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    72 / 148 (48.65%)
    28 / 73 (38.36%)
         occurrences all number
    134
    42
    Vomiting
         subjects affected / exposed
    45 / 148 (30.41%)
    16 / 73 (21.92%)
         occurrences all number
    67
    32
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 148 (6.76%)
    3 / 73 (4.11%)
         occurrences all number
    10
    3
    Rhinorrhoea
         subjects affected / exposed
    5 / 148 (3.38%)
    8 / 73 (10.96%)
         occurrences all number
    5
    12
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    72 / 148 (48.65%)
    30 / 73 (41.10%)
         occurrences all number
    136
    50
    Eczema
         subjects affected / exposed
    17 / 148 (11.49%)
    5 / 73 (6.85%)
         occurrences all number
    21
    5
    Dermatitis
         subjects affected / exposed
    15 / 148 (10.14%)
    4 / 73 (5.48%)
         occurrences all number
    16
    5
    Dermatitis atopic
         subjects affected / exposed
    8 / 148 (5.41%)
    5 / 73 (6.85%)
         occurrences all number
    9
    6
    Dermatitis diaper
         subjects affected / exposed
    7 / 148 (4.73%)
    6 / 73 (8.22%)
         occurrences all number
    8
    6
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    127 / 148 (85.81%)
    50 / 73 (68.49%)
         occurrences all number
    399
    121
    Eating disorder
         subjects affected / exposed
    125 / 148 (84.46%)
    43 / 73 (58.90%)
         occurrences all number
    335
    98
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    86 / 148 (58.11%)
    45 / 73 (61.64%)
         occurrences all number
    181
    105
    Upper respiratory tract infection
         subjects affected / exposed
    42 / 148 (28.38%)
    16 / 73 (21.92%)
         occurrences all number
    71
    30
    Gastroenteritis
         subjects affected / exposed
    14 / 148 (9.46%)
    13 / 73 (17.81%)
         occurrences all number
    19
    13
    Bronchiolitis
         subjects affected / exposed
    11 / 148 (7.43%)
    5 / 73 (6.85%)
         occurrences all number
    11
    5
    Exanthema subitum
         subjects affected / exposed
    10 / 148 (6.76%)
    6 / 73 (8.22%)
         occurrences all number
    10
    6
    Conjunctivitis
         subjects affected / exposed
    5 / 148 (3.38%)
    4 / 73 (5.48%)
         occurrences all number
    5
    4
    Pharyngitis
         subjects affected / exposed
    5 / 148 (3.38%)
    4 / 73 (5.48%)
         occurrences all number
    5
    4
    Tonsillitis
         subjects affected / exposed
    4 / 148 (2.70%)
    4 / 73 (5.48%)
         occurrences all number
    4
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jul 2013
    - Correction of omission; - Presentation of each commercially available routine vaccines has been changed into “as commercially available”; - A fourth dose of Prevenar-13 was included in the schedule treatment to complete the recommended dose schedule; - Other Secondary endpoints were added: The percentage of subjects with SBA titers ≥ 1:8 at baseline, one month after the third vaccination, at 12 months of age (prior to the booster dose) and at 13 months of age (one month after the booster dose) for each of the three indicator strains (H44/76, 5/99, NZ98/254) and strain M10713.
    05 Nov 2013
    - Exclusion criteria were modified; - Randomization method and stratification factors were clarified; - MMR and Varicella vaccines way of administration was better defined; - Timeframe for solicited data collection was corrected; - Description of statistical analysis for primary endpoint was modified.
    08 Jul 2014
    - Change of the legal entity responsible for the trial to Novartis Pharma Services AG; - The name of the serology manual was changed and protocol was updated with the new manual’s title; - Section 3.9 ”End of Study” was added to the protocol; - Exclusion criteria were modified to avoid extra clinic visit to the subjects; - Criteria for delay of vaccination and/or blood sampling was changed to avoid extra clinic visit to the subjects; - The extension of the period of observation for adverse events was better specified; - Blood pressure measurement was removed from the list of physical examination to be performed at clinical visit because it is not a routine practice in Taiwan to measure blood pressure of young children.
    14 Oct 2014
    - Inclusion criteria added; - The enrolment process was better specified in that the screening number assigned has to be assigned by the Investigator; - Correction of typo.

    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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