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    Clinical Trial Results:
    Immunogenicity and Safety Study of a Hexavalent DTaP-IPV-HB-Hib Combined Vaccine in a 3-dose Primary Series in Healthy Infants in Europe

    Summary
    EudraCT number
    2012-001055-39
    Trial protocol
    DE   CZ   ES  
    Global end of trial date
    27 Nov 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Apr 2016
    First version publication date
    21 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A3L39
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    U1111-1122-2329
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur SA
    Sponsor organisation address
    2, avenue Pont Pasteur, Lyon Cedex 07, France, F-69367
    Public contact
    Director, Clinical Development, Sanofi Pasteur SA, 33 (0)4 37 37 58 43, emmanuel.feroldi@sanofipasteur.com
    Scientific contact
    Director, Clinical Development, Sanofi Pasteur SA, 33 (0)4 37 37 58 43, emmanuel.feroldi@sanofipasteur.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000120-PIP01-11
    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
    10 Aug 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Groups 1 and 2 only To demonstrate the non-inferiority of the DTaP-IPV-HB-Hib vaccine to the control Infanrix hexa vaccine, both co-administered with Prevenar 13, in terms of seroprotection or vaccine response rates to PT, FHA, Hep B, and PRP antigens, 1 month after a 3-dose primary series.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were randomized and vaccinated in the study. Vaccinations were performed by qualified and trained study personnel. Subjects with allergy to any of the vaccine components were not vaccinated. After vaccination, subjects were also kept under clinical observation for 30 minutes to ensure their safety. Appropriate medical equipment was also available on site in case of any immediate allergic reactions.
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    21 Jan 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
    Spain: 265
    Country: Number of subjects enrolled
    Czech Republic: 276
    Country: Number of subjects enrolled
    Germany: 253
    Worldwide total number of subjects
    794
    EEA total number of subjects
    794
    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)
    794
    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
    The study subjects were enrolled from 21 January 2014 to 18 August 2014 at 25 clinic centers in Czech Republic, 12 in Spain, and 15 in Germany.

    Pre-assignment
    Screening details
    A total of 794 subjects who met all of the inclusion and none of the exclusion criteria were randomized and vaccinated in this study.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    This was an observer-blind study. The Investigator, subjects and parents, and Sponsor were blinded to vaccine treatment. To maintain the blind, the product preparation and administration, and the assessment of safety were performed by 2 different individuals in separate rooms. In the event of an emergency (i.e., serious adverse event) the code could be broken by the Investigator as explained in the code-breaking procedures outlined in the Operating Guidelines.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1
    Arm description
    Subjects received 3 doses of DTaP-IPV-HB-Hib vaccine coadministered with Prevenar 13 and RotaTeq, 1 injection each at 2, 3, and 4 months of age at the study sites in Germany and Czech Republic.
    Arm type
    Experimental

    Investigational medicinal product name
    DTap-IPV-HB-Hib combined vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular injection into the anterolateral area of the right thigh, 1 injection each at 2, 3, 4 months of age co-administered with Prevenar 13 and RotaTeq.

    Investigational medicinal product name
    Prevenar 13
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular into anterolateral area of the left thigh, 1 injection each at 2, 3, and 4 months co-administered with DTaP-IPV-HB-Hib and RotaTeq.

    Investigational medicinal product name
    RotaTeq
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    0.2 mL, oral route, 1 injection each at 2, 3, and 4 months co-administered with DTaP-IPV-HB-Hib and Prevenar 13.

    Arm title
    Group 2
    Arm description
    Subjects received 3 doses of Infanrix hexa co-administered with Prevenar 13 and RotaTeq, 1 injection each at 2, 3, and 4 months of age at the study sites in Germany and Czech Republic.
    Arm type
    Active comparator

    Investigational medicinal product name
    Infanrix hexa
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and suspension for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular into the anterolateral area of the right thigh, 1 injection each at 2, 3, and 4 months co-administered with Prevenar 13 and RotaTeq.

    Investigational medicinal product name
    Prevenar 13
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular into anterolateral area of the left thigh, 1 injection each at 2, 3, and 4 months co-administered with Infanrix hexa and RotaTeq.

    Investigational medicinal product name
    RotaTeq
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    0.2 mL, oral route, 1 injection each at 2, 3, and 4 months co-administered with Infanrix hexa and Prevenar 13.

    Arm title
    Group 3
    Arm description
    Subjects from the sites in Spain, they received 2 doses of DTaP-IPV-HB-Hib vaccine 1 injection each at 2 and 6 months of age and 1 dose of Pentavac at 4 months. DTaP-IPV-HB-Hib vaccine and Pentavac were co-administered with Prevenar 13 at 2 and 4 months of age and at 6 months (depending on local use and at the Investigator’s discretion), NeisVac-C at 2 months, and RotaTeq at 2, 4, and 6 months of age + Hep B vaccine at birth.
    Arm type
    Experimental

    Investigational medicinal product name
    DTap-IPV-HB-Hib combined vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular injection into the anterolateral area of the right thigh, 1 injection each at 2 and 6 months of age co-administered with Prevenar 13 and Pentavac.

    Investigational medicinal product name
    Prevenar 13
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular into anterolateral area of the left thigh, 1 injection each at 2 and 4 months co-administered with DTaP-IPV-HB-Hib and Pentavac.

    Investigational medicinal product name
    DTaP-IPV//PRP-T combined vaccine (Pentavac)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular into the anterolateral area of the right thigh, 1 injection each at 2 and 4 months co-administered with DTaP-IPV-HB-Hib vaccine and Prevenar 13.

    Investigational medicinal product name
    NeisVac-C
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular into the anterolateral area of the left thigh, 1 injection at 2 months of age.

    Investigational medicinal product name
    RotaTeq
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    0.2 mL, oral route, 1 administration each at 2, 4, and 6 months of age.

    Number of subjects in period 1
    Group 1 Group 2 Group 3
    Started
    266
    263
    265
    Completed
    265
    262
    263
    Not completed
    1
    1
    2
         Protocol deviation
             1
             -
             1
         Consent withdrawn by subject
             -
             1
             -
         Lost to follow-up
             -
             -
             1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1
    Reporting group description
    Subjects received 3 doses of DTaP-IPV-HB-Hib vaccine coadministered with Prevenar 13 and RotaTeq, 1 injection each at 2, 3, and 4 months of age at the study sites in Germany and Czech Republic.

    Reporting group title
    Group 2
    Reporting group description
    Subjects received 3 doses of Infanrix hexa co-administered with Prevenar 13 and RotaTeq, 1 injection each at 2, 3, and 4 months of age at the study sites in Germany and Czech Republic.

    Reporting group title
    Group 3
    Reporting group description
    Subjects from the sites in Spain, they received 2 doses of DTaP-IPV-HB-Hib vaccine 1 injection each at 2 and 6 months of age and 1 dose of Pentavac at 4 months. DTaP-IPV-HB-Hib vaccine and Pentavac were co-administered with Prevenar 13 at 2 and 4 months of age and at 6 months (depending on local use and at the Investigator’s discretion), NeisVac-C at 2 months, and RotaTeq at 2, 4, and 6 months of age + Hep B vaccine at birth.

    Reporting group values
    Group 1 Group 2 Group 3 Total
    Number of subjects
    266 263 265 794
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    266 263 265 794
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    0 0 0 0
        From 65-84 years
    0 0 0 0
        85 years and over
    0 0 0 0
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    63 ± 5.6 62.7 ± 5.4 62 ± 4.7 -
    Gender categorical
    Units: Subjects
        Female
    127 137 125 389
        Male
    139 126 140 405

    End points

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    End points reporting groups
    Reporting group title
    Group 1
    Reporting group description
    Subjects received 3 doses of DTaP-IPV-HB-Hib vaccine coadministered with Prevenar 13 and RotaTeq, 1 injection each at 2, 3, and 4 months of age at the study sites in Germany and Czech Republic.

    Reporting group title
    Group 2
    Reporting group description
    Subjects received 3 doses of Infanrix hexa co-administered with Prevenar 13 and RotaTeq, 1 injection each at 2, 3, and 4 months of age at the study sites in Germany and Czech Republic.

    Reporting group title
    Group 3
    Reporting group description
    Subjects from the sites in Spain, they received 2 doses of DTaP-IPV-HB-Hib vaccine 1 injection each at 2 and 6 months of age and 1 dose of Pentavac at 4 months. DTaP-IPV-HB-Hib vaccine and Pentavac were co-administered with Prevenar 13 at 2 and 4 months of age and at 6 months (depending on local use and at the Investigator’s discretion), NeisVac-C at 2 months, and RotaTeq at 2, 4, and 6 months of age + Hep B vaccine at birth.

    Primary: Seroprotection or Response to Pertussis toxoid, Filamentous hemagglutinin, Hepatitis B and Hib Polysaccharide Antigens After Vaccinations with Hexavalent DTaP-IPV-Hep B-PRP-T Combined Vaccine or Infanrix hexa™ Concomitantly Administered With Prevenar®13

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    End point title
    Seroprotection or Response to Pertussis toxoid, Filamentous hemagglutinin, Hepatitis B and Hib Polysaccharide Antigens After Vaccinations with Hexavalent DTaP-IPV-Hep B-PRP-T Combined Vaccine or Infanrix hexa™ Concomitantly Administered With Prevenar®13 [1]
    End point description
    End point was assessed in Groups 1 and 2. Anti-Pertussis toxoid (PT) and anti-Filamentous hemagglutinin (FHA) antibodies were measured by enzyme-linked immunosorbent assay (ELISA). Anti-Hepatitis B (Hep B) antibodies were measured by the commercially available VITROS ECi/ECiQ Immunodiagnostic System using chemiluminescence detection technology. Anti-Hib polysaccharide (PRP) concentrations were measured using a Farr-type radioimmunoassay (RIA). Seroprotection was defined as anti-Hep B antibody concentrations ≥ 10 mIU/mL and anti-PRP antibody concentrations ≥ 0.15 µg/mL. Vaccine response for PT and FHA were defined as follows: Post-dose 3 antibody concentrations ≥ 4X lower limit of quantitation (LLOQ), if Pre-dose 1 antibody concentrations < 4X LLOQ; Post-dose 3 antibody concentrations ≥ Pre-dose 1 antibody concentrations, if Pre-dose 1 antibody concentrations ≥ 4X LLOQ.
    End point type
    Primary
    End point timeframe
    1 month post-dose 3
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    Group 1 Group 2
    Number of subjects analysed
    237
    239
    Units: Percentage of subjects
    number (not applicable)
        Anti-PT
    98.3
    97.8
        Anti-FHA
    99.1
    94.8
        Anti-Hep B
    95.7
    98.7
        Anti-PRP
    91.1
    86.3
    Statistical analysis title
    Non-inferiority (Group 1 - Group 2); Anti-PT
    Statistical analysis description
    Non-inferiority analysis of seroprotection, vaccine response rates of DTaP-IPV-HB-Hib vs Infanrix hexa.
    Comparison groups
    Group 1 v Group 2
    Number of subjects included in analysis
    476
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    Method
    Parameter type
    Vaccine response (Group 1 - Group 2)
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.51
         upper limit
    3.44
    Notes
    [2] - The 95% confidence interval (CI) was calculated based on the Wilson score method without continuity correction. If the lower bound of the 95% CI was greater than - δ then the null hypothesis H0 was rejected and non-inferiority would be concluded. In this analysis, DTaP-IPV-HB-Hib vaccine was non-inferior to Infanrix hexa vaccine.
    Statistical analysis title
    Non-inferiority (Group 1 - Group 2); Anti-FHA
    Statistical analysis description
    Non-inferiority analysis of seroprotection, vaccine response rates of DTaP-IPV-HB-Hib vs Infanrix hexa.
    Comparison groups
    Group 1 v Group 2
    Number of subjects included in analysis
    476
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [3]
    Method
    Parameter type
    Vaccine response (Group 1 - Group 2)
    Point estimate
    4.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.23
         upper limit
    8.12
    Notes
    [3] - The 95% confidence interval (CI) was calculated based on the Wilson score method without continuity correction. If the lower bound of the 95% CI was greater than - δ then the null hypothesis H0 was rejected and non-inferiority would be concluded. In this analysis, DTaP-IPV-HB-Hib vaccine was non-inferior to Infanrix hexa vaccine.
    Statistical analysis title
    Non-inferiority (Group 1 - Group 2); Anti-Hep B
    Statistical analysis description
    Non-inferiority analysis of seroprotection, vaccine response rates of DTaP-IPV-HB-Hib vs Infanrix hexa.
    Comparison groups
    Group 1 v Group 2
    Number of subjects included in analysis
    476
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [4]
    Method
    Parameter type
    Seroprotection (Group 1 - Group 2)
    Point estimate
    -3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.59
         upper limit
    0.11
    Notes
    [4] - The 95% confidence interval (CI) was calculated based on the Wilson score method without continuity correction. If the lower bound of the 95% CI was greater than - δ then the null hypothesis H0 was rejected and non-inferiority would be concluded. In this analysis, DTaP-IPV-HB-Hib vaccine was non-inferior to Infanrix hexa vaccine.
    Statistical analysis title
    Non-inferiority (Group 1 - Group 2); Anti-PRP
    Statistical analysis description
    Non-inferiority analysis of seroprotection, vaccine response rates of DTaP-IPV-HB-Hib vs Infanrix hexa.
    Comparison groups
    Group 1 v Group 2
    Number of subjects included in analysis
    476
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [5]
    Method
    Parameter type
    Seroprotection (Group 1 - Group 2)
    Point estimate
    4.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.12
         upper limit
    10.74
    Notes
    [5] - The 95% confidence interval (CI) was calculated based on the Wilson score method without continuity correction. If the lower bound of the 95% CI was greater than - δ then the null hypothesis H0 was rejected and non-inferiority would be concluded. In this analysis, DTaP-IPV-HB-Hib vaccine was non-inferior to Infanrix hexa vaccine.

    Secondary: Summary of Vaccine Antibody Titers Before and After Dose 3 Vaccinations with Hexavalent DTaP-IPV-Hep B-PRP-T Combined Vaccine or Infanrix hexa™ Concomitantly Administered With Prevenar®13

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    End point title
    Summary of Vaccine Antibody Titers Before and After Dose 3 Vaccinations with Hexavalent DTaP-IPV-Hep B-PRP-T Combined Vaccine or Infanrix hexa™ Concomitantly Administered With Prevenar®13
    End point description
    Anti-Tetanus antibodies were measured by enzyme-linked immunosorbent assay. Anti-Diphtheria antibodies were measured by a toxin neutralization test. Anti-Hepatitis B (Hep B) antibodies were measured by VITROS ECi/ECiQ Immunodiagnostic System. Anti-Poliovirus types 1, 2, and 3 were measured by neutralization assay. Anti-Hib polysaccharide (PRP) concentrations were measured using a Farr-type radioimmunoassay. Anti-Diphtheria and anti-Tetanus titers were assessed ≥ 0.01 IU/mL, ≥ 0.1 IU/mL, and ≥ 1.0 IU/mL. Vaccine response was anti-PT or anti-FHA concentrations in EU/mL ≥4x LLOQ if pre-vaccination concentration < 4x LLOQ or ≥ pre-vaccination concentration if pre-vaccination concentrations ≥ 4x LLOQ. Anti-Polio 1, 2, and 3 titers were assessed ≥ 8 (1/dil). Anti-Hep B titers were assessed ≥ 10 mIU/mL. Anti-PRP titers were assessed ≥ 0.15 µg/mL. Pre-dose 1 values were not available for Anti-Diphtheria, Anti-Tetanus, Anti-Polio 1, 2, 3, Anti-Hep B, and Anti-PRP for Groups 1 and 2.
    End point type
    Secondary
    End point timeframe
    Pre- and Post-dose 3
    End point values
    Group 1 Group 2 Group 3
    Number of subjects analysed
    231
    231
    231
    Units: Percentage of subjects
    number (not applicable)
        Anti-Diphtheria; ≥ 0.01 IU/mL; Pre-dose 1
    0
    0
    60.8
        Anti-Diphtheria; ≥ 0.01 IU/mL; Post-dose 3
    100
    100
    100
        Anti-Diphtheria; ≥ 0.1 IU/mL; Pre-dose 1
    0
    0
    11.1
        Anti-Diphtheria; ≥ 0.1 IU/mL; Post-dose 3
    61.8
    58
    97.6
        Anti-Tetanus; ≥ 0.01 IU/mL; Pre-dose 1
    0
    0
    96.4
        Anti-Tetanus; ≥ 0.01 IU/mL; Post-dose 3
    100
    100
    100
        Anti-Tetanus; ≥ 0.1 IU/mL; Pre-dose 1
    0
    0
    85.5
        Anti-Tetanus; ≥ 0.1 IU/mL; Post-dose 3
    100
    100
    100
        Anti-PT; ≥LLOQ; Pre-dose 1
    63.1
    66.1
    63.1
        Anti-PT; ≥4 EU/mL; Post-dose 3
    100
    100
    100
        Anti-FHA; ≥LLOQ; Pre-dose 1
    91.9
    89.8
    89.2
        Anti-FHA; ≥4 EU/mL; Post-dose 3
    100
    100
    100
        Anti-Polio 1; ≥ 8 (1/dil); Pre-dose 1
    0
    0
    46.8
        Anti-Polio 1; ≥ 8 (1/dil); Post-dose 3
    100
    100
    100
        Anti-Polio 2; ≥ 8 (1/dil); Pre-dose 1
    0
    0
    56.7
        Anti-Polio 2; ≥ 8 (1/dil); Post-dose 3
    100
    100
    99.5
        Anti-Polio 3; ≥ 8 (1/dil); Pre-dose 1
    0
    0
    21.2
        Anti-Polio 3; ≥ 8 (1/dil); Post-dose 3
    100
    100
    100
        Anti-Hep B; ≥ 10 mIU/mL; Pre-dose 1
    0
    0
    39
        Anti-Hep B; ≥ 10 mIU/mL; Post-dose 3
    95.7
    98.7
    99.1
        Anti-PRP; ≥ 15 µg/mL; Pre-dose 1
    0
    0
    32.2
        Anti-PRP; ≥ 15 µg/mL; Post-dose 3
    91.1
    86.3
    100
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers (GMTs) of Antibodies Against Vaccine Antigens Following Vaccinations with Hexavalent DTaP-IPV-Hep B-PRP-T Combined Vaccine or Infanrix hexa™ Concomitantly Administered With Prevenar®13

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    End point title
    Geometric Mean Titers (GMTs) of Antibodies Against Vaccine Antigens Following Vaccinations with Hexavalent DTaP-IPV-Hep B-PRP-T Combined Vaccine or Infanrix hexa™ Concomitantly Administered With Prevenar®13
    End point description
    Anti-Pertussis toxoid (PT), anti-Filamentous hemagglutinin (FHA), and anti-Tetanus antibodies were measured by enzyme-linked immunosorbent assay (ELISA). Anti-Diphtheria antibodies were measured by a toxin neutralization test. Anti-Hepatitis B (Hep B) antibodies were measured by the commercially available VITROS ECi/ECiQ Immunodiagnostic System using chemiluminescence detection technology. Anti-Poliovirus types 1, 2, and 3 were measured by neutralization assay. Anti-Hib polysaccharide (PRP) concentrations were measured using a Farr-type radioimmunoassay (RIA).
    End point type
    Secondary
    End point timeframe
    Post-dose 3
    End point values
    Group 1 Group 2 Group 3
    Number of subjects analysed
    235
    236
    227
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Anti-Diphtheria
    0.163 (0.142 to 0.187)
    0.148 (0.13 to 0.169)
    0.79 (0.694 to 0.898)
        Anti-Tetanus
    0.759 (0.689 to 0.836)
    0.874 (0.791 to 0.965)
    2.21 (2 to 2.44)
        Anti-Pertussis toxoid
    116 (108 to 124)
    131 (121 to 141)
    97.1 (89.9 to 105)
        Anti-Filamentous hemagglutinin
    141 (131 to 151)
    84.3 (78 to 91)
    165 (153 to 178)
        Anti-Polio 1
    113 (96.7 to 133)
    268 (226 to 317)
    891 (760 to 1044)
        Anti-Polio 2
    191 (163 to 225)
    365 (305 to 437)
    2027 (1669 to 2462)
        Anti-Polio 3
    302 (261 to 351)
    662 (552 to 793)
    1485 (1243 to 1775)
        Anti-Hepatitis B
    207 (170 to 253)
    382 (324 to 450)
    2719 (2272 to 3255)
        Anti-PRP
    1.19 (0.978 to 1.45)
    0.6 (0.505 to 0.713)
    7.91 (6.75 to 9.27)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Immune Responses to Prevenar 13 and RotaTeq Antigens Following Co-administration with Hexavalent DTaP-IPV-Hep B-PRP-T Combined Vaccine or Infanrix hexa™

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    End point title
    Percentage of Subjects with Immune Responses to Prevenar 13 and RotaTeq Antigens Following Co-administration with Hexavalent DTaP-IPV-Hep B-PRP-T Combined Vaccine or Infanrix hexa™ [6]
    End point description
    Anti-rotavirus IgA antibodies in human serum was measured by enzyme-linked immunosorbent assay (ELISA). The pneumococcal capsular polysaccharide (PS) IgG ELISA was used to quantitate the amount of anti-streptococcus pneumonia PS (serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) antibodies in human serum. Immune responses were defined as Anti-rotavirus IgA ≥ 20 U/mL and for all pneumococcal serotypes ≥ 0.35 µg/mL.
    End point type
    Secondary
    End point timeframe
    Pre-dose 1 (Anti-RV IgA) and post-dose 3 (for Anti-RV IgA and all pneumococcal serotypes)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    Group 1 Group 2
    Number of subjects analysed
    234
    237
    Units: Percentage of subjects
    number (not applicable)
        Anti-Rotavirus IgA; Pre-dose 1
    0.9
    2.5
        Anti-Rotavirus IgA; Post-dose 3
    92.5
    89.5
        Pneumococcal Serotype 1; Post-dose 3
    99.1
    99.1
        Pneumococcal Serotype 3; Post-dose 3
    95.2
    96.8
        Pneumococcal Serotype 4; Post-dose 3
    98.6
    99.1
        Pneumococcal Serotype 5; Post-dose 3
    87
    95.4
        Pneumococcal Serotype 6A; Post-dose 3
    93.1
    93.2
        Pneumococcal Serotype 6B; Post-dose 3
    77
    86.4
        Pneumococcal Serotype 7F; Post-dose 3
    100
    100
        Pneumococcal Serotype 9V; Post-dose 3
    95.8
    97.7
        Pneumococcal Serotype 14; Post-dose 3
    99.5
    100
        Pneumococcal Serotype 18C; Post-dose 3
    98.6
    97.7
        Pneumococcal Serotype 19A; Post-dose 3
    99.1
    99.5
        Pneumococcal Serotype 19F; Post-dose 3
    100
    100
        Pneumococcal Serotype 23F; Post-dose 3
    92.6
    95
    No statistical analyses for this end point

    Secondary: Geometric Mean Concentrations (GMCs) of Prevenar and RotaTeq Vaccine Antibodies Following Co-administration with Hexavalent DTaP-IPV-Hep B-PRP-T Combined Vaccine or Infanrix hexa™

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    End point title
    Geometric Mean Concentrations (GMCs) of Prevenar and RotaTeq Vaccine Antibodies Following Co-administration with Hexavalent DTaP-IPV-Hep B-PRP-T Combined Vaccine or Infanrix hexa™ [7]
    End point description
    Anti-rotavirus IgA antibodies in human serum was measured by enzyme-linked immunosorbent assay (ELISA). The pneumococcal capsular polysaccharide (PS) IgG ELISA was used to quantitate the amount of anti-streptococcus pneumonia PS (serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) antibodies in human serum.
    End point type
    Secondary
    End point timeframe
    Post-dose 3
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    Group 1 Group 2
    Number of subjects analysed
    217
    220
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Anti-Rotavirus
    455 (350 to 593)
    322 (250 to 415)
        Pneumococcal Serotype 1
    1.84 (1.67 to 2.03)
    2.33 (2.12 to 2.57)
        Pneumococcal Serotype 3
    1.09 (0.995 to 1.19)
    1.33 (1.22 to 1.44)
        Pneumococcal Serotype 4
    2.06 (1.9 to 2.25)
    2.76 (2.52 to 3.03)
        Pneumococcal Serotype 5
    0.777 (0.704 to 0.858)
    0.996 (0.913 to 1.09)
        Pneumococcal Serotype 6A
    1.4 (1.24 to 1.58)
    1.67 (1.49 to 1.88)
        Pneumococcal Serotype 6B
    0.762 (0.662 to 0.877)
    1.09 (0.948 to 1.26)
        Pneumococcal Serotype 7F
    2.46 (2.26 to 2.69)
    2.89 (2.65 to 3.16)
        Pneumococcal Serotype 9V
    1.16 (1.06 to 1.27)
    1.46 (1.34 to 1.59)
        Pneumococcal Serotype 14
    6.78 (5.91 to 7.77)
    9.34 (8.36 to 10.4)
        Pneumococcal Serotype 18C
    1.62 (1.47 to 1.78)
    2.03 (1.84 to 2.24)
        Pneumococcal Serotype 19A
    3.3 (2.99 to 3.64)
    4.01 (3.63 to 4.43)
        Pneumococcal Serotype 19F
    3.19 (2.95 to 3.45)
    4.05 (3.74 to 4.39)
        Pneumococcal Serotype 23F
    1.33 (1.18 to 1.52)
    1.61 (1.42 to 1.83)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting Solicited Injection-site or Systemic Reaction After Any Vaccination with Hexavalent DTaP-IPV-Hep B-PRP-T Combined Vaccine or Infanrix hexa™ Concomitantly Administered With Prevenar®13

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    End point title
    Percentage of Subjects Reporting Solicited Injection-site or Systemic Reaction After Any Vaccination with Hexavalent DTaP-IPV-Hep B-PRP-T Combined Vaccine or Infanrix hexa™ Concomitantly Administered With Prevenar®13
    End point description
    Solicited injection site reactions: Pain (Tenderness), Erythema, and Swelling. Solicited systemic reactions: Pyrexia (Fever), Vomiting, Crying, Somnolence (Drowsiness), Anorexia (Appetite lost), and Irritability. Grade 3 Solicited injection site reactions: Pain, Cries when injected limb is moved or the movement of the injected limb is reduced; Erythema and Swelling, ≥ 50 mm. Grade 3 Solicited systemic reactions: Pyrexia (Fever), > 39.5°C; Vomiting, ≥ 6 episodes per 24 hours or requiring parenteral hydration; Crying abnormal, > 3 hours; Somnolence (Drowsiness), Sleeping most of the time or difficult to wake up; Appetite lost (Anorexia), Refuses ≥ 3 feeds/meals or refuses most feeds/meals; Irritability, Inconsolable.
    End point type
    Secondary
    End point timeframe
    Day 0 up to Day 7 post-any injection
    End point values
    Group 1 Group 2 Group 3
    Number of subjects analysed
    265
    261
    265
    Units: Percentage of subjects
    number (not applicable)
        Injection site Pain
    67.5
    67.8
    65.7
        Grade 3 Injection site Pain
    8.7
    6.9
    6
        Injection site Erythema
    61.5
    57.5
    43
        Grade 3 Injection site Erythema
    2.3
    1.1
    0.8
        Injection site Swelling
    48.7
    46
    32.1
        Grade 3 Injection site Swelling
    1.9
    1.9
    0.4
        Pyrexia
    72.8
    56.7
    58.9
        Grade 3 Pyrexia
    3
    1.1
    1.9
        Vomiting
    35.5
    27.6
    35.5
        Grade 3 Vomiting
    1.1
    0.8
    0.8
        Crying abnormal
    76.6
    74.3
    76.6
        Grade 3 Crying abnormal
    9.1
    8
    7.9
        Somnolence
    73.6
    70.1
    72.8
        Grade 3 Somnolence
    3.4
    1.5
    4.9
        Anorexia
    55.8
    48.7
    64.5
        Grade 3 Anorexia
    2.3
    1.9
    1.1
        Irritability
    78.9
    75.9
    83.8
        Grade 3 Irritability
    9.8
    8
    9.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting Solicited Injection-site or Systemic Reaction After Each Vaccinations with Hexavalent DTaP-IPV-Hep B-PRP-T Combined Vaccine or Infanrix hexa™ Concomitantly Administered With Prevenar®13

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    End point title
    Percentage of Subjects Reporting Solicited Injection-site or Systemic Reaction After Each Vaccinations with Hexavalent DTaP-IPV-Hep B-PRP-T Combined Vaccine or Infanrix hexa™ Concomitantly Administered With Prevenar®13
    End point description
    Solicited injection site reactions: Pain (Tenderness), Erythema, and Swelling. Solicited systemic reactions: Pyrexia (Fever), Vomiting, Crying, Somnolence (Drowsiness), Anorexia (Appetite lost), and Irritability. Grade 3 Solicited injection site reactions: Pain, Cries when injected limb is moved or the movement of the injected limb is reduced; Erythema and Swelling, ≥ 50 mm. Grade 3 Solicited systemic reactions: Pyrexia (Fever), > 39.5°C; Vomiting, ≥ 6 episodes per 24 hours or requiring parenteral hydration; Crying abnormal, > 3 hours; Somnolence (Drowsiness), Sleeping most of the time or difficult to wake up; Appetite lost (Anorexia), Refuses ≥ 3 feeds/meals or refuses most feeds/meals; Irritability, Inconsolable.
    End point type
    Secondary
    End point timeframe
    Day 0 up to Day 7 post-each injection
    End point values
    Group 1 Group 2 Group 3
    Number of subjects analysed
    265
    261
    265
    Units: Percentage of subjects
    number (not applicable)
        Injection site Pain; DTaP-IPV-HB-Hib site
    63.8
    0
    0
        Injection site Pain; DTaP-IPV-HB-Hib/Pentavac
    0
    0
    62.6
        Injection site Pain; Prevenar 13
    61.5
    60.5
    56.6
        Injection site Pain; Infanrix hexa
    0
    62.1
    0
        Inj. site Pain, Post-Inj. 1; DTaP-IPV-HB-Hib site
    44.5
    0
    0
        Pain, Post-Inj. 1; DTaP-IPV-HB-Hib/Pentavac
    0
    0
    49.8
        Pain, Post-Inj. 1; Prevenar 13
    42.3
    45.6
    46.4
        Pain, Post-Inj. 1; Infanrix hexa
    0
    46.4
    0
        Inj. site Pain, Post-Inj. 2; DTaP-IPV-HB-Hib site
    45.7
    0
    0
        Pain, Post-Inj. 2; DTaP-IPV-HB-Hib/Pentavac
    0
    0
    31.4
        Pain, Post-Inj. 2; Prevenar 13
    43.4
    39.1
    27.3
        Pain, Post-Inj. 2; Infanrix hexa
    0
    39.8
    0
        Inj. site Pain, Post-Inj. 3; DTaP-IPV-HB-Hib site
    33.7
    0
    0
        Pain, Post-Inj. 3; DTaP-IPV-HB-Hib/Pentavac
    0
    0
    35
        Pain, Post-Inj. 3; Prevenar 13
    32.2
    32.6
    31.8
        Pain, Post-Inj. 3; Infanrix hexa
    0
    37.5
    0
        Injection site Erythema; DTaP-IPV-HB-Hib site
    55.1
    0
    0
        Injection site Erythema; DTaP-IPV-HB-Hib/Pentavac
    0
    0
    37.4
        Injection site Erythema; Prevenar 13
    50.2
    46.7
    26.4
        Injection site Erythema; Infanrix hexa
    0
    48.3
    0
        Inj. site Erythema, Post-Inj. 1; DTaP-IPV-HB-Hib
    28.3
    0
    0
        Erythema, Post-Inj. 1; DTaP-IPV-HB-Hib/Pentavac
    0
    0
    14.7
        Erythema, Post-Inj. 1; Prevenar 13
    27.5
    23.8
    9.8
        Erythema, Post-Inj. 1; Infanrix hexa
    0
    24.1
    0
        Inj. site Erythema, Post-Inj. 2; DTaP-IPV-HB-Hib
    39.6
    0
    0
        Erythema, Post-Inj. 2; DTaP-IPV-HB-Hib/Pentavac
    0
    0
    16.3
        Erythema, Post-Inj. 2; Prevenar 13
    30.2
    29.5
    12.1
        Erythema, Post-Inj. 2; Infanrix hexa
    0
    33.7
    0
        Inj. site Erythema, Post-Inj. 3; DTaP-IPV-HB-Hib
    38.3
    0
    0
        Erythema, Post-Inj. 3; DTaP-IPV-HB-Hib/Pentavac
    0
    0
    20.9
        Erythema, Post-Inj. 3; Prevenar 13
    31.1
    28.4
    13.7
        Erythema, Post-Inj. 3; Infanrix hexa
    0
    31
    0
        Injection site Swelling; DTaP-IPV-HB-Hib site
    42.6
    0
    0
        Injection site Swelling; DTaP-IPV-HB-Hib/Pentavac
    0
    0
    26.8
        Injection site Swelling; Prevenar 13
    38.9
    36
    21.5
        Injection site Swelling; Infanrix hexa
    0
    38.3
    0
        Inj. site Swelling, Post-Inj. 1; DTaP-IPV-HB-Hib
    21.5
    0
    0
        Swelling, Post-Inj. 1; DTaP-IPV-HB-Hib/Pentavac
    0
    0
    15.1
        Swelling, Post-Inj. 1; Prevenar 13
    22.3
    18.4
    11.7
        Swelling, Post-Inj. 1; Infanrix hexa
    0
    17.6
    0
        Inj. site Swelling, Post-Inj. 2; DTaP-IPV-HB-Hib
    25.7
    0
    0
        Swelling, Post-Inj. 2; DTaP-IPV-HB-Hib/Pentavac
    0
    0
    11
        Swelling, Post-Inj. 2; Prevenar 13
    21.9
    21.5
    9.8
        Swelling, Post-Inj. 2; Infanrix hexa
    0
    19.9
    0
        Inj. site Swelling, Post-Inj. 3; DTaP-IPV-HB-Hib
    25.8
    0
    0
        Swelling, Post-Inj. 3; DTaP-IPV-HB-Hib/Pentavac
    0
    0
    13.3
        Swelling, Post-Inj. 3; Prevenar 13
    20.1
    23
    9
        Swelling, Post-Inj. 3; Infanrix hexa
    0
    25.7
    0
        Pyrexia
    72.8
    56.7
    58.9
        Pyrexia; Post-Injection 1
    54
    29.6
    34.1
        Pyrexia; Post-Injection 2
    51.7
    39.5
    24.6
        Pyrexia; Post-Injection 3
    30
    26.4
    40.1
        Vomiting
    35.5
    27.6
    35.5
        Vomiting; Post-Injection 1
    23
    13.4
    20
        Vomiting; Post-Injection 2
    18.5
    14.9
    12.5
        Vomiting; Post-Injection 3
    14.8
    9.6
    17.1
        Crying abnormal
    76.6
    74.3
    76.6
        Crying abnormal; Post-Injection 1
    59.6
    52.5
    57.4
        Crying abnormal; Post-Injection 2
    60.4
    52.9
    51.1
        Crying abnormal; Post-Injection 3
    39.8
    38.3
    49.8
        Somnolence
    73.6
    70.1
    72.8
        Somnolence; Post-Injection 1
    60.4
    54.8
    56.2
        Somnolence; Post-Injection 2
    49.1
    45.6
    43.9
        Somnolence; Post-Injection 3
    39.8
    34.1
    36.1
        Anorexia
    55.8
    48.7
    64.5
        Anorexia; Post-Injection 1
    39.6
    32.2
    49.1
        Anorexia; Post-Injection 2
    33.6
    25.3
    35.6
        Anorexia; Post-Injection 3
    23.9
    18.4
    36.9
        Irritability
    78.9
    75.9
    83.8
        Irritability; Post-Injection 1
    64.9
    55.6
    70.6
        Irritability; Post-Injection 2
    59.6
    51.3
    62.9
        Irritability; Post-Injection 3
    46.2
    44.8
    59.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data were collected from Day 0 up to Day 30 post-each vaccination.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12
    Reporting groups
    Reporting group title
    Group 1
    Reporting group description
    Subjects received 3 doses of DTaP-IPV-HB-Hib vaccine coadministered with Prevenar 13 and RotaTeq at 2, 3, and 4 months of age.

    Reporting group title
    Group 2
    Reporting group description
    Subjects received 3 doses of Infanrix hexa co-administered with Prevenar 13 and RotaTeq at 2, 3, and 4 months of age.

    Reporting group title
    Group 3
    Reporting group description
    Subjects received 2 doses of DTaP-IPV-HB-Hib vaccine at 2 and 6 months of age and 1 dose of Pentavac at 4 months. DTaP-IPV-HB-Hib vaccine and Pentavac were co-administered with Prevenar 13 at 2 and 4 months of age and at 6 months (depending on local use and at the Investigator’s discretion), NeisVac-C at 2 months, and RotaTeq at 2, 4, and 6 months of age.

    Serious adverse events
    Group 1 Group 2 Group 3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 265 (4.53%)
    9 / 261 (3.45%)
    11 / 265 (4.15%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 261 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    2 / 265 (0.75%)
    1 / 261 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 265 (0.00%)
    0 / 261 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain neoplasm
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 261 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemangioma
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 261 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cyanosis
         subjects affected / exposed
    0 / 265 (0.00%)
    0 / 261 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Coarctation of the aorta
         subjects affected / exposed
    0 / 265 (0.00%)
    0 / 261 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip dysplasia
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 261 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 261 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myoclonus
         subjects affected / exposed
    0 / 265 (0.00%)
    0 / 261 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Restlessness
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 261 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 261 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia strangulated
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 261 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diet refusal
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 261 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight gain poor
         subjects affected / exposed
    0 / 265 (0.00%)
    0 / 261 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    0 / 265 (0.00%)
    0 / 261 (0.00%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 265 (0.75%)
    1 / 261 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 265 (0.00%)
    0 / 261 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Exanthema subitum
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 261 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 261 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 261 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 261 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 261 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 261 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 261 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 265 (0.00%)
    0 / 261 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 265 (0.00%)
    0 / 261 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Group 1 Group 2 Group 3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    209 / 265 (78.87%)
    198 / 261 (75.86%)
    222 / 265 (83.77%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    34 / 265 (12.83%)
    22 / 261 (8.43%)
    12 / 265 (4.53%)
         occurrences all number
    45
    24
    13
    Nervous system disorders
    Any Somnolence
    alternative assessment type: Systematic
         subjects affected / exposed
    195 / 265 (73.58%)
    183 / 261 (70.11%)
    193 / 265 (72.83%)
         occurrences all number
    395
    351
    360
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    3 / 265 (1.13%)
    12 / 261 (4.60%)
    15 / 265 (5.66%)
         occurrences all number
    4
    14
    16
    General disorders and administration site conditions
    Any Injection site Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    179 / 265 (67.55%)
    177 / 261 (67.82%)
    174 / 265 (65.66%)
         occurrences all number
    640
    629
    583
    Any Injection site Erythema
    alternative assessment type: Systematic
         subjects affected / exposed
    163 / 265 (61.51%)
    150 / 261 (57.47%)
    114 / 265 (43.02%)
         occurrences all number
    516
    445
    230
    Any Injection site Swelling
    alternative assessment type: Systematic
         subjects affected / exposed
    129 / 265 (48.68%)
    120 / 261 (45.98%)
    85 / 265 (32.08%)
         occurrences all number
    363
    329
    184
    Any Pyrexia
    alternative assessment type: Systematic
         subjects affected / exposed
    193 / 265 (72.83%)
    148 / 261 (56.70%)
    156 / 265 (58.87%)
         occurrences all number
    359
    249
    260
    Psychiatric disorders
    Any Crying abnormal
    alternative assessment type: Systematic
         subjects affected / exposed
    203 / 265 (76.60%)
    194 / 261 (74.33%)
    203 / 265 (76.60%)
         occurrences all number
    423
    375
    418
    Any Irritability
    alternative assessment type: Systematic
         subjects affected / exposed
    209 / 265 (78.87%)
    198 / 261 (75.86%)
    222 / 265 (83.77%)
         occurrences all number
    452
    396
    509
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 265 (0.75%)
    2 / 261 (0.77%)
    17 / 265 (6.42%)
         occurrences all number
    2
    2
    18
    Any Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed
    94 / 265 (35.47%)
    72 / 261 (27.59%)
    94 / 265 (35.47%)
         occurrences all number
    149
    99
    131
    Metabolism and nutrition disorders
    Any Anorexia
    alternative assessment type: Systematic
         subjects affected / exposed
    148 / 265 (55.85%)
    127 / 261 (48.66%)
    171 / 265 (64.53%)
         occurrences all number
    257
    198
    321
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 265 (3.02%)
    15 / 261 (5.75%)
    20 / 265 (7.55%)
         occurrences all number
    10
    16
    24
    Respiratory tract infection
         subjects affected / exposed
    4 / 265 (1.51%)
    4 / 261 (1.53%)
    22 / 265 (8.30%)
         occurrences all number
    4
    4
    24
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 265 (0.00%)
    0 / 261 (0.00%)
    20 / 265 (7.55%)
         occurrences all number
    0
    0
    22
    Rhinitis
         subjects affected / exposed
    24 / 265 (9.06%)
    13 / 261 (4.98%)
    1 / 265 (0.38%)
         occurrences all number
    24
    16
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Dec 2013
    Administration of a third dose of pneumococcal conjugate vaccine (Prevenar 13) was added as optional based on local use and at the Investigator's discretion, immune response analysis was also to be assessed in Germany and Czech Republic, and the reference to the booster study was deleted (no diary cards were provided to subjects/parents at the end of the study in Spain).

    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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