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    Clinical Trial Results:
    Booster Effect and Safety of a DTaP-IPV-Hib Combined Vaccine, with or without Hep B, in Healthy Subjects 11 to 18 Months of Age Who Received a Hexavalent or Hexavalent/Pentavalent Combined Vaccine during the Primary Series

    Summary
    EudraCT number
    		 2012-001042-18
    Trial protocol
    		 DE   CZ   ES  
    Global end of trial date
    27 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Jul 2017
    First version publication date
    19 Jul 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    A3L40
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 U1111-1122-2362
    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@sanofi.com
    Scientific contact
    Director, Clinical Development, Sanofi Pasteur SA, 33 (0)4 37 37 58 43, emmanuel.feroldi@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001201-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
    20 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Immunogenicity Groups 1 and 2 • Assess the antibody persistence of DTaP-IPV-HB-Hib or Infanrix hexa following a 3-dose primary series at 2, 3, and 4 months of age (MoA) before the administration of a booster dose of either vaccine • Describe the immunogenicity and booster effect of the DTaP-IPV-HBHib or Infanrix hexa vaccine given as a booster dose at 11 to 15 MoA concomitantly with PCV13 (after a primary series with the same vaccine) • To describe the immunogenicity of a booster dose of PCV13 given from 11 to 15 MoA Group 3 • Assess the antibody persistence of all valences contained in the vaccines administered in a mixed schedule following a 3-dose primary series at 2, 4, and 6 MoA before the administration of a booster dose of Pentavac • Describe the immunogenicity and booster effect of Pentavac given at 18 MoA after the administration of a mixed schedule primary series combining a hexavalent and a pentavalent vaccine To describe the safety profile for group 1, 2 and 3
    Protection of trial subjects
    Only subjects that met all the study inclusion and no exclusion criteria were 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
    		 Subjects in this trial previously completed a 3-dose primary series of either DTaP-IPV-HB-Hib vaccine + PCV13, Infanrix hexa + PCV13, or DTaP-IPV-HB-Hib/Pentavac/DTaP-IPV-HB-Hib/PCV13 in Study A3L39.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    11 Nov 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: 198
    Country: Number of subjects enrolled
    Czech Republic: 262
    Country: Number of subjects enrolled
    Germany: 203
    Worldwide total number of subjects
    663
    EEA total number of subjects
    663
    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)
    663
    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
    		 Study subjects were enrolled from 11 November 2014 to September 23, 2015 at 25 clinic centers in Czech Republic, 14 centers in Germany, and 12 centers in Spain.

    Pre-assignment
    Screening details
    		 A total of 663 subjects who met all inclusion and no exclusion criteria were enrolled; 662 subjects were vaccinated.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1
    Arm description
    		 Subjects previously received DTaP-IPV-HB-Hib vaccine (blind-observer) in a 3-dose series at 2, 3, and 4 months in Study A3L39 and received a booster dose of DTaP-IPV-HB-Hib vaccine concomitantly with a booster dose of PCV13 at 11 to 15 months of age in the current study.
    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, booster dose co-adminstered with PCV13 at 11 to 15 months

    Investigational medicinal product name
    PCV13
    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 left thigh, booster dose co-adminstered with DTaP-IPV-HB-Hib vaccine at 11 to 15 months

    Arm title
    		 Group 2
    Arm description
    		 Subjects previously received Infanrix hexa (blind-observer) in a 3-dose series at 2, 3, and 4 months in Study A3L39 and received a booster dose of Infanrix hexa concomitantly with a booster dose of PCV13 at 11 to 15 months of age in the current study.
    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, booster dose co-administered with PCV13 at 11 to 15 months

    Investigational medicinal product name
    PCV13
    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 left thigh, booster dose co-adminstered with Infanrix hexa vaccine at 11 to 15 months

    Arm title
    		 Group 3
    Arm description
    		 Subjects previously received DTaP-IPV-HB-Hib vaccine (open-label) in a 2-dose series at 2 and 6 months and a dose of Pentavac (DTaP-IPV/Hib) vaccine in Study A3L39 and received a booster dose of Pentavac (open label) concomitantly with a booster dose of PCV13 at 18 months of age in the current study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pentavac (DTap-IPV/Hib) combined vaccine
    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, booster dose co-administered with a booster dose of PCV13 at 18 months

    Investigational medicinal product name
    PCV13
    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 left thigh, booster dose co-adminstered with Pentavac at 18 months

    Number of subjects in period 1
    		Group 1 Group 2 Group 3
    Started
    234
    231
    198
    Completed
    234
    230
    196
    Not completed
    0
    1
    2
         Consent withdrawn by subject
    -
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Subjects previously received DTaP-IPV-HB-Hib vaccine (blind-observer) in a 3-dose series at 2, 3, and 4 months in Study A3L39 and received a booster dose of DTaP-IPV-HB-Hib vaccine concomitantly with a booster dose of PCV13 at 11 to 15 months of age in the current study.

    Reporting group title
    Group 2
    Reporting group description
    		 Subjects previously received Infanrix hexa (blind-observer) in a 3-dose series at 2, 3, and 4 months in Study A3L39 and received a booster dose of Infanrix hexa concomitantly with a booster dose of PCV13 at 11 to 15 months of age in the current study.

    Reporting group title
    Group 3
    Reporting group description
    		 Subjects previously received DTaP-IPV-HB-Hib vaccine (open-label) in a 2-dose series at 2 and 6 months and a dose of Pentavac (DTaP-IPV/Hib) vaccine in Study A3L39 and received a booster dose of Pentavac (open label) concomitantly with a booster dose of PCV13 at 18 months of age in the current study.

    Reporting group values
    		 Group 1 Group 2 Group 3 Total
    Number of subjects
    		 234 231 198 663
    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)
    		 234 231 198 663
        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: months
        arithmetic mean (standard deviation)
    		 12.4 ( 0.5 ) 12.5 ( 0.6 ) 18.1 ( 0.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 110 119 102 331
        Male
    		 124 112 96 332

    End points

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    End points reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Subjects previously received DTaP-IPV-HB-Hib vaccine (blind-observer) in a 3-dose series at 2, 3, and 4 months in Study A3L39 and received a booster dose of DTaP-IPV-HB-Hib vaccine concomitantly with a booster dose of PCV13 at 11 to 15 months of age in the current study.

    Reporting group title
    Group 2
    Reporting group description
    		 Subjects previously received Infanrix hexa (blind-observer) in a 3-dose series at 2, 3, and 4 months in Study A3L39 and received a booster dose of Infanrix hexa concomitantly with a booster dose of PCV13 at 11 to 15 months of age in the current study.

    Reporting group title
    Group 3
    Reporting group description
    		 Subjects previously received DTaP-IPV-HB-Hib vaccine (open-label) in a 2-dose series at 2 and 6 months and a dose of Pentavac (DTaP-IPV/Hib) vaccine in Study A3L39 and received a booster dose of Pentavac (open label) concomitantly with a booster dose of PCV13 at 18 months of age in the current study.

    Primary: Antibody Persistence of DTaP-IPV-HB-Hib or Infanrix hexa™ Following a 3-dose Primary Series, Before a Booster Dose of DTaP-IPV-HB-Hib, Infanrix hexa™, or Pentavac and the Immunogenicity and Booster Effect After a Booster Dose of Any Vaccine

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    End point title
    		 Antibody Persistence of DTaP-IPV-HB-Hib or Infanrix hexa™ Following a 3-dose Primary Series, Before a Booster Dose of DTaP-IPV-HB-Hib, Infanrix hexa™, or Pentavac and the Immunogenicity and Booster Effect After a Booster Dose of Any Vaccine [1]
    End point description
    Anti-Diphtheria antibodies (Ab) were measured by a neutralization test. Anti-Tetanus, Anti-Pertussis Toxoid (PT), Anti-Filamentous Hemagglutinin (FHA) antibodies were measured by ELISA. Anti-Polio types 1, 2, and 3 were measured by neutralization assay. Anti-Hepatitis B (Hep B) were assessed by VITROS ECi/ECiQ. Anti-Haemophilus influenza type b polysaccharide covalently bound to the tetanus protein (PRP) Abs were measured by a radioimmunoassay. Anti-Diphtheria and Tetanus titers were assessed at ≥0.01 and 0.1 IU/mL. Anti-PT and FHA titers were assessed at ≥lower limit of quantitation (LLOQ) where LLOQ=2 EU/mL. Anti-Polio types 1, 2, and 3 were assessed at ≥8 (1/dil). Anti-Hep B titers were assessed at ≥10 mIU/mL and ≥100 mIU/mL (except post-booster in Group 3) and Anti-PRP titers at ≥0.15 and 1.0 µg/mL. For PT and FHA booster response, post-booster Ab concentrations ≥4-fold rise if pre-booster <4x LLOQ and post-booster Ab concentrations ≥2-fold rise if pre-booster ≥4x LLOQ.
    End point type
    Primary
    End point timeframe
    Post-dose 3 primary series, pre- and post-booster
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and study vaccine administered for this outcome.
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    225
    218
    189
    Units: Percentage of subjects
    number (not applicable)
        Anti-Diptheria; ≥0.01 IU/mL; Post-dose 3
    100
    100
    100
        Anti-Diptheria; ≥0.1 IU/mL; Post-dose 3
    62.6
    59.6
    97.1
        Anti-Diptheria; ≥0.01 IU/mL; Pre-booster
    98.5
    99.5
    98.8
        Anti-Diptheria; ≥0.1 IU/mL; Pre-booster
    64.3
    47.8
    47.5
        Anti-Diptheria; ≥0.01 IU/mL; Post-booster
    100
    100
    100
        Anti-Diptheria; ≥0.1 IU/mL; Post-booster
    100
    100
    100
        Anti-Tetanus; ≥0.01 IU/mL; Post-dose 3
    100
    100
    100
        Anti-Tetanus; ≥0.1 IU/mL; Post-dose 3
    99.5
    100
    100
        Anti-Tetanus; ≥0.01 IU/mL; Pre-booster
    100
    100
    100
        Anti-Tetanus; ≥0.1 IU/mL; Pre-booster
    85.6
    85.6
    98.8
        Anti-Tetanus; ≥0.01 IU/mL; Post-booster
    100
    100
    100
        Anti-Tetanus; ≥0.1 IU/mL; Post-booster
    100
    100
    100
        Anti-PT; ≥LLOQ; Post-dose 3
    100
    100
    100
        Anti-PT; ≥LLOQ; Pre-booster
    99.5
    100
    85.9
        Anti-FHA; ≥LLOQ; Post-dose 3
    100
    100
    100
        Anti-FHA; ≥LLOQ; Pre-booster
    100
    100
    100
        Anti-Polio 1; ≥8 (1/dil); Post-dose 3
    100
    100
    100
        Anti-Polio 1; ≥8 (1/dil); Pre-booster
    83.7
    93.6
    99.4
        Anti-Polio 1; ≥8 (1/dil); Post-booster
    99.5
    100
    100
        Anti-Polio 2; ≥8 (1/dil); Post-dose 3
    100
    100
    99.4
        Anti-Polio 2; ≥8 (1/dil); Pre-booster
    88.3
    90.7
    94.7
        Anti-Polio 2; ≥8 (1/dil); Post-booster
    100
    100
    100
        Anti-Polio 3; ≥8 (1/dil); Post-dose 3
    100
    100
    100
        Anti-Polio 3; ≥8 (1/dil); Pre-booster
    91.3
    93.5
    97.1
        Anti-Polio 3; ≥8 (1/dil); Post-booster
    100
    100
    100
        Anti-Hep B; ≥10 mIU/mL; Post-dose 3
    97.2
    98.6
    98.9
        Anti-Hep B; ≥100 mIU/mL; Post-dose 3
    73.7
    86.7
    96.1
        Anti-Hep B; ≥10 mIU/mL; Pre-booster
    86
    97.2
    92.4
        Anti-Hep B; ≥100 mIU/mL; Pre-booster
    44.8
    67.1
    71.9
        Anti-Hep B; ≥10 mIU/mL; Post-booster
    99.6
    100
    0
        Anti-Hep B; ≥100 mIU/mL; Post-booster
    94.2
    98.1
    0
        Anti-PRP; ≥0.15 µg/mL; Post-dose 3
    90.6
    85.5
    100
        Anti-PRP; ≥1.0 µg/mL; Post-dose 3
    61.8
    37.2
    96.1
        Anti-PRP; ≥0.15 µg/mL; Pre-booster
    72
    57.7
    87.6
        Anti-PRP; ≥1.0 µg/mL; Pre-booster
    27.1
    9.1
    36
        Anti-PRP; ≥0.15 µg/mL; Post-booster
    100
    99.5
    95.2
        Anti-PRP; ≥1.0 µg/mL; Post-booster
    96.6
    95.3
    84.4
    No statistical analyses for this end point

    Primary: Booster Vaccine Response Against Pertussis Toxoid and Filamentous Hemagglutinin Following Administration of DTaP-IPV-HB-Hib or Infanrix hexa™ in a 3-dose Primary Series and a Booster Dose of DTaP-IPV-HB-Hib, Infanrix hexa™, or Pentavac

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    End point title
    		 Booster Vaccine Response Against Pertussis Toxoid and Filamentous Hemagglutinin Following Administration of DTaP-IPV-HB-Hib or Infanrix hexa™ in a 3-dose Primary Series and a Booster Dose of DTaP-IPV-HB-Hib, Infanrix hexa™, or Pentavac [2]
    End point description
    Anti-Pertussis Toxoid (PT) and Anti-Filamentous Hemagglutinin (FHA) antibodies were measured by enzyme-linked immunosorbent assay. Booster vaccine response for PT and FHA antigens were defined as post-booster antibody concentrations ≥4-fold rise if pre-booster antibody concentrations <4X LLOQ or post-booster antibody concentration ≥2-fold rise if pre-booster antibody concentrations ≥4X LLOQ.
    End point type
    Primary
    End point timeframe
    Post-dose 3 primary series, pre- and post-booster
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and study vaccine administered for this outcome.
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    225
    218
    189
    Units: Percentage of subjects
    number (not applicable)
        Anti-PT
    97
    98
    99.4
        Anti-FHA
    94.8
    94.1
    94.2
    No statistical analyses for this end point

    Primary: Seroconversion Against Pertussis Toxoid and Filamentous Hemagglutinin Following Administration of DTaP-IPV-HB-Hib or Infanrix hexa™ in a 3-dose Primary Series and a Booster Dose of DTaP-IPV-HB-Hib, Infanrix hexa™, or Pentavac

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    End point title
    		 Seroconversion Against Pertussis Toxoid and Filamentous Hemagglutinin Following Administration of DTaP-IPV-HB-Hib or Infanrix hexa™ in a 3-dose Primary Series and a Booster Dose of DTaP-IPV-HB-Hib, Infanrix hexa™, or Pentavac [3]
    End point description
    Anti-Pertussis Toxoid (PT) and Anti-Filamentous Hemagglutinin (FHA) antibodies were measured by enzyme-linked immunosorbent assay. Seroconversion for PT and FHA antigens was defined as Anti-PT and Anti-FHA ≥4-fold antibody titers increase from Day 0 to Day 30.
    End point type
    Primary
    End point timeframe
    Post-booster
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and study vaccine administered for this outcome.
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    225
    218
    189
    Units: Percentage of subjects
    number (not applicable)
        Anti-PT
    78.8
    79.6
    95.8
        Anti-FHA
    60.4
    80.7
    83
    No statistical analyses for this end point

    Primary: Geometric Mean Titers of Antibodies Against Vaccine Antigens After a 3-Dose Primary Series with DTaP-IPV-HB-Hib, Infanrix hexa™, or Pentavac Before Administration of a Booster Dose and the Immunogenicity and Booster Effect After Booster of Either Vaccine

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    End point title
    		 Geometric Mean Titers of Antibodies Against Vaccine Antigens After a 3-Dose Primary Series with DTaP-IPV-HB-Hib, Infanrix hexa™, or Pentavac Before Administration of a Booster Dose and the Immunogenicity and Booster Effect After Booster of Either Vaccine [4]
    End point description
    Anti-Diphtheria antibodies (Ab) were measured by a toxin neutralization test. Anti-Tetanus, Anti-Pertussis Toxoid (PT), Anti-Filamentous Hemagglutinin (FHA) antibodies were measured by enzyme-linked immunosorbent assay. Anti-Poliovirus types 1, 2, and 3 were measured by neutralization assay. Anti-Hepatitis B (Hep B) were measured by VITROS ECi/ECiQ Immunodiagnostic System. Anti-Haemophilus influenza type b polysaccharide covalently bound to the tetanus protein (PRP) Abs were measured using a Farr-type radioimmunoassay.
    End point type
    Primary
    End point timeframe
    Post-dose 3 primary series, pre- and post-booster
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and study vaccine administered for this outcome.
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    225
    218
    189
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Anti-Diphteria; Post-dose 3
    0.174 (0.151 to 0.201)
    0.155 (0.135 to 0.177)
    0.735 (0.633 to 0.853)
        Anti-Diphteria; Pre-booster
    0.172 (0.141 to 0.208)
    0.107 (0.091 to 0.126)
    0.098 (0.082 to 0.118)
        Anti-Diphteria; Post-booster
    6.08 (5.08 to 7.27)
    4.1 (3.52 to 4.78)
    3.43 (3.05 to 3.85)
        Anti-Tetanus; Post-dose 3
    0.77 (0.693 to 0.856)
    0.872 (0.784 to 0.971)
    2.27 (2.04 to 2.53)
        Anti-Tetanus; Pre-booster
    0.272 (0.238 to 0.312)
    0.253 (0.222 to 0.287)
    1.16 (1.04 to 1.3)
        Anti-Tetanus; Post-booster
    4.32 (3.82 to 4.88)
    3.78 (3.39 to 4.21)
    6.85 (6.26 to 7.49)
        Anti-PT; Post-dose 3
    114 (106 to 123)
    133 (123 to 144)
    99.9 (91.7 to 109)
        Anti-PT; Pre-booster
    16.1 (14.5 to 17.9)
    21.4 (19.2 to 23.8)
    5.44 (4.66 to 6.35)
        Anti-PT; Post-booster
    112 (102 to 122)
    158 (144 to 173)
    113 (101 to 125)
        Anti-FHA; Post-dose 3
    139 (129 to 149)
    85.2 (78.6 to 92.3)
    167 (154 to 181)
        Anti-FHA; Pre-booster
    34.2 (30.9 to 37.9)
    24.9 (22.1 to 27.9)
    20.9 (17.6 to 24.7)
        Anti-FHA; Post-booster
    172 (158 to 187)
    173 (158 to 189)
    210 (189 to 232)
        Anti-Polio 1; Post-dose 3
    110 (93.6 to 130)
    269 (224 to 322)
    866 (725 to 1034)
        Anti-Polio 1; Pre-booster
    38.8 (30.8 to 48.8)
    80.6 (65.7 to 99)
    294 (239 to 363)
        Anti-Polio 1; Post-booster
    1070 (880 to 1302)
    2696 (2283 to 3184)
    1882 (1632 to 2170)
        Anti-Polio 2; Post-dose 3
    192 (162 to 227)
    358 (295 to 435)
    2119 (1707 to 2631)
        Anti-Polio 2; Pre-booster
    51 (41 to 63.5)
    75.6 (60.7 to 94.1)
    306 (241 to 390)
        Anti-Polio 2; Post-booster
    1858 (1576 to 2192)
    2887 (2449 to 3403)
    3085 (2622 to 3630)
        Anti-Polio 3; Post-dose 3
    300 (256 to 352)
    702 (584 to 845)
    1448 (1180 to 1777)
        Anti-Polio 3; Pre-booster
    68.7 (56.6 to 83.4)
    135 (109 to 166)
    258 (199 to 335)
        Anti-Polio 3; Post-booster
    2301 (1924 to 2752)
    3902 (3265 to 4662)
    3501 (3039 to 4033)
        Anti-Hep B; Post-dose 3
    230 (188 to 281)
    376 (316 to 448)
    2613 (2104 to 3245)
        Anti-Hep B; Pre-booster
    74.6 (59.7 to 93.2)
    169 (140 to 203)
    189 (144 to 248)
        Anti-Hep B; Post-booster
    2140 (1707 to 2683)
    4642 (3837 to 5616)
    0 (0 to 0)
        Anti-PRP; Post-dose 3
    1.32 (1.07 to 1.62)
    0.596 (0.497 to 0.714)
    8.85 (7.5 to 10.4)
        Anti-PRP; Pre-booster
    0.383 (0.308 to 0.476)
    0.173 (0.144 to 0.209)
    0.712 (0.569 to 0.891)
        Anti-PRP; Post-booster
    28.8 (23.6 to 35.1)
    16.5 (13.6 to 19.8)
    15.8 (11.6 to 21.3)
    No statistical analyses for this end point

    Primary: Geometric Mean Titer Ratios of Antibodies Against Vaccine Antigens After a 3-Dose Primary Series with DTaP-IPV-HB-Hib, Infanrix hexa™, or Pentavac Before a Booster Dose and the Immunogenicity and Booster Effect After Booster of Either Vaccine

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    End point title
    		 Geometric Mean Titer Ratios of Antibodies Against Vaccine Antigens After a 3-Dose Primary Series with DTaP-IPV-HB-Hib, Infanrix hexa™, or Pentavac Before a Booster Dose and the Immunogenicity and Booster Effect After Booster of Either Vaccine [5]
    End point description
    Anti-Diphtheria antibodies (Ab) were measured by a toxin neutralization test. Anti-Tetanus, Anti-Pertussis Toxoid (PT), Anti-Filamentous Hemagglutinin (FHA) antibodies were measured by enzyme-linked immunosorbent assay. Anti-Poliovirus types 1, 2, and 3 were measured by neutralization assay. Anti-Hepatitis B (Hep B) were measured by VITROS ECi/ECiQ Immunodiagnostic System. Anti-Haemophilus influenza type b polysaccharide covalently bound to the tetanus protein (PRP) Abs were measured using a Farr-type radioimmunoassay.
    End point type
    Primary
    End point timeframe
    Post-booster
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and study vaccine administered for this outcome.
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    225
    218
    189
    Units: Titer ratios
    geometric mean (confidence interval 95%)
        Anti-Diphtheria
    32.8 (26.6 to 40.4)
    38.4 (31.6 to 46.6)
    35.8 (30.6 to 41.8)
        Anti-Tetanus
    16.2 (14.3 to 18.3)
    15 (13.4 to 16.8)
    5.77 (5.13 to 6.49)
        Anti-PT
    7.28 (6.54 to 8.1)
    7.38 (6.69 to 8.14)
    21 (18.2 to 24.2)
        Anti-FHA
    5.07 (4.63 to 5.54)
    6.96 (6.26 to 7.74)
    10 (8.72 to 11.5)
        Anti-Polio 1
    26.8 (21.6 to 33.3)
    33.6 (27.1 to 41.7)
    6.26 (5.05 to 7.75)
        Anti-Polio 2
    36.8 (29.7 to 45.7)
    37.6 (31 to 45.7)
    9.15 (7.26 to 11.5)
        Anti-Polio 3
    33.7 (27.8 to 40.8)
    29.8 (24.4 to 36.3)
    12.2 (9.63 to 15.4)
        Anti-Hep B
    29.2 (25 to 33.9)
    27.9 (24.3 to 31.9)
    0 (0 to 0)
        Anti-PRP
    72.3 (59.3 to 88.2)
    91.8 (76.1 to 111)
    20 (14.4 to 27.6)
    No statistical analyses for this end point

    Primary: Percentage of Subjects with Immune Responses to Prevenar 13 Antigens Following Co-administration with DTaP-IPV-HB-Hib or Infanrix hexa™

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    End point title
    		 Percentage of Subjects with Immune Responses to Prevenar 13 Antigens Following Co-administration with DTaP-IPV-HB-Hib or Infanrix hexa™ [6] [7]
    End point description
    The pneumococcal capsular polysaccharide (PS) immunoglobulin G ELISA was used to quantitate the amount of anti-streptococcus pneumoniae PS (serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) antibodies in human serum. The percentage of subjects reported represent subjects with anti-pneumococcal serotype (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) antibody concentrations at ≥0.35 µg/mL.
    End point type
    Primary
    End point timeframe
    1 month post-booster
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and study vaccine administered for this outcome.
    [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: Pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) were only assessed in Groups 1 and 2.
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    225
    218
    Units: Percentage of subjects
    number (not applicable)
        Serotype 1
    100
    99.5
        Serotype 3
    82.7
    90.2
        Serotype 4
    99
    99.5
        Serotype 5
    98.1
    99
        Serotype 6A
    100
    100
        Serotype 6B
    99
    100
        Serotype 7F
    100
    100
        Serotype 9V
    99
    99.5
        Serotype 14
    100
    100
        Serotype 18C
    97.1
    98.6
        Serotype 19A
    100
    100
        Serotype 19F
    100
    100
        Serotype 23F
    99.5
    99
    No statistical analyses for this end point

    Primary: Geometric Mean Concentrations (GMCs) of Prevenar Antibodies Following Co-administration with DTaP-IPV-HB-Hib or Infanrix hexa™

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    End point title
    		 Geometric Mean Concentrations (GMCs) of Prevenar Antibodies Following Co-administration with DTaP-IPV-HB-Hib or Infanrix hexa™ [8] [9]
    End point description
    The pneumococcal capsular polysaccharide (PS) immunoglobulin G ELISA was used to quantitate the amount of anti-streptococcus pneumoniae PS (serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) antibodies in human serum. Anti-pneumococcal serotype 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F antibody concentrations were assessed at ≥0.35 µg/mL.
    End point type
    Primary
    End point timeframe
    1 month post-booster
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and study vaccine administered for this outcome.
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) were only assessed in Groups 1 and 2.
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    225
    218
    Units: Concentrations (1/dil)
    geometric mean (confidence interval 95%)
        Serotype 1
    2.44 (2.23 to 2.67)
    3.4 (3.09 to 3.75)
        Serotype 3
    0.708 (0.633 to 0.791)
    0.933 (0.828 to 1.05)
        Serotype 4
    2.11 (1.88 to 2.37)
    2.95 (2.63 to 3.3)
        Serotype 5
    1.36 (1.24 to 1.49)
    1.8 (1.63 to 1.97)
        Serotype 6A
    6.37 (5.78 to 7.03)
    7.45 (6.75 to 8.23)
        Serotype 6B
    5.43 (4.83 to 6.11)
    7.48 (6.79 to 8.24)
        Serotype 7F
    4.24 (3.86 to 4.65)
    5.27 (4.8 to 5.79)
        Serotype 9V
    1.51 (1.39 to 1.65)
    1.88 (1.72 to 2.05)
        Serotype 14
    9.7 (8.81 to 10.7)
    10.8 (9.86 to 11.9)
        Serotype 18C
    1.27 (1.14 to 1.42)
    2 (1.78 to 2.24)
        Serotype 19A
    8.91 (8.02 to 9.89)
    11.1 (9.96 to 12.3)
        Serotype 19F
    7.16 (6.47 to 7.92)
    9.4 (8.52 to 10.4)
        Serotype 23F
    2.95 (2.61 to 3.33)
    4.18 (3.7 to 4.74)
    No statistical analyses for this end point

    Primary: Percentage of Subjects Reporting Solicited Injection-site or Systemic Reaction After Booster Vaccinations with DTaP-IPV-HB-Hib, Infanrix hexa™, or Pentavac Concomitantly Administered With 13-Valent Pneumococcal Conjugate Vaccine (PCV13)

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    End point title
    		 Percentage of Subjects Reporting Solicited Injection-site or Systemic Reaction After Booster Vaccinations with DTaP-IPV-HB-Hib, Infanrix hexa™, or Pentavac Concomitantly Administered With 13-Valent Pneumococcal Conjugate Vaccine (PCV13) [10]
    End point description
    Solicited injection site reactions: Tenderness/Pain, Erythema, Swelling, and Extensive swelling of vaccinated limb. Solicited systemic reactions: Fever (Temperature)/Pyrexia, Vomiting, Crying abnormal, Drowsiness/Somnolence, Appetite lost/Anorexia, and Irritability. Grade 3 Solicited injection site reactions: Tenderness, Cries when injected limb is moved, or the movement of the injected limb is reduced; Erythema and Swelling, ≥50 mm; Extensive swelling of the arm, Not applicable. Grade 3 Solicited systemic reactions: Fever, >39.5°C or >103.1°F; Vomiting, ≥6 episodes per 24 hours or requiring parenteral hydration; Crying abnormal, >3 hours; Drowsiness, Sleeping most of the time or difficult to wake up; Appetite lost, Refuses ≥3 feeds/meals or refuses most meals; Irritability, Inconsolable.
    End point type
    Primary
    End point timeframe
    Day 0 up to Day 7 post-booster
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and study vaccine administered for this outcome.
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    234 [11]
    228
    198
    Units: Percentage of subjects
    number (not applicable)
        Any Inj. site Pain; DTaP-IPV-HB-Hib
    51.1
    0
    0
        Grade 3 Inj. site Pain; DTaP-IPV-HB-Hib
    6.8
    0
    0
        Any Inj. site Pain; Infanrix hexa
    0
    53.7
    0
        Grade 3 Inj. site Pain; Infanrix hexa
    0
    4.8
    0
        Any Inj. site Pain; Pentavac
    0
    0
    50.3
        Grade 3 Inj. site Pain; Pentavac
    0
    0
    5.1
        Any Inj. site Pain; Prevenar
    51.9
    52.9
    42.7
        Grade 3 Inj. site Pain; Prevenar
    6
    4.8
    4.9
        Any Inj. site Erythema; DTaP-IPV-HB-Hib
    41.3
    0
    0
        Grade 3 Inj. site Erythema; DTaP-IPV-HB-Hib
    0.9
    0
    0
        Any Inj. site Erythema; Infanrix hexa
    0
    44.9
    0
        Grade 3 Inj. site Erythema; Infanrix hexa
    0
    2.6
    0
        Any Inj. site Erythema; Pentavac
    0
    0
    12.2
        Grade 3 Inj. site Erythema; Pentavac
    0
    0
    0.5
        Any Inj. site Erythema; Prevenar
    37.4
    40.1
    6.7
        Grade 3 Inj. site Erythema; Prevenar
    0
    1.8
    0
        Any Inj. site Swelling; DTaP-IPV-HB-Hib
    23.1
    0
    0
        Grade 3 Inj. site Swelling; DTaP-IPV-HB-Hib
    1.3
    0
    0
        Any Inj. site Swelling; Infanrix hexa
    0
    27.8
    0
        Grade 3 Inj. site Swelling; Infanrix hexa
    0
    2.2
    0
        Any Inj. site Swelling; Pentavac
    0
    0
    13.7
        Grade 3 Inj. site Swelling; Pentavac
    0
    0
    0
        Any Inj. site Swelling; Prevenar
    19.6
    25.1
    6.1
        Grade 3 Inj. site Swelling; Prevenar
    0.4
    2.2
    0.6
        Any Extensive Swelling of Limb; DTaP-IPV-HB-Hib
    0
    0
    0
        Grade 3 Extensive Swelling of Limb;DTaP-IPV-HB-Hib
    0
    0
    0
        Any Extensive Swelling of Limb; Infanrix hexa
    0
    0.4
    0
        Grade 3 Extensive Swelling of Limb; Infanrix hexa
    0
    0.4
    0
        Any Extensive Swelling of Limb; Pentavac
    0
    0
    0
        Grade 3 Extensive Swelling of Limb; Pentavac
    0
    0
    0
        Any Extensive Swelling of Limb; Prevenar
    0
    0
    0
        Grade 3 Extensive Swelling of Limb; Prevenar
    0
    0
    0
        Any Pyrexia
    50.2
    43.6
    24.5
        Grade 3 Pyrexia
    5.1
    4
    1
        Any Vomiting
    8.5
    7
    4.6
        Grade 3 Vomiting
    0.9
    0.4
    0
        Any Crying abnormal
    45.5
    41.4
    41.1
        Grade 3 Crying abnormal
    3.8
    1.3
    1
        Any Somnolence
    48.5
    44.5
    38.6
        Grade 3 Somnolence
    0.9
    0
    0
        Any Anorexia
    38.7
    32.6
    39.6
        Grade 3 Anorexia
    2.6
    0.9
    1
        Any Irritability
    60.4
    56.8
    56.9
        Grade 3 Irritability
    2.1
    1.3
    0.5
    Notes
    [11] - For safety analyses, 236 subjects were included in Group 1 post-booster.
    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 7 post-booster vaccination.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Subjects previously received DTaP-IPV-HB-Hib vaccine (blind-observer) in a 3-dose series at 2, 3, and 4 months in Study A3L39 and received a booster dose of DTaP-IPV-HB-Hib vaccine concomitantly with a booster dose of PCV13 at 11 to 15 months of age in the current study.

    Reporting group title
    Group 2
    Reporting group description
    		 Subjects previously received Infanrix hexa (blind-observer) in a 3-dose series at 2, 3, and 4 months in Study A3L39 and received a booster dose of Infanrix hexa concomitantly with a booster dose of PCV13 at 11 to 15 months of age in the current study.

    Reporting group title
    Group 3
    Reporting group description
    		 Subjects previously received DTaP-IPV-HB-Hib vaccine (open-label) in a 2-dose series at 2 and 6 months and a dose of Pentavac (DTaP-IPV/Hib) vaccine in Study A3L39 and received a booster dose of Pentavac (open label) concomitantly with a booster dose of PCV13 at 18 months of age in the current study.

    Serious adverse events
    		 Group 1 Group 2 Group 3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 236 (0.42%)
    3 / 228 (1.32%)
    0 / 198 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    0 / 236 (0.00%)
    2 / 228 (0.88%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute pyelonephritis
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 228 (0.44%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 228 (0.00%)
    0 / 198 (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
    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
    142 / 236 (60.17%)
    129 / 228 (56.58%)
    112 / 198 (56.57%)
    Nervous system disorders
    Somnolence
    alternative assessment type: Systematic
         subjects affected / exposed
    114 / 236 (48.31%)
    101 / 228 (44.30%)
    76 / 198 (38.38%)
         occurrences all number
    114
    101
    76
    General disorders and administration site conditions
    Injection site Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    122 / 236 (51.69%)
    122 / 228 (53.51%)
    99 / 198 (50.00%)
         occurrences all number
    122
    122
    99
    Injection site Erythema
    alternative assessment type: Systematic
         subjects affected / exposed
    97 / 236 (41.10%)
    102 / 228 (44.74%)
    24 / 198 (12.12%)
         occurrences all number
    97
    102
    24
    Injection site Swelling
    alternative assessment type: Systematic
         subjects affected / exposed
    54 / 236 (22.88%)
    63 / 228 (27.63%)
    27 / 198 (13.64%)
         occurrences all number
    54
    63
    27
    Pyrexia
    alternative assessment type: Systematic
         subjects affected / exposed
    118 / 236 (50.00%)
    99 / 228 (43.42%)
    48 / 198 (24.24%)
         occurrences all number
    118
    99
    48
    Gastrointestinal disorders
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed
    20 / 236 (8.47%)
    16 / 228 (7.02%)
    9 / 198 (4.55%)
         occurrences all number
    20
    16
    9
    Psychiatric disorders
    Crying abnormal
    alternative assessment type: Systematic
         subjects affected / exposed
    107 / 236 (45.34%)
    94 / 228 (41.23%)
    81 / 198 (40.91%)
         occurrences all number
    107
    94
    81
    Irritability
    alternative assessment type: Systematic
         subjects affected / exposed
    142 / 236 (60.17%)
    129 / 228 (56.58%)
    112 / 198 (56.57%)
         occurrences all number
    142
    129
    112
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    2 / 236 (0.85%)
    3 / 228 (1.32%)
    10 / 198 (5.05%)
         occurrences all number
    2
    3
    10
    Metabolism and nutrition disorders
    Anorexia
    alternative assessment type: Systematic
         subjects affected / exposed
    91 / 236 (38.56%)
    74 / 228 (32.46%)
    78 / 198 (39.39%)
         occurrences all number
    91
    74
    78

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Aug 2014
    Details regarding technical issues with vaccine administration and country-specific information were further clarified.
    26 Feb 2015
    Definition of booster response was reworded to ensure consistency and information on assays used in the study were updated.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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