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    Clinical Trial Results:
    A Phase III Randomized, Open-Label, Active-Comparator Controlled Clinical Study to Evaluate the Safety, Tolerability, and Immunogenicity of V419 in Infants When Given at 2, 4, and 6 Months Concomitantly with Prevnar 13™ and RotaTeq™

    Summary
    EudraCT number
    2011-004095-10
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    09 May 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Feb 2016
    First version publication date
    24 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V419-005
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01337167
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck Sharp and Dohme Corp., A Subsidiary of Merck & Co. Inc.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, United States, 07033
    Public contact
    VP, Late Stage Development, Merck Sharp and Dohme Corp., A Subsidiary of Merck & Co., Inc., 1 800 672 6372, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    VP, Late Stage Development, Merck Sharp and Dohme Corp., A Subsidiary of Merck & Co., Inc., 1 800 672 6372, ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000394-PIP01-08
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 May 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 May 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    (1) To compare the immunogenicity of V419 with the component vaccine control(s). (2) To compare the immunogenicity of pertussis responses at one month after the Toddler dose of DAPTACEL after receiving an infant series of either 3 doses of V419 or PENTACEL
    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
    20 Apr 2011
    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
    United States: 1473
    Worldwide total number of subjects
    1473
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    1473
    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 20 April 2011 to 09 May 2013 at 39 clinical sites in the United States.

    Pre-assignment
    Screening details
    A total of 1473 subjects who met all of the inclusion criteria and none of the exclusion criteria were enrolled and randomized; however, only 1465 subjects received study vaccinations.

    Period 1
    Period 1 title
    Infant Series
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    V419
    Arm description
    V419 0.5 mL intramuscular (IM) at 2, 4, and 6 months of age; Daptacel™ 0.5 mL IM at 15 months of age; PedvaxHIB™ 0.5 mL IM at 15 months of age; Prevnar13™ 0.5 mL IM at 2, 4, 6, and 15 months of age; and RotaTeq™ 2 mL oral dose at 2, 4, and 6 months of age.
    Arm type
    Experimental

    Investigational medicinal product name
    PR5I
    Investigational medicinal product code
    V419
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection each at 2, 4, and 6 months.

    Investigational medicinal product name
    DAPTACEL™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection at 15 months.

    Investigational medicinal product name
    Prevnar13™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection each at 2, 4, 6, and 15 months.

    Investigational medicinal product name
    PedvaxHIB™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection at 15 months.

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

    Arm title
    Control
    Arm description
    PENTACEL™ 0.5 mL IM at 2, 4, and 6 months of age; Modified Process Hepatitis B vaccine 0.5 mL IM at 2 and 6 months of age; Daptacel™ 0.5 mL IM at 15 months of age; ActHIB™ 0.5 mL IM at 15 months of age; Prevnar13™ 0.5 mL IM at 2, 4, 6, and 15 months of age; and RotaTeq™ 2 mL oral dose at 2, 4, and 6 months of age.
    Arm type
    Active comparator

    Investigational medicinal product name
    PENTACEL™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection each at 2, 4, and 6 months.

    Investigational medicinal product name
    RECOMBIVAX HB™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection each at 2 and 6 months.

    Investigational medicinal product name
    DAPTACEL™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection at 15 months.

    Investigational medicinal product name
    ActHIB™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection at 15 months.

    Investigational medicinal product name
    Prevnar13™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection each at 2, 4, 6, and 15 months.

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

    Number of subjects in period 1
    V419 Control
    Started
    986
    487
    Completed
    924
    460
    Not completed
    62
    27
         Protocol deviation
             22
             9
         Death
             1
             1
         Physician decision
             3
             1
         Not vaccinated
             5
             3
         Non-compliance with study drug
             2
             1
         Adverse event, non-fatal
             1
             1
         Consent withdrawn by subject
             15
             4
         Lost to follow-up
             13
             7
    Period 2
    Period 2 title
    Interim Period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    V419
    Arm description
    V419 0.5 mL intramuscular (IM) at 2, 4, and 6 months of age; Daptacel™ 0.5 mL IM at 15 months of age; PedvaxHIB™ 0.5 mL IM at 15 months of age; Prevnar13™ 0.5 mL IM at 2, 4, 6, and 15 months of age; and RotaTeq™ 2 mL oral dose at 2, 4, and 6 months of age.
    Arm type
    Experimental

    Investigational medicinal product name
    PR5I
    Investigational medicinal product code
    V419
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection each at 2, 4, and 6 months.

    Investigational medicinal product name
    Prevnar13™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection each at 2, 4, 6, and 15 months.

    Investigational medicinal product name
    DAPTACEL™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection at 15 months.

    Investigational medicinal product name
    PedvaxHIB™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection at 15 months.

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

    Arm title
    Control
    Arm description
    PENTACEL™ 0.5 mL IM at 2, 4, and 6 months of age; Modified Process Hepatitis B vaccine 0.5 mL IM at 2 and 6 months of age; Daptacel™ 0.5 mL IM at 15 months of age; ActHIB™ 0.5 mL IM at 15 months of age; Prevnar13™ 0.5 mL IM at 2, 4, 6, and 15 months of age; and RotaTeq™ 2 mL oral dose at 2, 4, and 6 months of age.
    Arm type
    Active comparator

    Investigational medicinal product name
    PENTACEL™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection each at 2, 4, and 6 months.

    Investigational medicinal product name
    RECOMBIVAX HB™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection each at 2 and 6 months.

    Investigational medicinal product name
    DAPTACEL™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection at 15 months.

    Investigational medicinal product name
    ActHIB™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection at 15 months.

    Investigational medicinal product name
    Prevnar13™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection each at 2, 4, 6, and 15 months.

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

    Number of subjects in period 2
    V419 Control
    Started
    924
    460
    Completed
    843
    420
    Not completed
    81
    40
         Other protocol criterion not met
             -
             1
         Protocol deviation
             5
             3
         Physician decision
             6
             3
         Non-compliance with study drug
             1
             -
         Consent withdrawn by subject
             18
             10
         Lost to follow-up
             51
             23
    Period 3
    Period 3 title
    Toddler Dose Vaccinations
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    V419
    Arm description
    V419 0.5 mL intramuscular (IM) at 2, 4, and 6 months of age; Daptacel™ 0.5 mL IM at 15 months of age; PedvaxHIB™ 0.5 mL IM at 15 months of age; Prevnar13™ 0.5 mL IM at 2, 4, 6, and 15 months of age; and RotaTeq™ 2 mL oral dose at 2, 4, and 6 months of age.
    Arm type
    Experimental

    Investigational medicinal product name
    PR5I
    Investigational medicinal product code
    V419
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection each at 2, 4, and 6 months.

    Investigational medicinal product name
    DAPTACEL™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection at 15 months.

    Investigational medicinal product name
    Prevnar13™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection each at 2, 4, 6, and 15 months.

    Investigational medicinal product name
    PedvaxHIB™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection at 15 months.

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

    Arm title
    Control
    Arm description
    PENTACEL™ 0.5 mL IM at 2, 4, and 6 months of age; Modified Process Hepatitis B vaccine 0.5 mL IM at 2 and 6 months of age; Daptacel™ 0.5 mL IM at 15 months of age; ActHIB™ 0.5 mL IM at 15 months of age; Prevnar13™ 0.5 mL IM at 2, 4, 6, and 15 months of age; and RotaTeq™ 2 mL oral dose at 2, 4, and 6 months of age.
    Arm type
    Active comparator

    Investigational medicinal product name
    PENTACEL™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection each at 2, 4, and 6 months.

    Investigational medicinal product name
    RECOMBIVAX HB™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection each at 2 and 6 months.

    Investigational medicinal product name
    DAPTACEL™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection at 15 months.

    Investigational medicinal product name
    ActHIB™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection at 15 months.

    Investigational medicinal product name
    Prevnar13™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection each at 2, 4, 6, and 15 months.

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

    Number of subjects in period 3
    V419 Control
    Started
    843
    420
    Completed
    829
    407
    Not completed
    14
    13
         Protocol deviation
             -
             1
         Consent withdrawn by subject
             3
             -
         Lost to follow-up
             11
             12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    V419
    Reporting group description
    V419 0.5 mL intramuscular (IM) at 2, 4, and 6 months of age; Daptacel™ 0.5 mL IM at 15 months of age; PedvaxHIB™ 0.5 mL IM at 15 months of age; Prevnar13™ 0.5 mL IM at 2, 4, 6, and 15 months of age; and RotaTeq™ 2 mL oral dose at 2, 4, and 6 months of age.

    Reporting group title
    Control
    Reporting group description
    PENTACEL™ 0.5 mL IM at 2, 4, and 6 months of age; Modified Process Hepatitis B vaccine 0.5 mL IM at 2 and 6 months of age; Daptacel™ 0.5 mL IM at 15 months of age; ActHIB™ 0.5 mL IM at 15 months of age; Prevnar13™ 0.5 mL IM at 2, 4, 6, and 15 months of age; and RotaTeq™ 2 mL oral dose at 2, 4, and 6 months of age.

    Reporting group values
    V419 Control Total
    Number of subjects
    986 487 1473
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    986 487 1473
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    0 0 0
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    65.6 ± 7.5 65 ± 6.9 -
    Gender categorical
    Units: Subjects
        Female
    479 214 693
        Male
    507 273 780

    End points

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    End points reporting groups
    Reporting group title
    V419
    Reporting group description
    V419 0.5 mL intramuscular (IM) at 2, 4, and 6 months of age; Daptacel™ 0.5 mL IM at 15 months of age; PedvaxHIB™ 0.5 mL IM at 15 months of age; Prevnar13™ 0.5 mL IM at 2, 4, 6, and 15 months of age; and RotaTeq™ 2 mL oral dose at 2, 4, and 6 months of age.

    Reporting group title
    Control
    Reporting group description
    PENTACEL™ 0.5 mL IM at 2, 4, and 6 months of age; Modified Process Hepatitis B vaccine 0.5 mL IM at 2 and 6 months of age; Daptacel™ 0.5 mL IM at 15 months of age; ActHIB™ 0.5 mL IM at 15 months of age; Prevnar13™ 0.5 mL IM at 2, 4, 6, and 15 months of age; and RotaTeq™ 2 mL oral dose at 2, 4, and 6 months of age.
    Reporting group title
    V419
    Reporting group description
    V419 0.5 mL intramuscular (IM) at 2, 4, and 6 months of age; Daptacel™ 0.5 mL IM at 15 months of age; PedvaxHIB™ 0.5 mL IM at 15 months of age; Prevnar13™ 0.5 mL IM at 2, 4, 6, and 15 months of age; and RotaTeq™ 2 mL oral dose at 2, 4, and 6 months of age.

    Reporting group title
    Control
    Reporting group description
    PENTACEL™ 0.5 mL IM at 2, 4, and 6 months of age; Modified Process Hepatitis B vaccine 0.5 mL IM at 2 and 6 months of age; Daptacel™ 0.5 mL IM at 15 months of age; ActHIB™ 0.5 mL IM at 15 months of age; Prevnar13™ 0.5 mL IM at 2, 4, 6, and 15 months of age; and RotaTeq™ 2 mL oral dose at 2, 4, and 6 months of age.
    Reporting group title
    V419
    Reporting group description
    V419 0.5 mL intramuscular (IM) at 2, 4, and 6 months of age; Daptacel™ 0.5 mL IM at 15 months of age; PedvaxHIB™ 0.5 mL IM at 15 months of age; Prevnar13™ 0.5 mL IM at 2, 4, 6, and 15 months of age; and RotaTeq™ 2 mL oral dose at 2, 4, and 6 months of age.

    Reporting group title
    Control
    Reporting group description
    PENTACEL™ 0.5 mL IM at 2, 4, and 6 months of age; Modified Process Hepatitis B vaccine 0.5 mL IM at 2 and 6 months of age; Daptacel™ 0.5 mL IM at 15 months of age; ActHIB™ 0.5 mL IM at 15 months of age; Prevnar13™ 0.5 mL IM at 2, 4, 6, and 15 months of age; and RotaTeq™ 2 mL oral dose at 2, 4, and 6 months of age.

    Primary: Percentage of Subjects Responding to Polyribosylribitol Phosphate (PRP) Antigen

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    End point title
    Percentage of Subjects Responding to Polyribosylribitol Phosphate (PRP) Antigen
    End point description
    Subject serum samples were collected for testing with a radioimmunoassay for antibodies to Haemophilus influenza type b capsular polysaccharide polyribosylribitol phosphate (PRP). Sera response or endpoint was defined as a titer ≥0.15 µg/mL and ≥1.0 µg/mL. The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 3.
    End point type
    Primary
    End point timeframe
    Postdose 3 (Month 7)
    End point values
    V419 Control
    Number of subjects analysed
    765
    382
    Units: Percentage of subjects
    number (confidence interval 95%)
        PRP ≥1.0 μg/mL
    84.97 (82.24 to 87.43)
    75.39 (70.76 to 79.63)
        PRP ≥0.15 µg/mL
    97.25 (95.83 to 98.29)
    92.41 (89.28 to 94.86)
    Statistical analysis title
    Non-inferiority (PRP; ≥1.0 µg/mL)
    Statistical analysis description
    Estimates for response rate, rate difference (V419-Control), and p-value were based on the Miettinen and Nurminen method stratified by brand of birth dose of hepatitis B vaccine (RECOMBIVAX™ or other).
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1147
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    P-value
    < 0.001 [2]
    Method
    Miettinen and Nurminen
    Parameter type
    Estimated difference
    Point estimate
    9.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.83
         upper limit
    14.83
    Notes
    [1] - For PRP (≥1.0 µg/mL), if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥-10%) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [2] - One-side p-value
    Statistical analysis title
    Non-inferiority (PRP; ≥0.15 µg/mL)
    Statistical analysis description
    Estimates for response rate, rate difference (V419-Control), and p-value were based on the Miettinen and Nurminen method stratified by brand of birth dose of hepatitis B vaccine (RECOMBIVAX™ or other).
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1147
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [3]
    P-value
    < 0.001 [4]
    Method
    Miettinen and Nurminen
    Parameter type
    Estimated difference
    Point estimate
    4.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.23
         upper limit
    8.14
    Notes
    [3] - For PRP (≥0.15 µg/mL), if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥-5%) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [4] - One-sided p-value
    Statistical analysis title
    Secondary; Non-inferiority (PRP; ≥0.15 µg/mL)
    Statistical analysis description
    Estimates for response rate, rate difference (V419-Control), and p-value were based on the Miettinen and Nurminen method stratified by brand of birth dose of hepatitis B vaccine (RECOMBIVAX™ or other).
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1147
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [5]
    P-value
    < 0.001 [6]
    Method
    Miettinen and Nurminen
    Parameter type
    Estimated difference
    Point estimate
    4.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.23
         upper limit
    8.14
    Notes
    [5] - For PRP (≥0.15 µg/mL), if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥-10%) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [6] - One-sided p-value

    Primary: Percentage of Subjects Responding to Hepatitis B Surface Antigen

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    End point title
    Percentage of Subjects Responding to Hepatitis B Surface Antigen
    End point description
    Subject serum samples were collected for testing with an enhanced chemiluminescence assay for antibodies to Hepatitis B Surface Antigen (HBsAg). Sera response or endpoint was defined as a titer ≥10 milli International units (mIU)/mL. The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 3.
    End point type
    Primary
    End point timeframe
    Postdose 3 (Month 7)
    End point values
    V419 Control
    Number of subjects analysed
    688
    353
    Units: Percentage of subjects
    number (confidence interval 95%)
        HBsAg; ≥10 mIU/mL
    99.42 (98.52 to 99.84)
    98.58 (96.73 to 99.54)
    Statistical analysis title
    Non-inferiority (HBsAg; ≥10 mIU/mL)
    Statistical analysis description
    Estimates for response rate, rate difference (V419-Control), and p-value were based on the Miettinen and Nurminen method stratified by brand of birth dose of hepatitis B vaccine (RECOMBIVAX™ or other).
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1041
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [7]
    P-value
    < 0.001 [8]
    Method
    Miettinen and Nurminen
    Parameter type
    Estimated difference
    Point estimate
    0.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.35
         upper limit
    2.74
    Notes
    [7] - For HBsAg (≥10 mIU/mL), if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥-10%) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [8] - One-sided p-value

    Primary: Percentage of Subjects Responding to Diphtheria Toxin

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    End point title
    Percentage of Subjects Responding to Diphtheria Toxin
    End point description
    Subject serum samples were collected for testing with a micrometabolic inhibition test for neutralizing antibodies to diphtheria toxin. Sera response or endpoint was defined as a titer ≥0.1 International unit (IU)/mL. The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 3.
    End point type
    Primary
    End point timeframe
    Postdose 3 (Month 7)
    End point values
    V419 Control
    Number of subjects analysed
    786
    393
    Units: Percentage of subjects
    number (confidence interval 95%)
        Diphtheria Toxin ≥ 0.1 IU/mL
    82.44 (79.6 to 85.04)
    86.26 (82.45 to 89.51)
    Statistical analysis title
    Non-inferiority (Diphtheria; ≥0.1 IU/mL)
    Statistical analysis description
    Estimates for response rate, rate difference (V419-Control), and p-value were based on the Miettinen and Nurminen method stratified by brand of birth dose of hepatitis B vaccine (RECOMBIVAX™ or other).
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1179
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [9]
    P-value
    = 0.002 [10]
    Method
    Miettinen and Nurminen
    Parameter type
    Estimated difference
    Point estimate
    -3.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.02
         upper limit
    0.66
    Notes
    [9] - For Diphtheria (≥0.1 IU/mL), if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥-10%) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [10] - One-sided p-value

    Primary: Percentage of Subjects Responding to Tetanus Toxin

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    End point title
    Percentage of Subjects Responding to Tetanus Toxin
    End point description
    Subject serum samples were collected for testing with an enzyme-linked immunosorbent assay for anti-tetanus antibodies. Sera response or endpoint was defined as a titer ≥0.1 IU/mL. The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 3.
    End point type
    Primary
    End point timeframe
    Postdose 3 (Month 7)
    End point values
    V419 Control
    Number of subjects analysed
    787
    390
    Units: Percentage of subjects
    number (confidence interval 95%)
        Tetanus Toxin ≥ 0.1 IU/mL
    99.87 (99.29 to 100)
    99.49 (98.16 to 99.94)
    Statistical analysis title
    Non-inferiority (Tetanus; ≥0.1 IU/mL)
    Statistical analysis description
    Estimates for response rate, rate difference (V419-Control), and p-value were based on the Miettinen and Nurminen method stratified by brand of birth dose of hepatitis B vaccine (RECOMBIVAX™ or other).
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1177
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [11]
    P-value
    < 0.001 [12]
    Method
    Miettinen and Nurminen
    Parameter type
    Estimated difference
    Point estimate
    0.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.28
         upper limit
    1.74
    Notes
    [11] - For Tetanus (≥0.1 IU/mL), if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥-5%) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [12] - One-sided p-value

    Primary: Percentage of Subjects Responding to Pertussis Toxin

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    End point title
    Percentage of Subjects Responding to Pertussis Toxin
    End point description
    Subject serum samples were collected for testing with an ELISA for antibodies to pertussis toxin. Sera response or endpoint was defined as follows: 1) if the predose titer was < 4 times the lower limit of quantitation (4X LLOQ) then the post-dose titer was ≥4X LLOQ; 2) if the pre-dose titer was ≥4X LLOQ then the post-dose titer was ≥ the pre-dose titer. The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 3.
    End point type
    Primary
    End point timeframe
    Postdose 3 (Month 7)
    End point values
    V419 Control
    Number of subjects analysed
    796
    391
    Units: Percentage of subjects
    number (confidence interval 95%)
        Pertussis toxin
    98.12 (96.91 to 98.94)
    98.47 (96.69 to 99.43)
    Statistical analysis title
    Non-inferiority (Pertussis toxin)
    Statistical analysis description
    Estimates for response rate, rate difference (V419-Control), and p-value were based on the Miettinen and Nurminen method stratified by brand of birth dose of hepatitis B vaccine (RECOMBIVAX™ or other).
    Comparison groups
    Control v V419
    Number of subjects included in analysis
    1187
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [13]
    P-value
    < 0.001 [14]
    Method
    Miettinen and Nurminen
    Parameter type
    Estimated difference
    Point estimate
    -0.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    1.6
    Notes
    [13] - For Pertussis toxin, if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥-10%) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [14] - One-sided p-value

    Primary: Percentage of Subjects Responding to Pertussis Filamentous Hemagglutinin

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    End point title
    Percentage of Subjects Responding to Pertussis Filamentous Hemagglutinin
    End point description
    Subject serum samples were collected for testing with an ELISA for antibodies to Pertussis filamentous hemagglutinin (FHA). Sera response or endpoint was defined as follows: 1) if the pre-dose titer was <4X LLOQ then the post-dose titer was ≥4X LLOQ; 2) if the pre-dose titer was ≥4X LLOQ then the post-dose titer was ≥ the pre-dose titer. The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 3.
    End point type
    Primary
    End point timeframe
    Postdose 3 (Month 7)
    End point values
    V419 Control
    Number of subjects analysed
    796
    391
    Units: Percentage of subjects
    number (confidence interval 95%)
        Pertussis FHA
    87.31 (84.8 to 89.55)
    92.07 (88.93 to 94.55)
    Statistical analysis title
    Non-inferiority (Pertussis FHA)
    Statistical analysis description
    Estimates for response rate, rate difference (V419-Control), and p-value were based on the Miettinen and Nurminen method stratified by brand of birth dose of hepatitis B vaccine (RECOMBIVAX™ or other).
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1187
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [15]
    P-value
    = 0.001 [16]
    Method
    Miettinen and Nurminen
    Parameter type
    Estimated difference
    Point estimate
    -4.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.14
         upper limit
    -0.97
    Notes
    [15] - For Pertussis FHA, if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥-10%) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [16] - One-sided p-value

    Primary: Percentage of Subjects Responding to Pertussis Pertactin

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    End point title
    Percentage of Subjects Responding to Pertussis Pertactin
    End point description
    Subject serum samples were collected for testing with an ELISA for antibodies to Pertussis pertactin. Sera response or endpoint was defined as follows: 1) if the pre-dose titer was <4X LLOQ then the post-dose titer was ≥4X LLOQ; 2) if the pre-dose titer was ≥4X LLOQ then the post-dose titer was ≥ the pre-dose titer. The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 3.
    End point type
    Primary
    End point timeframe
    Postdose 3 (Month 7)
    End point values
    V419 Control
    Number of subjects analysed
    794
    390
    Units: Percentage of subjects
    number (confidence interval 95%)
        Pertussis Pertactin
    79.35 (76.36 to 82.11)
    82.05 (77.88 to 85.73)
    Statistical analysis title
    Non-inferiority (Pertussis Pertactin)
    Statistical analysis description
    Estimates for response rate, rate difference (V419-Control), and p-value were based on the Miettinen and Nurminen method stratified by brand of birth dose of hepatitis B vaccine (RECOMBIVAX™ or other).
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1184
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [17]
    P-value
    < 0.001 [18]
    Method
    Miettinen and Nurminen
    Parameter type
    Estimated difference
    Point estimate
    -2.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.27
         upper limit
    2.23
    Notes
    [17] - For Pertussis Pertactin, if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥-10%) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [18] - One-sided p-value

    Primary: Percentage of Subjects Responding to Pertussis Fimbriae

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    End point title
    Percentage of Subjects Responding to Pertussis Fimbriae
    End point description
    Subject serum samples were collected for testing with an ELISA for antibodies to pertussis fimbriae. Sera response or endpoint was defined as follows: 1) if the pre-dose titer was <4X LLOQ then the post-dose titer was ≥4X LLOQ; 2) if the pre-dose titer was ≥4X LLOQ then the post-dose titer was ≥ the pre-dose titer. The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 3.
    End point type
    Primary
    End point timeframe
    Postdose 3 (Month 7)
    End point values
    V419 Control
    Number of subjects analysed
    796
    391
    Units: Percentage of subjects
    number (confidence interval 95%)
        Pertussis Fimbriae
    90.2 (87.92 to 92.18)
    86.19 (82.37 to 89.45)
    Statistical analysis title
    Non-inferiority (Pertussis Fimbriae)
    Statistical analysis description
    Estimates for response rate, rate difference (V419-Control), and p-value were based on the Miettinen and Nurminen method stratified by brand of birth dose of hepatitis B vaccine (RECOMBIVAX™ or other).
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1187
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [19]
    P-value
    < 0.001 [20]
    Method
    Miettinen and Nurminen
    Parameter type
    Estimated difference
    Point estimate
    4.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.23
         upper limit
    8.28
    Notes
    [19] - For Pertussis Fimbriae, if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥-10%) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [20] - One-sided p-value

    Primary: Percentage of Subjects Responding to Poliovirus Type 1

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    End point title
    Percentage of Subjects Responding to Poliovirus Type 1
    End point description
    Subject serum samples were collected for testing with a micrometabolic inhibition test for neutralizing antibodies to Poliovirus Type 1. Sera response or endpoint was defined as a titer ≥8. The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 3.
    End point type
    Primary
    End point timeframe
    Postdose 3 (Month 7)
    End point values
    V419 Control
    Number of subjects analysed
    806
    398
    Units: Percentage of subjects
    number (confidence interval 95%)
        Poliovirus Type 1
    100 (99.54 to 100)
    98.24 (96.41 to 99.29)
    Statistical analysis title
    Non-inferiority (Poliovirus Type 1; ≥1:8 dilution)
    Statistical analysis description
    Estimates for response rate, rate difference (V419-Control), and p-value were based on the Miettinen and Nurminen method stratified by brand of birth dose of hepatitis B vaccine (RECOMBIVAX™ or other).
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1204
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [21]
    P-value
    < 0.001 [22]
    Method
    Miettinen and Nurminen
    Parameter type
    Estimated difference
    Point estimate
    1.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    3.59
    Notes
    [21] - For Poliovirus Type 1 (1:8 dilution), if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥-5%) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [22] - One-sided p-value
    Statistical analysis title
    Acceptability (Poliovirus Type 1; ≥1:8 dilution)
    Statistical analysis description
    Acceptability of Poliovirus Type 1
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1204
    Analysis specification
    Pre-specified
    Analysis type
    other [23]
    P-value
    < 0.001 [24]
    Method
    Clopper and Pearson
    Parameter type
    Response rate
    Point estimate
    100
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    99.54
         upper limit
    100
    Notes
    [23] - Acceptability requires that the lower bound of the 2-sided 95% confidence interval of the response rate is ≥90.
    [24] - One-sided P-value

    Primary: Percentage of Subjects Responding to Poliovirus Type 2

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    End point title
    Percentage of Subjects Responding to Poliovirus Type 2
    End point description
    Subject serum samples were collected for testing with a micrometabolic inhibition test for neutralizing antibodies to Poliovirus Type 2. Sera response or endpoint was defined as a titer ≥8. The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 3.
    End point type
    Primary
    End point timeframe
    Postdose 3 (Month 7)
    End point values
    V419 Control
    Number of subjects analysed
    801
    399
    Units: Percentage of subjects
    number (confidence interval 95%)
        Poliovirus Type 2
    100 (99.54 to 100)
    99.75 (98.61 to 99.99)
    Statistical analysis title
    Non-inferiority (Poliovirus Type 2; ≥1:8 dilution)
    Statistical analysis description
    Estimates for response rate, rate difference (V419-Control), and p-value were based on the Miettinen and Nurminen method stratified by brand of birth dose of hepatitis B vaccine (RECOMBIVAX™ or other).
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1200
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [25]
    P-value
    < 0.001 [26]
    Method
    Miettinen and Nurminen
    Parameter type
    Estimated difference
    Point estimate
    0.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.22
         upper limit
    1.42
    Notes
    [25] - For Poliovirus Type 2 (≥1:8 dilution), if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥-5%) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [26] - One-sided p-value
    Statistical analysis title
    Acceptability (Poliovirus Type 2; ≥1:8 dilution)
    Statistical analysis description
    Acceptability of Poliovirus Type 2
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1200
    Analysis specification
    Pre-specified
    Analysis type
    other [27]
    P-value
    < 0.001 [28]
    Method
    Clopper and Pearson
    Parameter type
    Response rate
    Point estimate
    100
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    99.54
         upper limit
    100
    Notes
    [27] - Acceptability requires that the lower bound of the 2-sided 95% confidence interval of the response rate is ≥90.
    [28] - One-sided P-value

    Primary: Percentage of Subjects Responding to Poliovirus Type 3

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    End point title
    Percentage of Subjects Responding to Poliovirus Type 3
    End point description
    Subject serum samples were collected for testing with a micrometabolic inhibition test for neutralizing Poliovirus Type 3. Sera response or endpoint was defined as a titer ≥8. The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 3.
    End point type
    Primary
    End point timeframe
    Postdose 3 (Month 7)
    End point values
    V419 Control
    Number of subjects analysed
    790
    396
    Units: Percentage of subjects
    number (confidence interval 95%)
        Poliovirus Type 3
    100 (99.53 to 100)
    99.75 (98.6 to 99.99)
    Statistical analysis title
    Non-inferiority (Poliovirus Type 3; ≥1:8 dilution)
    Statistical analysis description
    Estimates for response rate, rate difference (V419-Control), and p-value were based on the Miettinen and Nurminen method stratified by brand of birth dose of hepatitis B vaccine (RECOMBIVAX™ or other).
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1186
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [29]
    P-value
    < 0.001 [30]
    Method
    Miettinen and Nurminen
    Parameter type
    Estimated difference
    Point estimate
    0.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.24
         upper limit
    1.41
    Notes
    [29] - For Poliovirus Type 3 (≥1:8 dilution), if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥-5%) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [30] - One-sided P-value
    Statistical analysis title
    Acceptability (Poliovirus Type 3; ≥1:8 dilution)
    Statistical analysis description
    Acceptability of Poliovirus Type 3
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1186
    Analysis specification
    Pre-specified
    Analysis type
    other [31]
    P-value
    < 0.001 [32]
    Method
    Clopper and Pearson
    Parameter type
    Response rate
    Point estimate
    100
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    99.53
         upper limit
    100
    Notes
    [31] - Acceptability requires that the lower bound of the 2-sided 95% confidence interval of the response rate is ≥90.
    [32] - One-sided P-value

    Primary: Geometric Mean Concentrations (GMC) for Antibodies to Pertussis Toxin

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    End point title
    Geometric Mean Concentrations (GMC) for Antibodies to Pertussis Toxin
    End point description
    Subject serum samples were collected for testing with an ELISA for antibodies to pertussis toxin. The unit of measure is ELISA units/mL (EU/mL). The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 3.
    End point type
    Primary
    End point timeframe
    Postdose 3 (Month 7)
    End point values
    V419 Control
    Number of subjects analysed
    810
    400
    Units: EU/mL
    geometric mean (confidence interval 95%)
        Pertussis Toxin GMC
    110.4 (105.78 to 115.21)
    86.54 (81.87 to 91.48)
    Statistical analysis title
    Non-inferiority (Pertussis toxin; GMC)
    Statistical analysis description
    Estimates of GMC, GMC ratio (V419/control), and p-value were based on an ANCOVA model with natural log-transformed postvaccination titer as response variable, and vaccination group, natural log-transformed prevaccination titer, brand of birth dose of Hepatitis B vaccine as explanatory variables.
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1210
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [33]
    P-value
    < 0.001 [34]
    Method
    ANCOVA
    Parameter type
    GMC Ratio
    Point estimate
    1.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.2
         upper limit
    1.38
    Notes
    [33] - For Pertussis toxin (GMC), if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥0.67) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [34] - One-sided P-value

    Primary: Geometric Mean Concentrations (GMC) for Antibodies to Pertussis Filamentous Hemagglutinin

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    End point title
    Geometric Mean Concentrations (GMC) for Antibodies to Pertussis Filamentous Hemagglutinin
    End point description
    Subject serum samples were collected for testing with an ELISA for antibodies to pertussis filamentous hemagglutinin (FHA). The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 3.
    End point type
    Primary
    End point timeframe
    Postdose 3 (Month 7)
    End point values
    V419 Control
    Number of subjects analysed
    810
    400
    Units: EU/mL
    geometric mean (confidence interval 95%)
        Pertussis FHA GMC
    48.17 (45.68 to 50.8)
    74.44 (68.99 to 80.33)
    Statistical analysis title
    Non-inferiority (Pertussis FHA; GMC)
    Statistical analysis description
    Estimates of GMC, GMC ratio (V419/control), and p-value were based on an ANCOVA model with natural log-transformed postvaccination titer as response variable, and vaccination group, natural log-transformed prevaccination titer, brand of birth dose of Hepatitis B vaccine as explanatory variables.
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1210
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [35]
    P-value
    = 0.786 [36]
    Method
    ANCOVA
    Parameter type
    GMC Ratio
    Point estimate
    0.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.59
         upper limit
    0.7
    Notes
    [35] - For Pertussis FHA (GMC), if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥0.67) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was not achieved in this analysis.
    [36] - One-sided P-value

    Primary: Geometric Mean Concentrations (GMC) for Antibodies to Pertussis Pertactin

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    End point title
    Geometric Mean Concentrations (GMC) for Antibodies to Pertussis Pertactin
    End point description
    Subject serum samples were collected for testing with an ELISA for antibodies to pertussis pertactin. The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 3.
    End point type
    Primary
    End point timeframe
    Postdose 3 (Month 7)
    End point values
    V419 Control
    Number of subjects analysed
    808
    400
    Units: EU/mL
    geometric mean (confidence interval 95%)
        Pertussis Pertactin GMC
    56.22 (51.93 to 60.85)
    66.16 (59.5 to 73.57)
    Statistical analysis title
    Non-inferiority (Pertussis Pertactin; GMC)
    Statistical analysis description
    Estimates of GMC, GMC ratio (V419/control), and p-value were based on an ANCOVA model with natural log-transformed postvaccination titer as response variable, and vaccination group, natural log-transformed prevaccination titer, brand of birth dose of Hepatitis B vaccine as explanatory variables.
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1208
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [37]
    P-value
    < 0.001 [38]
    Method
    ANCOVA
    Parameter type
    GMC Ratio
    Point estimate
    0.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    0.95
    Notes
    [37] - For Pertussis Pertactin (GMC), if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥0.67) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [38] - One-sided p-value

    Primary: Geometric Mean Concentrations (GMC) for Antibodies to Pertussis Fimbriae

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    End point title
    Geometric Mean Concentrations (GMC) for Antibodies to Pertussis Fimbriae
    End point description
    Subject serum samples were collected for testing with an ELISA for antibodies to pertussis fimbriae.The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 3.
    End point type
    Primary
    End point timeframe
    Postdose 3 (Month 7)
    End point values
    V419 Control
    Number of subjects analysed
    809
    400
    Units: EU/mL
    geometric mean (confidence interval 95%)
        Pertussis Fimbriae GMC
    235.62 (221.43 to 250.73)
    185.54 (169.33 to 203.31)
    Statistical analysis title
    Non-inferiority (Pertussis Fimbriae; GMC)
    Statistical analysis description
    Estimates of GMC, GMC ratio (V419/control), and p-value were based on an ANCOVA model with natural log-transformed postvaccination titer as response variable, and vaccination group, natural log-transformed prevaccination titer, brand of birth dose of Hepatitis B vaccine as explanatory variables.
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1209
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [39]
    P-value
    < 0.001 [40]
    Method
    ANCOVA
    Parameter type
    GMC Ratio
    Point estimate
    1.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.15
         upper limit
    1.42
    Notes
    [39] - For Pertussis Fimbriae (GMC), if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥0.67) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [40] - One-sided p-value

    Primary: Percentage of Subjects Responding to Pertussis Toxin

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    End point title
    Percentage of Subjects Responding to Pertussis Toxin
    End point description
    Subject serum samples were collected for testing with an ELISA for antibodies to pertussis toxin. Sera response or endpoint was defined as follows: 1) if the pre-dose titer was <4X LLOQ then the post-dose titer was ≥4X LLOQ; 2) if the pre-dose titer was ≥4X LLOQ then the post-dose titer was ≥ the predose titer. The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 4.
    End point type
    Primary
    End point timeframe
    Postdose 4 (Month 16)
    End point values
    V419 Control
    Number of subjects analysed
    701
    349
    Units: Percentage of subjects
    number (confidence interval 95%)
        Pertussis Toxin
    99.29 (98.34 to 99.77)
    97.42 (95.16 to 98.81)
    Statistical analysis title
    Non-inferiority (Pertussis toxin)
    Statistical analysis description
    Estimates for response rate, rate difference (V419-Control), and p-value were based on the Miettinen and Nurminen method stratified by brand of birth dose of hepatitis B vaccine (RECOMBIVAX™ or other).
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1050
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [41]
    P-value
    < 0.001 [42]
    Method
    Miettinen and Nurminen
    Parameter type
    Mean difference (final values)
    Point estimate
    1.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.39
         upper limit
    4.18
    Notes
    [41] - For Pertussis Toxin, if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥-10%) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [42] - One-sided p-value

    Primary: Percentage of Subjects Responding to Pertussis Filamentous Hemagglutinin

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    End point title
    Percentage of Subjects Responding to Pertussis Filamentous Hemagglutinin
    End point description
    Subject serum samples were collected for testing with an ELISA for antibodies to pertussis filamentous hemagglutinin (FHA). Sera response or endpoint was defined as follows: 1) if the predose titer was <4X LLOQ then the postdose titer was ≥4X LLOQ; 2) if the predose titer was ≥4X LLOQ then the postdose titer was ≥ the predose titer. The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 4.
    End point type
    Primary
    End point timeframe
    Postdose 4 (Month 16)
    End point values
    V419 Control
    Number of subjects analysed
    699
    350
    Units: Percentage of subjects
    number (confidence interval 95%)
        Pertussis FHA
    94.42 (92.45 to 96)
    93.14 (89.97 to 95.56)
    Statistical analysis title
    Non-inferiority (Pertussis FHA)
    Statistical analysis description
    Estimates for response rate, rate difference (V419-Control), and p-value were based on the Miettinen and Nurminen method stratified by brand of birth dose of hepatitis B vaccine (RECOMBIVAX™ or other).
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1049
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [43]
    P-value
    < 0.001 [44]
    Method
    Miettinen and Nurminen
    Parameter type
    Mean difference (final values)
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.67
         upper limit
    4.78
    Notes
    [43] - For Pertussis FHA, if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥-10%) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [44] - One-sided p-value

    Primary: Percentage of Subjects Responding to Pertussis Pertactin

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    End point title
    Percentage of Subjects Responding to Pertussis Pertactin
    End point description
    Subject serum samples were collected for testing with an ELISA for antibodies to pertussis pertactin. Sera response or endpoint was defined as follows: 1) if the pre-dose titer was <4X LLOQ then the post-dose titer was ≥4X LLOQ; 2) if the pre-dose titer was ≥4X LLOQ then the post-dose titer was ≥ the pre-dose titer. The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 4.
    End point type
    Primary
    End point timeframe
    Postdose 4 (Month 16)
    End point values
    V419 Control
    Number of subjects analysed
    701
    351
    Units: Percentage of subjects
    number (confidence interval 95%)
        Pertussis Pertactin
    93.01 (90.86 to 94.78)
    93.45 (90.33 to 95.8)
    Statistical analysis title
    Non-inferiority (Pertussis Pertactin)
    Statistical analysis description
    Estimates for response rate, rate difference (V419-Control), and p-value were based on the Miettinen and Nurminen method stratified by brand of birth dose of hepatitis B vaccine (RECOMBIVAX™ or other).
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1052
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [45]
    P-value
    < 0.001 [46]
    Method
    Miettinen and Nurminen
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.46
         upper limit
    3.1
    Notes
    [45] - For Pertussis Pertactin, if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥-10%) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [46] - One-sided p-value

    Primary: Percentage of Subjects Responding to Pertussis Fimbriae

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    End point title
    Percentage of Subjects Responding to Pertussis Fimbriae
    End point description
    Subject serum samples were collected for testing with an ELISA for antibodies to pertussis fimbriae. Sera response or endpoint was defined as follows: 1) if the pre-dose titer was <4X LLOQ then the post-dose titer was ≥4X LLOQ; 2) if the pre-dose titer was ≥4X LLOQ then the post-dose titer was ≥ the predose titer. The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 4.
    End point type
    Primary
    End point timeframe
    Postdose 4 (Month 16)
    End point values
    V419 Control
    Number of subjects analysed
    700
    351
    Units: Percentage of subjects
    number (confidence interval 95%)
        Pertussis Fimbriae
    97.29 (95.79 to 98.36)
    91.17 (87.7 to 93.92)
    Statistical analysis title
    Non-inferiority (Pertussis Fimbriae)
    Statistical analysis description
    Estimates for response rate, rate difference (V419-Control), and p-value were based on the Miettinen and Nurminen method stratified by brand of birth dose of hepatitis B vaccine (RECOMBIVAX™ or other).
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1051
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [47]
    P-value
    < 0.001 [48]
    Method
    Miettinen and Nurminen
    Parameter type
    Mean difference (final values)
    Point estimate
    6.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.26
         upper limit
    9.78
    Notes
    [47] - For Pertussis Fimbriae, if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥-10%) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [48] - One-sided p-value

    Primary: Geometric Mean Concentrations (GMC) for Antibodies to Pertussis Toxin

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    End point title
    Geometric Mean Concentrations (GMC) for Antibodies to Pertussis Toxin
    End point description
    Subject serum samples were collected for testing with an ELISA for antibodies to pertussis toxin.
    End point type
    Primary
    End point timeframe
    Postdose 4 (Month 16)
    End point values
    V419 Control
    Number of subjects analysed
    713
    356
    Units: EU/mL
    geometric mean (confidence interval 95%)
        Pertussis Toxin GMC
    127.22 (121.17 to 133.57)
    91.31 (85.09 to 97.98)
    Statistical analysis title
    Non-inferiority (Pertussis toxin; GMC)
    Statistical analysis description
    Estimates of GMC, GMC ratio (V419/control), and p-value were based on an ANCOVA model with natural log-transformed postvaccination titer as response variable, and vaccination group, natural log-transformed prevaccination titer, brand of birth dose of Hepatitis B vaccine as explanatory variables.
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1069
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [49]
    P-value
    < 0.001 [50]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.28
         upper limit
    1.52
    Notes
    [49] - For Pertussis Toxin (GMC), if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥0.67) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [50] - One-sided p-value

    Primary: Geometric Mean Concentrations (GMC) for Antibodies to Pertussis Filamentous Hemagglutinin

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    End point title
    Geometric Mean Concentrations (GMC) for Antibodies to Pertussis Filamentous Hemagglutinin
    End point description
    Subject serum samples were collected for testing with an ELISA for antibodies to pertussis filamentous hemagglutinin (FHA). The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 4.
    End point type
    Primary
    End point timeframe
    Postdose 4 (Month 16)
    End point values
    V419 Control
    Number of subjects analysed
    710
    357
    Units: EU/mL
    geometric mean (confidence interval 95%)
        Pertussis FHA GMC
    88.92 (84.06 to 94.05)
    89.18 (82.54 to 96.35)
    Statistical analysis title
    Non-inferiority (Pertussis FHA; GMC)
    Statistical analysis description
    Estimates of GMC, GMC ratio (V19/control), and p-value were based on an ANCOVA model with natural log-transformed postvaccination titer as response variable, and vaccination group, natural log-transformed prevaccination titer, brand of birth dose of Hepatitis B vaccine as explanatory variables.
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1067
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [51]
    P-value
    < 0.001 [52]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.91
         upper limit
    1.1
    Notes
    [51] - For Pertussis FHA (GMC), if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥0.67) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [52] - One-sided p-value

    Primary: Geometric Mean Concentrations (GMC) for Antibodies to Pertussis Pertactin

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    End point title
    Geometric Mean Concentrations (GMC) for Antibodies to Pertussis Pertactin
    End point description
    Subject serum samples were collected for testing with an ELISA for antibodies to pertussis pertactin. The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 4.
    End point type
    Primary
    End point timeframe
    Postdose 4 (Month 16)
    End point values
    V419 Control
    Number of subjects analysed
    713
    358
    Units: EU/mL
    geometric mean (confidence interval 95%)
        Pertussis Pertactin GMC
    108.05 (99.88 to 116.9)
    139.35 (124.81 to 155.58)
    Statistical analysis title
    Non-inferiority (Pertussis Pertactin; GMC)
    Statistical analysis description
    Estimates of GMC, GMC ratio (V419/control), and p-value were based on an ANCOVA model with natural log-transformed postvaccination titer as response variable, and vaccination group, natural log-transformed prevaccination titer, brand of birth dose of Hepatitis B vaccine as explanatory variables.
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1071
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [53]
    P-value
    = 0.014 [54]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.68
         upper limit
    0.89
    Notes
    [53] - For Pertussis Pertactin (GMC), if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥0.67) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [54] - One-sided p-value

    Primary: Geometric Mean Concentrations (GMC) for Antibodies to Pertussis Fimbriae

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    End point title
    Geometric Mean Concentrations (GMC) for Antibodies to Pertussis Fimbriae
    End point description
    Subject serum samples were collected for testing with an ELISA for antibodies to pertussis fimbriae. The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 4.
    End point type
    Primary
    End point timeframe
    Postdose 4 (Month 16)
    End point values
    V419 Control
    Number of subjects analysed
    713
    358
    Units: EU/mL
    geometric mean (confidence interval 95%)
        Pertussis Fimbriae GMC
    658.5 (617.53 to 702.2)
    414.66 (371.41 to 462.94)
    Statistical analysis title
    Non-inferiority (Pertussis Fimbriae; GMC)
    Statistical analysis description
    Estimates of GMC, GMC ratio (V419/control), and p-value were based on an ANCOVA model with natural log-transformed postvaccination titer as response variable, and vaccination group, natural log-transformed prevaccination titer, brand of birth dose of Hepatitis B vaccine as explanatory variables.
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1071
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [55]
    P-value
    < 0.001 [56]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    1.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.41
         upper limit
    1.78
    Notes
    [55] - For Pertussis Fimbriae (GMC), if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥0.67) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [56] - One-sided p-value

    Secondary: Geometric Mean Concentrations (GMC) for Antibodies to Polyribosylribitol Phosphate (PRP) Antigen

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    End point title
    Geometric Mean Concentrations (GMC) for Antibodies to Polyribosylribitol Phosphate (PRP) Antigen
    End point description
    Subject serum samples were collected for testing with a radioimmunoassay for antibodies to Haemophilus influenza type b capsular polysaccharide polyribosylribitol phosphate (PRP). The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 3.
    End point type
    Secondary
    End point timeframe
    Postdose 3 (Month 7)
    End point values
    V419 Control
    Number of subjects analysed
    765
    382
    Units: µg/mL
    geometric mean (confidence interval 95%)
        PRP GMC
    5.11 (4.55 to 5.73)
    3.18 (2.66 to 3.81)
    Statistical analysis title
    Non-inferiority (PRP; GMC)
    Statistical analysis description
    Estimates of GMC, GMC ratio (V419/control), and p-value were based on an ANCOVA model with natural log-transformed postvaccination titer as response variable, and vaccination group, natural log-transformed prevaccination titer, brand of birth dose of Hepatitis B vaccine as explanatory variables.
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1147
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [57]
    P-value
    < 0.001 [58]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    1.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.32
         upper limit
    1.98
    Notes
    [57] - For PRP (GMC), if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥0.67) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [58] - One-sided p-value

    Secondary: Geometric Mean Concentrations (GMC) for Antibodies for Immunoglobulin A (IgA) Antibodies to Rotavirus

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    End point title
    Geometric Mean Concentrations (GMC) for Antibodies for Immunoglobulin A (IgA) Antibodies to Rotavirus
    End point description
    Subject serum samples were collected for testing with an ELISA for IgA antibodies to rotavirus. The analysis population included subjects who met the inclusion criteria, were not protocol violators, had a vaccination window of 42 to 84 days after the previous dose, and a blood draw sample window for the endpoint of 28 to 51 days after dose 3.
    End point type
    Secondary
    End point timeframe
    Postdose 3 (Month 7)
    End point values
    V419 Control
    Number of subjects analysed
    522
    274
    Units: units/mL
    geometric mean (confidence interval 95%)
        IgA Antibodies to Rotavirus GMC
    278.19 (246.99 to 313.32)
    274.46 (232.83 to 323.52)
    Statistical analysis title
    Non-inferiority (Rotavirus IgA; GMC)
    Statistical analysis description
    Estimates of GMC, GMC ratio (V419/control), and p-value were based on an ANCOVA model with natural log-transformed postvaccination titer as response variable, and vaccination group, natural log-transformed prevaccination titer, brand of birth dose of Hepatitis B vaccine as explanatory variables.
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    796
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [59]
    P-value
    < 0.001 [60]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.83
         upper limit
    1.24
    Notes
    [59] - For Rotavirus IgA (GMC), if the lower bound of the 2-sided 95% confidence interval for the group difference was above the prespecified non-inferiority margin (≥0.67) then the non-inferiority was achieved and indicated that V419 group immunogenicity was non-inferior to the Control group. Non-inferiority was achieved in this analysis.
    [60] - One-sided p-value

    Secondary: Percentage of Subjects Reporting Solicited Injection-site and Systemic Reactions Within Five Days Following Any Infant Dose Vaccination in the V419 and Control Groups

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    End point title
    Percentage of Subjects Reporting Solicited Injection-site and Systemic Reactions Within Five Days Following Any Infant Dose Vaccination in the V419 and Control Groups
    End point description
    Solicited injection site reactions: Pain, Erythema, and Swelling. Solicited systemic reactions: Pyrexia, Vomiting, Crying abnormal, Somnolence, Decreased appetite, and Irritability. Grade 3 Solicited injection site reaction: Pain, Cries when injected limb is moved or the movement of the injected limb is reduced; Erythema and Swelling, >5 cm. Grade 3 Solicited systemic reactions: Pyrexia, ≥39.5°C (≥103.1°F) rectal; Vomiting, ≥6 episodes per 24 hours or requiring parenteral hydration; Crying abnormal, >3 hours; Somnolence, Sleeping most of the time or difficult to wake up; Decreased appetite, Refuses ≥3 feeds or refuses most feeds; Irritability, Inconsolable. Subjects included in these analyses were All Subjects as Treated population and were defined as all vaccinated subjects with safety follow up.
    End point type
    Secondary
    End point timeframe
    Day 0 up to Day 5 post-any Infant dose
    End point values
    V419 Control
    Number of subjects analysed
    981
    484
    Units: Percentage of subjects
    number (not applicable)
        Any Injection site Pain
    73.4
    71.8
        Grade 3 Injection site Pain
    5.9
    4.6
        Any Injection site Erythema
    48.8
    42.2
        Grade 3 Injection site Erythema
    0.2
    0.6
        Any Injection site Swelling
    40.1
    34.8
        Grade 3 Injection site Swelling
    0.3
    0.4
        Any Pyrexia
    47.4
    34.4
        Grade 3 Pyrexia
    1.5
    1.2
        Any Vomiting
    25.7
    21.5
        Grade 3 Vomiting
    0.4
    0.6
        Any Crying abnormal
    74.8
    72.3
        Grade 3 Crying abnormal
    7.9
    8.3
        Any Somnolence
    74.1
    71.6
        Grade 3 Somnolence
    3.5
    2.9
        Any Decreased Appetite
    48.9
    43.3
        Grade 3 Decreased Appetite
    1.3
    0.4
        Any Irritability
    83.1
    81.8
        Grade 3 Irritability
    7.7
    5.8
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting Solicited Adverse Events Related to V419 or Control Within Five Days Following Any Infant Dose Vaccination

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    End point title
    Percentage of Subjects Reporting Solicited Adverse Events Related to V419 or Control Within Five Days Following Any Infant Dose Vaccination
    End point description
    Solicited systemic reactions: Pyrexia, Vomiting, Crying abnormal, Somnolence, Decreased appetite, and Irritability. Subjects included in this analyses were All Subjects as Treated population and were defined as all vaccinated subjects with safety follow up.
    End point type
    Secondary
    End point timeframe
    Day 0 up to Day 5 post-any Infant dose
    End point values
    V419 Control
    Number of subjects analysed
    981
    484
    Units: Percentage of subjects
    number (not applicable)
        Any Pyrexia
    45.1
    32.1
        Any Vomiting
    20.8
    16.4
        Any Crying abnormal
    71.4
    68.5
        Any Somnolence
    68.5
    66.7
        Any Decreased appetite
    45.7
    40.2
        Any Irritability
    79.6
    77.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting Solicited Adverse Events Related to V419 or Control Within Five Days By Vaccination Visit Following Each Infant Dose Vaccination

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    End point title
    Percentage of Subjects Reporting Solicited Adverse Events Related to V419 or Control Within Five Days By Vaccination Visit Following Each Infant Dose Vaccination
    End point description
    Solicited systemic reactions: Pyrexia, Vomiting, Crying abnormal, Somnolence, Decreased appetite, and Irritability.
    End point type
    Secondary
    End point timeframe
    Day 0 up to Day 5 post-each Infant dose
    End point values
    V419 Control
    Number of subjects analysed
    981
    484
    Units: Percentage of subjects
    number (not applicable)
        Any Pyrexia, Visit 1
    16.1
    12.6
        Any Pyrexia, Visit 2
    26.6
    16.4
        Any Pyrexia, Visit 3
    26.6
    16.2
        Any Vomiting, Visit 1
    11.2
    7.9
        Any Vomiting, Visit 2
    10.2
    8.5
        Any Vomiting, Visit 3
    8
    4.6
        Any Crying abnormal, Visit 1
    50.9
    48.7
        Any Crying abnormal, Visit 2
    48.4
    42.9
        Any Crying abnormal, Visit 3
    42
    36.1
        Any Somnolence, Visit 1
    54.6
    54
        Any Somnolence, Visit 2
    42.9
    41.4
        Any Somnolence, Visit 3
    38.3
    35
        Any Decreased appetite, Visit 1
    27.4
    24
        Any Decreased appetite, Visit 2
    24.1
    19.8
        Any Decreased appetite, Visit 3
    20.9
    17.3
        Any Irritability, Visit 1
    63.2
    60.5
        Any Irritability, Visit 2
    56.6
    52.7
        Any Irritability, Visit 3
    52.7
    48.8
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Elevated Temperature By Severity Within Five Days Following Any Infant Dose Vaccination in the V419 and Control Groups

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    End point title
    Percentage of Subjects With Elevated Temperature By Severity Within Five Days Following Any Infant Dose Vaccination in the V419 and Control Groups
    End point description
    Maximum temperature (all routes) was based on actual temperatures recorded with no adjustments to the measurement route. Maximum temperature (rectal) was required of all subjects if the reading by another method was ≥38.0°C. Percentages were based on the number of subjects in the population with safety follow-up and temperature data.
    End point type
    Secondary
    End point timeframe
    Day 0 up to Day 5 post-any Infant dose
    End point values
    V419 Control
    Number of subjects analysed
    981
    484
    Units: Percentage of subjects
    number (not applicable)
        Maximum temperature (all routes); <38.0°C
    51.1
    64.3
        Max. temp. (all routes); ≥38°C and <38.5°C
    24.2
    19.1
        Max. temp. (all routes); ≥38.5°C and <39.5°C
    22.7
    15.5
        Max. temp. (all routes); ≥39.5°C
    2
    1.1
        Maximum temperature (rectal); <38°C
    44.5
    57.7
        Maximum temperature (rectal); ≥38°C and <38.5°C
    24.3
    17.9
        Maximum temperature (rectal); ≥38.5°C and <39.5°C
    21.6
    14.9
        Maximum temperature (rectal); ≥39.5°C
    2
    0.9
    Statistical analysis title
    Estimated Difference; All routes, <38°C
    Statistical analysis description
    The estimated difference was calculated for the V419 group minus the Control group.
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1465
    Analysis specification
    Pre-specified
    Analysis type
    other [61]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -13.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.4
         upper limit
    -7.7
    Notes
    [61] - The 95% confidence intervals were based on the unstratified Miettinen and Nurminen method.
    Statistical analysis title
    Est. Difference; All routes, ≥38°C and <38.5°C
    Statistical analysis description
    The estimated difference was calculated for the V419 group minus the Control group.
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1465
    Analysis specification
    Pre-specified
    Analysis type
    other [62]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    5.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    9.5
    Notes
    [62] - The 95% confidence intervals were based on the unstratified Miettinen and Nurminen method.
    Statistical analysis title
    Est. Difference; All routes, ≥38.5°C and <39.5°C
    Statistical analysis description
    The estimated difference was calculated for the V419 group minus the Control group.
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1465
    Analysis specification
    Pre-specified
    Analysis type
    other [63]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    7.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.8
         upper limit
    11.2
    Notes
    [63] - The 95% confidence intervals were based on the unstratified Miettinen and Nurminen method.
    Statistical analysis title
    Est. Difference; All routes, ≥39.5°C
    Statistical analysis description
    The estimated difference was calculated for the V419 group minus the Control group.
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1465
    Analysis specification
    Pre-specified
    Analysis type
    other [64]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    2.2
    Notes
    [64] - The 95% confidence intervals were based on the unstratified Miettinen and Nurminen method.
    Statistical analysis title
    Estimated Difference; Rectal, <38°C
    Statistical analysis description
    The estimated difference was calculated for the V419 group minus the Control group.
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1465
    Analysis specification
    Pre-specified
    Analysis type
    other [65]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -13.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.6
         upper limit
    -7.7
    Notes
    [65] - The 95% confidence intervals were based on the unstratified Miettinen and Nurminen method.
    Statistical analysis title
    Estimated Difference; Rectal, ≥38°C and <38.5°C
    Statistical analysis description
    The estimated difference was calculated for the V419 group minus the Control group.
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1465
    Analysis specification
    Pre-specified
    Analysis type
    other [66]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    6.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.9
         upper limit
    10.8
    Notes
    [66] - The 95% confidence intervals were based on the unstratified Miettinen and Nurminen method.
    Statistical analysis title
    Estimated Difference; Rectal, ≥38.5°C and <39.5°C
    Statistical analysis description
    The estimated difference was calculated for the V419 group minus the Control group.
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1465
    Analysis specification
    Pre-specified
    Analysis type
    other [67]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    6.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.4
         upper limit
    10.7
    Notes
    [67] - The 95% confidence intervals were based on the unstratified Miettinen and Nurminen method.
    Statistical analysis title
    Estimated Difference; Rectal, ≥39.5°C
    Statistical analysis description
    The estimated difference was calculated for the V419 group minus the Control group.
    Comparison groups
    V419 v Control
    Number of subjects included in analysis
    1465
    Analysis specification
    Pre-specified
    Analysis type
    other [68]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    2.4
    Notes
    [68] - The 95% confidence intervals were based on the unstratified Miettinen and Nurminen method.

    Secondary: Percentage of Subjects With Pyrexia, Febrile Convulsion and Convulsion Following Any Infant Dose Vaccination in the V419 and Control Groups

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    End point title
    Percentage of Subjects With Pyrexia, Febrile Convulsion and Convulsion Following Any Infant Dose Vaccination in the V419 and Control Groups
    End point description
    The percentage of subjects with adverse events (AE), serious adverse events (SAE), and vaccine-related SAE (pyrexia, febrile convulsion, and convulsion) with an incidence >0% in 1 or more vaccination groups is reported.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 181 post-any Infant dose
    End point values
    V419 Control
    Number of subjects analysed
    981
    484
    Units: Percentage of subjects
    number (not applicable)
        Pyrexia (AE, Days 1-15)
    49.3
    35.6
        Febrile convulsion (AE, Days 1-15)
    0
    0
        Convulsion (AE, Days 1-15)
    0
    0
        Pyrexia (SAE, Days 1-15)
    0
    0
        Febrile convulsion (SAE, Days 1-15)
    0
    0
        Convulsion (SAE, Days 1-15)
    0
    0
        Pyrexia (SAE, Days 1-181)
    0
    0.2
        Febrile convulsion (SAE, Days 1-181)
    0.2
    0
        Convulsion (SAE, Days 1-181)
    0.1
    0.4
        Pyrexia (Vaccine-related SAE, Days 1-181)
    0
    0
        Febrile convulsion (Related SAE, Days 1-181)
    0
    0
        Convulsion (Vaccine-related SAE, Days 1-181)
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs: up to 6 months after vaccination 3 (the last infant vaccination) and up to 15 days after vaccination 4 (the toddler vaccination); Vaccine-related SAEs and deaths: up to Month 16 (duration of the study); Other AEs: up to 15 days after any vaccination
    Adverse event reporting additional description
    The All Subjects as Treated population included all randomized subjects who received at least one dose of study vaccine and had safety follow up.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16
    Reporting groups
    Reporting group title
    V419 group
    Reporting group description
    V419 0.5 mL intramuscular (IM) at 2, 4, and 6 months of age; Daptacel™ 0.5 mL IM at 15 months of age; PedvaxHIB™ 0.5 mL IM at 15 months of age; Prevnar13™ 0.5 mL IM at 2, 4, 6, and 15 months of age; and RotaTeq™ 2 mL oral dose at 2, 4, and 6 months of age.

    Reporting group title
    Control group
    Reporting group description
    PENTACEL™ 0.5 mL IM at 2, 4, and 6 months of age; Modified Process Hepatitis B vaccine 0.5 mL IM at 2 and 6 months of age; Daptacel™ 0.5 mL IM at 15 months of age; ActHIB™ 0.5 mL IM at 15 months of age; Prevnar13™ 0.5 mL IM at 2, 4, 6, and 15 months of age; and RotaTeq™ 2 mL oral dose at 2, 4, and 6 months of age.

    Serious adverse events
    V419 group Control group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    58 / 980 (5.92%)
    32 / 483 (6.63%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Kawasaki's disease
         subjects affected / exposed
    0 / 980 (0.00%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device expulsion
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 980 (0.00%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Foreign body
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 980 (0.00%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post concussion syndrome
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fractured base
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    0 / 980 (0.00%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Urine output decreased
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 980 (0.10%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Pyloric stenosis
         subjects affected / exposed
    0 / 980 (0.00%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    0 / 980 (0.00%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    0 / 980 (0.00%)
    2 / 483 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Apparent life threatening event
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asphyxia
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 980 (0.00%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    2 / 980 (0.20%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial hyperreactivity
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 980 (0.10%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infantile apnoeic attack
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 980 (0.00%)
    2 / 483 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 980 (0.10%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 980 (0.10%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyskinesia
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dystonia
         subjects affected / exposed
    0 / 980 (0.00%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile convulsion
         subjects affected / exposed
    2 / 980 (0.20%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Movement disorder
         subjects affected / exposed
    0 / 980 (0.00%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonic convulsion
         subjects affected / exposed
    0 / 980 (0.00%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal fistula
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    4 / 980 (0.41%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Abnormal weight gain
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    12 / 980 (1.22%)
    2 / 483 (0.41%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 980 (0.00%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    6 / 980 (0.61%)
    5 / 483 (1.04%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 980 (0.00%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Croup infectious
         subjects affected / exposed
    4 / 980 (0.41%)
    3 / 483 (0.62%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis viral
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    5 / 980 (0.51%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Human herpesvirus 6 infection
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    2 / 980 (0.20%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 980 (0.00%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis enteroviral
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    0 / 980 (0.00%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 980 (0.10%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 980 (0.51%)
    2 / 483 (0.41%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    6 / 980 (0.61%)
    4 / 483 (0.83%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Roseola
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    2 / 980 (0.20%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 980 (0.20%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 980 (0.10%)
    0 / 483 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    0 / 980 (0.00%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    0 / 980 (0.00%)
    1 / 483 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    V419 group Control group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    939 / 980 (95.82%)
    458 / 483 (94.82%)
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    755 / 980 (77.04%)
    369 / 483 (76.40%)
         occurrences all number
    1863
    887
    General disorders and administration site conditions
    Irritability
         subjects affected / exposed
    853 / 980 (87.04%)
    415 / 483 (85.92%)
         occurrences all number
    2390
    1109
    Pyrexia
         subjects affected / exposed
    560 / 980 (57.14%)
    216 / 483 (44.72%)
         occurrences all number
    1015
    356
    Injection site bruising
         subjects affected / exposed
    62 / 980 (6.33%)
    36 / 483 (7.45%)
         occurrences all number
    103
    61
    Crying
         subjects affected / exposed
    788 / 980 (80.41%)
    370 / 483 (76.60%)
         occurrences all number
    1934
    857
    Injection site erythema
         subjects affected / exposed
    597 / 980 (60.92%)
    277 / 483 (57.35%)
         occurrences all number
    2665
    1365
    Injection site pain
         subjects affected / exposed
    826 / 980 (84.29%)
    391 / 483 (80.95%)
         occurrences all number
    4276
    2234
    Injection site swelling
         subjects affected / exposed
    513 / 980 (52.35%)
    219 / 483 (45.34%)
         occurrences all number
    1974
    989
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    61 / 980 (6.22%)
    22 / 483 (4.55%)
         occurrences all number
    68
    25
    Vomiting
         subjects affected / exposed
    282 / 980 (28.78%)
    125 / 483 (25.88%)
         occurrences all number
    432
    186
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    577 / 980 (58.88%)
    271 / 483 (56.11%)
         occurrences all number
    1087
    469
    Infections and infestations
    Otitis media
         subjects affected / exposed
    69 / 980 (7.04%)
    26 / 483 (5.38%)
         occurrences all number
    76
    28
    Upper respiratory tract infection
         subjects affected / exposed
    100 / 980 (10.20%)
    40 / 483 (8.28%)
         occurrences all number
    108
    41

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Dec 2010
    The analysis of the pertussis responses at one month post-Toddler dose of DAPTACEL™ was moved to a primary objective and hypothesis, an additional statistical criterion for the non-inferiority analysis of the anti-PRP response at one month post-third dose of PR5I or Control was added, an acceptability criterion of 90% (lower bound of the 2-sided 95% CI >90%) for the observed seroprotection rate in the PR5I group was added as a primary endpoint for Inactivated Poliovirus (Types 1, 2, and 3), name of the company was changed to Merck Sharp & Dohme Corp. throughout the document and protocol, pneumococcal conjugate vaccine was changed to Prevnar13™, sample size increased to 1440 subjects, PR5I group sample size increased to 960 subjects, and changes were made throughout the protocol, including all references to Interactive Voice Response System being changed to Interactive Response Technology.
    03 Mar 2011
    Revised statistical criteria for the non-inferiority analysis of the anti-PRP response at one month post-third dose of PR5I or Control, analysis of anti-PRP GMTs was moved to a secondary endpoint, and other changes to the text regarding change in the primary and secondary endpoints and analysis methods and revisions for the purpose of clarity.
    08 Mar 2012
    Revised the primary objective and hypothesis as well as statistical criteria for the acceptability of Inactivated Poliovirus response, approved the modified manufacturing process for RECOMBIVAX HB™ by the FDA and information related to the new vaccine supply shippers.
    24 Jan 2013
    Added a new primary statistical analysis method for all GMT analyses to account for missing baseline titers, added a second Per Protocol Population (Per Protocol-Revised Window) in addition to the existing Per Protocol Original Window to account for subjects who received study vaccinations and/or blood draws outside of narrow protocol-defined visit windows, added 2 sensitivity analyses (analysis of GMT endpoints with no baseline adjustment and analysis of GMT endpoints based on data from subjects with both baseline and postvaccination titers to support the ANCOVA with missing imputation for missing baseline titers primary analysis for GMT endpoints), and added revised systemic corticosteroid use criteria to the description of protocol violations for which a subject was excluded from the Per Protocol Population.

    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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