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    Clinical Trial Results:
    A phase III, randomized, open-label, multicentre study to assess the immunogenicity, safety and reactogenicity of GlaxoSmithKline Biologicals’ combined DTPa-IPV/Hib vaccine administered as a three-dose primary vaccination course at 2-4-6 months of age in healthy infants in South Korea.

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2012-004137-16
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    24 Feb 2012

    Results information
    Results version number
    		 v2
    This version publication date
    08 Jul 2016
    First version publication date
    02 Jul 2015
    Other versions
    		 v1 (removed from public view) , v3
    Version creation reason
    • Correction of full data set
    Data correction due to a system error in EudraCT – Results

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    114260
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01309646
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l’Institut 89, Rixensart, Belgium, B-1330
    Public contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Mar 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Feb 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Feb 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that the immunogenicity of GSK Biologicals’ DTPa-IPV/Hib vaccine administered at 2, 4 and 6 months of age is non-inferior to that of the concomitant administration of GSK Biologicals’ DTPa-IPV and Hib vaccines, in terms of immune response to all vaccine antigens, one month after the third dose of the primary vaccination.
    Protection of trial subjects
    All subjects were supervised closely for at least 30 minutes following vaccination with appropriate medical treatment readily available. Vaccines were administered by qualified and trained personnel. Vaccines were administered only to eligible subjects that had no contraindications to any components of the vaccines. Subjects were followed-up for one month (minimum 30 days) following administration of the last dose of study vaccines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Mar 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
    Korea, Republic of: 454
    Worldwide total number of subjects
    454
    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)
    454
    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
    		 -

    Pre-assignment
    Screening details
    		 During the screening the following steps occurred: check for inclusion/exclusion criteria, contraindications/precautions, medical history of the subjects and signing informed consent forms.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Infanrix-IPV+Hib Group
    Arm description
    		 Subjects aged between, and including, 42 and 69 days at the time of first vaccination received 3 doses of Infanrix-IPV+Hib at 2, 4 and 6 months of age, 3 doses of Synflorix at 6 weeks, 3.5 and 5.5 months of age and 2 doses of Rotarix at 6 weeks and 3.5 months of age. The Infanrix-IPV+Hib was administered intramuscularly in the right thigh, the Synflorix vaccine was administered intramuscularly in the left thigh and the Rotarix vaccine was administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Infanrix-IPV+Hib
    Investigational medicinal product code
    Other name
    DTPa-IPV/Hib
    Pharmaceutical forms
    Powder and suspension for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular, 3 doses at 2,4 and 6 months of age.

    Investigational medicinal product name
    Synflorix
    Investigational medicinal product code
    Other name
    10Pn-PD-DiT
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular, 3 doses at 6 weeks, 3.5 and 5.5 months of age.

    Investigational medicinal product name
    Rotarix
    Investigational medicinal product code
    Other name
    HRV
    Pharmaceutical forms
    Powder and solvent for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Oral, 2 doses at 6 weeks and 3.5 months of age.

    Arm title
    		 Infanrix IPV Group
    Arm description
    		 Subjects aged between, and including, 42 and 69 days at the time of first vaccination received 3 doses of Infanrix IPV and Hiberix co-administered at separate injection sites at 2, 4 and 6 months of age, 3 dose of Synflorix at 6 weeks, 3.5 and 5.5 months of age and 2 doses of Rotarix at 6 weeks and 3.5 months of age. The Infanrix IPV was administered intramuscularly in the right thigh, the Synflorix and Hiberix vaccines were administered intramuscularly in the left thigh and the Rotarix vaccine was administered orally.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Infanrix IPV
    Investigational medicinal product code
    Other name
    DTPa-IPV
    Pharmaceutical forms
    Powder and suspension for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular, 3 doses co-administered at 2, 4 and 6 months of age with Hiberix™.

    Investigational medicinal product name
    Hiberix
    Investigational medicinal product code
    Other name
    Hib
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular, 3 doses co-administered at 2, 4 and 6 months of age with Infanrix™ IPV.

    Investigational medicinal product name
    Synflorix
    Investigational medicinal product code
    Other name
    10Pn-PD-DiT
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular, 3 doses at 6 weeks, 3.5 and 5.5 months of age.

    Investigational medicinal product name
    Rotarix
    Investigational medicinal product code
    Other name
    HRV
    Pharmaceutical forms
    Powder and solvent for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Oral, 2 doses at 6 weeks and 3.5 months of age.

    Number of subjects in period 1
    		Infanrix-IPV+Hib Group Infanrix IPV Group
    Started
    226
    228
    Completed
    224
    227
    Not completed
    2
    1
         Consent withdrawn by subject
    1
    -
         Protocol Violation
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Infanrix-IPV+Hib Group
    Reporting group description
    		 Subjects aged between, and including, 42 and 69 days at the time of first vaccination received 3 doses of Infanrix-IPV+Hib at 2, 4 and 6 months of age, 3 doses of Synflorix at 6 weeks, 3.5 and 5.5 months of age and 2 doses of Rotarix at 6 weeks and 3.5 months of age. The Infanrix-IPV+Hib was administered intramuscularly in the right thigh, the Synflorix vaccine was administered intramuscularly in the left thigh and the Rotarix vaccine was administered orally.

    Reporting group title
    Infanrix IPV Group
    Reporting group description
    		 Subjects aged between, and including, 42 and 69 days at the time of first vaccination received 3 doses of Infanrix IPV and Hiberix co-administered at separate injection sites at 2, 4 and 6 months of age, 3 dose of Synflorix at 6 weeks, 3.5 and 5.5 months of age and 2 doses of Rotarix at 6 weeks and 3.5 months of age. The Infanrix IPV was administered intramuscularly in the right thigh, the Synflorix and Hiberix vaccines were administered intramuscularly in the left thigh and the Rotarix vaccine was administered orally.

    Reporting group values
    		 Infanrix-IPV+Hib Group Infanrix IPV Group Total
    Number of subjects
    		 226 228 454
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: weeks
        arithmetic mean (standard deviation)
    		 8.8 ± 1.1 8.8 ± 1.09 -
    Gender categorical
    Units: Subjects
        Female
    		 98 116 214
        Male
    		 128 112 240

    End points

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    End points reporting groups
    Reporting group title
    Infanrix-IPV+Hib Group
    Reporting group description
    		 Subjects aged between, and including, 42 and 69 days at the time of first vaccination received 3 doses of Infanrix-IPV+Hib at 2, 4 and 6 months of age, 3 doses of Synflorix at 6 weeks, 3.5 and 5.5 months of age and 2 doses of Rotarix at 6 weeks and 3.5 months of age. The Infanrix-IPV+Hib was administered intramuscularly in the right thigh, the Synflorix vaccine was administered intramuscularly in the left thigh and the Rotarix vaccine was administered orally.

    Reporting group title
    Infanrix IPV Group
    Reporting group description
    		 Subjects aged between, and including, 42 and 69 days at the time of first vaccination received 3 doses of Infanrix IPV and Hiberix co-administered at separate injection sites at 2, 4 and 6 months of age, 3 dose of Synflorix at 6 weeks, 3.5 and 5.5 months of age and 2 doses of Rotarix at 6 weeks and 3.5 months of age. The Infanrix IPV was administered intramuscularly in the right thigh, the Synflorix and Hiberix vaccines were administered intramuscularly in the left thigh and the Rotarix vaccine was administered orally.

    Primary: Number of seroprotected subjects for anti-diphtheria (anti-D) and anti-tetanus (anti-T) antibodies

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    End point title
    		 Number of seroprotected subjects for anti-diphtheria (anti-D) and anti-tetanus (anti-T) antibodies
    End point description
    A seroprotected subject was defined as a vaccinated subject who had an anti-D and anti-T antibody concentration greater to or above (≥) 0.1 international units per milliliter (IU/mL). The Month 5 results are the primary outcome variables.
    End point type
    Primary
    End point timeframe
    At Month 0 and Month 5
    End point values
    		 Infanrix-IPV+Hib Group Infanrix IPV Group
    Number of subjects analysed
    213
    217
    Units: Subjects
        Anti-D at Month 0
    29
    30
        Anti-D at Month 5
    213
    217
        Anti-T at Month 0
    64
    76
        Anti-T at Month 5
    213
    217
    Statistical analysis title
    		 Difference in seroprotection rates for anti-D
    Statistical analysis description
    To demonstrate that the immunogenicity of the Infanrix™-IPV+Hib vaccine administered at 2, 4 and 6 months of age was non-inferior to that of the concomitant administration of the Infanrix™ IPV and Hiberix™ vaccines, in terms of immune response to all vaccine antigens, one month after the third dose of the primary vaccination.
    Comparison groups
    Infanrix IPV Group v Infanrix-IPV+Hib Group
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Difference in seroprotection rate
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.74
         upper limit
    		 1.78
    Notes
    [1] - UL of the standardized asymptotic 95% CI on the group difference [Infanrix-IPV+Hib Group minus Infanrix IPV Group]in percentage of seroprotected subjects ≤ 10%
    Statistical analysis title
    		 Difference in seroprotection rates for anti-T
    Statistical analysis description
    To demonstrate that the immunogenicity of the Infanrix™-IPV+Hib vaccine administered at 2, 4 and 6 months of age was non-inferior to that of the concomitant administration of the Infanrix™ IPV and Hiberix™ vaccines, in terms of immune response to all vaccine antigens, one month after the third dose of the primary vaccination.
    Comparison groups
    Infanrix-IPV+Hib Group v Infanrix IPV Group
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Difference in seroprotection rate
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.74
         upper limit
    		 1.78
    Notes
    [2] - UL of the standardized asymptotic 95% CI on the group difference [Infanrix-IPV+Hib Group minus Infanrix IPV Group]in percentage of seroprotected subjects ≤ 10%

    Primary: Number of seroprotected subjects for anti-polyribosyl-ribitol-phosphate (anti-PRP) antibodies

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    End point title
    		 Number of seroprotected subjects for anti-polyribosyl-ribitol-phosphate (anti-PRP) antibodies
    End point description
    A seroprotected subject was defined as a vaccinated subject who had an anti-PRP antibody concentration ≥ 0.15 micrograms per milliliter (µg/mL). The Month 5 results are the primary outcome variables.
    End point type
    Primary
    End point timeframe
    At Month 0 and Month 5
    End point values
    		 Infanrix-IPV+Hib Group Infanrix IPV Group
    Number of subjects analysed
    213
    217
    Units: Subjects
        Anti-PRP at Month 0
    91
    109
        Anti-PRP at Month 5
    213
    217
    Statistical analysis title
    		 Difference in seroprotection rates for anti-PRP
    Statistical analysis description
    To demonstrate that the immunogenicity of the Infanrix™-IPV+Hib vaccine administered at 2, 4 and 6 months of age was non-inferior to that of the concomitant administration of the Infanrix™ IPV and Hiberix™ vaccines, in terms of immune response to all vaccine antigens, one month after the third dose of the primary vaccination.
    Comparison groups
    Infanrix-IPV+Hib Group v Infanrix IPV Group
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Difference in seroprotection rate
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.74
         upper limit
    		 1.78
    Notes
    [3] - UL of the standardized asymptotic 95% CI on the group difference [Infanrix-IPV+Hib Group minus Infanrix IPV Group] in percentage of seroprotected subjects ≤ 10%

    Primary: Concentrations for anti-D and anti-T antibodies

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    End point title
    		 Concentrations for anti-D and anti-T antibodies [4]
    End point description
    Concentrations were expressed as geometric mean concentrations (GMCs). The seroprotection cut-off of the assay was 0.1 IU/mL.
    End point type
    Primary
    End point timeframe
    At Month 0 and Month 5
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 Infanrix-IPV+Hib Group Infanrix IPV Group
    Number of subjects analysed
    213
    217
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Anti-D at Month 0
    0.058 (0.055 to 0.061)
    0.06 (0.056 to 0.064)
        Anti-D at Month 5
    8.096 (7.52 to 8.717)
    8.692 (8.125 to 9.298)
        Anti-T at Month 0
    0.081 (0.072 to 0.09)
    0.091 (0.08 to 0.103)
        Anti-T at Month 5
    10.259 (9.654 to 10.902)
    12.421 (11.599 to 13.301)
    No statistical analyses for this end point

    Primary: Number of subjects seroprotected for anti-Polio virus type 1, 2 and 3 antibodies

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    End point title
    		 Number of subjects seroprotected for anti-Polio virus type 1, 2 and 3 antibodies
    End point description
    End point type
    Primary
    End point timeframe
    At one month after (POST) Dose 3
    End point values
    		 Infanrix-IPV+Hib Group Infanrix IPV Group
    Number of subjects analysed
    212
    216
    Units: Subjects
        Anti-Polio 1, POST [N=212;216]
    212
    216
        Anti-Polio 2, POST [N=204;211]
    204
    211
        Anti-polio 3, POST [N=198;199]
    197
    197
    Statistical analysis title
    		 Difference in seroprotection rates for anti-Polio1
    Statistical analysis description
    To demonstrate that the immunogenicity of the Infanrix™-IPV+Hib vaccine administered at 2, 4 and 6 months of age was non-inferior to that of the concomitant administration of GSK Biologicals’ Infanrix™ IPV and Hiberix™ vaccines, in terms of immune response to anti-Polio type 1 antibodies, one month after the third dose of the primary vaccination.
    Comparison groups
    Infanrix IPV Group v Infanrix-IPV+Hib Group
    Number of subjects included in analysis
    428
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 Difference in seroprotection rates
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.75
         upper limit
    		 1.78
    Notes
    [5] - The upper limits of the standardized asymptotic 95% confidence interval (CI) on the group differences [Infanrix IPV Group minus Infanrix-IPV+Hib Group] in percentages of subjects seroprotected against poliovirus type 1 was ≤ 10%.
    Statistical analysis title
    		 Difference in seroprotection rates for anti-Polio2
    Statistical analysis description
    To demonstrate that the immunogenicity of the Infanrix™-IPV+Hib vaccine administered at 2, 4 and 6 months of age was non-inferior to that of the concomitant administration of GSK Biologicals’ Infanrix™ IPV and Hiberix™ vaccines, in terms of immune response to anti-Polio type 2 antibodies, one month after the third dose of the primary vaccination.
    Comparison groups
    Infanrix-IPV+Hib Group v Infanrix IPV Group
    Number of subjects included in analysis
    428
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Difference in seroprotection rates
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.79
         upper limit
    		 1.85
    Notes
    [6] - The upper limits of the standardized asymptotic 95% confidence interval (CI) on the group differences [Infanrix IPV Group minus Infanrix-IPV+Hib Group] in percentages of subjects seroprotected against poliovirus type 2 was ≤ 10%.
    Statistical analysis title
    		 Difference in seroprotection rates for anti-Polio3
    Statistical analysis description
    To demonstrate that the immunogenicity of the Infanrix™-IPV+Hib vaccine administered at 2, 4 and 6 months of age was non-inferior to that of the concomitant administration of GSK Biologicals’ Infanrix™ IPV and Hiberix™ vaccines, in terms of immune response to anti-Polio type 3 antibodies, one month after the third dose of the primary vaccination.
    Comparison groups
    Infanrix IPV Group v Infanrix-IPV+Hib Group
    Number of subjects included in analysis
    428
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 Difference in seroprotection rates
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.14
         upper limit
    		 1.89
    Notes
    [7] - The upper limits of the standardized asymptotic 95% confidence interval (CI) on the group differences [Infanrix IPV Group minus Infanrix-IPV+Hib Group] in percentages of subjects seroprotected against poliovirus type 3 was ≤ 10%.

    Primary: Anti-pertussis toxoid (PT), anti-filamentous haemagglutinin (FHA) and anti-pertactin (PRN) antibody concentrations

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    End point title
    		 Anti-pertussis toxoid (PT), anti-filamentous haemagglutinin (FHA) and anti-pertactin (PRN) antibody concentrations
    End point description
    End point type
    Primary
    End point timeframe
    At one month after (POST) Dose 3
    End point values
    		 Infanrix-IPV+Hib Group Infanrix IPV Group
    Number of subjects analysed
    213
    217
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-PT [N=213;217]
    54.2 (50.4 to 58.3)
    56 (51.8 to 60.5)
        Anti-FHA [N=213;217]
    125 (115.4 to 135.4)
    134.2 (124.2 to 145)
        Anti-PRN [N=213;217]
    125.8 (116 to 136.5)
    133.4 (123 to 144.6)
    Statistical analysis title
    		 Difference in GMC ratio for anti-PT
    Statistical analysis description
    To demonstrate that the immunogenicity of the Infanrix™-IPV+Hib vaccine administered at 2, 4 and 6 months of age was non-inferior to that of the concomitant administration of GSK Biologicals’ Infanrix™ IPV and Hiberix™ vaccines, in terms of immune response to anti-PT antigens, one month after the third dose of the primary vaccination.
    Comparison groups
    Infanrix IPV Group v Infanrix-IPV+Hib Group
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in GMC ratio
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.15
    Notes
    [8] - The upper limits of the 95% confidence interval (CI) on the group ratio [Infanrix IPV Group divided by Infanrix-IPV+Hib Group] of geometric mean concentrations (GMCs) of antibodies against pertussis toxoid (PT) was ≤ 1.5.
    Statistical analysis title
    		 Difference in GMC ratio for anti-FHA
    Statistical analysis description
    To demonstrate that the immunogenicity of the Infanrix™-IPV+Hib vaccine administered at 2, 4 and 6 months of age was non-inferior to that of the concomitant administration of GSK Biologicals’ Infanrix™ IPV and Hiberix™ vaccines, in terms of immune response to anti-FHA antigens, one month after the third dose of the primary vaccination.
    Comparison groups
    Infanrix-IPV+Hib Group v Infanrix IPV Group
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in GMC ratio
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.97
         upper limit
    		 1.21
    Notes
    [9] - The upper limits of the 95% confidence interval (CI) on the group ratio [Infanrix IPV Group divided by Infanrix-IPV+Hib Group] of geometric mean concentrations (GMCs) of antibodies against filamentous haemagglutinin (FHA) was ≤ 1.5.
    Statistical analysis title
    		 Difference in GMC ratio for anti-PRN
    Statistical analysis description
    To demonstrate that the immunogenicity of the Infanrix™-IPV+Hib vaccine administered at 2, 4 and 6 months of age was non-inferior to that of the concomitant administration of GSK Biologicals’ Infanrix™ IPV and Hiberix™ vaccines, in terms of immune response to anti-PRN antigens, one month after the third dose of the primary vaccination.
    Comparison groups
    Infanrix-IPV+Hib Group v Infanrix IPV Group
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [10]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in GMC ratio
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 1.21
    Notes
    [10] - The upper limits of the 95% confidence interval (CI) on the group ratio [Infanrix IPV Group divided by Infanrix-IPV+Hib Group] of geometric mean concentrations (GMCs) of antibodies against pertactin (PRN) was ≤ 1.5.

    Primary: Number of subjects with anti-PT, anti-FHA and anti-PRN antibody concentrations equal to or above (≥) the cut-off value of 5 ELISA units per millilitre (EL.U/mL)

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    End point title
    		 Number of subjects with anti-PT, anti-FHA and anti-PRN antibody concentrations equal to or above (≥) the cut-off value of 5 ELISA units per millilitre (EL.U/mL) [11]
    End point description
    Results for the one month after (POST) Dose 3 vaccination timepoint were the primary outcome.
    End point type
    Primary
    End point timeframe
    Prior to vaccination (PRE) and one month after (POST) Dose 3
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 Infanrix-IPV+Hib Group Infanrix IPV Group
    Number of subjects analysed
    213
    217
    Units: Subjects
        Anti-PT, PRE [N=212;216]
    27
    34
        Anti-PT, POST [N=213;217]
    213
    217
        Anti-FHA, PRE [N=211;214]
    170
    178
        Anti-FHA, POST [N=213;217]
    213
    217
        Anti-PRN, PRE [N=213;217]
    25
    30
        Anti-PRN, POST [N=213;217]
    213
    217
    No statistical analyses for this end point

    Secondary: Number of subjects with any solicited local symptoms

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    End point title
    		 Number of subjects with any solicited local symptoms
    End point description
    Assessed solicited local symptoms were pain, redness and swelling at the injection site. Any = incidence of a particular symptom regardless of intensity grade.
    End point type
    Secondary
    End point timeframe
    During the 4-day (Days 0-3) follow-up period after any vaccination with Infanrix™-IPV+Hib or Infanrix™ IPV + Hiberix™
    End point values
    		 Infanrix-IPV+Hib Group Infanrix IPV Group
    Number of subjects analysed
    224
    227
    Units: Subjects
        Any Pain
    143
    146
        Any Redness
    177
    167
        Any Swelling
    130
    121
    No statistical analyses for this end point

    Secondary: Number of subjects with any solicited general symptoms

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    End point title
    		 Number of subjects with any solicited general symptoms
    End point description
    Assessed solicited general symptoms were drowsiness, irritability/fussiness, loss of appetite and fever [defined as tympanic temperature ≥ 37.5 degrees Celsius (°C)]. Any = incidence of a particular symptom regardless of intensity grade.
    End point type
    Secondary
    End point timeframe
    During the 4-day (Days 0-3) follow-up period after any vaccination with Infanrix™-IPV+Hib or Infanrix™ IPV + Hiberix™
    End point values
    		 Infanrix-IPV+Hib Group Infanrix IPV Group
    Number of subjects analysed
    224
    227
    Units: Subjects
        Any Drowsiness
    153
    147
        Any Irritability/Fussiness
    181
    182
        Any Loss of appetite
    120
    103
        Temperature ≥ 37.5°C
    83
    81
    No statistical analyses for this end point

    Secondary: Number of subjects with any unsolicited adverse events (AEs)

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    End point title
    		 Number of subjects with any unsolicited adverse events (AEs)
    End point description
    Unsolicited AE covers any AE reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any = any unsolicited AE regardless of intensity or relationship to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 31-day (Days 0-30) follow-up period after any vaccination with Infanrix™-IPV+Hib or Infanrix™ IPV + Hiberix™
    End point values
    		 Infanrix-IPV+Hib Group Infanrix IPV Group
    Number of subjects analysed
    224
    227
    Units: Subjects
        Any AEs
    130
    123
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects with any serious adverse events (SAEs)
    End point description
    Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.
    End point type
    Secondary
    End point timeframe
    During the entire study period (from Month 0 to Month 5 ½)
    End point values
    		 Infanrix-IPV+Hib Group Infanrix IPV Group
    Number of subjects analysed
    224
    227
    Units: Subjects
        Any SAEs
    25
    21
    No statistical analyses for this end point

    Secondary: Concentrations of anti-PRN antibodies

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    End point title
    		 Concentrations of anti-PRN antibodies
    End point description
    Concentrations were expressed as geometric mean concentrations (GMCs). The seropositivity cut-off of the assay was 5 EL.U/mL.
    End point type
    Secondary
    End point timeframe
    At Month 0 and Month 5
    End point values
    		 Infanrix-IPV+Hib Group Infanrix IPV Group
    Number of subjects analysed
    213
    217
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-PRN at Month 0
    2.9 (2.7 to 3)
    3.1 (2.8 to 3.3)
        Anti-PRN at Month 5
    125.8 (116 to 136.5)
    133.4 (123 to 144.6)
    No statistical analyses for this end point

    Secondary: Concentrations of anti-PRP antibodies

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    End point title
    		 Concentrations of anti-PRP antibodies
    End point description
    Concentrations were expressed as geometric mean concentrations (GMCs). The seroprotection cut-off of the assay was 0.15 µg/mL.
    End point type
    Secondary
    End point timeframe
    At Month 0 and Month 5
    End point values
    		 Infanrix-IPV+Hib Group Infanrix IPV Group
    Number of subjects analysed
    213
    217
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-PRP at Month 0
    0.165 (0.143 to 0.191)
    0.219 (0.184 to 0.26)
        Anti-PRP at Month 5
    8.456 (7.283 to 9.819)
    18.7 (16.353 to 21.384)
    No statistical analyses for this end point

    Secondary: Number of subjects with a vaccine response

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    End point title
    		 Number of subjects with a vaccine response
    End point description
    Vaccine response was defined as antibody concentration ≥ 5 EL.U/mL at post vaccination, for initially seronegative subjects, and at least maintenance of antibody concentration from pre to post-vaccination (i.e. antibody concentration at post vaccination ≥ 1 fold the pre-vaccination antibody concentration), for initially seropositive subjects.
    End point type
    Secondary
    End point timeframe
    At Month 5
    End point values
    		 Infanrix-IPV+Hib Group Infanrix IPV Group
    Number of subjects analysed
    213
    217
    Units: Subjects
    213
    216
    No statistical analyses for this end point

    Secondary: Number of seroprotected subjects for anti-Polio type 1, 2 and 3

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    End point title
    		 Number of seroprotected subjects for anti-Polio type 1, 2 and 3
    End point description
    End point type
    Secondary
    End point timeframe
    Prior to vaccination (PRE)
    End point values
    		 Infanrix-IPV+Hib Group Infanrix IPV Group
    Number of subjects analysed
    211
    216
    Units: Subjects
        Anti-Polio 1, PRE [N=211;216]
    104
    89
        Anti-Polio 2, PRE [N=211;214]
    119
    108
        Anti-Polio 3, PRE [N=211;216]
    41
    31
    No statistical analyses for this end point

    Secondary: Anti-Polio type 1, 2 and 3 antibody titers

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    End point title
    		 Anti-Polio type 1, 2 and 3 antibody titers
    End point description
    End point type
    Secondary
    End point timeframe
    Prior to vaccination (PRE) and one month after (POST) Dose 3
    End point values
    		 Infanrix-IPV+Hib Group Infanrix IPV Group
    Number of subjects analysed
    212
    216
    Units: Titers
    geometric mean (confidence interval 95%)
        Anti-Polio 1, PRE [N=211;216]
    9.5 (8.3 to 11)
    9.4 (8 to 11)
        Anti-Polio 1, POST [N=212;216]
    328.8 (289.8 to 373.1)
    372.7 (323.8 to 428.9)
        Anti-Polio 2, PRE [N=211;214]
    10.8 (9.4 to 12.5)
    8.8 (7.7 to 9.9)
        Anti-Polio 2 POST [N=204;211]
    340.6 (295.4 to 392.6)
    400.2 (347.6 to 460.7)
        Anti-Polio 3, PRE [N=211;216]
    5.5 (5 to 6.1)
    4.9 (4.5 to 5.3)
        Anti-Polio 3, POST [N=198;199]
    377.7 (322.3 to 442.6)
    465.3 (390.3 to 554.7)
    No statistical analyses for this end point

    Secondary: Anti-PT, anti-FHA and anti-PRN antibody concentrations

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    End point title
    		 Anti-PT, anti-FHA and anti-PRN antibody concentrations
    End point description
    End point type
    Secondary
    End point timeframe
    Prior to vaccination (PRE)
    End point values
    		 Infanrix-IPV+Hib Group Infanrix IPV Group
    Number of subjects analysed
    213
    217
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-PT, PRE [N=212;216]
    3 (2.8 to 3.2)
    3.1 (2.9 to 3.3)
        Anti-FHA, PRE [N=211;214]
    10.5 (9.3 to 12)
    11.7 (10.3 to 13.3)
        Anti-PRN, PRE [N=213;217]
    2.9 (2.7 to 3)
    3.1 (2.8 to 3.3)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAE(s): during the entire study period (Month 0 to Month 5 ½); Solicited local/general symptoms: during the 4-day (Days 0-3) follow-up period after any vaccination; Unsolicited AE(s): during the 31-day (Days 0-30) follow-up period after any vaccination.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Infanrix IPV Group
    Reporting group description
    		 Subjects aged between, and including, 42 and 69 days at the time of first vaccination received 3 doses of Infanrix IPV and Hiberix co-administered at separate injection sites at 2, 4 and 6 months of age, 3 dose of Synflorix at 6 weeks, 3.5 and 5.5 months of age and 2 doses of Rotarix at 6 weeks and 3.5 months of age. The Infanrix IPV was administered intramuscularly in the right thigh, the Synflorix and Hiberix vaccines were administered intramuscularly in the left thigh and the Rotarix vaccine was administered orally.

    Reporting group title
    Infanrix-IPV+Hib Group
    Reporting group description
    		 Subjects aged between, and including, 42 and 69 days at the time of first vaccination received 3 doses of Infanrix-IPV+Hib at 2, 4 and 6 months of age, 3 doses of Synflorix at 6 weeks, 3.5 and 5.5 months of age and 2 doses of Rotarix at 6 weeks and 3.5 months of age. The Infanrix-IPV+Hib was administered intramuscularly in the right thigh, the Synflorix vaccine was administered intramuscularly in the left thigh and the Rotarix vaccine was administered orally.

    Serious adverse events
    		 Infanrix IPV Group Infanrix-IPV+Hib Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 227 (9.25%)
    25 / 224 (11.16%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Skull fracture
         subjects affected / exposed
    1 / 227 (0.44%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    1 / 227 (0.44%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intussusception
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 224 (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
    Vesicoureteric reflux
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 224 (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
    Bronchiolitis
         subjects affected / exposed
    5 / 227 (2.20%)
    7 / 224 (3.13%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    6 / 227 (2.64%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 227 (0.44%)
    5 / 224 (2.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 227 (0.44%)
    4 / 224 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    3 / 227 (1.32%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 227 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 227 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Croup infectious
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 224 (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 bronchitis
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Infanrix IPV Group Infanrix-IPV+Hib Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    220 / 227 (96.92%)
    218 / 224 (97.32%)
    General disorders and administration site conditions
    Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    146 / 227 (64.32%)
    143 / 224 (63.84%)
         occurrences all number
    146
    143
    Redness
    alternative assessment type: Systematic
         subjects affected / exposed
    167 / 227 (73.57%)
    177 / 224 (79.02%)
         occurrences all number
    167
    177
    Swelling
    alternative assessment type: Systematic
         subjects affected / exposed
    121 / 227 (53.30%)
    130 / 224 (58.04%)
         occurrences all number
    121
    130
    Drowsiness
    alternative assessment type: Systematic
         subjects affected / exposed
    147 / 227 (64.76%)
    153 / 224 (68.30%)
         occurrences all number
    147
    153
    Irritability/Fussiness
    alternative assessment type: Systematic
         subjects affected / exposed
    182 / 227 (80.18%)
    181 / 224 (80.80%)
         occurrences all number
    182
    181
    Loss of appetite
    alternative assessment type: Systematic
         subjects affected / exposed
    103 / 227 (45.37%)
    120 / 224 (53.57%)
         occurrences all number
    103
    120
    Temperature (Tympanic)
    alternative assessment type: Systematic
         subjects affected / exposed
    81 / 227 (35.68%)
    83 / 224 (37.05%)
         occurrences all number
    81
    83
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    10 / 227 (4.41%)
    29 / 224 (12.95%)
         occurrences all number
    10
    29
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    29 / 227 (12.78%)
    37 / 224 (16.52%)
         occurrences all number
    29
    37
    Upper respiratory tract infection
         subjects affected / exposed
    29 / 227 (12.78%)
    34 / 224 (15.18%)
         occurrences all number
    29
    34
    Bronchitis
         subjects affected / exposed
    14 / 227 (6.17%)
    14 / 224 (6.25%)
         occurrences all number
    14
    14
    Bronchiolitis
         subjects affected / exposed
    13 / 227 (5.73%)
    14 / 224 (6.25%)
         occurrences all number
    13
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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