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    Clinical Trial Results:
    A phase IIIb, open label, randomized, multicenter study of the im-munogenicity and safety of a booster dose of Kinrix when co-administered with varicella vaccine (Varivax®, Merck and Company) and MMR vaccine (M-M-R®II, Merck and Company), compared to that of a booster dose of Kinrix co-administered with MMR vaccine only, in healthy children 4 to 6 years of age.

    Summary
    EudraCT number
    		 2011-002946-11
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    15 Jun 2010

    Results information
    Results version number
    		 v3(current)
    This version publication date
    16 Sep 2018
    First version publication date
    05 Jul 2015
    Other versions
    		 v1 (removed from public view) , v2
    Version creation reason
    • Correction of full data set
    Minor corrections of the full study results.

    Trial information

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    Trial identification
    Sponsor protocol code
    111852
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00871117
    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
    24 Sep 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Jan 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jun 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the non-inferiority of Kinrix co-administered with Varivax and M-M-RII compared to Kinrix co-administered with M-M-RII only in terms of diphtheria (D), tetanus (T), pertussis (PT), filamentous hemagglutinin (FHA), and pertactin (PRN) booster response and poliovirus geaometric mean titres (GMTs), one month after vaccination with Kinrix.
    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 from the time the subject consents to participate in the study until she/he is discharged.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Mar 2009
    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: 478
    Worldwide total number of subjects
    478
    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)
    0
    Children (2-11 years)
    478
    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
    		 478 subjects were enrolled, but 2 subjects who received a subject number were not vaccinated. Therefore the total amount of subjects used for the analysis was 476.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Kinrix + M-M-R II + Varivax
    Arm description
    		 Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GSK Biologicals’Kinrix
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose administered intramuscularly in the deltoid region of the left upper arm at Day 0

    Investigational medicinal product name
    Merck and Company’s M-M-R II
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One dose administered subcutaneously in the deltoid of the right upper arm at Day 0

    Investigational medicinal product name
    Merck and Company’s Varivax
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One dose at Day 0 administered subcutaneously in the deltoid region of the right lower arm

    Arm title
    		 Kinrix + M-M-R II -> Varivax
    Arm description
    		 Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    GSK Biologicals’Kinrix
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose administered intramuscularly in the deltoid region of the left upper arm at Day 0

    Investigational medicinal product name
    Merck and Company’s M-M-R II
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One dose administered subcutaneously in the deltoid of the right upper arm at Day 0

    Investigational medicinal product name
    Merck and Company’s Varivax
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One dose administered subcutaneously in the deltoid region of the right lower arm at Day 30

    Number of subjects in period 1 [1]
    		Kinrix + M-M-R II + Varivax Kinrix + M-M-R II -> Varivax
    Started
    239
    237
    Completed
    234
    227
    Not completed
    5
    10
         Others
    -
    4
         Lost to follow-up
    5
    6
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 478 subjects were enrolled, but 2 subjects who received a subject number were not vaccinated. Therefore the total amount of subjects used for the analysis was 476.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Kinrix + M-M-R II + Varivax
    Reporting group description
    		 Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.

    Reporting group title
    Kinrix + M-M-R II -> Varivax
    Reporting group description
    		 Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.

    Reporting group values
    		 Kinrix + M-M-R II + Varivax Kinrix + M-M-R II -> Varivax Total
    Number of subjects
    		 239 237 476
    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: years
        arithmetic mean (standard deviation)
    		 4.2 ( 0.41 ) 4.2 ( 0.37 ) -
    Gender categorical
    Units: Subjects
        Female
    		 129 123 252
        Male
    		 110 114 224
    Race/Ethnicity
    Units: Subjects
        African heritage/African American
    		 27 23 50
        American Indian or Alaskan Native
    		 35 33 68
        Asian-Central/South Asian heritage
    		 7 11 18
        Asian-East Asian heritage
    		 3 5 8
        Asian-South East Asian heritage
    		 13 17 30
        Native Hawaiian or Other Pacific Islander
    		 2 3 5
        White-Arabic/North African heritage
    		 1 6 7
        White-Caucasian/European heritage
    		 109 107 216
        Unspecified
    		 42 32 74

    End points

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    End points reporting groups
    Reporting group title
    Kinrix + M-M-R II + Varivax
    Reporting group description
    		 Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.

    Reporting group title
    Kinrix + M-M-R II -> Varivax
    Reporting group description
    		 Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.

    Primary: Number of subjects with booster responses to diphteria and tetanus

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    End point title
    		 Number of subjects with booster responses to diphteria and tetanus
    End point description
    Anti-diphteria (anti-D) and anti-tetanus (anti-T) booster response was defined as: - initially seronegative subjects (sero-) (pre-booster antibody concentration below cut-off of < 0.1 international units per milliliter (IU/mL)) with an increase of at least four times the cut-off one month after vaccination (post-booster antibody concentration ≥0.4 IU/mL) - initially seropositive subjects (sero+) (pre-booster antibody concentration ≥0.1 IU/mL) with an increase of at least four times the pre-booster antibody concentration one month after vaccination.
    End point type
    Primary
    End point timeframe
    One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.
    End point values
    		 Kinrix + M-M-R II + Varivax Kinrix + M-M-R II -> Varivax
    Number of subjects analysed
    211
    209
    Units: Subjects
        Anti-D (N=211;209)
    209
    207
        Anti-T (N=211;208)
    208
    203
    Statistical analysis title
    		 Difference in booster response rates for anti-D
    Statistical analysis description
    To demonstrate the non-inferiority of DTaP-IPV vaccine co-administered with Varicella and MMR vaccines compared to DTaP-IPV vaccine co-administered with MMR only in terms of diphtheria (D) booster response one month after vaccination with DTaP-IPV vaccine.
    Comparison groups
    Kinrix + M-M-R II + Varivax v Kinrix + M-M-R II -> Varivax
    Number of subjects included in analysis
    420
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Difference in booster response rates
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.54
         upper limit
    		 2.58
    Notes
    [1] - Lower limit of the standardized asymptotic 95% confidence interval (CI) for the between-group differences in booster response to diphtheria was greater than or equal to (≥)-10%.
    Statistical analysis title
    		 Difference in booster response rates for anti-T
    Statistical analysis description
    To demonstrate the non-inferiority of DTaP-IPV vaccine co-administered with Varicella and MMR vaccines compared to DTaP-IPV vaccine co-administered with MMR only in terms of tetanus (T) booster response one month after vaccination with DTaP-IPV vaccine.
    Comparison groups
    Kinrix + M-M-R II + Varivax v Kinrix + M-M-R II -> Varivax
    Number of subjects included in analysis
    420
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Difference in booster response rates
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.99
         upper limit
    		 4.26
    Notes
    [2] - Lower limit of the standardized asymptotic 95% CI for the between-group differences in booster response to tetanus was ≥ -10%.

    Primary: Number of subjects with anti-pertussis toxoid (anti-PT), anti-filamentous hemagglutinin (FHA) and anti-pertactin (anti-PRN) booster responses, measured in Enzyme-Linked Immunosorbent Assay Units per milliliter (EL.U/mL)

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    End point title
    		 Number of subjects with anti-pertussis toxoid (anti-PT), anti-filamentous hemagglutinin (FHA) and anti-pertactin (anti-PRN) booster responses, measured in Enzyme-Linked Immunosorbent Assay Units per milliliter (EL.U/mL)
    End point description
    Anti-PT, anti-FHA and anti-PRN booster response : - initially sero- (pre-booster antibody concentration below cut-off < 5.0 EL.U/mL) with increase of at least four times cut-off one month after vaccination (concentration post-booster ≥20.0 EL.U/mL) - initially sero+ with pre-booster antibody concentration ≥5.0 EL.U/mL and < 20.0 EL.U/mL with increase of at least four times pre-booster concentration one month post-booster - initially sero+ with pre-booster antibody concentration ≥20.0 EL.U/mL with an increase of at least two times the pre-booster antibody concentration one month post-booster
    End point type
    Primary
    End point timeframe
    One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.
    End point values
    		 Kinrix + M-M-R II + Varivax Kinrix + M-M-R II -> Varivax
    Number of subjects analysed
    220
    212
    Units: Subjects
        Anti-PT (N=218;210)
    207
    201
        Anti-FHA (N=216;210)
    213
    209
        Anti-PRN (N=220;212)
    220
    209
    Statistical analysis title
    		 Difference in vaccine response rates for anti-PT
    Statistical analysis description
    To demonstrate the non-inferiority of DTaP-IPV vaccine co-administered with Varicella and MMR vaccines compared to DTaP-IPV vaccine co-administered with MMR only in terms of pertussis toxoid (PT) booster response one month after vaccination with DTaP-IPV vaccine.
    Comparison groups
    Kinrix + M-M-R II + Varivax v Kinrix + M-M-R II -> Varivax
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Difference in booster response rates
    Point estimate
    -0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.07
         upper limit
    		 3.51
    Notes
    [3] - Lower limit of the standardized asymptotic 95% CI for the between-group differences in booster response to PT was ≥ -10%.
    Statistical analysis title
    		 Difference in vaccine response rates for anti-FHA
    Statistical analysis description
    To demonstrate the non-inferiority of DTaP-IPV vaccine co-administered with Varicella and MMR vaccines compared to DTaP-IPV vaccine co-administered with MMR only in terms of filamentous hemagglutinin (FHA) booster response one month after vaccination with DTaP-IPV vaccine.
    Comparison groups
    Kinrix + M-M-R II + Varivax v Kinrix + M-M-R II -> Varivax
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Difference in booster response rates
    Point estimate
    -0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.59
         upper limit
    		 1.39
    Notes
    [4] - Lower limit of the standardized asymptotic 95% CI for the between-group differences in booster response to FHA was ≥ -10%.
    Statistical analysis title
    		 Difference in vaccine response rates for anti-PRN
    Statistical analysis description
    To demonstrate the non-inferiority of DTaP-IPV vaccine co-administered with Varicella and MMR vaccines compared to DTaP-IPV vaccine co-administered with MMR only in terms of pertactin (PRN) booster response one month after vaccination with DTaP-IPV vaccine.
    Comparison groups
    Kinrix + M-M-R II + Varivax v Kinrix + M-M-R II -> Varivax
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 Difference in booster response rates
    Point estimate
    1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 4.08
    Notes
    [5] - Lower limit of the standardized asymptotic 95% CI for the between-group differences in booster response to PRN, was ≥ -10%.

    Primary: Geometric Mean Titers (GMTs) for antibodies to poliovirus types 1, 2 and 3

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    End point title
    		 Geometric Mean Titers (GMTs) for antibodies to poliovirus types 1, 2 and 3
    End point description
    Titers are expressed as GMTs.
    End point type
    Primary
    End point timeframe
    One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.
    End point values
    		 Kinrix + M-M-R II + Varivax Kinrix + M-M-R II -> Varivax
    Number of subjects analysed
    219
    212
    Units: Titer
    geometric mean (confidence interval 95%)
        Anti-Polio 1 (N=219;211)
    1638.4 (1441 to 1863)
    1789.9 (1559 to 2054.9)
        Anti-Polio 2 (N=218;212)
    1572.9 (1387.8 to 1782.7)
    1902.6 (1678.6 to 2156.5)
        Anti-Polio 3 (N=219;212)
    2588.4 (2282.7 to 2935)
    3189.6 (2798.2 to 3635.7)
    Statistical analysis title
    		 Adjusted GMT ratio for anti-Polio1
    Statistical analysis description
    To demonstrate the non-inferiority of DTaP-IPV vaccine co-administered with Varicella and MMR vaccines compared to DTaP-IPV vaccine co-administered with MMR only in terms of poliovirus type 1 geometric mean titers (GMTs), one month after vaccination with DTaP-IPV vaccine.
    Comparison groups
    Kinrix + M-M-R II + Varivax v Kinrix + M-M-R II -> Varivax
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Adjusted GMT ratio
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.1
    Notes
    [6] - Lower limit of the 95% CI for the GMT ratios for poliovirus type 1 antigens was ≥0.67
    Statistical analysis title
    		 Adjusted GMT ratio for anti-Polio2
    Statistical analysis description
    To demonstrate the non-inferiority of DTaP-IPV vaccine co-administered with Varicella and MMR vaccines compared to DTaP-IPV vaccine co-administered with MMR only in terms of poliovirus type 2 geometric mean titers (GMTs), one month after vaccination with DTaP-IPV vaccine.
    Comparison groups
    Kinrix + M-M-R II + Varivax v Kinrix + M-M-R II -> Varivax
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 Adjusted GMT ratio
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 0.99
    Notes
    [7] - Lower limit of the 95% CI for the GMT ratios of poliovirus type 2 antigens was ≥0.67
    Statistical analysis title
    		 Adjusted GMT ratio for anti-Polio3
    Statistical analysis description
    To demonstrate the non-inferiority of DTaP-IPV vaccine co-administered with Varicella and MMR vaccines compared to DTaP-IPV vaccine co-administered with MMR only in terms of poliovirus type 3 geometric mean titers (GMTs), one month after vaccination with DTaP-IPV vaccine.
    Comparison groups
    Kinrix + M-M-R II + Varivax v Kinrix + M-M-R II -> Varivax
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 Adjusted GMT ratio
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.01
    Notes
    [8] - Lower limit of the 95% CI for the GMT ratios of poliovirus type 3 antigens was ≥0.67

    Secondary: Number of subjects with anti-D and anti-T antibody concentrations above cut-off value

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    End point title
    		 Number of subjects with anti-D and anti-T antibody concentrations above cut-off value
    End point description
    Cut-off value was defined as greater than or equal to 1.0 international units per milliliter (IU/mL).
    End point type
    Secondary
    End point timeframe
    One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.
    End point values
    		 Kinrix + M-M-R II + Varivax Kinrix + M-M-R II -> Varivax
    Number of subjects analysed
    217
    212
    Units: Subjects
        Anti-D
    217
    212
        Anti-T
    217
    209
    No statistical analyses for this end point

    Secondary: Geometric Mean Concentrations (GMCs) for anti-D and anti-T antibodies

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    End point title
    		 Geometric Mean Concentrations (GMCs) for anti-D and anti-T antibodies
    End point description
    Concentrations were expressed as GMCs in IU/mL.
    End point type
    Secondary
    End point timeframe
    One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.
    End point values
    		 Kinrix + M-M-R II + Varivax Kinrix + M-M-R II -> Varivax
    Number of subjects analysed
    217
    212
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Anti-D
    14.273 (12.989 to 15.684)
    14.809 (13.397 to 16.371)
        Anti-T
    8.658 (7.888 to 9.504)
    8.138 (7.323 to 9.045)
    No statistical analyses for this end point

    Secondary: GMCs for anti-PT, anti-FHA, anti-PRN antibodies

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    End point title
    		 GMCs for anti-PT, anti-FHA, anti-PRN antibodies
    End point description
    Concentrations are expressed as GMCs in Enzyme-Linked Immunosorbent Assay (ELISA) Units per milliliter (EL.U/mL).
    End point type
    Secondary
    End point timeframe
    One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.
    End point values
    		 Kinrix + M-M-R II + Varivax Kinrix + M-M-R II -> Varivax
    Number of subjects analysed
    220
    212
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-PT
    96.5 (85.8 to 108.6)
    101.3 (89.2 to 115.1)
        Anti-FHA
    968.9 (886.9 to 1058.4)
    968.2 (876 to 1070.1)
        Anti-PRN
    627.1 (543.2 to 724)
    620.4 (530.3 to 725.8)
    No statistical analyses for this end point

    Secondary: Number of subjects with an anti-polio 1, 2, 3 booster response

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    End point title
    		 Number of subjects with an anti-polio 1, 2, 3 booster response
    End point description
    Anti-poliovirus 1, anti-poliovirus 2 and anti-poliovirus 3 booster response: - initially seronegative subjects (pre-booster antibody titer below cut-off of 8 ED50) with an antibody titer ≥ 32 ED50 one month after vaccination - initially seropositive subjects (pre-booster antibody titers ≥ 8 ED50) with an increase at least four times the pre-booster antibody titer one month after vaccination. ED50 is defined here as the reverse of the dilution resulting in 50% inhibition. The lowest dilution at which serum samples were tested is 1:8 from which a test was considered positive.
    End point type
    Secondary
    End point timeframe
    One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.
    End point values
    		 Kinrix + M-M-R II + Varivax Kinrix + M-M-R II -> Varivax
    Number of subjects analysed
    215
    211
    Units: Subjects
        Anti-polio 1 (N=215;209)
    211
    202
        Anti-polio 2 (N=214;211)
    204
    207
        Anti-polio 3 (N=215;211)
    213
    207
    No statistical analyses for this end point

    Secondary: Number of subjects seroprotected against diphteria and tetanus

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    End point title
    		 Number of subjects seroprotected against diphteria and tetanus
    End point description
    Seroprotection status was defined as: * anti-D antibody concentration greater than or equal to 0.1 IU/mL * anti-T antibody concentration greater than or equal to 0.1 IU/mL
    End point type
    Secondary
    End point timeframe
    One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.
    End point values
    		 Kinrix + M-M-R II + Varivax Kinrix + M-M-R II -> Varivax
    Number of subjects analysed
    217
    212
    Units: Subjects
        Anti-D
    217
    212
        Anti-T
    217
    212
    No statistical analyses for this end point

    Secondary: Number of subjects seroprotected against poliovirus 1, 2 and 3

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    End point title
    		 Number of subjects seroprotected against poliovirus 1, 2 and 3
    End point description
    Seroprotection was defined: * anti-poliovirus type 1, 2 or 3 antibody titer greater than or equal to 8 ED50. ED50 is defined here as the reverse of the dilution resulting in 50% inhibition.
    End point type
    Secondary
    End point timeframe
    One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.
    End point values
    		 Kinrix + M-M-R II + Varivax Kinrix + M-M-R II -> Varivax
    Number of subjects analysed
    219
    212
    Units: Subjects
        Anti-Polio 1 (N=219;211)
    219
    211
        Anti-Polio 2 (N=218;212)
    218
    212
        Anti-Polio 3 (N=219;212)
    219
    212
    No statistical analyses for this end point

    Secondary: Number of subjects seropositive for anti-PT, anti-FHA and anti-PRN antibodies

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    End point title
    		 Number of subjects seropositive for anti-PT, anti-FHA and anti-PRN antibodies
    End point description
    Seropositivity was defined as a concentration greater than or equal to 5.0 EL.U/mL
    End point type
    Secondary
    End point timeframe
    One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.
    End point values
    		 Kinrix + M-M-R II + Varivax Kinrix + M-M-R II -> Varivax
    Number of subjects analysed
    220
    212
    Units: Subjects
        anti-PT
    220
    212
        anti-FHA
    220
    212
        anti-PRN
    220
    212
    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
    Solicited local symptoms included pain, redness and swelling at the injection site. Any was defined as incidence of a particular symptom regardless of intensity grade.
    End point type
    Secondary
    End point timeframe
    Within 4 days (Day 0 to 3) after booster immunization * for Kinrix + M-M-R II -> Varivax Group before vaccination with Varivax
    End point values
    		 Kinrix + M-M-R II + Varivax Kinrix + M-M-R II -> Varivax
    Number of subjects analysed
    230
    230
    Units: Subjects
        Any Pain
    156
    166
        Any Redness
    115
    114
        Any Swelling
    95
    84
    No statistical analyses for this end point

    Secondary: Number of subjects with unsolicited adverse events

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    End point title
    		 Number of subjects with unsolicited adverse events
    End point description
    An unsolicited adverse event is any adverse event (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product) reported in addition to those solicited during the clinical study. Also any "solicited" symptom with onset outside the specified period of follow-up for solicited symptoms will be reported as an unsolicited adverse event.
    End point type
    Secondary
    End point timeframe
    Up to 31 days (Day 0 through Day 30) after booster vaccination * for Kinrix + M-M-R II -> Varivax Group before vaccination with Varivax
    End point values
    		 Kinrix + M-M-R II + Varivax Kinrix + M-M-R II -> Varivax
    Number of subjects analysed
    239
    237
    Units: Subjects
        Number of subjects with unsolicited adverse events
    75
    72
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects with serious adverse events (SAEs)
    End point description
    Serious adverse events are medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject.
    End point type
    Secondary
    End point timeframe
    During the entire study period (from Day 0 to 6 months post-vaccination)
    End point values
    		 Kinrix + M-M-R II + Varivax Kinrix + M-M-R II -> Varivax
    Number of subjects analysed
    239
    237
    Units: Subjects
        Number of subjects with serious adverse events (SA
    0
    1
    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
    Solicited general symptoms included fever [temperature equal to or greater than 37.5 degrees Celsius (°C)], drowsiness and loss of appetite. Any was defined as incidence of a particular symptom regardless of intensity grade.
    End point type
    Secondary
    End point timeframe
    Within 4 days (Day 0 to 3) after booster immunization * for Kinrix + M-M-R II -> Varivax Group before vaccination with Varivax
    End point values
    		 Kinrix + M-M-R II + Varivax Kinrix + M-M-R II -> Varivax
    Number of subjects analysed
    230
    230
    Units: Subjects
        Any Drowsiness
    61
    66
        Any Loss of appetite
    60
    57
        Any Temperature (Axillary)
    58
    68
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited local/general Adverse Events (AEs) during the first 4 days (Day 0-3) post vaccination ; unsolicited AEs during the 31 days (Days 0-30) post vaccination and SAEs during the entire study period (from Day 0 to 6 months post-vaccination).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Kinrix + M-M-R II -> Varivax
    Reporting group description
    		 Subjects received at Day 0 one dose of Kinrix,intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.

    Reporting group title
    Kinrix + M-M-R II + Varivax
    Reporting group description
    		 Subjects received at Day 0 one dose of Kinrix,intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm, and one dose of Varivax subcutaneously in the deltoid region of the right lower arm.

    Serious adverse events
    		 Kinrix + M-M-R II -> Varivax Kinrix + M-M-R II + Varivax
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 239 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Infections and infestations
    Croup infectious
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 239 (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
    		 Kinrix + M-M-R II -> Varivax Kinrix + M-M-R II + Varivax
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    230 / 237 (97.05%)
    228 / 239 (95.40%)
    General disorders and administration site conditions
    Pain
         subjects affected / exposed [1]
    166 / 230 (72.17%)
    156 / 230 (67.83%)
         occurrences all number
    166
    156
    Redness
         subjects affected / exposed [2]
    114 / 230 (49.57%)
    115 / 230 (50.00%)
         occurrences all number
    114
    115
    Swelling
         subjects affected / exposed [3]
    84 / 230 (36.52%)
    95 / 230 (41.30%)
         occurrences all number
    84
    95
    Drowsiness
         subjects affected / exposed [4]
    66 / 230 (28.70%)
    61 / 230 (26.52%)
         occurrences all number
    66
    61
    Loss of appetite
         subjects affected / exposed [5]
    57 / 230 (24.78%)
    60 / 230 (26.09%)
         occurrences all number
    57
    60
    Fever
         subjects affected / exposed [6]
    68 / 230 (29.57%)
    58 / 230 (25.22%)
         occurrences all number
    68
    58
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This solicited local symptom was only collected from subjects with their symptom sheets completed.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This solicited local symptom was only collected from subjects with their symptom sheets completed.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This solicited local symptom was only collected from subjects with their symptom sheets completed.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This solicited general symptom was only collected from subjects with their symptom sheets completed.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This solicited general symptom was only collected from subjects with their symptom sheets completed.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This solicited general symptom was only collected from subjects with their symptom sheets completed.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jan 2009
    Both Kinrix and the second dose of Varivax are indicated in children 4-6 years of age, and there is great potential for the vaccines to be given concurrently. To date there are no data examining the concurrent administration of Kinrix and Varivax. The aim of this trial is to demonstrate that co-administered Varivax does not negatively affect the immunogenicity or reactogenicity of Kinrix.

    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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