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    Clinical Trial Results:
    A Phase IIIb, open, randomized, controlled, multicenter study of the immunogenicity and safety of GlaxoSmithKline Biologicals' inactivated hepatitis A vaccine (Havrix) [720 El.U/ 0.5 mL dose] administered on a 0, 6-month schedule concomitantly with GlaxoSmithKline Biologicals' DTaP vaccine (Infanrix) and Aventis Pasteur's Haemophilus b conjugate (Tetanus Toxoid Conjugate) vaccine (ActHIB) in healthy children 15 months of age.

    Summary
    EudraCT number
    		 2015-001530-25
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    03 Dec 2007

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Apr 2023
    First version publication date
    02 Aug 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Correction of full data set and alignment between registries.

    Trial information

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    Trial identification
    Sponsor protocol code
    208109/232
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00197236
    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 May 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Dec 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Dec 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate non-inferiority of the anti-HAV immune response (with respect to both seropositivity rates and GMCs) 31 days following the second dose of Havrix when the first dose of Havrix is co-administered with Infanrix and ActHIB (HAV+DTaP+HIB Group) compared to Havrix given alone (HAV Group). To demonstrate the non-inferiority of the anti-diphtheria (D) and anti-tetanus (T) seroprotection rates; anti-pertussis (PT), anti-filamentous hemagglutinin (FHA) and anti-pertactin (PRN) GMCs and vaccine response rates; and anti-polyribosylribitol phosphate (PRP) seroprotection rate 31 days following the co-administration of Infanrix and ActHIB with the first dose of Havrix (HAV+DTaP+HIB Group) compared to Infanrix and ActHIB given alone (DTaP+HIB→HAV Group).
    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
    11 Nov 2003
    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: 468
    Worldwide total number of subjects
    468
    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)
    468
    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
    		 Of the total of 468 subjects enrolled, only 394 were vaccinated and as such considered as 'started'.

    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
    		 Havrix Group
    Arm description
    		 Subjects received one dose of Havrix at Day 0 followed by a second dose of Havrix at Month 6-9.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Havrix
    Investigational medicinal product code
    Other name
    HAV
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    2 intramuscular injections, 6 months apart

    Arm title
    		 Havrix + Infanrix + ActHIB Group
    Arm description
    		 Subjects received one dose of Havrix co-administered with Infanrix and ActHIB vaccines at Day 0 followed by a second dose of Havrix at Month 6-9.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Havrix
    Investigational medicinal product code
    Other name
    HAV
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    2 intramuscular injections, 6 months apart

    Investigational medicinal product name
    Infanrix
    Investigational medicinal product code
    Other name
    DTPa
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 intramuscular injection

    Investigational medicinal product name
    ActHIB
    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
    1 intramuscular injection

    Arm title
    		 Infanrix + ActHIB→Havrix Group
    Arm description
    		 Subjects received Infanrix co-administered with ActHIB at Day 0, followed by one dose of Havix at Day 30 and a second dose of Havrix at Month 7-10.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Havrix
    Investigational medicinal product code
    Other name
    HAV
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    2 intramuscular injections, 6 months apart

    Investigational medicinal product name
    Infanrix
    Investigational medicinal product code
    Other name
    DTPa
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 intramuscular injection

    Investigational medicinal product name
    ActHIB
    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
    1 intramuscular injection

    Number of subjects in period 1 [1]
    		Havrix Group Havrix + Infanrix + ActHIB Group Infanrix + ActHIB→Havrix Group
    Started
    135
    127
    132
    Completed
    121
    110
    109
    Not completed
    14
    17
    23
         Adverse event, serious fatal
    1
    -
    1
         Consent withdrawn by subject
    7
    3
    11
         Returned out of specified time window
    -
    -
    1
         Study drug/medication expiration
    1
    -
    3
         Lost to follow-up
    5
    14
    6
         Protocol deviation
    -
    -
    1
    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: Of the total of 468 subjects enrolled, only 394 were vaccinated and as such considered as 'started'.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Havrix Group
    Reporting group description
    		 Subjects received one dose of Havrix at Day 0 followed by a second dose of Havrix at Month 6-9.

    Reporting group title
    Havrix + Infanrix + ActHIB Group
    Reporting group description
    		 Subjects received one dose of Havrix co-administered with Infanrix and ActHIB vaccines at Day 0 followed by a second dose of Havrix at Month 6-9.

    Reporting group title
    Infanrix + ActHIB→Havrix Group
    Reporting group description
    		 Subjects received Infanrix co-administered with ActHIB at Day 0, followed by one dose of Havix at Day 30 and a second dose of Havrix at Month 7-10.

    Reporting group values
    		 Havrix Group Havrix + Infanrix + ActHIB Group Infanrix + ActHIB→Havrix Group Total
    Number of subjects
    		 135 127 132 394
    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: months
        arithmetic mean (standard deviation)
    		 15.1 ± 0.36 15.1 ± 0.3 15 ± 0.21 -
    Gender categorical
    Units: Subjects
        Female
    		 55 64 67 186
        Male
    		 80 63 65 208

    End points

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    End points reporting groups
    Reporting group title
    Havrix Group
    Reporting group description
    		 Subjects received one dose of Havrix at Day 0 followed by a second dose of Havrix at Month 6-9.

    Reporting group title
    Havrix + Infanrix + ActHIB Group
    Reporting group description
    		 Subjects received one dose of Havrix co-administered with Infanrix and ActHIB vaccines at Day 0 followed by a second dose of Havrix at Month 6-9.

    Reporting group title
    Infanrix + ActHIB→Havrix Group
    Reporting group description
    		 Subjects received Infanrix co-administered with ActHIB at Day 0, followed by one dose of Havix at Day 30 and a second dose of Havrix at Month 7-10.

    Primary: Number of seropositive subjects for anti-hepatitis A virus (HAV) antibodies following the second dose of Havrix

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    End point title
    		 Number of seropositive subjects for anti-hepatitis A virus (HAV) antibodies following the second dose of Havrix
    End point description
    Subjects are defined as being anti-HAV seropositive if their anti-HAV antibody concentration is ≥ 15 milli-International Units per milliliter (mIU/mL).
    End point type
    Primary
    End point timeframe
    31 days following the second dose of Havrix
    End point values
    		 Havrix Group Havrix + Infanrix + ActHIB Group Infanrix + ActHIB→Havrix Group
    Number of subjects analysed
    88
    84
    77
    Units: Subjects
        Anti-hepatitis A virus (HAV) antibodies
    88
    84
    77
    Statistical analysis title
    		 Non-inferiority of HAV + DTaP + Hib vs. HAV
    Statistical analysis description
    Non-inferiority of the anti-HAV immune response (with respect to seropositivity rates) 31 days following the second dose of HAV when the first dose of HAV was co-administered with DTaP and Hib vaccines (Havrix + Infanrix + ActHIB Group) compared to HAV given alone (Havrix Group). Non-inferiority was to rule out more than a 5% decrease in the anti-HAV seropositivity rate between the Havrix + Infanrix + ActHIB Group and the Havrix Group 31 days following the second dose of HAV.
    Comparison groups
    Havrix + Infanrix + ActHIB Group v Havrix Group
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in seropositivity rate
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.4
         upper limit
    		 4.21

    Primary: Number of anti-diphtheria, anti-tetanus and anti-polyribosylribitol phosphate (PRP) seroprotected subjects

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    End point title
    		 Number of anti-diphtheria, anti-tetanus and anti-polyribosylribitol phosphate (PRP) seroprotected subjects [1]
    End point description
    Subjects are defined as being anti-diphtheria, anti-tetanus and anti-PRP seroprotected if their anti-diphtheria and anti-tetanus antibody concentration is ≥ 0.1 International Units per milliliter (IU/mL) and if their anti-PRP antibody concentration is ≥ 1 microgram per milliliter (μg/mL), respectively.
    End point type
    Primary
    End point timeframe
    31 days following the administration of Infanrix and ActHIB
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This outcome measure concerns subjects in the Havrix + Infanrix + ActHIB Group and Infanrix + ActHIBHavrix Group.
    End point values
    		 Havrix + Infanrix + ActHIB Group Infanrix + ActHIB→Havrix Group
    Number of subjects analysed
    90
    80
    Units: Subjects
        Anti-diphtheria (n=89, 80)
    89
    80
        Anti-tetanus (n=88, 80)
    88
    80
        Anti-PRP (n=90, 79)
    90
    77
    Statistical analysis title
    		 Non-inferiority of HAV+DTaP+Hib vs. DTaP+Hib→HAV
    Statistical analysis description
    Non-inferiority of the anti-diphtheria (D) seroprotection rates, 31 days following the co-administration of DTaP and Hib vaccines with the first dose of HAV(Havrix + Infanrix + ActHIB Group) compared to DTaP and Hib vaccines given alone(Infanrix+ActHIB→Havrix Group).Non-inferiority was to rule out more than a 10% decrease in the anti-D seroprotection rates between the Havrix + Infanrix + ActHIB Group and Infanrix + ActHIB→Havrix Group 31 days following the administration of DTaP and Hib vaccines
    Comparison groups
    Havrix + Infanrix + ActHIB Group v Infanrix + ActHIB→Havrix Group
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in seroprotection rate
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.16
         upper limit
    		 4.61
    Statistical analysis title
    		 Non-inferiority of HAV+DTaP+Hib vs. DTaP+Hib→HAV
    Statistical analysis description
    Non-inferiority of the anti-tetanus (T) seroprotection rates, 31 days following the co-administration of DTaP and Hib vaccines with the first dose of HAV(Havrix + Infanrix + ActHIB Group) compared to DTaP and Hib vaccines given alone(Infanrix+ActHIB→Havrix Group).Non-inferiority was to rule out more than a 10% decrease in the anti-T seroprotection rates between the Havrix + Infanrix + ActHIB Group and Infanrix + ActHIB→Havrix Group 31 days following the administration of DTaP and Hib vaccines.
    Comparison groups
    Havrix + Infanrix + ActHIB Group v Infanrix + ActHIB→Havrix Group
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in seroprotection rates
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.21
         upper limit
    		 4.61
    Statistical analysis title
    		 Non-inferiority of HAV+DTaP+Hib vs. DTaP+Hib→HAV
    Statistical analysis description
    Non-inferiority of the anti-polyribosylribitol phosphate (PRP) seroprotection rate, 31 days following the co-administration of DTaP and Hib vaccines with the first dose of HAV(Havrix + Infanrix + ActHIB Group) compared to DTaP and Hib vaccines given alone(Infanrix+ActHIB→Havrix Group).Non-inferiority was to rule out more than a 10% decrease in the anti-PRP seroprotection rate between the Havrix + Infanrix + ActHIB Group and Infanrix + ActHIB→Havrix Group 31 days post DTaP and Hib administration.
    Comparison groups
    Infanrix + ActHIB→Havrix Group v Havrix + Infanrix + ActHIB Group
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in seroprotection rate
    Point estimate
    2.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.64
         upper limit
    		 8.8

    Primary: Number of vaccine responders for anti-pertussis toxoid (PT), anti-filamentous hemagglutinin (FHA) and anti-pertactin (PRN)

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    End point title
    		 Number of vaccine responders for anti-pertussis toxoid (PT), anti-filamentous hemagglutinin (FHA) and anti-pertactin (PRN) [2]
    End point description
    Subjects are considered as being vaccine responders if they were initially seronegative and become seropositive (≥ 5 Enzyme Linked Immunosorbent Assay Units per Milliliter (EL.U/mL)), or were initially seropositive and have a 2-fold increase above pre-study concentrations.
    End point type
    Primary
    End point timeframe
    31 days following the administration of Infanrix and ActHIB
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This outcome measure concerns subjects in the Havrix + Infanrix + ActHIB Group and Infanrix + ActHIBHavrix Group.
    End point values
    		 Havrix + Infanrix + ActHIB Group Infanrix + ActHIB→Havrix Group
    Number of subjects analysed
    88
    76
    Units: Subjects
        Anti-PT (n=88,74)
    87
    71
        Anti-FHA (n=88,76)
    85
    75
        Anti-PRN (n=88,75)
    86
    74
    Statistical analysis title
    		 Non-inferiority of HAV+DTaP+Hib vs. DTaP+Hib→HAV
    Statistical analysis description
    Non-inferiority of the anti-pertussis toxin (PT) vaccine response rates 31 days following the co-administration of DTaP and Hib vaccines with the first dose of HAV (Havrix + Infanrix + ActHIB Group) compared to DTaP and Hib vaccines given alone. Non-inferiority was to rule out more than a 10% decrease in the anti-PT between the Havrix + Infanrix + ActHIB Group and the Infanrix + ActHIB→Havrix Group 31 days following the administration of DTaP and Hib vaccines.
    Comparison groups
    Havrix + Infanrix + ActHIB Group v Infanrix + ActHIB→Havrix Group
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in vaccine response rate
    Point estimate
    2.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 10.28
    Statistical analysis title
    		 Non-inferiority of HAV+DTaP+Hib vs. DTaP+Hib→HAV
    Statistical analysis description
    Non-inferiority of the anti-filamentous hemagglutinin (FHA) vaccine response rates 31 days following the co-administration of DTaP and Hib vaccines with the first dose of HAV (Havrix + Infanrix + ActHIB Group) compared to DTaP and Hib vaccines given alone. Non-inferiority was to rule out more than a 10% decrease in the anti-FHA between the Havrix + Infanrix + ActHIB Group and the Infanrix + ActHIB→Havrix Group 31 days following the administration of DTaP and Hib vaccines.
    Comparison groups
    Havrix + Infanrix + ActHIB Group v Infanrix + ActHIB→Havrix Group
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in vaccine response rate
    Point estimate
    -2.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.44
         upper limit
    		 4.02
    Statistical analysis title
    		 Non-inferiority of HAV+DTaP+Hib vs. DTaP+Hib→HAV
    Statistical analysis description
    Non-inferiority of the anti-pertactin (PRN) vaccine response rates 31 days following the co-administration of DTaP and Hib vaccines with the first dose of HAV (Havrix + Infanrix + ActHIB Group) compared to DTaP and Hib vaccines given alone. Non-inferiority was to rule out more than a 10% decrease in the anti-PRN between the Havrix + Infanrix + ActHIB Group and the Infanrix + ActHIB→Havrix Group 31 days following the administration of DTaP and Hib vaccines.
    Comparison groups
    Havrix + Infanrix + ActHIB Group v Infanrix + ActHIB→Havrix Group
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in vaccine response rate
    Point estimate
    -0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.77
         upper limit
    		 5.13

    Primary: Anti-hepatitis virus A (HAV) antibody geometric mean concentrations (GMC) following the second dose of Havrix

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    End point title
    		 Anti-hepatitis virus A (HAV) antibody geometric mean concentrations (GMC) following the second dose of Havrix
    End point description
    Anti-hepatitis A (HAV) antibody geometric mean concentrations (GMC) are expressed as milli-International Units per milliliter (mIU/mL).
    End point type
    Primary
    End point timeframe
    31 days following the second dose of Havrix
    End point values
    		 Havrix Group Havrix + Infanrix + ActHIB Group Infanrix + ActHIB→Havrix Group
    Number of subjects analysed
    88
    84
    77
    Units: mIU/mL
    geometric mean (confidence interval 95%)
        Anti-hepatitis virus A (HAV) antibodies
    1700.4 (1306 to 2213.7)
    1904.4 (1552.7 to 2335.7)
    1625.1 (1378.2 to 1916.3)
    Statistical analysis title
    		 Non-inferiority of HAV + DTaP + Hib vs. HAV
    Statistical analysis description
    Non-inferiority of the anti-HAV immune response (with respect to Geometric Mean Concentrations [GMCs]) 31 days following the second dose of HAV when the first dose of HAV was co-administered with DTaP and Hib vaccines (Havrix + Infanrix + ActHIB Group) compared to HAV given alone (Havrix Group). Non-inferiority was to rule out more than a 2-fold decrease in the anti-HAV antibody GMC between the Havrix + Infanrix + ActHIB Group and the Havrix Group 31 days following the second dose of HAV.
    Comparison groups
    Havrix + Infanrix + ActHIB Group v Havrix Group
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Adjusted GMC ratio
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.59

    Primary: Anti-pertussis toxoid (PT), anti-filamentous hemagglutinin (FHA), anti-pertactin (PRN) geometric mean concentrations following the administration of DTaP and Hib vaccines

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    End point title
    		 Anti-pertussis toxoid (PT), anti-filamentous hemagglutinin (FHA), anti-pertactin (PRN) geometric mean concentrations following the administration of DTaP and Hib vaccines [3]
    End point description
    Anti-PT, anti-FHA and anti-PRN antibody geometric mean concentrations (GMC) are expressed as EL.U/mL.
    End point type
    Primary
    End point timeframe
    31 days following the administration of Infanrix and ActHIB vaccines
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This outcome measure concerns subjects in the Havrix + Infanrix + ActHIB Group and Infanrix + ActHIBHavrix Group.
    End point values
    		 Havrix + Infanrix + ActHIB Group Infanrix + ActHIB→Havrix Group
    Number of subjects analysed
    89
    80
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-PT
    87.8 (76.8 to 100.4)
    90.8 (78.9 to 104.5)
        Anti-FHA
    558.4 (482.9 to 645.7)
    519.8 (446 to 605.8)
        Anti-PRN
    349 (288.8 to 421.9)
    304.6 (241.2 to 384.6)
    Statistical analysis title
    		 Non-inferiority of HAV+DTaP+Hib vs. DTaP+Hib→HAV
    Statistical analysis description
    Non-inferiority of anti-PT antibody GMCs 31 days following the co-administration of DTaP and Hib vaccines with the first dose of HAV (Havrix + Infanrix + ActHIB Group) compared to DTaP and Hib vaccines given alone (Infanrix + ActHIB→Havrix Group). Non-inferiority was to rule out more than a 1.5-fold decrease in the anti-PT GMCs between the Havrix + Infanrix+ ActHIB Group and the Infanrix + ActHIB→Havrix Group 31 days following the administration of DTaP and Hib vaccines.
    Comparison groups
    Infanrix + ActHIB→Havrix Group v Havrix + Infanrix + ActHIB Group
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Adjusted GMC ratio
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.11
    Statistical analysis title
    		 Non-inferiority of HAV+DTaP+Hib vs. DTaP+Hib→HAV
    Statistical analysis description
    Non-inferiority of anti-FHA antibody GMCs 31 days following the co-administration of DTaP and Hib vaccines with the first dose of HAV (Havrix + Infanrix + ActHIB Group) compared to DTaP and Hib vaccines given alone (Infanrix + ActHIB→Havrix Group). Non-inferiority was to rule out more than a 1.5-fold decrease in the anti-FHA GMCs between the Havrix + Infanrix+ ActHIB Group and the Infanrix + ActHIB→Havrix Group 31 days following the administration of DTaP and Hib vaccines.
    Comparison groups
    Infanrix + ActHIB→Havrix Group v Havrix + Infanrix + ActHIB Group
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Adjusted GMC ratio
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.2
    Statistical analysis title
    		 Non-inferiority of HAV+DTaP+Hib vs. DTaP+Hib→HAV
    Statistical analysis description
    Non-inferiority of anti-PRN antibody GMCs 31 days following the co-administration of DTaP and Hib vaccines with the first dose of HAV (Havrix + Infanrix + ActHIB Group) compared to DTaP and Hib vaccines given alone (Infanrix + ActHIB→Havrix Group). Non-inferiority was to rule out more than a 1.5-fold decrease in the anti-PRN GMCs between the Havrix + Infanrix+ ActHIB Group and the Infanrix + ActHIB→Havrix Group 31 days following the administration of DTaP and Hib vaccines.
    Comparison groups
    Havrix + Infanrix + ActHIB Group v Infanrix + ActHIB→Havrix Group
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Adjusted GMC ratio
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.36

    Secondary: Anti-diphtheria and anti-tetanus antibody geometric mean concentrations (GMC)

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    End point title
    		 Anti-diphtheria and anti-tetanus antibody geometric mean concentrations (GMC) [4]
    End point description
    GMCs are expressed as International Units per milliliter (IU/mL).
    End point type
    Secondary
    End point timeframe
    31 days following the administration of Infanrix and ActHIB
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This outcome measure concerns subjects in the Havrix + Infanrix + ActHIB Group and Infanrix + ActHIBHavrix Group.
    End point values
    		 Havrix + Infanrix + ActHIB Group Infanrix + ActHIB→Havrix Group
    Number of subjects analysed
    89
    80
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Anti-diphtheria (n= 89, 80)
    11.3 (9.8 to 13.1)
    10.3 (8.7 to 12.3)
        Anti-tetanus (n= 88, 80)
    7 (5.9 to 8.2)
    7.3 (6 to 8.8)
    No statistical analyses for this end point

    Secondary: Anti-polyribosylribitol phosphate (PRP) antibody geometric mean concentrations (GMC)

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    End point title
    		 Anti-polyribosylribitol phosphate (PRP) antibody geometric mean concentrations (GMC) [5]
    End point description
    GMCs are expressed as microgram/milliliter (µg/mL).
    End point type
    Secondary
    End point timeframe
    31 days following the administration of Infanrix and ActHIB
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This outcome measure concerns subjects in the Havrix + Infanrix + ActHIB Group and Infanrix + ActHIBHavrix Group.
    End point values
    		 Havrix + Infanrix + ActHIB Group Infanrix + ActHIB→Havrix Group
    Number of subjects analysed
    90
    79
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-polyribosylribitol phosphate (PRP) antibodies
    60.8 (45.9 to 80.4)
    41 (30 to 55.9)
    No statistical analyses for this end point

    Secondary: Number of subjects seropositive for anti-pertussis toxoid (PT), anti-filamentous hemagglutinin (FHA), anti-pertactin (PRN) and anti-polyribosylribitol phosphate (PRP)

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    End point title
    		 Number of subjects seropositive for anti-pertussis toxoid (PT), anti-filamentous hemagglutinin (FHA), anti-pertactin (PRN) and anti-polyribosylribitol phosphate (PRP) [6]
    End point description
    Seropositivity is defined as antibody concentrations ≥ 5 Enzyme Linked Immunosorbent Assay Units per Milliliter (EL.U/mL) for anti-PT, anti-FHA and anti-PRN antibodies and as antibody concentrations ≥ 0.15 microgram/milliliter (µg/mL) for anti-PRP antibodies.
    End point type
    Secondary
    End point timeframe
    31 days following the administration of Infanrix and ActHIB
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This outcome measure concerns subjects in the Havrix + Infanrix + ActHIB Group and Infanrix + ActHIBHavrix Group.
    End point values
    		 Havrix + Infanrix + ActHIB Group Infanrix + ActHIB→Havrix Group
    Number of subjects analysed
    90
    80
    Units: Subjects
        Anti-PT (n= 89, 80)
    89
    80
        Anti-FHA (n= 89, 80)
    89
    80
        Anti-PRN (n= 89, 80)
    89
    80
        Anti-PRP (n= 90, 79)
    90
    79
    No statistical analyses for this end point

    Secondary: Number of seropositive subjects for anti-hepatitis A virus (HAV) antibodies following the first dose of Havrix

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    End point title
    		 Number of seropositive subjects for anti-hepatitis A virus (HAV) antibodies following the first dose of Havrix [7]
    End point description
    Subjects are defined as being anti-HAV seropositive if their anti-HAV antibody concentration is ≥ 15 milli-International Units per milliliter (mIU/mL).
    End point type
    Secondary
    End point timeframe
    31 days following the first dose of Havrix
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This outcome measure concerns subjects in the Havrix Group and Havrix + Infanrix + ActHIB Group.
    End point values
    		 Havrix Group Havrix + Infanrix + ActHIB Group
    Number of subjects analysed
    94
    89
    Units: Subjects
        Anti-hepatitis A virus (HAV) antibodies
    82
    77
    No statistical analyses for this end point

    Secondary: Anti-hepatitis A virus (HAV) antibody geometric mean concentrations (GMC) following the first dose of Havrix

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    End point title
    		 Anti-hepatitis A virus (HAV) antibody geometric mean concentrations (GMC) following the first dose of Havrix [8]
    End point description
    Anti-hepatitis A (HAV) antibody geometric mean concentrations (GMC) are expressed as milli-International Units per milliliter (mIU/mL).
    End point type
    Secondary
    End point timeframe
    31 days following the first dose of Havrix
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This outcome measure concerns subjects in the Havrix Group and Havrix + Infanrix + ActHIB Group.
    End point values
    		 Havrix Group Havrix + Infanrix + ActHIB Group
    Number of subjects analysed
    94
    89
    Units: mIU/mL
    geometric mean (confidence interval 95%)
        Anti-hepatitis A virus (HAV) antibodies
    51.5 (41.7 to 63.7)
    51.5 (41.8 to 63.5)
    No statistical analyses for this end point

    Secondary: Number of subjects with vaccine response to Havrix

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    End point title
    		 Number of subjects with vaccine response to Havrix
    End point description
    Vaccine response to Havrix is defined as post-vaccination anti-HAV antibody concentrations ≥ 15 mIU/mL in initially seronegative subjects or a ≥ 2-fold increase above the pre-vaccination anti-HAV antibody concentration in initially seropositive subjects.
    End point type
    Secondary
    End point timeframe
    31 days following the second dose
    End point values
    		 Havrix Group Havrix + Infanrix + ActHIB Group Infanrix + ActHIB→Havrix Group
    Number of subjects analysed
    86
    83
    74
    Units: Subjects
        Vaccine response to Havrix™
    86
    83
    74
    No statistical analyses for this end point

    Secondary: Number of subjects reporting solicited local adverse events (AEs)

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    End point title
    		 Number of subjects reporting solicited local adverse events (AEs)
    End point description
    Solicited local AEs assessed include pain, redness and swelling. Data across doses are presented in the table.
    End point type
    Secondary
    End point timeframe
    4-day period following each dose of study vaccine(s)
    End point values
    		 Havrix Group Havrix + Infanrix + ActHIB Group Infanrix + ActHIB→Havrix Group
    Number of subjects analysed
    130
    118
    122
    Units: Subjects
        Pain
    44
    60
    70
        Redness
    34
    54
    63
        Swelling
    21
    38
    46
    No statistical analyses for this end point

    Secondary: Number of subjects reporting solicited general adverse events (AEs)

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    End point title
    		 Number of subjects reporting solicited general adverse events (AEs)
    End point description
    Solicited general AEs assessed include drowsiness, axillary fever ≥ 37.5°C, irritability and loss of appetite. Data across doses are presented in the table.
    End point type
    Secondary
    End point timeframe
    4-day period following each dose of study vaccine(s)
    End point values
    		 Havrix Group Havrix + Infanrix + ActHIB Group Infanrix + ActHIB→Havrix Group
    Number of subjects analysed
    130
    118
    123
    Units: Subjects
        Drowsiness
    44
    50
    53
        Fever
    16
    26
    31
        Irritability
    56
    62
    70
        Loss of appetite
    33
    40
    48
    No statistical analyses for this end point

    Secondary: Number of subjects reporting unsolicited adverse events (AEs)

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    End point title
    		 Number of subjects reporting unsolicited adverse events (AEs)
    End point description
    An Adverse Event is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
    End point type
    Secondary
    End point timeframe
    31-day period following each dose of study vaccine(s)
    End point values
    		 Havrix Group Havrix + Infanrix + ActHIB Group Infanrix + ActHIB→Havrix Group
    Number of subjects analysed
    135
    127
    132
    Units: Subjects
        AEs
    75
    69
    71
    No statistical analyses for this end point

    Secondary: Number of subjects reporting serious adverse events (SAEs), new chronic illnesses and medically significant events

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    End point title
    		 Number of subjects reporting serious adverse events (SAEs), new chronic illnesses and medically significant events
    End point description
    Since the related information about medically significant events was not specifically collected and new chronic illnesses were only collected in the extended safety follow-up phase, all unsolicited adverse events (AEs) throughout the study are reported in the table without identifying which event was a medically significant or new chronic illness.
    End point type
    Secondary
    End point timeframe
    Active Phase and the 6-months Extended Safety Follow-up (ESFU) Phase.
    End point values
    		 Havrix Group Havrix + Infanrix + ActHIB Group Infanrix + ActHIB→Havrix Group
    Number of subjects analysed
    135
    127
    132
    Units: Subjects
        SAEs (n= 135, 127, 132)
    5
    2
    4
        AEs during Active Phase (n= 135, 127, 132)
    80
    74
    72
        AEs during ESFU (n=119,111,109)
    11
    10
    7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The occurrence of reported AEs (all/related) was not available and is encoded as equal to the number of subjects affected.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Havrix Group
    Reporting group description
    		 Subjects received one dose of Havrix at Day 0 followed by a second dose of Havrix at Month 6-9.

    Reporting group title
    Havrix + Infanrix + ActHIB Group
    Reporting group description
    		 Subjects received one dose of Havrix co-administered with Infanrix and ActHIB vaccines at Day 0 followed by a second dose of Havrix at Month 6-9.

    Reporting group title
    Infanrix + ActHIB→Havrix Group
    Reporting group description
    		 Subjects received Infanrix co-administered with ActHIB at Day 0, followed by one dose of Havix at Day 30 and a second dose of Havrix at Month 7-10.

    Serious adverse events
    		 Havrix Group Havrix + Infanrix + ActHIB Group Infanrix + ActHIB→Havrix Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 135 (3.70%)
    2 / 127 (1.57%)
    4 / 132 (3.03%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 127 (0.79%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Developmental delay
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 127 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 127 (0.79%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 127 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 127 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 127 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 127 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Expressive language disorder
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 127 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 127 (0.79%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 127 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 127 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 127 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Havrix Group Havrix + Infanrix + ActHIB Group Infanrix + ActHIB→Havrix Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    95 / 135 (70.37%)
    105 / 127 (82.68%)
    107 / 132 (81.06%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    9 / 135 (6.67%)
    7 / 127 (5.51%)
    9 / 132 (6.82%)
         occurrences all number
    9
    7
    9
    Pain at the injection site
    alternative assessment type: Systematic
         subjects affected / exposed
    44 / 135 (32.59%)
    60 / 127 (47.24%)
    70 / 132 (53.03%)
         occurrences all number
    44
    60
    70
    Redness at the injection site
    alternative assessment type: Systematic
         subjects affected / exposed
    34 / 135 (25.19%)
    54 / 127 (42.52%)
    63 / 132 (47.73%)
         occurrences all number
    34
    54
    63
    Swelling at the injection site
    alternative assessment type: Systematic
         subjects affected / exposed
    21 / 135 (15.56%)
    38 / 127 (29.92%)
    46 / 132 (34.85%)
         occurrences all number
    21
    38
    46
    Drowsiness
    alternative assessment type: Systematic
         subjects affected / exposed
    44 / 135 (32.59%)
    50 / 127 (39.37%)
    53 / 132 (40.15%)
         occurrences all number
    44
    50
    53
    Fever
    alternative assessment type: Systematic
         subjects affected / exposed
    16 / 135 (11.85%)
    26 / 127 (20.47%)
    31 / 132 (23.48%)
         occurrences all number
    16
    26
    31
    Irritability
    alternative assessment type: Systematic
         subjects affected / exposed
    56 / 135 (41.48%)
    62 / 127 (48.82%)
    70 / 132 (53.03%)
         occurrences all number
    56
    62
    70
    Loss of appetite
    alternative assessment type: Systematic
         subjects affected / exposed
    33 / 135 (24.44%)
    40 / 127 (31.50%)
    48 / 132 (36.36%)
         occurrences all number
    33
    40
    48
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    9 / 135 (6.67%)
    4 / 127 (3.15%)
    7 / 132 (5.30%)
         occurrences all number
    9
    4
    7
    Teething
         subjects affected / exposed
    3 / 135 (2.22%)
    8 / 127 (6.30%)
    4 / 132 (3.03%)
         occurrences all number
    3
    8
    4
    Vomiting
         subjects affected / exposed
    7 / 135 (5.19%)
    4 / 127 (3.15%)
    4 / 132 (3.03%)
         occurrences all number
    7
    4
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 135 (5.93%)
    4 / 127 (3.15%)
    14 / 132 (10.61%)
         occurrences all number
    8
    4
    14
    Rhinorrhea
         subjects affected / exposed
    5 / 135 (3.70%)
    4 / 127 (3.15%)
    14 / 132 (10.61%)
         occurrences all number
    5
    4
    14
    Infections and infestations
    Otitis media
         subjects affected / exposed
    13 / 135 (9.63%)
    11 / 127 (8.66%)
    22 / 132 (16.67%)
         occurrences all number
    13
    11
    22
    Upper respiratory tract infection
         subjects affected / exposed
    18 / 135 (13.33%)
    18 / 127 (14.17%)
    16 / 132 (12.12%)
         occurrences all number
    18
    18
    16
    Viral infection
         subjects affected / exposed
    3 / 135 (2.22%)
    7 / 127 (5.51%)
    3 / 132 (2.27%)
         occurrences all number
    3
    7
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Mar 2005
    Rationale: Included the GMCs for anti-PT, anti-FHA and anti-PRN antibodies as a co-primary objective/endpoint rather than as a secondary one, Increase in the sample size from 750 to 840 in order to test the immune response with respect to GMCs for anti-PT, anti-FHA and anti-PRN antibodies as a co-primary objective/endpoint, Deletion of a history of non-response to any vaccine in the current routine immunization schedule as an exclusion criteria, Captured the brand of Hib vaccine used for pre-study priming, Provided instructions regarding the administration of concomitant influenza vaccine, Provided updated contact information for the Medical Monitor and the Study Manager, Included the additional descriptive analyses evaluating seroresponse at a level of 1.0 IU/mL for antibodies to diphtheria and tetanus antigens.

    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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