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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 Merck and Company, Inc. measles-mumps-rubella vaccine (M-M-RII) and Merck and Company, Inc. varicella vaccine (VARIVAX) to healthy children 15 months of age.

    Summary
    EudraCT number
    		 2015-001509-15
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    09 Jun 2009

    Results information
    Results version number
    		 v2(current)
    This version publication date
    28 Mar 2023
    First version publication date
    31 Jul 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
    208109/231
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00197015
    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
    15 Feb 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jun 2009
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jun 2009
    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 M-M-RII and VARIVAX (HAV+MMR+V Group) compared to Havrix given alone (HAV Group), To demonstrate the non-inferiority of the anti-measles, anti-mumps, anti-rubella and anti-varicella immune responses (with respect to seroconversion rates for anti-measles, anti-mumps and anti-varicella and seroresponse rate for anti-rubella) 42 days following the co-administration of M-M-RII and VARIVAX with the first dose of Havrix (HAV+MMR+V Group) compared to when M-M-RII and VARIVAX are given alone (MMR+V→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
    06 Oct 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: 1474
    Worldwide total number of subjects
    1474
    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)
    1474
    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
    		 While the total numbers of subjects enrolled in the study was 1474, the total number of subjects that entered the study was 1241. The remaining subjects received a subject number but no vaccine dose and were therefore excluded from the analysis and group assignment.

    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
    		 HAV Group
    Arm description
    		 Subjects received 2 doses of Havrix (1 dose at Day 0 and 1 dose between Month 6 and Month 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 doses administered intramuscularly, in the left anterolateral thigh.

    Arm title
    		 HAV+MMR+V Group
    Arm description
    		 Subjects received 1 dose of Havrix, coadministered with M-M-R II and VARIVAX, at Day 0 and 1 dose of Havrix between Month 6 and Month 9
    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 doses administered intramuscularly, in the left anterolateral thigh.

    Investigational medicinal product name
    M-M-R II
    Investigational medicinal product code
    Other name
    MMR
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 dose administered subcutaneously, in the deltoid region.

    Investigational medicinal product name
    VARIVAX
    Investigational medicinal product code
    Other name
    Varicella
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 dose administered subcutaneously, in the deltoid region.

    Arm title
    		 MMR+V→HAV Group
    Arm description
    		 Subjects received 1 dose of M-M-R II and VARIVAX at Day 0 and then 2 doses of Havrix (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)
    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 doses administered intramuscularly, in the left anterolateral thigh.

    Investigational medicinal product name
    M-M-R II
    Investigational medicinal product code
    Other name
    MMR
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 dose administered subcutaneously, in the deltoid region.

    Investigational medicinal product name
    VARIVAX
    Investigational medicinal product code
    Other name
    Varicella
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 dose administered subcutaneously, in the deltoid region.

    Number of subjects in period 1 [1]
    		HAV Group HAV+MMR+V Group MMR+V→HAV Group
    Started
    324
    462
    455
    Completed
    274
    385
    366
    Not completed
    50
    77
    89
         Adverse event, serious fatal
    3
    1
    -
         Consent withdrawn by subject
    17
    34
    37
         Unspecified
    2
    2
    3
         Lost to follow-up
    28
    37
    46
         Protocol deviation
    -
    3
    3
    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: While the total number of subjects enrolled in the study was 1474, the total number of subjects that entered the study was 1241. The remaining subjects received a subject number but no vaccine dose and were therefore excluded from the analysis and group assignment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    HAV Group
    Reporting group description
    		 Subjects received 2 doses of Havrix (1 dose at Day 0 and 1 dose between Month 6 and Month 9)

    Reporting group title
    HAV+MMR+V Group
    Reporting group description
    		 Subjects received 1 dose of Havrix, coadministered with M-M-R II and VARIVAX, at Day 0 and 1 dose of Havrix between Month 6 and Month 9

    Reporting group title
    MMR+V→HAV Group
    Reporting group description
    		 Subjects received 1 dose of M-M-R II and VARIVAX at Day 0 and then 2 doses of Havrix (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)

    Reporting group values
    		 HAV Group HAV+MMR+V Group MMR+V→HAV Group Total
    Number of subjects
    		 324 462 455 1241
    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 ± 0.27 15 ± 0.25 15 ± 0.22 -
    Gender categorical
    Units: Subjects
        Female
    		 154 232 208 594
        Male
    		 170 230 247 647

    End points

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    End points reporting groups
    Reporting group title
    HAV Group
    Reporting group description
    		 Subjects received 2 doses of Havrix (1 dose at Day 0 and 1 dose between Month 6 and Month 9)

    Reporting group title
    HAV+MMR+V Group
    Reporting group description
    		 Subjects received 1 dose of Havrix, coadministered with M-M-R II and VARIVAX, at Day 0 and 1 dose of Havrix between Month 6 and Month 9

    Reporting group title
    MMR+V→HAV Group
    Reporting group description
    		 Subjects received 1 dose of M-M-R II and VARIVAX at Day 0 and then 2 doses of Havrix (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)

    Primary: Anti-hepatitis A virus (HAV) antibody concentrations in HAV and HAV+MMR+V groups

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    End point title
    		 Anti-hepatitis A virus (HAV) antibody concentrations in HAV and HAV+MMR+V groups [1]
    End point description
    Concentrations are given as geometric mean concentrations (GMCs) expressed as milli-international units per milliliter (mIU/mL).
    End point type
    Primary
    End point timeframe
    31 days following the second dose of Havrix
    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 applies to subjects from the HAV and HAV+MMR+V Groups.
    End point values
    		 HAV Group HAV+MMR+V Group
    Number of subjects analysed
    206
    286
    Units: mIU/mL
    geometric mean (confidence interval 95%)
        Anti-hepatitis A virus (HAV) antibodies
    1390.4 (1186.3 to 1629.6)
    1895.2 (1682.7 to 2134.5)
    Statistical analysis title
    		 Non-inferiority of HAV+MMR+V vs. HAV vaccine
    Statistical analysis description
    To demonstrate non-inferiority of the anti-hepatitis A virus (HAV) immune response (with respect to geometric mean concentrations [GMCs]) 31 days following the second dose of HAV when the first dose of HAV is co-administered with MMR and Varicella (HAV+MMR+V Group) compared to HAV given alone (HAV Group). Non-inferiority was to rule out more than a 2-fold decrease in the anti-HAV GMC between the HAV+MMR+V Group and the HAV Group 31 days following the second dose of HAV.
    Comparison groups
    HAV+MMR+V Group v HAV Group
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Adjusted GMC ratio
    Point estimate
    1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.14
         upper limit
    		 1.74

    Primary: Number of subjects with anti-hepatitis A virus (HAV) antibody concentration equal or above the cut-off value in HAV and HAV+MMR+V groups

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    End point title
    		 Number of subjects with anti-hepatitis A virus (HAV) antibody concentration equal or above the cut-off value in HAV and HAV+MMR+V groups [2]
    End point description
    Anti-HAV antibody cut-off value assessed include 15 milli-international units per milliliter (mIU/mL).
    End point type
    Primary
    End point timeframe
    31 days following the second dose of Havrix
    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 applies to subjects in the HAV and HAV+MMR+V Groups.
    End point values
    		 HAV Group HAV+MMR+V Group
    Number of subjects analysed
    206
    286
    Units: Subjects
    204
    285
    Statistical analysis title
    		 Non-inferiority of HAV+MMR+V vs. HAV vaccine
    Statistical analysis description
    To demonstrate non-inferiority of the anti-hepatitis A virus (HAV) immune response (than a 5% decrease in the anti-HAV seropositivity rate) 31 days following the second dose of HAV when the first dose of HAV is co-administered with MMR and Varicella (HAV+MMR+V Group) compared to HAV given alone (HAV Group). Non-inferiority was to rule out more than a 5% decrease in the anti-HAV seropositivity rate between the HAV+MMR+V Group and the HAV Group 31 days following the second dose of HAV.
    Comparison groups
    HAV+MMR+V Group v HAV Group
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in seropositivity rate
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.71
         upper limit
    		 3.06

    Primary: Number of subjects seroconverted for anti-measles, anti-mumps and anti-varicella antibodies in HAV+MMR+V and MMR+V→HAV groups

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    End point title
    		 Number of subjects seroconverted for anti-measles, anti-mumps and anti-varicella antibodies in HAV+MMR+V and MMR+V→HAV groups [3]
    End point description
    Seroconversion is defined as the appearance of antibodies with titers greater than or equal to the predefined cut-off value in the serum of subject seronegative before vaccination. Cut-off values assessed include 150 milli-international units per milliliter (mIU/mL) for anti-measles antibodies, 28 Effective Dose 50 (ED50) for anti-mumps antibodies and 1:5 for anti-varicella antibodies.
    End point type
    Primary
    End point timeframe
    42 days following the administration of M-M-R II and VARIVAX
    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 applies to subjects in the HAV+MMR+V and MMR+VHAV Groups.
    End point values
    		 HAV+MMR+V Group MMR+V→HAV Group
    Number of subjects analysed
    268
    250
    Units: Subjects
        Anti-measles (n= 250, 268)
    267
    247
        Anti-mumps (n= 197, 212)
    207
    193
        Anti-varicella (n= 171, 193)
    187
    168
    Statistical analysis title
    		 Non-inferiority of HAV+MMR+V vs. MMR+V→HAV
    Statistical analysis description
    To demonstrate the non-inferiority of the anti-measles (with respect to seroconversion rates) 42 days following the co-administration of MMR and Varicella with the first dose of HAV (HAV+MMR+V Group) compared to when MMR and Varicella are given alone (MMR+V→HAV Group). Non-inferiority was to rule out more than a 5% decrease in anti-measles seroconversion rates between the HAV+MMR+V Group and the MMR+V→HAV Group 42 days following the administration of MMR and Varicella.
    Comparison groups
    HAV+MMR+V Group v MMR+V→HAV Group
    Number of subjects included in analysis
    518
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in seroconevrsion rate
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 3.14
    Statistical analysis title
    		 Non-inferiority of HAV+MMR+V vs. MMR+V→HAV
    Statistical analysis description
    To demonstrate the non-inferiority of the anti-mumps (with respect to seroconversion rates) 42 days following the co-administration of MMR and Varicella with the first dose of HAV (HAV+MMR+V Group) compared to when MMR and Varicella are given alone (MMR+V→HAV Group). Non-inferiority was to rule out more than a 5% decrease in anti-mumps seroconversion rates between the HAV+MMR+V Group and the MMR+V→HAV Group 42 days following the administration of MMR and Varicella.
    Comparison groups
    HAV+MMR+V Group v MMR+V→HAV Group
    Number of subjects included in analysis
    518
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in seroconversion rate
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.23
         upper limit
    		 3.43
    Statistical analysis title
    		 Non-inferiority of HAV+MMR+V vs. MMR+V→HAV
    Statistical analysis description
    To demonstrate the non-inferiority of the anti-rubella (with respect to seroresponse rate) 42 days following the co-administration of MMR and Varicella with the first dose of HAV (HAV+MMR+V Group) compared to when MMR and Varicella are given alone (MMR+V→HAV Group). Non-inferiority was to rule out more than a 5% decrease in the anti-rubella seroresponse rate between the HAV+MMR+V Group and the MMR+V→HAV Group 42 days following the administration of MMR and Varicella.
    Comparison groups
    HAV+MMR+V Group v MMR+V→HAV Group
    Number of subjects included in analysis
    518
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in seroresponse rate
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.69
         upper limit
    		 1.92
    Statistical analysis title
    		 Non-inferiority of HAV+MMR+V vs. MMR+V→HAV
    Statistical analysis description
    To demonstrate the non-inferiority of the anti-varicella (with respect to seroconversion rates) 42 days following the co-administration of MMR and Varicella with the first dose of HAV (HAV+MMR+V Group) compared to when MMR and Varicella are given alone (MMR+V→HAV Group). Non-inferiority was to rule out more than a 10% decrease in the anti-varicella seroconversion rates between the HAV+MMR+V Group and the MMR+V→HAV Group 42 days following the administration of MMR and Varicella.
    Comparison groups
    HAV+MMR+V Group v MMR+V→HAV Group
    Number of subjects included in analysis
    518
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in seroconversion rates
    Point estimate
    -1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.11
         upper limit
    		 2.28

    Primary: Number of subjects with vaccine response for anti-rubella antibodies in HAV+MMR+V and MMR+V→HAV groups

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    End point title
    		 Number of subjects with vaccine response for anti-rubella antibodies in HAV+MMR+V and MMR+V→HAV groups [4] [5]
    End point description
    Vaccine response is defined as the appearance of antibodies with titers greater than or equal to the predefined cut-off value in the serum of subject seronegative before vaccination. Cut-off value assessed include 10 milli-international units per milliliter (mIU/mL).
    End point type
    Primary
    End point timeframe
    42 days following administration of M-M-R II and VARIVAX
    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: This outcome measure applies to subjects in the HAV+MMR+V and MMR+VHAV Groups.
    [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 applies to subjects in the HAV+MMR+V and MMR+VHAV Groups.
    End point values
    		 HAV+MMR+V Group MMR+V→HAV Group
    Number of subjects analysed
    271
    247
    Units: Subjects
        Vaccine response for anti-rubella antibodies
    270
    246
    No statistical analyses for this end point

    Secondary: Anti-measles, anti-mumps, anti-rubella and anti-varicella antibody titers in HAV+MMR+V and MMR+V→HAV groups

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    End point title
    		 Anti-measles, anti-mumps, anti-rubella and anti-varicella antibody titers in HAV+MMR+V and MMR+V→HAV groups [6]
    End point description
    Titers are given as geometric mean titers (GMTs).
    End point type
    Secondary
    End point timeframe
    42 days following the administration of M-M-R II and VARIVAX
    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 applies to subjects in the HAV+MMR+V and MMR+VHAV Groups.
    End point values
    		 HAV+MMR+V Group MMR+V→HAV Group
    Number of subjects analysed
    304
    269
    Units: titers
    geometric mean (confidence interval 95%)
        Anti-measles (n= 269, 301)
    3136.3 (2922 to 3366.3)
    3218.3 (2940.9 to 3521.8)
        Anti-rubella (n= 269, 304)
    76 (70.7 to 81.7)
    88.3 (81.9 to 95.3)
        Anti-varicella (n= 218, 260)
    286.9 (252.1 to 326.5)
    281.7 (246.7 to 321.8)
        Anti-mumps (n= 244, 276)
    170.3 (152.2 to 190.5)
    215.7 (190.9 to 243.7)
    No statistical analyses for this end point

    Secondary: Anti-hepatitis A virus (HAV) antibody concentrations in HAV and HAV+MMR+V groups

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    End point title
    		 Anti-hepatitis A virus (HAV) antibody concentrations in HAV and HAV+MMR+V groups [7]
    End point description
    Concentrations are given as geometric mean concentrations (GMCs).
    End point type
    Secondary
    End point timeframe
    42 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 applies to subjects from the HAV and HAV+MMR+V Groups.
    End point values
    		 HAV Group HAV+MMR+V Group
    Number of subjects analysed
    228
    306
    Units: milli-international units per milliliter
    geometric mean (confidence interval 95%)
        Anti-hepatitis A virus (HAV) antibodies
    43.1 (37.9 to 49.1)
    43.5 (39.3 to 48.2)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-hepatitis A virus (HAV) antibody concentration equal or above the cut-off value in HAV and HAV+MMR+V groups

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    End point title
    		 Number of subjects with anti-hepatitis A virus (HAV) antibody concentration equal or above the cut-off value in HAV and HAV+MMR+V groups [8]
    End point description
    Anti-HAV antibody cut-off value assessed include 15 milli-international units per millilitre (mIU/mL).
    End point type
    Secondary
    End point timeframe
    42 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 applies to subjects from the HAV and HAV+MMR+V Groups.
    End point values
    		 HAV Group HAV+MMR+V Group
    Number of subjects analysed
    228
    306
    Units: Subjects
        Anti-hepatitis A virus (HAV) antibodies
    194
    276
    No statistical analyses for this end point

    Secondary: Anti-hepatitis A virus (HAV) antibody concentrations in MMR+V→HAV Group

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    End point title
    		 Anti-hepatitis A virus (HAV) antibody concentrations in MMR+V→HAV Group [9]
    End point description
    Concentrations are given as geometric mean concentrations (GMCs).
    End point type
    Secondary
    End point timeframe
    31 days following the second dose of Havrix
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This outcome measure applies to subjects from the MMR+VHAV Group only.
    End point values
    		 MMR+V→HAV Group
    Number of subjects analysed
    237
    Units: milli-international units per milliliter
    geometric mean (confidence interval 95%)
        Anti-hepatitis A virus (HAV) antibodies
    1770.3 (1569.9 to 1996.4)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-hepatitis A virus (HAV) antibody concentrations above the cut-off value in MMR+V→HAV Group

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    End point title
    		 Number of subjects with anti-hepatitis A virus (HAV) antibody concentrations above the cut-off value in MMR+V→HAV Group [10]
    End point description
    Anti-HAV antibody cut-off value assessed include 15 milli-international units per millilitre (mIU/mL).
    End point type
    Secondary
    End point timeframe
    31 days following the second dose of Havrix
    Notes
    [10] - 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 applies to subjects from the MMR+VHAV Group only.
    End point values
    		 MMR+V→HAV Group
    Number of subjects analysed
    237
    Units: Subjects
        Anti-hepatitis A virus (HAV) antibodies
    237
    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 was defined as: 1) a detectable anti-hepatitis A virus (HAV) antibody concentration 31 days following the second dose in subjects who were initially seronegative; and 2) a 2-fold increase in anti-HAV antibody concentrations above the pre-study concentration 31 days following the second dose in subjects who were initially seropositive.
    End point type
    Secondary
    End point timeframe
    31 days following the second dose of Havrix
    End point values
    		 HAV Group HAV+MMR+V Group MMR+V→HAV Group
    Number of subjects analysed
    194
    259
    224
    Units: Subjects
        Vaccine response to Havrix®
    192
    257
    224
    No statistical analyses for this end point

    Secondary: Number of subjects reporting solicited local symptoms

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    End point title
    		 Number of subjects reporting solicited local symptoms
    End point description
    Solicited local symptoms assessed include pain, rash (local), redness and swelling.
    End point type
    Secondary
    End point timeframe
    During the 4-day period following each dose of vaccine
    End point values
    		 HAV Group HAV+MMR+V Group MMR+V→HAV Group
    Number of subjects analysed
    304
    419
    411
    Units: Subjects
        Pain
    103
    187
    162
        Rash (local)
    0
    4
    3
        Redness
    97
    151
    149
        Swelling
    45
    82
    70
    No statistical analyses for this end point

    Secondary: Number of subjects reporting solicited general symptoms

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    End point title
    		 Number of subjects reporting solicited general symptoms
    End point description
    Solicited general symptoms assessed include drowsiness, fever, irritability, loss of appetite and rash (general).
    End point type
    Secondary
    End point timeframe
    During the 4-day period following each dose of vaccine
    End point values
    		 HAV Group HAV+MMR+V Group MMR+V→HAV Group
    Number of subjects analysed
    304
    411
    424
    Units: Subjects
        Drowsiness
    95
    178
    179
        Fever
    54
    80
    110
        Irritability
    144
    216
    238
        Loss of appetite
    94
    154
    170
        Rash (general)
    5
    10
    7
    No statistical analyses for this end point

    Secondary: Number of subjects reporting measles, mumps, rubella and varicella specific solicited general adverse events

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    End point title
    		 Number of subjects reporting measles, mumps, rubella and varicella specific solicited general adverse events [11]
    End point description
    Specific adverse events assessed include papules, vesicles, crusts, parotid/salivary gland swelling and suspected signs of meningitis/febrile seizures.
    End point type
    Secondary
    End point timeframe
    During the 43-day period following each dose of vaccine
    Notes
    [11] - 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 applies to subjects in the HAV+MMR+V and MMR+VHAV Groups.
    End point values
    		 HAV+MMR+V Group MMR+V→HAV Group
    Number of subjects analysed
    462
    455
    Units: Subjects
        Papules
    23
    23
        Vesicles
    17
    17
        Crusts
    12
    12
        Parotid/salivary gland swelling
    1
    0
        Suspected signs of meningitidis/febrile seizures
    2
    1
    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
    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.
    End point type
    Secondary
    End point timeframe
    During the 31-day period following each dose of vaccine
    End point values
    		 HAV Group HAV+MMR+V Group MMR+V→HAV Group
    Number of subjects analysed
    324
    462
    455
    Units: Subjects
        AEs
    186
    249
    286
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects reporting serious adverse events (SAEs)
    End point description
    SAEs assessed include 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 Active Phase (from Day 0 up to Day 31 after the second dose) and the Extended Safety Follow-up Phase of the study (from Day 31 after the second dose up to study end)
    End point values
    		 HAV Group HAV+MMR+V Group MMR+V→HAV Group
    Number of subjects analysed
    324
    462
    455
    Units: subjects
        Active Phase (n= 324, 462, 455)
    1
    5
    6
        Extended Safety Follow-up Phase (n=287,395,276)
    6
    11
    6
    No statistical analyses for this end point

    Secondary: Number of subjects reporting new chronic illnesses

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    End point title
    		 Number of subjects reporting new chronic illnesses
    End point description
    New Chronic illnesses include autoimmune disorders, asthma, type I diabetes, allergies.
    End point type
    Secondary
    End point timeframe
    During the Active Phase (from Day 0 up to Day 31 after the second dose) and the Extended Safety Follow-up Phase of the study (from Day 31 after the second dose up to study end)
    End point values
    		 HAV Group HAV+MMR+V Group MMR+V→HAV Group
    Number of subjects analysed
    324
    462
    455
    Units: subjects
        Active Phase (n= 324, 462, 455)
    0
    0
    0
        Extended Safety Follow-Up Phase (n=287,395,376)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects reporting medically significant events

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    End point title
    		 Number of subjects reporting medically significant events
    End point description
    Medically significant events include, but are not limited to, diabetes, autoimmune disease, asthma, allergies and/or conditions prompting emergency room or physician office visits that are not related to well-child care, vaccination or common acute illnesses (e.g., upper respiratory infection, otitis media, pharyngitis, gastroenteritis, injury and visits for routine physical examination).
    End point type
    Secondary
    End point timeframe
    During the Active Phase (from Day 0 up to Day 31 after the second dose) and the Extended Safety Follow-up Phase of the study (from Day 31 after the second dose up to study end)
    End point values
    		 HAV Group HAV+MMR+V Group MMR+V→HAV Group
    Number of subjects analysed
    324
    462
    455
    Units: Subjects
        Active Phase (n= 324, 455, 462)
    0
    0
    0
        Extended Safety Follow-Up Phase (n= 287, 376, 395)
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs: From Day 0 to 31 (active phase); Day 31 to last contact (ESFU). Solicited local and general symptoms: during the 4-day period (Days 0-3) post-vaccination. Unsolicited AEs: during the 31-day period (Days 0-30) post-vaccination
    Adverse event reporting additional description
    The number of occurrences reported for solicited symptoms, adverse events, and serious adverse events were not available for posting. The number of subjects affected by each specific event was indicated as the number of occurrences.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    HAV Group
    Reporting group description
    		 Subjects received 2 doses of Havrix (1 dose at Day 0 and 1 dose between Month 6 and Month 9)

    Reporting group title
    MMR+V→HAV Group
    Reporting group description
    		 Subjects received 1 dose of M-M-R II and VARIVAX at Day 0 and then 2 doses of Havrix (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)

    Reporting group title
    HAV+MMR+V Group
    Reporting group description
    		 Subjects received 1 dose of Havrix, coadministered with M-M-R II and VARIVAX, at Day 0 and 1 dose of Havrix between Month 6 and Month 9

    Serious adverse events
    		 HAV Group MMR+V→HAV Group HAV+MMR+V Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 324 (2.16%)
    12 / 455 (2.64%)
    16 / 462 (3.46%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Leukaemia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 455 (0.00%)
    0 / 462 (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
    Injury, poisoning and procedural complications
    Burns second degree
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 455 (0.22%)
    0 / 462 (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
    Chemical poisoning
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 455 (0.22%)
    0 / 462 (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
    Humerus fracture
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 455 (0.22%)
    0 / 462 (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
    Accidental overdose
         subjects affected / exposed
    0 / 324 (0.00%)
    0 / 455 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Animal bite
         subjects affected / exposed
    0 / 324 (0.00%)
    0 / 455 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 324 (0.00%)
    0 / 455 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Mental retardation
         subjects affected / exposed
    0 / 324 (0.00%)
    0 / 455 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autism
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 455 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 455 (0.00%)
    0 / 462 (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
    General disorders and administration site conditions
    Sudden death
         subjects affected / exposed
    0 / 324 (0.00%)
    0 / 455 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 455 (0.22%)
    0 / 462 (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
    Ileus
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 455 (0.22%)
    0 / 462 (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
    Adenoidal hypertrophy
         subjects affected / exposed
    0 / 324 (0.00%)
    0 / 455 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed [1]
    0 / 287 (0.00%)
    0 / 376 (0.00%)
    1 / 395 (0.25%)
         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
    Breathing-related sleep disorder
         subjects affected / exposed
    0 / 324 (0.00%)
    0 / 455 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 455 (0.22%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 455 (0.22%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    0 / 324 (0.00%)
    0 / 455 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 324 (0.00%)
    0 / 455 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 455 (0.22%)
    0 / 462 (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
    Gastroenteritis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 455 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed [2]
    1 / 287 (0.35%)
    1 / 376 (0.27%)
    0 / 395 (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
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 324 (0.00%)
    0 / 455 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 455 (0.00%)
    0 / 462 (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
    Localised infection
         subjects affected / exposed
    0 / 324 (0.00%)
    0 / 455 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 324 (0.00%)
    0 / 455 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    0 / 324 (0.00%)
    0 / 455 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 455 (0.22%)
    0 / 462 (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
    Subcutaneous abscess
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 455 (0.22%)
    0 / 462 (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
    Viral infection
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 455 (0.22%)
    0 / 462 (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
    Metabolism and nutrition disorders
    Dehydratation
         subjects affected / exposed
    2 / 324 (0.62%)
    1 / 455 (0.22%)
    2 / 462 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: For a given subject cohort and the analysis of a given measurement, missing or non evaluable measurements were not replaced. Therefore, an analysis excluded data points for subjects with missing or non-evaluable measurements i.e. analysis of solicited symptoms will exclude vaccinated subjects without documented Diary Cards.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: For a given subject cohort and the analysis of a given measurement, missing or non evaluable measurements were not replaced. Therefore, an analysis excluded data points for subjects with missing or non-evaluable measurements i.e. analysis of solicited symptoms will exclude vaccinated subjects without documented Diary Cards.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 HAV Group MMR+V→HAV Group HAV+MMR+V Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    251 / 324 (77.47%)
    366 / 455 (80.44%)
    363 / 462 (78.57%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    34 / 324 (10.49%)
    68 / 455 (14.95%)
    56 / 462 (12.12%)
         occurrences all number
    34
    68
    56
    Papules
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 324 (0.00%)
    23 / 455 (5.05%)
    23 / 462 (4.98%)
         occurrences all number
    0
    23
    23
    Drowsiness
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    95 / 304 (31.25%)
    179 / 411 (43.55%)
    178 / 424 (41.98%)
         occurrences all number
    95
    179
    178
    Fever
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    54 / 304 (17.76%)
    110 / 411 (26.76%)
    80 / 424 (18.87%)
         occurrences all number
    54
    110
    80
    Irritability
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    144 / 304 (47.37%)
    238 / 411 (57.91%)
    216 / 424 (50.94%)
         occurrences all number
    144
    238
    216
    Loss of appetite
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    94 / 304 (30.92%)
    170 / 411 (41.36%)
    154 / 424 (36.32%)
         occurrences all number
    94
    170
    154
    Pain
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    103 / 304 (33.88%)
    162 / 411 (39.42%)
    187 / 419 (44.63%)
         occurrences all number
    103
    162
    187
    Redness
    alternative assessment type: Systematic
         subjects affected / exposed [8]
    97 / 304 (31.91%)
    149 / 411 (36.25%)
    151 / 419 (36.04%)
         occurrences all number
    97
    149
    151
    Swelling
    alternative assessment type: Systematic
         subjects affected / exposed [9]
    45 / 304 (14.80%)
    70 / 411 (17.03%)
    82 / 419 (19.57%)
         occurrences all number
    45
    70
    82
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    16 / 324 (4.94%)
    39 / 455 (8.57%)
    22 / 462 (4.76%)
         occurrences all number
    16
    39
    22
    Teething
         subjects affected / exposed
    25 / 324 (7.72%)
    24 / 455 (5.27%)
    19 / 462 (4.11%)
         occurrences all number
    25
    24
    19
    Vomiting
         subjects affected / exposed
    14 / 324 (4.32%)
    30 / 455 (6.59%)
    12 / 462 (2.60%)
         occurrences all number
    14
    30
    12
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    21 / 324 (6.48%)
    20 / 455 (4.40%)
    23 / 462 (4.98%)
         occurrences all number
    21
    20
    23
    Rhinorrhoea
         subjects affected / exposed
    20 / 324 (6.17%)
    22 / 455 (4.84%)
    17 / 462 (3.68%)
         occurrences all number
    20
    22
    17
    Infections and infestations
    Otitis media
         subjects affected / exposed
    35 / 324 (10.80%)
    79 / 455 (17.36%)
    65 / 462 (14.07%)
         occurrences all number
    35
    79
    65
    Upper respiratory tract infection
         subjects affected / exposed
    31 / 324 (9.57%)
    64 / 455 (14.07%)
    58 / 462 (12.55%)
         occurrences all number
    31
    64
    58
    Nasopharyngitis
         subjects affected / exposed
    19 / 324 (5.86%)
    19 / 455 (4.18%)
    19 / 462 (4.11%)
         occurrences all number
    19
    19
    19
    Notes
    [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: For a given subject cohort and the analysis of a given measurement, missing or non evaluable measurements were not replaced. Therefore, an analysis excluded data points for subjects with missing or non-evaluable measurements i.e. analysis of solicited symptoms will exclude vaccinated subjects without documented Diary Cards.
    [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: For a given subject cohort and the analysis of a given measurement, missing or non evaluable measurements were not replaced. Therefore, an analysis excluded data points for subjects with missing or non-evaluable measurements i.e. analysis of solicited symptoms will exclude vaccinated subjects without documented Diary Cards.
    [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: For a given subject cohort and the analysis of a given measurement, missing or non evaluable measurements were not replaced. Therefore, an analysis excluded data points for subjects with missing or non-evaluable measurements i.e. analysis of solicited symptoms will exclude vaccinated subjects without documented Diary Cards.
    [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: For a given subject cohort and the analysis of a given measurement, missing or non evaluable measurements were not replaced. Therefore, an analysis excluded data points for subjects with missing or non-evaluable measurements i.e. analysis of solicited symptoms will exclude vaccinated subjects without documented Diary Cards.
    [7] - 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: For a given subject cohort and the analysis of a given measurement, missing or non evaluable measurements were not replaced. Therefore, an analysis excluded data points for subjects with missing or non-evaluable measurements i.e. analysis of solicited symptoms will exclude vaccinated subjects without documented Diary Cards.
    [8] - 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: For a given subject cohort and the analysis of a given measurement, missing or non evaluable measurements were not replaced. Therefore, an analysis excluded data points for subjects with missing or non-evaluable measurements i.e. analysis of solicited symptoms will exclude vaccinated subjects without documented Diary Cards.
    [9] - 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: For a given subject cohort and the analysis of a given measurement, missing or non evaluable measurements were not replaced. Therefore, an analysis excluded data points for subjects with missing or non-evaluable measurements i.e. analysis of solicited symptoms will exclude vaccinated subjects without documented Diary Cards.

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Mar 2006
    The primary reasons for this amendment are: • to revise the clinically acceptable non-inferiority limits for the seroconversion rates for measles, mumps (i.e., from 10% to 5%) and the seroresponse rate for rubella (i.e., from 10% to 5%), • to increase the sample size of both the HAV+MMR+V and the MMR+V→HAV Groups to 554 subjects in order to meet the revised non-inferiority limits and to ensure an adequate number of subjects enrolled given the high-drop-out rate between Visits 1 and 2, •to delete the inclusion of the HAV Group in the randomization of the additional 388 subjects to be enrolled because there was sufficient data available for the administration of Havrix only.

    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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