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    Clinical Trial Results:
    A phase III, open, randomized, multicentre, multicountry study to compare the reactogenicity and evaluate the safety and immunogenicity of GSK Bio’s combined hepatitis A / hepatitis B vaccine (at least 720 EL.U of hepatitis A antigen and 20 µg of hepatitis B surface antigen per dose of 1 ml) administered according to a 0, 6 month schedule by intramuscular injection versus Twinrix™ Junior (at least 360 EL.U of hepatitis A antigen and 10 µg of hepatitis B surface antigen per dose of 0.5 ml) administered according to a 0, 1, 6 month schedule by intramuscular injection in healthy children between 1 to 11 years old.

    Summary
    EudraCT number
    		 2015-001515-12
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    25 Feb 2008

    Results information
    Results version number
    		 v1
    This version publication date
    13 May 2016
    First version publication date
    26 Jul 2015
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    208127/120,/132,/133,/134,/137
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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 Disclosure Advisor, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Disclosure Advisor, 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
    10 Dec 2004
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Feb 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    For the primary study: To demonstrate that the combined hepatitis A / hepatitis B (720/20) vaccine is not more reactogenic than Twinrix™ Junior. For the long term follow up (LTFU): To evaluate anti-HAV and anti-HBs antibody persistence at Year 2, Year 3, Year 4 and Year 5 after the first vaccine dose of the primary vaccination course (a two-dose schedule of Twinrix Adult 720/20 vaccine or a three-dose schedule of Twinrix Junior 360/10 vaccine). To evaluate the immune memory in the subjects who became seronegative for anti-HAV antibodies (i.e. anti-HAV antibody concentrations < 15 mIU/ml) or had anti-HBs antibody concentrations < 10 mIU/ml at the long-term blood sampling time-point (i.e. Year 2, 3, 4 or 5) and who received the challenge dose (administered 6 to 12 months after the Year 5 time-point).
    Protection of trial subjects
    All subjects were supervised for 30 min after vaccination/product administration with appropriate medical treatment readily available. Vaccines/products were administered by qualified and trained personnel. Vaccines/products were administered only to eligible subjects that had no contraindications to any components of the vaccines/products. Subjects were followed-up for 30 days after the last vaccination/product administration.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Sep 2001
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 229
    Country: Number of subjects enrolled
    Belgium: 61
    Country: Number of subjects enrolled
    Spain: 110
    Country: Number of subjects enrolled
    Sweden: 110
    Worldwide total number of subjects
    510
    EEA total number of subjects
    281
    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)
    100
    Children (2-11 years)
    410
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

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

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Twinrix Adult
    Arm description
    		 Subjects received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Twinrix™ Adult
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular injection in the left deltoid, 2 doses, Adult formulation in primary study.

    Arm title
    		 Twinrix Junior
    Arm description
    		 Subjects received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Twinrix™ Junior
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular injection in the left deltoid, 3 doses, junior formulation in primary study.

    Number of subjects in period 1
    		Twinrix Adult Twinrix Junior
    Started
    254
    256
    Completed
    249
    250
    Not completed
    5
    6
         Consent withdrawn by subject
    4
    1
         Migrated/moved from study area
    -
    2
         Lost to follow-up
    -
    2
         Protocol deviation
    1
    1
    Period 2
    Period 2 title
    Year 2 - Year 5
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Twinrix Adult Y2-Y5
    Arm description
    		 Subjects previously received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Twinrix™ Adult
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular injection in the left deltoid, 2 doses, Adult formulation in primary study.

    Arm title
    		 Twinrix Junior Y2-Y5
    Arm description
    		 Subjects previously received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Twinrix™ Junior
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular injection in the left deltoid, 3 doses, junior formulation in primary study.

    Number of subjects in period 2 [1]
    		Twinrix Adult Y2-Y5 Twinrix Junior Y2-Y5
    Started
    139
    137
    Completed
    139
    137
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all subjects returned for the follow-up phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Twinrix Adult
    Reporting group description
    		 Subjects received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation).

    Reporting group title
    Twinrix Junior
    Reporting group description
    		 Subjects received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation).

    Reporting group values
    		 Twinrix Adult Twinrix Junior Total
    Number of subjects
    		 254 256 510
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (standard deviation)
    		 6.2 ± 3.11 5.8 ± 3.17 -
    Gender categorical
    Units: Subjects
        Female
    		 112 117 229
        Male
    		 142 139 281

    End points

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    End points reporting groups
    Reporting group title
    Twinrix Adult
    Reporting group description
    		 Subjects received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation).

    Reporting group title
    Twinrix Junior
    Reporting group description
    		 Subjects received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation).
    Reporting group title
    Twinrix Adult Y2-Y5
    Reporting group description
    		 Subjects previously received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation).

    Reporting group title
    Twinrix Junior Y2-Y5
    Reporting group description
    		 Subjects previously received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation).

    Primary: Anti-hepatitis A (HAV) antibody concentrations

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    End point title
    		 Anti-hepatitis A (HAV) antibody concentrations [1]
    End point description
    Geometric mean concentration for anti-HAV antibodies expressed as Milli-International Units per milliliter (mIU/mL)
    End point type
    Primary
    End point timeframe
    Year 2 (Month 24), Year 3 (Month 36), Year 4 (Month 48) and Year 5 (Month 60)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 Twinrix Adult Y2-Y5 Twinrix Junior Y2-Y5
    Number of subjects analysed
    129
    119
    Units: mIU/mL
    geometric mean (confidence interval 95%)
        At year 2 (n=107; 94)
    1122.2 (937.7 to 1343)
    1377.8 (1114 to 1704.2)
        At year 3 (n=129; 119)
    737.5 (845.8 to 1178.9)
    1347.1 (1145.1 to 1584.8)
        At year 4 (n=115; 105)
    576.8 (623.6 to 872.3)
    915.9 (774 to 1084)
        At year 5 (n=103; 101)
    998.6 (473.6 to 702.5)
    698.4 (585.1 to 833.7)
    No statistical analyses for this end point

    Primary: Anti-hepatitis B (HBs) antibody concentrations

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    End point title
    		 Anti-hepatitis B (HBs) antibody concentrations [2]
    End point description
    Geometric mean concentration for anti-HBs antibodies expressed as Milli-International Units per milliliter (mIU/mL).
    End point type
    Primary
    End point timeframe
    Year 2 (Month 24), Year 3 (Month 36), Year 4 (Month 48) and Year 5 (Month 60)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 Twinrix Adult Y2-Y5 Twinrix Junior Y2-Y5
    Number of subjects analysed
    129
    119
    Units: mIU/mL
    geometric mean (confidence interval 95%)
        At year 2 (n=107; 94)
    479.9 (356.6 to 646)
    830.6 (609.5 to 1131.9)
        At year 3 (n=129; 119)
    325.1 (244.7 to 431.8)
    695.1 (516.5 to 935.5)
        At year 4 (n=115; 105)
    270.2 (201 to 363.3)
    519.7 (378.5 to 713.6)
        At year 5 (n=102; 100)
    150.2 (110.5 to 204.3)
    283.7 (208.6 to 386)
    No statistical analyses for this end point

    Primary: Anti-HAV antibody concentrations in subjects receiving the additional vaccine dose.

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    End point title
    		 Anti-HAV antibody concentrations in subjects receiving the additional vaccine dose. [3]
    End point description
    Any subjects becoming seronegative for anti-HAV antibodies (i.e. titres < 15 mIU/ml) at any long term time point, were to receive an additional vaccine dose administered between 6 to 12 months after Year 5 time point.
    End point type
    Primary
    End point timeframe
    Before and one month after additional vaccination
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 Twinrix Adult Y2-Y5 Twinrix Junior Y2-Y5
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: mIU/mL
        geometric mean (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [4] - No subjects became seronegative for anti-HAV antibodies.
    [5] - No subjects became seronegative for anti-HAV antibodies.
    No statistical analyses for this end point

    Primary: Anti-HBs antibody concentrations in subjects receiving the additional vaccine dose.

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    End point title
    		 Anti-HBs antibody concentrations in subjects receiving the additional vaccine dose. [6]
    End point description
    Subjects losing seroprotective anti-HBs antibody titres (i.e. titres < 10 mIU/ml) at any long term time point, received an Engerix™ challenge dose. The table presents the geometric mean concentrations for anti-HBs antibodies, expressed as Milli-International Units per milliliter (mIU/mL).
    End point type
    Primary
    End point timeframe
    Before and One month after additional vaccination
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 Twinrix Adult Y2-Y5 Twinrix Junior Y2-Y5
    Number of subjects analysed
    11
    5
    Units: mIU/mL
    geometric mean (confidence interval 95%)
        Before vaccination (n= 6; 1)
    4.9 (2.1 to 11.1)
    2.4 (0.9 to 6.5)
        Post vaccination (n= 11; 5)
    521.3 (158.2 to 1718.1)
    509.7 (173.5 to 1497.9)
    No statistical analyses for this end point

    Primary: Number of subjects receiving an additional vaccine dose and reporting solicited local symptoms in children aged 1 to 5 years.

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    End point title
    		 Number of subjects receiving an additional vaccine dose and reporting solicited local symptoms in children aged 1 to 5 years. [7]
    End point description
    Solicited local symptoms assessed include pain, redness and swelling at the vaccine injection site. Any= regardless of intensity grade; Grade 3 Pain= spontaneously painful
    End point type
    Primary
    End point timeframe
    during the 4-day follow-up period after any vaccination
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 Twinrix Adult Twinrix Junior
    Number of subjects analysed
    112
    122
    Units: subjects
        Pain, any
    53
    56
        Pain, Grade 3
    2
    1
        Redness, any
    31
    45
        Redness, >25 mm
    1
    2
        Swelling, any
    26
    29
        Swelling, >25 mm
    1
    2
    No statistical analyses for this end point

    Primary: Number of subjects receiving an additional vaccine dose and reporting solicited local symptoms in children aged 6 to 11 years.

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    End point title
    		 Number of subjects receiving an additional vaccine dose and reporting solicited local symptoms in children aged 6 to 11 years. [8]
    End point description
    Solicited local symptoms assessed include pain, redness and swelling at the vaccine injection site. Any= regardless of intensity grade; Grade 3 Pain= spontaneously painful
    End point type
    Primary
    End point timeframe
    during the 4-day follow-up period after any vaccination
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 Twinrix Adult Twinrix Junior
    Number of subjects analysed
    138
    125
    Units: subjects
        Pain, any
    82
    72
        Pain, Grade 3
    3
    2
        Redness, any
    32
    31
        Redness, >25mm
    0
    1
        Swelling, any
    13
    23
        Swelling, >25mm
    0
    2
    No statistical analyses for this end point

    Primary: Number of subjects receiving an additional vaccine dose and reporting solicited general symptoms in children aged 1 to 5 years.

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    End point title
    		 Number of subjects receiving an additional vaccine dose and reporting solicited general symptoms in children aged 1 to 5 years. [9]
    End point description
    Solicited general symptoms assessed include drowsiness, irritability/fussiness, loss of appetite and fever. Any= regardless of intensity grade or relationship to vaccination; grade 3= prevented normal activity; Related= considered by the investigator to be causally related to the vaccination
    End point type
    Primary
    End point timeframe
    during the 4-day follow-up period after any vaccination
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 Twinrix Adult Twinrix Junior
    Number of subjects analysed
    112
    122
    Units: subjects
        Drowsiness, Any
    24
    39
        Drowsiness, Grade 3
    2
    3
        Drowsiness, Related
    23
    36
        Irritability/Fussiness, Any
    36
    52
        Irritability/Fussiness, Grade 3
    0
    1
        Irritability/Fussiness, Related
    29
    48
        Loss of appetite, Any
    20
    37
        Loss of appetite, Grade 3
    2
    0
        Loss of appetite, Related
    16
    33
        Fever (axillary), ≥37°C
    13
    19
        Fever (axillary), >39.5°C
    0
    1
        Fever (axillary), Related
    13
    16
    No statistical analyses for this end point

    Primary: Number of subjects receiving an additional vaccine dose and reporting solicited general symptoms in children aged 6 to 11 years.

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    End point title
    		 Number of subjects receiving an additional vaccine dose and reporting solicited general symptoms in children aged 6 to 11 years. [10]
    End point description
    Solicited general symptoms assessed include fatigue, fever, gastrointestinal symptoms and headache. Any= regardless of intensity grade or relationship to vaccination; grade 3= prevented normal activity; Related= considered by the investigator to be causally related to the vaccination
    End point type
    Primary
    End point timeframe
    during the 4-day follow-up period after any vaccination
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 Twinrix Adult Twinrix Junior
    Number of subjects analysed
    138
    125
    Units: subjects
        Fatigue, Any
    30
    36
        Fatigue, Grade 3
    1
    3
        Fatigue, Related
    28
    30
        Gastrointestinal, Any
    21
    26
        Gastrointestinal, Grade 3
    1
    4
        Gastrointestinal, Related
    14
    17
        Headache, Any
    25
    40
        Headache, Grade 3
    1
    1
        Headache, Related
    20
    30
        Fever (axillary), ≥37°C
    8
    16
        Fever (axillary), >39.5°C
    0
    1
        Fever (axillary), Related
    5
    8
    No statistical analyses for this end point

    Secondary: Number of subjects reporting Serious Adverse Events (SAEs) determined by the investigator to have a causal relationship to primary vaccination or due to lack of vaccine efficacy.

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    End point title
    		 Number of subjects reporting Serious Adverse Events (SAEs) determined by the investigator to have a causal relationship to primary vaccination or due to lack of vaccine efficacy.
    End point description
    A serious adverse event (SAE) is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.
    End point type
    Secondary
    End point timeframe
    From last study visit of the primary study up to Year 5 long term follow-up
    End point values
    		 Twinrix Adult Y2-Y5 Twinrix Junior Y2-Y5
    Number of subjects analysed
    139
    137
    Units: subjects
        SAE(s)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects receiving an additional vaccine dose and reporting solicited local symptoms

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    End point title
    		 Number of subjects receiving an additional vaccine dose and reporting solicited local symptoms
    End point description
    Solicited local symptoms assessed include pain, redness and swelling at the vaccine injection site. Any= regardless of intensity grade; Grade 3 Pain= spontaneously painful
    End point type
    Secondary
    End point timeframe
    during the 4-day follow-up period after additional vaccination
    End point values
    		 Twinrix Adult Y2-Y5 Twinrix Junior Y2-Y5
    Number of subjects analysed
    11
    5
    Units: subjects
        Pain, any
    6
    0
        Pain, grade 3
    0
    0
        Redness, any
    1
    0
        Redness, >20mm
    0
    0
        Swelling, any
    0
    0
        Swelling, >20mm
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects receiving an additional vaccine dose and reporting solicited general symptoms.

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    End point title
    		 Number of subjects receiving an additional vaccine dose and reporting solicited general symptoms.
    End point description
    Solicited general symptoms assessed include fatigue, fever, gastrointestinal symptoms and headache. Any= regardless of intensity grade or relationship to vaccination; grade 3= prevented normal activity; Related= considered by the investigator to be causally related to the vaccination
    End point type
    Secondary
    End point timeframe
    During the 4-day follow-up period after additional vaccination
    End point values
    		 Twinrix Adult Y2-Y5 Twinrix Junior Y2-Y5
    Number of subjects analysed
    11
    5
    Units: subjects
        Fatigue, any
    3
    0
        Fatigue, grade 3
    0
    0
        Fatigue, related
    3
    0
        Fever (axillary), ≥37°C
    0
    0
        Fever (axillary), >39.5°C
    0
    0
        Fever (axillary), related
    0
    0
        Gastrointestinal, any
    2
    0
        Gastrointestinal, grade 3
    0
    0
        Gastrointestinal, related
    2
    0
        Headache, any
    4
    0
        Headache, grade 3
    0
    0
        Headache, related
    4
    0
    No statistical analyses for this end point

    Secondary: Number of subjects receiving an additional vaccine dose and reporting unsolicited adverse events (AEs).

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    End point title
    		 Number of subjects receiving an additional vaccine dose and 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
    During the 30-day follow-up period after additional vaccination.
    End point values
    		 Twinrix Adult Y2-Y5 Twinrix Junior Y2-Y5
    Number of subjects analysed
    11
    5
    Units: subjects
        AEs
    2
    0
    No statistical analyses for this end point

    Secondary: Number of subjects receiving an additional vaccine dose and reporting any Serious Adverse Events

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    End point title
    		 Number of subjects receiving an additional vaccine dose and reporting any Serious Adverse Events
    End point description
    A serious adverse event (SAE) is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.
    End point type
    Secondary
    End point timeframe
    At least one month after vaccination
    End point values
    		 Twinrix Adult Y2-Y5 Twinrix Junior Y2-Y5
    Number of subjects analysed
    11
    5
    Units: subjects
        SAEs
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects receiving an additional vaccine dose and reporting unsolicited adverse events (AEs).

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    End point title
    		 Number of subjects receiving an additional vaccine dose and 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
    During the 30-day follow-up period after additional vaccination.
    End point values
    		 Twinrix Adult Twinrix Junior
    Number of subjects analysed
    254
    254 [11]
    Units: subjects
        AEs
    139
    169
    Notes
    [11] - Safety data were not available for 2 subjects
    No statistical analyses for this end point

    Secondary: Number of subjects receiving an additional vaccine dose and reporting any Serious Adverse Events

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    End point title
    		 Number of subjects receiving an additional vaccine dose and reporting any Serious Adverse Events
    End point description
    A serious adverse event (SAE) is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.
    End point type
    Secondary
    End point timeframe
    At least one month after vaccination
    End point values
    		 Twinrix Adult Twinrix Junior
    Number of subjects analysed
    254
    254 [12]
    Units: subjects
        SAEs
    5
    5
    Notes
    [12] - Safety data were not available for 2 subjects
    No statistical analyses for this end point

    Secondary: Anti-hepatitis A (HAV) antibody concentrations

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    End point title
    		 Anti-hepatitis A (HAV) antibody concentrations
    End point description
    Geometric mean concentration for anti-HAV antibodies expressed as Milli-International Units per milliliter (mIU/mL)
    End point type
    Secondary
    End point timeframe
    Before (PRE) and 7 Months after vaccination (POST)
    End point values
    		 Twinrix Adult Twinrix Junior
    Number of subjects analysed
    201
    188
    Units: mIU/mL
    geometric mean (confidence interval 95%)
        PRE (N=154;138)
    7.5 (7.5 to 7.5)
    7.5 (7.5 to 7.5)
        POST (N=201;188)
    8412.1 (7483 to 9456.5)
    9256.8 (8160 to 10501.2)
    No statistical analyses for this end point

    Secondary: Anti-hepatitis B (HBs) antibody concentrations

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    End point title
    		 Anti-hepatitis B (HBs) antibody concentrations
    End point description
    Geometric mean concentration for anti-HBs antibodies expressed as Milli-International Units per milliliter (mIU/mL).
    End point type
    Secondary
    End point timeframe
    Before (PRE) and 7 Months after vaccination (POST)
    End point values
    		 Twinrix Adult Twinrix Junior
    Number of subjects analysed
    201
    188
    Units: mIU/mL
    geometric mean (confidence interval 95%)
        PRE (N=154;138)
    7894.4 (1.7 to 1.7)
    1.7 (1.7 to 1.7)
        POST (N=201;188)
    1.7 (6130.9 to 10165.1)
    13683.1 (11314.5 to 16547.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited symtoms: During the 4-day (Day 0-3) follow-up period after the additional vaccination. Unsolicited AEs: During the 31-day (Day 0-30) period after the additional vaccination; SAEs: During the entire study period
    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
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    7.1
    Reporting groups
    Reporting group title
    Twinrix Adult
    Reporting group description
    		 Subjects received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation).

    Reporting group title
    Twinrix Junior
    Reporting group description
    		 Subjects received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation).

    Serious adverse events
    		 Twinrix Adult Twinrix Junior
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 254 (1.97%)
    5 / 254 (1.97%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Injury
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 254 (1.57%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Eczema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Glomerulonephritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection viral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Twinrix Adult Twinrix Junior
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    135 / 254 (53.15%)
    128 / 254 (50.39%)
    Nervous system disorders
    Syncope vasovagal (FU)
         subjects affected / exposed [1]
    1 / 11 (9.09%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Headache (AEs) (Primary)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    13 / 254 (5.12%)
    18 / 254 (7.09%)
         occurrences all number
    13
    18
    General disorders and administration site conditions
    Redness at the injection site (FU)
         subjects affected / exposed [2]
    1 / 11 (9.09%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Pain at the injection site (FU)
         subjects affected / exposed [3]
    6 / 11 (54.55%)
    0 / 5 (0.00%)
         occurrences all number
    6
    0
    Fatigue (FU)
         subjects affected / exposed [4]
    3 / 11 (27.27%)
    0 / 5 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorder (FU)
         subjects affected / exposed [5]
    2 / 11 (18.18%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Headache (FU)
         subjects affected / exposed [6]
    4 / 11 (36.36%)
    0 / 5 (0.00%)
         occurrences all number
    4
    0
    Pain (Primary)
         subjects affected / exposed [7]
    135 / 250 (54.00%)
    128 / 247 (51.82%)
         occurrences all number
    135
    128
    Redness (Primary)
         subjects affected / exposed [8]
    63 / 250 (25.20%)
    76 / 247 (30.77%)
         occurrences all number
    63
    76
    Swelling (Primary)
         subjects affected / exposed [9]
    39 / 250 (15.60%)
    52 / 247 (21.05%)
         occurrences all number
    39
    52
    Drowsiness (Primary)
         subjects affected / exposed [10]
    24 / 112 (21.43%)
    39 / 122 (31.97%)
         occurrences all number
    24
    39
    Irritability/Fussiness (Primary)
         subjects affected / exposed [11]
    36 / 112 (32.14%)
    52 / 122 (42.62%)
         occurrences all number
    36
    52
    Loss of appetite (Primary)
         subjects affected / exposed [12]
    20 / 112 (17.86%)
    37 / 122 (30.33%)
         occurrences all number
    20
    37
    Fever (Primary)
         subjects affected / exposed
    21 / 254 (8.27%)
    35 / 254 (13.78%)
         occurrences all number
    21
    35
    Fatigue (Primary)
         subjects affected / exposed [13]
    30 / 138 (21.74%)
    36 / 125 (28.80%)
         occurrences all number
    30
    36
    Gastrointestinal (Primary)
         subjects affected / exposed [14]
    21 / 138 (15.22%)
    26 / 125 (20.80%)
         occurrences all number
    21
    26
    Headache (Primary)
         subjects affected / exposed [15]
    25 / 138 (18.12%)
    40 / 125 (32.00%)
         occurrences all number
    25
    40
    Fever (AEs) (Primary)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    14 / 254 (5.51%)
    26 / 254 (10.24%)
         occurrences all number
    14
    26
    Injection site reaction (Primary)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    17 / 254 (6.69%)
    21 / 254 (8.27%)
         occurrences all number
    17
    21
    Blood and lymphatic system disorders
    Pharyngitis (Primary)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    21 / 254 (8.27%)
    31 / 254 (12.20%)
         occurrences all number
    21
    31
    Reproductive system and breast disorders
    Balanitis (FU)
         subjects affected / exposed [16]
    1 / 11 (9.09%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Vomiting (Primary)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    15 / 254 (5.91%)
    16 / 254 (6.30%)
         occurrences all number
    15
    16
    Diarrhea (Primary)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 254 (3.94%)
    13 / 254 (5.12%)
         occurrences all number
    10
    13
    Respiratory, thoracic and mediastinal disorders
    Coughing (Primary)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    11 / 254 (4.33%)
    34 / 254 (13.39%)
         occurrences all number
    11
    34
    Musculoskeletal and connective tissue disorders
    Arthralgia (FU)
         subjects affected / exposed [17]
    1 / 11 (9.09%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Upper respiratory tract infection (Primary)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    35 / 254 (13.78%)
    54 / 254 (21.26%)
         occurrences all number
    35
    54
    Rhinitis (Primary)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    13 / 254 (5.12%)
    27 / 254 (10.63%)
         occurrences all number
    13
    27
    Otitis media (Primary)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    11 / 254 (4.33%)
    15 / 254 (5.91%)
         occurrences all number
    11
    15
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: There were less subjects enrolled in the follow-up phase of the study than in the primary phase.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: There were less subjects enrolled in the follow-up phase of the study than in the primary phase.
    [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: There were less subjects enrolled in the follow-up phase of the study than in the primary phase.
    [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: There were less subjects enrolled in the follow-up phase of the study than in the primary phase.
    [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: There were less subjects enrolled in the follow-up phase of the study than in the primary phase.
    [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: There were less subjects enrolled in the follow-up phase of the study than in the primary phase.
    [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: Solicited local and general symptoms were only tabulated for subjects with a symptom sheet filled-in.
    [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: Solicited local and general symptoms were only tabulated for subjects with a symptom sheet filled-in.
    [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: Solicited local and general symptoms were only tabulated for subjects with a symptom sheet filled-in.
    [10] - 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: Solicited local and general symptoms were only tabulated for subjects with a symptom sheet filled-in.
    [11] - 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: Solicited local and general symptoms were only tabulated for subjects with a symptom sheet filled-in.
    [12] - 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: Solicited local and general symptoms were only tabulated for subjects with a symptom sheet filled-in.
    [13] - 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: Solicited local and general symptoms were only tabulated for subjects with a symptom sheet filled-in.
    [14] - 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: Solicited local and general symptoms were only tabulated for subjects with a symptom sheet filled-in.
    [15] - 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: Solicited local and general symptoms were only tabulated for subjects with a symptom sheet filled-in.
    [16] - 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: There were less subjects enrolled in the follow-up phase of the study than in the primary phase.
    [17] - 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: There were less subjects enrolled in the follow-up phase of the study than in the primary phase.

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jul 2001
    • To account for the competitive enrolment that is to be used for this study, extra randomization numbers and vaccine supplies will be needed at the study centres. • The study site in The Netherlands under Professor R.A. Coutinho and the study site in Croatia under Professor Berislav Borčić will now not be used and, in consequence, can be deleted from the study protocol. To replace these two sites, a new study site in Belgium has been incorporated (UCL, Brussels under Dr Etienne Sokal). • Anne Howard has been appointed as the Australian Study Monitor for this project, replacing Serge De Bartolo, therefore, her contact details are now included. • Inmaculada Nuñez Arias has been appointed as one of the Spanish Study Monitors for this project, replacing Sandra Sistiaga, therefore, her contact details are now included. • The section of the title pages requiring the signatures of the Principal Investigators has been deleted due to its redundancy in the modified protocol.

    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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