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    Clinical Trial Results:
    An open multicentre, multicountry study to evaluate long-term anti-body persistence and immune memory between Years 11 and 15 after the primary study HAB-084 in which healthy adolescents were vaccinated with Twinrix™ Adult following a two-dose schedule or Twinrix™ Junior following a three-dose schedule.

    Summary
    EudraCT number
    		 2015-001517-27
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    18 Jul 2008

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 May 2016
    First version publication date
    02 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    208127/084,100566/567/568/569/570
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00197119
    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, 044 2089-904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089-904466, 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
    22 Dec 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jul 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jul 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    For primary study: To demonstrate, that the immunogenicity elicited by the combined hepatitis A / hepatitis B vaccine Twinrix™™™™™™ is at least equivalent to that of Twinrix™ Junior vaccine, by measuring the anti-hepatitis A virus (anti-HAV) and anti-hepatitis B surface antigen (anti-HBs) antibody levels reached at month 7. For the long term follow-up (LTFU): To evaluate anti-HAV and anti-HBs antibody persistence at Year 6 (i.e. Month 72), Year 7 (i.e. Month 84), Year 8 (i.e. Month 96), Year 9 (i.e. Month 108) and Year 10 (i.e. Month 120) after the first vaccine dose of the two-dose or three-dose primary vaccination.
    Protection of trial subjects
    The subjects were observed closely for at least 30 minutes after administration of additional vaccine dose, with appropriate medical treatment readily available in case of a rare anaphylactic reaction following the administration of vaccine.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Apr 1998
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 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
    Belgium: 155
    Country: Number of subjects enrolled
    Czech Republic: 145
    Worldwide total number of subjects
    300
    EEA total number of subjects
    300
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    300
    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
    		 At the time of initiation of the long-term follow-up study, the investigators contacted the subjects who had consented to participate in the long-term follow-up studies. At each subsequent visit, subjects who were present at the previous long-term blood sampling time points were contacted again.

    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
    Primary 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
    		 Twinrix Junior Group
    Arm description
    		 Subjects received Twinrix™ Junior (360/10) in a 0, 1, 6 month schedule in the primary study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Twinrix Paediatric
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    3 doses administered intramuscularly in the deltoid region.

    Arm title
    		 Twinrix Adult Group
    Arm description
    		 Subjects received Twinrix™ Adult (720/20) in a 0, 6 month schedule in the primary study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Twinrix Adult
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    2 doses administered intramuscularly in the deltoid region.

    Number of subjects in period 1
    		Twinrix Junior Group Twinrix Adult Group
    Started
    150
    150
    Completed
    148
    149
    Not completed
    2
    1
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Twinrix Junior Group
    Reporting group description
    		 Subjects received Twinrix™ Junior (360/10) in a 0, 1, 6 month schedule in the primary study.

    Reporting group title
    Twinrix Adult Group
    Reporting group description
    		 Subjects received Twinrix™ Adult (720/20) in a 0, 6 month schedule in the primary study.

    Reporting group values
    		 Twinrix Junior Group Twinrix Adult Group Total
    Number of subjects
    		 150 150 300
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 13.4 ( 1.01 ) 13.4 ( 1.07 ) -
    Gender categorical
    Units: Subjects
        Female
    		 72 78 150
        Male
    		 78 72 150

    End points

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    End points reporting groups
    Reporting group title
    Twinrix Junior Group
    Reporting group description
    		 Subjects received Twinrix™ Junior (360/10) in a 0, 1, 6 month schedule in the primary study.

    Reporting group title
    Twinrix Adult Group
    Reporting group description
    		 Subjects received Twinrix™ Adult (720/20) in a 0, 6 month schedule in the primary study.

    Subject analysis set title
    Year 6 Twinrix Junior Group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects received Twinrix™ Junior (360/10) in a 0, 1, 6 month schedule in the primary study.

    Subject analysis set title
    Year 6 Twinrix Adult Group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects received Twinrix™ Adult (720/20) in a 0, 6 month schedule in the primary study.

    Subject analysis set title
    Year 7 Twinrix Junior Group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects received Twinrix™ Junior (360/10) in a 0, 1, 6 month schedule in the primary study. 4 subjects who participated in the Year 6 follow-up time point did not return for this time point.

    Subject analysis set title
    Year 7 Twinrix Adult Group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects received Twinrix™ Adult (720/20) in a 0, 6 month schedule in the primary study. 4 subjects who participated in the Year 6 follow-up time point did not return for this time point.

    Subject analysis set title
    Year 8 Twinrix Junior Group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects received Twinrix™ Junior (360/10) in a 0, 1, 6 month schedule in the primary study.

    Subject analysis set title
    Year 8 Twinrix Adult Group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects received Twinrix™ Adult (720/20) in a 0, 6 month schedule in the primary study. One additional subject (compared to Year 7) participated in the current follow-up time point.

    Subject analysis set title
    Year 9 Twinrix Junior Group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects received Twinrix™ Junior (360/10) in a 0, 1, 6 month schedule in the primary study. One subject participating in the Year 8 time point did not return for the current time point.

    Subject analysis set title
    Year 9 Twinrix Adult Group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects received Twinrix™ Adult (720/20) in a 0, 6 month schedule in the primary study. One subject participating in the Year 8 time point did not return for the current time point.

    Subject analysis set title
    Year 10 Twinrix Junior Group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects received Twinrix™ Junior (360/10) in a 0, 1, 6 month schedule in the primary study. One subject participating in the Year 9 time point did not return for the current time point.

    Subject analysis set title
    Year 10 Twinrix Adult Group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects received Twinrix™ Adult (720/20) in a 0, 6 month schedule in the primary study. Six subjects participating in the Year 9 time point did not return for the current time point.

    Primary: Antibody titers against hepatitis A and B viruses

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    End point title
    		 Antibody titers against hepatitis A and B viruses
    End point description
    Antibody titers were summarized by Geometric Mean Concentrations (GMCs) with their 95% CIs.
    End point type
    Primary
    End point timeframe
    At Month 7
    End point values
    		 Twinrix Junior Group Twinrix Adult Group
    Number of subjects analysed
    147
    142
    Units: mIU/mL
    geometric mean (confidence interval 95%)
        anti-HAV
    4174 (3659.5 to 4760.8)
    5486.9 (4797.4 to 6275.7)
        anti-HBs
    5054.3 (4129.9 to 6185.6)
    4948.6 (3624.8 to 6755.8)
    Statistical analysis title
    		 Combined response rate to anti-HAV and anti-HBs
    Statistical analysis description
    To demonstrate that the immunogenicity elicited by the Twinrix Adult vaccine is at least equivalent to that of Twinrix Junior vaccine, by measuring the anti-hepatitis A virus (anti-HAV) and anti-hepatitis B surface antigen (anti-HBs) antibody levels reached at Month 7. This was concluded if the lower limit of the exact 90% CI for the difference [Twinrix Adult - Twinrix Junior] in the proportion of subjects with the combined antibody response rate at Month 7 was ≥ -10%.
    Comparison groups
    Twinrix Junior Group v Twinrix Adult Group
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Combined response rate difference
    Point estimate
    -2.11
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -7.04
         upper limit
    		 1.92

    Primary: Number of subjects seroconverted for anti-hepatitis A virus (anti-HAV) antibodies

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    End point title
    		 Number of subjects seroconverted for anti-hepatitis A virus (anti-HAV) antibodies [1]
    End point description
    Seroconversion was defined as evolution of antibody concentrations (anti-HAV) ≥ the lowest sensitivity limit of the serological assay in a subject who was seronegative in pre-vaccination blood sample. An increase in antibody concentration from less than 1 mlU/mL to ≥ 1 mlU/mL was considered to be a seroconversion.
    End point type
    Primary
    End point timeframe
    At Month 7.
    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 Junior Group Twinrix Adult Group
    Number of subjects analysed
    147
    142
    Units: Subjects
        anti-HAV
    147
    142
    No statistical analyses for this end point

    Primary: Number of subjects seroprotected for anti-hepatitis B surface antigen (anti-HBs) antibodies

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    End point title
    		 Number of subjects seroprotected for anti-hepatitis B surface antigen (anti-HBs) antibodies [2]
    End point description
    Seroprotection was defined as anti-HBs concentration ≥ 10 mIU/mL.
    End point type
    Primary
    End point timeframe
    At Month 7.
    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 Junior Group Twinrix Adult Group
    Number of subjects analysed
    147
    142
    Units: Subjects
        anti-HBs
    147
    139
    No statistical analyses for this end point

    Primary: Number of subjects with anti-hepatitis A virus (HAV) antibody concentrations above the cut-off value

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    End point title
    		 Number of subjects with anti-hepatitis A virus (HAV) antibody concentrations above the cut-off value [3]
    End point description
    Anti-HAV antibody concentration cut-off value assessed was ≥ 15 milli-International Units per milliliter (mIU/mL).
    End point type
    Primary
    End point timeframe
    At Year 6, 7, 8, 9 and 10 after the first vaccine dose of a two-dose or three-dose primary 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
    		 Year 6 Twinrix Junior Group Year 6 Twinrix Adult Group Year 7 Twinrix Junior Group Year 7 Twinrix Adult Group Year 8 Twinrix Junior Group Year 8 Twinrix Adult Group Year 9 Twinrix Junior Group Year 9 Twinrix Adult Group Year 10 Twinrix Junior Group Year 10 Twinrix Adult Group
    Number of subjects analysed
    113
    100
    105
    92
    104
    93
    103
    90
    100
    77
    Units: Subjects
        Anti-HAV ≥ 15 mIU/mL
    113
    100
    105
    92
    104
    93
    103
    90
    100
    77
    No statistical analyses for this end point

    Primary: Number of Subjects With Anti-Hepatitis B Surface Antigen (HBs) Antibody Concentrations Above the Cut-Off Value

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    End point title
    		 Number of Subjects With Anti-Hepatitis B Surface Antigen (HBs) Antibody Concentrations Above the Cut-Off Value [4]
    End point description
    Anti-HBs antibody concentration cut-off value assessed was ≥ 3.3 mIU/mL.
    End point type
    Primary
    End point timeframe
    At Year 6, 7, 8, 9 and 10 after the first vaccine dose of a two-dose or three-dose primary vaccination.
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed
    End point values
    		 Year 6 Twinrix Junior Group Year 6 Twinrix Adult Group Year 7 Twinrix Junior Group Year 7 Twinrix Adult Group Year 8 Twinrix Junior Group Year 8 Twinrix Adult Group Year 9 Twinrix Junior Group Year 9 Twinrix Adult Group Year 10 Twinrix Junior Group Year 10 Twinrix Adult Group
    Number of subjects analysed
    113
    100
    105
    92
    104
    93
    103
    90
    101
    78
    Units: Subjects
        anti-HBs ≥ 3.3 mIU/mL
    100
    93
    98
    85
    96
    84
    96
    86
    97
    75
    No statistical analyses for this end point

    Primary: Number of subjects reporting Serious adverse events (SAE) causally related to primary vaccination or related to hepatitis A or B infection or related to study participation (blood sampling)

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    End point title
    		 Number of subjects reporting Serious adverse events (SAE) causally related to primary vaccination or related to hepatitis A or B infection or related to study participation (blood sampling) [5]
    End point description
    An 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
    Primary
    End point timeframe
    From Year 6 through to Year 10
    Notes
    [5] - 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
    		 Year 6 Twinrix Junior Group Year 6 Twinrix Adult Group Year 7 Twinrix Junior Group Year 7 Twinrix Adult Group Year 8 Twinrix Junior Group Year 8 Twinrix Adult Group Year 9 Twinrix Junior Group Year 9 Twinrix Adult Group Year 10 Twinrix Junior Group Year 10 Twinrix Adult Group
    Number of subjects analysed
    126
    118
    122
    114
    122
    115
    121
    114
    120
    108
    Units: Subjects
        SAE(s)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Antibody titers against hepatitis A and hepatitis B viruses.

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    End point title
    		 Antibody titers against hepatitis A and hepatitis B viruses.
    End point description
    Antibody titers were summarized by Geometric Mean Concentrations (GMCs) with their 95% CIs.
    End point type
    Secondary
    End point timeframe
    At months 1, 2, and 6.
    End point values
    		 Twinrix Junior Group Twinrix Adult Group
    Number of subjects analysed
    148
    142
    Units: mlU/mL
    geometric mean (confidence interval 95%)
        anti-HAV, M1 (N=148,142)
    227.4 (196.4 to 263.2)
    348.7 (302.4 to 402.2)
        anti-HAV, M2 (N=146,142)
    548.8 (472.7 to 637.2)
    244.7 (213.6 to 280.5)
        anti-HAV, M6 (N=147,142)
    298.8 (263.1 to 339.4)
    178 (159.4 to 198.7)
        anti-HBs, M1 (N=148,142)
    9.8 (7.2 to 13.3)
    14.3 (10.4 to 19.7)
        anti-HBs, M2 (N=146,142)
    42.1 (33.3 to 53.1)
    9.9 (7.7 to 12.6)
        anti-HBs, M6 (N=147,142)
    305.3 (249 to 374.1)
    20.1 (16 to 25.3)
    No statistical analyses for this end point

    Secondary: Number of subjects seroconverted for anti-hepatitis A virus (anti-HAV) antibodies

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    End point title
    		 Number of subjects seroconverted for anti-hepatitis A virus (anti-HAV) antibodies
    End point description
    Seroconversion was defined as evolution of antibody concentrations (anti-HAV) ≥ the lowest sensitivity limit of the serological assay in a subject who was seronegative vaccination. An increase in antibody concentration from less than 1 mlU/mL to ≥ 1 mlU/mL was considered to be a seroconversion.
    End point type
    Secondary
    End point timeframe
    At months 1, 2, and 6.
    End point values
    		 Twinrix Junior Group Twinrix Adult Group
    Number of subjects analysed
    148
    142
    Units: Subjects
        anti-HAV, M1 (N=148,142)
    138
    141
        anti-HAV, M2 (N=146,142)
    145
    142
        anti-HAV, M6 (N=147,142)
    146
    142
    No statistical analyses for this end point

    Secondary: Number of subjects seroprotected for anti-hepatitis B surface antigen (anti-HBs) antibodies.

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    End point title
    		 Number of subjects seroprotected for anti-hepatitis B surface antigen (anti-HBs) antibodies.
    End point description
    Seroprotections was defined as anti-HBs concentration ≥ 10 mIU/mL.
    End point type
    Secondary
    End point timeframe
    At months 1, 2, and 6.
    End point values
    		 Twinrix Junior Group Twinrix Adult Group
    Number of subjects analysed
    148
    142
    Units: Subjects
        anti-HBs, M1 (N=148,142)
    43
    61
        anti-HBs, M2 (N=146,142)
    125
    54
        anti-HBs, M6 (N=147,142)
    144
    97
    No statistical analyses for this end point

    Secondary: Number of subjects with any and Grade 3 solicited local symptoms.

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    End point title
    		 Number of subjects with any and Grade 3 solicited local symptoms.
    End point description
    Solicited local symptoms assessed were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = spontaneously painful (prevents normal activities). Grade 3 redness/swelling = redness/swelling spreading beyond 50 millimeters (mm) of injection site.
    End point type
    Secondary
    End point timeframe
    During the three days (days 0-4) follow-up period after each vaccine dose (Dose 1, 2 and 3)
    End point values
    		 Twinrix Junior Group Twinrix Adult Group
    Number of subjects analysed
    149
    149
    Units: Subjects
        Any Pain; Dose 1 (N=149,149)
    53
    68
        Grade 3 Pain; Dose 1 (N=149,149)
    0
    3
        Any Redness; Dose 1 (N=149,149)
    15
    24
        Grade 3 Redness; Dose 1 (N=149,149)
    0
    0
        Any Swelling; Dose 1 (N=149,149)
    3
    4
        Grade 3 Swelling; Dose 1 (N=149,149)
    0
    0
        Any Pain; Dose 2 (N=148,149)
    56
    83
        Grade 3 Pan; Dose 2 (N=148,149)
    0
    2
        Any Redness; Dose 2 (N=148,149)
    13
    24
        Grade 3 Redness; Dose 2 (N=148,149)
    0
    0
        Any Swelling; Dose 2 (N=148,149)
    7
    9
        Grade 3 Swelling; Dose 2 (N=148,149)
    1
    0
        Any Pain; Dose 3 (N=148,0)
    65
    0
        Grade 3 Pain; Dose 3 (N=148,0)
    0
    0
        Any Redness; Dose 3 (N=148,0)
    25
    0
        Grade 3 Redness; Dose 3 (N=148,0)
    0
    0
        Any Swelling; Dose 3 (N=148,0)
    12
    0
        Grade 3 Swelling; Dose 3 (N=148,0)
    0
    0
        Any Pain; Across Doses (N=149,149)
    95
    99
        Grade 3 pain; Across Doses (N=149,149)
    0
    5
        Any Redness; Across Doses (N=149,149)
    35
    34
        Grade 3 Redness; Across Doses (N=149,149)
    0
    0
        Any Swelling; Across Doses (N=149,149)
    19
    11
        Grade 3 Swelling; Across Doses (N=149,149)
    1
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with any, grade 3 and related solicited general symptoms

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    End point title
    		 Number of subjects with any, grade 3 and related solicited general symptoms
    End point description
    Solicited general symptoms assessed were fatigue, fever (defined as rectal temperature ≥38°C), gastrointestinal symptoms (GS), and headache. Any was defined as incidence of the specified symptoms regardless of intensity or relationship to study vaccine. Grade 3 was defined as an event that prevented normal activity and Grade 3 fever (oral/axillary route) = temperature > 39.0 degree Celsius (°C). Related was defined as an event assessed by the investigator as causally related to the study vaccination.
    End point type
    Secondary
    End point timeframe
    During the three days (days 0-4) follow-up period after each vaccine dose (Dose 1, 2 and 3).
    End point values
    		 Twinrix Junior Group Twinrix Adult Group
    Number of subjects analysed
    149
    149
    Units: Subjects
        Any Fatigue; Dose 1 (N=149,149)
    34
    48
        Grade 3 Fatigue; Dose 1 (N=149,149)
    3
    0
        Related Fatigue; Dose 1 (N=149,149)
    16
    23
        Any Temperature; Dose 1 (N=149,149)
    3
    2
        Grade 3 Temperature; Dose 1 (N=149,149)
    0
    0
        Related Temperature; Dose 1 (N=149,149)
    2
    1
        Any GS; Dose 1 (N=149,149)
    8
    11
        Grade 3 GS; Dose 1 (N=149,149)
    0
    0
        Related GS; Dose 1 (N=149,149)
    5
    6
        Any Headache; Dose 1 (N=149,149)
    21
    24
        Grade 3 Headache; Dose 1 (N=149,149)
    0
    0
        Related Headache; Dose 1 (N=149,149)
    10
    13
        Any Fatigue; Dose 2 (N=148,149)
    25
    39
        Grade 3 Fatigue; Dose 2 (N=148,149)
    1
    0
        Related Fatigue; Dose 2 (N=148,149)
    10
    19
        Any temperature; Dose 2 (N=148,149)
    1
    3
        Grade 3 Temperature; Dose 2 (N=148,149)
    0
    0
        Related Temperature (N=148,149)
    1
    1
        Any GS; Dose 2 (N=148,149)
    5
    5
        Grade 3 GS; Dose 2 (N=148,149)
    0
    1
        Related GS; Dose 2 (N=148,149)
    0
    3
        Any Headache; Dose 2 (N=148,149)
    20
    23
        Grade 3 Headache; Dose 2 (N=148,149)
    0
    0
        Related Headache; Dose 2 (N=148,149)
    10
    16
        Any Fatigue; Dose 3 (N=148,0)
    27
    0
        Grade 3 Fatigue; Dose 3 (N=148,0)
    1
    0
        Related Fatigue; Dose 3 (N=148,0)
    16
    0
        Any Temperature; Dose 3 (N=148,0)
    2
    0
        Grade 3 Temperature; Dose 3 (N=148,0)
    0
    0
        Related Temperature; Dose 3 (N=148,0)
    1
    0
        Any GS; Dose 3 (N=148,0)
    2
    0
        Grade 3 GS; Dose 3 (N=148,0)
    0
    0
        Related GS; Dose 3 (N=148,0)
    1
    0
        Any Headache; Dose 3 (N=148,0)
    21
    0
        Grade 3 Headache; Dose 3 (N=148,0)
    1
    0
        Related Headache; Dose 3 (N=148,0)
    11
    0
        Any Fatigue; Across Doses (N=149,149)
    54
    59
        Grade 3 Fatigue; Across Doses (N=149,149)
    3
    0
        Related Fatigue; Across Doses (N=149,149)
    32
    35
        Any Temperature; Across Doses (N=149,149)
    5
    5
        Grade 3 Temperature; Across Doses (N=149,149)
    0
    0
        Related Temperature; Across Doses (N=149,149)
    3
    2
        Any GS; Across Doses (N=149,149)
    13
    15
        Grade 3 GS; Across Doses (N=149,149)
    0
    1
        Related GS; Across Doses (N=149,149)
    6
    9
        Any Headache; Across Doses (N=149,149)
    44
    37
        Grade 3 Headache; Across Doses (N=149,149)
    1
    0
        Related Headache; Across Doses (N=149,149)
    22
    24
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any unsolicited Adverse Events (AEs)

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    End point title
    		 Number of subjects reporting any unsolicited Adverse Events (AEs)
    End point description
    An unsolicited AE covers 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. Any was defined as an adverse event (AE) reported in addition to those solicited during the clinical study. Any solicited symptom with onset outside the specified period of follow-up for solicited symptoms was reported as an unsolicited adverse event.
    End point type
    Secondary
    End point timeframe
    Within 31 days (days0-30) after each vaccine dose
    End point values
    		 Twinrix Junior Group Twinrix Adult Group
    Number of subjects analysed
    149
    149
    Units: Subjects
        any AE (s)
    47
    38
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects with Serious adverse events (SAEs)
    End point description
    SAEs assessed included medical occurrences that were fatal, life threatening, disabling/incapacitating or resulted in hospitalization, prolonged a hospital stay or was associated with congenital abnormality in offspring, cancer or overdose (either accidental or intentional). Any was defined as occurrence of any symptom regardless of intensity grade or relation to vaccination and related was an event assessed by the investigator as causally related to the study vaccination.
    End point type
    Secondary
    End point timeframe
    During the course of the study (7 months)
    End point values
    		 Twinrix Junior Group Twinrix Adult Group
    Number of subjects analysed
    150
    150
    Units: Subjects
        Any SAE(s)
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Primary study- SAEs: During the course of the study, solicited local and general symptoms: During the 3 days (days 0-4) post each dose, unsolicited AEs: Within 31 days (days 0-30) post each dose. LFTU- SAEs: From Years 6 to 10
    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. Other (non-serious) adverse event data was not collected during this long-term follow-up phase of the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    7.1
    Reporting groups
    Reporting group title
    Twinrix Junior Group
    Reporting group description
    		 Subjects received Twinrix™ Junior (360/10) in a 0, 1, 6 month schedule in the primary study.

    Reporting group title
    Twinrix Adult Group
    Reporting group description
    		 Subjects received Twinrix™ Adult (720/20) in a 0, 6 month schedule in the primary study.

    Serious adverse events
    		 Twinrix Junior Group Twinrix Adult Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 149 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Twinrix Junior Group Twinrix Adult Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    95 / 149 (63.76%)
    99 / 149 (66.44%)
    Nervous system disorders
    Headache; Dose 1
    alternative assessment type: Systematic
         subjects affected / exposed
    21 / 149 (14.09%)
    24 / 149 (16.11%)
         occurrences all number
    21
    24
    Headache; Dose 3
         subjects affected / exposed [1]
    21 / 148 (14.19%)
    0 / 149 (0.00%)
         occurrences all number
    21
    0
    Headache; Across Doses
    alternative assessment type: Systematic
         subjects affected / exposed
    44 / 149 (29.53%)
    37 / 149 (24.83%)
         occurrences all number
    44
    37
    General disorders and administration site conditions
    Pain; Dose 1
    alternative assessment type: Systematic
         subjects affected / exposed
    53 / 149 (35.57%)
    68 / 149 (45.64%)
         occurrences all number
    53
    68
    Pain; Dose 2
    alternative assessment type: Systematic
         subjects affected / exposed [2]
    56 / 148 (37.84%)
    83 / 149 (55.70%)
         occurrences all number
    56
    83
    Pain; Dose 3
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    65 / 148 (43.92%)
    0 / 149 (0.00%)
         occurrences all number
    65
    0
    Redness; Dose 1
    alternative assessment type: Systematic
         subjects affected / exposed
    15 / 149 (10.07%)
    24 / 149 (16.11%)
         occurrences all number
    15
    24
    Redness; Dose 2
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    13 / 148 (8.78%)
    24 / 149 (16.11%)
         occurrences all number
    13
    24
    Redness; Dose 3
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    25 / 148 (16.89%)
    0 / 149 (0.00%)
         occurrences all number
    25
    0
    Swelling; Dose 1
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 149 (2.01%)
    4 / 149 (2.68%)
         occurrences all number
    3
    4
    Swelling; Dose 2
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    7 / 148 (4.73%)
    9 / 149 (6.04%)
         occurrences all number
    7
    9
    Swelling; Dose 3
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    12 / 148 (8.11%)
    0 / 149 (0.00%)
         occurrences all number
    12
    0
    Pain; Across Doses
    alternative assessment type: Systematic
         subjects affected / exposed
    95 / 149 (63.76%)
    99 / 149 (66.44%)
         occurrences all number
    95
    99
    Redness; Across Doses
    alternative assessment type: Systematic
         subjects affected / exposed
    35 / 149 (23.49%)
    34 / 149 (22.82%)
         occurrences all number
    35
    34
    Swelling; Across Doses
    alternative assessment type: Systematic
         subjects affected / exposed
    19 / 149 (12.75%)
    11 / 149 (7.38%)
         occurrences all number
    19
    11
    Fatigue; Dose 1
    alternative assessment type: Systematic
         subjects affected / exposed
    34 / 149 (22.82%)
    48 / 149 (32.21%)
         occurrences all number
    34
    48
    Fatigue; Dose 2
    alternative assessment type: Systematic
         subjects affected / exposed [8]
    25 / 148 (16.89%)
    39 / 149 (26.17%)
         occurrences all number
    25
    39
    Fatigue; Dose 3
    alternative assessment type: Systematic
         subjects affected / exposed [9]
    27 / 148 (18.24%)
    0 / 149 (0.00%)
         occurrences all number
    27
    0
    Headache; Dose 2
    alternative assessment type: Systematic
         subjects affected / exposed [10]
    20 / 148 (13.51%)
    23 / 149 (15.44%)
         occurrences all number
    20
    23
    Fatigue; Across Doses
    alternative assessment type: Systematic
         subjects affected / exposed
    54 / 149 (36.24%)
    59 / 149 (39.60%)
         occurrences all number
    54
    59
    Gastrointestinal disorders
    Gastrointestinal symptoms; Dose 1
    alternative assessment type: Systematic
         subjects affected / exposed
    8 / 149 (5.37%)
    11 / 149 (7.38%)
         occurrences all number
    8
    11
    Gastrointestinal symptoms; Across Doses
    alternative assessment type: Systematic
         subjects affected / exposed
    13 / 149 (8.72%)
    15 / 149 (10.07%)
         occurrences all number
    13
    15
    Respiratory, thoracic and mediastinal disorders
    Pharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    11 / 149 (7.38%)
    7 / 149 (4.70%)
         occurrences all number
    11
    7
    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: 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.
    [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: 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.
    [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.
    [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.
    [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.
    [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.
    [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.
    [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.
    [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.
    [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: 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.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jan 2008
    Because a high proportion of subjects returned for the long-term follow-up visits up to Year 9, the follow-up period was further extended. It was intended to prolong the follow-up until Year 15 after primary vaccination. At which time the immune memory to HAV and HBs was evaluated by the administration of a challenge dose. In order to describe the extended follow-up according to current standards, a new study protocol describing the additional five years (Y11-Y15) of follow-up and the challenge phase of the study was written. The protocol was consequently amended to reflect that the challenge dose was not administered at Year 10 after primary vaccination.

    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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