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    Clinical Trial Results:
    An open study to evaluate the immunogenicity, safety, and reactogenicity of GlaxoSmithKline Biologicals' commercially available combined hepatitis A / hepatitis B vaccine (TWINRIX ADULT) containing 720 ELISA units of hepatitis A antigen and 20 μg of hepatitis B surface antigen, administered following a two-dose (0, 6 months) schedule in healthy children between the ages of 1 and 11 years.

    Summary
    EudraCT number
    		 2015-001516-35
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    15 Apr 2009

    Results information
    Results version number
    		 v2(current)
    This version publication date
    11 Jul 2021
    First version publication date
    09 Jul 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Minor corrections in safety section and alignment between registries.

    Trial information

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    Trial identification
    Sponsor protocol code
    100561,100562,100563,100564,100565
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00289744
    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
    07 Oct 2009
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Apr 2009
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Apr 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • 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 two-dose pri-mary vaccination. • To evaluate the immune memory (after a primary two-dose schedule of TWINRIX™ ADULT 720/20 vaccine) in subjects who became seronegative for anti-HAV antibod-ies (i.e. titres < 15 mIU/ml) or lost seroprotective titres for anti-HBs antibodies (i.e. titres < 10 mIU/ml) at Year 6, 7, 8, 9 or 10 and subjects who received an additional vaccine dose (administered between 6 to 12 months after the Year 10 time point).
    Protection of trial subjects
    All subjects were observed closely for at least 30 minutes following vaccination with appropriate medical treatment readily available in case of a rare anaphylactic reaction.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Feb 2004
    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
    Belgium: 178
    Worldwide total number of subjects
    178
    EEA total number of subjects
    178
    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)
    30
    Children (2-11 years)
    148
    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
    		 All subjects enrolled in the primary study (208127/076) were invited to come back for the long-term follow-up visits at Year 6 to 10. The enrollment in the protocol section reflects the amount of subjects who came back at year 6. At follow up timepoints less subjects came back.

    Pre-assignment
    Screening details
    		 25 subjects lost seroprotective concentrations for anti-HBs antibodies at blood sampling time-points Years 6 to 10 and were offered an additional dose of Engerix™-B after Year 10 (additional dose phase). These subjects are presented in separate sub-groups for analysis purposes while as per study protocol, the single experimental group is Twinrix.

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

    Arms
    Arm title
    		 Twinrix Group
    Arm description
    		 Subjects who received 2 doses (at Day 0 and Month 6) of Twinrix™ in the primary study (study 208127/076)
    Arm type
    		 Experimental

    Investigational medicinal product name
    TWINRIX™ ADULT
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    2 doses administered intramuscularly (IM) in primary study

    Number of subjects in period 1
    		Twinrix Group
    Started
    178
    Completed
    178

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Twinrix Group
    Reporting group description
    		 Subjects who received 2 doses (at Day 0 and Month 6) of Twinrix™ in the primary study (study 208127/076)

    Reporting group values
    		 Twinrix Group Total
    Number of subjects
    		 178 178
    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)
    		 13.1 ± 2.82 -
    Gender categorical
    Units: Subjects
        Female
    		 91 91
        Male
    		 87 87
    Subject analysis sets

    Subject analysis set title
    Engerix-B Additional Dose (Adult)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who received 2 doses (at Day 0 and Month 6) of Twinrix™ in the primary study (study 208127/076). Subjects were now 16 years and above and received an additional dose of EngerixTM-B (adult dose).

    Subject analysis set title
    Engerix-B Additional Dose (Pediatric)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who received 2 doses (at Day 0 and Month 6) of Twinrix™ in the primary study (study 208127/076). Subjects were now under the age of 16 years and received an additional dose of EngerixTM-B (pediatric dose).

    Subject analysis sets values
    		 Engerix-B Additional Dose (Adult) Engerix-B Additional Dose (Pediatric)
    Number of subjects
    19
    6
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    17.8 ± 2.22
    12.7 ± 1.03
    Gender categorical
    Units: Subjects
        Female
    10
    4
        Male
    9
    2

    End points

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    End points reporting groups
    Reporting group title
    Twinrix Group
    Reporting group description
    		 Subjects who received 2 doses (at Day 0 and Month 6) of Twinrix™ in the primary study (study 208127/076)

    Subject analysis set title
    Engerix-B Additional Dose (Adult)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who received 2 doses (at Day 0 and Month 6) of Twinrix™ in the primary study (study 208127/076). Subjects were now 16 years and above and received an additional dose of EngerixTM-B (adult dose).

    Subject analysis set title
    Engerix-B Additional Dose (Pediatric)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who received 2 doses (at Day 0 and Month 6) of Twinrix™ in the primary study (study 208127/076). Subjects were now under the age of 16 years and received an additional dose of EngerixTM-B (pediatric dose).

    Primary: Anti-hepatitis A virus (anti-HAV) antibody concentration

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    End point title
    		 Anti-hepatitis A virus (anti-HAV) antibody concentration [1]
    End point description
    End point type
    Primary
    End point timeframe
    At Years 6, 7, 8, 9, and 10.
    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 Group
    Number of subjects analysed
    142
    Units: milli-international units per milliliter
    geometric mean (confidence interval 95%)
        Year 6 (n=142)
    692.3 (600.9 to 797.5)
        Year 7 (n=136)
    753.6 (650.2 to 873.5)
        Year 8 (n=132)
    544.4 (476.9 to 621.4)
        Year 9 (n=121)
    479.5 (413.3 to 556.3)
        Year 10 (n=120)
    601.6 (510.6 to 708.8)
    No statistical analyses for this end point

    Primary: Anti-hepatitis B surface antigen (anti-HBs) antibody concentration

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    End point title
    		 Anti-hepatitis B surface antigen (anti-HBs) antibody concentration [2]
    End point description
    End point type
    Primary
    End point timeframe
    At Years 6, 7, 8, 9 and 10
    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 Group
    Number of subjects analysed
    142
    Units: milli-international units per milliliter
    geometric mean (confidence interval 95%)
        Year 6 (n= 142)
    206.2 (149.3 to 284.8)
        Year 7 (n= 136)
    157.5 (113.7 to 218.4)
        Year 8 (n= 132)
    102.7 (74.7 to 141.1)
        Year 9 (n = 121)
    89.1 (64.9 to 122.5)
        Year 10 (n= 120)
    80.7 (58.1 to 112)
    No statistical analyses for this end point

    Primary: Anti-hepatitis B surface antigen (anti-HBs) antibody concentration

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    End point title
    		 Anti-hepatitis B surface antigen (anti-HBs) antibody concentration [3]
    End point description
    End point type
    Primary
    End point timeframe
    Before and 1 month after the additional dose administration
    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
    		 Engerix-B Additional Dose (Adult) Engerix-B Additional Dose (Pediatric)
    Number of subjects analysed
    19
    6
    Units: milli-international units per milliliter
    geometric mean (confidence interval 95%)
        Pre-vaccination
    10.4 (8 to 13.5)
    8.7 (3.3 to 23)
        1 month after vaccination
    1431.9 (730.2 to 2807.9)
    565.9 (163.9 to 1953.5)
    No statistical analyses for this end point

    Primary: Number of subjects with immune response to the additional dose of Engerix™-B

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    End point title
    		 Number of subjects with immune response to the additional dose of Engerix™-B [4]
    End point description
    Immune response was defined as: - anti-hepatitis B surface antigen (anti-HBs) antibody concentration equal or above to 10 milli-international units per milliliter (mIU/mL) at 1 month post-challenge dose in subjects seronegative at the pre-challenge time-points - at least a 4-fold increase in anti-HBs antibody concentrations at 1 month post-challenge dose in subjects seropositive at the pre-challenge time-points.
    End point type
    Primary
    End point timeframe
    One month after the additional dose administration
    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
    		 Engerix-B Additional Dose (Adult) Engerix-B Additional Dose (Pediatric)
    Number of subjects analysed
    19
    6
    Units: Subjects
        Engerix™-B dose
    19
    6
    No statistical analyses for this end point

    Primary: Number of subjects reporting serious adverse events (SAEs) assessed by the investigator as causally related to primary vaccination, study procedures or lack of vaccine efficacy

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    End point title
    		 Number of subjects reporting serious adverse events (SAEs) assessed by the investigator as causally related to primary vaccination, study procedures or lack of vaccine efficacy [5]
    End point description
    Serious adverse events (SAEs) assessed include medical occurrences that result in death, is 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
    Primary
    End point timeframe
    At Years 6, 7, 8, 9 and 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
    		 Twinrix Group
    Number of subjects analysed
    178
    Units: Subjects
        Year 6 (n= 178)
    0
        Year 7 (n= 175)
    0
        Year 8 (n= 174)
    0
        Year 9 (n= 173)
    0
        Year 10 (n= 171)
    0
    No statistical analyses for this end point

    Primary: Number of subjects reporting solicited local and general symptoms

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    End point title
    		 Number of subjects reporting solicited local and general symptoms [6]
    End point description
    Solicited local symptoms assessed include pain, redness and swelling. Solicited general symptoms assessed include fatigue, fever, gatrointestinal symptoms and headache.
    End point type
    Primary
    End point timeframe
    During the 4-day follow-up period after additional dose
    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
    		 Engerix-B Additional Dose (Adult) Engerix-B Additional Dose (Pediatric)
    Number of subjects analysed
    19
    6
    Units: Subjects
        Pain
    6
    3
        Redness
    2
    1
        Swelling
    1
    0
        Fatigue
    2
    3
        Fever
    0
    1
        Gastrointestinal symptoms
    2
    1
        Headache
    3
    0
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects reporting unsolicited adverse events (AEs) [7]
    End point description
    Unsolicited adverse event (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
    Primary
    End point timeframe
    During the 30-day follow-up period after additional dose
    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
    		 Engerix-B Additional Dose (Adult) Engerix-B Additional Dose (Pediatric)
    Number of subjects analysed
    19
    6
    Units: Subjects
        AEs
    1
    1
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects reporting serious adverse events (SAEs) [8]
    End point description
    Serious adverse events (SAEs) assessed include medical occurrences that result in death, is 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
    Primary
    End point timeframe
    During the 30-day follow-up period after additional dose
    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
    		 Engerix-B Additional Dose (Adult) Engerix-B Additional Dose (Pediatric)
    Number of subjects analysed
    19
    6
    Units: Subjects
        SAEs
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs: At each time-point of the long-term follow-up period & during the 30-day follow-up period after the additional dose. Other AEs: During the 4-day (solicited AEs) or the 30-day (unsolicited AEs) follow-up period after the additional dose.
    Adverse event reporting additional description
    Safety results were only collected for those subjects receiving an additional vaccine dose (adult or pediatric).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Engerix-B Additional Dose (Adult)
    Reporting group description
    		 Subjects who received 2 doses (at Day 0 and Month 6) of Twinrix™ in the primary study (study 208127/076). Subjects were now 16 years and above and received an additional dose of EngerixTM-B (adult dose).

    Reporting group title
    Engerix-B Additional Dose (Pediatric)
    Reporting group description
    		 Subjects who received 2 doses (at Day 0 and Month 6) of Twinrix™ in the primary study (study 208127/076). Subjects were now under the age of 16 years and received an additional dose of EngerixTM-B (pediatric dose).

    Serious adverse events
    		 Engerix-B Additional Dose (Adult) Engerix-B Additional Dose (Pediatric)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Engerix-B Additional Dose (Adult) Engerix-B Additional Dose (Pediatric)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 19 (42.11%)
    3 / 6 (50.00%)
    Nervous system disorders
    Syncope
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    6 / 19 (31.58%)
    3 / 6 (50.00%)
         occurrences all number
    6
    3
    Redness
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Swelling
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    2 / 19 (10.53%)
    3 / 6 (50.00%)
         occurrences all number
    2
    3
    Fever
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Gastrointestinal symptoms
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Headache
         subjects affected / exposed
    3 / 19 (15.79%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Oct 2000
    The clinical study protocol 2018127/076 (HAB-076) was designed to evaluate TWINRIX™ ADULT (720/20) vaccine administered according to a 0, 6 month schedule to healthy children aged 1 to 11 years. The protocol was previously amended to evaluate the persistence of humoral immune response up to five years after the first vaccine dose of the primary vaccination. Results from the primary study have shown the vaccine to be safe with a good immune response (anti-HAV seropositivity rate of 100% and anti-HBs seroprotection rate of 98.5%, one month after the primary vaccination course i.e. at Month 7). Long-term data of subjects who returned for a blood sampling visit five years after the first vaccine dose of the primary vaccination course have shown that, anti-HAV seropositivity persisted in all subjects (100%) and anti-HBs seroprotection persisted in 85.8% of subjects. The protocol is currently being amended to evaluate the persistence of humoral immune response 6 years (72 months), 7 years (84 months), 8 years (96 months),9 years (108 months) and 10 years (120 months) after the first vaccine dose of the primary vaccination. To evaluate the long-term antibody persistence, subjects will be bled at Years 6, 7, 8, 9 and 10 (intervals to be respected at ± 2 months) after the first vaccine dose of the primary vaccination course, to determine their anti-HAV and anti-HBs antibody titres. If a subject becomes seronegative for anti-HAV antibodies or loses seroprotective titres for anti-HBs antibodies (i.e. titres < 10 mIU/ml) at the long-term blood sampling time point, he/ she will be offered an additional vaccine dose, in order to assess the immune memory after a primary two-dose schedule of TWINRIX™ ADULT (720/20) vaccine. A blood sample will be taken on the day of the additional vaccination and after one month to evaluate the immune response following this 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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