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    Clinical Trial Results:
    A phase IV, open, multicentric study to evaluate the immune response to a hepatitis B challenge dose in healthy subjects, 72 to 78 months after they received a primary vaccination course of GSK Biologicals’ Engerix™-B (thiomersal-free 20 µg or preservative-free 10 µg) vaccine, in the primary study HBV-280.

    Summary
    EudraCT number
    2007-000261-38
    Trial protocol
    BE  
    Global end of trial date
    14 May 2008

    Results information
    Results version number
    v1(current)
    This version publication date
    13 May 2016
    First version publication date
    04 Dec 2014
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    108988
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00524576
    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 2089904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 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
    14 May 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 May 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    14 May 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the immune response to a challenge dose of hepatitis B vaccine administered in subjects who previously received a complete hepatitis B primary vaccination course, 72 to 78 months ago.
    Protection of trial subjects
    As with all injectable vaccines, appropriate medical treatment was always readily available in case of anaphylactic reactions following the administration of the vaccine. For this reason, the subjects remained under medical supervision for 30 minutes after vaccination.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Nov 2007
    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
    Australia: 67
    Country: Number of subjects enrolled
    Belgium: 77
    Worldwide total number of subjects
    144
    EEA total number of subjects
    77
    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)
    72
    Adults (18-64 years)
    72
    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
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Engerix 2 doses + challenge dose
    Arm description
    Subjects received 2 doses of Engerix™-B (Month 0 and 6) and a placebo at Month 1 in the primary study and a single dose of Engerix™-B during the booster study.
    Arm type
    Experimental

    Investigational medicinal product name
    Biological: Engerix™-B
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 2 doses of Engerix™-B (Month 0 and 6) and a placebo at Month 1 in the primary study and a single dose of Engerix™-B during the booster study.

    Arm title
    Engerix 3 doses + challenge dose
    Arm description
    Subjects received 3 doses of Engerix™-B (Month 0, 1 and 6) in the primary study and a single dose of Engerix™-B during the booster study.
    Arm type
    Experimental

    Investigational medicinal product name
    Engerix™-B
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 3 doses of Engerix™-B (Month 0, 1 and 6) in the primary study and a single dose of Engerix™-B during the booster study.

    Number of subjects in period 1
    Engerix 2 doses + challenge dose Engerix 3 doses + challenge dose
    Started
    97
    47
    Completed
    97
    47

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Engerix 2 doses + challenge dose
    Reporting group description
    Subjects received 2 doses of Engerix™-B (Month 0 and 6) and a placebo at Month 1 in the primary study and a single dose of Engerix™-B during the booster study.

    Reporting group title
    Engerix 3 doses + challenge dose
    Reporting group description
    Subjects received 3 doses of Engerix™-B (Month 0, 1 and 6) in the primary study and a single dose of Engerix™-B during the booster study.

    Reporting group values
    Engerix 2 doses + challenge dose Engerix 3 doses + challenge dose Total
    Number of subjects
    97 47 144
    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)
    19.5 ± 1.22 19.3 ± 1.46 -
    Gender categorical
    Units: Subjects
        Female
    50 23 73
        Male
    47 24 71

    End points

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    End points reporting groups
    Reporting group title
    Engerix 2 doses + challenge dose
    Reporting group description
    Subjects received 2 doses of Engerix™-B (Month 0 and 6) and a placebo at Month 1 in the primary study and a single dose of Engerix™-B during the booster study.

    Reporting group title
    Engerix 3 doses + challenge dose
    Reporting group description
    Subjects received 3 doses of Engerix™-B (Month 0, 1 and 6) in the primary study and a single dose of Engerix™-B during the booster study.

    Primary: Number of participants with immunological response to challenge dose in terms of anti-hepatitis B surface antigen (anti-HBs) antibody concentration

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    End point title
    Number of participants with immunological response to challenge dose in terms of anti-hepatitis B surface antigen (anti-HBs) antibody concentration [1]
    End point description
    Immune response defined as: *For initially seronegative subjects (anti-HBs antibody concentration <3.3 milli-international unit per milliliter [mIU/mL] before vaccination) antibody concentration ≥ 10mIU/mL at post booster. *For initially seropositive subjects: antibody concentration at post booster ≥ 4-fold the pre-vaccination antibody concentration.
    End point type
    Primary
    End point timeframe
    30 days post-challenge dose
    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
    Engerix 2 doses + challenge dose Engerix 3 doses + challenge dose
    Number of subjects analysed
    53
    21
    Units: Subjects
        (anti-HBs) antibody concentration
    53
    21
    No statistical analyses for this end point

    Secondary: Number of participants with anti-HBs antibody concentrations above the cut-off value

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    End point title
    Number of participants with anti-HBs antibody concentrations above the cut-off value
    End point description
    Anti-HBs antibody cut-off values assessed include 3.3, 10 and 100 mIU/mL.
    End point type
    Secondary
    End point timeframe
    30 days post-challenge dose
    End point values
    Engerix 2 doses + challenge dose Engerix 3 doses + challenge dose
    Number of subjects analysed
    53
    21
    Units: Subjects
        ≥ 3.3 mIU/mL
    53
    21
        ≥ 10 mIU/mL
    53
    21
        ≥ 100 mIU/mL
    50
    20
    No statistical analyses for this end point

    Secondary: Concentration of anti-HBs antibodies

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    End point title
    Concentration of anti-HBs antibodies
    End point description
    Concentrations given as geometric mean concentration (GMC) and expressed in mIU/mL.
    End point type
    Secondary
    End point timeframe
    30 days post-challenge dose
    End point values
    Engerix 2 doses + challenge dose Engerix 3 doses + challenge dose
    Number of subjects analysed
    53
    21
    Units: mIU/mL
    geometric mean (confidence interval 95%)
        Concentration of anti-HBs antibodies
    6214.1 (3213.1 to 12018)
    16564.3 (6394.9 to 42905.6)
    No statistical analyses for this end point

    Secondary: Number of participants reporting solicited local symptoms

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    End point title
    Number of participants reporting solicited local symptoms
    End point description
    Solicited local symptoms assessed include pain, redness and swelling.
    End point type
    Secondary
    End point timeframe
    During the 4-day follow-up period (Day 0-3) after the challenge dose
    End point values
    Engerix 2 doses + challenge dose Engerix 3 doses + challenge dose
    Number of subjects analysed
    55
    22
    Units: Subjects
        Pain
    22
    4
        Redness
    11
    1
        Swelling
    9
    0
    No statistical analyses for this end point

    Secondary: Number of participants reporting solicited general symptoms

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    End point title
    Number of participants reporting solicited general symptoms
    End point description
    Solicited general symptoms assessed include fatigue, fever, gastrointestinal symptoms, and headache.
    End point type
    Secondary
    End point timeframe
    During the 4-day follow-up period (Day 0-3) after the challenge dose
    End point values
    Engerix 2 doses + challenge dose Engerix 3 doses + challenge dose
    Number of subjects analysed
    55
    22
    Units: Subjects
        Fatigue
    19
    7
        Fever ≥ 37.5 degree Celsius
    1
    0
        Gastrointestinal disorder
    7
    4
        Headache
    14
    4
    No statistical analyses for this end point

    Secondary: Number of participants reporting unsolicited adverse events (AE)

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    End point title
    Number of participants reporting unsolicited adverse events (AE)
    End point description
    An AE 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 31-day follow-up period (Day 0-30) after the challenge dose
    End point values
    Engerix 2 doses + challenge dose Engerix 3 doses + challenge dose
    Number of subjects analysed
    55
    22
    Units: Subjects
        Participants reporting AE
    19
    5
    No statistical analyses for this end point

    Secondary: Number of participants reporting serious adverse events (SAE)

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    End point title
    Number of participants reporting serious adverse events (SAE)
    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
    Secondary
    End point timeframe
    During the 31-day follow-up period (Day 0-30) after the challenge dose
    End point values
    Engerix 2 doses + challenge dose Engerix 3 doses + challenge dose
    Number of subjects analysed
    97
    47
    Units: Subjects
        Participants reporting SAE
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious Adverse events (SAE) = Day 0 to Day 30. Solicited local and general symptoms =During the 4-day (Days 0-3) post-challenge dose period. Unsolicited AEs = during the 31-day (Day 0-30) follow-up period after the HBV challenge dose.
    Adverse event reporting additional description
    For the other adverse events: Data from the Australian center were not included following data quality issues detected at the investigator site.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    Engerix 2 doses + challenge dose
    Reporting group description
    Subjects received 2 doses of Engerix™-B (Month 0 and 6) and a placebo at Month 1 in the primary study and a single dose of Engerix™-B during the booster study.

    Reporting group title
    Engerix 3 doses + challenge dose
    Reporting group description
    Subjects received 3 doses of Engerix™-B (Month 0, 1 and 6) in the primary study and a single dose of Engerix™-B during the booster study.

    Serious adverse events
    Engerix 2 doses + challenge dose Engerix 3 doses + challenge dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 97 (0.00%)
    0 / 47 (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
    Engerix 2 doses + challenge dose Engerix 3 doses + challenge dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 97 (22.68%)
    7 / 47 (14.89%)
    Nervous system disorders
    Headache (AE)
         subjects affected / exposed [1]
    4 / 55 (7.27%)
    2 / 22 (9.09%)
         occurrences all number
    4
    2
    General disorders and administration site conditions
    Pain
    alternative assessment type: Systematic
         subjects affected / exposed [2]
    22 / 55 (40.00%)
    4 / 22 (18.18%)
         occurrences all number
    22
    4
    Redness
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    11 / 55 (20.00%)
    1 / 22 (4.55%)
         occurrences all number
    11
    1
    Swelling
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    9 / 55 (16.36%)
    0 / 22 (0.00%)
         occurrences all number
    9
    0
    Fatigue
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    19 / 55 (34.55%)
    7 / 22 (31.82%)
         occurrences all number
    19
    7
    Gastrointestinal disorder
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    7 / 55 (12.73%)
    4 / 22 (18.18%)
         occurrences all number
    7
    4
    Headache (Solicited Symptom)
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    14 / 55 (25.45%)
    4 / 22 (18.18%)
         occurrences all number
    14
    4
    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: The number of subjects exposed to the adverse event may differ from the total number of subjects exposed for the reporting group as for the unsolicited adverse events, not all subjects reported an event and hence, were considered as subjects without an event.
    [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 the solicited local and general symptoms, not all subjects had their symptom sheets completed therefore, the analysis of the solicited symptoms based on the Total Vaccinated cohort included only subjects with documented safety data (i.e. symptom sheet completed).
    [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 the solicited local and general symptoms, not all subjects had their symptom sheets completed therefore, the analysis of the solicited symptoms based on the Total Vaccinated cohort included only subjects with documented safety data (i.e. symptom sheet completed).
    [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 the solicited local and general symptoms, not all subjects had their symptom sheets completed therefore, the analysis of the solicited symptoms based on the Total Vaccinated cohort included only subjects with documented safety data (i.e. symptom sheet completed).
    [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 the solicited local and general symptoms, not all subjects had their symptom sheets completed therefore, the analysis of the solicited symptoms based on the Total Vaccinated cohort included only subjects with documented safety data (i.e. symptom sheet completed).
    [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 the solicited local and general symptoms, not all subjects had their symptom sheets completed therefore, the analysis of the solicited symptoms based on the Total Vaccinated cohort included only subjects with documented safety data (i.e. symptom sheet completed).
    [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 the solicited local and general symptoms, not all subjects had their symptom sheets completed therefore, the analysis of the solicited symptoms based on the Total Vaccinated cohort included only subjects with documented safety data (i.e. symptom sheet completed).

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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