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    Clinical Trial Results:
    An open, phase IV, multicentre, study to assess the long-term persistence of antibodies against hepatitis B and the immune response to a hepatitis B vaccine challenge in healthy children aged 11-12 years, previously vaccinated with GlaxoSmithKline (GSK) Biologicals’ DTPa-HBV-IPV/Hib vaccine (Infanrix hexa™) or GSK Biologicals’ DTPa-IPV/Hib and HBV (Engerix™- B) vaccines at the ages of 3, 5 and 11 months in clinical trial DTPa-HBV-IPV-031 (217744/031).

    Summary
    EudraCT number
    		 2009-016911-39
    Trial protocol
    		 SK  
    Global end of trial date
    26 Nov 2010

    Results information
    Results version number
    		 v1
    This version publication date
    18 Apr 2016
    First version publication date
    30 Oct 2014
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    113954
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01138098
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l'Institut 89, Rixensart, Belgium, 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
    20 Jun 2011
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Jun 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Nov 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the anti-HBs antibody response to a challenge dose of HBV vaccine in subjects aged 11-12 years, vaccinated in infancy with three doses of Infanrix hexa or Engerix-B at 3, 5 and 11 months of age.
    Protection of trial subjects
    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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Jun 2010
    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
    Slovakia: 185
    Worldwide total number of subjects
    185
    EEA total number of subjects
    185
    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)
    185
    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
    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
    		 Infanrix-hexa/Engerix-B Group
    Arm description
    		 Subjects aged 11-12 year old received 3 doses of Infanrix-hexa vaccine in the primary study (NCT01457495) and a challenge dose of Engerix-B vaccine in this study. Engerix-B was administered as a single dose intramuscularly into the deltoid region of the non-dominant arm.
    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
    Intramuscular, single dose

    Arm title
    		 Infanrix-IPV+Hib/Engerix-B Group
    Arm description
    		 Subjects aged 11-12 year old received 3 doses of Infanrix-IPV+Hib and Engerix-B vaccines in the primary study (NCT01457495) and a challenge dose of Engerix-B vaccine in this study. Engerix-B was administered as a single dose intramuscularly into the deltoid region of the non-dominant arm.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Engerix™-B
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular, single dose

    Number of subjects in period 1
    		Infanrix-hexa/Engerix-B Group Infanrix-IPV+Hib/Engerix-B Group
    Started
    95
    90
    Completed
    95
    90

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Infanrix-hexa/Engerix-B Group
    Reporting group description
    		 Subjects aged 11-12 year old received 3 doses of Infanrix-hexa vaccine in the primary study (NCT01457495) and a challenge dose of Engerix-B vaccine in this study. Engerix-B was administered as a single dose intramuscularly into the deltoid region of the non-dominant arm.

    Reporting group title
    Infanrix-IPV+Hib/Engerix-B Group
    Reporting group description
    		 Subjects aged 11-12 year old received 3 doses of Infanrix-IPV+Hib and Engerix-B vaccines in the primary study (NCT01457495) and a challenge dose of Engerix-B vaccine in this study. Engerix-B was administered as a single dose intramuscularly into the deltoid region of the non-dominant arm.

    Reporting group values
    		 Infanrix-hexa/Engerix-B Group Infanrix-IPV+Hib/Engerix-B Group Total
    Number of subjects
    		 95 90 185
    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
        geometric mean (standard deviation)
    		 11.3 ± 0.46 11.3 ± 0.47 -
    Gender categorical
    Units: Subjects
        Female
    		 45 35 80
        Male
    		 50 55 105

    End points

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    End points reporting groups
    Reporting group title
    Infanrix-hexa/Engerix-B Group
    Reporting group description
    		 Subjects aged 11-12 year old received 3 doses of Infanrix-hexa vaccine in the primary study (NCT01457495) and a challenge dose of Engerix-B vaccine in this study. Engerix-B was administered as a single dose intramuscularly into the deltoid region of the non-dominant arm.

    Reporting group title
    Infanrix-IPV+Hib/Engerix-B Group
    Reporting group description
    		 Subjects aged 11-12 year old received 3 doses of Infanrix-IPV+Hib and Engerix-B vaccines in the primary study (NCT01457495) and a challenge dose of Engerix-B vaccine in this study. Engerix-B was administered as a single dose intramuscularly into the deltoid region of the non-dominant arm.

    Primary: Number of subjects with anti-hepatitis B (anti-HBs) antibody concentration equal to or above (≥) 100 milli-International units per milliliter (mIU/mL)

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    End point title
    		 Number of subjects with anti-hepatitis B (anti-HBs) antibody concentration equal to or above (≥) 100 milli-International units per milliliter (mIU/mL) [1]
    End point description
    A decrease in the specificity of the anti-HB enzyme-linked immunosorbent assay (ELISA) had been observed in some studies for low levels of antibody (10-100 mIU/mL). All the available blood samples initially tested with ELISA were re-tested using the Chemi Luminescence Immuno Assay (CLIA) approved by the US Food and Drug Administration (FDA). The table shows updated results following partial or complete retesting/reanalysis.
    End point type
    Primary
    End point timeframe
    One month after a challenge dose of Engerix™-B vaccine
    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
    		 Infanrix-hexa/Engerix-B Group Infanrix-IPV+Hib/Engerix-B Group
    Number of subjects analysed
    94
    89
    Units: Subjects
        Anti-HBs ≥ 100 mIU/mL
    88
    84
    No statistical analyses for this end point

    Secondary: Number of subjects with an anamnestic response to a challenge dose

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    End point title
    		 Number of subjects with an anamnestic response to a challenge dose
    End point description
    The anamnestic response was defined as: at least (≥) a 4-fold rise in post-challenge dose anti-HBs antibody concentrations in subjects seropositive at the pre-challenge dose time point. - Post-challenge dose anti-HBs antibody concentrations ≥ 10 mIU/mL in seronegative subjects at the pre-challenge dose time point. A seropositive/seronegative subject is a subject with anti-HBs antibody concentration ≥/lower than (<) 6.2 mIU/mL. A decrease in the specificity of the anti-HB ELISA had been observed in some studies for low levels of antibody (10-100 mIU/mL). All the available blood samples initially tested with ELISA were re-tested using the Chemi Luminescence Immuno Assay (CLIA) approved by the US Food and Drug Administration (FDA). The table shows updated results following partial or complete retesting/reanalysis and the initial 3.3 mIU/mL seropositivity cut-off was revised into the new 6.2 mIU/mL cut-off.
    End point type
    Secondary
    End point timeframe
    Before and one month after a challenge dose of Engerix™-B vaccine
    End point values
    		 Infanrix-hexa/Engerix-B Group Infanrix-IPV+Hib/Engerix-B Group
    Number of subjects analysed
    94
    89
    Units: Subjects
        Anamnestic response
    91
    86
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-HBs antibody concentration ≥ 6.2 mIU/mL

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    End point title
    		 Number of subjects with anti-HBs antibody concentration ≥ 6.2 mIU/mL
    End point description
    A seropositive subject was defined as a subject with anti-HBs antibody concentration ≥ the 6.2 mIU/mLcut-off. A decrease in the specificity of the anti-HB ELISA had been observed in some studies for low levels of antibody (10-100 mIU/mL). All the available blood samples initially tested with ELISA were re-tested using the Chemi Luminescence Immuno Assay (CLIA) approved by the US Food and Drug Administration (FDA). The table shows updated results following partial or complete retesting/reanalysis and the initial 3.3 mIU/mL seropositivity cut-off was revised into the new 6.2 mIU/mL cut-off.
    End point type
    Secondary
    End point timeframe
    Before and one month after a challenge dose of Engerix™-B vaccine
    End point values
    		 Infanrix-hexa/Engerix-B Group Infanrix-IPV+Hib/Engerix-B Group
    Number of subjects analysed
    95
    89
    Units: Subjects
        ≥ 6.2 mIU/mL [pre-challenge dose] (N=95, 89)
    53
    57
        ≥ 6.2 mIU/mL [post-challenge dose] (N=94, 89)
    92
    88
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-HBs antibody concentration ≥ 10 mIU/mL

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    End point title
    		 Number of subjects with anti-HBs antibody concentration ≥ 10 mIU/mL
    End point description
    A seroprotected subject was defined as a subject with anti-HBs antibody concentration ≥ 10 mIU/mL. A decrease in the specificity of the anti-HB enzyme-linked immunosorbent assay (ELISA) had been observed in some studies for low levels of antibody (10-100 mIU/mL). All the available blood samples initially tested with ELISA were re-tested using the Chemi Luminescence Immuno Assay (CLIA) approved by the US Food and Drug Administration (FDA). The table shows updated results following partial or complete retesting/reanalysis.
    End point type
    Secondary
    End point timeframe
    Before and one month after a challenge dose of Engerix™-B vaccine
    End point values
    		 Infanrix-hexa/Engerix-B Group Infanrix-IPV+Hib/Engerix-B Group
    Number of subjects analysed
    95
    89
    Units: Subjects
        ≥ 10 mIU/mL [pre-challenge dose] (N=95, 89)
    46
    52
        ≥ 10 mIU/mL [post-challenge dose] (N=94, 89)
    91
    88
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-HBs antibody concentration ≥ 100 mIU/mL

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    End point title
    		 Number of subjects with anti-HBs antibody concentration ≥ 100 mIU/mL
    End point description
    A seroprotected subject was defined as a subject with anti-HBs antibody concentration ≥ 10 mIU/mL. A decrease in the specificity of the anti-HB ELISA had been observed in some studies for low levels of antibody (10-100 mIU/mL). All the available blood samples initially tested with ELISA were re-tested using the Chemi Luminescence Immuno Assay (CLIA) approved by the US Food and Drug Administration (FDA). The table shows updated results following partial or complete retesting/reanalysis.
    End point type
    Secondary
    End point timeframe
    Before the challenge dose of Engerix™-B vaccine
    End point values
    		 Infanrix-hexa/Engerix-B Group Infanrix-IPV+Hib/Engerix-B Group
    Number of subjects analysed
    95
    89
    Units: Subjects
        ≥ 100 mIU/mL [pre-challenge dose]
    14
    17
    No statistical analyses for this end point

    Secondary: Number of subjects reporting solicited local symptoms

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    End point title
    		 Number of subjects reporting solicited local symptoms
    End point description
    Solicited local symptoms assessed were pain, redness and swelling.
    End point type
    Secondary
    End point timeframe
    During the 4-day (Days 0-3) follow-up period after a challenge dose of Engerix™-B vaccine
    End point values
    		 Infanrix-hexa/Engerix-B Group Infanrix-IPV+Hib/Engerix-B Group
    Number of subjects analysed
    95
    90
    Units: Subjects
        Pain
    30
    24
        Redness
    25
    22
        Swelling
    15
    8
    No statistical analyses for this end point

    Secondary: Number of subjects reporting solicited general symptoms

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    End point title
    		 Number of subjects reporting solicited general symptoms
    End point description
    Solicited general symptoms assessed were fatigue, gastrointestinal, headache and temperature (Temperature is defined as axillary temparature equal to or above 37.5 degrees Celsius (°C)).
    End point type
    Secondary
    End point timeframe
    During the 4-day (Days 0-3) follow-up period after a challenge dose of Engerix™-B vaccine
    End point values
    		 Infanrix-hexa/Engerix-B Group Infanrix-IPV+Hib/Engerix-B Group
    Number of subjects analysed
    95
    90
    Units: Subjects
        Fatigue
    23
    22
        Gastrointestinal
    9
    9
        Headache
    19
    14
        Temperature ≥ 37.5°C
    1
    3
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects reporting unsolicited adverse events (AEs)
    End point description
    An unsolicited adverse event is any adverse event (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product) reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms.
    End point type
    Secondary
    End point timeframe
    During the 31-day (Days 0-30) follow-up period after a challenge dose of Engerix™-B vaccine
    End point values
    		 Infanrix-hexa/Engerix-B Group Infanrix-IPV+Hib/Engerix-B Group
    Number of subjects analysed
    95
    90
    Units: Subjects
        Unsolicited AEs
    5
    7
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects reporting serious adverse events (SAEs)
    End point description
    SAEs assessed include medical occurrences that results in death, are life threatening, require hospitalization or prolongation of hospitalization, results in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subjects.
    End point type
    Secondary
    End point timeframe
    After the challenge dose of Engerix™-B vaccine up to the study end
    End point values
    		 Infanrix-hexa/Engerix-B Group Infanrix-IPV+Hib/Engerix-B Group
    Number of subjects analysed
    95
    90
    Units: Subjects
        SAEs
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited symptoms: During the 4-day (Days 0-3) follow-up period after the challenge dose of Engerix-B vaccine. SAEs: after the challenge dose of Engerix-B vaccine up to the study end
    Adverse event reporting additional description
    The occurrence of reported AEs (all/related) was not available and is encoded as equal to the number of subjects affected.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Infanrix-hexa/Engerix-B Group
    Reporting group description
    		 Subjects aged 11-12 year old received 3 doses of Infanrix-hexa vaccine in the primary study (NCT01457495) and a challenge dose of Engerix-B vaccine in this study. Engerix-B was administered as a single dose intramuscularly into the deltoid region of the non-dominant arm.

    Reporting group title
    Infanrix-IPV+Hib/Engerix-B Group
    Reporting group description
    		 Subjects aged 11-12 year old received 3 doses of Infanrix-IPV+Hib and Engerix-B vaccines in the primary study (NCT01457495) and a challenge dose of Engerix-B vaccine in this study. Engerix-B was administered as a single dose intramuscularly into the deltoid region of the non-dominant arm.

    Serious adverse events
    		 Infanrix-hexa/Engerix-B Group Infanrix-IPV+Hib/Engerix-B Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 90 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Infections and infestations
    Infection
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Infanrix-hexa/Engerix-B Group Infanrix-IPV+Hib/Engerix-B Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 95 (31.58%)
    24 / 90 (26.67%)
    General disorders and administration site conditions
    Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    30 / 95 (31.58%)
    24 / 90 (26.67%)
         occurrences all number
    30
    24
    Redness
    alternative assessment type: Systematic
         subjects affected / exposed
    25 / 95 (26.32%)
    22 / 90 (24.44%)
         occurrences all number
    25
    22
    Swelling
    alternative assessment type: Systematic
         subjects affected / exposed
    15 / 95 (15.79%)
    8 / 90 (8.89%)
         occurrences all number
    15
    8
    Fatigue
    alternative assessment type: Systematic
         subjects affected / exposed
    23 / 95 (24.21%)
    22 / 90 (24.44%)
         occurrences all number
    23
    22
    Gastrointestinal
    alternative assessment type: Systematic
         subjects affected / exposed
    9 / 95 (9.47%)
    9 / 90 (10.00%)
         occurrences all number
    9
    9
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    19 / 95 (20.00%)
    14 / 90 (15.56%)
         occurrences all number
    19
    14

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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