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    Clinical Trial Results:
    A phase IV, open-label, non-randomised, multicentre study to assess the long-term persistence of immunity to hepatitis B in adults vaccinated 20 to 30 years ago with 3 or 4 doses of GSK Biologicals’ hepatitis B vaccine, Engerix-B

    Summary
    EudraCT number
    		 2015-004099-31
    Trial protocol
    		 BE  
    Global end of trial date
    01 May 2017

    Results information
    Results version number
    		 v3(current)
    This version publication date
    08 Dec 2018
    First version publication date
    11 May 2018
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    To align with the US Results Summary, updated post NIH review.

    Trial information

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    Trial identification
    Sponsor protocol code
    116811
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02901951
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l'Institut, 89, Rixensart, Belgium, B-1330
    Public contact
    Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, (44)2089 904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, (44)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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    01 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the persistence of immunity to hepatitis B in terms of anti-hepatitis B surface antigen (anti-HBs) anamnestic response to an Engerix-B (HBV vaccine) challenge dose, in adult subjects vaccinated with three or four doses of HBV vaccine 20 to 30 years ago.
    Protection of trial subjects
    All vaccinated subjects were observed closely for at least 30 minutes following the administration of the vaccine, with appropriate medical treatment readily available in case of anaphylaxis.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Oct 2016
    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: 53
    Country: Number of subjects enrolled
    Canada: 50
    Worldwide total number of subjects
    103
    EEA total number of subjects
    53
    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)
    0
    Adults (18-64 years)
    103
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects aged between and including 40 to 60 years were enrolled in this study, in compliance with the inclusion criteria, which required the documented evidence of previous vaccination with three or four consecutive doses of Engerix-B administered in adulthood (i.e. at least 18 years of age).

    Pre-assignment
    Screening details
    		 106 subjects were enrolled in the study but 3 subjects were withdrawn before vaccine administration. Therefore, the number of subjects started is 103.

    Pre-assignment period milestones
    Number of subjects started
    		 103
    Number of subjects completed
    		 103

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 HBV Group
    Arm description
    		 Subjects aged 40 to 60 years old who received 3 or 4 doses of Engerix-B (HBV vaccine) 20 to 30 years ago and were administered with a single challenge dose of HBV vaccine in this study at Day 0 (Visit 1).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Engerix-B
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular administration of single challenge dose of Engerix-B vaccine in the deltoid region of the non-dominant arm.

    Number of subjects in period 1
    		HBV Group
    Started
    103
    Completed
    103

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    HBV Group
    Reporting group description
    		 Subjects aged 40 to 60 years old who received 3 or 4 doses of Engerix-B (HBV vaccine) 20 to 30 years ago and were administered with a single challenge dose of HBV vaccine in this study at Day 0 (Visit 1).

    Reporting group values
    		 HBV Group Total
    Number of subjects
    		 103
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.6 ( 5.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 87 87
        Male
    		 16 16
    Race/Ethnicity, Customized
    Units: Subjects
        White - Caucasian / European Heritage
    		 103 103

    End points

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    End points reporting groups
    Reporting group title
    HBV Group
    Reporting group description
    		 Subjects aged 40 to 60 years old who received 3 or 4 doses of Engerix-B (HBV vaccine) 20 to 30 years ago and were administered with a single challenge dose of HBV vaccine in this study at Day 0 (Visit 1).

    Primary: Percentage of subjects with an anamnestic response to the HBV challenge dose, based on the last available time point before the challenge dose

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    End point title
    		 Percentage of subjects with an anamnestic response to the HBV challenge dose, based on the last available time point before the challenge dose [1]
    End point description
    Anamnestic response to the challenge dose was defined as: At least (i.e. greater than or equal to [≥]) 4-fold rise in one month post-vaccination anti-hepatitis B surface antigen (anti-HBs) antibody concentrations in previously seropositive subjects (Subjects with anti-HBs antibody concentration ≥ 6.2 milli International Unit/Milliliter (mIU/mL) at the pre-challenge dose time point); In previously seronegative subjects (Subjects with anti-HBs antibody concentration < 6.2 mIU/mL at the pre-challenge dose time point), anti-HBs antibody concentrations ≥10 mIU/mL at one month post-challenge dose time-point.
    End point type
    Primary
    End point timeframe
    7 days after the challenge dose (Day 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 scope of this end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 HBV Group
    Number of subjects analysed
    101
    Units: Percentage of subjects
    number (confidence interval 95%)
        < 6.2 mIU/mL (N=6)
    66.7 (22.3 to 95.7)
        ≥ 6.2 mIU/mL (N=95)
    85.3 (76.5 to 91.7)
    No statistical analyses for this end point

    Primary: Percentage of subjects with an anamnestic response to the HBV challenge dose, based on the last available time point before the challenge dose

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    End point title
    		 Percentage of subjects with an anamnestic response to the HBV challenge dose, based on the last available time point before the challenge dose [2]
    End point description
    Anamnestic response to the challenge dose was defined as: At least (i.e. ≥ 4-fold rise in one month post-vaccination anti-HBs antibody concentrations in previously seropositive subjects (Subjects with anti-HBs antibody concentration ≥ 6.2 mIU/mL at the pre-challenge dose time point); In previously seronegative subjects (Subjects with anti-HBs antibody concentration < 6.2 mIU/mL at the pre-challenge dose time point), anti-HBs antibody concentrations ≥10 mIU/mL at one month post-challenge dose time-point.
    End point type
    Primary
    End point timeframe
    30 days after the challenge dose (Day 30)
    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 scope of this end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 HBV Group
    Number of subjects analysed
    101
    Units: Percentage of subjects
    number (confidence interval 95%)
        < 6.2 mIU/mL (N=6)
    100 (54.1 to 100)
        ≥ 6.2 mIU/mL (N=95)
    100 (96.2 to 100)
    No statistical analyses for this end point

    Secondary: Percentage of subjects with anti-HBs antibody concentrations equal to or above cut-off values

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    End point title
    		 Percentage of subjects with anti-HBs antibody concentrations equal to or above cut-off values
    End point description
    Percentage of subjects with anti-HBs antibody concentrations ≥ 6.2 mIU/mL, ≥ 10 mIU/mL and ≥ 100 mIU/mL.
    End point type
    Secondary
    End point timeframe
    At the pre-challenge dose time-point (Day 0), at 7 days post-challenge time-point (Day 7) and at 30 days post-challenge time-point (Day 30)
    End point values
    		 HBV Group
    Number of subjects analysed
    101
    Units: Percentage of subjects
    number (confidence interval 95%)
        ≥ 6.2 mIU/mL [Day 0]
    94.1 (87.5 to 97.8)
        ≥ 10 mIU/mL [Day 0]
    90.1 (82.5 to 95.1)
        ≥ 100 mIU/mL [Day 0]
    61.4 (51.2 to 70.9)
        ≥ 6.2 mIU/mL [Day 7]
    98.0 (93.0 to 99.8)
        ≥ 10 mIU/mL [Day 7]
    97.0 (91.6 to 99.4)
        ≥ 100 mIU/mL [Day 7]
    92.1 (85.0 to 96.5)
        ≥ 6.2 mIU/mL [Day 30]
    100 (96.4 to 100)
        ≥ 10 mIU/mL [Day 30]
    100 (96.4 to 100)
        ≥ 100 mIU/mL [Day 30]
    98.0 (93.0 to 99.8)
    No statistical analyses for this end point

    Secondary: Anti-HBs antibody concentrations

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    End point title
    		 Anti-HBs antibody concentrations
    End point description
    Anti-HBs antibody concentrations were expressed as Geometric Mean Concentrations (GMCs) in mIU/mL.
    End point type
    Secondary
    End point timeframe
    At the pre-challenge dose time-point (Day 0), at 7 days post-challenge dose time-point (Day 7) and at 30 days post-challenge dose time-point (Day 30)
    End point values
    		 HBV Group
    Number of subjects analysed
    101
    Units: mIU/mL
    geometric mean (confidence interval 95%)
        At Day 0
    184.6 (121.5 to 280.3)
        At Day 7
    3840.0 (2330.0 to 6328.6)
        At Day 30
    48999.1 (33572.7 to 71513.7)
    No statistical analyses for this end point

    Secondary: Number of subjects with any solicited local adverse events (AEs)

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    End point title
    		 Number of subjects with any solicited local adverse events (AEs)
    End point description
    Assessed solicited local symptoms were injection site pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 4-day (Days 0-3) follow-up period after the challenge dose
    End point values
    		 HBV Group
    Number of subjects analysed
    103
    Units: Participants
        Any Pain
    40
        Any Redness (mm)
    4
        Any Swelling (mm)
    3
    No statistical analyses for this end point

    Secondary: Number of subjects with any solicited general AEs

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    End point title
    		 Number of subjects with any solicited general AEs
    End point description
    Assessed solicited general symptoms were fatigue, fever (defined as axillary temperature ≥ 37.5 degrees Celsius [°C]) , gastrointestinal symptoms (nausea, vomiting, diarrhoea and/or abdominal pain) and headache. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 4-day (Days 0-3) follow-up period after the challenge dose
    End point values
    		 HBV Group
    Number of subjects analysed
    103
    Units: Participants
        Any Fatigue
    27
        Any Gastrointestinal symptoms
    10
        Any Headache
    20
        Any Fever
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with any unsolicited AEs

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    End point title
    		 Number of subjects with any unsolicited AEs
    End point description
    An unsolicited 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. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 31-day (Days 0-30) follow-up period after the challenge dose
    End point values
    		 HBV Group
    Number of subjects analysed
    103
    Units: Participants
        Participants
    41
    No statistical analyses for this end point

    Secondary: Number of subjects with any serious adverse events (SAEs)

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    End point title
    		 Number of subjects with any serious adverse events (SAEs)
    End point description
    SAEs assessed included any untoward medical occurrences that resulted in death, was life threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity or congenital anomaly/birth defect in the offspring of a study subject. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.
    End point type
    Secondary
    End point timeframe
    During the entire study period (Day 0 to Day 30)
    End point values
    		 HBV Group
    Number of subjects analysed
    103
    Units: Participants
        Participants
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited local & general AEs: during 4-day (Days 0-3) follow-up period after challenge dose; Unsolicited AEs: during 31-day (Days 0-30) follow-up period after challenge dose; SAEs: during the entire study period (Day 0 to Day 30).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    HBV Group
    Reporting group description
    		 Subjects aged 40 to 60 years old who received 3 or 4 doses of HBV vaccine 20 to 30 years ago and were administered with a single challenge dose of HBV vaccine in this study at Day 0 (Visit 1).

    Serious adverse events
    		 HBV Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 103 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 HBV Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    75 / 103 (72.82%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    29 / 103 (28.16%)
         occurrences all number
    30
    Injection site erythema
         subjects affected / exposed
    4 / 103 (3.88%)
         occurrences all number
    4
    Injection site pain
         subjects affected / exposed
    40 / 103 (38.83%)
         occurrences all number
    40
    Injection site swelling
         subjects affected / exposed
    3 / 103 (2.91%)
         occurrences all number
    3
    Injection site pruritus
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Menopausal symptoms
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 103 (2.91%)
         occurrences all number
    3
    Dyspnoea
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Nasal congestion
         subjects affected / exposed
    2 / 103 (1.94%)
         occurrences all number
    3
    Oropharyngeal pain
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Pharyngeal erythema
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Rhinorrhoea
         subjects affected / exposed
    2 / 103 (1.94%)
         occurrences all number
    3
    Sinus pain
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Sneezing
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Throat irritation
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 103 (1.94%)
         occurrences all number
    2
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Meniscus injury
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Procedural pain
         subjects affected / exposed
    3 / 103 (2.91%)
         occurrences all number
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    25 / 103 (24.27%)
         occurrences all number
    26
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    2 / 103 (1.94%)
         occurrences all number
    2
    Lacrimation increased
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Frequent bowel movements
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Gastrointestinal disorder
         subjects affected / exposed
    10 / 103 (9.71%)
         occurrences all number
    10
    Lip swelling
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 103 (3.88%)
         occurrences all number
    4
    Arthralgia
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Joint warmth
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    2 / 103 (1.94%)
         occurrences all number
    2
    Neck pain
         subjects affected / exposed
    2 / 103 (1.94%)
         occurrences all number
    2
    Pain in extremity
         subjects affected / exposed
    3 / 103 (2.91%)
         occurrences all number
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    6 / 103 (5.83%)
         occurrences all number
    6
    Sinusitis
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 103 (2.91%)
         occurrences all number
    3
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences all number
    1

    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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