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    Clinical Trial Results:
    An open-label, controlled, multi-centre study of the immunogenicity and safety of a challenge dose of HBVAXPRO® to explore the anamnestic immune response in healthy children vaccinated 10 years ago with a primary series (3 doses) of either HEXAVAC® or INFANRIX®-HEXA

    Summary
    EudraCT number
    2013-001602-28
    Trial protocol
    IT  
    Global end of trial date
    04 Feb 2015

    Results information
    Results version number
    v2(current)
    This version publication date
    02 Jul 2016
    First version publication date
    23 Apr 2016
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Global end of trial date corrected to comply with protocol definition (date of final collection of data for the primary endpoint).

    Trial information

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    Trial identification
    Sponsor protocol code
    HXV02C
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02012998
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur MSD S.N.C.
    Sponsor organisation address
    162 avenue Jean Jaurès - CS 50712, Lyon Cedex 07, France, 69367
    Public contact
    Clinical Trials Disclosure, Sanofi Pasteur MSD S.N.C., ClinicalTrialsDisclosure@spmsd.com
    Scientific contact
    Clinical Trials Disclosure, Sanofi Pasteur MSD S.N.C., ClinicalTrialsDisclosure@spmsd.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
    04 Feb 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Feb 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    # To describe, in subjects vaccinated with 3 doses of HEXAVAC® as infants, the percentage of subjects with an anti-HBs concentration ≥10 mIU/mL 1 month after a challenge dose of HBVAXPRO® 5 µg given at least 10 years later # To describe, in subjects vaccinated with 3 doses of INFANRIX®-HEXA as infants, the percentage of subjects with an anti-HBs concentration ≥10 mIU/mL 1 month after a challenge dose of HBVAXPRO® 5 µg given at least 10 years later Note: "HBVAXPRO® 5 µg" was referred to "HBVAXPRO" to facilitate reading.
    Protection of trial subjects
    Healthy subjects with sensitivity and/or allergy to any component of HBVAXPRO were excluded. Vaccine was administered by qualified study personnel. After each vaccination, subjects were kept under observation for at least 20 minutes to ensure their safety.
    Background therapy
    Subjects were previously vaccinated with a 3-doses primary series of HEXAVAC or a 3-doses primary series of INFANRIX-HEXA as infants (at about 3, 5, and 12 months of life). They received the 3rd dose of HEXAVAC or INFANRIX-HEXA at least 10 years before the challenge dose of HBVAXPRO.
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Jan 2014
    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
    Italy: 751
    Worldwide total number of subjects
    751
    EEA total number of subjects
    751
    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)
    451
    Adolescents (12-17 years)
    300
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study subjects were enrolled in 8 active centres in Italy.

    Pre-assignment
    Screening details
    753 subjects were screened. 751 subjects were enrolled and vaccinated. 749 subjects completed the study.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    This study was open-label as all the subjects received 1 dose of HBVAXPRO. Nevertheless, subjects were recruited from 2 different cohorts based on their vaccination history: vaccination with a 3-doses primary series of HEXAVAC or INFANRIX-HEXA during infancy. Immunogenicity assays were performed by laboratory staff (personnel and the analysts) who were blinded for the vaccine each subject had received as primo-vaccination.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    HEXAVAC / HBVAXPRO
    Arm description
    # Subjects previously vaccinated with a 3-doses primary series of HEXAVAC (at 3, 5, and 12 months of life) received 1 challenge dose of HBVAXPRO (Hepatitis B virus surface antigen, recombinant (HBsAg) 5 μg, adsorbed on amorphous aluminium hydroxyphosphate sulphate 0.25 mg) by intramuscular (IM) route at least 10 years after the 3rd dose of the primary series. # Blood samples were collected on Day 0 (D0) before challenge dose (pre-challenge dose) and 1 month (D21 to D35) after the challenge dose (post-challenge dose).
    Arm type
    Experimental

    Investigational medicinal product name
    HBVAXPRO®
    Investigational medicinal product code
    Other name
    HBVAXPRO
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM route (deltoid region), 1 dose at least 10 years after the 3rd dose of the primary series.

    Arm title
    INFANRIX-HEXA / HBVAXPRO
    Arm description
    # Subjects previously vaccinated with a 3-doses primary series of INFANRIX-HEXA (at 3, 5, and 12 months of life) received 1 challenge dose of HBVAXPRO (Hepatitis B virus surface antigen, recombinant (HBsAg) 5 μg, adsorbed on amorphous aluminium hydroxyphosphate sulphate 0.25 mg) by IM route at least 10 years after the 3rd dose of the primary series. # Blood samples were collected on Day 0 (D0) before challenge dose (pre-challenge dose) and 1 month (D21 to D35) after the challenge dose (post-challenge dose).
    Arm type
    Experimental

    Investigational medicinal product name
    HBVAXPRO®
    Investigational medicinal product code
    Other name
    HBVAXPRO
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM route (deltoid region), 1 dose at least 10 years after the 3rd dose of the primary series.

    Number of subjects in period 1
    HEXAVAC / HBVAXPRO INFANRIX-HEXA / HBVAXPRO
    Started
    409
    342
    Completed
    408
    341
    Not completed
    1
    1
         Subject not available to continue (other city)
             1
             -
         Lost to follow-up
             -
             1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    HEXAVAC / HBVAXPRO
    Reporting group description
    # Subjects previously vaccinated with a 3-doses primary series of HEXAVAC (at 3, 5, and 12 months of life) received 1 challenge dose of HBVAXPRO (Hepatitis B virus surface antigen, recombinant (HBsAg) 5 μg, adsorbed on amorphous aluminium hydroxyphosphate sulphate 0.25 mg) by intramuscular (IM) route at least 10 years after the 3rd dose of the primary series. # Blood samples were collected on Day 0 (D0) before challenge dose (pre-challenge dose) and 1 month (D21 to D35) after the challenge dose (post-challenge dose).

    Reporting group title
    INFANRIX-HEXA / HBVAXPRO
    Reporting group description
    # Subjects previously vaccinated with a 3-doses primary series of INFANRIX-HEXA (at 3, 5, and 12 months of life) received 1 challenge dose of HBVAXPRO (Hepatitis B virus surface antigen, recombinant (HBsAg) 5 μg, adsorbed on amorphous aluminium hydroxyphosphate sulphate 0.25 mg) by IM route at least 10 years after the 3rd dose of the primary series. # Blood samples were collected on Day 0 (D0) before challenge dose (pre-challenge dose) and 1 month (D21 to D35) after the challenge dose (post-challenge dose).

    Reporting group values
    HEXAVAC / HBVAXPRO INFANRIX-HEXA / HBVAXPRO Total
    Number of subjects
    409 342 751
    Age categorical
    Age at challenge dose
    Units: Subjects
        10.9-13.4 years (min-max)
    409 342 751
    Age continuous
    Age at challenge dose
    Units: years
        arithmetic mean (standard deviation)
    11.9 ± 0.5 11.8 ± 0.5 -
    Gender categorical
    Units: Subjects
        Female
    222 198 420
        Male
    187 144 331
    Time interval between the 3rd and the challenge doses
    Time interval between the last Hexavalent dose (HEXAVAC or INFANRIX-HEXA) and the challenge dose of HBVAXPRO
    Units: Years
        median (full range (min-max))
    11 (10 to 12.3) 10.8 (10 to 12.2) -

    End points

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    End points reporting groups
    Reporting group title
    HEXAVAC / HBVAXPRO
    Reporting group description
    # Subjects previously vaccinated with a 3-doses primary series of HEXAVAC (at 3, 5, and 12 months of life) received 1 challenge dose of HBVAXPRO (Hepatitis B virus surface antigen, recombinant (HBsAg) 5 μg, adsorbed on amorphous aluminium hydroxyphosphate sulphate 0.25 mg) by intramuscular (IM) route at least 10 years after the 3rd dose of the primary series. # Blood samples were collected on Day 0 (D0) before challenge dose (pre-challenge dose) and 1 month (D21 to D35) after the challenge dose (post-challenge dose).

    Reporting group title
    INFANRIX-HEXA / HBVAXPRO
    Reporting group description
    # Subjects previously vaccinated with a 3-doses primary series of INFANRIX-HEXA (at 3, 5, and 12 months of life) received 1 challenge dose of HBVAXPRO (Hepatitis B virus surface antigen, recombinant (HBsAg) 5 μg, adsorbed on amorphous aluminium hydroxyphosphate sulphate 0.25 mg) by IM route at least 10 years after the 3rd dose of the primary series. # Blood samples were collected on Day 0 (D0) before challenge dose (pre-challenge dose) and 1 month (D21 to D35) after the challenge dose (post-challenge dose).

    Subject analysis set title
    HEXAVAC / HBVAXPRO anti-HBs <10 mIU/mL at baseline
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects previously vaccinated with a 3-doses primary series of HEXAVAC (at 3, 5, and 12 months of life) with anti-HBs antibody (Ab) concentration <10 mIU/mL at baseline, i.e., at D0 before HBVAXPRO challenge dose.

    Subject analysis set title
    HEXAVAC / HBVAXPRO anti-HBs ≥10 mIU/mL at baseline
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects previously vaccinated with a 3-doses primary series of HEXAVAC (at 3, 5, and 12 months of life) with anti-HBs Ab concentration ≥10 mIU/mL at baseline, i.e., at D0 before HBVAXPRO challenge dose.

    Subject analysis set title
    INFANRIX-HEXA / HBVAXPRO anti-HBs <10 mIU/mL at baseline
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects previously vaccinated with a 3-doses primary series of INFANRIX-HEXA (at 3, 5, and 12 months of life) with anti-HBs Ab concentration <10 mIU/mL at baseline, i.e., at D0 before HBVAXPRO challenge dose.

    Subject analysis set title
    INFANRIX-HEXA / HBVAXPRO anti-HBs ≥10 mIU/mL at baseline
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects previously vaccinated with a 3-doses primary series of INFANRIX-HEXA (at 3, 5, and 12 months of life) with anti-HBs Ab concentration ≥10 mIU/mL at baseline, i.e., at D0 before HBVAXPRO challenge dose.

    Subject analysis set title
    All subjects
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received at least 1 dose of HBVAXPRO and who had any safety follow-up data.

    Primary: Percentage of subjects with anti-HBs Ab concentration ≥10 mIU/mL 1 month after HBVAXPRO challenge dose (POST-CHALLENGE)

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    End point title
    Percentage of subjects with anti-HBs Ab concentration ≥10 mIU/mL 1 month after HBVAXPRO challenge dose (POST-CHALLENGE) [1]
    End point description
    Percentage of subjects with an anti-HBs Ab concentration ≥10 mIU/mL measured by Microparticle Enzyme Immunoassay (MEIA) - AxSYM® AUSAB 1 month after HBVAXPRO challenge dose, given at least 10 years after the 3rd dose of either HEXAVAC or INFANRIX-HEXA. Analysis was done on the Per Protocol Set (PPS), i.e. all the vaccinated subjects excluding those with a serology-confirmed diagnosis of Hepatitis B infection or with important protocol deviations which may have interfered with the immunogenicity evaluation.
    End point type
    Primary
    End point timeframe
    1 month after HBVAXPRO challenge dose (post-challenge).
    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: Objectives were only descriptive. Thus no formal statistical hypothesis was tested in this study.
    End point values
    HEXAVAC / HBVAXPRO INFANRIX-HEXA / HBVAXPRO
    Number of subjects analysed
    396
    336
    Units: Percentage of subjects
    number (confidence interval 95%)
        Post-challenge anti-HBs ≥10 mIU/mL
    83.6 (79.6 to 87.1)
    96.4 (93.8 to 98.1)
    No statistical analyses for this end point

    Secondary: Percentage of subjects with anti-HBs Ab concentration ≥10 mIU/mL before HBVAXPRO challenge dose (PRE-CHALLENGE)

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    End point title
    Percentage of subjects with anti-HBs Ab concentration ≥10 mIU/mL before HBVAXPRO challenge dose (PRE-CHALLENGE)
    End point description
    Percentage of subjects with an anti-HBs Ab concentration ≥10 mIU/mL measured by MEIA - AxSYM® AUSAB at Day 0 (D0) before HBVAXPRO challenge dose (pre-challenge), at least 10 years after the 3rd dose of either HEXAVAC or INFANRIX-HEXA. Analysis was done on the Per Protocol Set (PPS), i.e. all the vaccinated subjects excluding those with a serology-confirmed diagnosis of Hepatitis B infection or with important protocol deviations which may have interfered with the immunogenicity evaluation.
    End point type
    Secondary
    End point timeframe
    Before HBVAXPRO challenge dose (pre-challenge).
    End point values
    HEXAVAC / HBVAXPRO INFANRIX-HEXA / HBVAXPRO
    Number of subjects analysed
    394 [2]
    336
    Units: Percentage of subjects
    number (confidence interval 95%)
        Pre-challenge anti-HBs ≥10 mIU/mL
    23.9 (19.7 to 28.4)
    69 (63.8 to 74)
    Notes
    [2] - Pre-challenge blood samples of 2 subjects were considered as missing due to suspected inversion.
    No statistical analyses for this end point

    Secondary: Geometric Mean Concentrations (GMCs) of anti-HBs Abs before (PRE-CHALLENGE) and 1 month after HBVAXPRO challenge dose (POST-CHALLENGE)

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    End point title
    Geometric Mean Concentrations (GMCs) of anti-HBs Abs before (PRE-CHALLENGE) and 1 month after HBVAXPRO challenge dose (POST-CHALLENGE)
    End point description
    Anti-HBs Ab concentrations were measured by MEIA - AxSYM® AUSAB before (pre-challenge) and 1 month after HBVAXPRO challenge dose (post-challenge), given at least 10 years after the 3rd dose of either HEXAVAC or INFANRIX-HEXA. Ab concentrations are expressed in mIU/mL. Analysis was done on the Per Protocol Set (PPS), i.e. all the vaccinated subjects excluding those with a serology-confirmed diagnosis of Hepatitis B infection or with important protocol deviations which may have interfered with the immunogenicity evaluation. Note: (N=***, ***) represents the number of assessed subjects in the "HEXAVAC / HBVAXPRO" and "INFANRIX-HEXA / HBVAXPRO" groups, respectively.
    End point type
    Secondary
    End point timeframe
    Before (pre-challenge) and 1 month after HBVAXPRO challenge dose (post-challenge).
    End point values
    HEXAVAC / HBVAXPRO INFANRIX-HEXA / HBVAXPRO
    Number of subjects analysed
    396
    336
    Units: mIU/mL
    geometric mean (confidence interval 95%)
        Pre-challenge anti-HBs GMC (N=394, 336)
    7.7 (7 to 8.3)
    26.8 (22.9 to 31.4)
        Post-challenge anti-HBs GMC (N=396, 336)
    191.9 (152.8 to 241)
    1823.8 (1449 to 2295.5)
    No statistical analyses for this end point

    Secondary: GMCs of anti-HBs Abs before (PRE-CHALLENGE) and 1 month after HBVAXPRO challenge dose (POST-CHALLENGE) by subset of subjects defined according to pre-challenge anti-HBs Ab concentrations (<10 or ≥10 mIU/mL)

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    End point title
    GMCs of anti-HBs Abs before (PRE-CHALLENGE) and 1 month after HBVAXPRO challenge dose (POST-CHALLENGE) by subset of subjects defined according to pre-challenge anti-HBs Ab concentrations (<10 or ≥10 mIU/mL)
    End point description
    Anti-HBs Ab concentrations were measured by MEIA - AxSYM® AUSAB before (pre-challenge) and 1 month after HBVAXPRO challenge dose (post-challenge), given at least 10 years after the 3rd dose of either HEXAVAC or INFANRIX-HEXA. Ab concentrations are expressed in mIU/mL. Analysis was done on the Per Protocol Set (PPS), i.e. all the vaccinated subjects excluding those with a serology-confirmed diagnosis of Hepatitis B infection or with important protocol deviations which may have interfered with the immunogenicity evaluation.
    End point type
    Secondary
    End point timeframe
    Before (pre-challenge) and 1 month after HBVAXPRO challenge dose (post-challenge).
    End point values
    HEXAVAC / HBVAXPRO anti-HBs <10 mIU/mL at baseline HEXAVAC / HBVAXPRO anti-HBs ≥10 mIU/mL at baseline INFANRIX-HEXA / HBVAXPRO anti-HBs <10 mIU/mL at baseline INFANRIX-HEXA / HBVAXPRO anti-HBs ≥10 mIU/mL at baseline
    Number of subjects analysed
    300
    94
    104
    232
    Units: mIU/mL
    geometric mean (confidence interval 95%)
        Pre-challenge anti-HBs GMC
    5 (5 to 5)
    29.8 (25.2 to 35.2)
    5 (5 to 5)
    56.8 (49 to 65.9)
        Post-challenge anti-HBs GMC
    91.1 (72.5 to 114.5)
    2113.4 (1608.2 to 2777.5)
    221.6 (148.7 to 330.3)
    4691.6 (3927.4 to 5604.4)
    No statistical analyses for this end point

    Secondary: Geometric Mean of individual anti-HBs Ab Concentration post-/pre-challenge Ratios (GMCRs) 1 month after HBVAXPRO challenge dose (POST-CHALLENGE)

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    End point title
    Geometric Mean of individual anti-HBs Ab Concentration post-/pre-challenge Ratios (GMCRs) 1 month after HBVAXPRO challenge dose (POST-CHALLENGE)
    End point description
    Anti-HBs Ab concentrations were measured by MEIA - AxSYM® AUSAB before (pre-challenge) and 1 month after HBVAXPRO challenge dose (post-challenge), given at least 10 years after the 3rd dose of either HEXAVAC or INFANRIX-HEXA. Individual post- (1 month)/pre-challenge (D0) anti-HBs Ab concentration ratios were calculated. Analysis was done on the Per Protocol Set (PPS), i.e. all the vaccinated subjects excluding those with a serology-confirmed diagnosis of Hepatitis B infection or with important protocol deviations which may have interfered with the immunogenicity evaluation.
    End point type
    Secondary
    End point timeframe
    1 month after HBVAXPRO challenge dose (post-challenge).
    End point values
    HEXAVAC / HBVAXPRO INFANRIX-HEXA / HBVAXPRO
    Number of subjects analysed
    394
    336
    Units: Not applicable
    number (confidence interval 95%)
        Anti-HBs GMCR
    25.2 (20.8 to 30.6)
    68.1 (57.6 to 80.5)
    No statistical analyses for this end point

    Secondary: Geometric Mean of individual anti-HBs Ab Concentration post-/pre-challenge Ratios (GMCRs) 1 month after HBVAXPRO challenge dose (POST-CHALLENGE) by subset of subjects defined according to pre-challenge anti-HBs Ab concentrations (<10 or ≥10 mIU/mL)

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    End point title
    Geometric Mean of individual anti-HBs Ab Concentration post-/pre-challenge Ratios (GMCRs) 1 month after HBVAXPRO challenge dose (POST-CHALLENGE) by subset of subjects defined according to pre-challenge anti-HBs Ab concentrations (<10 or ≥10 mIU/mL)
    End point description
    Anti-HBs Ab concentrations were measured by MEIA - AxSYM® AUSAB before (pre-challenge) and 1 month after HBVAXPRO challenge dose (post-challenge), given at least 10 years after the 3rd dose of either HEXAVAC or INFANRIX-HEXA. Individual post- (1 month)/pre-challenge (D0) anti-HBs Ab concentration ratios were calculated. Analysis was done on the Per Protocol Set (PPS), i.e. all the vaccinated subjects excluding those with a serology-confirmed diagnosis of Hepatitis B infection or with important protocol deviations which may have interfered with the immunogenicity evaluation.
    End point type
    Secondary
    End point timeframe
    1 month after HBVAXPRO challenge dose (post-challenge).
    End point values
    HEXAVAC / HBVAXPRO anti-HBs <10 mIU/mL at baseline HEXAVAC / HBVAXPRO anti-HBs ≥10 mIU/mL at baseline INFANRIX-HEXA / HBVAXPRO anti-HBs <10 mIU/mL at baseline INFANRIX-HEXA / HBVAXPRO anti-HBs ≥10 mIU/mL at baseline
    Number of subjects analysed
    300
    94
    104
    232
    Units: Not applicable
    number (confidence interval 95%)
        Anti-HBs GMCR
    18.2 (14.5 to 22.9)
    70.9 (54.3 to 92.6)
    44.3 (29.7 to 66.1)
    82.6 (70.5 to 96.7)
    No statistical analyses for this end point

    Secondary: Percentage of subjects with anti-HBs Ab concentration ≥10 mIU/mL 1 month after HBVAXPRO challenge dose (POST-CHALLENGE) in subjects with pre-challenge anti-HBs concentration <10 mIU/mL

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    End point title
    Percentage of subjects with anti-HBs Ab concentration ≥10 mIU/mL 1 month after HBVAXPRO challenge dose (POST-CHALLENGE) in subjects with pre-challenge anti-HBs concentration <10 mIU/mL
    End point description
    Percentage of subjects with an anti-HBs concentration ≥10 mIU/mL measured by MEIA - AxSYM® AUSAB 1 month after HBVAXPRO challenge dose (post-challenge) in subjects with pre-challenge anti-HBs concentration <10 mIU/mL. Analysis was done on the Per Protocol Set (PPS), i.e. all the vaccinated subjects excluding those with a serology-confirmed diagnosis of Hepatitis B infection or with important protocol deviations which may have interfered with the immunogenicity evaluation.
    End point type
    Secondary
    End point timeframe
    1 month after HBVAXPRO challenge dose (post-challenge).
    End point values
    HEXAVAC / HBVAXPRO anti-HBs <10 mIU/mL at baseline INFANRIX-HEXA / HBVAXPRO anti-HBs <10 mIU/mL at baseline
    Number of subjects analysed
    300
    104
    Units: Percentage of subjects
    number (confidence interval 95%)
        Post-challenge anti-HBs ≥10 mIU/mL
    78.7 (73.6 to 83.2)
    88.5 (80.7 to 93.9)
    No statistical analyses for this end point

    Secondary: Global summary of safety from D0 to D14 after HBVAXPRO challenge dose

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    End point title
    Global summary of safety from D0 to D14 after HBVAXPRO challenge dose
    End point description
    Adverse events (AEs) were recorded as follows. 1/ From D0 to D4 after vaccination: # solicited injection-site adverse reactions (ISRs: injection-site erythema, injection-site swelling, and injection-site pain), and # solicited systemic AE pyrexia (defined as body temperature ≥38.0°C). 2/ From D0 to D14 after vaccination: unsolicited ISRs (including erythema, swelling, and pain from D5 to D14), and # unsolicited systemic AEs. AEs at injection sites were always considered as vaccine-related (ISRs). The investigator had to assess whether systemic AEs were vaccine-related systemic AEs or not to HBVAXPRO. The percentage of subjects presenting at least once the considered events is reported hereafter. Analysis was done on the Safety Analysis Set, i.e., all subjects who received at least 1 dose of HBVAXPRO and who had any safety follow-up data.
    End point type
    Secondary
    End point timeframe
    From Day 0 (D0) to D14 after HBVAXPRO challenge dose.
    End point values
    All subjects
    Number of subjects analysed
    750
    Units: Percentage of subjects
    number (confidence interval 95%)
        At least 1 AE (D0-D14)
    46.1 (42.5 to 49.8)
        At least 1 vaccine-related AE (D0-D14)
    41.3 (37.8 to 45)
        At least 1 ISR (D0-D14)
    40.7 (37.1 to 44.3)
        At least 1 solicited ISR (D0-D4)
    40.5 (37 to 44.1)
        At least 1 other ISR (D0-D14)
    0.3 (0 to 1)
        At least 1 systemic AE (D0-D14)
    11.7 (9.5 to 14.3)
        At least 1 pyrexia (D0-D4)
    0.8 (0.3 to 1.7)
        At least 1 other systemic AE (D0-D14)
    11.6 (9.4 to 14.1)
        At least 1 vaccine-related systemic AE (D0-D14)
    1.9 (1 to 3.1)
        At least 1 vaccine-related pyrexia (D0-D4)
    0.3 (0 to 1)
        At least 1 other vaccine-related syst. AE (D0-D14)
    1.7 (0.9 to 2.9)
    No statistical analyses for this end point

    Secondary: Percentage of subjects reporting ISRs from D0 to D14 after HBVAXPRO challenge dose

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    End point title
    Percentage of subjects reporting ISRs from D0 to D14 after HBVAXPRO challenge dose
    End point description
    ISRs occurring after HBVAXPRO challenge dose were recorded as follows: # From D0 to D4 after vaccination: solicited ISRs, i.e., injection-site erythema, injection-site swelling, and injection-site pain. # From D0 to D14 after vaccination: unsolicited ISRs (including erythema, swelling, and pain from D5 to D14). AEs at injection-site were always considered as related to vaccine (ISRs). The percentage of subjects presenting at least once the considered events is reported hereafter. Analysis was done on the Safety Analysis Set, i.e., all subjects who received at least 1 dose of HBVAXPRO and who had any safety follow-up data.
    End point type
    Secondary
    End point timeframe
    From Day 0 (D0) to D14 after HBVAXPRO challenge dose.
    End point values
    All subjects
    Number of subjects analysed
    750
    Units: Percentage of subjects
    number (not applicable)
        Solicited injection-site erythema (D0-D4)
    2.4
        Solicited injection-site swelling (D0-D4)
    3.5
        Solicited injection-site pain (D0-D4)
    39.3
        Unsolicited injection-site bruising (D0-D14)
    0.1
        Unsolicited injection-site swelling (D5-D14)
    0.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Systemic adverse events (AEs) were collected from D0 to D14 after HBVAXPRO challenge dose. Serious AEs (SAEs) and deaths were collected throughout the study.
    Adverse event reporting additional description
    Analysis was done on the Safety Analysis Set, i.e., all subjects who received at least 1 dose of HBVAXPRO and who had any safety follow-up data. Unsolicited non-serious systemic AEs (vaccine-related or not) with incidence ≥1% are presented hereafter. 2 subjects reported 1 SAE each; none of them was assessed as related to HBVAXPRO challenge dose.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    All subjects
    Reporting group description
    # Subjects previously vaccinated with a 3-doses primary series of HEXAVAC or INFANRIX-HEXA (at 3, 5, and 12 months of life) received 1 challenge dose of HBVAXPRO by IM route at least 10 years after the 3rd dose of the primary series. # Respectively, 87 (11.6%) subjects reported at least 1 unsolicited systemic AE, and 13 (1.7%) subjects reported at least 1 vaccine-related unsolicited systemic AE within 14 days after vaccination. Note: Unsolicited non-serious systemic AEs with incidence ≥1% are presented hereafter. If each non-serious systemic AE with incidence ≥1% had been reported by a different subject, the number of subjects reporting at least 1 non-serious systemic AE with incidence ≥1% would have been 51.

    Serious adverse events
    All subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 750 (0.27%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Schwannoma
         subjects affected / exposed
    1 / 750 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Multiple sclerosis
         subjects affected / exposed
    1 / 750 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    All subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    51 / 750 (6.80%)
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    12 / 750 (1.60%)
         occurrences all number
    12
    Nervous system disorders
    Headache
         subjects affected / exposed
    27 / 750 (3.60%)
         occurrences all number
    28
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    5 / 750 (0.67%)
         occurrences all number
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 750 (0.93%)
         occurrences all number
    9

    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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