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    Clinical Trial Results:
    A phase III, single-blinded, randomized, multicentric study to compare the immunogenicity of GlaxoSmithKline Biologicals' thiomersal-free 2-dose Engerix™-B (20 mcg) and 3-dose preservative-free Engerix™-B (10 mcg) vaccines administered intramuscularly according to a 0, 6 month and 0, 1, 6 month schedule, respectively, and to evaluate safety and reactogenicity of each vaccine in healthy adolescent volunteers (11 to 15 years).

    Summary
    EudraCT number
    		 2015-001531-20
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    27 Apr 2016
    First version publication date
    01 Aug 2015
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    103860/280,101695,101696,/697,/698
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00343915
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l’Institut 89, Rixensart, Belgium, B-1330
    Public contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089-904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089-904466, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    30 Nov 2005
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Dec 2004
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    For the primary Epoch: To demonstrate non-inferiority of the immune response induced by (thiomersal-free) Engerix™-B (20 mcg HBsAg) administered as a 2-dose vaccination schedule compared to (preservative-free) Engerix™-B (10 mcg HBsAg) administered as a 3-dose vaccination schedule, one month after the full vaccination course (month 7). For the long term follow-up (LTFU): To evaluate anti-HBs antibody persistence at Months 30, 42, 54 and 66 after the first vaccine dose of primary vac-cination.
    Protection of trial subjects
    The vaccinees were observed closely for at least 15 minutes, with appropriate medical treatment readily available in case of a rare anaphylactic reaction following the administration of vaccines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Apr 2004
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 66 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 110
    Country: Number of subjects enrolled
    Belgium: 274
    Worldwide total number of subjects
    384
    EEA total number of subjects
    274
    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)
    384
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All subjects who participated in the primary vaccination study, in which they received either 2 or 3 doses of GSK Biologicals hepatitis B vaccine, and who consented to participate in the long-term follow-up were contacted by the investigators. No additional subjects were recruited during this long-term follow-up study.

    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
    		 2-dose Engerix
    Arm description
    		 subjects received 2 doses of adult (thiomersal-free) HBV formulation, one at 0 and 6 months, respectively and placebo (physiological saline) at 1 month.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Engerix™-B (thiomersal-free) 20µg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    In the primary study: 2 deep intramuscular injections (Months 0, & 6) in the deltoid region of the non-dominant arm.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    In the primary study: 1 deep intramuscular injection (month 1) in the deltoid region of the non-dominant arm.

    Arm title
    		 3-dose Engerix
    Arm description
    		 Subjects received 3 doses of paediatric (preservative-free) HBV formulation one at 0, 1 and 6 months, respectively.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    10 μg Engerix™-B (preservative-free)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    In the primary study: 3 deep intramuscular injections (months 0, 1 & 6) in the deltoid region of the non-dominant arm.

    Number of subjects in period 1
    		2-dose Engerix 3-dose Engerix
    Started
    258
    126
    Completed
    254
    123
    Not completed
    4
    3
         Consent withdrawn by subject
    1
    -
         Unspecified
    1
    -
         Lost to follow-up
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    2-dose Engerix
    Reporting group description
    		 subjects received 2 doses of adult (thiomersal-free) HBV formulation, one at 0 and 6 months, respectively and placebo (physiological saline) at 1 month.

    Reporting group title
    3-dose Engerix
    Reporting group description
    		 Subjects received 3 doses of paediatric (preservative-free) HBV formulation one at 0, 1 and 6 months, respectively.

    Reporting group values
    		 2-dose Engerix 3-dose Engerix Total
    Number of subjects
    		 258 126 384
    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)
    		 12.9 ± 1.23 12.7 ± 1.32 -
    Gender categorical
    Units: Subjects
        Female
    		 132 61 193
        Male
    		 126 65 191

    End points

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    End points reporting groups
    Reporting group title
    2-dose Engerix
    Reporting group description
    		 subjects received 2 doses of adult (thiomersal-free) HBV formulation, one at 0 and 6 months, respectively and placebo (physiological saline) at 1 month.

    Reporting group title
    3-dose Engerix
    Reporting group description
    		 Subjects received 3 doses of paediatric (preservative-free) HBV formulation one at 0, 1 and 6 months, respectively.

    Primary: Number of subjects seroprotected for anti-hepatitis B surface antigen (anti-HBs) antibody.

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    End point title
    		 Number of subjects seroprotected for anti-hepatitis B surface antigen (anti-HBs) antibody.
    End point description
    A seroprotected subject was defined as a subject with anti-HBs antibody concentrations ≥ 10 mIU/mL.
    End point type
    Primary
    End point timeframe
    At Month 7
    End point values
    		 2-dose Engerix 3-dose Engerix
    Number of subjects analysed
    241
    113
    Units: Subjects
        Month 7 (N=241, 113)
    233
    111
    Statistical analysis title
    		 Non-inf. of HBV 20μg 2-dose vs. HBV 10μg 3-dose
    Statistical analysis description
    Non-inferiority of the immune response induced by thiomersal-free HBV (20 µg HBsAg per dose) administered as a 2-dose vaccination schedule compared to preservative-free HBV (10 µg HBsAg per dose) administered as a 3-dose vaccination schedule, one month after the full vaccination course (Month 7).
    Comparison groups
    2-dose Engerix v 3-dose Engerix
    Number of subjects included in analysis
    354
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in anti-HBs
    Point estimate
    -1.5
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -6.4
         upper limit
    		 3.8

    Primary: Number of subjects seroprotected for anti-hepatitis B surface antigen (anti-HBs) antibody.

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    End point title
    		 Number of subjects seroprotected for anti-hepatitis B surface antigen (anti-HBs) antibody. [1]
    End point description
    A seroprotected subject was defined as a subject with anti-HBs antibody concentrations ≥ 10 mIU/mL.
    End point type
    Primary
    End point timeframe
    At Month 30, Month 42, Month 54 and Month 66
    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
    		 2-dose Engerix 3-dose Engerix
    Number of subjects analysed
    166
    80
    Units: Subjects
        Month 30 (N=140, 64)
    122
    62
        Month 42 (N=166, 80)
    139
    74
        Month 54 (N=147, 76)
    124
    72
        Month 66 (N=132, 70)
    105
    64
    No statistical analyses for this end point

    Primary: Antibody titers against hepatitis-B virus.

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    End point title
    		 Antibody titers against hepatitis-B virus. [2]
    End point description
    Antibody titers were summarized by Geometric Mean Concentrations (GMCs) with their 95% CIs.
    End point type
    Primary
    End point timeframe
    At Month 30, Month 42, Month 54 and Month 66.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 2-dose Engerix 3-dose Engerix
    Number of subjects analysed
    166
    80
    Units: mIU/mL
    geometric mean (confidence interval 95%)
        Month 30 (N=140, 64)
    229 (162.1 to 323.5)
    708.3 (409.6 to 1224.8)
        Month 42 (N=166, 80)
    159.7 (118.3 to 215.7)
    417.9 (267.3 to 653.6)
        Month 54 (N=147, 76)
    123.6 (92.7 to 165)
    277.6 (176.5 to 436.7)
        Month 66 (N=132, 70)
    82.1 (60.7 to 111)
    225.2 (142.6 to 355.9)
    No statistical analyses for this end point

    Secondary: Antibody titers against hepatitis-B virus.

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    End point title
    		 Antibody titers against hepatitis-B virus.
    End point description
    Antibody titers were summarized by Geometric Mean Concentrations (GMCs) with their 95% CIs.
    End point type
    Secondary
    End point timeframe
    At Months 1, 2, 6 and 7
    End point values
    		 2-dose Engerix 3-dose Engerix
    Number of subjects analysed
    241
    113
    Units: mIU/mL
    geometric mean (confidence interval 95%)
        Month 1 (N=240, 112)
    28.8 (16.8 to 49.2)
    28.7 (9.4 to 87.8)
        Month 2 (N=240, 113)
    17.6 (11.1 to 27.8)
    29.4 (21.6 to 40.1)
        Month 6 (N=239, 113)
    18.8 (14.7 to 24.1)
    90 (68.6 to 117.9)
        Month 7 (N=241, 113)
    2738.5 (2071.4 to 3620.5)
    7238.3 (5247.3 to 9984.7)
    No statistical analyses for this end point

    Secondary: Number of subjects seroprotected for anti-HBs antibody.

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    End point title
    		 Number of subjects seroprotected for anti-HBs antibody.
    End point description
    A seroprotected subject was defined as a subject with anti-HBs antibody concentrations ≥ 10 mIU/mL.
    End point type
    Secondary
    End point timeframe
    At Months 1, 2 and 6.
    End point values
    		 2-dose Engerix 3-dose Engerix
    Number of subjects analysed
    240
    113
    Units: Subjects
        Month 1 (N=240, 112)
    31
    8
        Month 2 (N=240, 113)
    27
    63
        Month 6 (N=239, 113)
    63
    99
    No statistical analyses for this end point

    Secondary: Number of subjects with any and Grade 3 solicited local symptoms.

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    End point title
    		 Number of subjects with any and Grade 3 solicited local symptoms.
    End point description
    Solicited local symptoms assessed were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = spontaneously painful. Grade 3 redness/swelling = redness/swelling spreading beyond 50 millimeters (mm) of injection site.
    End point type
    Secondary
    End point timeframe
    During the 4-day (Day 0-3) follow-up period after each vaccination and overall.
    End point values
    		 2-dose Engerix 3-dose Engerix
    Number of subjects analysed
    253
    121
    Units: Subjects
        Any Pain; Dose 1 (N=253, 121)
    121
    44
        Grade 3 Pain; Dose 1 (N=253, 121)
    6
    3
        Any Redness; Dose 1 (N=253, 121)
    30
    10
        Grade 3 Redness; Dose 1 (N=253, 121)
    0
    1
        Any Swelling; Dose 1 (N=253, 121)
    18
    8
        Grade 3 Swelling; Dose 1 (N=253, 121)
    2
    2
        Any Pain; Dose 2 (N=252, 119)
    42
    38
        Grade 3 Pain; Dose 2 (N=252, 119)
    3
    2
        Any Redness; Dose 2 (N=252, 119)
    15
    15
        Grade 3 Redness; Dose 2 (N=252, 119)
    1
    0
        Any Swelling; Dose 2 (N=252, 119)
    8
    5
        Grade 3 Swelling; Dose 2 (N=252, 119)
    1
    0
        Any Pain; Dose 3 (N=250, 118)
    106
    35
        Grade 3 Pain; Dose 3 (N=250, 118)
    4
    1
        Any Redness; Dose 3 (N=250, 118)
    29
    11
        Grade 3 Redness; Dose 3 (N=250, 118)
    0
    0
        Any Swelling; Dose 3 (N=250, 118)
    14
    6
        Grade 3 Swelling; Dose 3 (N=250, 118)
    0
    0
        Any Pain; Across Doses (N=253, 121)
    155
    74
        Grade 3 Pain; Across Doses (N=253,121)
    8
    6
        Any Redness; Across Doses (N=253,121)
    50
    28
        Grade 3 Redness; Across Doses (N=253, 121)
    0
    1
        Any Swelling; Across Doses (N=253,121)
    27
    15
        Grade 3 Swelling; Across Doses (N=253, 121)
    2
    2
    No statistical analyses for this end point

    Secondary: Number of subjects with any, grade 3 and related solicited general symptoms.

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    End point title
    		 Number of subjects with any, grade 3 and related solicited general symptoms.
    End point description
    Solicited general symptoms assessed were fatigue, gastrointestinal symptoms, headache, and fever. Any was defined as incidence of the specified symptoms regardless of intensity or relationship to study vaccine.Gastrointestinal symptoms included nausea, vomiting, diarrhea and abdominal pain. Grade 3 fever was defined as fever (axillary temperature) > 38.5°C. Grade 3 symptoms were defined as symptoms which prevented normal everyday activities. Related = general symptom assessed by the investigator as causally related to the vaccination.
    End point type
    Secondary
    End point timeframe
    During the 4-day (Day 0-3) follow-up period after each vaccination and overall.
    End point values
    		 2-dose Engerix 3-dose Engerix
    Number of subjects analysed
    253
    121
    Units: Subjects
        Any Fatigue; Dose 1 (N=253, 121)
    50
    26
        Grade 3 Fatigue; Dose 1 (N=253, 121)
    1
    1
        Related Fatigue; Dose 1 (N=253, 121)
    29
    16
        Any Gastrointestinal; Dose 1 (N=253,121)
    26
    4
        Grade 3 Gastrointestinal; Dose 1 (N=253, 121)
    3
    0
        Related Gastrointestinal; Dose 1 (N=253, 121)
    11
    3
        Any Headache; Dose 1 (N=253, 121)
    57
    29
        Grade 3 Headache; Dose 1 (N=253,121)
    0
    1
        Related Headache; Dose 1 (N=253,121)
    33
    15
        Any Temperature; Dose 1 (N=253,121)
    4
    2
        Grade 3 Temperature; Dose 1 (N=253,121)
    0
    0
        Related Temperature; Dose 1 (N=253,121)
    3
    2
        Any Fatigue; Dose 2 (N=252, 119)
    37
    18
        Grade 3 Fatigue; Dose 2 (N=252, 119)
    2
    0
        Related Fatigue; Dose 2 (N=252, 119)
    23
    13
        Any Gastrointestinal; Dose 2 (N=252,119)
    20
    7
        Grade 3 Gastrointestinal; Dose 2(N=252, 119)
    0
    0
        Related Gastrointestinal; Dose 2 (N=252, 119)
    7
    5
        Any Headache; Dose 2 (N=252, 119)
    40
    21
        Grade 3 Headache; Dose 2 (N=252,119)
    0
    0
        Related Headache; Dose 2 (N=252,119)
    24
    11
        Any Temperature; Dose 2 (N=252,119)
    5
    5
        Grade 3 Temperature; Dose 2 (N=252,119)
    1
    0
        Related Temperature; Dose 2 (N=252,119)
    5
    4
        Any Fatigue; Dose 3 (N=250, 118)
    49
    20
        Grade 3 Fatigue; Dose 3 (N=250, 118)
    3
    2
        Related Fatigue; Dose 3 (N=250, 118)
    30
    8
        Any Gastrointestinal; Dose 3 (N=250,118)
    17
    14
        Grade 3 Gastrointestinal; Dose 3 (N=250, 118)
    3
    2
        Related Gastrointestinal; Dose 3 (N=250, 118)
    6
    6
        Any Headache; Dose 3 (N=250, 118)
    36
    20
        Grade 3 Headache; Dose 3 (N=250,118)
    1
    1
        Related Headache; Dose 3 (N=250,118)
    22
    12
        Any Temperature; Dose 3 (N=250,118)
    13
    9
        Grade 3 Temperature; Dose 3 (N=250,118)
    1
    0
        Related Temperature; Dose 3 (N=250,118)
    7
    5
        Any Fatigue; Across Doses (N=253,121)
    77
    46
        Grade 3 Fatigue; Across Doses (N=253,121)
    4
    3
        Related Fatigue; Across Doses (N=253,121)
    51
    30
        Any Gastrointestinal; Across Doses (N=253, 121)
    36
    21
        Grade 3 Gastrointestinal; Across Doses (N=253,121)
    6
    2
        Related Gastrointestinal; Across Doses (N=253,121)
    17
    14
        Any Headache; Across Doses (N=253,121)
    78
    46
        Grade 3 Headache; Across Doses (N=253, 121)
    1
    2
        Related Headache; Across Doses (N=253, 121)
    49
    30
        Any Temperature; Across Doses (N=253, 121)
    17
    14
        Grade 3 Temperature; Across Doses (N=253, 121)
    1
    0
        Related Temperature; Across Doses (N=253, 121)
    10
    10
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any, grade 3 and related unsolicited adverse events (AEs).

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    End point title
    		 Number of subjects reporting any, grade 3 and related unsolicited adverse events (AEs).
    End point description
    An unsolicited AE covers 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 (Day 0-30) follow-up period after each vaccination and overall.
    End point values
    		 2-dose Engerix 3-dose Engerix
    Number of subjects analysed
    257
    125
    Units: Subjects
        Any AE(s)
    112
    54
        Grade 3 AE(s)
    31
    15
        Related AE(s)
    9
    1
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects with serious adverse events (SAEs).
    End point description
    Serious adverse events (SAEs) assessed include medical occurrences that resulted in death, were life threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity or was a congenital anomaly/birth defect in the offspring of a study subject.
    End point type
    Secondary
    End point timeframe
    During the entire study period (Month 0 to Month 66).
    End point values
    		 2-dose Engerix 3-dose Engerix
    Number of subjects analysed
    257
    125
    Units: Subjects
        Any SAE(s)
    4
    1
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects with serious adverse events (SAEs).
    End point description
    Serious adverse events (SAEs) assessed include medical occurrences that resulted in death, were life threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity or was a congenital anomaly/birth defect in the offspring of a study subject.
    End point type
    Secondary
    End point timeframe
    At Month 30, Month 42, Month 54 & Month 66.
    End point values
    		 2-dose Engerix 3-dose Engerix
    Number of subjects analysed
    179
    88
    Units: Subjects
        Month 30 (N=179, 88)
    0
    0
        Month 42 (N=174, 84)
    0
    0
        Month 54 (N=166, 79)
    0
    0
        Month 66 (N=158, 76)
    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: during the entire study period (Month 0-66), Solicited local and general symptoms: During the 4-day (Days 0-3) post vaccination period and unsolicited adverse events: up to Month 7.
    Adverse event reporting additional description
    Non-serious adverse events were not assessed during the long term follow-up period (Month 30-66).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    8.1
    Reporting groups
    Reporting group title
    2-dose Engerix
    Reporting group description
    		 Subjects received 2 doses of adult (thiomersal-free) HBV formulation, one at 0 and 6 months, respectively and placebo (physiological saline) at 1 month.

    Reporting group title
    3-dose Engerix
    Reporting group description
    		 Subjects received 3 doses of pediatric (preservative-free) HBV formulation one at 0, 1 and 6 months, respectively.

    Serious adverse events
    		 2-dose Engerix 3-dose Engerix
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 257 (1.56%)
    1 / 125 (0.80%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    1 / 257 (0.39%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileitis
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection bacterial
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 125 (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
    		 2-dose Engerix 3-dose Engerix
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    155 / 257 (60.31%)
    74 / 125 (59.20%)
    General disorders and administration site conditions
    Pain; Dose 1
    alternative assessment type: Systematic
         subjects affected / exposed [1]
    121 / 253 (47.83%)
    44 / 121 (36.36%)
         occurrences all number
    121
    44
    Redness; Dose 1
    alternative assessment type: Systematic
         subjects affected / exposed
    30 / 257 (11.67%)
    10 / 125 (8.00%)
         occurrences all number
    30
    10
    Swelling; Dose 1
    alternative assessment type: Systematic
         subjects affected / exposed
    18 / 257 (7.00%)
    8 / 125 (6.40%)
         occurrences all number
    18
    8
    Pain; Dose 2
    alternative assessment type: Systematic
         subjects affected / exposed [2]
    42 / 252 (16.67%)
    38 / 119 (31.93%)
         occurrences all number
    42
    38
    Redness; Dose 2
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    15 / 252 (5.95%)
    15 / 119 (12.61%)
         occurrences all number
    15
    15
    Swelling; Dose 2
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    8 / 252 (3.17%)
    5 / 119 (4.20%)
         occurrences all number
    8
    5
    Pain; Dose 3
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    106 / 250 (42.40%)
    35 / 118 (29.66%)
         occurrences all number
    106
    35
    Redness; Dose 3
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    29 / 250 (11.60%)
    11 / 118 (9.32%)
         occurrences all number
    29
    11
    Swelling; Dose 3
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    14 / 250 (5.60%)
    6 / 118 (5.08%)
         occurrences all number
    14
    6
    Pain; Across Doses
    alternative assessment type: Systematic
         subjects affected / exposed [8]
    155 / 253 (61.26%)
    74 / 121 (61.16%)
         occurrences all number
    155
    74
    Redness; Across Doses
    alternative assessment type: Systematic
         subjects affected / exposed [9]
    50 / 253 (19.76%)
    28 / 121 (23.14%)
         occurrences all number
    50
    28
    Swelling; Across Doses
    alternative assessment type: Systematic
         subjects affected / exposed [10]
    27 / 253 (10.67%)
    15 / 121 (12.40%)
         occurrences all number
    27
    15
    Fatigue; Dose 1
    alternative assessment type: Systematic
         subjects affected / exposed [11]
    50 / 253 (19.76%)
    26 / 121 (21.49%)
         occurrences all number
    50
    26
    Fatigue; Dose 2
    alternative assessment type: Systematic
         subjects affected / exposed [12]
    37 / 252 (14.68%)
    18 / 119 (15.13%)
         occurrences all number
    37
    18
    Fatigue; Dose 3
    alternative assessment type: Systematic
         subjects affected / exposed [13]
    49 / 250 (19.60%)
    20 / 118 (16.95%)
         occurrences all number
    49
    20
    Fatigue; Across Doses
    alternative assessment type: Systematic
         subjects affected / exposed [14]
    77 / 253 (30.43%)
    46 / 121 (38.02%)
         occurrences all number
    77
    46
    Headache; Dose 1
    alternative assessment type: Systematic
         subjects affected / exposed [15]
    57 / 253 (22.53%)
    29 / 121 (23.97%)
         occurrences all number
    57
    29
    Headache; Dose 2
    alternative assessment type: Systematic
         subjects affected / exposed [16]
    40 / 252 (15.87%)
    21 / 119 (17.65%)
         occurrences all number
    40
    21
    Headache, Dose 3
    alternative assessment type: Systematic
         subjects affected / exposed [17]
    36 / 250 (14.40%)
    20 / 118 (16.95%)
         occurrences all number
    36
    20
    Headache; Across Doses
    alternative assessment type: Systematic
         subjects affected / exposed [18]
    78 / 253 (30.83%)
    46 / 121 (38.02%)
         occurrences all number
    78
    46
    Fever; Dose 1
    alternative assessment type: Systematic
         subjects affected / exposed [19]
    4 / 253 (1.58%)
    2 / 121 (1.65%)
         occurrences all number
    4
    2
    Fever; Dose 2
    alternative assessment type: Systematic
         subjects affected / exposed [20]
    5 / 252 (1.98%)
    5 / 119 (4.20%)
         occurrences all number
    5
    5
    Fever; Dose 3
    alternative assessment type: Systematic
         subjects affected / exposed [21]
    13 / 250 (5.20%)
    9 / 118 (7.63%)
         occurrences all number
    13
    9
    Fever; Across Doses
    alternative assessment type: Systematic
         subjects affected / exposed [22]
    17 / 253 (6.72%)
    14 / 121 (11.57%)
         occurrences all number
    17
    14
    Headache
         subjects affected / exposed
    28 / 257 (10.89%)
    10 / 125 (8.00%)
         occurrences all number
    28
    10
    Gastrointestinal disorders
    Gastrointestinal symptoms; Dose 1
    alternative assessment type: Systematic
         subjects affected / exposed [23]
    26 / 253 (10.28%)
    4 / 121 (3.31%)
         occurrences all number
    26
    4
    Gastrointestinal symptoms; Dose 2
    alternative assessment type: Systematic
         subjects affected / exposed [24]
    20 / 252 (7.94%)
    7 / 119 (5.88%)
         occurrences all number
    20
    7
    Gastrointestinal symptoms; Dose 3
    alternative assessment type: Systematic
         subjects affected / exposed [25]
    17 / 250 (6.80%)
    14 / 118 (11.86%)
         occurrences all number
    17
    14
    Gastrointestinal symptoms; Across Doses
    alternative assessment type: Systematic
         subjects affected / exposed
    36 / 257 (14.01%)
    21 / 125 (16.80%)
         occurrences all number
    36
    21
    Respiratory, thoracic and mediastinal disorders
    Pharyngitis
         subjects affected / exposed
    15 / 257 (5.84%)
    5 / 125 (4.00%)
         occurrences all number
    15
    5
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    26 / 257 (10.12%)
    22 / 125 (17.60%)
         occurrences all number
    26
    22
    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: For a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [8] - 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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [9] - 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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [10] - 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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [11] - 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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [12] - 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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [13] - 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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [14] - 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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [15] - 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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [16] - 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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [17] - 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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [18] - 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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [19] - 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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [20] - 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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [21] - 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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [22] - 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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [23] - 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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [24] - 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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).
    [25] - 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 a given subject cohort and the analysis of a given measurement, non-evaluable measurements were not replaced. Therefore, an analysis excluded data points of subjects with missing or non-evaluable measurements (e.g., analysis of solicited symptoms excluded vaccinated subjects without documented symptom sheets).

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Feb 2004
    The clinical study protocol 103860/280 (HBV-280) was designed to evaluate the immunogenicity of 3-dose primary vaccination course of preservative-free Engerix™-B (10 μg HBsAg) administered at 0, 1, 6 months compared to a 2-dosevaccination course of thiomersal-free Engerix™-B (20 μg HBsAg) administered at 0, 6 months. Results from the primary study have shown the vaccine to be safe with a good immune response. Anti-HBs seroprotection rate was 96.7% in group receiving thiomersal-free Engerix™-B (20 μg HBsAg) and 98.2% in group receiving preservative-free Engerix™-B (10 μg HBsAg), one month after the primary vaccination course i.e. at Month 7. The protocol is currently being amended to evaluate the persistence of humoral immune response at Month 30, 42, 54 and 66 after the first dose of primary vaccination. To evaluate the long-term antibody persistence, volunteers will be bled at Months 30, 42, 54 and 66 (intervals to be respected at ± 2 months) after the first vaccine dose of the primary vaccination course, to determine their anti-HBs antibody titres. If a subject loses seroprotective titres for anti-HBs antibodies (i.e. titres < 10 mIU/ml) at the long-term blood sampling time point (i.e. Month 30, 42, 54 and 66), he/ she will be offered an additional vaccine dose of commercial Engerix™-B (to be administered between 6 to 12 months after Month 66 time point), in order to assess the immune memory after a primary three-dose schedule of preservative-free Engerix™-B (10 μg HBsAg) or primary two -dose schedule of thiomersal-free Engerix™-B (20 μg HBsAg) administered at 0, 6 months (see Section 5.3). A blood sample will be taken on the day of the additional vaccination and after one month to evaluate the immune response following this vaccination.
    08 Dec 2006
    The protocol is currently being amended to state that subjects who had antibody concentrations <10 mIU/ml will not receive an additional vaccine dose in this study, as all subjects in this study ( irrespective of their seroprotective status), will be approached to participate in another study, 108988 (HBV-314 BST:280). Study HBV-314, will be conducted in subjects primed in study HBV-280, after completion of the last follow-up (Month 66), and will evaluate immunological memory to hepatitis B in terms of the ability to mount an anamnestic response to an additional vaccine dose of hepatitis B vaccine . Thus, all study procedures related to additional vaccine dose in the second protocol amendment of study 103860 (HBV-280) dated 2 February 2004 are not applicable.

    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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