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    Clinical Trial Results:
    A phase I/II, observer-blind, randomized, controlled study to assess the immunogenicity and safety of GlaxoSmithKline Biologicals’ HPV-16/18 L1/AS04 vaccine administered intramuscularly according to a 0, 1, 6 month schedule in healthy male subjects aged 10-18 years.

    Summary
    EudraCT number
    		 2005-005943-24
    Trial protocol
    		 FI  
    Global end of trial date
    19 Jun 2007

    Results information
    Results version number
    		 v2(current)
    This version publication date
    20 Mar 2023
    First version publication date
    08 Jan 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Correction of full data set and alignment between registries.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    580299/011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00309166
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l'Institut 89, Rixensart, Belgium, 1330
    Public contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 004 2089904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 004 2089904466, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Dec 2007
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jun 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate 1 month after the third dose (i.e. at Month 7), the immune responses to the candidate HPV-16/18 vaccine (as determined by anti-HPV-16/18 ELISA) in healthy male subjects aged 10-18 years old.
    Protection of trial subjects
    As with all injectable vaccines, appropriate medical treatment was always readily available in case of anaphylactic reactions following the administration of the vaccine. For this reason, the vaccinee remained under medical supervision for 30 minutes after vaccination.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Apr 2006
    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
    Finland: 270
    Worldwide total number of subjects
    270
    EEA total number of subjects
    270
    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)
    11
    Adolescents (12-17 years)
    240
    Adults (18-64 years)
    19
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 During the screening the following steps occurred: check for inclusion/exclusion criteria, contraindications/precautions, medical history of the subjects and signing informed consent forms.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cervarix Group
    Arm description
    		 Healthy male subjects between and including 10 to 18 years of age at the time of the first vaccination, who were administered 3 doses of Cervarix (HPV-16/18 L1 VLP AS04) vaccine, intramuscularly into the deltoid region of the non-dominant arm, according to a 0, 1 and 6-month schedule. The subjects were followed up for 7 months after the first dose and an additional telephone contact was foreseen at Month 12.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cervarix
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    All subjects received an intramuscular injection into the deltoid of the non-dominant arm according to a 0, 1 and 6-month schedule and were followed up for 7 months after the first dose. Additionally, a telephone contact was foreseen at Month 12.

    Arm title
    		 Engerix-B Group
    Arm description
    		 Healthy male subjects between and including 10 to 18 years of age at the time of the first vaccination, who were administered 3 doses of Engerix-B (HBV) vaccine, intramuscularly into the deltoid region of the non-dominant arm, according to a 0, 1 and 6-month schedule. The subjects were followed up for 7 months after the first dose and an additional telephone contact was foreseen at Month 12.
    Arm type
    		 Active comparator

    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
    All subjects received an intramuscular injection into the deltoid of the non-dominant arm according to a 0, 1 and 6-month schedule and were followed up for 7 months after the first dose. Additionally, a telephone contact was foreseen at Month 12.

    Number of subjects in period 1
    		Cervarix Group Engerix-B Group
    Started
    181
    89
    Completed
    176
    86
    Not completed
    5
    3
         Consent withdrawn by subject
    4
    3
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cervarix Group
    Reporting group description
    		 Healthy male subjects between and including 10 to 18 years of age at the time of the first vaccination, who were administered 3 doses of Cervarix (HPV-16/18 L1 VLP AS04) vaccine, intramuscularly into the deltoid region of the non-dominant arm, according to a 0, 1 and 6-month schedule. The subjects were followed up for 7 months after the first dose and an additional telephone contact was foreseen at Month 12.

    Reporting group title
    Engerix-B Group
    Reporting group description
    		 Healthy male subjects between and including 10 to 18 years of age at the time of the first vaccination, who were administered 3 doses of Engerix-B (HBV) vaccine, intramuscularly into the deltoid region of the non-dominant arm, according to a 0, 1 and 6-month schedule. The subjects were followed up for 7 months after the first dose and an additional telephone contact was foreseen at Month 12.

    Reporting group values
    		 Cervarix Group Engerix-B Group Total
    Number of subjects
    		 181 89 270
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 9 2 11
        Adolescents (12-17 years)
    		 156 84 240
        Adults (18-64 years)
    		 16 3 19
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        geometric mean (standard deviation)
    		 14.4 ± 2.14 14.4 ± 2.02 -
    Gender categorical
    Units: Subjects
        Males
    		 181 89 270

    End points

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    End points reporting groups
    Reporting group title
    Cervarix Group
    Reporting group description
    		 Healthy male subjects between and including 10 to 18 years of age at the time of the first vaccination, who were administered 3 doses of Cervarix (HPV-16/18 L1 VLP AS04) vaccine, intramuscularly into the deltoid region of the non-dominant arm, according to a 0, 1 and 6-month schedule. The subjects were followed up for 7 months after the first dose and an additional telephone contact was foreseen at Month 12.

    Reporting group title
    Engerix-B Group
    Reporting group description
    		 Healthy male subjects between and including 10 to 18 years of age at the time of the first vaccination, who were administered 3 doses of Engerix-B (HBV) vaccine, intramuscularly into the deltoid region of the non-dominant arm, according to a 0, 1 and 6-month schedule. The subjects were followed up for 7 months after the first dose and an additional telephone contact was foreseen at Month 12.

    Primary: Number of seroconverted subjects for anti-HPV-16 and HPV-18

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    End point title
    		 Number of seroconverted subjects for anti-HPV-16 and HPV-18 [1]
    End point description
    Seroconversion was defined as the appearance of anti-HPV-16 and/or anti-HPV-18 antibodies (anti-HPV-16 titres ≥8 ELISA units per milliliter [EL.U/mL] and anti-HPV-18 titres greater than or equal to (≥) 7 EL.U/mL) in the serum of subjects seronegative before vaccination.
    End point type
    Primary
    End point timeframe
    At Month 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 analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 Cervarix Group Engerix-B Group
    Number of subjects analysed
    163
    86
    Units: Subjects
        HPV-16 (N=163, 83)
    163
    1
        HPV-18 (N=150, 86)
    150
    2
    No statistical analyses for this end point

    Primary: Antibody titers against HPV-16 (anti-HPV-16) and HPV-18 (anti-HPV-18)

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    End point title
    		 Antibody titers against HPV-16 (anti-HPV-16) and HPV-18 (anti-HPV-18) [2]
    End point description
    Titers were given as geometric mean titers(GMT).
    End point type
    Primary
    End point timeframe
    At Month 7
    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
    		 Cervarix Group Engerix-B Group
    Number of subjects analysed
    171
    86
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        HPV-16 (N=171, 86)
    22564.8 (19800.3 to 25715.4)
    4.2 (4 to 4.5)
        HPV-18 (N=170, 86)
    8460.3 (7306.1 to 9796.8)
    3.6 (3.4 to 3.8)
    No statistical analyses for this end point

    Secondary: Number of seroconverted subjects for HPV-16 and HPV-18

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    End point title
    		 Number of seroconverted subjects for HPV-16 and HPV-18
    End point description
    Seroconversion was defined as the appearance of anti-HPV-16 and/or anti-HPV-18 antibodies (anti-HPV-16 titres ≥8 ELISA units per milliliter [EL.U/mL] and anti-HPV-18 titres ≥7 EL.U/mL) in the serum of subjects seronegative before vaccination.
    End point type
    Secondary
    End point timeframe
    At Month 2
    End point values
    		 Cervarix Group Engerix-B Group
    Number of subjects analysed
    165
    86
    Units: Subjects
        HPV-16 (N=165, 83)
    165
    0
        HPV-18 (N=152, 86)
    152
    4
    No statistical analyses for this end point

    Secondary: Antibody titers against HPV-16 (anti-HPV-16) and HPV-18 (anti-HPV-18)

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    End point title
    		 Antibody titers against HPV-16 (anti-HPV-16) and HPV-18 (anti-HPV-18)
    End point description
    Titers were given as GMTs.
    End point type
    Secondary
    End point timeframe
    At Month 2
    End point values
    		 Cervarix Group Engerix-B Group
    Number of subjects analysed
    173
    86
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        HPV-16 (N=173, 86)
    5254.5 (4704.9 to 5868.2)
    4.1 (4 to 4.3)
        HPV-18 (N=172, 86)
    3696.9 (3275.9 to 4172.1)
    3.7 (3.5 to 3.8)
    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
    The solicited symptoms assessed were pain, redness and swelling. Any = any solicited local symptom irrespective of intensity grade; Grade 3 pain = pain that prevented normal activity; Grade 3 redness/swelling = redness/swelling beyond (>) 50 mm.
    End point type
    Secondary
    End point timeframe
    Within 7 days (Day 0 - 6) after each dose and across doses, up to 7 months
    End point values
    		 Cervarix Group Engerix-B Group
    Number of subjects analysed
    180
    88
    Units: Subjects
        Pain, Dose 1 (N=180, 88)
    149
    25
        Grade 3, Pain, Dose 1 (N=180, 88)
    1
    0
        Redness, Dose 1 (N=180, 88)
    24
    12
        Grade 3, Redness, Dose 1 (N=180, 88)
    0
    0
        Swelling, Dose 1 (N=180, 88)
    7
    3
        Grade 3, Swelling, Dose 1 (N=180, 88)
    0
    0
        Pain, Dose 2 (N=172, 86)
    114
    16
        Grade 3, Pain, Dose 2 (N=172, 86)
    2
    0
        Redness, Dose 2 (N=172, 86)
    30
    8
        Grade 3, Redness, Dose 2 (N=172, 86)
    0
    0
        Swelling, Dose 2 (N=172, 86)
    20
    2
        Grade 3, Swelling, Dose 2 (N=172, 86)
    0
    1
        Pain, Dose 3 (N=171, 85)
    115
    16
        Grade 3, Pain, Dose 3 (N=171, 85)
    7
    0
        Redness, Dose 3 (N=171, 85)
    33
    9
        Grade 3, Redness, Dose 3 (N=171, 85)
    0
    0
        Swelling, Dose 3 (N=171, 85)
    29
    3
        Grade 3, Swelling, Dose 3 (N=171, 85)
    2
    0
        Pain, Across doses (N=180, 88)
    159
    39
        Grade 3, Pain, Across doses (N=180, 88)
    8
    0
        Redness, Across doses (N=180, 88)
    51
    15
        Grade 3, Redness, Across doses (N=180, 88)
    0
    0
        Swelling, Across doses (N=180, 88)
    36
    7
        Grade 3, Swelling, Across doses (N=180, 88)
    2
    1
    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
    The solicited general symptoms assessed were Arthralgia, Fatigue, Fever (defined as axillary temperature ≥37.5 °C), Gastrointestinal, Headache, Myalgia, Rash and Urticaria. Any = any solicited general symptom irrespective of intensity grade or relationship to vaccination; Grade 3 = symptom that prevented normal activity; Grade 3 fever = temperature > 39.0 °C; Related = symptoms considered by the investigator to have a causal relationship to vaccination.
    End point type
    Secondary
    End point timeframe
    Within 7 days (Days 0-6) after each dose and across doses, up to 7 months
    End point values
    		 Cervarix Group Engerix-B Group
    Number of subjects analysed
    180
    88
    Units: Subjects
        Arthralgia, Dose 1 (N=180, 88)
    17
    7
        Grade 3, Athralgia, Dose 1 (N=180, 88)
    0
    0
        Related, Athralgia, Dose 1 (N=180, 88)
    10
    3
        Fatigue, Dose 1 (N=180, 88)
    51
    32
        Grade 3, Fatigue, Dose 1 (N=180, 88)
    1
    0
        Related, Fatigue, Dose 1 (N=180, 88)
    26
    18
        Fever (axillary), Dose 1 (N=180, 88)
    24
    11
        Grade 3, Fever, Dose 1 (N=180, 88)
    0
    0
        Related, Fever, Dose 1 (N=180, 88)
    1
    1
        Gastrointestinal, Dose 1 (N=180, 88)
    33
    10
        Grade 3, Gastrointestinal, Dose 1 (N=180, 88)
    2
    0
        Related, Gastrointestinal, Dose 1 (N=180, 88)
    15
    5
        Headache, Dose 1 (N=180, 88)
    51
    21
        Grade 3, Headache, Dose 1 (N=180, 88)
    0
    0
        Related, Headache, Dose 1 (N=180, 88)
    24
    7
        Myalgia, Dose 1 (N=180, 88)
    67
    16
        Grade 3, Mylagia, Dose 1 (N=180, 88)
    1
    0
        Related, Mylagia, Dose 1 (N=180, 88)
    45
    7
        Rash, Dose 1 (N=180, 88)
    8
    1
        Grade 3, Rash, Dose 1 (N=180, 88)
    0
    0
        Related, Rash, Dose 1 (N=180, 88)
    2
    1
        Urticaria, Dose 1 (N=180, 88)
    3
    0
        Grade 3, Urticaria, Dose 1 (N=180, 88)
    0
    0
        Related, Urticaria, Dose 1 (N=180, 88)
    1
    0
        Arthralgia, Dose 2 (N=173, 86)
    6
    3
        Grade 3, Arthralgia, Dose 2 (173, 86)
    0
    1
        Related, Arthralgia, Dose 2 (N=173, 86)
    3
    0
        Fatigue, Dose 2 (N=173, 86)
    35
    14
        Grade 3, Fatigue, Dose 2 (N=173, 86)
    1
    0
        Related, Fatigue, Dose 2 (N=173, 86)
    21
    9
        Fever (axillary), Dose 2 (N=173, 86)
    14
    6
        Grade 3, Fever, Dose 2 (N=173, 86)
    0
    0
        Related, Fever, Dose 2 (N=173, 86)
    1
    0
        Gastrointestinal, Dose 2 (N=173, 86)
    18
    4
        Grade 3, Gastrointestinal, Dose 2 (N=173, 86)
    1
    1
        Related, Gastrointestinal, Dose 2 (N=173, 86)
    7
    0
        Headache, Dose 2 (N=173, 86)
    30
    13
        Grade 3, Headache, Dose 2 (N=173, 86)
    2
    1
        Related, Headache, Dose 2 (N=173, 86)
    14
    7
        Myalgia, Dose 2 (N=173, 86)
    35
    8
        Grade 3, Maylagia, Dose 2 (N=173, 86)
    1
    0
        Related, Maylagia, Dose 2 (N=173, 86)
    27
    7
        Rash, Dose 2 (N=173, 86)
    8
    2
        Grade 3, Rash, Dose 2 (N=173, 86)
    0
    0
        Related, Rash, Dose 2 (N=173, 86)
    3
    0
        Urticaria, Dose 2 (N=173, 86)
    1
    2
        Grade 3, Urticaria, Dose 2 (N=173, 86)
    0
    0
        Related, Urticaria, Dose 2 (N=173, 86)
    0
    0
        Arthralgia, Dose 3 (N=170, 85)
    12
    3
        Grade 3, Arthralgia, Dose 3 (N=170, 85)
    0
    0
        Related, Arthtralgia, Dose 3 (N=170, 85)
    12
    3
        Fatigue, Dose 3 (N=170, 85)
    44
    15
        Grade 3, Fatigue, Dose 3 (N=170, 85)
    2
    0
        Related, Fatigue, Dose 3 (N=170, 85)
    30
    11
        Fever (axillary), Dose 3 (N=170, 85)
    14
    4
        Grade 3, Fever, Dose 3 (N=170, 85)
    0
    0
        Related, Fever, Dose 3 (N=170, 85)
    1
    0
        Gastrointestinal, Dose 3 (N=170, 85)
    10
    5
        Grade 3, Gastrointestinal, Dose 3 (N=170, 85)
    1
    0
        Related, Gastrointestinal, Dose 3 (N=170, 85)
    8
    4
        Headache, Dose 3 (N=170, 85)
    30
    11
        Grade 3, Headache, Dose 3 (N=170, 85)
    3
    0
        Related, Headache, Dose 3 (N=170, 85)
    17
    8
        Myalgia, Dose 3 (N=170, 85)
    39
    8
        Grade 3, Mylagia, Dose 3 (N=170, 85)
    1
    0
        Related, Mylagia, Dose 3 (N=170, 85)
    35
    6
        Rash, Dose 3 (N=170, 85)
    3
    2
        Grade 3, Rash, Dose 3 (N=170, 85)
    0
    0
        Related, Rash, Dose 3 (N=170, 85)
    1
    0
        Urticaria, Dose 3 (N=170, 85)
    0
    0
        Grade 3, Urticaria, Dose 3 (N=170, 85)
    0
    0
        Related, Urticaria, Dose 3 (N=170, 85)
    0
    0
        Arthralgia, Across doses (N=180, 88)
    29
    10
        Grade 3, Arthralgia, Across doses (N=180, 88)
    0
    1
        Related, Arthralgia, Across doses (N=180, 88)
    22
    5
        Fatigue, Across doses (N=180, 88)
    82
    42
        Grade 3, Fatigue, Across doses (N=180, 88)
    4
    0
        Fever (axillary), Across doses (N=180, 88)
    35
    17
        Grade 3, Fever, Across doses (N=180, 88)
    0
    0
        Related, Fever, Across doses (N=180, 88)
    3
    1
        Gastrointestinal, Across doses (N=180, 88)
    40
    14
        Grade 3, Gastrointestinal, Across dose (N=180, 88)
    4
    1
        Related, Gastrointestinal, Across dose (N=180, 88)
    19
    7
        Headache, Across doses (N=180, 88)
    77
    33
        Grade 3, Headache, Across doses (N=180, 88)
    5
    1
        Related, Headache, Across doses (N=180, 88)
    43
    16
        Related, Fatigue, Across doses (N=180, 88)
    54
    33
        Myalgia, Across doses (N=180, 88)
    88
    23
        Grade 3, Mylagia, Across doses (N=180, 88)
    3
    0
        Related, Mylagia, Across doses (N=180, 88)
    70
    14
        Rash, Across doses (N=180, 88)
    16
    5
        Grade 3, Rash, Across doses (N=180, 88)
    0
    0
        Related, Rash, Across doses (N=180, 88)
    5
    1
        Urticaria, Across doses (N=180, 88)
    4
    2
        Grade 3, Urticaria, Across doses (N=180, 88)
    0
    0
        Related, Urticaria, Across doses (N=180, 88)
    1
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with any, Grade 3 and related unsolicited adverse events (AEs)

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    End point title
    		 Number of subjects with any, Grade 3 and related unsolicited adverse events (AEs)
    End point description
    Solicited general symptoms assessed were arthralgia, fatigue, fever (defined as axillary temperature ≥37.5 °C), gastrointestinal, headache, myalgia, rash and urticaria. Any = any solicited general symptom irrespective of intensity grade or relationship to vaccination; Grade 3 = symptom that prevented normal activity; Grade 3 fever = temperature > 39.0 °C; Related = symptoms considered by the investigator to have a causal relationship to vaccination.
    End point type
    Secondary
    End point timeframe
    Within 30 days (Day 0-29) after any vaccination, up to 7 months
    End point values
    		 Cervarix Group Engerix-B Group
    Number of subjects analysed
    181
    89
    Units: Subjects
        Any AEs
    68
    31
        Grade 3 AEs
    5
    2
        Related AEs
    5
    1
    No statistical analyses for this end point

    Secondary: Number of subjects with New Onset of Chronic Diseases (NOCDs) and other medically significant conditions

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    End point title
    		 Number of subjects with New Onset of Chronic Diseases (NOCDs) and other medically significant conditions
    End point description
    NOCDs include asthma, Chron`s disease, dermatitis atopic. MSCs include AEs prompting emergency room or physician visits that are not related to common diseases or routine visits for physical examination or vaccination, or serious adverse events (SAEs) that are not related to common diseases. Common diseases include upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections and injury.
    End point type
    Secondary
    End point timeframe
    Throughout the active phase of the study (up to Month 7) and the extended safety follow-up (from Month 7 up to Month 12)
    End point values
    		 Cervarix Group Engerix-B Group
    Number of subjects analysed
    181
    89
    Units: Subjects
        NOCDs, Month 7 (N=181, 89)
    2
    1
        MSCs, Month 7 (N=181, 89)
    22
    10
        NOCDs, Month 7 to 12 (N=175,86)
    0
    0
        MSCs, Month 7 to 12 (N=175,86)
    1
    2
    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 result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.
    End point type
    Secondary
    End point timeframe
    Throughout the active phase of the study (up to Month 7) and the extended safety follow-up (from Month 7 up to Month 12)
    End point values
    		 Cervarix Group Engerix-B Group
    Number of subjects analysed
    181
    89
    Units: Number
        SAEs, Month 7 (N=181,89)
    2
    0
        SAEs, Month 12 (N=175, 86)
    1
    1
    No statistical analyses for this end point

    Secondary: Number of subjects with clinically relevant abnormalities in biochemical and haematological parameters

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    End point title
    		 Number of subjects with clinically relevant abnormalities in biochemical and haematological parameters
    End point description
    The occurence of clinically relevant abnormalities was assessed in the following biochemical and haematological parameters: alanine aminotransferase [ALT], basophils [BAS], creatinine [CREA], eosinophils [EOS] and hematocrit [Hem]. Levels of haematological/biochemical parameters assessed in terms of normal, below and above laboratory values were - normal, below, above and missing.
    End point type
    Secondary
    End point timeframe
    At Month 2 and Month 7, post-vaccination
    End point values
    		 Cervarix Group Engerix-B Group
    Number of subjects analysed
    172
    86
    Units: Subjects
        Alt, Normal, Month 2, Normal (N=172, 86)
    166
    79
        Alt, Normal, Month 2, Below (N=172, 86)
    3
    0
        Alt, Normal, Month 2, Above (N=172, 86)
    3
    2
        Alt, Normal, Month 2, Missing (N=172, 86)
    0
    5
        Alt, Normal, Month 7, Normal (N=171, 84)
    165
    81
        Alt, Normal, Month 7, Below (N=171, 84)
    1
    9
        Alt, Normal, Month 7, Above (N=171, 84)
    5
    3
        Alt, Below, Month 2, Normal (N=1, 0)
    0
    0
        Alt, Below, Month 2, Below (N=1, 0)
    1
    0
        Alt, Below, Month 2, Above (N=1, 0)
    0
    0
        Alt, Below, Month 7, Normal (N=1, 0)
    0
    0
        Alt, Below, Month 7, Below (N=1, 0)
    1
    0
        Alt, Below, Month 7, Above (N=1, 0)
    0
    0
        Alt, Above, Month 2, Normal (N=4, 1)
    2
    0
        Alt, Above, Month 2, Below (N=4, 1)
    0
    0
        Alt, Above, Month 2, Above (N=4, 1)
    2
    0
        Alt, Above, Month 2, Missing (N=4, 1)
    0
    1
        Alt, Above, Month 7, Normal (N=3, 1)
    2
    0
        Alt, Above, Month 7, Below (N=3, 1)
    0
    0
        Alt, Above, Month 7, Above (N=3, 1)
    1
    1
        BAS Normal, Month 2, Normal (N=146, 76)
    140
    65
        BAS Normal, Month 2, Below (N=146, 76)
    0
    0
        BAS Normal, Month 2, Above (N=146, 76)
    3
    3
        BAS Normal, Month 2, Missing (N=146, 76)
    3
    8
        BAS Normal, Month 7, Normal (N=145, 74)
    134
    66
        BAS Normal, Month 7, Below (N=145, 74)
    0
    0
        BAS Normal, Month 7, Above (N=145, 74)
    11
    8
        BAS Above, Month 2, Normal (N=18, 6)
    12
    5
        BAS Above, Month 2, Below (N=18, 6)
    0
    0
        BAS Above, Month 2, Above (N=18, 6)
    6
    1
        BAS Above, Month 7, Normal (N=18, 6)
    14
    4
        BAS Above, Month 7, Below (N=18, 6)
    0
    0
        BAS Above, Month 7, Above (N=18, 6)
    4
    2
        EOS Normal, Month 2, Normal (N=125, 68)
    102
    48
        EOS Normal, Month 2, Below (N=125, 68)
    4
    2
        EOS Normal, Month 2, Above (N=125, 68)
    17
    10
        EOS Normal, Month 2, Missing (N=125, 68)
    2
    8
        EOS Normal, Month 7, Normal (N=125, 67)
    108
    54
        EOS Normal, Month 7, Below (N=125, 67)
    8
    4
        EOS Normal, Month 7, Above (N=125, 67)
    9
    9
        EOS Below, Month 2, Normal (N=4, 3)
    4
    2
        EOS Below, Month 2, Below (N=4, 3)
    0
    1
        EOS Below, Month 2, Above (N=4, 3)
    0
    0
        EOS Below, Month 7, Normal (N=4, 2)
    2
    1
        EOS Below, Month 7, Below (N=4, 2)
    2
    1
        EOS Below, Month 7, Above (N=4, 2)
    0
    0
        EOS Above, Month 2, Normal (N=36, 11)
    6
    5
        EOS Above, Month 2, Below (N=36, 11)
    0
    0
        EOS Above, Month 2, Above (N=36, 11)
    30
    6
        EOS Above, Month 7, Normal (N=35, 11)
    8
    5
        EOS Above, Month 7, Below (N=35, 11)
    0
    0
        EOS Above, Month 7, Above (N=35, 11)
    27
    6
        CREA Normal, Month 2, Normal (N=163, 82)
    158
    76
        CREA Normal, Month 2, Below (N=163, 82)
    0
    0
        CREA Normal, Month 2, Above (N=163, 82)
    5
    0
        CREA Normal, Month 2, Missing (N=163, 82)
    0
    6
        CREA Normal, Month 7, Normal (N=161, 80)
    159
    79
        CREA Normal, Month 7, Below (N=161, 80)
    0
    0
        CREA Normal, Month 7, Above (N=161, 80)
    2
    1
        CREA Above, Month 2, Normal (N=13, 5)
    10
    3
        CREA Above, Month 2, Below (N=13, 5)
    0
    0
        CREA Above, Month 2, Above (N=13, 5)
    3
    2
        CREA Above, Month 7, Normal (N=13, 5)
    10
    5
        CREA Above, Month 7, Below (N=13, 5)
    0
    0
        CREA Above, Month 7, Above (N=13, 5)
    3
    0
        HEM Normal, Month 2, Normal (N=159, 81)
    155
    76
        HEM Normal, Month 2, Below (N=159, 81)
    2
    0
        HEM Normal, Month 2, Above (N=159, 81)
    2
    0
        HEM Normal, Month 2, Missing (N=159, 81)
    0
    5
        HEM Normal, Month 7, Normal (N=158, 79)
    147
    73
        HEM Normal, Month 7, Below (N=158, 79)
    9
    6
        HEM Normal, Month 7, Above (N=158, 79)
    2
    0
        HEM Below, Month 2, Normal (N=4, 1)
    3
    1
        HEM Below, Month 2, Below (N=4, 1)
    1
    0
        HEM Below, Month 2, Above (N=4, 1)
    0
    0
        HEM Below, Month 7, Normal (N=4, 1)
    2
    1
        HEM Below, Month 7, Below (N=4, 1)
    2
    0
        HEM Below, Month 7, Above (N=4, 1)
    0
    0
        HEM Above, Month 2, Normal (N=6, 2)
    3
    0
        HEM Above, Month 2, Below (N=6, 2)
    0
    0
        HEM Above, Month 2, Above (N=6, 2)
    3
    1
        HEM Above, Month 2, Missing (N=6, 2)
    0
    1
        HEM Above, Month 7, Normal (N=6, 2)
    6
    1
        HEM Above, Month 7, Below (N=6, 2)
    0
    0
        HEM Above, Month 7, Above (N=6, 2)
    0
    1
    No statistical analyses for this end point

    Secondary: Number of subjects with clinically relevant abnormalities in biochemical and haematological parameters

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    End point title
    		 Number of subjects with clinically relevant abnormalities in biochemical and haematological parameters
    End point description
    The occurence of clinically relevant abnormalities was assessed in the following biochemical and haematological parameters: lymphocytes [LYM], monocytes [MON], neutrophils [NEU], platelets [PLA], red blood cells [RBC] and white blood cells [WBC]. Levels of haematological/biochemical parameters assessed in terms of normal, below and above laboratory values were - normal, below, above and missing.
    End point type
    Secondary
    End point timeframe
    At Month 2 and Month 7, post-vaccination
    End point values
    		 Cervarix Group Engerix-B Group
    Number of subjects analysed
    164
    82
    Units: Subjects
        Lym, Normal, Month 2, Normal (N=142, 71)
    117
    56
        Lym, Normal, Month 2, Below (N=142, 71)
    5
    1
        Lym, Normal, Month 2, Above (N=142, 71)
    18
    6
        Lym, Normal, Month 2, Missing (N=142, 71)
    2
    8
        Lym, Normal, Month 7, Normal (N=142, 69)
    126
    63
        Lym, Normal, Month 7, Below (N=142, 69)
    4
    1
        Lym, Normal, Month 7, Above (N=142, 69)
    12
    5
        Lym, Below , Month 2, Normal (N=3, 1)
    1
    1
        Lym, Below , Month 2, Below (N=3, 1)
    2
    0
        Lym, Below , Month 2, Above (N=3, 1)
    0
    0
        Lym, Below , Month 7, Normal (N=3, 1)
    2
    1
        Lym, Below , Month 7, Below (N=3, 1)
    1
    0
        Lym, Below , Month 7, Above (N=3, 1)
    0
    0
        Lym, Above, Month 2, Normal (N=20, 10)
    11
    5
        Lym, Above, Month 2, Below (N=20, 10)
    1
    0
        Lym, Above, Month 2, Above (N=20, 10)
    8
    5
        Lym, Above, Month 7, Normal (N=19, 10)
    11
    8
        Lym, Above, Month 7, Below (N=19, 10)
    0
    0
        Lym, Above, Month 7, Above (N=19, 10)
    8
    2
        MON Normal, Month 2, Normal (N=108, 50)
    92
    38
        MON Normal, Month 2, Below (N=108, 50)
    0
    0
        MON Normal, Month 2, Above (N=108, 50)
    15
    5
        MON Normal, Month 2, Missing (N=108, 50)
    1
    7
        MON Normal, Month 7, Normal (N=108, 48)
    93
    43
        MON Normal, Month 7, Below (N=108, 48)
    0
    1
        MON Normal, Month 7, Above (N=108, 48)
    15
    4
        MON Below, Month 2, Normal (N=1, 3)
    1
    3
        MON Below, Month 2, Below (N=1, 3)
    0
    0
        MON Below, Month 2, Above (N=1, 3)
    0
    0
        MON Below, Month 7, Normal (N=1, 3)
    0
    3
        MON Below, Month 7, Below (N=1, 3)
    1
    0
        MON Below, Month 7, Above (N=1, 3)
    0
    0
        MON Above, Month 2, Normal (N=56, 29)
    7
    8
        MON Above, Month 2, Below (N=56, 29)
    0
    0
        MON Above, Month 2, Above (N=56, 29)
    48
    20
        MON Above, Month 2, Missing (N=56, 29)
    1
    1
        MON Above, Month 7, Normal (N=55, 29)
    13
    7
        MON Above, Month 7, Below (N=55, 29)
    0
    0
        MON Above, Month 7, Above (N=55, 29)
    42
    22
        NEU Normal, Month 2, Normal (N=152, 74)
    130
    60
        NEU Normal, Month 2, Below (N=152, 74)
    20
    6
        NEU Normal, Month 2, Above (N=152, 74)
    0
    0
        NEU Normal, Month 2, Missing (N=152, 74)
    2
    8
        NEU Normal, Month 7, Normal (N=152, 72)
    135
    63
        NEU Normal, Month 7, Below (N=152, 72)
    14
    8
        NEU Normal, Month 7, Above (N=152, 72)
    3
    1
        NEU Below, Month 2, Normal (N=13, 8)
    10
    5
        NEU Below, Month 2, Below (N=13, 8)
    3
    3
        NEU Below, Month 2, Above (N=13, 8)
    0
    0
        NEU Below, Month 7, Normal (N=12, 8)
    8
    6
        NEU Below, Month 7, Below (N=12, 8)
    3
    2
        NEU Below, Month 7, Above (N=12, 8)
    1
    0
        PLA Normal, Month 2, Normal (N=164, 78)
    158
    68
        PLA Normal, Month 2, Below (N=164, 78)
    3
    2
        PLA Normal, Month 2, Above (N=164, 78)
    3
    2
        PLA Normal, Month 2, Missing (N=164, 78)
    0
    6
        PLA Normal, Month 7, Normal (N=163, 76)
    156
    71
        PLA Normal, Month 7, Below (N=163, 76)
    2
    1
        PLA Normal, Month 7, Above (N=163, 76)
    5
    4
        PLA Below, Month 2, Normal (N=2, 3)
    0
    2
        PLA Below, Month 2, Below (N=2, 3)
    2
    1
        PLA Below, Month 2, Above (N=2, 3)
    0
    0
        PLA Below, Month 7, Normal (N=2, 3)
    1
    0
        PLA Below, Month 7, Below (N=2, 3)
    1
    2
        PLA Below, Month 7, Above (N=2, 3)
    0
    0
        PLA Below, Month 7, Missing (N=2, 3)
    0
    1
        PLA Above, Month 2, Normal (N=3, 3)
    2
    1
        PLA Above, Month 2, Below (N=3, 3)
    0
    0
        PLA Above, Month 2, Above (N=3, 3)
    1
    2
        PLA Above, Month 7, Normal (N=3, 3)
    0
    0
        PLA Above, Month 7, Below (N=3, 3)
    0
    0
        PLA Above, Month 7, Above (N=3, 3)
    3
    3
        RBC Normal, Month 2, Normal (N=154, 82)
    149
    75
        RBC Normal, Month 2, Below (N=154, 82)
    0
    0
        RBC Normal, Month 2, Above (N=154, 82)
    5
    2
        RBC Normal, Month 2, Missing (N=154, 82)
    0
    5
        RBC Normal, Month 7, Normal (N=153, 80)
    148
    78
        RBC Normal, Month 7, Below (N=153, 80)
    2
    1
        RBC Normal, Month 7, Above (N=153, 80)
    3
    1
        RBC Below, Month 2, Normal (N=2, 0)
    2
    0
        RBC Below, Month 2, Below (N=2, 0)
    0
    0
        RBC Below, Month 2, Above (N=2, 0)
    0
    0
        RBC Below, Month 7, Normal (N=2, 0)
    2
    0
        RBC Below, Month 7, Below (N=2, 0)
    0
    0
        RBC Below, Month 7, Above (N=2, 0)
    0
    0
        RBC Above, Month 2, Normal (N=13, 2)
    7
    0
        RBC Above, Month 2, Below (N=13, 2)
    0
    0
        RBC Above, Month 2, Above (N=13, 2)
    6
    1
        RBC Above, Month 2, Missing (N=13, 2)
    0
    1
        RBC Above, Month 7, Normal (N=13, 2)
    7
    0
        RBC Above, Month 7, Below (N=13, 2)
    0
    0
        RBC Above, Month 7, Above (N=13, 2)
    6
    1
        RBC Above, Month 7, Missing (N=13, 2)
    0
    1
        WBC Normal, Month 2, Normal (N=155, 75)
    142
    62
        WBC Normal, Month 2, Below (N=155, 75)
    7
    3
        WBC Normal, Month 2, Above (N=155, 75)
    6
    4
        WBC Normal, Month 2, Missing (N=155, 75)
    0
    6
        WBC Normal, Month 7, Normal (N=154, 73)
    133
    66
        WBC Normal, Month 7, Below (N=154, 73)
    4
    2
        WBC Normal, Month 7, Above (N=154, 73)
    17
    4
        WBC Normal, Month 7, Missing (N=154, 73)
    0
    1
        WBC Below, Month 2, Normal (N=4, 2)
    4
    1
        WBC Below, Month 2, Below (N=4, 2)
    0
    1
        WBC Below, Month 2, Above (N=4, 2)
    0
    0
        WBC Below, Month 7, Normal (N=4, 2)
    4
    2
        WBC Below, Month 7, Below (N=4, 2)
    0
    0
        WBC Below, Month 7, Above (N=4, 2)
    0
    0
        WBC Above, Month 2, Normal (N=10, 7)
    10
    7
        WBC Above, Month 2, Below (N=10, 7)
    0
    0
        WBC Above, Month 2, Above (N=10, 7)
    0
    0
        WBC Above, Month 7, Normal (N=10, 7)
    9
    6
        WBC Above, Month 7, Below (N=10, 7)
    0
    0
        WBC Above, Month 7, Above (N=10, 7)
    1
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited AEs: during the 7-day (Days 0-6) post-vaccination period. Unsolicited AEs: during the 30-day (Days 0-29) post-vaccination period. SAEs: Throughout the entire study period (active phase and extended safety follow-up): up to Month 12
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    9.1
    Reporting groups
    Reporting group title
    Engerix-B Group
    Reporting group description
    		 Healthy male subjects between and including 10 to 18 years of age at the time of the first vaccination, who were administered 3 doses of Engerix-B (HBV) vaccine, intramuscularly into the deltoid region of the non-dominant arm, according to a 0, 1 and 6-month schedule. The subjects were followed up for 7 months after the first dose and an additional telephone contact was foreseen at Month 12.

    Reporting group title
    Cervarix Group
    Reporting group description
    		 Healthy male subjects between and including 10 to 18 years of age at the time of the first vaccination, who were administered 3 doses of Cervarix (HPV-16/18 L1 VLP AS04) vaccine, intramuscularly into the deltoid region of the non-dominant arm, according to a 0, 1 and 6-month schedule. The subjects were followed up for 7 months after the first dose and an additional telephone contact was foreseen at Month 12.

    Serious adverse events
    		 Engerix-B Group Cervarix Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 89 (1.12%)
    3 / 181 (1.66%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Epilepsy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 181 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Crohn’s disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 181 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteochondrosis
    Additional description: This serious adverse event was recorded during the ESFU phase, which only included subjects that could have been contacted by telephone for the Safety follow-up at Month 12, hence the number of participants at risk is different.
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 181 (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
    Appendicitis
    Additional description: This serious adverse event was recorded during the ESFU phase, which only included subjects that could have been contacted by telephone for the Safety follow-up at Month 12, hence the number of participants at risk is different.
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 181 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Engerix-B Group Cervarix Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    73 / 89 (82.02%)
    170 / 181 (93.92%)
    Nervous system disorders
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    40 / 89 (44.94%)
    82 / 181 (45.30%)
         occurrences all number
    56
    131
    General disorders and administration site conditions
    Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    19 / 89 (21.35%)
    39 / 181 (21.55%)
         occurrences all number
    24
    56
    Pain
         subjects affected / exposed
    42 / 89 (47.19%)
    159 / 181 (87.85%)
         occurrences all number
    61
    130
    Swelling
         subjects affected / exposed
    7 / 89 (7.87%)
    36 / 181 (19.89%)
         occurrences all number
    8
    56
    Fatigue
    alternative assessment type: Non-systematic
         subjects affected / exposed
    42 / 89 (47.19%)
    82 / 181 (45.30%)
         occurrences all number
    61
    130
    Gastrointestinal disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    14 / 89 (15.73%)
    40 / 181 (22.10%)
         occurrences all number
    19
    61
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    15 / 89 (16.85%)
    51 / 181 (28.18%)
         occurrences all number
    29
    87
    Rash
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 89 (5.62%)
    16 / 181 (8.84%)
         occurrences all number
    5
    20
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 89 (11.24%)
    31 / 181 (17.13%)
         occurrences all number
    13
    38
    Myalgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    23 / 89 (25.84%)
    88 / 181 (48.62%)
         occurrences all number
    32
    142
    Infections and infestations
    Nasopharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 89 (3.37%)
    12 / 181 (6.63%)
         occurrences all number
    3
    13

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Nov 2006
    Human papillomavirus (HPV) infection has been clearly established as the central cause of cervical cancer. GlaxoSmithKline (GSK) Biological has developed a virus-like particle (VLP) vaccine against the oncogenic types HPV-16 and HPV-18 (which are the most common oncogenic HPV types, found in approximately 70% of all cervical cancers) formulated with the AS04 adjuvant system. AS04 is comprised of aluminum salts and 3-O-desacyl-4’-monophosphoryl lipid A (MPL). This vaccine (HPV-16/18 L1/AS04) has been shown to be safe and immunogenic in previous trials, and has prevented incident and persistent HPV 16/18 infection and their associated lesions in women in study 580299/001 (HPV-001).

    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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