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    Clinical Trial Results:
    A phase IIIb, randomized, open, multicentre study to evaluate the immunogenicity and safety of GlaxoSmithKline Biologicals’ HPV-16/18 L1 VLP AS04 vaccine (Cervarix™) co-administrated with GlaxoSmithKline Biologicals’ Hepatitis B vaccine (Engerix-B™) in healthy female subjects aged 9 - 15 years.

    Summary
    EudraCT number
    		 2007-007783-14
    Trial protocol
    		 NL   SE  
    Global end of trial date
    08 Jan 2010

    Results information
    Results version number
    		 v1
    This version publication date
    11 May 2016
    First version publication date
    22 Nov 2014
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    111507
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00652938
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l'Institut 89, Rixensart, Belgium, 1330-B
    Public contact
    Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, 044 2089904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, 044 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
    11 May 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Aug 2009
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jan 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    •To demonstrate non-inferiority of the hepatitis B immune response at Month 7 when hepatitis B vaccine is co-administered with HPV-16/18 vaccine at Months 0, 1 and 6 (HPV+HepB group) as compared to when hepatitis B vaccine is administered alone at Months 0, 1 and 6 (HepB group). •To demonstrate non-inferiority of the HPV immune response at Month 7 when the HPV-16/18 vaccine is co-administered with hepatitis B vaccine (HPV+HepB group) as compared to when the HPV-16/18 vaccine is administered alone (HPV group).
    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
    09 Apr 2008
    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
    Netherlands: 325
    Country: Number of subjects enrolled
    Sweden: 419
    Worldwide total number of subjects
    744
    EEA total number of subjects
    744
    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)
    744
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 744
    Number of subjects completed
    		 741

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 No vaccination received: 3
    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cervarix&Engerix Group
    Arm description
    		 Subjects received 3 doses of Cervarix™ (Human Papillomavirus [HPV] vaccine) co-administered with Engerix™ (Hepatitis B [HBV] vaccine) according to a 0, 1, 6-month schedule.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    HPV Vaccine (GSK580299) Cervarix TM,Engerix B
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 3 doses of Cervarix™ (Human Papillomavirus [HPV] vaccine) co-administered with Engerix™ (Hepatitis B [HBV] vaccine) according to a 0, 1, 6-month schedule.

    Arm title
    		 Cervarix Group
    Arm description
    		 Subjects received 3 doses of Cervarix™ (Human Papillomavirus [HPV] vaccine) according to a 0, 1, 6-month schedule.
    Arm type
    		 Experimental

    Investigational medicinal product name
    HPV Vaccine (GSK580299) Cervarix TM
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 3 doses of Cervarix™ (Human Papillomavirus [HPV] vaccine) according to a 0, 1, 6-month schedule.

    Arm title
    		 Engerix Group
    Arm description
    		 Subjects received 3 doses of Engerix™ (Hepatitis B [HBV] vaccine) according to a 0, 1, 6-month schedule.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Engerix B
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 3 doses of Engerix™ (Hepatitis B [HBV] vaccine) according to a 0, 1, 6-month schedule.

    Number of subjects in period 1 [1]
    		Cervarix&Engerix Group Cervarix Group Engerix Group
    Started
    247
    247
    247
    Completed
    246
    240
    242
    Not completed
    1
    7
    5
         Consent withdrawn by subject
    -
    6
    1
         Fear of blood sampling
    -
    1
    -
         Adverse event, non-fatal
    1
    -
    2
         Lost to follow-up
    -
    -
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: While the total numbers of subjects enrolled in the study was 744, the total number of subjects that entered the study was 741. The remaining 3 subjects received a subject number but no vaccine dose and were therefore excluded from the analysis and group assignment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cervarix&Engerix Group
    Reporting group description
    		 Subjects received 3 doses of Cervarix™ (Human Papillomavirus [HPV] vaccine) co-administered with Engerix™ (Hepatitis B [HBV] vaccine) according to a 0, 1, 6-month schedule.

    Reporting group title
    Cervarix Group
    Reporting group description
    		 Subjects received 3 doses of Cervarix™ (Human Papillomavirus [HPV] vaccine) according to a 0, 1, 6-month schedule.

    Reporting group title
    Engerix Group
    Reporting group description
    		 Subjects received 3 doses of Engerix™ (Hepatitis B [HBV] vaccine) according to a 0, 1, 6-month schedule.

    Reporting group values
    		 Cervarix&Engerix Group Cervarix Group Engerix Group Total
    Number of subjects
    		 247 247 247 741
    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
        median (standard deviation)
    		 11.4 ( 2.17 ) 11.3 ( 2.14 ) 11.4 ( 2.17 ) -
    Gender categorical
    Units: Subjects
        Female
    		 247 247 247 741
        Male
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Cervarix&Engerix Group
    Reporting group description
    		 Subjects received 3 doses of Cervarix™ (Human Papillomavirus [HPV] vaccine) co-administered with Engerix™ (Hepatitis B [HBV] vaccine) according to a 0, 1, 6-month schedule.

    Reporting group title
    Cervarix Group
    Reporting group description
    		 Subjects received 3 doses of Cervarix™ (Human Papillomavirus [HPV] vaccine) according to a 0, 1, 6-month schedule.

    Reporting group title
    Engerix Group
    Reporting group description
    		 Subjects received 3 doses of Engerix™ (Hepatitis B [HBV] vaccine) according to a 0, 1, 6-month schedule.

    Primary: Number of subjects with anti-Hepatitis B surface antigen (anti-HBs) Antibody Concentrations above the cut-off value for seroprotection

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    End point title
    		 Number of subjects with anti-Hepatitis B surface antigen (anti-HBs) Antibody Concentrations above the cut-off value for seroprotection [1] [2]
    End point description
    Only groups which had received the HBV vaccine were included in the analysis. Subjects included were seronegative for anti-HBs (antibody titer < 3.3 milli International Units per milliliter (mIU/mL)) prior to vaccination. Anti-HBs antibody cut-off value for seroprotection assessed included 10 mIU/mL.
    End point type
    Primary
    End point timeframe
    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
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only groups which had received the HBV vaccine were included in the analysis.
    End point values
    		 Cervarix&Engerix Group Engerix Group
    Number of subjects analysed
    194
    181
    Units: Subjects
    190
    181
    No statistical analyses for this end point

    Primary: Number of Subjects With Anti-human Papillomavirus 16 and 18 (Anti-HPV-16 and Anti-HPV-18) Antibody Concentrations Above the Cut-off Value for seroconversion

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    End point title
    		 Number of Subjects With Anti-human Papillomavirus 16 and 18 (Anti-HPV-16 and Anti-HPV-18) Antibody Concentrations Above the Cut-off Value for seroconversion [3] [4]
    End point description
    Only groups which had received the HPV vaccine were included in the analysis. Anti-HPV-16 antibody cut-off value assessed included 8 Enzyme-linked Immunosorbent Assay (ELISA) units per milliliter (EL.U/mL) and anti-HPV-18 antibody cut-off value assessed included 7 EL.U/mL. Subjects included were seronegative for anti-HPV-16 (antibody titer < 8 EL.U/mL) and anti-HPV-18 (antibody titer < 7 EL.U/mL) prior to vaccination.
    End point type
    Primary
    End point timeframe
    Month 7
    Notes
    [3] - 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
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only groups which had received the HPV vaccine were included in the analysis.
    End point values
    		 Cervarix&Engerix Group Cervarix Group
    Number of subjects analysed
    207
    202
    Units: Subjects
        Anti-HPV-16 (N= 207; 200)
    205
    200
        Anti-HPV-18 (N= 200; 202)
    199
    202
    No statistical analyses for this end point

    Primary: Anti-HPV-16/18 antibody titres

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    End point title
    		 Anti-HPV-16/18 antibody titres [5] [6]
    End point description
    Antibody titers for Anti-HPV-16 and Anti-HPV-18 are expressed as Geometric Mean Titers (GMTs). Only groups which had received the HPV vaccine were included in the analysis. Subjects included were seronegative for anti-HPV-16 (antibody titer < 8 EL.U/mL) and anti-HPV-18 (antibody titer < 7 EL.U/mL) prior to vaccination.
    End point type
    Primary
    End point timeframe
    Month 7
    Notes
    [5] - 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
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only groups which had received the HPV vaccine were included in the analysis.
    End point values
    		 Cervarix&Engerix Group Cervarix Group
    Number of subjects analysed
    207
    202
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-HPV-16 (N=207; 200)
    19819.8 (16856.9 to 23303.6)
    21712.6 (19460.2 to 24225.6)
        Anti-HPV-18 (N=200; 202)
    8835.1 (7636.3 to 10222.1)
    8838.6 (7948.5 to 9828.4)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Anti-HBs Antibody Concentrations Above the Cut-off Value for Seroconversion

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    End point title
    		 Number of Subjects With Anti-HBs Antibody Concentrations Above the Cut-off Value for Seroconversion [7]
    End point description
    Only groups which had received the HBV vaccine were included in the analysis. Subjects included were seronegative for anti-HBs (antibody titer < 3.3 mIU/mL) prior to vaccination. Anti-HBs antibody cut-off value for seroconversion assessed included 3.3 mIU/mL.
    End point type
    Secondary
    End point timeframe
    Month 7
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only groups which had received the HBV vaccine were included in the analysis.
    End point values
    		 Cervarix&Engerix Group Engerix Group
    Number of subjects analysed
    194
    181
    Units: Subjects
    192
    181
    No statistical analyses for this end point

    Secondary: Anti-HBs Antibody Titres

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    End point title
    		 Anti-HBs Antibody Titres [8]
    End point description
    Antibody titers for anti-HBs are given as Geometric Mean Titers (GMTs) in mIU/mL. Only groups which had received the HBV vaccine were included in the analysis. Subjects included were seronegative for anti-HBs (antibody titer < 3.3 mIU/mL) prior to vaccination.
    End point type
    Secondary
    End point timeframe
    Month 7
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only groups which had received the HBV vaccine were included in the analysis.
    End point values
    		 Cervarix&Engerix Group Engerix Group
    Number of subjects analysed
    194
    181
    Units: mIU/mL
        geometric mean (confidence interval 95%)
    1280.9 (973.3 to 1685.7)
    3107.7 (2473.1 to 3905.1)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Anti-HPV-16 and Anti-HPV-18 Antibody Concentrations Above the Cut-off Value for Seroconversion

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    End point title
    		 Number of Subjects With Anti-HPV-16 and Anti-HPV-18 Antibody Concentrations Above the Cut-off Value for Seroconversion [9]
    End point description
    Only groups which had received the HPV vaccine were included in the analysis. Anti-HPV-16 antibody cut-off value assessed included 8 Enzyme-linked Immunosorbent Assay (ELISA) units per milliliter (EL.U/mL) and anti-HPV-18 antibody cut-off value assessed included 7 EL.U/mL. Subjects included were seronegative for anti-HPV-16 (antibody titer < 8 EL.U/mL) and anti-HPV-18 (antibody titer < 7 EL.U/mL) prior to vaccination.
    End point type
    Secondary
    End point timeframe
    Month 2
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only groups which had received the HPV vaccine were included in the analysis.
    End point values
    		 Cervarix&Engerix Group Cervarix Group
    Number of subjects analysed
    207
    201
    Units: Subjects
        Anti-HPV-16 (N= 207; 199)
    207
    199
        Anti-HPV-18 (N= 200; 201)
    200
    201
    No statistical analyses for this end point

    Secondary: Anti-HPV-16/18 Antibody Titres

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    End point title
    		 Anti-HPV-16/18 Antibody Titres [10]
    End point description
    Antibody titers for Anti-HPV-16 and Anti-HPV-18 are expressed as Geometric Mean Titers (GMTs). Only groups which had received the HPV vaccine were included in the analysis. Subjects included were seronegative for anti-HPV-16 (antibody titer < 8 EL.U/mL) and anti-HPV-18 (antibody titer < 7 EL.U/mL) prior to vaccination.
    End point type
    Secondary
    End point timeframe
    Month 2
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only groups which had received the HPV vaccine were included in the analysis.
    End point values
    		 Cervarix&Engerix Group Cervarix Group
    Number of subjects analysed
    207
    201
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-HPV-16 (N= 207; 199)
    4894.7 (4472.5 to 5356.7)
    5069.2 (4581.2 to 5609.1)
        Anti-HPV-18 (N= 200; 201)
    4790.4 (4338.9 to 5288.8)
    4663.8 (4228.2 to 5144.3)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Anti-Hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Above the Cut-off Value for Seroconversion

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    End point title
    		 Number of Subjects With Anti-Hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Above the Cut-off Value for Seroconversion [11]
    End point description
    Only groups which had received the HBV vaccine were included in the analysis. Subjects included were seronegative for anti-HBs (antibody titer < 3.3 mIU/mL) prior to vaccination. Anti-HBs antibody cut-off value for seroconversion assessed included 3.3 mIU/mL.
    End point type
    Secondary
    End point timeframe
    Month 2
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only groups which had received the HBV vaccine were included in the analysis.
    End point values
    		 Cervarix&Engerix Group Engerix Group
    Number of subjects analysed
    194
    178
    Units: Subjects
    165
    168
    No statistical analyses for this end point

    Secondary: Number of Subjects With Anti-Hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Above the Cut-off Value for Seroprotection

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    End point title
    		 Number of Subjects With Anti-Hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Above the Cut-off Value for Seroprotection [12]
    End point description
    Only groups which had received the HBV vaccine were included in the analysis. Subjects included were seronegative for anti-HBs (antibody titer < 3.3 milli International Units per milliliter (mIU/mL)) prior to vaccination vaccination. Anti-HBs antibody cut-off value for seroprotection assessed included 10 mIU/mL.
    End point type
    Secondary
    End point timeframe
    Month 2
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only groups which had received the HBV vaccine were included in the analysis.
    End point values
    		 Cervarix&Engerix Group Engerix Group
    Number of subjects analysed
    194
    178
    Units: Subjects
    128
    142
    No statistical analyses for this end point

    Secondary: Anti-HBs antibody titers

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    End point title
    		 Anti-HBs antibody titers [13]
    End point description
    Anti-HBs antibody titers are given as GMTs in mIU/mL. Only groups which had received the HBV vaccine were included in the analysis. Subjects included were seronegative for anti-HBs (antibody titer < 3.3 mIU/mL) prior to vaccination.
    End point type
    Secondary
    End point timeframe
    Month 2
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only groups which had received the HBV vaccine were included in the analysis.
    End point values
    		 Cervarix&Engerix Group Engerix Group
    Number of subjects analysed
    194
    178
    Units: mIU/mL
        geometric mean (confidence interval 95%)
    13.6 (11.4 to 16.2)
    26.9 (22.1 to 32.8)
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Any Solicited Local Symptoms

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    End point title
    		 Number of Subjects Reporting Any Solicited Local Symptoms
    End point description
    Solicited local symptoms included injection site pain, redness and swelling. Any solicited local symptom is occurrence of a symptom regardless of its intensity.
    End point type
    Secondary
    End point timeframe
    During the 7-day period (Days 0 - 6) following vaccination
    End point values
    		 Cervarix&Engerix Group Cervarix Group Engerix Group
    Number of subjects analysed
    247
    245
    246
    Units: Subjects
        Pain
    244
    238
    182
        Redness
    122
    127
    63
        Swelling
    120
    111
    47
    No statistical analyses for this end point

    Secondary: Number of subjects reporting grade 3 solicited local symptoms

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    End point title
    		 Number of subjects reporting grade 3 solicited local symptoms
    End point description
    Solicited local symptoms include injection site pain, redness and swelling. Grade 3 pain is pain that prevented normal everyday activities. Grade 3 redness is redness that was > 50 mm. Grade 3 swelling is swelling that was > 50 mm.
    End point type
    Secondary
    End point timeframe
    During the 7-day period (Days 0-6) following vaccination
    End point values
    		 Cervarix&Engerix Group Cervarix Group Engerix Group
    Number of subjects analysed
    247
    245
    246
    Units: Subjects
        Pain
    54
    35
    4
        Redness
    12
    5
    1
        Swelling
    17
    13
    1
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any solicited general symptoms

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    End point title
    		 Number of subjects reporting any solicited general symptoms
    End point description
    Solicited general symptoms included arthralgia, fatigue, gastrointestinal, headache, myalgia, rash, temperature in degrees celsius (axillary) and urticaria. Any solicited general symptom is the occurence of the symptom regardless of its intensity or relationship to study vaccination.
    End point type
    Secondary
    End point timeframe
    During the 7-day (Days 0-6) period following vaccination
    End point values
    		 Cervarix&Engerix Group Cervarix Group Engerix Group
    Number of subjects analysed
    247
    245
    246
    Units: Subjects
        Arthralgia
    31
    23
    26
        Fatigue
    130
    107
    104
        Gastrointestinal
    65
    67
    70
        Headache
    136
    131
    129
        Myalgia
    55
    55
    53
        Rash
    10
    14
    11
        Temperature
    32
    23
    36
        Urticaria
    5
    5
    6
    No statistical analyses for this end point

    Secondary: Number of subjects reporting grade 3 solicited general symptoms

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    End point title
    		 Number of subjects reporting grade 3 solicited general symptoms
    End point description
    Solicited general symptoms included arthralgia, fatigue, gastrointestinal, headache, myalgia, rash, temperature in degrees celsius (axillary) and urticaria. Grade 3 arthralgia, fatigue, gastrointestinal, headache, myalgia and rash were symptoms that prevented normal activity. Grade 3 temperature was temperature > 39 degrees Celsius. Grade 3 urticaria was urticaria distributed on at least 4 body areas.
    End point type
    Secondary
    End point timeframe
    During the 7-day (Days 0-6) period following vaccination
    End point values
    		 Cervarix&Engerix Group Cervarix Group Engerix Group
    Number of subjects analysed
    247
    245
    246
    Units: Subjects
        Arthralgia
    1
    0
    0
        Fatigue
    8
    8
    9
        Gastrointestinal
    4
    6
    8
        Headache
    13
    11
    4
        Myalgia
    2
    2
    1
        Rash
    0
    1
    0
        Temperature
    3
    2
    3
        Urticaria
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Number of subjects reporting related solicited general symptoms

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    End point title
    		 Number of subjects reporting related solicited general symptoms
    End point description
    Solicited general symptoms included arthralgia, fatigue, gastrointestinal, headache, myalgia, rash, temperature in degrees celsius (axillary) and urticaria. Related solicited general symptoms were those symptoms assessed by the investigators as related to the study vaccination.
    End point type
    Secondary
    End point timeframe
    During the 7-day period (Days 0 - 6) following vaccination
    End point values
    		 Cervarix&Engerix Group Cervarix Group Engerix Group
    Number of subjects analysed
    247
    245
    246
    Units: Subjects
        Arthralgia
    18
    16
    12
        Fatigue
    89
    70
    51
        Gastrointestinal
    35
    40
    25
        Headache
    77
    71
    57
        Myalgia
    40
    40
    20
        Rash
    8
    8
    4
        Temperature
    13
    10
    6
        Urticaria
    4
    4
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects reporting any, grade 3 and causally related to vaccination unsolicited adverse events (AEs)

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    End point title
    		 Number of Subjects reporting any, grade 3 and causally related to vaccination unsolicited adverse events (AEs)
    End point description
    Unsolicited AE covers any AE reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Grade 3 AE was an AE that prevented normal activities. Related AE was an AE that was assessed by the investigator as related to the study vaccination.
    End point type
    Secondary
    End point timeframe
    During the 30-day period (Days 0 - 29) following any vaccination
    End point values
    		 Cervarix&Engerix Group Cervarix Group Engerix Group
    Number of subjects analysed
    247
    247
    247
    Units: Subjects
        Any AEs
    130
    99
    99
        Grade 3 AEs
    19
    19
    16
        Related AEs
    43
    19
    25
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any and causally related to vaccination serious adverse events (SAEs)

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    End point title
    		 Number of subjects reporting any and causally related to vaccination serious adverse events (SAEs)
    End point description
    SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. Related SAEs were SAEs assessed by the investigators as related to the vaccination. * Grade 3 SAEs were not assessed.
    End point type
    Secondary
    End point timeframe
    Throughout the active phase of the study (up to Month 7).
    End point values
    		 Cervarix&Engerix Group Cervarix Group Engerix Group
    Number of subjects analysed
    247
    247
    247
    Units: Subjects
        Any
    2
    1
    0
        Related
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any and causally related to vaccination SAEs

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    End point title
    		 Number of subjects reporting any and causally related to vaccination SAEs
    End point description
    SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. * Grade 3 SAEs were not assessed.
    End point type
    Secondary
    End point timeframe
    Throughout the safety follow-up (month 7 up to Month 12).
    End point values
    		 Cervarix&Engerix Group Cervarix Group Engerix Group
    Number of subjects analysed
    247
    247
    247
    Units: Subjects
        Any
    1
    1
    1
        Related
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects reporting medically significant conditions

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    End point title
    		 Number of subjects reporting medically significant conditions
    End point description
    Medically significant conditions (i.e., AEs prompting emergency room or physician visits that are not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or SAEs that are not related to common diseases).
    End point type
    Secondary
    End point timeframe
    Throughout the active phase of the study (up to Month 7)
    End point values
    		 Cervarix&Engerix Group Cervarix Group Engerix Group
    Number of subjects analysed
    247
    247
    247
    Units: Subjects
    31
    28
    42
    No statistical analyses for this end point

    Secondary: Number of subjects reporting medically significant conditions

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    End point title
    		 Number of subjects reporting medically significant conditions
    End point description
    Medically significant conditions (i.e., AEs prompting emergency room or physician visits that are not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or SAEs that are not related to common diseases).
    End point type
    Secondary
    End point timeframe
    Throughout the safety follow-up (month 7 up to Month 12)
    End point values
    		 Cervarix&Engerix Group Cervarix Group Engerix Group
    Number of subjects analysed
    247
    247
    247
    Units: Subjects
    0
    2
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited symptoms were collected during the 7-day period (Days 0 - 6) following vaccination, unsolicited AEs during the 30-day period (Days 0 - 29) following any vaccination and SAEs during the whole study period, up to Month 12.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Cervarix&Engerix Group
    Reporting group description
    		 Subjects received 3 doses of Cervarix™ (Human Papillomavirus [HPV] vaccine) co-administered with Engerix™ (Hepatitis B [HBV] vaccine) according to a 0, 1, 6-month schedule.

    Reporting group title
    Cervarix Group
    Reporting group description
    		 Subjects received 3 doses of Cervarix™ (Human Papillomavirus [HPV] vaccine) according to a 0, 1, 6-month schedule.

    Reporting group title
    Engerix Group
    Reporting group description
    		 Subjects received 3 doses of Engerix™ (Hepatitis B [HBV] vaccine) according to a 0, 1, 6-month schedule.

    Serious adverse events
    		 Cervarix&Engerix Group Cervarix Group Engerix Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 247 (1.21%)
    2 / 247 (0.81%)
    1 / 247 (0.40%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Traumatic brain injury
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 247 (0.00%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 247 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 247 (0.40%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 247 (0.00%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 247 (0.40%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 247 (0.00%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cervarix&Engerix Group Cervarix Group Engerix Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    244 / 247 (98.79%)
    238 / 247 (96.36%)
    182 / 247 (73.68%)
    General disorders and administration site conditions
    Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    244 / 247 (98.79%)
    238 / 247 (96.36%)
    182 / 247 (73.68%)
         occurrences all number
    244
    238
    182
    Redness
    alternative assessment type: Systematic
         subjects affected / exposed
    122 / 247 (49.39%)
    127 / 247 (51.42%)
    63 / 247 (25.51%)
         occurrences all number
    122
    127
    63
    Swelling
    alternative assessment type: Systematic
         subjects affected / exposed
    120 / 247 (48.58%)
    111 / 247 (44.94%)
    47 / 247 (19.03%)
         occurrences all number
    120
    111
    47
    Arthralgia
    alternative assessment type: Systematic
         subjects affected / exposed
    31 / 247 (12.55%)
    23 / 247 (9.31%)
    26 / 247 (10.53%)
         occurrences all number
    31
    23
    26
    Fatigue
    alternative assessment type: Systematic
         subjects affected / exposed
    130 / 247 (52.63%)
    107 / 247 (43.32%)
    104 / 247 (42.11%)
         occurrences all number
    130
    107
    104
    Gastrointestinal
    alternative assessment type: Systematic
         subjects affected / exposed
    65 / 247 (26.32%)
    67 / 247 (27.13%)
    70 / 247 (28.34%)
         occurrences all number
    65
    67
    70
    Headache (Solicited Symptom)
    alternative assessment type: Systematic
         subjects affected / exposed
    136 / 247 (55.06%)
    131 / 247 (53.04%)
    129 / 247 (52.23%)
         occurrences all number
    136
    131
    129
    Myalgia
    alternative assessment type: Systematic
         subjects affected / exposed
    55 / 247 (22.27%)
    55 / 247 (22.27%)
    53 / 247 (21.46%)
         occurrences all number
    55
    55
    53
    Rash
    alternative assessment type: Systematic
         subjects affected / exposed
    10 / 247 (4.05%)
    14 / 247 (5.67%)
    11 / 247 (4.45%)
         occurrences all number
    10
    14
    11
    Temperature
    alternative assessment type: Systematic
         subjects affected / exposed
    32 / 247 (12.96%)
    23 / 247 (9.31%)
    36 / 247 (14.57%)
         occurrences all number
    32
    23
    36
    Nasopharyngitis
         subjects affected / exposed
    29 / 247 (11.74%)
    27 / 247 (10.93%)
    26 / 247 (10.53%)
         occurrences all number
    29
    27
    26
    Headache (AE)
         subjects affected / exposed
    17 / 247 (6.88%)
    19 / 247 (7.69%)
    9 / 247 (3.64%)
         occurrences all number
    17
    19
    9
    Oropharyngeal pain
         subjects affected / exposed
    13 / 247 (5.26%)
    13 / 247 (5.26%)
    7 / 247 (2.83%)
         occurrences all number
    13
    13
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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