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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 co-administered with GlaxoSmithKline Biologicals’ inactivated hepatitis A and hepatitis B vaccine adsorbed (Twinrix® Paediatric) in healthy female subjects aged 9–15 years.

    Summary
    EudraCT number
    		 2007-004347-30
    Trial protocol
    		 SE   HU   DK  
    Global end of trial date
    28 Apr 2009

    Results information
    Results version number
    		 v2(current)
    This version publication date
    16 Apr 2021
    First version publication date
    22 Nov 2014
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Minor corrections in safety section.

    Trial information

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    Trial identification
    Sponsor protocol code
    110886
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00578227
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l’Institut 89, Rixensart, Belgium, B-1330
    Public contact
    Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, 44 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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Apr 2009
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Apr 2009
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Apr 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    •To demonstrate non-inferiority of the hepatitis A immune response when HAB is co-administered with HPV-16/18 vaccine at Month 0, 1 and 6 compared to when HAB is administered alone at Month 0, 1 and 6. •To demonstrate non-inferiority of the hepatitis B immune response in terms of proportion of subjects who are seroprotected for anti-HBs at Month 7 when HAB is co-administered with HPV-16/18 vaccine at Month 0, 1 and 6 compared to when HAB is administered alone at Month 0, 1 and 6. • To demonstrate non-inferiority of the HPV-16/18 immune response at Month 7 when the HPV-16/18 vaccine is co-administered with HAB compared to when the HPV-16/18 vaccine is administered alone.
    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
    12 Dec 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 220
    Country: Number of subjects enrolled
    Canada: 113
    Country: Number of subjects enrolled
    Denmark: 213
    Country: Number of subjects enrolled
    Hungary: 268
    Worldwide total number of subjects
    814
    EEA total number of subjects
    701
    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)
    814
    Adolescents (12-17 years)
    0
    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
    		 Although the total number of enrolled subjects for this study was 814, one subject did not receive any study vaccine and was therefore not considered as started in the 'Participant Flow' section.

    Pre-assignment period milestones
    Number of subjects started
    		 814
    Number of subjects completed
    		 813 [1]

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 No vaccination received: 1
    Notes
    [1] - The number of subjects reported to be in the pre-assignment period is not consistent with the number starting period 1. It is expected that the number completing the pre-assignment period are also present in the arms in period 1.
    Justification: Although the total number of enrolled subjects for this study was 814, 1 subject did not receive any study vaccine and was therefore not considered as having started the study.
    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
    No

    Arm title
    		 Cervarix™ & Twinrix™ Group
    Arm description
    		 Subjects received 3 doses of Human Papilloma Virus (HPV) vaccine co-administered with combined Hepatitis A & Hepatitis B (HAB) vaccine (Months 0, 1 & 6).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cervarix™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The vaccine was administered at Day 0, Month 1 and Month 6. Vaccines were administered intramuscularly in the deltoid region of the non-dominant arm when administered alone or in both arms when co-administered.

    Investigational medicinal product name
    Twinrix™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The vaccine was administered at Day 0, at Month 1 and Month 6. Vaccines were administered intramuscularly in the deltoid region of the non-dominant arm when administered alone or in both arms when co-administered.

    Arm title
    		 Cervarix™ Group
    Arm description
    		 Subjects received 3 doses of HPV vaccine (Months 0, 1 & 6).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cervarix™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The vaccine was administered at Day 0, Month 1 and Month 6. Vaccines were administered intramuscularly in the deltoid region of the non-dominant arm when administered alone or in both arms when co-administered.

    Arm title
    		 Twinrix™ Group
    Arm description
    		 Subjects received 3 doses of HAB vaccine (Months 0, 1 & 6).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Twinrix™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The vaccine was administered at Day 0, at Month 1 and Month 6. Vaccines were administered intramuscularly in the deltoid region of the non-dominant arm when administered alone or in both arms when co-administered.

    Number of subjects in period 1
    		Cervarix™ & Twinrix™ Group Cervarix™ Group Twinrix™ Group
    Started
    272
    270
    271
    Completed
    267
    268
    267
    Not completed
    5
    2
    4
         Consent withdrawn by subject
    5
    1
    3
         Lost to follow-up
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Cervarix™ & Twinrix™ Group
    Reporting group description
    		 Subjects received 3 doses of Human Papilloma Virus (HPV) vaccine co-administered with combined Hepatitis A & Hepatitis B (HAB) vaccine (Months 0, 1 & 6).

    Reporting group title
    Cervarix™ Group
    Reporting group description
    		 Subjects received 3 doses of HPV vaccine (Months 0, 1 & 6).

    Reporting group title
    Twinrix™ Group
    Reporting group description
    		 Subjects received 3 doses of HAB vaccine (Months 0, 1 & 6).

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Although the total number of enrolled subjects for this study was 814, 1 subject did not receive any study vaccine and was therefore not considered as having started the study.
    Reporting group values
    		 Cervarix™ & Twinrix™ Group Cervarix™ Group Twinrix™ Group Total
    Number of subjects
    		 272 270 271
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        geometric mean (standard deviation)
    		 11.2 ( 2.04 ) 11.2 ( 2.02 ) 11.2 ( 1.99 ) -
    Gender categorical
    Units: Subjects
        Female
    		 272 270 271 813
        Male
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Cervarix™ & Twinrix™ Group
    Reporting group description
    		 Subjects received 3 doses of Human Papilloma Virus (HPV) vaccine co-administered with combined Hepatitis A & Hepatitis B (HAB) vaccine (Months 0, 1 & 6).

    Reporting group title
    Cervarix™ Group
    Reporting group description
    		 Subjects received 3 doses of HPV vaccine (Months 0, 1 & 6).

    Reporting group title
    Twinrix™ Group
    Reporting group description
    		 Subjects received 3 doses of HAB vaccine (Months 0, 1 & 6).

    Primary: Number of subjects seroconverted for anti-hepatitis A (anti-HAV) antibodies

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    End point title
    		 Number of subjects seroconverted for anti-hepatitis A (anti-HAV) antibodies [1] [2]
    End point description
    Seroconversion is defined as the appearance of anti-HAV antibodies [i.e., antibody titer greater than or equal to 15 milli-international units/milliliter (mIU/mL)] in the sera of subjects seronegative (antibody titer below 15 mIU/mL) 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
    [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: The analysis was only performed on subjects who had received HAB vaccination.
    End point values
    		 Cervarix™ & Twinrix™ Group Twinrix™ Group
    Number of subjects analysed
    240
    242
    Units: Subjects
    240
    242
    No statistical analyses for this end point

    Primary: Anti-Heptatis A (HAV) antibody titers.

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    End point title
    		 Anti-Heptatis A (HAV) antibody titers. [3] [4]
    End point description
    Titers are given as Geometric Mean Titers (GMTs) expressed as mIU/mL.
    End point type
    Primary
    End point timeframe
    At 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: The analysis was only performed on subjects who had received HAB vaccination.
    End point values
    		 Cervarix™ & Twinrix™ Group Twinrix™ Group
    Number of subjects analysed
    240
    242
    Units: mIU/mL
        geometric mean (confidence interval 95%)
    4504.2 (3993 to 5080.8)
    5288.4 (4713.3 to 5933.7)
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects seroprotected for anti-hepatitis B surface antigen (anti-HBs) antibodies [5] [6]
    End point description
    A subject seroprotected against HBs is a subject with antibody titers greater than or equal to 10 mIU/mL.
    End point type
    Primary
    End point timeframe
    At 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: The analysis was only performed on subjects who had received HAB vaccination.
    End point values
    		 Cervarix™ & Twinrix™ Group Twinrix™ Group
    Number of subjects analysed
    178
    161
    Units: Subjects
    175
    161
    No statistical analyses for this end point

    Primary: Number of subjects seroconverted for anti-human Papilloma virus 16 (anti-HPV-16) and anti-human Papilloma virus 18 (anti-HPV-18) antibodies

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    End point title
    		 Number of subjects seroconverted for anti-human Papilloma virus 16 (anti-HPV-16) and anti-human Papilloma virus 18 (anti-HPV-18) antibodies [7] [8]
    End point description
    Seroconversion is defined as the appearance of antibodies with titers greater than or equal to the predefined cut-off value in the serum of subject seronegative before vaccination. Cut-off values = 8 enzyme-linked immunosorbent assay units per milliliter (EL.U/mL) for anti-HPV-16 antibodies and 7 EL.U/mL for anti-HPV-18 antibodies.
    End point type
    Primary
    End point timeframe
    At Month 7
    Notes
    [7] - 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
    [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: The analysis was only performed on subjects who had received HPV vaccination.
    End point values
    		 Cervarix™ & Twinrix™ Group Cervarix™ Group
    Number of subjects analysed
    239
    241
    Units: Subjects
        Anti-HPV-16 (n= 229, 233)
    228
    223
        Anti-HPV-18 (n= 239, 241)
    238
    241
    No statistical analyses for this end point

    Primary: Anti-human Papilloma virus 16 (anti-HPV-16) and anti-human Papilloma virus 18 (anti-HPV-18) antibody titers

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    End point title
    		 Anti-human Papilloma virus 16 (anti-HPV-16) and anti-human Papilloma virus 18 (anti-HPV-18) antibody titers [9] [10]
    End point description
    Titers are given as Geometric Mean Titers (GMTs) expressed as Enzyme-linked Immunosorbent Assay Units Per Milliliter (EL.U/mL).
    End point type
    Primary
    End point timeframe
    At Month 7
    Notes
    [9] - 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
    [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: The analysis was only performed on subjects who had received HPV vaccination.
    End point values
    		 Cervarix™ & Twinrix™ Group Cervarix™ Group
    Number of subjects analysed
    239
    241
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-HPV-16 GMTs (n= 229, 233)
    22993.5 (20093.4 to 26312)
    26981.9 (23909.5 to 30449.1)
        Anti-HPV-18 GMTs (n= 239, 241)
    8671.2 (7651.7 to 9826.6)
    11182.7 (9924.8 to 12600.1)
    No statistical analyses for this end point

    Secondary: Anti-HBs antibody Titers

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    End point title
    		 Anti-HBs antibody Titers [11]
    End point description
    Titers are given as Geometric Mean Titers (GMTs) expressed as mIU/mL.
    End point type
    Secondary
    End point timeframe
    At Month 7
    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: The analysis was only performed on subjects who had received HAB vaccination.
    End point values
    		 Cervarix™ & Twinrix™ Group Twinrix™ Group
    Number of subjects analysed
    178
    161
    Units: mIU/mL
        geometric mean (confidence interval 95%)
    3136.5 (2436 to 4038.4)
    5646.5 (4481.3 to 7114.6)
    No statistical analyses for this end point

    Secondary: Number of subjects seroconverted for anti-HBs antibodies

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    End point title
    		 Number of subjects seroconverted for anti-HBs antibodies [12]
    End point description
    Seroconversion is defined as the appearance of anti-HBs antibodies (i.e., antibody titer greater than or equal to 3.3 mIU/mL) in the sera of subjects seronegative (with antibody titers below 3.3 mIU/mL) before vaccination.
    End point type
    Secondary
    End point timeframe
    At month 7
    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: The analysis was only performed on subjects who had received HAB vaccination.
    End point values
    		 Cervarix™ & Twinrix™ Group Twinrix™ Group
    Number of subjects analysed
    178
    161
    Units: Subjects
    175
    161
    No statistical analyses for this end point

    Secondary: Number of subjects seroconverted for anti-human Papilloma virus 16 (anti-HPV-16) and anti-human Papilloma virus 18 (anti-HPV-18) antibodies in vaccine recipients aged 9 years

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    End point title
    		 Number of subjects seroconverted for anti-human Papilloma virus 16 (anti-HPV-16) and anti-human Papilloma virus 18 (anti-HPV-18) antibodies in vaccine recipients aged 9 years [13]
    End point description
    Seroconversion is defined as the appearance of antibodies with titers greater than or equal to the predefined cut-off value in the serum of subject seronegative before vaccination. Cut-off values = 8 enzyme-linked immunosorbent assay units per milliliter (EL.U/mL) for anti-HPV-16 antibodies and 7 EL.U/mL for anti-HPV-18 antibodies. All 9-year subjects who received 3 doses of HPV vaccine alone or co-administered with HAB vaccine were included in this analysis.
    End point type
    Secondary
    End point timeframe
    At Month 7
    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: The analysis was only performed on subjects who had received HPV vaccination.
    End point values
    		 Cervarix™ Group
    Number of subjects analysed
    161
    Units: Subjects
        Anti-HPV-16 (n= 156)
    156
        Anti-HPV-18 (n= 161)
    161
    No statistical analyses for this end point

    Secondary: Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibody Titers in vaccine recipients aged 9 years

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    End point title
    		 Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibody Titers in vaccine recipients aged 9 years [14]
    End point description
    Titers are given as Geometric Mean Titers (GMTs) expressed as Enzyme-linked Immunosorbent Assay Units Per Milliliter (EL.U/mL). All 9-year subjects who received 3 doses of HPV vaccine alone or co-administered with HAB vaccine were included in this analysis.
    End point type
    Secondary
    End point timeframe
    At Month 7
    Notes
    [14] - 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: The analysis was only performed on subjects who had received HPV vaccination.
    End point values
    		 Cervarix™ Group
    Number of subjects analysed
    161
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-HPV-16 GMTs (n= 156)
    32170.2 (27985.5 to 36980.7)
        Anti-HPV-18 GMTs (n= 161)
    12257.1 (10644.6 to 14113.9)
    No statistical analyses for this end point

    Secondary: Number of subjects seroconverted for anti-HAV antibodies

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    End point title
    		 Number of subjects seroconverted for anti-HAV antibodies [15]
    End point description
    Seroconversion is defined as the appearance of anti-HAV antibodies (i.e., antibody titer greater than or equal to 15 mIU/mL) in the sera of subjects seronegative (antibody titer below 15 mIU/mL) before vaccination.
    End point type
    Secondary
    End point timeframe
    One month after the second dose of vaccine
    Notes
    [15] - 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: The analysis was only performed on subjects who had received HAB vaccination.
    End point values
    		 Cervarix™ & Twinrix™ Group Twinrix™ Group
    Number of subjects analysed
    113
    113
    Units: Subjects
    112
    112
    No statistical analyses for this end point

    Secondary: Anti-HAV antibody titers

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    End point title
    		 Anti-HAV antibody titers [16]
    End point description
    Titers are given as geometric mean titers (GMTs) expressed as mIU/mL.
    End point type
    Secondary
    End point timeframe
    One month after the second dose of vaccine
    Notes
    [16] - 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: The analysis was only performed on subjects who had received HAB vaccination.
    End point values
    		 Cervarix™ & Twinrix™ Group Twinrix™ Group
    Number of subjects analysed
    113
    113
    Units: mIU/mL
        geometric mean (confidence interval 95%)
    467 (374.4 to 582.5)
    513.9 (418.7 to 630.6)
    No statistical analyses for this end point

    Secondary: Number of subjects seroconverted and number of subjects seroprotected for anti-HBs antibodies

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    End point title
    		 Number of subjects seroconverted and number of subjects seroprotected for anti-HBs antibodies [17]
    End point description
    Seroconversion is defined as the appearance of anti-HBs antibodies (i.e., antibody titer greater than or equal to 3.3 mIU/mL) in the sera of subjects seronegative (with antibody titers below 3.3 mIU/mL) before vaccination. A seroprotected subject against HBs is a subject with antibody titers greater than or equal to 10 mIU/mL.
    End point type
    Secondary
    End point timeframe
    One month after the second dose of vaccine
    Notes
    [17] - 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: The analysis was only performed on subjects who had received HAB vaccination.
    End point values
    		 Cervarix™ & Twinrix™ Group Twinrix™ Group
    Number of subjects analysed
    70
    58
    Units: Subjects
        Seroconverted
    68
    56
        Seroprotected
    60
    53
    No statistical analyses for this end point

    Secondary: Anti-HBs antibody titers

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    End point title
    		 Anti-HBs antibody titers [18]
    End point description
    Titers are given as geometric mean titers (GMTs) expressed as mIU/mL.
    End point type
    Secondary
    End point timeframe
    One month after the second dose of vaccine
    Notes
    [18] - 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: The analysis was only performed on subjects who had received HAB vaccination.
    End point values
    		 Cervarix™ & Twinrix™ Group Twinrix™ Group
    Number of subjects analysed
    70
    58
    Units: mIU/mL
        geometric mean (confidence interval 95%)
    33.7 (24.9 to 45.8)
    43 (30.1 to 61.3)
    No statistical analyses for this end point

    Secondary: Number of subjects seroconverted for anti-human Papilloma virus 16 (anti-HPV-16) and anti-human Papilloma virus 18 (anti-HPV-18) antibodies

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    End point title
    		 Number of subjects seroconverted for anti-human Papilloma virus 16 (anti-HPV-16) and anti-human Papilloma virus 18 (anti-HPV-18) antibodies [19]
    End point description
    Seroconversion is defined as the appearance of antibodies with titers greater than or equal to the predefined cut-off value in the serum of subject seronegative before vaccination. Cut-off values assessed include 8 enzyme-linked immunosorbent assay units per milliliter (EL.U/mL) for anti-HPV-16 antibodies and 7 EL.U/mL for anti-HPV-18 antibodies.
    End point type
    Secondary
    End point timeframe
    One month after the second dose of vaccine
    Notes
    [19] - 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: The analysis was only performed on subjects who had received HPV vaccination.
    End point values
    		 Cervarix™ & Twinrix™ Group Cervarix™ Group
    Number of subjects analysed
    112
    112
    Units: Subjects
        Anti-HPV-16 (n=105, 107)
    105
    106
        Anti-HPV-18 (n= 112, 112)
    112
    111
    No statistical analyses for this end point

    Secondary: Anti-human Papilloma virus 16 (anti-HPV-16) and anti-human Papilloma virus 18 (anti-HPV-18) antibody titers

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    End point title
    		 Anti-human Papilloma virus 16 (anti-HPV-16) and anti-human Papilloma virus 18 (anti-HPV-18) antibody titers [20]
    End point description
    Titers are given as Geometric Mean Titers (GMTs) expressed as EL.U/mL.
    End point type
    Secondary
    End point timeframe
    One month after the second dose of vaccine
    Notes
    [20] - 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: The analysis was only performed on subjects who had received HPV vaccination.
    End point values
    		 Cervarix™ & Twinrix™ Group Cervarix™ Group
    Number of subjects analysed
    112
    112
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-HPV-16 GMTs (n= 105, 107)
    5215.2 (4598.2 to 5915)
    4967.2 (4142.5 to 5956.1)
        Anti-HPV-18 GMTs (n= 112, 112)
    4496.8 (3899.4 to 5185.8)
    4266.5 (3562.9 to 5109)
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Solicited Local Symptoms

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    End point title
    		 Number of Subjects Reporting Solicited Local Symptoms
    End point description
    Solicited local symptoms assessed include injection site pain, redness and swelling. Data are presented across doses.
    End point type
    Secondary
    End point timeframe
    During the 7-day period (Day 0-6) following vaccination
    End point values
    		 Cervarix™ & Twinrix™ Group Cervarix™ Group Twinrix™ Group
    Number of subjects analysed
    269
    270
    271
    Units: Subjects
        Pain
    251
    250
    202
        Redness
    155
    170
    74
        Swelling
    146
    137
    56
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Solicited General Symptoms

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    End point title
    		 Number of Subjects Reporting Solicited General Symptoms
    End point description
    Solicited general symptoms assessed include arthralgia, fatigue, gastrointestinal symptoms, headache, myalgia, rash, temperature [axillary route, greater than or equal to 37.5 degree Celsius (°C)] and urticaria.
    End point type
    Secondary
    End point timeframe
    During the 7-day period following vaccination
    End point values
    		 Cervarix™ & Twinrix™ Group Cervarix™ Group Twinrix™ Group
    Number of subjects analysed
    269
    270
    271
    Units: Subjects
        Arthralgia
    50
    45
    40
        Fatigue
    122
    133
    119
        Fever
    24
    28
    14
        Gastrointestinal
    70
    65
    72
        Headache
    125
    124
    110
        Myalgia
    103
    99
    75
        Rash
    18
    21
    12
        Urticaria
    6
    11
    9
    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 include adverse events (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, cervico-vaginal yeast infections, menstrual cycle abnormalities and injury.
    End point type
    Secondary
    End point timeframe
    Throughout the active phase of the study (up to Month 7)
    End point values
    		 Cervarix™ & Twinrix™ Group Cervarix™ Group Twinrix™ Group
    Number of subjects analysed
    272
    270
    271
    Units: Subjects
    22
    23
    31
    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 include adverse events (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, cervico-vaginal yeast infections, menstrual cycle abnormalities and injury.
    End point type
    Secondary
    End point timeframe
    Throughout the safety follow-up (from Month 7 up to Month 12)
    End point values
    		 Cervarix™ & Twinrix™ Group Cervarix™ Group Twinrix™ Group
    Number of subjects analysed
    272
    270
    271
    Units: Subjects
    2
    2
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Unsolicited Adverse Events

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    End point title
    		 Number of Subjects Reporting Unsolicited Adverse Events
    End point description
    Unsolicited adverse events include any adverse event 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.
    End point type
    Secondary
    End point timeframe
    During the 30-day period following any vaccination
    End point values
    		 Cervarix™ & Twinrix™ Group Cervarix™ Group Twinrix™ Group
    Number of subjects analysed
    272
    270
    271
    Units: Subjects
    83
    96
    83
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Serious Adverse Events (SAE)

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    End point title
    		 Number of Subjects Reporting Serious Adverse Events (SAE)
    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.
    End point type
    Secondary
    End point timeframe
    Throughout the study (up to Month 12)
    End point values
    		 Cervarix™ & Twinrix™ Group Cervarix™ Group Twinrix™ Group
    Number of subjects analysed
    272
    270
    271
    Units: Subjects
    2
    4
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 0 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™ & Twinrix™ Group
    Reporting group description
    		 Subjects received 3 doses of Human Papilloma Virus (HPV) vaccine co-administered with combined Hepatitis A & Hepatitis B (HAB) vaccine (Months 0, 1 & 6).

    Reporting group title
    Cervarix™ Group
    Reporting group description
    		 Subjects received 3 doses of HPV vaccine (Months 0, 1 & 6).

    Reporting group title
    Twinrix™ Group
    Reporting group description
    		 Subjects received 3 doses of HAB vaccine (Months 0, 1 & 6).

    Serious adverse events
    		 Cervarix™ & Twinrix™ Group Cervarix™ Group Twinrix™ Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 272 (0.74%)
    3 / 270 (1.11%)
    4 / 271 (1.48%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 272 (0.00%)
    1 / 270 (0.37%)
    0 / 271 (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
    Concussion
         subjects affected / exposed
    1 / 272 (0.37%)
    0 / 270 (0.00%)
    0 / 271 (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
    Head injury
         subjects affected / exposed
    0 / 272 (0.00%)
    0 / 270 (0.00%)
    1 / 271 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 272 (0.00%)
    0 / 270 (0.00%)
    1 / 271 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous injury
         subjects affected / exposed
    0 / 272 (0.00%)
    0 / 270 (0.00%)
    1 / 271 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 272 (0.37%)
    0 / 270 (0.00%)
    0 / 271 (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
    Syncope
         subjects affected / exposed
    0 / 272 (0.00%)
    1 / 270 (0.37%)
    0 / 271 (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
    Depression
         subjects affected / exposed
    0 / 272 (0.00%)
    0 / 270 (0.00%)
    1 / 271 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 272 (0.00%)
    0 / 270 (0.00%)
    1 / 271 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 272 (0.00%)
    1 / 270 (0.37%)
    0 / 271 (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
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    0 / 272 (0.00%)
    1 / 270 (0.37%)
    0 / 271 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cervarix™ & Twinrix™ Group Cervarix™ Group Twinrix™ Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    258 / 272 (94.85%)
    256 / 270 (94.81%)
    224 / 271 (82.66%)
    General disorders and administration site conditions
    Pain at injection site
    alternative assessment type: Systematic
         subjects affected / exposed
    251 / 272 (92.28%)
    250 / 270 (92.59%)
    202 / 271 (74.54%)
         occurrences all number
    251
    250
    202
    Redness at injection site
    alternative assessment type: Systematic
         subjects affected / exposed
    155 / 272 (56.99%)
    170 / 270 (62.96%)
    74 / 271 (27.31%)
         occurrences all number
    155
    170
    74
    Swelling at injection site
    alternative assessment type: Systematic
         subjects affected / exposed
    146 / 272 (53.68%)
    137 / 270 (50.74%)
    56 / 271 (20.66%)
         occurrences all number
    146
    137
    56
    Arthralgia
    alternative assessment type: Systematic
         subjects affected / exposed
    50 / 272 (18.38%)
    45 / 270 (16.67%)
    40 / 271 (14.76%)
         occurrences all number
    50
    45
    40
    Fever
    alternative assessment type: Systematic
         subjects affected / exposed
    24 / 272 (8.82%)
    28 / 270 (10.37%)
    14 / 271 (5.17%)
         occurrences all number
    24
    28
    14
    Gastrointestinal symptoms
    alternative assessment type: Systematic
         subjects affected / exposed
    70 / 272 (25.74%)
    65 / 270 (24.07%)
    72 / 271 (26.57%)
         occurrences all number
    70
    65
    72
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    125 / 272 (45.96%)
    124 / 270 (45.93%)
    110 / 271 (40.59%)
         occurrences all number
    125
    124
    110
    Myalgia
    alternative assessment type: Systematic
         subjects affected / exposed
    103 / 272 (37.87%)
    99 / 270 (36.67%)
    75 / 271 (27.68%)
         occurrences all number
    103
    99
    75
    Rash
    alternative assessment type: Systematic
         subjects affected / exposed
    18 / 272 (6.62%)
    21 / 270 (7.78%)
    12 / 271 (4.43%)
         occurrences all number
    18
    21
    12
    Fatigue
    alternative assessment type: Systematic
         subjects affected / exposed
    122 / 272 (44.85%)
    133 / 270 (49.26%)
    119 / 271 (43.91%)
         occurrences all number
    122
    133
    119
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 272 (2.21%)
    21 / 270 (7.78%)
    13 / 271 (4.80%)
         occurrences all number
    6
    21
    13

    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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