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    Clinical Trial Results:
    A Phase 2, Randomized, Active-Controlled, Observer-Blinded Trial, to Assess the Safety, Tolerability, and Immunogenicity of Gardasil® (HPV) Vaccine and Bivalent Rlp2086 Vaccine When Administered Concomitantly In Healthy Subjects Aged ≥ 11 to <18 Years

    Summary
    EudraCT number
    		 2013-002137-38
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    06 Jul 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jun 2016
    First version publication date
    01 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    B1971011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01461993
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Alias ID: 6108A1-2007
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Clinical Trials.gov Call Center, Pfizer Inc, 001 8007181021, ClinicalTrials.govCallCenter@pfizer.com
    Scientific contact
    Clinical Trials.gov Call Center, Pfizer Inc, 001 8007181021, ClinicalTrials.govCallCenter@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001037-PIP02-11
    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
    15 May 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the immune response (based on geometric mean titer [GMT]) induced by Gardasil given with bivalent recombinant lipoprotein 2086 (rLP2086) vaccine (Group1) is noninferior to the immune response induced by Gardasil alone (Group3) as measured 1month after the 3rd vaccination (Visit5) with Gardasil in both groups. The immune response to all 4 components of Gardasil will be assessed. To demonstrate the immune response (based on GMT) induced by bivalent rLP2086 vaccine given with Gardasil (Group1) is noninferior to the immune response induced by bivalent rLP2086 vaccine alone (Group2) as measured by serum bactericidal assay using human complement performed with 2 MnB test strains, 1 expressing LP2086 subfamily A and 1 expressing lipoprotein 2086 (LP2086) subfamily B proteins, when measured 1 month after the third vaccination (Visit5) with bivalent rLP2086 vaccine in both groups. To evaluate the safety profile of bivalent rLP2086 vaccine as measured by proportion of subject
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Sep 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 2499
    Worldwide total number of subjects
    2499
    EEA total number of subjects
    0
    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)
    440
    Adolescents (12-17 years)
    2059
    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
    		 The total subjects enrolled were 2499 and the study started on 28 September 2011 and completed on 06 July 2013.

    Period 1
    Period 1 title
    Overall Period (Over All Study)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1: rLP2086 + Gardasil
    Arm description
    		 Randomized to receive on a 0, 2-, 6- month schedule.
    Arm type
    		 Experimental

    Investigational medicinal product name
    rLP2086
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Bivalent rLP2086 was administered at a dose of 0.5 milliliter (mL) into the upper deltoid muscle of the left arm.

    Investigational medicinal product name
    Gardasil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Gardasil was administered at a dose of 0.5 mL into the upper deltoid muscle of the right arm.

    Arm title
    		 Group 2: rLP2086 + Saline
    Arm description
    		 Randomized to receive on a 0, 2-, 6- month schedule.
    Arm type
    		 Experimental

    Investigational medicinal product name
    rLP2086
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Bivalent rLP2086 was administered at a dose of 0.5 mL into the upper deltoid muscle of the left arm.

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Saline was administered at a dose of 0.5 mL into the upper deltoid muscle of the right arm.

    Arm title
    		 Group 3: Saline + Gardasil
    Arm description
    		 Randomized to receive on a 0, 2, 6 month schedule.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Saline was administered at a dose of 0.5 mL into the upper deltoid muscle of the right arm.

    Investigational medicinal product name
    Gardasil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Gardasil was administered at a dose of 0.5 mL into the upper deltoid muscle of the right arm.

    Number of subjects in period 1
    		Group 1: rLP2086 + Gardasil Group 2: rLP2086 + Saline Group 3: Saline + Gardasil
    Started
    999
    998
    502
    Completed
    848
    841
    438
    Not completed
    151
    157
    64
         Did not meet entrance criteria
    2
    3
    -
         Adverse Event
    9
    11
    3
         No longer met eligibility criteria
    13
    18
    10
         Withdrawal by Subject
    60
    53
    16
         Protocol Violation
    10
    9
    7
         Unspecified
    13
    15
    6
         Lost to follow-up
    44
    48
    22

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1: rLP2086 + Gardasil
    Reporting group description
    		 Randomized to receive on a 0, 2-, 6- month schedule.

    Reporting group title
    Group 2: rLP2086 + Saline
    Reporting group description
    		 Randomized to receive on a 0, 2-, 6- month schedule.

    Reporting group title
    Group 3: Saline + Gardasil
    Reporting group description
    		 Randomized to receive on a 0, 2, 6 month schedule.

    Reporting group values
    		 Group 1: rLP2086 + Gardasil Group 2: rLP2086 + Saline Group 3: Saline + Gardasil Total
    Number of subjects
    		 999 998 502 2499
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 13.7 ± 1.94 13.6 ± 1.93 13.6 ± 1.86 -
    Gender categorical
    Units: Subjects
        Female
    		 341 332 170 843
        Male
    		 658 666 332 1656

    End points

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    End points reporting groups
    Reporting group title
    Group 1: rLP2086 + Gardasil
    Reporting group description
    		 Randomized to receive on a 0, 2-, 6- month schedule.

    Reporting group title
    Group 2: rLP2086 + Saline
    Reporting group description
    		 Randomized to receive on a 0, 2-, 6- month schedule.

    Reporting group title
    Group 3: Saline + Gardasil
    Reporting group description
    		 Randomized to receive on a 0, 2, 6 month schedule.

    Primary: Geometric Mean Titer (GMT) of Human Papillomavirus (HPV) Antigens

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    End point title
    		 Geometric Mean Titer (GMT) of Human Papillomavirus (HPV) Antigens [1]
    End point description
    End point type
    Primary
    End point timeframe
    1 month after Vaccination 3
    Notes
    [1] - 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: This end point was planned to be reported for subjects in rLP2086 + Gardasil and Saline + Gardasil groups only.
    End point values
    		 Group 1: rLP2086 + Gardasil Group 3: Saline + Gardasil
    Number of subjects analysed
    813
    423
    Units: Titer
    geometric mean (confidence interval 95%)
        HPV-6
    451.8 (417.5 to 489.01)
    550.3 (490.44 to 617.58)
        HPV-11
    892.9 (839.52 to 949.57)
    1084.3 (997.28 to 1178.96)
        HPV-16
    3695.4 (3426.32 to 3985.67)
    4763.4 (4285.85 to 5294.21)
        HPV-18
    744 (687.67 to 804.96)
    1047.4 (939 to 1168.25)
    Statistical analysis title
    		 HPV-6
    Statistical analysis description
    The non-inferiority criteria margin was 1.5-fold.
    Comparison groups
    Group 1: rLP2086 + Gardasil v Group 3: Saline + Gardasil
    Number of subjects included in analysis
    1236
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 0.94
    Statistical analysis title
    		 HPV-11
    Comparison groups
    Group 3: Saline + Gardasil v Group 1: rLP2086 + Gardasil
    Number of subjects included in analysis
    1236
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 0.91
    Statistical analysis title
    		 HPV-16
    Comparison groups
    Group 1: rLP2086 + Gardasil v Group 3: Saline + Gardasil
    Number of subjects included in analysis
    1236
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 0.88
    Statistical analysis title
    		 HPV-18
    Comparison groups
    Group 1: rLP2086 + Gardasil v Group 3: Saline + Gardasil
    Number of subjects included in analysis
    1236
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 0.81

    Primary: Serum Bactericidal Assay Using Human Complement (hSBA) GMTs of PMB80 [A22] and PMB2948 [B24]

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    End point title
    		 Serum Bactericidal Assay Using Human Complement (hSBA) GMTs of PMB80 [A22] and PMB2948 [B24] [2]
    End point description
    End point type
    Primary
    End point timeframe
    1 month after Vaccination 3
    Notes
    [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: This end point was planned to be reported for subjects in rLP2086 + Gardasil and rLP2086 + Saline groups only.
    End point values
    		 Group 1: rLP2086 + Gardasil Group 2: rLP2086 + Saline
    Number of subjects analysed
    814
    812
    Units: Titer
    geometric mean (confidence interval 95%)
        PMB80 [A22] (N= 803, 801)
    25.8 (50.22 to 56.66)
    57.8 (54.44 to 61.44)
        PMB2948 [B24] (N= 788, 793)
    53.3 (24.14 to 27.56)
    28 (26.24 to 29.87)
    Statistical analysis title
    		 PMB80 [A22]
    Statistical analysis description
    The non-inferiority criteria margin was 1.5-fold.
    Comparison groups
    Group 1: rLP2086 + Gardasil v Group 2: rLP2086 + Saline
    Number of subjects included in analysis
    1626
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1
    Statistical analysis title
    		 PMB2948 [B24]
    Statistical analysis description
    The non-inferiority criteria margin was 1.5-fold.
    Comparison groups
    Group 1: rLP2086 + Gardasil v Group 2: rLP2086 + Saline
    Number of subjects included in analysis
    1626
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.01

    Primary: Percentage of Subjects With at Least One Adverse Event (AE)

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    End point title
    		 Percentage of Subjects With at Least One Adverse Event (AE) [3]
    End point description
    End point type
    Primary
    End point timeframe
    Vaccination 1 up to 1 month after Vaccination 3
    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: Only descriptive data was planned to be reported for this outcome measure.
    End point values
    		 Group 1: rLP2086 + Gardasil Group 2: rLP2086 + Saline Group 3: Saline + Gardasil
    Number of subjects analysed
    992
    990
    501
    Units: Percentage of subjects
        number (not applicable)
    43.9
    41.7
    49.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving Seroconversion for Human Papillomavirus (HPV)

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    End point title
    		 Percentage of Subjects Achieving Seroconversion for Human Papillomavirus (HPV) [4]
    End point description
    End point type
    Secondary
    End point timeframe
    1 month after Vaccination 3
    Notes
    [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: This end point was planned to be reported for subjects in rLP2086 + Gardasil and Saline + Gardasil groups only.
    End point values
    		 Group 1: rLP2086 + Gardasil Group 3: Saline + Gardasil
    Number of subjects analysed
    809
    419
    Units: Percentage of subjects
    number (not applicable)
        HPV-6 (N= 802, 414)
    99.4
    99.3
        HPV-11 (N= 801, 417)
    99.6
    99.5
        HPV-16 (N= 800, 413)
    99.6
    99.5
        HPV-18 (N= 805, 418)
    99.5
    99
    No statistical analyses for this end point

    Secondary: Percentage of Baseline Seropositive Participants: Group 1 and 3 Participants

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    End point title
    		 Percentage of Baseline Seropositive Participants: Group 1 and 3 Participants [5]
    End point description
    End point type
    Secondary
    End point timeframe
    Before vaccination 1
    Notes
    [5] - 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: This end point was planned to be reported for subjects in rLP2086 + Gardasil and Saline + Gardasil groups only.
    End point values
    		 Group 1: rLP2086 + Gardasil Group 3: Saline + Gardasil
    Number of subjects analysed
    814
    423
    Units: Percentage of subjects
    number (not applicable)
        HPV-6
    1.4
    2.1
        HPV-11
    1.5
    1.4
        HPV-16
    1.6
    2.4
        HPV-18
    1
    1.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Serum Bactericidal Assay Using Human Complement (hSBA) Titer Greater Than or Equal to (>=) Lower Limit of Quantitation (LLOQ)

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    End point title
    		 Percentage of Subjects With Serum Bactericidal Assay Using Human Complement (hSBA) Titer Greater Than or Equal to (>=) Lower Limit of Quantitation (LLOQ) [6]
    End point description
    End point type
    Secondary
    End point timeframe
    Before vaccination 1, 1 month after vaccination (Vac) 2, 3
    Notes
    [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: This end point was planned to be reported for subjects in rLP2086 + Gardasil and rLP2086 + Saline groups only.
    End point values
    		 Group 1: rLP2086 + Gardasil Group 2: rLP2086 + Saline
    Number of subjects analysed
    814
    812
    Units: Before vaccination 1, 1 month after vacc
    number (not applicable)
        Before Vaccination 1:PMB80[A22] 1:16 (N= 794, 799)
    13.7
    16.4
        1 month after Vac 2: PMB80[A22] 1:16 (N= 794, 801)
    83
    85.8
        1 month after Vac 3: PMB80[A22] 1:16 (N= 803, 801)
    94
    96.3
        Before Vaccination 1:PMB2001[A56] 1:8(N= 757, 740)
    9.2
    9.3
        1 month after Vac 2: PMB2001[A56] 1:8 (N= 790,795)
    97.5
    98.5
        1 month after Vac 3: PMB2001[A56] 1:8 (N= 796,802)
    98.9
    99.4
        Before Vaccination 1:PMB2948[B24] 1:8(N= 801, 793)
    5.1
    6.9
        1 month after Vac 2: PMB2948[B24] 1:8 (N= 770,770)
    70.6
    74.2
        1 month after Vac 3: PMB2948[B24] 1:8 (N= 788,793)
    90.5
    92.6
        Before Vaccination 1:PMB2707[B44] 1:8(N= 806, 805)
    1.4
    2.5
        1 month after Vac 2: PMB2707[B44] 1:8 (N= 783,776)
    54.5
    57.1
        1 month after Vac 3: PMB2707[B44] 1:8 (N= 799,795)
    82.7
    85.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Serum Bactericidal Assay Using Human Complement (hSBA) Titer >= Prespecified Titer Level

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    End point title
    		 Percentage of Subjects With Serum Bactericidal Assay Using Human Complement (hSBA) Titer >= Prespecified Titer Level [7]
    End point description
    End point type
    Secondary
    End point timeframe
    Before Vaccination 1, 1 month after Vaccination 2, 3
    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: This end point was planned to be reported for subjects in rLP2086 + Gardasil and rLP2086 + Saline groups only.
    End point values
    		 Group 1: rLP2086 + Gardasil Group 2: rLP2086 + Saline
    Number of subjects analysed
    814
    812
    Units: Percentage of subjects
    number (not applicable)
        Before Vaccination 1: PMB80 [A22] 1:4 (N=794,799)
    15.2
    18.8
        Before Vaccination 1: PMB80 [A22] 1:8 (N=794,799)
    14.2
    17.4
        Before Vaccination 1: PMB80 [A22] 1:32 (N=794,799)
    9.4
    10.6
        Before Vaccination 1: PMB80 [A22] 1:64 (N=794,799)
    2.8
    3.6
        Before Vaccination 1: PMB80[A22] 1:128 (N=794,799)
    0.5
    0.8
        1 month after Vac 2: PMB80 [A22] 1:4 (N=794,801)
    83.8
    86.3
        1 month after Vac 2: PMB80 [A22] 1:8 (N=794,801)
    83.2
    86.1
        1 month after Vac 2: PMB80 [A22] 1:32 (N=794,801)
    66.9
    69.7
        1 month after Vac 2: PMB80 [A22] 1:64 (N=794,801)
    35.9
    35.8
        1 month after Vac 2: PMB80 [A22] 1:128 (N=794,801)
    11
    13
        1 month after Vac 3: PMB80 [A22] 1:4 (N=803,801)
    94.3
    96.4
        1 month after Vac 3: PMB80 [A22] 1:8 (N=803,801)
    94.3
    96.4
        1 month after Vac 3: PMB80 [A22] 1:32 (N=803,801)
    86.3
    87
        1 month after Vac 3: PMB80 [A22] 1:64 (N=803,801)
    58
    61
        1 month after Vac 3: PMB80 [A22] 1:128 (N=803,801)
    28.1
    31.6
        Before Vaccination 1: PMB2001[A56] 1:4 (N=757,740)
    10.4
    10.5
        Before Vaccination 1: PMB2001[A56] 1:16(N=757,740)
    9
    9.1
        Before Vaccination 1: PMB2001[A56] 1:32(N=757,740)
    8.1
    7.7
        Before Vaccination 1: PMB2001[A56] 1:64(N=757,740)
    4.9
    4.6
        Before Vaccination 1:PMB2001[A56] 1:128(N=757,740)
    1.7
    1.5
        1 month after Vac 2: PMB2001 [A56] 1:4 (N=790,795)
    97.8
    98.7
        1 month after Vac 2: PMB2001[A56] 1:16 (N=790,795)
    97.2
    98.4
        1 month after Vac 2: PMB2001[A56] 1:32 (N=790,795)
    91.3
    93.7
        1 month after Vac 2: PMB2001[A56] 1:64 (N=790,795)
    71.6
    76.6
        1 month after Vac 2: PMB2001[A56] 1:128(N=790,795)
    40.4
    41.5
        1 month after Vac 3: PMB2001 [A56] 1:4 (n=796,802)
    99.1
    99.4
        1 month after Vac 3: PMB2001[A56] 1:16 (N=796,802)
    98.9
    99.4
        1 month after Vac 3: PMB2001[A56] 1:32 (N=796,802)
    96.7
    97.3
        1 month after Vac 3: PMB2001[A56] 1:64 (N=796,802)
    88.1
    89.2
        1 month after Vac 3: PMB2001[A56] 1:128(N=796,802)
    63.6
    67.2
        Before Vaccination 1: PMB2948[B24] 1:4 (N=801,793)
    6.1
    8.4
        Before Vaccination 1: PMB2948[B24] 1:16(N=801,793)
    4.1
    5.4
        Before Vaccination 1: PMB2948[B24] 1:32(N=801,793)
    1.7
    3
        Before Vaccination 1: PMB2948[B24] 1:64(N=801,793)
    0.6
    1
        Before Vaccination 1:PMB2948[B24] 1:128(N=801,793)
    0.1
    0.5
        1 month after Vac 2: PMB2948 [B24] 1:4 (N=770,770)
    71.9
    77.1
        1 month after Vac 2: PMB2948[B24] 1:16 (N=770,770)
    65.2
    68.8
        1 month after Vac 2: PMB2948[B24] 1:32 (N=770,770)
    33.9
    38.7
        1 month after Vac 2: PMB2948[B24] 1:64 (N=770,770)
    13.1
    12.5
        1 month after Vac 2: PMB2948[B24] 1:128(N=770,770)
    5.3
    5.6
        1 month after Vac 3: PMB2948 [B24] 1:4 (N=788,793)
    91.1
    92.8
        1 month after Vac 3: PMB2948[B24] 1:16 (N=788,793)
    86.3
    89.2
        1 month after Vac 3: PMB2948[B24] 1:32 (N=788,793)
    57.2
    60.9
        1 month after Vac 3: PMB2948[B24] 1:64 (N=788,793)
    23.9
    25.2
        1 month after Vac 3: PMB2948[B24] 1:128(N=788,793)
    7.6
    8.4
        Before Vaccination 1: PMB2707[B44] 1:4 (N=806,805)
    1.7
    3.2
        Before Vaccination 1: PMB2707[B44] 1:16(N=806,805)
    1.2
    2.1
        Before Vaccination 1: PMB2707[B44] 1:32(N=806,805)
    0.6
    1.4
        Before Vaccination 1: PMB2707[B44] 1:64(N=806,805)
    0.1
    0.7
        Before Vaccination 1:PMB2707[B44] 1:128(N=806,805)
    0
    0.2
        1 month after Vac 2: PMB2707 [B44] 1:4 (N=783,776)
    57.7
    60.1
        1 month after Vac 2: PMB2707[B44] 1:16 (N=783,776)
    46.4
    49.9
        1 month after Vac 2: PMB2707[B44] 1:32 (N=783,776)
    25.7
    26.9
        1 month after Vac 2: PMB2707[B44] 1:64 (N=783,776)
    11.2
    11.9
        1 month after Vac 2: PMB2707[B44] 1:128(N=783,776)
    5
    5.7
        1 month after Vac 3: PMB2707 [B44] 1:4 (N=799,795)
    84.4
    86.5
        1 month after Vac 3: PMB2707[B44] 1:16 (N=799,795)
    78
    82.4
        1 month after Vac 3: PMB2707[B44] 1:32 (N=799,795)
    57.7
    62.3
        1 month after Vac 3: PMB2707[B44] 1:64 (N=799,795)
    34.7
    39.4
        1 month after Vac 3: PMB2707[B44] 1:128(N=799,795)
    15.1
    18.4
    No statistical analyses for this end point

    Secondary: Serum Bactericidal Assay Using Human Complement (hSBA) Geometric Mean Titer (GMT)

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    End point title
    		 Serum Bactericidal Assay Using Human Complement (hSBA) Geometric Mean Titer (GMT) [8]
    End point description
    End point type
    Secondary
    End point timeframe
    Before Vaccination 1, 1 month after Vaccination 2, 3
    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: This end point was planned to be reported for subjects in rLP2086 + Gardasil and rLP2086 + Saline groups only.
    End point values
    		 Group 1: rLP2086 + Gardasil Group 2: rLP2086 + Saline
    Number of subjects analysed
    814
    812
    Units: Titer
    geometric mean (confidence interval 95%)
        Before Vaccination 1: PMB80 [A22] (N=794,799)
    9.6 (9.28 to 9.96)
    9.9 (9.58 to 10.33)
        1 month after Vac 2: PMB80 [A22] (N=794,801)
    31.9 (29.96 to 33.94)
    33.7 (31.69 to 35.85)
        Before Vaccination 1: PMB2001 [A56] (N=757,740)
    5 (4.78 to 5.32)
    5 (4.75 to 5.28)
        1 month after Vac 2: PMB2001 [A56] (N=790,795)
    70.6 (66.17 to 75.34)
    76.3 (71.93 to 80.99)
        1 month after Vac 3: PMB2001 [A56] (N=796,802)
    117.2 (110.14 to 124.76)
    128.2 (120.65 to 136.27)
        Before Vaccination 1: PMB2948 [B24] (N=801,793)
    4.3 (4.23 to 4.46)
    4.5 (4.35 to 4.65)
        1 month after Vac 2: PMB2948 [B24] (N=770,770)
    15 (13.88 to 16.15)
    16.3 (15.15 to 17.62)
        Before Vaccination 1: PMB2707 [B44] (N=806,805)
    4.1 (4.04 to 4.15)
    4.2 (4.1 to 4.31)
        1 month after Vac 2: PMB2707 [B44] (N=783,776)
    11.1 (10.21 to 12.01)
    11.9 (10.94 to 12.96)
        1 month after Vac 3: PMB2707 [B44] (N=799,795)
    27.2 (24.99 to 29.68)
    31.9 (29.25 to 34.82)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE reported from Vaccination 1 to 1 month after last administration of investigational product (bivalent rLP2086/saline/Gardasil). SAE reported from Vaccination 1 to 6 months after last of investigational product (bivalent rLP2086/saline/Gardasil)
    Adverse event reporting additional description
    Events collected on case report form were reported.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Group 1: rLP2086 + Gardasil
    Reporting group description
    		 Randomized to receive on a 0, 2-, 6- month schedule.

    Reporting group title
    Group 2: rLP2086 + Saline
    Reporting group description
    		 Randomized to receive on a 0, 2-, 6- month schedule.

    Reporting group title
    Group 3: Saline + Gardasil
    Reporting group description
    		 Randomized to receive on a 0, 2-, 6- month schedule

    Serious adverse events
    		 Group 1: rLP2086 + Gardasil Group 2: rLP2086 + Saline Group 3: Saline + Gardasil
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 992 (1.21%)
    16 / 990 (1.62%)
    4 / 501 (0.80%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Nodular fasciitis
         subjects affected / exposed
    0 / 992 (0.00%)
    1 / 990 (0.10%)
    0 / 501 (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
    Injury, poisoning and procedural complications
    Burns first degree
         subjects affected / exposed
    1 / 992 (0.10%)
    0 / 990 (0.00%)
    0 / 501 (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
    Concussion
         subjects affected / exposed
    0 / 992 (0.00%)
    1 / 990 (0.10%)
    0 / 501 (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
    Fibula fracture
         subjects affected / exposed
    0 / 992 (0.00%)
    1 / 990 (0.10%)
    0 / 501 (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
    Humerus fracture
         subjects affected / exposed
    0 / 992 (0.00%)
    1 / 990 (0.10%)
    0 / 501 (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
    Pelvic fracture
         subjects affected / exposed
    0 / 992 (0.00%)
    1 / 990 (0.10%)
    0 / 501 (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
    Road traffic accident
         subjects affected / exposed
    1 / 992 (0.10%)
    0 / 990 (0.00%)
    0 / 501 (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
    Skull fracture
         subjects affected / exposed
    1 / 992 (0.10%)
    0 / 990 (0.00%)
    0 / 501 (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
    Tibia fracture
         subjects affected / exposed
    0 / 992 (0.00%)
    1 / 990 (0.10%)
    0 / 501 (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
    Wrist fracture
         subjects affected / exposed
    0 / 992 (0.00%)
    1 / 990 (0.10%)
    0 / 501 (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
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 992 (0.10%)
    0 / 990 (0.00%)
    0 / 501 (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
    Nervous system disorders
    Migraine
         subjects affected / exposed
    1 / 992 (0.10%)
    0 / 990 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 992 (0.00%)
    1 / 990 (0.10%)
    0 / 501 (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
    Blood and lymphatic system disorders
    Lymphoid tissue hyperplasia
         subjects affected / exposed
    1 / 992 (0.10%)
    0 / 990 (0.00%)
    0 / 501 (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
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    0 / 992 (0.00%)
    1 / 990 (0.10%)
    0 / 501 (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
    Haemorrhoids
         subjects affected / exposed
    0 / 992 (0.00%)
    0 / 990 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary dyskinesia
         subjects affected / exposed
    0 / 992 (0.00%)
    0 / 990 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 992 (0.00%)
    1 / 990 (0.10%)
    0 / 501 (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
    Psychiatric disorders
    Depression suicidal
         subjects affected / exposed
    2 / 992 (0.20%)
    0 / 990 (0.00%)
    0 / 501 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 992 (0.10%)
    1 / 990 (0.10%)
    0 / 501 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Affective disorder
         subjects affected / exposed
    0 / 992 (0.00%)
    1 / 990 (0.10%)
    0 / 501 (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
    Anxiety
         subjects affected / exposed
    1 / 992 (0.10%)
    0 / 990 (0.00%)
    0 / 501 (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
    Bipolar disorder
         subjects affected / exposed
    0 / 992 (0.00%)
    1 / 990 (0.10%)
    0 / 501 (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
    Cyclothymic disorder
         subjects affected / exposed
    0 / 992 (0.00%)
    0 / 990 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 992 (0.00%)
    1 / 990 (0.10%)
    0 / 501 (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
    Oppositional defiant disorder
         subjects affected / exposed
    1 / 992 (0.10%)
    0 / 990 (0.00%)
    0 / 501 (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
    Musculoskeletal and connective tissue disorders
    Epiphysiolysis
         subjects affected / exposed
    0 / 992 (0.00%)
    1 / 990 (0.10%)
    0 / 501 (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
    2 / 992 (0.20%)
    1 / 990 (0.10%)
    0 / 501 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 992 (0.00%)
    1 / 990 (0.10%)
    0 / 501 (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: 1%
    Non-serious adverse events
    		 Group 1: rLP2086 + Gardasil Group 2: rLP2086 + Saline Group 3: Saline + Gardasil
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    308 / 992 (31.05%)
    289 / 990 (29.19%)
    168 / 501 (33.53%)
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    16 / 992 (1.61%)
    20 / 990 (2.02%)
    10 / 501 (2.00%)
         occurrences all number
    18
    23
    12
    Joint injury
         subjects affected / exposed
    12 / 992 (1.21%)
    5 / 990 (0.51%)
    2 / 501 (0.40%)
         occurrences all number
    13
    5
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    50 / 992 (5.04%)
    38 / 990 (3.84%)
    21 / 501 (4.19%)
         occurrences all number
    54
    43
    23
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    50 / 992 (5.04%)
    43 / 990 (4.34%)
    21 / 501 (4.19%)
         occurrences all number
    73
    55
    28
    Pyrexia
         subjects affected / exposed
    15 / 992 (1.51%)
    11 / 990 (1.11%)
    5 / 501 (1.00%)
         occurrences all number
    15
    11
    5
    Fatigue
         subjects affected / exposed
    10 / 992 (1.01%)
    8 / 990 (0.81%)
    3 / 501 (0.60%)
         occurrences all number
    10
    9
    3
    Injection site swelling
         subjects affected / exposed
    11 / 992 (1.11%)
    8 / 990 (0.81%)
    2 / 501 (0.40%)
         occurrences all number
    13
    9
    2
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    12 / 992 (1.21%)
    10 / 990 (1.01%)
    6 / 501 (1.20%)
         occurrences all number
    13
    10
    6
    Nausea
         subjects affected / exposed
    15 / 992 (1.51%)
    6 / 990 (0.61%)
    2 / 501 (0.40%)
         occurrences all number
    15
    6
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    19 / 992 (1.92%)
    16 / 990 (1.62%)
    14 / 501 (2.79%)
         occurrences all number
    20
    17
    15
    Oropharyngeal pain
         subjects affected / exposed
    12 / 992 (1.21%)
    23 / 990 (2.32%)
    6 / 501 (1.20%)
         occurrences all number
    14
    24
    6
    Nasal congestion
         subjects affected / exposed
    10 / 992 (1.01%)
    12 / 990 (1.21%)
    7 / 501 (1.40%)
         occurrences all number
    10
    12
    8
    Asthma
         subjects affected / exposed
    11 / 992 (1.11%)
    4 / 990 (0.40%)
    4 / 501 (0.80%)
         occurrences all number
    12
    5
    4
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    13 / 992 (1.31%)
    10 / 990 (1.01%)
    10 / 501 (2.00%)
         occurrences all number
    13
    10
    10
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 992 (0.91%)
    11 / 990 (1.11%)
    10 / 501 (2.00%)
         occurrences all number
    9
    11
    10
    Pain in extremity
         subjects affected / exposed
    11 / 992 (1.11%)
    8 / 990 (0.81%)
    4 / 501 (0.80%)
         occurrences all number
    13
    9
    4
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    49 / 992 (4.94%)
    53 / 990 (5.35%)
    29 / 501 (5.79%)
         occurrences all number
    56
    57
    29
    Pharyngitis
         subjects affected / exposed
    20 / 992 (2.02%)
    36 / 990 (3.64%)
    9 / 501 (1.80%)
         occurrences all number
    22
    38
    9
    Nasopharyngitis
         subjects affected / exposed
    23 / 992 (2.32%)
    23 / 990 (2.32%)
    14 / 501 (2.79%)
         occurrences all number
    27
    29
    16
    Pharyngitis streptococcal
         subjects affected / exposed
    18 / 992 (1.81%)
    14 / 990 (1.41%)
    15 / 501 (2.99%)
         occurrences all number
    19
    14
    15
    Gastroenteritis
         subjects affected / exposed
    23 / 992 (2.32%)
    11 / 990 (1.11%)
    8 / 501 (1.60%)
         occurrences all number
    25
    11
    8
    Viral infection
         subjects affected / exposed
    14 / 992 (1.41%)
    10 / 990 (1.01%)
    11 / 501 (2.20%)
         occurrences all number
    14
    10
    11
    Sinusitis
         subjects affected / exposed
    18 / 992 (1.81%)
    11 / 990 (1.11%)
    5 / 501 (1.00%)
         occurrences all number
    18
    12
    5
    Gastroenteritis viral
         subjects affected / exposed
    9 / 992 (0.91%)
    8 / 990 (0.81%)
    8 / 501 (1.60%)
         occurrences all number
    10
    8
    8
    Acute sinusitis
         subjects affected / exposed
    5 / 992 (0.50%)
    13 / 990 (1.31%)
    6 / 501 (1.20%)
         occurrences all number
    5
    14
    6
    Otitis media
         subjects affected / exposed
    11 / 992 (1.11%)
    9 / 990 (0.91%)
    2 / 501 (0.40%)
         occurrences all number
    12
    9
    2
    Pneumonia
         subjects affected / exposed
    7 / 992 (0.71%)
    7 / 990 (0.71%)
    6 / 501 (1.20%)
         occurrences all number
    7
    8
    6
    Viral pharyngitis
         subjects affected / exposed
    2 / 992 (0.20%)
    6 / 990 (0.61%)
    8 / 501 (1.60%)
         occurrences all number
    2
    6
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Nov 2011
    The concomitant treatment section was amended to clarify the guidance for the administration of non study vaccines (other than meningococcal conjugate vaccine [MCV4] and tetanus, diphtheria, and acellular pertussis [Tdap] vaccine) at any time during the study.
    18 Sep 2012
    1. Volume of blood draw increased from 10 mL to approximately 20 mL. 2. Added exclusion criterion related to allergen immunotherapy. 3. Added clarification that protocol deviations that exclude subjects from the evaluable immunogenicity population should be determined by the sponsor’s global medical monitor.

    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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