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    Clinical Trial Results:
    Evaluation of Safety and Immunogenicity of GARDASIL™ in Healthy Females Between 9 and 26 Years of Age in Sub-Saharan Africa

    Summary
    EudraCT number
    		 2017-000110-35
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    15 Apr 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Mar 2017
    First version publication date
    24 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V501-046
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01245764
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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
    15 Apr 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Apr 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Apr 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study was designed to determine the safety, tolerability and immunogenicity of a 3-dose regimen of GARDASIL™ administered to healthy females between 9 and 26 years of age in Sub-Saharan Africa. Data from the current study are needed in order to complement existing extensive safety data from the GARDASIL™ clinical trials program, and confirm that GARDASIL™ may be administered safely and will induce immune responses in populations from and living in Sub-Saharan Africa, as GARDASIL™ has not previously been studied in this region of the world. In Phase A of the study, healthy females between 9 and 12 years of age were randomized (4:1) to receive the 3-dose regimen of GARDASIL™ or placebo, and those between 13 and 26 years old received GARDASIL™. In Phase B of the study, participants who received placebo in Phase A had the option to receive the 3-dose regimen of GARDASIL™.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Mar 2011
    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
    Ghana: 30
    Country: Number of subjects enrolled
    Kenya: 90
    Country: Number of subjects enrolled
    Senegal: 130
    Worldwide total number of subjects
    250
    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)
    75
    Adolescents (12-17 years)
    70
    Adults (18-64 years)
    105
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Healthy female participants between 9 and 26 years of age in sub-Saharan Africa were enrolled into the study.

    Pre-assignment
    Screening details
    		 A total of 257 participants were screened and 250 were randomized.

    Period 1
    Period 1 title
    Study Phase A
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Gardasil 9 to 12 Years Old
    Arm description
    		 GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A and safety evaluation continued to Month 12 (total study duration up to 12 months). Participants did not continue to study Phase B.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GARDASIL™
    Investigational medicinal product code
    Other name
    Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine, V501
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A

    Arm title
    		 Gardasil 13 to 15 Years Old
    Arm description
    		 GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A and safety evaluation continued to Month 12 (total study duration up to 12 months). Participants did not continue to study Phase B.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GARDASIL™
    Investigational medicinal product code
    Other name
    Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine, V501
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A

    Arm title
    		 Gardasil 16 to 26 Years Old
    Arm description
    		 GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A and safety evaluation continued to Month 12 (total study duration up to 12 months). Participants did not continue to study Phase B.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GARDASIL™
    Investigational medicinal product code
    Other name
    Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine, V501
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A

    Arm title
    		 Placebo 9 to 12 Years Old
    Arm description
    		 Placebo to GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A. After database lock and unblinding for study Phase A, participants had the option to receive GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase B. Safety evaluation continued to Month 7 of study Phase B (total study duration up to 19 months)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A

    Number of subjects in period 1
    		Gardasil 9 to 12 Years Old Gardasil 13 to 15 Years Old Gardasil 16 to 26 Years Old Placebo 9 to 12 Years Old
    Started
    80
    30
    120
    20
    Completed Vaccinations in Study Phase A
    77
    28
    117
    19
    Completed
    71
    25
    110
    17
    Not completed
    9
    5
    10
    3
         Unknown
    3
    2
    3
    1
         Lost to follow-up
    -
    -
    5
    -
         Protocol deviation
    6
    3
    2
    2
    Period 2
    Period 2 title
    Study Phase B
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Placebo 9 to 12 Years Old (Gardasil in Phase B)
    Arm description
    		 Placebo to GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. After database lock and unblinding for study Phase A, participants accepted the option to receive GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase B.
    Arm type
    		 Catch-up vaccination

    Investigational medicinal product name
    GARDASIL™
    Investigational medicinal product code
    Other name
    Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine, V501
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase B

    Number of subjects in period 2 [1]
    		Placebo 9 to 12 Years Old (Gardasil in Phase B)
    Started
    17
    Completed
    17
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Phase B was voluntary.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Gardasil 9 to 12 Years Old
    Reporting group description
    		 GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A and safety evaluation continued to Month 12 (total study duration up to 12 months). Participants did not continue to study Phase B.

    Reporting group title
    Gardasil 13 to 15 Years Old
    Reporting group description
    		 GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A and safety evaluation continued to Month 12 (total study duration up to 12 months). Participants did not continue to study Phase B.

    Reporting group title
    Gardasil 16 to 26 Years Old
    Reporting group description
    		 GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A and safety evaluation continued to Month 12 (total study duration up to 12 months). Participants did not continue to study Phase B.

    Reporting group title
    Placebo 9 to 12 Years Old
    Reporting group description
    		 Placebo to GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A. After database lock and unblinding for study Phase A, participants had the option to receive GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase B. Safety evaluation continued to Month 7 of study Phase B (total study duration up to 19 months)

    Reporting group values
    		 Gardasil 9 to 12 Years Old Gardasil 13 to 15 Years Old Gardasil 16 to 26 Years Old Placebo 9 to 12 Years Old Total
    Number of subjects
    		 80 30 120 20 250
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.7 ( 1 ) 13.8 ( 0.8 ) 21.3 ( 2.9 ) 10.5 ( 1.1 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 80 30 120 20 250
        Male
    		 0 0 0 0 0
    Age
    Units: Subjects
        <9 years
    		 0 0 0 0 0
        9 to 12 years
    		 80 0 0 20 100
        13 to 15 years
    		 0 30 0 0 30
        16 to 26 years
    		 0 0 120 0 120
        >26 years
    		 0 0 0 0 0
    Race/Ethnicity
    Units: Subjects
        Black
    		 80 30 119 20 249
        Native Hawaiian or Other Pacific Island
    		 0 0 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Gardasil 9 to 12 Years Old
    Reporting group description
    		 GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A and safety evaluation continued to Month 12 (total study duration up to 12 months). Participants did not continue to study Phase B.

    Reporting group title
    Gardasil 13 to 15 Years Old
    Reporting group description
    		 GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A and safety evaluation continued to Month 12 (total study duration up to 12 months). Participants did not continue to study Phase B.

    Reporting group title
    Gardasil 16 to 26 Years Old
    Reporting group description
    		 GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A and safety evaluation continued to Month 12 (total study duration up to 12 months). Participants did not continue to study Phase B.

    Reporting group title
    Placebo 9 to 12 Years Old
    Reporting group description
    		 Placebo to GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A. After database lock and unblinding for study Phase A, participants had the option to receive GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase B. Safety evaluation continued to Month 7 of study Phase B (total study duration up to 19 months)
    Reporting group title
    Placebo 9 to 12 Years Old (Gardasil in Phase B)
    Reporting group description
    		 Placebo to GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. After database lock and unblinding for study Phase A, participants accepted the option to receive GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase B.

    Subject analysis set title
    Gardasil 9 to 26 Years Old
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A and safety evaluation continued to Month 12 (total study duration up to 12 months). This subject analysis set includes randomized participants who received at least one vaccination in Study Phase A.

    Subject analysis set title
    Placebo 9 to 12 Years Old
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Placebo to GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A. This subject analysis set includes randomized participants who received at least one vaccination in Study Phase A.

    Subject analysis set title
    Gardasil 9 to 12 Years Old
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. This subject analysis set includes participants who received at least one vaccination in Study Phase A.

    Subject analysis set title
    Gardasil 13 to 15 Years Old
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. This subject analysis set includes participants who received at least one vaccination in Study Phase A.

    Subject analysis set title
    Gardasil 16 to 26 Years Old
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. This subject analysis set includes participants who received at least one vaccination in Study Phase A.

    Subject analysis set title
    Placebo 9 to 12 Years Old
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Placebo 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. This subject analysis set includes participants who received at least one vaccination in Study Phase A.

    Primary: Number of Participants Who Seroconvert to Human Papillomavirus (HPV) Type 6

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    End point title
    		 Number of Participants Who Seroconvert to Human Papillomavirus (HPV) Type 6 [1]
    End point description
    Seroconversion was defined as achieving an anti-HPV Type 6 competitive Luminex Immunoassay (cLIA) level of >=20 milli Merck U/mL. The dilution-corrected limit of detection for the Type 6 cLIA was 4.2 milli Merck U/mL. Participants analyzed included those who received all 3 vaccinations in study Phase A and provided a sample for Month 7 serology testing. This analysis pooled results for participants receiving GARDASIL and compared these with results for participants receiving placebo.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3 in Study Phase A)
    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: No between-group statistical analyses were conducted for this endpoint.
    End point values
    		 Gardasil 9 to 26 Years Old Placebo 9 to 12 Years Old
    Number of subjects analysed
    147
    13
    Units: Participants
    147
    1
    No statistical analyses for this end point

    Primary: Number of Participants Who Seroconvert to HPV Type 11

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    End point title
    		 Number of Participants Who Seroconvert to HPV Type 11 [2]
    End point description
    Seroconversion was defined as achieving an anti-HPV Type 11 cLIA level of >=16 milli Merck U/mL. The dilution-corrected limit of detection for the Type 11 cLIA was 3.9 milli Merck U/mL. Participants analyzed included those who received all 3 vaccinations in study Phase A and provided a sample for Month 7 serology testing. This analysis pooled results for participants receiving GARDASIL and compared these with results for participants receiving placebo.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3 in Study Phase A)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No between-group statistical analyses were conducted for this endpoint
    End point values
    		 Gardasil 9 to 26 Years Old Placebo 9 to 12 Years Old
    Number of subjects analysed
    147
    13
    Units: Participants
    147
    1
    No statistical analyses for this end point

    Primary: Number of Participants Who Seroconvert to HPV Type 16

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    End point title
    		 Number of Participants Who Seroconvert to HPV Type 16 [3]
    End point description
    Seroconversion was defined as achieving an anti-HPV Type 16 cLIA level of >=20 milli Merck U/mL. The dilution-corrected limit of detection for the Type 16 cLIA was 9.7 milli Merck U/mL. Participants analyzed included those who received all 3 vaccinations in study Phase A and provided a sample for Month 7 serology testing. This analysis pooled results for participants receiving GARDASIL and compared these with results for participants receiving placebo.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3 in Study Phase A)
    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: No between-group statistical analyses were conducted for this endpoint
    End point values
    		 Gardasil 9 to 26 Years Old Placebo 9 to 12 Years Old
    Number of subjects analysed
    160
    14
    Units: Participants
    160
    0
    No statistical analyses for this end point

    Primary: Number of Participants Who Seroconvert to HPV Type 18

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    End point title
    		 Number of Participants Who Seroconvert to HPV Type 18 [4]
    End point description
    Seroconversion was defined as achieving an anti-HPV Type 18 cLIA level of >=24 milli Merck U/mL. The dilution-corrected limit of detection for the Type 18 cLIA was 5.8 milli Merck U/mL. Participants analyzed included those who received all 3 vaccinations in study Phase A and provided a sample for Month 7 serology testing. This analysis pooled results for participants receiving GARDASIL and compared these with results for participants receiving placebo.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3 in Study Phase A)
    Notes
    [4] - 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: No between-group statistical analyses were conducted for this endpoint
    End point values
    		 Gardasil 9 to 26 Years Old Placebo 9 to 12 Years Old
    Number of subjects analysed
    156
    14
    Units: Participants
    156
    0
    No statistical analyses for this end point

    Primary: Number of Participants With Injection-site Adverse Experiences

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    End point title
    		 Number of Participants With Injection-site Adverse Experiences [5]
    End point description
    Participants were prompted to report injection-site experiences of pain, erythema, or swelling and were also asked to report any other injection-site adverse experiences. The analysis included all participants receiving at least 1 vaccination in study Phase A and who had postvaccination follow-up.
    End point type
    Primary
    End point timeframe
    Up to Day 5 after any vaccination in Study Phase A
    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: No statistical analysis was conducted for this endpoint.
    End point values
    		 Gardasil 9 to 12 Years Old Gardasil 13 to 15 Years Old Gardasil 16 to 26 Years Old Placebo 9 to 12 Years Old
    Number of subjects analysed
    79
    29
    119
    19
    Units: Participants
    54
    21
    88
    9
    No statistical analyses for this end point

    Primary: Number of Participants With Elevated Temperature (Oral Temperature >=100 °F)

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    End point title
    		 Number of Participants With Elevated Temperature (Oral Temperature >=100 °F)
    End point description
    The analysis included all participants receiving at least 1 vaccination in study Phase A and who had temperature data
    End point type
    Primary
    End point timeframe
    Up to Day 5 after any vaccination in Study Phase A
    End point values
    		 Gardasil 9 to 12 Years Old Gardasil 13 to 15 Years Old Gardasil 16 to 26 Years Old Placebo 9 to 12 Years Old
    Number of subjects analysed
    79
    29
    119
    19
    Units: Participants
    9
    6
    7
    5
    Statistical analysis title
    		 Analysis of Maximum Temperatures
    Statistical analysis description
    Analysis compared the difference in percentage of participants with elevated temperature
    Comparison groups
    Gardasil 9 to 12 Years Old v Placebo 9 to 12 Years Old
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.097
    Method
    		 Miettinen and Nurminen
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -14.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -38.4
         upper limit
    		 2.2

    Primary: Number of Participants With Serious Adverse Experiences

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    End point title
    		 Number of Participants With Serious Adverse Experiences [6]
    End point description
    A serious adverse experience is any adverse experience that results in death, is life threatening, results in persistent or significant disability/incapacity, results in or prolongs existing inpatient hospitalization, is a congenital anomaly/birth defect, is a cancer, is an overdose, or is another important medical event that may jeopardize the participant and may require medical or surgical intervention. The analysis included all participants receiving at least 1 vaccination in study Phase A or B and who had postvaccination follow-up.
    End point type
    Primary
    End point timeframe
    From the time informed consent is signed through the last study visit (up to 19 months)
    Notes
    [6] - 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: No statistical analysis was conducted for this endpoint.
    End point values
    		 Gardasil 9 to 12 Years Old Gardasil 13 to 15 Years Old Gardasil 16 to 26 Years Old Placebo 9 to 12 Years Old
    Number of subjects analysed
    79
    29
    119
    19
    Units: Participants
    0
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Geometric Mean Titer (GMT) of Anti-HPV Type 6 Antibody

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    End point title
    		 Geometric Mean Titer (GMT) of Anti-HPV Type 6 Antibody
    End point description
    Anti-HPV Type 6 antibodies were measured by cLIA. The seropositive cut-off threshold for this assay is defined as 20 milli Merck U/mL. A value of 9999 indicates that the GMT was <10 milli Merck U/mL. Participants analyzed included those who received all 3 vaccinations in study Phase A and provided a sample for Month 7 serology testing. This analysis pooled results for participants receiving GARDASIL and compared these with results for participants receiving placebo.
    End point type
    Secondary
    End point timeframe
    Month 7 (1 month postdose 3 in Study Phase A)
    End point values
    		 Gardasil 9 to 26 Years Old Placebo 9 to 12 Years Old
    Number of subjects analysed
    147
    13
    Units: Milli Merck U/mL
        geometric mean (confidence interval 95%)
    602 (526 to 689)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: GMT of Anti-HPV Type 11 Antibody

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    End point title
    		 GMT of Anti-HPV Type 11 Antibody
    End point description
    Anti-HPV Type 11 antibodies were measured by cLIA. The seropositive cut-off threshold for this assay is defined as 16 milli Merck U/mL. A value of 9999 indicates that the GMT was <7 milli Merck U/mL. Participants analyzed included those who received all 3 vaccinations in study Phase A and provided a sample for Month 7 serology testing. This analysis pooled results for participants receiving GARDASIL and compared these with results for participants receiving placebo.
    End point type
    Secondary
    End point timeframe
    Month 7 (1 month postdose 3 in Study Phase A)
    End point values
    		 Gardasil 9 to 26 Years Old Placebo 9 to 12 Years Old
    Number of subjects analysed
    147
    13
    Units: Milli Merck U/mL
        geometric mean (confidence interval 95%)
    626 (545 to 718)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: GMT of Anti-HPV Type 16 Antibody

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    End point title
    		 GMT of Anti-HPV Type 16 Antibody
    End point description
    Anti-HPV Type 16 antibodies were measured by cLIA. The seropositive cut-off threshold for this assay is defined as 20 milli Merck U/mL. A value of 9999 indicates that the GMT was <9 milli Merck U/mL. Participants analyzed included those who received all 3 vaccinations in study Phase A and provided a sample for Month 7 serology testing. This analysis pooled results for participants receiving GARDASIL and compared these with results for participants receiving placebo.
    End point type
    Secondary
    End point timeframe
    Month 7 (1 month postdose 3 in Study Phase A)
    End point values
    		 Gardasil 9 to 26 Years Old Placebo 9 to 12 Years Old
    Number of subjects analysed
    160
    14
    Units: Milli Merck U/mL
        geometric mean (confidence interval 95%)
    3786 (3360 to 4265)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: GMT of Anti-HPV Type 18 Antibody

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    End point title
    		 GMT of Anti-HPV Type 18 Antibody
    End point description
    Anti-HPV Type 18 antibodies were measured by cLIA. The seropositive cut-off threshold for this assay is defined as 24 milli Merck U/mL. A value of 9999 indicates that the GMT was <15 milli Merck U/mL. Participants analyzed included those who received all 3 vaccinations in study Phase A and provided a sample for Month 7 serology testing. This analysis pooled results for participants receiving GARDASIL and compared these with results for participants receiving placebo.
    End point type
    Secondary
    End point timeframe
    Month 7 (1 month postdose 3 in Study Phase A)
    End point values
    		 Gardasil 9 to 26 Years Old Placebo 9 to 12 Years Old
    Number of subjects analysed
    156
    14
    Units: Milli Merck U/mL
        geometric mean (confidence interval 95%)
    811 (708 to 928)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events were assessed up to 19 months from study start. Other adverse events were assessed up to 15 days after each vaccination in study Phase A.
    Adverse event reporting additional description
    The analysis included all participants receiving at least one vaccination and had at least one postvaccination follow-up visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Gardasil 9 to 12 Years Old
    Reporting group description
    		 GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A and safety evaluation continued to Month 12 (total study duration up to 12 months). Participants did not continue to study Phase B.

    Reporting group title
    Gardasil 13 to 15 Years Old
    Reporting group description
    		 GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A and safety evaluation continued to Month 12 (total study duration up to 12 months). Participants did not continue to study Phase B.

    Reporting group title
    Placebo 9 to 12 Years Old
    Reporting group description
    		 Placebo to GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A. After database lock and unblinding for study Phase A, participants had the option to receive GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase B. Safety evaluation continued to Month 7 of study Phase B (total study duration up to 19 months).

    Reporting group title
    Gardasil 16 to 26 Years Old
    Reporting group description
    		 GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A and safety evaluation continued to Month 12 (total study duration up to 12 months). Participants did not continue to study Phase B.

    Serious adverse events
    		 Gardasil 9 to 12 Years Old Gardasil 13 to 15 Years Old Placebo 9 to 12 Years Old Gardasil 16 to 26 Years Old
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 29 (0.00%)
    0 / 19 (0.00%)
    1 / 119 (0.84%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Pregnancy, puerperium and perinatal conditions
    Foetal distress syndrome
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 29 (0.00%)
    0 / 19 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Gardasil 9 to 12 Years Old Gardasil 13 to 15 Years Old Placebo 9 to 12 Years Old Gardasil 16 to 26 Years Old
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    61 / 79 (77.22%)
    22 / 29 (75.86%)
    15 / 19 (78.95%)
    103 / 119 (86.55%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 29 (3.45%)
    1 / 19 (5.26%)
    3 / 119 (2.52%)
         occurrences all number
    1
    1
    1
    3
    Headache
         subjects affected / exposed
    27 / 79 (34.18%)
    12 / 29 (41.38%)
    5 / 19 (26.32%)
    41 / 119 (34.45%)
         occurrences all number
    37
    16
    7
    58
    Somnolence
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 29 (0.00%)
    1 / 19 (5.26%)
    0 / 119 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    8 / 79 (10.13%)
    3 / 29 (10.34%)
    1 / 19 (5.26%)
    15 / 119 (12.61%)
         occurrences all number
    12
    4
    1
    21
    Injection site pain
         subjects affected / exposed
    53 / 79 (67.09%)
    20 / 29 (68.97%)
    9 / 19 (47.37%)
    88 / 119 (73.95%)
         occurrences all number
    113
    46
    21
    188
    Injection site swelling
         subjects affected / exposed
    23 / 79 (29.11%)
    8 / 29 (27.59%)
    4 / 19 (21.05%)
    31 / 119 (26.05%)
         occurrences all number
    37
    9
    7
    48
    Pyrexia
         subjects affected / exposed
    9 / 79 (11.39%)
    6 / 29 (20.69%)
    5 / 19 (26.32%)
    9 / 119 (7.56%)
         occurrences all number
    12
    7
    8
    10
    Eye disorders
    Eye pain
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 29 (0.00%)
    1 / 19 (5.26%)
    0 / 119 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Myopia
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 29 (0.00%)
    1 / 19 (5.26%)
    0 / 119 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 79 (8.86%)
    2 / 29 (6.90%)
    1 / 19 (5.26%)
    8 / 119 (6.72%)
         occurrences all number
    8
    3
    1
    8
    Dyspepsia
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 29 (3.45%)
    1 / 19 (5.26%)
    2 / 119 (1.68%)
         occurrences all number
    0
    1
    1
    4
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 29 (3.45%)
    0 / 19 (0.00%)
    11 / 119 (9.24%)
         occurrences all number
    0
    1
    0
    16
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 29 (0.00%)
    1 / 19 (5.26%)
    0 / 119 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Malaria
         subjects affected / exposed
    2 / 79 (2.53%)
    2 / 29 (6.90%)
    1 / 19 (5.26%)
    2 / 119 (1.68%)
         occurrences all number
    3
    2
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    2 / 79 (2.53%)
    1 / 29 (3.45%)
    0 / 19 (0.00%)
    13 / 119 (10.92%)
         occurrences all number
    2
    2
    0
    14
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 29 (0.00%)
    1 / 19 (5.26%)
    3 / 119 (2.52%)
         occurrences all number
    0
    0
    1
    3

    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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