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    Clinical Trial Results:
    A Randomized, Double-Blinded, Controlled with GARDASIL® (Human Papillomavirus Vaccine [Types 6, 11, 16, 18] (Recombinant, adsorbed)), Phase 3 Clinical Trial to Study the Immunogenicity and Tolerability of V503 (9-Valent Human Papillomavirus [HPV] L1 Virus-Like Particle [VLP] Vaccine) in 16- to 26-year-old men.

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    2013-003399-10
    Trial protocol
    DE   BE   NL  
    Global end of trial date
    22 Apr 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Apr 2016
    First version publication date
    23 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GDS07C
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02114385
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur MSD S.N.C.
    Sponsor organisation address
    162 avenue Jean Jaurès - CS 50712, Lyon Cedex 07, France, 69367
    Public contact
    Clinical Trials Disclosure, Sanofi Pasteur MSD S.N.C., ClinicalTrialsDisclosure@spmsd.com
    Scientific contact
    Clinical Trials Disclosure, Sanofi Pasteur MSD S.N.C., ClinicalTrialsDisclosure@spmsd.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
    22 Apr 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Apr 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to demonstrate that administration of the 9-valent HPV L1 VLP (9vHPV) vaccine induces non-inferior Geometric Mean Titres (GMTs) for serum anti-HPV 6, 11, 16, and 18, compared to GARDASIL® (qHPV) in 16- to 26-year-old men.
    Protection of trial subjects
    Healthy men with known allergy to any vaccine component were excluded. Vaccines were administered by qualified study personnel. After each vaccination, subjects were kept under observation for at least 30 minutes to ensure their safety.
    Background therapy
    -
    Evidence for comparator
    # 9vHPV vaccine (= V503) is a prophylactic 9-valent HPV (Types 6, 11, 16, 18, 31, 33, 45, 52, and 58) L1 virus-like particle (VLP) vaccine that is composed of VLPs of the 4 HPV types (Types 6, 11, 16, and 18) contained in qHPV vaccine (= GARDASIL®, a quadrivalent prophylactic HPV vaccine), plus the VLPs of 5 additional oncogenic HPV types (Types 31, 33, 45, 52, and 58). # qHPV vaccine has been approved by the European Medicines Agency (EMA) in September 2006 and is currently approved and marketed in over 100 countries. # This study was designed to provide a direct comparison of immunogenicity and tolerability of the 9vHPV vaccine versus qHPV vaccine in young men, 16 to 26 years of age.
    Actual start date of recruitment
    24 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 155
    Country: Number of subjects enrolled
    Belgium: 276
    Country: Number of subjects enrolled
    Germany: 69
    Worldwide total number of subjects
    500
    EEA total number of subjects
    500
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    75
    Adults (18-64 years)
    425
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study subjects were enrolled in 7 active centres in 3 European countries (Belgium, Germany, and The Netherlands) between 24 March 2014 and 17 September 2014.

    Pre-assignment
    Screening details
    502 subjects were screened. 500 subjects were randomised. 490 subjects received all 3 doses of 9vHPV or qHPV vaccine. 489 subjects completed the study.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Blinded vaccines were presented in the same sealed outer packaging. The subjects, investigators (and his/her staff), laboratory staff, and the Sponsor remained blinded to subject vaccine allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    9vHPV vaccine
    Arm description
    # Subjects received 3 doses of 9vHPV vaccine* by intramuscular (IM) route: dose 1 at Visit 1 (V1, Day 1), dose 2 at V2 (2 months after Day 1, ±3 weeks), and dose 3 at V3 (6 months after Day 1, ±4 weeks). # Subjects were blood sampled (i) before vaccination (V1), and (ii) at V4, i.e., 3 to 7 weeks after V3 = Post-Dose 3. *9vHPV vaccine = V503 = 9-valent HPV (Types 6, 11, 16, 18, 31, 33, 45, 52, and 58) L1 virus-like particle (VLP) vaccine (recombinant, absorbed)
    Arm type
    Experimental

    Investigational medicinal product name
    9-valent HPV VLP
    Investigational medicinal product code
    9vHPV
    Other name
    V503, GARDASIL®9
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM route (deltoid muscle of the nondominant arm), 3 doses: dose 1 at V1 (Day 1), dose 2 at V2 (2 months after Day 1, ±3 weeks), and dose 3 at V3 (6 months after Day 1, ±4 weeks).

    Arm title
    qHPV vaccine
    Arm description
    # Subjects received 3 doses of qHPV vaccine* by intramuscular (IM) route: dose 1 at V1 (Day 1), dose 2 at V2 (2 months after Day 1, ±3 weeks), and dose 3 at V3 (6 months after Day 1, ±4 weeks). # Subjects were blood sampled (i) before vaccination (V1), and (ii) at V4, i.e., 3 to 7 weeks after V3 = Post-Dose 3. *qHPV vaccine = GARDASIL® = 4-valent HPV (Types 6, 11, 16 and 18) L1 virus-like particle (VLP) vaccine (recombinant, absorbed)
    Arm type
    Active comparator

    Investigational medicinal product name
    GARDASIL®
    Investigational medicinal product code
    qHPV
    Other name
    SILGARD®
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM route (deltoid muscle of the nondominant arm), 3 doses: dose 1 at V1 (Day 1), dose 2 at V2 (2 months after Day 1, ±3 weeks), and dose 3 at V3 (6 months after Day 1, ±4 weeks).

    Number of subjects in period 1
    9vHPV vaccine qHPV vaccine
    Started
    249
    251
    Completed
    246
    243
    Not completed
    3
    8
         Consent withdrawn by subject
    3
    2
         Lost to follow-up
    -
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    9vHPV vaccine
    Reporting group description
    # Subjects received 3 doses of 9vHPV vaccine* by intramuscular (IM) route: dose 1 at Visit 1 (V1, Day 1), dose 2 at V2 (2 months after Day 1, ±3 weeks), and dose 3 at V3 (6 months after Day 1, ±4 weeks). # Subjects were blood sampled (i) before vaccination (V1), and (ii) at V4, i.e., 3 to 7 weeks after V3 = Post-Dose 3. *9vHPV vaccine = V503 = 9-valent HPV (Types 6, 11, 16, 18, 31, 33, 45, 52, and 58) L1 virus-like particle (VLP) vaccine (recombinant, absorbed)

    Reporting group title
    qHPV vaccine
    Reporting group description
    # Subjects received 3 doses of qHPV vaccine* by intramuscular (IM) route: dose 1 at V1 (Day 1), dose 2 at V2 (2 months after Day 1, ±3 weeks), and dose 3 at V3 (6 months after Day 1, ±4 weeks). # Subjects were blood sampled (i) before vaccination (V1), and (ii) at V4, i.e., 3 to 7 weeks after V3 = Post-Dose 3. *qHPV vaccine = GARDASIL® = 4-valent HPV (Types 6, 11, 16 and 18) L1 virus-like particle (VLP) vaccine (recombinant, absorbed)

    Reporting group values
    9vHPV vaccine qHPV vaccine Total
    Number of subjects
    249 251 500
    Age categorical
    Units: Subjects
        16-17 years old
    37 38 75
        18-26 years old
    212 213 425
    Age continuous
    Age at 1st dose
    Units: years
        arithmetic mean (standard deviation)
    20.8 ± 2.7 21.3 ± 3 -
    Gender categorical
    Units: Subjects
        Female
    0 0 0
        Male
    249 251 500

    End points

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    End points reporting groups
    Reporting group title
    9vHPV vaccine
    Reporting group description
    # Subjects received 3 doses of 9vHPV vaccine* by intramuscular (IM) route: dose 1 at Visit 1 (V1, Day 1), dose 2 at V2 (2 months after Day 1, ±3 weeks), and dose 3 at V3 (6 months after Day 1, ±4 weeks). # Subjects were blood sampled (i) before vaccination (V1), and (ii) at V4, i.e., 3 to 7 weeks after V3 = Post-Dose 3. *9vHPV vaccine = V503 = 9-valent HPV (Types 6, 11, 16, 18, 31, 33, 45, 52, and 58) L1 virus-like particle (VLP) vaccine (recombinant, absorbed)

    Reporting group title
    qHPV vaccine
    Reporting group description
    # Subjects received 3 doses of qHPV vaccine* by intramuscular (IM) route: dose 1 at V1 (Day 1), dose 2 at V2 (2 months after Day 1, ±3 weeks), and dose 3 at V3 (6 months after Day 1, ±4 weeks). # Subjects were blood sampled (i) before vaccination (V1), and (ii) at V4, i.e., 3 to 7 weeks after V3 = Post-Dose 3. *qHPV vaccine = GARDASIL® = 4-valent HPV (Types 6, 11, 16 and 18) L1 virus-like particle (VLP) vaccine (recombinant, absorbed)

    Primary: Non-inferiority of Geometric Mean Titres (GMTs) of anti-HPV types 6, 11, 16 and 18 antibodies (Abs) Post-Dose 3 (V4) of 9vHPV versus qHPV vaccine

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    End point title
    Non-inferiority of Geometric Mean Titres (GMTs) of anti-HPV types 6, 11, 16 and 18 antibodies (Abs) Post-Dose 3 (V4) of 9vHPV versus qHPV vaccine
    End point description
    Anti-HPV types 6, 11, 16 and 18 Ab titres were measured by competitive Luminex ImmunoAssay (cLIA) 3 to 7 weeks Post-Dose 3 of 9vHPV versus qHPV vaccine (V4). Ab titres are expressed in milli Merck units (mMU)/mL. Analysis was done on the HPV specific Per Protocol Sets (PPS), i.e., subjects who received all 3 vaccinations, and seronegative to the relevant HPV type at Day 1, excluding those with protocol deviation which could interfere with the immunogenicity evaluation. Note: (N=***, ***) represents the number of assessed subjects in the "9vHPV vaccine" and "qHPV vaccine", respectively.
    End point type
    Primary
    End point timeframe
    3 to 7 weeks Post-Dose 3 of 9vHPV versus qHPV vaccine.
    End point values
    9vHPV vaccine qHPV vaccine
    Number of subjects analysed
    234
    237
    Units: mMU/mL
    geometric mean (confidence interval 95%)
        Anti-HPV 6 GMT (N=228, 226)
    758.3 (665.9 to 863.4)
    618.4 (554 to 690.3)
        Anti-HPV 11 GMT (N=228, 226)
    681.7 (608.9 to 763.4)
    769.1 (683.5 to 865.3)
        Anti-HPV 16 GMT (N=234, 237)
    3924.1 (3513.8 to 4382.3)
    3787.9 (3378.4 to 4247)
        Anti-HPV 18 GMT (N=234, 236)
    884.3 (766.4 to 1020.4)
    790.9 (683 to 915.7)
    Statistical analysis title
    Non-inferiority for HPV 6
    Statistical analysis description
    The estimate of the 9vHPV vaccine/qHPV vaccine GMT ratio for HPV 6 was calculated with its P-value and its 2-sided 95% confidence interval (CI) using an ANOVA model including group and age strata as independent variables. If the lower bound of the 95% CI was greater than 0.5 (i.e., the non-inferiority margin), it was concluded that 9vHPV GMT was non-inferior to qHPV GMT. Analysis was done on the HPV 6 specific PPS. N= 454 (9vHPV vaccine: 228, qHPV vaccine: 226).
    Comparison groups
    9vHPV vaccine v qHPV vaccine
    Number of subjects included in analysis
    471
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001
    Method
    ANOVA
    Parameter type
    GMT ratio
    Point estimate
    1.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.04
         upper limit
    1.45
    Statistical analysis title
    Non-inferiority for HPV 11
    Statistical analysis description
    The estimate of the 9vHPV vaccine/qHPV vaccine GMT ratio for HPV 11 was calculated with its P-value and its 2-sided 95% confidence interval (CI) using an ANOVA model including group and age stratum as independent variables. If the lower bound of the 95% CI was greater than 0.5 (i.e., the non-inferiority margin), it was concluded that 9vHPV GMT was non-inferior to qHPV GMT. Analysis was done on the HPV 11 specific PPS. N= 454 (9vHPV vaccine: 228, qHPV vaccine: 226).
    Comparison groups
    9vHPV vaccine v qHPV vaccine
    Number of subjects included in analysis
    471
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001
    Method
    ANOVA
    Parameter type
    GMT ratio
    Point estimate
    0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    1.04
    Statistical analysis title
    Non-inferiority for HPV 16
    Statistical analysis description
    The estimate of the 9vHPV vaccine/qHPV vaccine GMT ratio for HPV 16 was calculated with its P-value and its 2-sided 95% confidence interval (CI) using an ANOVA model including group and age stratum as independent variables. If the lower bound of the 95% CI was greater than 0.5 (i.e., the non-inferiority margin), it was concluded that 9vHPV GMT was non-inferior to qHPV GMT. Analysis was done on the HPV 16 specific PPS. N= 471 (9vHPV vaccine: 234, qHPV vaccine: 237).
    Comparison groups
    9vHPV vaccine v qHPV vaccine
    Number of subjects included in analysis
    471
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001
    Method
    ANOVA
    Parameter type
    GMT ratio
    Point estimate
    1.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    1.21
    Statistical analysis title
    Non-inferiority for HPV 18
    Statistical analysis description
    The estimate of the 9vHPV vaccine/qHPV vaccine GMT ratio for HPV 18 was calculated with its P-value and its 2-sided 95% confidence interval (CI) using an ANOVA model including group and age stratum as independent variables. If the lower bound of the 95% CI was greater than 0.5 (i.e., the non-inferiority margin), it was concluded that 9vHPV GMT was non-inferior to qHPV GMT. Analysis was done on the HPV 18 specific PPS. N= 470 (9vHPV vaccine: 234, qHPV vaccine: 236).
    Comparison groups
    9vHPV vaccine v qHPV vaccine
    Number of subjects included in analysis
    471
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001
    Method
    ANOVA
    Parameter type
    GMT ratio
    Point estimate
    1.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.91
         upper limit
    1.37

    Secondary: Seroconversion rates for anti-HPV types 6, 11, 16, and 18 Abs Post-Dose 3 (V4) of 9vHPV or qHPV vaccine

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    End point title
    Seroconversion rates for anti-HPV types 6, 11, 16, and 18 Abs Post-Dose 3 (V4) of 9vHPV or qHPV vaccine
    End point description
    The seroconversion rates to HPV types 6, 11, 16, and 18 defined as Ab titres ≥30 mMU/mL for anti-HPV 6, ≥16 mMU/mL for anti-HPV 11, ≥20 mMU/mL for anti-HPV 16, and ≥24 mMU/mL for anti-HPV 18 were determined 3 to 7 weeks Post-Dose 3 of 9vHPV or qHPV vaccine (V4). Ab titres were measured by cLIA. Analysis was done on the HPV specific Per Protocol Sets (PPS), i.e., subjects who received all 3 vaccinations, and seronegative to the relevant HPV type at Day 1, excluding those with protocol deviation which could interfere with the immunogenicity evaluation. Note: (N=***, ***) represents the number of assessed subjects in the "9vHPV vaccine" and "qHPV vaccine" groups, respectively.
    End point type
    Secondary
    End point timeframe
    3 to 7 weeks Post-Dose 3 of 9vHPV versus qHPV vaccine.
    End point values
    9vHPV vaccine qHPV vaccine
    Number of subjects analysed
    234
    237
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-HPV 6 ≥30 mMU/mL (N=228, 226)
    98.2 (95.6 to 99.5)
    98.7 (96.2 to 99.7)
        Anti-HPV 11 ≥16 mMU/mL (N=228, 226)
    100 (98.4 to 100)
    100 (98.4 to 100)
        Anti-HPV 16 ≥20 mMU/mL (N=234, 237)
    100 (98.4 to 100)
    100 (98.5 to 100)
        Anti-HPV 18 ≥24 mMU/mL (N=234, 236)
    99.6 (97.6 to 100)
    99.6 (97.7 to 100)
    No statistical analyses for this end point

    Secondary: GMTs of anti-HPV types 31, 33, 45, 52, and 58 Abs Post-Dose 3 (V4) of 9vHPV or qHPV vaccine

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    End point title
    GMTs of anti-HPV types 31, 33, 45, 52, and 58 Abs Post-Dose 3 (V4) of 9vHPV or qHPV vaccine
    End point description
    Anti-HPV types 31, 33, 45, 52, and 58 Ab titres were measured by cLIA 3 to 7 weeks Post-Dose 3 of 9vHPV or qHPV vaccine (V4). Ab titres are expressed in mMU/mL. Analysis was done on the HPV specific Per Protocol Sets (PPS), i.e., subjects who received all 3 vaccinations, and seronegative to the relevant HPV type at Day 1, excluding those with protocol deviation which could interfere with the immunogenicity evaluation. Note: (N=***, ***) represents the number of assessed subjects in the "9vHPV vaccine" and "qHPV vaccine" groups, respectively.
    End point type
    Secondary
    End point timeframe
    3 to 7 weeks Post-Dose 3 of 9vHPV versus qHPV vaccine.
    End point values
    9vHPV vaccine qHPV vaccine
    Number of subjects analysed
    236
    237
    Units: mMU/mL
    geometric mean (confidence interval 95%)
        Anti-HPV 31 GMT (N=234, 237)
    794.4 (694.2 to 909.2)
    14.8 (12.5 to 17.5)
        Anti-HPV 33 GMT (N=236, 236)
    460.5 (410.6 to 516.4)
    3.4 (3.1 to 3.7)
        Anti-HPV 45 GMT (N=232, 236)
    262.9 (226.2 to 305.5)
    2.5 (2.3 to 2.8)
        Anti-HPV 52 GMT (N=235, 236)
    430.7 (377.8 to 491)
    1.9 (1.8 to 2.1)
        Anti-HPV 58 GMT (N=232, 233)
    691 (614.9 to 776.5)
    5.7 (5 to 6.5)
    No statistical analyses for this end point

    Secondary: Seroconversion rates for anti-HPV types 31, 33, 45, 52, and 58 Abs Post-Dose 3 (V4) of 9vHPV or qHPV vaccine

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    End point title
    Seroconversion rates for anti-HPV types 31, 33, 45, 52, and 58 Abs Post-Dose 3 (V4) of 9vHPV or qHPV vaccine
    End point description
    The seroconversion rates to HPV types 31, 33, 45, 52, and 58 defined as Ab titres ≥10 mMU/mL for anti-HPV 31, and ≥8 mMU/mL for anti-HPV 33, anti-HPV 45, anti-HPV 52, and anti HPV 58 were determined 3 to 7 weeks Post-Dose 3 of 9vHPV or qHPV vaccine (V4). Ab titres were measured by cLIA. Analysis was done on the HPV specific Per Protocol Sets (PPS), i.e., subjects who received all 3 vaccinations, and seronegative to the relevant HPV type at Day 1, excluding those with protocol deviation which could interfere with the immunogenicity evaluation. Note: (N=***, ***) represents the number of assessed subjects in the "9vHPV vaccine" and "qHPV vaccine" groups, respectively.
    End point type
    Secondary
    End point timeframe
    3 to 7 weeks Post-Dose 3 of 9vHPV versus qHPV vaccine.
    End point values
    9vHPV vaccine qHPV vaccine
    Number of subjects analysed
    236
    237
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-HPV 31 ≥10 mMU/mL (N=234, 237)
    100 (98.4 to 100)
    61.6 (55.1 to 67.8)
        Anti-HPV 33 ≥8 mMU/mL (N=236, 236)
    100 (98.4 to 100)
    16.9 (12.4 to 22.4)
        Anti-HPV 45 ≥8 mMU/mL (N=232, 236)
    100 (98.4 to 100)
    9.3 (5.9 to 13.8)
        Anti-HPV 52 ≥8 mMU/mL (N=235, 236)
    100 (98.4 to 100)
    2.5 (0.9 to 5.5)
        Anti-HPV 58 ≥8 mMU/mL (N=232, 233)
    100 (98.4 to 100)
    36.1 (29.9 to 42.6)
    No statistical analyses for this end point

    Secondary: Global summary of safety from D1 to D15 after any vaccination (3 doses of 9vHPV or qHPV)

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    End point title
    Global summary of safety from D1 to D15 after any vaccination (3 doses of 9vHPV or qHPV)
    End point description
    Adverse events (AEs) were recorded as follows. 1/ From D1 to D5 after each vaccination: # oral temperature ≥37.8°C, # solicited (erythema, pain, and swelling at injection-site) and # other injection-site adverse reactions (ISRs). 2/ From D1 to D15 after each vaccination: systemic AEs. AEs at injection sites were always considered as related to vaccine (ISRs). The investigator had to assess whether systemic AEs were vaccine-related systemic AEs or not. The percentage of subjects presenting at least once the considered events after any vaccination is reported hereafter. Analyses following any doses were based on the vaccines corresponding to the highest number of doses received by the subject. Analysis was done on the Safety Analysis Set, i.e., all subjects who received at least 1 dose of the study vaccines and who had safety follow-up data.
    End point type
    Secondary
    End point timeframe
    From Day 1 (D1) to D15 after any vaccination (3 doses of 9vHPV or qHPV).
    End point values
    9vHPV vaccine qHPV vaccine
    Number of subjects analysed
    248
    248
    Units: Percentage of subjects
    number (confidence interval 95%)
        At least 1 AE (D1-D15)
    82.3 (76.9 to 86.8)
    81.9 (76.5 to 86.4)
        At least 1 vaccine-related AE (D1-D15)
    81.5 (76 to 86.1)
    79 (73.4 to 83.9)
        At least 1 ISR (D1-D5)
    79 (73.4 to 83.9)
    72.2 (66.2 to 77.7)
        At least 1 solicited ISR (D1-D5)
    78.6 (73 to 83.6)
    71.4 (65.3 to 76.9)
        At least 1 other ISR (D1-D5)
    9.7 (6.3 to 14.1)
    9.3 (6 to 13.6)
        At least 1 severe ISR (D1-D5)
    1.2 (0.3 to 3.5)
    1.6 (0.4 to 4.1)
        At least 1 systemic AE (D1-D15)
    40.7 (34.6 to 47.1)
    40.3 (34.2 to 46.7)
        At least 1 vaccine-related systemic AE (D1-D15)
    23 (17.9 to 28.7)
    21.8 (16.8 to 27.4)
    No statistical analyses for this end point

    Secondary: Percentage of subjects reporting ISRs from D1 to D5 after any vaccination (3 doses of 9vHPV or qHPV)

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    End point title
    Percentage of subjects reporting ISRs from D1 to D5 after any vaccination (3 doses of 9vHPV or qHPV)
    End point description
    The percentage of subjects presenting at least once solicited (erythema, pain, and swelling) or other ISRs from D1 to D5 after any vaccination (3 doses of 9vHPV or qHPV) is reported hereafter. AEs at injection-site were always considered as related to vaccine (ISRs). Analyses following any doses were based on the vaccines corresponding to the highest number of doses received by the subject. Analysis was done on the Safety Analysis Set, i.e., all subjects who received at least 1 dose of the study vaccines and who had safety follow-up data.
    End point type
    Secondary
    End point timeframe
    From Day 1 (D1) to D5 after any vaccination (3 doses of 9vHPV or qHPV).
    End point values
    9vHPV vaccine qHPV vaccine
    Number of subjects analysed
    248
    248
    Units: Percentage of subjects
    number (not applicable)
        Solicited injection-site erythema
    15.3
    17.3
        Solicited injection-site swelling
    14.5
    9.3
        Solicited injection-site pain
    77.8
    70.2
        Unsolicited injection-site movement impairment
    2
    3.6
        Unsolicited injection-site induration
    1.6
    2.4
        Unsolicited injection-site pruritus
    1.6
    2
        Unsolicited injection-site haematoma
    1.6
    0.8
        Unsolicited injection-site haemorrhage
    0.8
    0.4
        Unsolicited injection-site bruising
    0.4
    0.4
        Unsolicited injection-site joint pain
    0.4
    0.4
        Unsolicited injection-site reaction
    0
    0.8
        Unsolicited injection-site lymphadenopathy
    0.4
    0
        Unsolicited injection-site paraesthesia
    0.4
    0
        Unsolicited injection-site urticaria
    0.4
    0
        Unsolicited injection-site warmth
    0.4
    0
    No statistical analyses for this end point

    Secondary: Percentage of subjects reporting oral temperature [37.8°C-38.9°C[ or [38.9°C-39.9°C[ from D1 to D5 after any vaccination (3 doses of 9vHPV or qHPV)

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    End point title
    Percentage of subjects reporting oral temperature [37.8°C-38.9°C[ or [38.9°C-39.9°C[ from D1 to D5 after any vaccination (3 doses of 9vHPV or qHPV)
    End point description
    Maximum oral temperatures recorded daily were reported from D1 to D5 after any vaccination (3 doses of 9vHPV or qHPV). The percentage of subjects presenting at least once temperature [37.8°C-38.9°C[ and [38.9°C-39.9°C[ is presented hereafter. Analyses following any doses were based on the vaccines corresponding to the highest number of doses received by the subject. Analysis was done on the Safety Analysis Set, i.e., all subjects who received at least 1 dose of the study vaccines and who had safety follow-up data.
    End point type
    Secondary
    End point timeframe
    From Day 1 (D1) to D5 after any vaccination (3 doses of 9vHPV or qHPV).
    End point values
    9vHPV vaccine qHPV vaccine
    Number of subjects analysed
    248
    248
    Units: Percentage of subjects
    number (not applicable)
        Oral temperature [37.8°C-38.9°C[
    2.8
    2
        Oral temperature [38.9°C-39.9°C[
    0
    0.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Systemic adverse events (AEs) were collected from D1 to D15 after each dose of 9vHPV or qHPV vaccine. Serious AEs and deaths were collected throughout the study.
    Adverse event reporting additional description
    Analysis of AEs was done on the Safety Analysis Set, i.e., all subjects who received at least 1 dose of the study vaccines and who had safety follow-up data. Unsolicited non-serious systemic AEs (vaccine-related or not) with incidence ≥1% are presented hereafter. None of the serious AEs were vaccine-related.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    9vHPV vaccine
    Reporting group description
    # Subjects received 3 doses of 9vHPV vaccine (V503) by IM route: dose 1 at Visit 1 (Day 1), dose 2 at Visit 2 (2 months after Day 1, ±3 weeks), and dose 3 at Visit 3 (6 months after Day 1, ±4 weeks). # Respectively, 101 (40.7%) subjects reported at least 1 unsolicited systemic AE, and 57 (23%) subjects reported at least 1 vaccine-related unsolicited systemic AE within 15 days after any vaccination (3 doses of 9vHPV vaccine).

    Reporting group title
    qHPV vaccine
    Reporting group description
    # Subjects received 3 doses of qHPV vaccine (GARDASIL®) by IM route: dose 1 at Visit 1 (Day 1), dose 2 at Visit 2 (2 months after Day 1, ±3 weeks), and dose 3 at Visit 3 (6 months after Day 1, ±4 weeks). # Respectively, 100 (40.3%) subjects reported at least 1 unsolicited systemic AE, and 54 (21.8%) subjects reported at least 1 vaccine-related unsolicited systemic AE within 15 days after any vaccination (3 doses of qHPV vaccine).

    Serious adverse events
    9vHPV vaccine qHPV vaccine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 248 (0.00%)
    6 / 248 (2.42%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Foot fracture
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament injury
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    9vHPV vaccine qHPV vaccine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    101 / 248 (40.73%)
    100 / 248 (40.32%)
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    8 / 248 (3.23%)
    9 / 248 (3.63%)
         occurrences all number
    8
    10
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    3 / 248 (1.21%)
    1 / 248 (0.40%)
         occurrences all number
    3
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    6 / 248 (2.42%)
    0 / 248 (0.00%)
         occurrences all number
    6
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    29 / 248 (11.69%)
    37 / 248 (14.92%)
         occurrences all number
    43
    51
    Dizziness
         subjects affected / exposed
    5 / 248 (2.02%)
    1 / 248 (0.40%)
         occurrences all number
    5
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    9 / 248 (3.63%)
    8 / 248 (3.23%)
         occurrences all number
    12
    11
    Fatigue
         subjects affected / exposed
    8 / 248 (3.23%)
    9 / 248 (3.63%)
         occurrences all number
    8
    9
    Hangover
         subjects affected / exposed
    1 / 248 (0.40%)
    5 / 248 (2.02%)
         occurrences all number
    1
    8
    Influenza like illness
         subjects affected / exposed
    3 / 248 (1.21%)
    2 / 248 (0.81%)
         occurrences all number
    4
    2
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    3 / 248 (1.21%)
    0 / 248 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 248 (2.82%)
    12 / 248 (4.84%)
         occurrences all number
    8
    12
    Nausea
         subjects affected / exposed
    6 / 248 (2.42%)
    5 / 248 (2.02%)
         occurrences all number
    7
    7
    Abdominal pain upper
         subjects affected / exposed
    3 / 248 (1.21%)
    2 / 248 (0.81%)
         occurrences all number
    3
    3
    Abdominal pain
         subjects affected / exposed
    3 / 248 (1.21%)
    1 / 248 (0.40%)
         occurrences all number
    3
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    5 / 248 (2.02%)
    2 / 248 (0.81%)
         occurrences all number
    5
    2
    Musculoskeletal stiffness
         subjects affected / exposed
    3 / 248 (1.21%)
    2 / 248 (0.81%)
         occurrences all number
    4
    2
    Pain in extremity
         subjects affected / exposed
    3 / 248 (1.21%)
    1 / 248 (0.40%)
         occurrences all number
    4
    1
    Back pain
         subjects affected / exposed
    3 / 248 (1.21%)
    0 / 248 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    11 / 248 (4.44%)
    14 / 248 (5.65%)
         occurrences all number
    13
    16
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 248 (1.21%)
    7 / 248 (2.82%)
         occurrences all number
    4
    7
    Rhinitis
         subjects affected / exposed
    5 / 248 (2.02%)
    4 / 248 (1.61%)
         occurrences all number
    5
    5
    Gastroenteritis
         subjects affected / exposed
    4 / 248 (1.61%)
    4 / 248 (1.61%)
         occurrences all number
    4
    4
    Influenza
         subjects affected / exposed
    2 / 248 (0.81%)
    3 / 248 (1.21%)
         occurrences all number
    2
    3
    Oral herpes
         subjects affected / exposed
    3 / 248 (1.21%)
    1 / 248 (0.40%)
         occurrences all number
    3
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Feb 2014
    Country-specific protocol amendment for the Netherlands: - at the EC’s request, the withdrawal criteria were clarified to specify that subjects could be withdrawn for any event likely to affect the safety of the subject, or any serious GCP issue (previously “administrative reasons”), - the phone number for immediate reporting of adverse events was corrected, - the instructions to Investigators for immediate reporting of adverse events were clarified, - reporting of medical errors to the Sponsor was added.
    04 Mar 2014
    Country-specific protocol amendment for Germany: - the address for the Sponsor Sanofi Pasteur MSD was updated, as their offices had moved, - the Coordinating Investigator and instructions for immediate reporting of adverse events for France were removed, as the clinical trial application was withdrawn in France, - a justification of the choice of non-inferiority margin was added to the statistical methods and the sample size and power calculations section.
    31 Mar 2014
    Protocol amendment applicable to all countries: Same as Protocol Amendment 2 (issued on 4 March 2014) which was only applicable to Germany.

    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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