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    Clinical Trial Results:
    A Open-label, Randomized, Multicenter Study of the Safety, Tolerability, and Immunogenicity of GARDASIL™ Given Concomitantly with REPEVAX™ in Healthy Adolescents 11-17 Years of Age

    Summary
    EudraCT number
    		 2006-000764-85
    Trial protocol
    		 FI   DE   DK   BE  
    Global end of trial date
    24 May 2007

    Results information
    Results version number
    		 v2(current)
    This version publication date
    07 Oct 2016
    First version publication date
    08 Sep 2016
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    V501-024
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00337428
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, New Jersey, 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
    24 May 2007
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 May 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    24 May 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to demonstrate the following: 1) Antibody response to HPV types 6, 11, 16, and 18 was not impaired when a first dose of REPEVAX™ was administered concomitantly with the first dose of Quadrivalent Human Papillomavirus (qHPV) vaccine (GARDASIL™/Silgard™) compared to the administration of qHPV vaccine (GARDASIL™/Silgard™) alone. (2) Antibody response to diphtheria, tetanus, pertussis and poliomyelitis was not impaired when the first dose of qHPV vaccine (GARDASIL™/Silgard™) was administered concomitantly with a first dose of REPEVAX™ compared to the administration of REPEVAX™ alone. (3) Concomitant administration of the first dose of qHPV vaccine (GARDASIL™/Silgard™) with REPEVAX™ was generally well tolerated compared to when the first dose of qHPV vaccine (GARDASIL™/Silgard™) was given separately from REPEVAX™.
    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. The following additional measure for this study were in place for the protection of trial participants: Participants were observed for 30 minutes each vaccination for any immediate reaction or evidence of allergic phenomena.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 May 2006
    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
    Belgium: 99
    Country: Number of subjects enrolled
    Denmark: 160
    Country: Number of subjects enrolled
    Finland: 374
    Country: Number of subjects enrolled
    Germany: 210
    Worldwide total number of subjects
    843
    EEA total number of subjects
    843
    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)
    477
    Adolescents (12-17 years)
    366
    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 study enrolled healthy participants, 11-17 years old, with 0 lifetime sexual partners, vaccinated against diphtheria, tetanus, pertussis and polio but had not received the vaccine in the past 5 years or any prior human papillomavirus (HPV) vaccine. Additional inclusion and exclusion criteria applied.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 qHPV Vaccine + REPEVAX™ (Concomitant)
    Arm description
    		 Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant (qHPV) vaccine and REPEVAX™ administered on Day 1 at different injection sites.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant (qHPV) Vaccine from Current Manufacturing Facility (CMF)
    Investigational medicinal product code
    Other name
    GARDASIL™/Silgard™
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Administered as a 0.5-mL intramuscular injection at Day 1, Month 2, and Month 6

    Investigational medicinal product name
    Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant (qHPV) Vaccine from Final Manufacturing Facility (FMF)
    Investigational medicinal product code
    Other name
    GARDASIL™/Silgard™
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Administered as a 0.5-mL intramuscular injection at Day 1, Month 2, and Month 6

    Investigational medicinal product name
    REPEVAX™ (Concomitant)
    Investigational medicinal product code
    Other name
    dTap-IPV
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Administered as a single 0.5-mL intramuscular dose at Day in a limb opposite that of qHPV injection

    Arm title
    		 qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Arm description
    		 Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant (qHPV) vaccine administered on Day 1 followed by REPEVAX™ administered at Month 1.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant (qHPV) Vaccine from Current Manufacturing Facility (CMF)
    Investigational medicinal product code
    Other name
    GARDASIL™/Silgard™
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Administered as a 0.5-mL intramuscular injection at Day 1, Month 2, and Month 6

    Investigational medicinal product name
    Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant (qHPV) Vaccine from Final Manufacturing Facility (FMF)
    Investigational medicinal product code
    Other name
    GARDASIL™/Silgard™
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Administered as a 0.5-mL intramuscular injection at Day 1, Month 2, and Month 6

    Investigational medicinal product name
    REPEVAX™ (Non-Concomitant)
    Investigational medicinal product code
    Other name
    dTap-IPV
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Administered as a single 0.5-mL intramuscular dose at Month 1 in a limb opposite that of qHPV injection

    Number of subjects in period 1
    		qHPV Vaccine + REPEVAX™ (Concomitant) qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Started
    419
    424
    Completed
    415
    421
    Not completed
    4
    3
         Consent withdrawn by subject
    1
    2
         Unwilling to Continue
    1
    -
         Lack of Time
    1
    1
         Anorexia (unrelated to vaccine)
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    qHPV Vaccine + REPEVAX™ (Concomitant)
    Reporting group description
    		 Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant (qHPV) vaccine and REPEVAX™ administered on Day 1 at different injection sites.

    Reporting group title
    qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Reporting group description
    		 Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant (qHPV) vaccine administered on Day 1 followed by REPEVAX™ administered at Month 1.

    Reporting group values
    		 qHPV Vaccine + REPEVAX™ (Concomitant) qHPV Vaccine + REPEVAX™ (Non-concomitant) Total
    Number of subjects
    		 419 424 843
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 229 248 477
        Adolescents (12-17 years)
    		 190 176 366
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 12.1 ± 1.5 12.1 ± 1.5 -
    Gender Categorical
    Units: Subjects
        Female
    		 295 288 583
        Male
    		 124 136 260
    Race/Ethnicity
    Units: Subjects
        Asian
    		 1 3 4
        Black
    		 3 3 6
        Multi-racial
    		 2 3 5
        White
    		 413 415 828

    End points

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    End points reporting groups
    Reporting group title
    qHPV Vaccine + REPEVAX™ (Concomitant)
    Reporting group description
    		 Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant (qHPV) vaccine and REPEVAX™ administered on Day 1 at different injection sites.

    Reporting group title
    qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Reporting group description
    		 Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant (qHPV) vaccine administered on Day 1 followed by REPEVAX™ administered at Month 1.

    Primary: Geometric Mean Titers (GMTs) for HPV Types 6, 11, 16, and 18 Antibody at Month 7 (4 Weeks Postdose 3)

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    End point title
    		 Geometric Mean Titers (GMTs) for HPV Types 6, 11, 16, and 18 Antibody at Month 7 (4 Weeks Postdose 3)
    End point description
    Serum antibodies to HPV Types 6, 11, 16, and 18 were measured with a Competitive Luminex Immunoassay. Titers were reported in milli Merck Units (mMU)/milliliter (mL). GMTs from participants who received qHPV vaccine and REPEVAX™ together at Day 1 (concomitant) were compared to GMTs from participants who received qHPV vaccine at Day 1 followed by REPEVAX™ 1 month later (non-concomitant). An analysis of non-inferiority compared GMTs for each HPV type using an ANOVA model with a response of log individual titers and fixed effects for treatment group, manufacturing facility, study site, and the treatment-by-site interaction. The analysis was performed in the per-protocol population that included participants with no major protocol violations, who were seronegative at baseline to the relevant HPV type, and had post-vaccination data.
    End point type
    Primary
    End point timeframe
    Up to 7 Months (4 Weeks Postdose 3)
    End point values
    		 qHPV Vaccine + REPEVAX™ (Concomitant) qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects analysed
    419
    424
    Units: milli Merck Units (mMU)/milliliter (mL)
    geometric mean (confidence interval 95%)
        Anti-HPV Type 6 (n = 367, 376)
    1151.3 (1007.5 to 1315.7)
    1244.9 (1092.4 to 1418.6)
        Anti-HPV Type 11 (n = 367, 376)
    1338.3 (1209 to 1481.4)
    1460.7 (1322.4 to 1613.3)
        Anti-HPV Type 16 (n = 370, 378)
    5835.7 (5195.7 to 6554.6)
    6508.1 (5810.3 to 7289.6)
        Anti-HPV Type 18 (n = 372, 378)
    1096 (958.8 to 1252.8)
    1308.8 (1148.1 to 1491.9)
    Statistical analysis title
    		 GMTs for Anti-HPV Type 6
    Statistical analysis description
    Analysis of non-inferiority of the GMTs for Anti-HPV Type 6 induced in participants who received concomitant compared with non-concomitant administration of qHPV vaccine and REPEVAX. Non-inferiority of GMT was demonstrated if there was <2-fold decrease in GMT for concomitant compared to non-concomitant administration and the lower limit of the 95% CI for the GMT ratio (concomitant/non-concomitant) was >0.5.¶
    Comparison groups
    qHPV Vaccine + REPEVAX™ (Concomitant) v qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects included in analysis
    843
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 GMTs for Anti-HPV Type 11
    Statistical analysis description
    Analysis of non-inferiority of the GMTs for Anti-HPV Type 11 induced in participants who received concomitant compared with non-concomitant administration of qHPV vaccine and REPEVAX. Non-inferiority of GMT was demonstrated if there was <2-fold decrease in GMT for concomitant compared to non-concomitant administration and the lower limit of the 95% CI for the GMT ratio (concomitant/non-concomitant) was >0.5.¶
    Comparison groups
    qHPV Vaccine + REPEVAX™ (Concomitant) v qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects included in analysis
    843
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 GMTs for Anti-HPV Type 16
    Statistical analysis description
    Analysis of non-inferiority of the GMTs for Anti-HPV Type 16 induced in participants who received concomitant compared with non-concomitant administration of qHPV vaccine and REPEVAX. Non-inferiority of GMT was demonstrated if there was <2-fold decrease in GMT for concomitant compared to non-concomitant administration and the lower limit of the 95% CI for the GMT ratio (concomitant/non-concomitant) was >0.5.¶
    Comparison groups
    qHPV Vaccine + REPEVAX™ (Concomitant) v qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects included in analysis
    843
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 GMTs for Anti-HPV Type 18
    Statistical analysis description
    Analysis of non-inferiority of the GMTs for Anti-HPV Type 18 induced in participants who received concomitant compared with non-concomitant administration of qHPV vaccine and REPEVAX. Non-inferiority of GMT was demonstrated if there was <2-fold decrease in GMT for concomitant compared to non-concomitant administration and the lower limit of the 95% CI for the GMT ratio (concomitant/non-concomitant) was >0.5.¶
    Comparison groups
    qHPV Vaccine + REPEVAX™ (Concomitant) v qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects included in analysis
    843
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval

    Primary: Number of Participants Who Seroconverted for HPV Types 6, 11, 16, and 18 by Month 7 (4 Weeks Postdose 3)

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    End point title
    		 Number of Participants Who Seroconverted for HPV Types 6, 11, 16, and 18 by Month 7 (4 Weeks Postdose 3)
    End point description
    Seroconversion to HPV Types 6, 11, 16, and 18 was defined as changing serostatus from seronegative to seropositive as measured by GMT. Cutoff values for HPV seropositivity are ≥20 mMU/mL for Type 6 and 16, ≥16 mMU/mL for Type 11, and ≥24 mMU/mL for Type 18. Seroconversion of participants who received qHPV vaccine and REPEVAX™ together at Day 1 (concomitant) was compared to seroconversion of participants who received qHPV vaccine at Day 1 followed by REPEVAX™ 1 month later (non-concomitant). An analysis of non-inferiority compared seroconversion for each HPV type using methods developed by Miettinen and Nurminen adjusting for manufacturing facility for qHPV vaccine. The analysis was performed in the per-protocol population that included participants with no major protocol violations, who were seronegative at baseline to the relevant HPV type, and had post-vaccination data.
    End point type
    Primary
    End point timeframe
    Up to 7 Months (4 Weeks Postdose 3)
    End point values
    		 qHPV Vaccine + REPEVAX™ (Concomitant) qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects analysed
    419
    424
    Units: Number of Participants
        Anti-HPV Type 6 (n = 367, 376)
    367
    375
        Anti-HPV Type 11 (n = 367, 376)
    367
    376
        Anti-HPV Type 16 (n = 370, 378)
    370
    378
        Anti-HPV Type 18 (n = 372, 378)
    372
    378
    Statistical analysis title
    		 Seroconversion for Anti-HPV Type 6
    Statistical analysis description
    Analysis of non-inferiority of seroconversion for Anti-HPV Type 6 in participants who received concomitant compared with non-concomitant administration of qHPV vaccine and REPEVAX. Non-inferiority for seroconversion was demonstrated if there was <5 percentage point decrease in seroconversion for concomitant compared to non-concomitant administration and the lower limit of the 95% CI for the percentage point difference (concomitant-non-concomitant) was >-5.
    Comparison groups
    qHPV Vaccine + REPEVAX™ (Concomitant) v qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects included in analysis
    843
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 Miettinen and Nurminen
    Confidence interval
    Statistical analysis title
    		 Seroconversion for Anti-HPV Type 11
    Statistical analysis description
    Analysis of non-inferiority of seroconversion for Anti-HPV Type 11 in participants who received concomitant compared with non-concomitant administration of qHPV vaccine and REPEVAX. Non-inferiority for seroconversion was demonstrated if there was <5 percentage point decrease in seroconversion for concomitant compared to non-concomitant administration and the lower limit of the 95% CI for the percentage point difference (concomitant-non-concomitant) was >-5.
    Comparison groups
    qHPV Vaccine + REPEVAX™ (Concomitant) v qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects included in analysis
    843
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 Miettinen and Nurminen
    Confidence interval
    Statistical analysis title
    		 Seroconversion for Anti-HPV Type 16
    Statistical analysis description
    Analysis of non-inferiority of seroconversion for Anti-HPV Type 16 in participants who received concomitant compared with non-concomitant administration of qHPV vaccine and REPEVAX. Non-inferiority for seroconversion was demonstrated if there was <5 percentage point decrease in seroconversion for concomitant compared to non-concomitant administration and the lower limit of the 95% CI for the percentage point difference (concomitant-non-concomitant) was >-5.
    Comparison groups
    qHPV Vaccine + REPEVAX™ (Concomitant) v qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects included in analysis
    843
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 Miettinen and Nurminen
    Confidence interval
    Statistical analysis title
    		 Seroconversion for Anti-HPV Type 18
    Statistical analysis description
    Analysis of non-inferiority of seroconversion for Anti-HPV Type 18 in participants who received concomitant compared with non-concomitant administration of qHPV vaccine and REPEVAX. Non-inferiority for seroconversion was demonstrated if there was <5 percentage point decrease in seroconversion for concomitant compared to non-concomitant administration and the lower limit of the 95% CI for the percentage point difference (concomitant-non-concomitant) was >-5.
    Comparison groups
    qHPV Vaccine + REPEVAX™ (Concomitant) v qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects included in analysis
    843
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 Miettinen and Nurminen
    Confidence interval

    Primary: Geometric Mean Titers (GMTs) for Pertussis Toxoid (Anti-PT), Filamentous Haemagglutin (Anti-FHA), Pertactin (Anti-PRN), and Fimbrial Agglutinogens (Anti-FIM) Antibodies One Month Post-vaccination With REPEVAX™

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    End point title
    		 Geometric Mean Titers (GMTs) for Pertussis Toxoid (Anti-PT), Filamentous Haemagglutin (Anti-FHA), Pertactin (Anti-PRN), and Fimbrial Agglutinogens (Anti-FIM) Antibodies One Month Post-vaccination With REPEVAX™
    End point description
    Serum antibodies to Pertussis Toxoid Antibody (Anti-PT), Filamentous Haemagglutin Antibody (Anti-FHA), Pertactin (Anti-PRN), and Fimbrial Agglutinogens Antibody (Anti-FIM)were measured with an enzyme-linked immunosorbent assay (ELISA). Titers were reported in ELISA units/mL (ELU/mL) and the lower limit of quantitation for the assay is 5.0, 3.0, 5.0, and 5.0 ELU/mL for Anti-PT, Anti-FHA, Anti-PRN, and Anti-FIM, respectively. GMTs from participants who received qHPV vaccine and REPEVAX™ together at Day 1 (concomitant) were compared to GMTs from participants who received qHPV vaccine at Day 1 followed by REPEVAX™ 1 month later (non-concomitant). An analysis of non-inferiority compared GMTs using an ANOVA model with a response of log individual titers and fixed effects for treatment group, manufacturing facility, study site, and the treatment-by-site interaction.
    End point type
    Primary
    End point timeframe
    Up to 1 Month (1 Month Postdose1)
    End point values
    		 qHPV Vaccine + REPEVAX™ (Concomitant) qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects analysed
    419
    424
    Units: ELU/mL
    geometric mean (confidence interval 95%)
        GMTs for Anti-PT (n = 381, 378)
    38.1 (33.2 to 43.7)
    35.7 (31.1 to 40.9)
        GMTs for Anti-FHA (n = 382, 381)
    140.3 (127.5 to 154.4)
    140.7 (127.9 to 154.7)
        GMTs for Anti-PRN (n = 382, 381)
    504.1 (442.7 to 574)
    552.8 (485.9 to 629.1)
        GMTs for Anti-FIM (n = 381, 381)
    561.2 (478.9 to 657.7)
    506.4 (432.5 to 592.8)
    Statistical analysis title
    		 GMTs for Anti-PT
    Statistical analysis description
    Analysis of non-inferiority of the GMTs for Anti-PT induced in participants who received concomitant compared with non-concomitant administration of qHPV vaccine and REPEVAX. Non-inferiority of GMT was demonstrated if there was <1.5-fold decrease in GMT for concomitant compared to non-concomitant administration and the lower limit of the 95% CI for the GMT ratio (concomitant/non-concomitant) was >0.67.
    Comparison groups
    qHPV Vaccine + REPEVAX™ (Concomitant) v qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects included in analysis
    843
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 GMTs for Anti-FHA
    Statistical analysis description
    Analysis of non-inferiority of the GMTs for Anti-FHA induced in participants who received concomitant compared with non-concomitant administration of qHPV vaccine and REPEVAX. Non-inferiority of GMT was demonstrated if there was <1.5-fold decrease in GMT for concomitant compared to non-concomitant administration and the lower limit of the 95% CI for the GMT ratio (concomitant/non-concomitant) was >0.67.
    Comparison groups
    qHPV Vaccine + REPEVAX™ (Concomitant) v qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects included in analysis
    843
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 GMTs for Anti-PRN
    Statistical analysis description
    Analysis of non-inferiority of the GMTs for Anti-PRN induced in participants who received concomitant compared with non-concomitant administration of qHPV vaccine and REPEVAX. Non-inferiority of GMT was demonstrated if there was <1.5-fold decrease in GMT for concomitant compared to non-concomitant administration and the lower limit of the 95% CI for the GMT ratio (concomitant/non-concomitant) was >0.67.
    Comparison groups
    qHPV Vaccine + REPEVAX™ (Concomitant) v qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects included in analysis
    843
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 GMTs for Anti-FIM
    Statistical analysis description
    Analysis of non-inferiority of the GMTs for Anti-FIM induced in participants who received concomitant compared with non-concomitant administration of qHPV vaccine and REPEVAX. Non-inferiority of GMT was demonstrated if there was <1.5-fold decrease in GMT for concomitant compared to non-concomitant administration and the lower limit of the 95% CI for the GMT ratio (concomitant/non-concomitant) was >0.67.
    Comparison groups
    qHPV Vaccine + REPEVAX™ (Concomitant) v qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects included in analysis
    843
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval

    Primary: Number of Participants Who Achieved Acceptable Levels of Titers to Diphtheria (Diphtheria ≥ 0.1 IU/mL) One Month Post-vaccination With REPEVAX™

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    End point title
    		 Number of Participants Who Achieved Acceptable Levels of Titers to Diphtheria (Diphtheria ≥ 0.1 IU/mL) One Month Post-vaccination With REPEVAX™
    End point description
    Diphtheria antitoxin titers were measured using a neutralization assay in Vero cell culture that compares the antitoxin level in the serum of participants with the World Health Organization International Standard for Diphtheria Antitoxin. An acceptable level of response was defined as ≥0.1 International Units (IU)/milliliter (mL). Response levels of participants who received qHPV vaccine and REPEVAX™ together at Day 1 (concomitant) were compared to participants who received qHPV vaccine at Day 1 followed by REPEVAX™ 1 month later (non-concomitant). An analysis of non-inferiority compared response levels using methods developed by Miettinen and Nurminen adjusting for manufacturing facility for qHPV vaccine. The analysis was performed in the per-protocol population that included participants with no major protocol violations, who were seronegative at baseline to the relevant HPV type, and had post-vaccination data.
    End point type
    Primary
    End point timeframe
    Up to 1 Month (1 Month Postdose 1)
    End point values
    		 qHPV Vaccine + REPEVAX™ (Concomitant) qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects analysed
    380
    380
    Units: Number of Participants
    380
    379
    Statistical analysis title
    		 Participants With ≥ 0.1 IU/mL Antitoxin Titers
    Statistical analysis description
    Non-inferiority was demonstrated if there was <10 percentage point decrease in the percent of participants with ≥ 0.1 IU/mL for concomitant group compared to non-concomitant group and the lower limit of the 95% CI for the percentage point difference is greater than -10.
    Comparison groups
    qHPV Vaccine + REPEVAX™ (Concomitant) v qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects included in analysis
    760
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 Miettinen and Nurminen
    Confidence interval

    Primary: Number of Participants Who Achieved Acceptable Levels of Titers to Tetanus (Tetanus ≥0.1 IU/mL) One Month Post-vaccination With REPEVAX™

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    End point title
    		 Number of Participants Who Achieved Acceptable Levels of Titers to Tetanus (Tetanus ≥0.1 IU/mL) One Month Post-vaccination With REPEVAX™
    End point description
    Tetanus antitoxin titers were measured using an indirect, non-competitive enzyme immunoassay (EIA) that compares the antitoxin level in the serum of participants with the World Health Organization International Standard for Tetanus Immunoglobulin. An acceptable level of response was defined as ≥0.1 International Units (IU)/milliliter (mL). Response levels of participants who received qHPV vaccine and REPEVAX™ together at Day 1 (concomitant) were compared to participants who received qHPV vaccine at Day 1 followed by REPEVAX™ 1 month later (non-concomitant). An analysis of non-inferiority compared response levels using methods developed by Miettinen and Nurminen adjusting for manufacturing facility for qHPV vaccine. The analysis was performed in the per-protocol population that included participants with no major protocol violations, who were seronegative at baseline to the relevant HPV type, and had post-vaccination data.
    End point type
    Primary
    End point timeframe
    Up to 1 Month (1 Month Postdose 1)
    End point values
    		 qHPV Vaccine + REPEVAX™ (Concomitant) qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects analysed
    381
    380
    Units: Number of Participants
    381
    380
    Statistical analysis title
    		 Participants With ≥0.1 IU/mL Tetanus Titers
    Comparison groups
    qHPV Vaccine + REPEVAX™ (Concomitant) v qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects included in analysis
    761
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 Miettinen and Nurminen
    Confidence interval

    Primary: Number of Participants Who Achieved Acceptable Levels of Titers to Poliovirus Types 1, 2 and 3 (≥1:8 Dilution) One Month Post-vaccination With REPEVAX™

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    End point title
    		 Number of Participants Who Achieved Acceptable Levels of Titers to Poliovirus Types 1, 2 and 3 (≥1:8 Dilution) One Month Post-vaccination With REPEVAX™
    End point description
    Poliovirus antibody was measured using a poliovirus neutralization assay that assesses the ability of serial dilutions of participant sera to neutralize known amounts of type-specific Sabin poliovirus strains (Types 1, 2, and 3). An acceptable level of response was defined as participants who achieve detectable serum neutralizing antibodies (Neut Abs) at a ≥1:8 dilution (Dil) of sera. The response of participants who received qHPV vaccine and REPEVAX™ together at Day 1 (concomitant) was compared to participants who received qHPV vaccine at Day 1 followed by REPEVAX™ 1 month later (non-concomitant). An analysis of non-inferiority compared response levels using methods developed by Miettinen and Nurminen adjusting for manufacturing facility for qHPV vaccine. The analysis was performed in the per-protocol population that included participants with no major protocol violations, who were seronegative at baseline to the relevant HPV type, and had post-vaccination data.
    End point type
    Primary
    End point timeframe
    Up to 1 Month (1 Month Postdose 1)
    End point values
    		 qHPV Vaccine + REPEVAX™ (Concomitant) qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects analysed
    419
    424
    Units: Number of Participants
        Poliovirus Type 1 (n = 367, 377)
    367
    376
        Poliovirus Type 2 (n = 369, 377)
    369
    376
        Poliovirus Type 3 (n = 361, 375)
    360
    375
    Statistical analysis title
    		 Participants With Type 1 Neut Abs at ≥1:8 Dil
    Comparison groups
    qHPV Vaccine + REPEVAX™ (Concomitant) v qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects included in analysis
    843
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 Miettinen and Nurminen
    Confidence interval
    Statistical analysis title
    		 Participants With Type 2 Neut Abs at ≥1:8 Dil
    Comparison groups
    qHPV Vaccine + REPEVAX™ (Concomitant) v qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects included in analysis
    843
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 Miettinen and Nurminen
    Confidence interval
    Statistical analysis title
    		 Participants With Type 3 Neut Abs at ≥1:8 Dil
    Comparison groups
    qHPV Vaccine + REPEVAX™ (Concomitant) v qHPV Vaccine + REPEVAX™ (Non-concomitant)
    Number of subjects included in analysis
    843
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 Miettinen and Nurminen
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were collected from Day 1 until Month 7.
    Adverse event reporting additional description
    AEs were collected on participants who received ≥1 dose of study vaccine (qHPV or Repevax). Fevers and injection-site AEs were reported for Days 1-5 and all other AEs for Days 1-15. Injection-site AEs are reported separately for those associated with qHPV (AE term-qHPV) and those that are associated with Repevax (AE term-Repevax).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.1
    Reporting groups
    Reporting group title
    qHPV Vaccine + Repevax concomitant
    Reporting group description
    		 Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant (qHPV) vaccine and REPEVAX™ administered on Day 1 at different injection sites. The number exposed reflects 1 participant who was randomized into the Non-Concomitant Vaccination group and received study vaccines concomitantly and appears in the qHPV vaccine + Repevax (Concomitant Column).

    Reporting group title
    qHPV Vaccine + Repevax non-concomitant
    Reporting group description
    		 Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant (qHPV) vaccine administered on Day 1 followed by REPEVAX™ administered at Month 1. The number exposed reflects 1 participant who was randomized into the Non-Concomitant Vaccination group and received study vaccines concomitantly and appears in the qHPV vaccine + Repevax (Concomitant Column).

    Serious adverse events
    		 qHPV Vaccine + Repevax concomitant qHPV Vaccine + Repevax non-concomitant
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 420 (0.24%)
    3 / 423 (0.71%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Ligament rupture
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus lesion
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hyperventilation
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Ligament disorder
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 qHPV Vaccine + Repevax concomitant qHPV Vaccine + Repevax non-concomitant
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    405 / 420 (96.43%)
    406 / 423 (95.98%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    2 / 420 (0.48%)
    0 / 423 (0.00%)
         occurrences all number
    2
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 420 (0.48%)
    2 / 423 (0.47%)
         occurrences all number
    2
    2
    Axillary pain
         subjects affected / exposed
    2 / 420 (0.48%)
    2 / 423 (0.47%)
         occurrences all number
    2
    2
    Chills
         subjects affected / exposed
    3 / 420 (0.71%)
    1 / 423 (0.24%)
         occurrences all number
    3
    1
    Facial pain
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    13 / 420 (3.10%)
    8 / 423 (1.89%)
         occurrences all number
    13
    8
    Feeling cold
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Feeling of body temperature change
         subjects affected / exposed
    0 / 420 (0.00%)
    2 / 423 (0.47%)
         occurrences all number
    0
    2
    Influenza like illness
         subjects affected / exposed
    3 / 420 (0.71%)
    2 / 423 (0.47%)
         occurrences all number
    3
    2
    Injection site bruising-qHPV
         subjects affected / exposed
    6 / 420 (1.43%)
    5 / 423 (1.18%)
         occurrences all number
    6
    5
    Injection site discolouration-qHPV
         subjects affected / exposed
    1 / 420 (0.24%)
    1 / 423 (0.24%)
         occurrences all number
    1
    1
    Injection site erythema-qHPV
         subjects affected / exposed
    77 / 420 (18.33%)
    63 / 423 (14.89%)
         occurrences all number
    98
    85
    Injection site haematoma-qHPV
         subjects affected / exposed
    5 / 420 (1.19%)
    7 / 423 (1.65%)
         occurrences all number
    5
    8
    Injection site haemorrhage-qHPV
         subjects affected / exposed
    3 / 420 (0.71%)
    4 / 423 (0.95%)
         occurrences all number
    3
    4
    Injection site induration-qHPV
         subjects affected / exposed
    4 / 420 (0.95%)
    5 / 423 (1.18%)
         occurrences all number
    4
    5
    Injection site irritation-qHPV
         subjects affected / exposed
    1 / 420 (0.24%)
    2 / 423 (0.47%)
         occurrences all number
    2
    2
    Injection site movement impairment-qHPV
         subjects affected / exposed
    1 / 420 (0.24%)
    3 / 423 (0.71%)
         occurrences all number
    2
    5
    Injection site nodule-qHPV
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Injection site pain-qHPV
         subjects affected / exposed
    335 / 420 (79.76%)
    304 / 423 (71.87%)
         occurrences all number
    641
    630
    Injection site pruritus-qHPV
         subjects affected / exposed
    8 / 420 (1.90%)
    11 / 423 (2.60%)
         occurrences all number
    8
    11
    Injection site reaction-qHPV
         subjects affected / exposed
    1 / 420 (0.24%)
    1 / 423 (0.24%)
         occurrences all number
    1
    1
    Injection site swelling-qHPV
         subjects affected / exposed
    89 / 420 (21.19%)
    90 / 423 (21.28%)
         occurrences all number
    131
    119
    Injection site warmth-qHPV
         subjects affected / exposed
    1 / 420 (0.24%)
    2 / 423 (0.47%)
         occurrences all number
    1
    3
    Local swelling
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Malaise
         subjects affected / exposed
    5 / 420 (1.19%)
    2 / 423 (0.47%)
         occurrences all number
    5
    2
    Pyrexia
         subjects affected / exposed
    50 / 420 (11.90%)
    55 / 423 (13.00%)
         occurrences all number
    53
    60
    Vessel puncture site pain
         subjects affected / exposed
    1 / 420 (0.24%)
    1 / 423 (0.24%)
         occurrences all number
    1
    1
    Injection site anaesthesia-Repevax
         subjects affected / exposed
    1 / 420 (0.24%)
    1 / 423 (0.24%)
         occurrences all number
    1
    1
    Injection site bruising-Repevax
         subjects affected / exposed
    4 / 420 (0.95%)
    2 / 423 (0.47%)
         occurrences all number
    4
    2
    Injection site discolouration-Repevax
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Injection site erythema-Repevax
         subjects affected / exposed
    77 / 420 (18.33%)
    79 / 423 (18.68%)
         occurrences all number
    77
    80
    Injection site haematoma-Repevax
         subjects affected / exposed
    3 / 420 (0.71%)
    4 / 423 (0.95%)
         occurrences all number
    3
    4
    Injection site haemorrhage-Repevax
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Injection site induration-Repevax
         subjects affected / exposed
    3 / 420 (0.71%)
    3 / 423 (0.71%)
         occurrences all number
    3
    3
    Injection site irritation-Repevax
         subjects affected / exposed
    4 / 420 (0.95%)
    5 / 423 (1.18%)
         occurrences all number
    4
    5
    Injection site mass-Repevax
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Injection site movement impairment-Repevax
         subjects affected / exposed
    3 / 420 (0.71%)
    3 / 423 (0.71%)
         occurrences all number
    3
    3
    Injection site nodule-Repevax
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Injection site pain-Repevax
         subjects affected / exposed
    350 / 420 (83.33%)
    346 / 423 (81.80%)
         occurrences all number
    383
    373
    Injection site papule-Repevax
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Injection site pruritus-Repevax
         subjects affected / exposed
    4 / 420 (0.95%)
    7 / 423 (1.65%)
         occurrences all number
    4
    7
    Injection site rash-Repevax
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Injection site reaction-Repevax
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Injection site swelling-Repevax
         subjects affected / exposed
    130 / 420 (30.95%)
    131 / 423 (30.97%)
         occurrences all number
    132
    132
    Injection site warmth-Repevax
         subjects affected / exposed
    4 / 420 (0.95%)
    2 / 423 (0.47%)
         occurrences all number
    4
    2
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 420 (0.00%)
    2 / 423 (0.47%)
         occurrences all number
    0
    2
    Seasonal allergy
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    2
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    4 / 420 (0.95%)
    3 / 423 (0.71%)
         occurrences all number
    4
    4
    Metrorrhagia
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchitis chronic
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    14 / 420 (3.33%)
    11 / 423 (2.60%)
         occurrences all number
    15
    11
    Dyspnoea
         subjects affected / exposed
    3 / 420 (0.71%)
    0 / 423 (0.00%)
         occurrences all number
    3
    0
    Epistaxis
         subjects affected / exposed
    2 / 420 (0.48%)
    1 / 423 (0.24%)
         occurrences all number
    2
    2
    Nasal congestion
         subjects affected / exposed
    2 / 420 (0.48%)
    3 / 423 (0.71%)
         occurrences all number
    2
    3
    Pharyngolaryngeal pain
         subjects affected / exposed
    22 / 420 (5.24%)
    24 / 423 (5.67%)
         occurrences all number
    23
    29
    Rhinitis allergic
         subjects affected / exposed
    2 / 420 (0.48%)
    1 / 423 (0.24%)
         occurrences all number
    2
    2
    Rhinorrhoea
         subjects affected / exposed
    1 / 420 (0.24%)
    2 / 423 (0.47%)
         occurrences all number
    2
    2
    Throat irritation
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Eating disorder
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Listless
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Sleep disorder
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Body temperature increased
         subjects affected / exposed
    0 / 420 (0.00%)
    2 / 423 (0.47%)
         occurrences all number
    0
    2
    Heart rate increased
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Arthropod sting
         subjects affected / exposed
    0 / 420 (0.00%)
    2 / 423 (0.47%)
         occurrences all number
    0
    2
    Brain contusion
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Concussion
         subjects affected / exposed
    1 / 420 (0.24%)
    2 / 423 (0.47%)
         occurrences all number
    1
    2
    Contusion
         subjects affected / exposed
    0 / 420 (0.00%)
    2 / 423 (0.47%)
         occurrences all number
    0
    2
    Excoriation
         subjects affected / exposed
    0 / 420 (0.00%)
    2 / 423 (0.47%)
         occurrences all number
    0
    2
    Fracture
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Joint injury
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Joint sprain
         subjects affected / exposed
    2 / 420 (0.48%)
    1 / 423 (0.24%)
         occurrences all number
    2
    1
    Muscle strain
         subjects affected / exposed
    0 / 420 (0.00%)
    3 / 423 (0.71%)
         occurrences all number
    0
    3
    Post-traumatic pain
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    2
    Procedural dizziness
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Procedural pain
         subjects affected / exposed
    2 / 420 (0.48%)
    2 / 423 (0.47%)
         occurrences all number
    3
    4
    Thermal burn
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Wound
         subjects affected / exposed
    2 / 420 (0.48%)
    0 / 423 (0.00%)
         occurrences all number
    2
    0
    Incision site haemorrhage
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    14 / 420 (3.33%)
    10 / 423 (2.36%)
         occurrences all number
    15
    11
    Headache
         subjects affected / exposed
    132 / 420 (31.43%)
    112 / 423 (26.48%)
         occurrences all number
    193
    168
    Hyperaesthesia
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Loss of consciousness
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Migraine
         subjects affected / exposed
    0 / 420 (0.00%)
    3 / 423 (0.71%)
         occurrences all number
    0
    3
    Paraesthesia
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Somnolence
         subjects affected / exposed
    2 / 420 (0.48%)
    0 / 423 (0.00%)
         occurrences all number
    2
    0
    Syncope
         subjects affected / exposed
    2 / 420 (0.48%)
    1 / 423 (0.24%)
         occurrences all number
    2
    1
    Syncope vasovagal
         subjects affected / exposed
    1 / 420 (0.24%)
    1 / 423 (0.24%)
         occurrences all number
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Hypochromasia
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Lymphadenitis
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Ear pain
         subjects affected / exposed
    4 / 420 (0.95%)
    2 / 423 (0.47%)
         occurrences all number
    4
    3
    Motion sickness
         subjects affected / exposed
    2 / 420 (0.48%)
    0 / 423 (0.00%)
         occurrences all number
    2
    0
    Vertigo
         subjects affected / exposed
    2 / 420 (0.48%)
    2 / 423 (0.47%)
         occurrences all number
    2
    2
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 420 (0.24%)
    1 / 423 (0.24%)
         occurrences all number
    1
    1
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Eye pain
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Eye pruritus
         subjects affected / exposed
    0 / 420 (0.00%)
    2 / 423 (0.47%)
         occurrences all number
    0
    2
    Lacrimation increased
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Ocular discomfort
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Photophobia
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    20 / 420 (4.76%)
    12 / 423 (2.84%)
         occurrences all number
    26
    16
    Abdominal pain lower
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    14 / 420 (3.33%)
    16 / 423 (3.78%)
         occurrences all number
    15
    18
    Aphthous stomatitis
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    9 / 420 (2.14%)
    18 / 423 (4.26%)
         occurrences all number
    9
    21
    Dyspepsia
         subjects affected / exposed
    1 / 420 (0.24%)
    1 / 423 (0.24%)
         occurrences all number
    1
    2
    Enteritis
         subjects affected / exposed
    0 / 420 (0.00%)
    2 / 423 (0.47%)
         occurrences all number
    0
    2
    Gastritis
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Gingivitis
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Lip swelling
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    21 / 420 (5.00%)
    19 / 423 (4.49%)
         occurrences all number
    27
    21
    Stomatitis
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    2
    Teething
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Toothache
         subjects affected / exposed
    2 / 420 (0.48%)
    2 / 423 (0.47%)
         occurrences all number
    2
    2
    Vomiting
         subjects affected / exposed
    11 / 420 (2.62%)
    11 / 423 (2.60%)
         occurrences all number
    11
    13
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Eczema
         subjects affected / exposed
    2 / 420 (0.48%)
    1 / 423 (0.24%)
         occurrences all number
    2
    1
    Erythema
         subjects affected / exposed
    3 / 420 (0.71%)
    2 / 423 (0.47%)
         occurrences all number
    3
    2
    Hyperhidrosis
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    3 / 420 (0.71%)
    2 / 423 (0.47%)
         occurrences all number
    3
    2
    Rash
         subjects affected / exposed
    3 / 420 (0.71%)
    2 / 423 (0.47%)
         occurrences all number
    3
    2
    Rash macular
         subjects affected / exposed
    1 / 420 (0.24%)
    1 / 423 (0.24%)
         occurrences all number
    1
    1
    Rash pruritic
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Subcutaneous nodule
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    4 / 420 (0.95%)
    1 / 423 (0.24%)
         occurrences all number
    4
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 420 (1.43%)
    8 / 423 (1.89%)
         occurrences all number
    6
    9
    Back pain
         subjects affected / exposed
    5 / 420 (1.19%)
    5 / 423 (1.18%)
         occurrences all number
    5
    5
    Bone pain
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Coccydynia
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Groin pain
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Growing pains
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Joint swelling
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    2 / 420 (0.48%)
    1 / 423 (0.24%)
         occurrences all number
    2
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 420 (0.24%)
    2 / 423 (0.47%)
         occurrences all number
    1
    2
    Myalgia
         subjects affected / exposed
    3 / 420 (0.71%)
    5 / 423 (1.18%)
         occurrences all number
    4
    5
    Neck pain
         subjects affected / exposed
    3 / 420 (0.71%)
    3 / 423 (0.71%)
         occurrences all number
    3
    3
    Pain in extremity
         subjects affected / exposed
    8 / 420 (1.90%)
    6 / 423 (1.42%)
         occurrences all number
    10
    8
    Sensation of heaviness
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Tendonitis
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Blister infected
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Bronchitis
         subjects affected / exposed
    1 / 420 (0.24%)
    2 / 423 (0.47%)
         occurrences all number
    1
    2
    Cystitis
         subjects affected / exposed
    1 / 420 (0.24%)
    1 / 423 (0.24%)
         occurrences all number
    1
    1
    Ear infection
         subjects affected / exposed
    0 / 420 (0.00%)
    2 / 423 (0.47%)
         occurrences all number
    0
    2
    Gastroenteritis
         subjects affected / exposed
    10 / 420 (2.38%)
    7 / 423 (1.65%)
         occurrences all number
    11
    9
    Hordeolum
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Infection
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    11 / 420 (2.62%)
    10 / 423 (2.36%)
         occurrences all number
    12
    13
    Laryngitis
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Lice infestation
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Localised infection
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    25 / 420 (5.95%)
    28 / 423 (6.62%)
         occurrences all number
    25
    29
    Oral herpes
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Otitis externa
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Otitis media
         subjects affected / exposed
    1 / 420 (0.24%)
    2 / 423 (0.47%)
         occurrences all number
    1
    2
    Pharyngitis
         subjects affected / exposed
    6 / 420 (1.43%)
    2 / 423 (0.47%)
         occurrences all number
    6
    2
    Pneumonia
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    2 / 420 (0.48%)
    7 / 423 (1.65%)
         occurrences all number
    2
    7
    Rhinitis
         subjects affected / exposed
    19 / 420 (4.52%)
    20 / 423 (4.73%)
         occurrences all number
    21
    23
    Sialoadenitis
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    6 / 420 (1.43%)
    2 / 423 (0.47%)
         occurrences all number
    6
    2
    Tinea versicolour
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Tonsillitis
         subjects affected / exposed
    0 / 420 (0.00%)
    3 / 423 (0.71%)
         occurrences all number
    0
    3
    Upper respiratory tract infection
         subjects affected / exposed
    21 / 420 (5.00%)
    10 / 423 (2.36%)
         occurrences all number
    23
    12
    Urinary tract infection
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Viral infection
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Viral tonsillitis
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    1 / 420 (0.24%)
    2 / 423 (0.47%)
         occurrences all number
    1
    2
    Hypoglycaemia
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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