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    Clinical Trial Results:
    A Phase 3, Open-Label, Randomized Trial to Investigate the Immunogenicity and Safety of the Co-administration of a Subcutaneous Dengue Tetravalent Vaccine (Live, Attenuated) (TDV) and an Intramuscular Recombinant 9-Valent Human Papillomavirus (9vHPV) Vaccine in Subjects Aged ≥9 to <15 Years in an Endemic Country for Dengue

    Summary
    EudraCT number
    		 2022-003339-24
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    19 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Feb 2024
    First version publication date
    01 Feb 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    DEN-308
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04313244
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Takeda Vaccines, Inc.
    Sponsor organisation address
    40 Landsdowne Street, Cambridge, United States, MA 02139
    Public contact
    Study Director, Takeda Vaccines, Inc., TrialDisclosures@takeda.com
    Scientific contact
    Study Director, Takeda Vaccines, Inc., TrialDisclosures@takeda.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
    19 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to demonstrate the non-inferiority (NI) of the immune response to 2 doses of 9vHPV vaccine, 1 co-administered with TDV, compared with 2 doses of 9vHPV vaccine administered alone.
    Protection of trial subjects
    Each participant signed an informed consent form before participating in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 May 2021
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Thailand: 614
    Worldwide total number of subjects
    614
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    369
    Adolescents (12-17 years)
    245
    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
    		 Participants took part in the study at 4 investigative sites in Thailand from 15 May 2021 to 19 July 2022.

    Pre-assignment
    Screening details
    		 Healthy participants aged ≥9 to <15 years in endemic areas for dengue were enrolled in this study to receive recombinant 9-valent human papillomavirus vaccine (9vHPV) alone or with tetravalent dengue vaccine (TDV).

    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
    		 9vHPV+TDV
    Arm description
    		 Participants received 0.5 mL 9vHPV intramuscularly (IM) and 0.5 mL TDV subcutaneously (SC) once on Day 1 (Month 0) followed by 0.5 mL TDV SC once on Day 90 (Month 3) and 0.5 mL 9vHPV IM once on Day 180 (Month 6).
    Arm type
    		 Experimental

    Investigational medicinal product name
    9vHPV vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL 9vHPV IM administered once on Day 1 (Month 0) followed by 0.5 mL once on Day 180 (Month 6).

    Investigational medicinal product name
    Dengue Tetravalent Vaccine (TDV)
    Investigational medicinal product code
    Other name
    TAK-003
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL TDV administered SC once on Day 1 (Month 0) followed by 0.5 mL once on Day 90 (Month 3).

    Arm title
    		 9vHPV
    Arm description
    		 Participants received 0.5 mL 9vHPV IM once on Day 1 (Month 0) followed by 0.5 mL 9vHPV IM once on Day 180 (Month 6).
    Arm type
    		 Experimental

    Investigational medicinal product name
    9vHPV vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL 9vHPV vaccine IM will be administered once on Day 1 (Month 0) followed by 0.5 mL 9vHPV vaccine IM once on Day 180 (Month 6).

    Number of subjects in period 1
    		9vHPV+TDV 9vHPV
    Started
    307
    307
    Completed
    302
    304
    Not completed
    5
    3
         Withdrawal of Consent
    3
    3
         Invalid Informed Consent Form (ICF)
    1
    -
         Met Exclusion Criteria
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    9vHPV+TDV
    Reporting group description
    		 Participants received 0.5 mL 9vHPV intramuscularly (IM) and 0.5 mL TDV subcutaneously (SC) once on Day 1 (Month 0) followed by 0.5 mL TDV SC once on Day 90 (Month 3) and 0.5 mL 9vHPV IM once on Day 180 (Month 6).

    Reporting group title
    9vHPV
    Reporting group description
    		 Participants received 0.5 mL 9vHPV IM once on Day 1 (Month 0) followed by 0.5 mL 9vHPV IM once on Day 180 (Month 6).

    Reporting group values
    		 9vHPV+TDV 9vHPV Total
    Number of subjects
    		 307 307
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 11.1 ( 1.60 ) 11.3 ( 1.59 ) -
    Gender categorical
    Units: Subjects
        Female
    		 150 156 306
        Male
    		 157 151 308
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 307 307 614
        Unknown or Not Reported
    		 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 307 307 614
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 0 0 0
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Region of Enrollment
    Units: Subjects
        Thailand Thailand
    		 307 307 614
    Height
    Units: centimeters (cm)
        arithmetic mean (standard deviation)
    		 ( ) 148.18 ( 11.374 ) -
    Weight
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    		 ( ) 44.37 ( 14.271 ) -
    Body Mass Index (BMI)
    BMI=weight (kg) / [height (m)]^2
    Units: kilograms per meter square (kg/m^2)
        arithmetic mean (standard deviation)
    		 ( ) 19.88 ( 4.762 ) -
    Subject analysis sets

    Subject analysis set title
    9vHPV+TDV
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants will receive 0.5 mL 9vHPV IM with 0.5 mL TDV SC once on Day 1 (Month 0) followed by 0.5 mL TDV SC once on Day 90 (Month 3) and 0.5 mL 9vHPV IM once on Day 180 (Month 6). This analysis set included all participants with data available for height, weight, and body mass index (BMI) at the Baseline.

    Subject analysis sets values
    		 9vHPV+TDV
    Number of subjects
    306
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    Gender categorical
    Units: Subjects
        Female
        Male
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Unknown or Not Reported
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
        Asian
        Native Hawaiian or Other Pacific Islander
        Black or African American
        White
        More than one race
        Unknown or Not Reported
    Region of Enrollment
    Units: Subjects
        Thailand Thailand
    Height
    Units: centimeters (cm)
        arithmetic mean (standard deviation)
    147.68 ( 12.244 )
    Weight
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    44.21 ( 15.913 )
    Body Mass Index (BMI)
    BMI=weight (kg) / [height (m)]^2
    Units: kilograms per meter square (kg/m^2)
        arithmetic mean (standard deviation)
    19.78 ( 4.912 )

    End points

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    End points reporting groups
    Reporting group title
    9vHPV+TDV
    Reporting group description
    		 Participants received 0.5 mL 9vHPV intramuscularly (IM) and 0.5 mL TDV subcutaneously (SC) once on Day 1 (Month 0) followed by 0.5 mL TDV SC once on Day 90 (Month 3) and 0.5 mL 9vHPV IM once on Day 180 (Month 6).

    Reporting group title
    9vHPV
    Reporting group description
    		 Participants received 0.5 mL 9vHPV IM once on Day 1 (Month 0) followed by 0.5 mL 9vHPV IM once on Day 180 (Month 6).

    Subject analysis set title
    9vHPV+TDV
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants will receive 0.5 mL 9vHPV IM with 0.5 mL TDV SC once on Day 1 (Month 0) followed by 0.5 mL TDV SC once on Day 90 (Month 3) and 0.5 mL 9vHPV IM once on Day 180 (Month 6). This analysis set included all participants with data available for height, weight, and body mass index (BMI) at the Baseline.

    Primary: Geometric Mean Titers (GMTs) for Human Papillomavirus (HPV) Types 6, 11, 16, 18, 31, 33, 45, 52, 58

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    End point title
    		 Geometric Mean Titers (GMTs) for Human Papillomavirus (HPV) Types 6, 11, 16, 18, 31, 33, 45, 52, 58 [1]
    End point description
    GMTs for HPV were measured by immunoglobulin G binding assay (IgGBA) assay. HPV-6, HPV-11, HPV-16, HPV-18, HPV-31, HPV-33, HPV-45, HPV-52 and HPV-58 were the types of HPV analyzed. The Per-protocol Set (PPS) excluded all participants seropositive to any HPV type at Baseline and included all participants from the Full Analysis Set (FAS) who had no major protocol violations. Overall number of participants analyzed is the number of participants available for analyses.
    End point type
    Primary
    End point timeframe
    Day 210 (Month 7)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As prespecified in the protocol, only descriptive statistics were planned to be analysed and reported for this endpoint.
    End point values
    		 9vHPV+TDV 9vHPV
    Number of subjects analysed
    237
    234
    Units: titer
    geometric mean (confidence interval 95%)
        HPV-6
    1633.693 (1465.31 to 1821.43)
    1790.986 (1556.08 to 2061.35)
        HPV-11
    1342.745 (1225.64 to 1471.04)
    1325.192 (1164.58 to 1507.95)
        HPV-16
    7777.694 (6989.76 to 8654.45)
    7822.564 (6701.83 to 9130.71)
        HPV-18
    2309.629 (2075.91 to 2569.66)
    2506.309 (2182.67 to 2877.93)
        HPV-31
    1690.941 (1529.39 to 1869.55)
    1736.943 (1515.05 to 1991.33)
        HPV-33
    1138.716 (1019.66 to 1271.67)
    1179.469 (1033.66 to 1345.84)
        HPV-45
    504.033 (453.46 to 560.24)
    584.198 (509.91 to 669.31)
        HPV-52
    585.606 (533.44 to 642.87)
    561.007 (492.77 to 638.69)
        HPV-58
    1163.600 (1060.23 to 1277.05)
    1284.504 (1130.63 to 1459.32)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Seropositivity for HPV Types 6, 11, 16, 18, 31, 33, 45, 52 and 58 as Measured by Immunoglobulin G Binding Assay (IgGBA)

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    End point title
    		 Percentage of Participants with Seropositivity for HPV Types 6, 11, 16, 18, 31, 33, 45, 52 and 58 as Measured by Immunoglobulin G Binding Assay (IgGBA)
    End point description
    Seropositive for HPV is defined as anti-HPV titers greater or equal to the prespecified cutoffs for any of the 9 HPV serotypes: HPV-6, HPV-11, HPV-16, HPV-18, HPV-31, HPV-33, HPV-45, HPV-52 and HPV-58, measured by IgGBA. The serostatus cut-off is the antibody titer level above the assay’s lower limit of quantification that reliably distinguishes sera samples classified by clinical likelihood of HPV infection and positive or negative status by previous versions of IgGBA or equivalent assay. The serostatus cut-offs for the 9 HPV serotypes: HPV-6= 9, HPV-11= 6, HPV-16= 5, HPV-18= 5, HPV-31= 3, HPV-33= 4, HPV-45= 3, HPV-52= 5 and HPV-58= 5. Percentages are rounded off to the nearest decimal point. The PPS excluded all participants seropositive to any HPV type at Baseline and included all participants from the FAS who had no major protocol violations. Overall number of participants analyzed is the number of participants available for analyses.
    End point type
    Secondary
    End point timeframe
    Day 210 (Month 7)
    End point values
    		 9vHPV+TDV 9vHPV
    Number of subjects analysed
    237
    234
    Units: percentage of participants
    number (confidence interval 95%)
        HPV-6
    100.0 (98.5 to 100.0)
    99.1 (96.9 to 99.9)
        HPV-11
    100.0 (98.5 to 100.0)
    99.1 (96.9 to 99.9)
        HPV-16
    100.0 (98.5 to 100.0)
    99.1 (96.9 to 99.9)
        HPV-18
    100.0 (98.5 to 100.0)
    99.1 (96.9 to 99.9)
        HPV-31
    100.0 (98.5 to 100.0)
    99.1 (96.9 to 99.9)
        HPV-33
    100.0 (98.5 to 100.0)
    99.1 (96.9 to 99.9)
        HPV-45
    100.0 (98.5 to 100.0)
    99.1 (96.9 to 99.9)
        HPV-52
    100.0 (98.5 to 100.0)
    99.1 (96.9 to 99.9)
        HPV-58
    100.0 (98.5 to 100.0)
    99.1 (96.9 to 99.9)
    No statistical analyses for this end point

    Secondary: GMTs of Neutralizing Antibodies for Each of the 4 Dengue Serotypes

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    End point title
    		 GMTs of Neutralizing Antibodies for Each of the 4 Dengue Serotypes [2]
    End point description
    GMTs of neutralizing antibodies for each of the 4 dengue serotypes were measured by microneutralization test 50% (MNT50). The four dengue serotypes: DENV-1, DENV-2, DENV-3 and DENV-4. As prespecified in the protocol, the data for this outcome measure was collected and analyzed for participants in the 9vHPV+TDV arm group only. The PPS excluded all participants seropositive to any HPV type at Baseline and included all participants from the FAS who had no major protocol violations. Overall number of participants analyzed is the number of participants available for analyses.
    End point type
    Secondary
    End point timeframe
    Day 120 (Month 4)
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the protocol, the data for this outcome measure was collected and analyzed for participants in the 9vHPV+TDV arm group only.
    End point values
    		 9vHPV+TDV
    Number of subjects analysed
    238
    Units: titer
    geometric mean (confidence interval 95%)
        DENV-1
    719.1 (577.8 to 895.0)
        DENV-2
    1691.4 (1411.0 to 2027.4)
        DENV-3
    555.4 (462.8 to 666.6)
        DENV-4
    494.3 (420.8 to 580.6)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Seropositivity for Each of the 4 Dengue Serotypes

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    End point title
    		 Percentage of Participants with Seropositivity for Each of the 4 Dengue Serotypes [3]
    End point description
    Seropositivity is defined as a reciprocal neutralizing antibody titer ≥10 for any of the 4 dengue serotypes. The four dengue serotypes: DENV-1, DENV-2, DENV-3 and DENV-4. As prespecified in the protocol, the data for this outcome measure was collected and analyzed for participants in the 9vHPV+TDV arm group only. Percentages are rounded off to the nearest decimal point. The PPS excluded all participants seropositive to any HPV type at Baseline and included all participants from the FAS who had no major protocol violations. Overall number of participants analyzed is the number of participants available for analyses.
    End point type
    Secondary
    End point timeframe
    Day 120 (Month 4)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the protocol, the data for this outcome measure was collected and analyzed for participants in the 9vHPV+TDV arm group only.
    End point values
    		 9vHPV+TDV
    Number of subjects analysed
    238
    Units: percentage of participants
    number (confidence interval 95%)
        DENV-1
    100.0 (98.5 to 100.0)
        DENV-2
    99.6 (97.7 to 100.0)
        DENV-3
    100.0 (98.5 to 100.0)
        DENV-4
    100.0 (98.5 to 100.0)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Seropositivity for Multiple (2, 3 or 4) Dengue Serotypes

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    End point title
    		 Percentage of Participants with Seropositivity for Multiple (2, 3 or 4) Dengue Serotypes [4]
    End point description
    Seropositivity is defined as a reciprocal neutralizing antibody titer ≥10 for any of the 4 dengue serotypes. The dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. Seropositive for multiple dengue serotypes were summarized for categories with at least one participant with event: trivalent (seropositive for 3 dengue serotypes), and tetravalent (seropositive for all 4 dengue serotypes). As prespecified in the protocol, the data for this outcome measure was collected and analyzed for participants in the 9vHPV+TDV arm group only. Percentages are rounded off to the nearest decimal point. The PPS excluded all participants seropositive to any HPV type at Baseline and included all participants from the FAS who had no major protocol violations. Overall number of participants analyzed is the number of participants available for analyses.
    End point type
    Secondary
    End point timeframe
    Day 120 (Month 4)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the protocol, the data for this outcome measure was collected and analyzed for participants in the 9vHPV+TDV arm group only.
    End point values
    		 9vHPV+TDV
    Number of subjects analysed
    238
    Units: percentage of participants
    number (confidence interval 95%)
        Trivalent
    0.4 (0.0 to 2.3)
        Tetravalent
    99.6 (97.7 to 100.0)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Solicited Local Adverse Events for 7 Days Following Vaccination by Severity 

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    End point title
    		 Percentage of Participants with Solicited Local Adverse Events for 7 Days Following Vaccination by Severity 
    End point description
    Solicited local adverse events (AEs) (at injection site) were collected by participants using diary cards within 7 days after vaccination and included: Pain [Grade 0 (no pain), 1 (mild: no interference with daily activity), 2 (moderate: interference with daily activity with or without treatment) and 3 (severe: prevents daily activity with or without treatment)]; erythema and swelling [Grade 0 (<25 millimeters [mm]), 1 (25 - ≤ 50 mm), 2 (>50 - ≤ 100 mm), 3 (> 100 mm)]. Percentages are rounded off to the nearest decimal point. The data for solicited local adverse events after any vaccination are presented. Only those categories with at least 1 participant with event are reported. Safety Set included all randomized participants who received at least 1 dose of IPs.
    End point type
    Secondary
    End point timeframe
    Up to 7 days (Day of vaccination + 6 subsequent days) after each vaccination
    End point values
    		 9vHPV+TDV 9vHPV
    Number of subjects analysed
    307
    307
    Units: percentage of participants
    number (not applicable)
        Pain: Mild
    54.1
    42.8
        Pain: Moderate
    9.5
    6.5
        Pain: Severe
    0.7
    0
        Erythema: Mild
    7.5
    0
        Erythema: Moderate
    0.7
    0
        Swelling: Mild
    3.3
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Solicited Systemic Adverse Events (AEs) for 14 Days Following Vaccination by Severity

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    End point title
    		 Percentage of Participants with Solicited Systemic Adverse Events (AEs) for 14 Days Following Vaccination by Severity
    End point description
    Solicited systemic AEs were collected by participants using diary cards within 14 days after vaccination and included fever, headache, asthenia, malaise, and myalgia. Severity grades were: Grade 0: none, Grade 1: mild (no interference with daily activity), Grade 2: moderate (interference with daily activity with or without treatment), Grade 3: severe (prevents normal daily activity with or without treatment). Fever is defined as body temperature greater than or equal to 38°C (100.4 degrees Fahrenheit [°F]). Only categories with at least one participant with event following any vaccination are reported. Percentages are rounded off to the nearest decimal point. The data for solicited systemic adverse events after any vaccination are presented. Only those categories with at least 1 participant with event are reported. Safety Set included all randomized participants who received at least 1 dose of IPs.
    End point type
    Secondary
    End point timeframe
    Up to 14 days (Day of vaccination + 13 subsequent days) after each vaccination
    End point values
    		 9vHPV+TDV 9vHPV
    Number of subjects analysed
    307
    307
    Units: percentage of participants
    number (not applicable)
        Headache: Mild
    20.0
    18.0
        Headache: Moderate
    3.0
    0.7
        Headache: Severe
    0.3
    0
        Asthenia: Mild
    16.7
    12.1
        Asthenia: Moderate
    2.0
    1.0
        Asthenia: Severe
    0.3
    0
        Malaise: Mild
    17.7
    10.5
        Malaise: Moderate
    2.0
    1.3
        Malaise: Severe
    0.3
    0
        Myalgia: Mild
    36.1
    27.8
        Myalgia: Moderate
    7.9
    2.3
        Myalgia: Severe
    0.3
    0.3
        Fever: 38.0°C-<38.5°C
    2.0
    0.3
        Fever: 38.5°C-<39.0°C
    0.3
    0
        Fever: 39.0°C-<39.5°C
    0.3
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with any Unsolicited AEs for 28 Days Following Vaccination

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    End point title
    		 Percentage of Participants with any Unsolicited AEs for 28 Days Following Vaccination
    End point description
    An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a study vaccine; it does not necessarily have to have a causal relationship with study vaccine administration. Percentages are rounded off to the nearest decimal point. The data for unsolicited adverse events after any vaccination are presented. Safety Set included all randomized participants who received at least 1 dose of IPs.
    End point type
    Secondary
    End point timeframe
    Up to 28 days (Day of vaccination + 27 subsequent days) after each vaccination
    End point values
    		 9vHPV+TDV 9vHPV
    Number of subjects analysed
    307
    307
    Units: percentage of participants
        number (not applicable)
    8.8
    2.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Serious Adverse Events (SAEs)

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    End point title
    		 Percentage of Participants with Serious Adverse Events (SAEs)
    End point description
    An SAE is defined as any untoward medical occurrence or effect that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important which may require intervention to prevent the items listed above or may expose the participant to danger. Safety Set included all randomized participants who received at least 1 dose of IPs.
    End point type
    Secondary
    End point timeframe
    From first vaccination (Day 1 [Month 0]) through end of study (Day 360 [Month 12])
    End point values
    		 9vHPV+TDV 9vHPV
    Number of subjects analysed
    307
    307
    Units: percentage of participants
        number (not applicable)
    10.1
    7.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality and serious adverse events: From first vaccination (Day 1 [Month 0]) through end of study (Day 360 [Month 12]); Non-serious adverse events: Unsolicited adverse events: Up to 28 days (day of vaccination + 27 days) after each vaccination
    Adverse event reporting additional description
    Safety Set included all randomized participants who received at least 1 dose of IPs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26
    Reporting groups
    Reporting group title
    9vHPV
    Reporting group description
    		 Participants received 0.5 mL 9vHPV IM once on Day 1 (Month 0) followed by 0.5 mL 9vHPV IM once on Day 180 (Month 6).

    Reporting group title
    9vHPV+TDV
    Reporting group description
    		 Participants received 0.5 mL 9vHPV IM and 0.5 mL TDV SC once on Day 1 (Month 0) followed by 0.5 mL TDV SC once on Day 90 (Month 3) and 0.5 mL 9vHPV IM once on Day 180 (Month 6).

    Serious adverse events
    		 9vHPV 9vHPV+TDV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 307 (7.17%)
    31 / 307 (10.10%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Foreign body in gastrointestinal tract
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    19 / 307 (6.19%)
    26 / 307 (8.47%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 26
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 307 (0.65%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 307 (0.33%)
         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: 0%
    Non-serious adverse events
    		 9vHPV 9vHPV+TDV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    223 / 307 (72.64%)
    253 / 307 (82.41%)
    Injury, poisoning and procedural complications
    Wound
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 307 (0.33%)
         occurrences all number
    0
    1
    Skin abrasion
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 307 (0.33%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    59 / 307 (19.22%)
    71 / 307 (23.13%)
         occurrences all number
    93
    207
    Syncope
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 307 (0.33%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    1 / 307 (0.33%)
    8 / 307 (2.61%)
         occurrences all number
    1
    11
    Asthenia
         subjects affected / exposed
    40 / 307 (13.03%)
    58 / 307 (18.89%)
         occurrences all number
    79
    159
    Malaise
         subjects affected / exposed
    36 / 307 (11.73%)
    62 / 307 (20.20%)
         occurrences all number
    61
    153
    Injection site pain
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 307 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 307 (0.00%)
    2 / 307 (0.65%)
         occurrences all number
    0
    2
    Swelling
         subjects affected / exposed
    52 / 307 (16.94%)
    64 / 307 (20.85%)
         occurrences all number
    147
    319
    Pain
         subjects affected / exposed
    184 / 307 (59.93%)
    225 / 307 (73.29%)
         occurrences all number
    359
    983
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 307 (0.33%)
         occurrences all number
    0
    1
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 307 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Flatulence
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 307 (0.00%)
         occurrences all number
    1
    0
    Aphthous ulcer
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 307 (0.33%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 307 (0.33%)
    2 / 307 (0.65%)
         occurrences all number
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 307 (0.33%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 307 (0.00%)
    2 / 307 (0.65%)
         occurrences all number
    0
    2
    Erythema
         subjects affected / exposed
    57 / 307 (18.57%)
    92 / 307 (29.97%)
         occurrences all number
    146
    501
    Rash
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 307 (0.33%)
         occurrences all number
    0
    1
    Urticaria
         subjects affected / exposed
    1 / 307 (0.33%)
    1 / 307 (0.33%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    93 / 307 (30.29%)
    135 / 307 (43.97%)
         occurrences all number
    181
    475
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 307 (0.00%)
    2 / 307 (0.65%)
         occurrences all number
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 307 (0.00%)
    3 / 307 (0.98%)
         occurrences all number
    0
    3
    Gastroenteritis
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 307 (0.33%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 307 (0.33%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Mar 2021
    The following changes were implemented as per Amendment 2: 1. Update in responsibilities of the signatory investigator. 2. Addition of trial risk management. 3. Administrative change of the details of the medical director and clinical project oversight manager. 4. Deletion of proprietary table showing lower limits of quantification and serostatus cut-offs for each of the 9 vaccine HPV types.

    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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    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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