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    Clinical Trial Results:
    Immunogenicity and Safety of a Tetravalent Dengue Vaccine Administered Concomitantly or Sequentially with Adacel® in Healthy Subjects Aged 9 to 60 Years in the Philippines

    Summary
    EudraCT number
    2019-003136-23
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    10 Dec 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Jun 2020
    First version publication date
    21 Jun 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CYD66
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02992418
    WHO universal trial number (UTN)
    U1111-1161-3294
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur
    Sponsor organisation address
    14, Espace Henry Vallée, Lyon, France, 69007
    Public contact
    Trial Transparency Team, Sanofi Pasteur, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi Pasteur, Contact-US@sanofi.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
    07 Apr 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Dec 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    - To demonstrate the non-inferiority of the humoral immune response to the Tetanus Toxoid (T), Reduced Diphtheria Toxoid (D) and Acellular Pertussis Vaccine Adsorbed (ap) (Tdap) booster dose concomitantly administered with the first dose of CYD dengue vaccine as compared to sequential administration, measured 28 days after Tdap booster dose. - To demonstrate the non-inferiority of the humoral immune response to the first dose of CYD dengue vaccine concomitantly administered with Tdap as compared to sequential administration, measured 28 days after the first dose of CYD dengue vaccine.
    Protection of trial subjects
    Vaccinations were performed by qualified and trained study personnel. Subjects with allergy to any of the vaccine components were not vaccinated. After vaccination, subjects were also kept under clinical observation for 30 minutes to ensure their safety. Appropriate medical equipment was also available on site in case of any immediate allergic reactions.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    19 Dec 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Philippines: 688
    Worldwide total number of subjects
    688
    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)
    172
    Adolescents (12-17 years)
    172
    Adults (18-64 years)
    344
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study subjects were enrolled from 19 December 2016 to 17 April 2017 at 4 centres in the Philippines. A total of 688 subjects were enrolled and randomised in this study.

    Pre-assignment
    Screening details
    Safety signal was identified in seronegative subjects, which led to IDMC recommendation to not vaccinate them anymore. As no Health Authority feedback was received on amendment 1, study was stopped prematurely before 3rd (last) injection of CYD dengue vaccine and no subjects received 3rd CYD dengue dose. All subjects were followed for safety.

    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
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration)
    Arm description
    Subjects received 1 booster dose of Tdap vaccine 0.5 millilitre (mL) intramuscular (IM) injection at Month 1, and 2 doses of CYD dengue vaccine 0.5 mL subcutaneous (SC) injection at Month 1 (concomitantly with Tdap booster dose) and at Month 7.
    Arm type
    Experimental

    Investigational medicinal product name
    Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine (Tdap)
    Investigational medicinal product code
    Other name
    Adacel®
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM injection at Month 1.

    Investigational medicinal product name
    CYD Dengue Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, SC injection at Month 1 and Month 7, respectively.

    Arm title
    CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Arm description
    Subjects received 1 booster dose of Tdap vaccine 0.5 mL IM injection at Day 0 and 2 doses of CYD dengue vaccine 0.5 mL SC injection at Month 1 (sequentially, one month after the Tdap booster dose) and at Month 7.
    Arm type
    Experimental

    Investigational medicinal product name
    Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine (Tdap)
    Investigational medicinal product code
    Other name
    Adacel®
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM injection at Month 1.

    Investigational medicinal product name
    CYD Dengue Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, SC injection at Month 1 and Month 7, respectively.

    Number of subjects in period 1
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Started
    346
    342
    Safety Analysis Set (SafAS)
    338
    342
    Completed
    0
    0
    Not completed
    346
    342
         Voluntary withdrawal not due to an adverse event
    11
    12
         Non-compliance with the protocol
    308
    308
         Lost to follow-up
    27
    22

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration)
    Reporting group description
    Subjects received 1 booster dose of Tdap vaccine 0.5 millilitre (mL) intramuscular (IM) injection at Month 1, and 2 doses of CYD dengue vaccine 0.5 mL subcutaneous (SC) injection at Month 1 (concomitantly with Tdap booster dose) and at Month 7.

    Reporting group title
    CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Reporting group description
    Subjects received 1 booster dose of Tdap vaccine 0.5 mL IM injection at Day 0 and 2 doses of CYD dengue vaccine 0.5 mL SC injection at Month 1 (sequentially, one month after the Tdap booster dose) and at Month 7.

    Reporting group values
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration) Total
    Number of subjects
    346 342 688
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    26.2 ± 16.3 27.1 ± 16.7 -
    Gender categorical
    Units: Subjects
        Female
    187 193 380
        Male
    159 149 308
    Dengue Baseline Status
    Dengue immune subjects were defined as subjects with titers greater than or equal to (>=) 10 (1/dilution) for at least one serotype with the parental dengue virus strain. Dengue non-immune subjects were defined as subjects with titers less than (<) 10 (1/dilution) for all serotypes with parental dengue virus strains with available and ‘valid’ results.
    Units: Subjects
        Dengue immune
    314 315 629
        Dengue non-immune
    32 27 59

    End points

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    End points reporting groups
    Reporting group title
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration)
    Reporting group description
    Subjects received 1 booster dose of Tdap vaccine 0.5 millilitre (mL) intramuscular (IM) injection at Month 1, and 2 doses of CYD dengue vaccine 0.5 mL subcutaneous (SC) injection at Month 1 (concomitantly with Tdap booster dose) and at Month 7.

    Reporting group title
    CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Reporting group description
    Subjects received 1 booster dose of Tdap vaccine 0.5 mL IM injection at Day 0 and 2 doses of CYD dengue vaccine 0.5 mL SC injection at Month 1 (sequentially, one month after the Tdap booster dose) and at Month 7.

    Primary: Geometric Mean Concentrations (GMCs) of Antibodies Against Pertussis Antigens (Pertussis Toxoid, Filamentous Hemagglutinin, Pertactin, and Fimbriae 2+3) 28 Days After Dose of Tdap Vaccine in Previously Dengue Immune Subjects

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    End point title
    Geometric Mean Concentrations (GMCs) of Antibodies Against Pertussis Antigens (Pertussis Toxoid, Filamentous Hemagglutinin, Pertactin, and Fimbriae 2+3) 28 Days After Dose of Tdap Vaccine in Previously Dengue Immune Subjects
    End point description
    GMCs against each pertussis antigens (pertussis toxoid [PT], filamentous hemagglutinin [FHA], pertactin [PRN], fimbriae types 2 and 3 [FIM2+3]) were assessed using an enzyme-linked immunosorbent assay (ELISA) method and were measured in ELISA unit/millilitre (EU/mL). Dengue immune subjects at Baseline were defined as subjects with titers >=10 (1/dilution) for at least one serotype with the parental dengue virus strain. Analysis was performed on per protocol analysis set of Tdap (PPT) population which included subjects who received at least one dose of Tdap and had no relevant protocol deviations. Here, 'n' = subjects with available data for each specified category.
    End point type
    Primary
    End point timeframe
    28 days after Tdap vaccination
    End point values
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects analysed
    312
    314
    Units: EU/mL
    geometric mean (confidence interval 95%)
        Anti-PT (n = 300, 310)
    65.2 (57.7 to 73.8)
    76.0 (67.9 to 85.1)
        Anti-FHA (n = 308, 314)
    273 (248 to 299)
    267 (241 to 296)
        Anti-PRN (n = 311, 314)
    50.6 (41.4 to 61.9)
    44.9 (36.7 to 55.0)
        Anti-FIM2+3 (n = 309, 312)
    705 (586 to 847)
    643 (537 to 770)
    Statistical analysis title
    Anti-PT
    Comparison groups
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) v CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects included in analysis
    626
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    Parameter type
    GMC ratio
    Point estimate
    0.848
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.721
         upper limit
    0.997
    Notes
    [1] - The non-inferiority was demonstrated if the lower limit of the two-sided 95% confidence interval (CI) of the ratio of GMCs between groups (Group 1/ Group 2) was greater than (>) 1/1.5 for each antigen. Overall non-inferiority was demonstrated if the 4 antigens achieved non-inferiority.
    Statistical analysis title
    Anti-FHA
    Comparison groups
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) v CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects included in analysis
    626
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    Method
    Parameter type
    GMC ratio
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.892
         upper limit
    1.18
    Notes
    [2] - The non-inferiority was demonstrated if the lower limit of the two-sided 95% CI of the ratio of GMCs between groups (Group 1/ Group 2) was > 1/1.5 for each antigen. Overall non-inferiority was demonstrated if the 4 antigens achieved non-inferiority.
    Statistical analysis title
    Anti-PRN
    Comparison groups
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) v CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects included in analysis
    626
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [3]
    Method
    Parameter type
    GMC ratio
    Point estimate
    1.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.836
         upper limit
    1.46
    Notes
    [3] - The non-inferiority was demonstrated if the lower limit of the two-sided 95% CI of the ratio of GMCs between groups (Group 1/ Group 2) was > 1/1.5 for each antigen. Overall non-inferiority was demonstrated if the 4 antigens achieved non-inferiority.
    Statistical analysis title
    Anti-FIM2+3
    Comparison groups
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) v CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects included in analysis
    626
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [4]
    Method
    Parameter type
    GMC ratio
    Point estimate
    1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.827
         upper limit
    1.33
    Notes
    [4] - The non-inferiority was demonstrated if the lower limit of the two-sided 95% CI of the ratio of GMCs between groups (Group 1/ Group 2) was > 1/1.5 for each antigen. Overall non-inferiority was demonstrated if the 4 antigens achieved non-inferiority.

    Primary: Percentage of Subjects With Seroprotection Against Diphtheria and Tetanus Antigens 28 Days After the Dose of Tdap Vaccine in the Previously Dengue Immune Subjects

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    End point title
    Percentage of Subjects With Seroprotection Against Diphtheria and Tetanus Antigens 28 Days After the Dose of Tdap Vaccine in the Previously Dengue Immune Subjects
    End point description
    Seroprotection against diphtheria (Anti-D) and tetanus (Anti-T) antigens was performed by Micrometabolic Inhibition Test - Toxin Neutralization assay (MIT-TNA) and ELISA, respectively. Seroprotection was defined as anti-D and anti-T Ab concentration superior to 0.1 international units (IU)/mL. Dengue immune subjects at Baseline were defined as subjects with titers >=10 (1/dilution) for at least one serotype with the parental dengue virus strain. Analysis was performed on PPT population. Here, ‘n’=subjects with available data for each specified category.
    End point type
    Primary
    End point timeframe
    28 days after Tdap vaccination
    End point values
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects analysed
    312
    314
    Units: percentage of subjects
    number (confidence interval 95%)
        Anti-D (n = 312, 314)
    90.1 (86.2 to 93.1)
    89.8 (85.9 to 92.9)
        Anti-T (n = 309, 314)
    98.4 (96.3 to 99.5)
    99.0 (97.2 to 99.8)
    Statistical analysis title
    Anti-D
    Comparison groups
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) v CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects included in analysis
    626
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [5]
    Method
    Parameter type
    Percentage difference
    Point estimate
    0.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.53
         upper limit
    5.04
    Notes
    [5] - The non-inferiority was demonstrated if the lower limit of all the 95% CI of the difference was > -10% for all antigens.
    Statistical analysis title
    Anti-T
    Comparison groups
    CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration) v CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration)
    Number of subjects included in analysis
    626
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [6]
    Method
    Parameter type
    Percentage difference
    Point estimate
    -0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.87
         upper limit
    1.37
    Notes
    [6] - The non-inferiority was demonstrated if the lower limit of all the 95% CI of the difference was > -10% for all antigens.

    Primary: Geometric Mean Titers (GMTs) of Antibodies Against Each Dengue Virus Serotype 28 Days After the First Dose of CYD Dengue Vaccination in the Previously Dengue Immune Subjects

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    End point title
    Geometric Mean Titers (GMTs) of Antibodies Against Each Dengue Virus Serotype 28 Days After the First Dose of CYD Dengue Vaccination in the Previously Dengue Immune Subjects
    End point description
    The GMTs against each of the four parenteral dengue virus serotypes (1, 2, 3 and 4) of CYD dengue vaccine were assessed using the 50% plaque reduction neutralization test (PRNT50) assay method. Dengue immune subjects at Baseline were defined as subjects with titers >=10 (1/dilution) for at least one serotype with the parental dengue virus strain. Titers were measured in terms of 1/dilution. Analysis was performed on per-protocol analysis set for CYD dengue vaccine (PPC) population which included subjects who received the first dose of CYD dengue vaccine and had no relevant protocol deviations.
    End point type
    Primary
    End point timeframe
    28 days after first CYD dengue vaccination
    End point values
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects analysed
    312
    308
    Units: titers
    geometric mean (confidence interval 95%)
        Serotype 1
    513 (427 to 617)
    461 (384 to 552)
        Serotype 2
    677 (588 to 780)
    568 (489 to 661)
        Serotype 3
    653 (558 to 765)
    706 (603 to 828)
        Serotype 4
    378 (324 to 442)
    472 (404 to 551)
    Statistical analysis title
    Serotype 1
    Comparison groups
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) v CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [7]
    Method
    Parameter type
    GMT ratio
    Point estimate
    1.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.862
         upper limit
    1.44
    Notes
    [7] - The non-inferiority was demonstrated if the lower limit of the two-sided 95% CI of the ratio of GMTs between groups (Group 1/Group 2) was > 1/2 for each serotype. Overall non-inferiority was demonstrated if all 4 serotypes achieved non-inferiority.
    Statistical analysis title
    Serotype 2
    Comparison groups
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) v CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [8]
    Method
    Parameter type
    GMT ratio
    Point estimate
    1.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.97
         upper limit
    1.47
    Notes
    [8] - The non-inferiority was demonstrated if the lower limit of the two-sided 95% CI of the ratio of GMTs between groups (Group 1/Group 2) was > 1/2 for each serotype. Overall non-inferiority was demonstrated if all 4 serotypes achieved non-inferiority.
    Statistical analysis title
    Serotype 3
    Comparison groups
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) v CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [9]
    Method
    Parameter type
    GMT ratio
    Point estimate
    0.925
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.739
         upper limit
    1.16
    Notes
    [9] - The non-inferiority was demonstrated if the lower limit of the two-sided 95% CI of the ratio of GMTs between groups (Group 1/Group 2) was > 1/2 for each serotype. Overall non-inferiority was demonstrated if all 4 serotypes achieved non-inferiority.
    Statistical analysis title
    Serotype 4
    Comparison groups
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) v CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [10]
    Method
    Parameter type
    GMT ratio
    Point estimate
    0.802
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.644
         upper limit
    0.999
    Notes
    [10] - The non-inferiority was demonstrated if the lower limit of the two-sided 95% CI of the ratio of GMTs between groups (Group 1/Group 2) was > 1/2 for each serotype. Overall non-inferiority was demonstrated if all 4 serotypes achieved non-inferiority.

    Secondary: Geometric Mean Titers of Antibodies Against Each Dengue Virus Serotype at Baseline and 28 Days After the First Dose of CYD Dengue Vaccination in the Previously Dengue Immune Subjects

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    End point title
    Geometric Mean Titers of Antibodies Against Each Dengue Virus Serotype at Baseline and 28 Days After the First Dose of CYD Dengue Vaccination in the Previously Dengue Immune Subjects
    End point description
    The GMTs against each of the four parenteral dengue virus serotypes (1, 2, 3 and 4) of CYD dengue vaccine were assessed using PRNT50 assay method. Dengue immune subjects at Baseline were defined as subjects with titers >=10 (1/dilution) for at least one serotype with the parental dengue virus strain. Titers were measured in terms of 1/dilution. Analysis was performed on the subset of FAS population who received at least one dose of the study vaccines (CYD dengue or Tdap) and were immune to dengue at baseline. Here, 'number of subjects analysed'=subjects evaluable for this end-point and ‘n’=subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Pre-vaccination 1) and 28 days after the first CYD dengue vaccination
    End point values
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects analysed
    314
    315
    Units: titers
    geometric mean (confidence interval 95%)
        Serotype 1: Pre-vaccination 1 (n=314,315)
    265 (218 to 322)
    250 (208 to 300)
        Serotype 1: 28 days post-vaccination 1 (n=313,315)
    513 (427 to 616)
    468 (392 to 560)
        Serotype 2: Pre-vaccination 1 (n=314,315)
    404 (350 to 467)
    343 (294 to 401)
        Serotype 2: 28days post-vaccination 1 (n=313,315)
    679 (589 to 781)
    577 (497 to 671)
        Serotype 3: Pre-vaccination 1 (n=314, 315)
    327 (274 to 391)
    327 (280 to 383)
        Serotype 3: 28 days post-vaccination 1 (n=313,315)
    655 (559 to 767)
    709 (605 to 830)
        Serotype 4: Pre-vaccination 1 (n=314, 315)
    136 (115 to 160)
    172 (150 to 197)
        Serotype 4: 28 days post-vaccination 1 (n=313,315)
    379 (325 to 443)
    478 (410 to 557)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Neutralizing Antibody Titers Against Each of the 4 Dengue Virus Serotypes of CYD at Baseline and 28 Days After first Dose of CYD Dengue Vaccination in the Previously Dengue Immune Subjects

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    End point title
    Percentage of Subjects With Neutralizing Antibody Titers Against Each of the 4 Dengue Virus Serotypes of CYD at Baseline and 28 Days After first Dose of CYD Dengue Vaccination in the Previously Dengue Immune Subjects
    End point description
    The GMTs against each of the four parenteral dengue virus serotypes (1, 2, 3 and 4) of CYD dengue vaccine were assessed using PRNT50 assay method. Dengue immune subjects at Baseline were defined as subjects with titers >=10 (1/dilution) for at least one serotype with the parental dengue virus strain. Analysis was performed on the subset of FAS population who were immune to dengue at baseline. Here, 'number of subjects analysed'=subjects evaluable for this end-point and ‘n’=subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Pre-vaccination 1) and 28 days after the first CYD dengue vaccination
    End point values
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects analysed
    314
    315
    Units: percentage of subjects
    number (confidence interval 95%)
        Serotype 1: Pre-vaccination 1 (n=314,315)
    92.7 (89.2 to 95.3)
    93.3 (90.0 to 95.8)
        Serotype 1: 28 days post-vaccination 1 (n=313,315)
    97.8 (95.4 to 99.1)
    98.4 (96.3 to 99.5)
        Serotype 2: Pre-vaccination 1 (n=314,315)
    98.1 (95.9 to 99.3)
    96.5 (93.8 to 98.2)
        Serotype 2: 28 days post-vaccination 1 (n=313,315)
    100.0 (98.8 to 100.0)
    99.0 (97.2 to 99.8)
        Serotype 3: Pre-vaccination 1 (n=314, 315)
    95.5 (92.6 to 97.5)
    97.1 (94.6 to 98.7)
        Serotype 3: 28 days post-vaccination 1 (n=313,315)
    100.0 (98.8 to 100.0)
    99.7 (98.2 to 100.0)
        Serotype 4: Pre-vaccination 1 (n=314, 315)
    93.0 (89.6 to 95.6)
    97.5 (95.1 to 98.9)
        Serotype 4: 28 days post-vaccination 1 (n=313,315)
    99.4 (97.7 to 99.9)
    100.0 (98.8 to 100.0)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Neutralizing Antibody Titers Above Pre-defined Thresholds Against at Least 1, 2, 3, or 4 Serotypes of CYD at Baseline and 28 Days After the First Dose of CYD Dengue Vaccination in the Previously Dengue Immune Subjects

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    End point title
    Percentage of Subjects With Neutralizing Antibody Titers Above Pre-defined Thresholds Against at Least 1, 2, 3, or 4 Serotypes of CYD at Baseline and 28 Days After the First Dose of CYD Dengue Vaccination in the Previously Dengue Immune Subjects
    End point description
    Dengue neutralizing antibody levels against each of the 4 dengue virus serotypes (1, 2, 3, and 4) were measured by PRNT50. Dengue immune subjects at Baseline were defined as subjects with titers >=10 (1/dilution) for at least one serotype with the parental dengue virus strain. Percentage of subjects with neutralizing antibody titers above pre-defined thresholds (>=10 and >=100 [1/dilution]) against at least 1, 2, 3, or 4 serotypes of CYD were reported. Analysis was performed on the subset of FAS population who were immune to dengue at baseline. Here, 'number of subjects analysed'=subjects evaluable for this end-point and ‘n’=subjects with available data for each specified categories. Here, 'dil'=dilution and "vac"=vaccination in the specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline (Pre-vaccination 1) and 28 days after the first CYD dengue vaccination
    End point values
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects analysed
    314
    315
    Units: percentage of subjects
    number (confidence interval 95%)
        At least 1Serotype:pre-vac1:>=10(1/dil)(n=314,315)
    100.0 (98.8 to 100.0)
    100.0 (98.8 to 100.0)
        At least1Serotype:pre-vac1:>=100(1/dil)(n=314,315)
    97.8 (95.5 to 99.1)
    97.1 (94.6 to 98.7)
        At least1Serotype:post-vac1:>=10(1/dil)(n=313,315)
    100.0 (98.8 to 100.0)
    100.0 (98.8 to 100.0)
        Atleast1Serotype:post-vac1:>=100(1/dil)(n=313,315)
    99.7 (98.2 to 100.0)
    99.7 (98.2 to 100.0)
        At least 2Serotype:pre-vac1:>=10(1/dil)(n=314,315)
    96.5 (93.8 to 98.2)
    98.1 (95.9 to 99.3)
        At least2Serotype:pre-vac1:>=100(1/dil)(n=314,315)
    84.4 (79.9 to 88.2)
    87.0 (82.8 to 90.5)
        At least2Serotype:post-vac1:>=10(1/dil)(n=313,315)
    100.0 (98.8 to 100.0)
    99.7 (98.2 to 100.0)
        Atleast2Serotype:post-vac1:>=100(1/dil)(n=313,315)
    95.8 (93.0 to 97.8)
    96.5 (93.8 to 98.2)
        At least 3Serotype:pre-vac1:>=10(1/dil)(n=314,315)
    93.6 (90.3 to 96.1)
    95.2 (92.3 to 97.3)
        At least3Serotype:pre-vac1:>=100(1/dil)(n=314,315)
    76.1 (71.0 to 80.7)
    76.8 (71.8 to 81.4)
        Atleast 3Serotype:post-vac1:>=10(1/dil)(n=313,315)
    99.7 (98.2 to 100.0)
    99.4 (97.7 to 99.9)
        Atleast3Serotype:post-vac1:>=100(1/dil)(n=313,315)
    90.4 (86.6 to 93.4)
    92.1 (88.5 to 94.8)
        At least 4Serotype:pre-vac1:>=10(1/dil)(n=314,315)
    89.2 (85.2 to 92.4)
    91.1 (87.4 to 94.0)
        At least4Serotype:pre-vac1:>=100(1/dil)(n=314,315)
    52.9 (47.2 to 58.5)
    54.3 (48.6 to 59.9)
        At least4Serotype:post-vac1:>=10(1/dil)(n=313,315)
    97.4 (95.0 to 98.9)
    98.1 (95.9 to 99.3)
        Atleast4Serotype:post-vac1:>=100(1/dil)(n=313,315)
    73.8 (68.6 to 78.6)
    75.6 (70.4 to 80.2)
    No statistical analyses for this end point

    Secondary: Geometric Mean Concentrations of Serum Antibodies Against Pertussis Antigens (Pertussis Toxoid, Filamentous Hemagglutinin, Pertactin, and Fimbriae 2+3) at Baseline and 28 Days After the dose of Tdap Vaccine in the Previously Dengue Immune Subjects

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    End point title
    Geometric Mean Concentrations of Serum Antibodies Against Pertussis Antigens (Pertussis Toxoid, Filamentous Hemagglutinin, Pertactin, and Fimbriae 2+3) at Baseline and 28 Days After the dose of Tdap Vaccine in the Previously Dengue Immune Subjects
    End point description
    GMCs against each pertussis antigens (PT, FHA, PRN, FIM2+3) were assessed using ELISA assay method and were measured in EU/mL. Dengue immune subjects at Baseline were defined as subjects with titers >=10 (1/dilution) for at least one serotype with the parental dengue virus strain. Analysis was performed on the subset of FAS population who were immune to dengue at baseline. Here, 'number of subjects analysed'=subjects evaluable for this end-point and 'n' = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Pre-vaccination) and 28 days after the Tdap vaccination
    End point values
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects analysed
    314
    315
    Units: EU/mL
    geometric mean (confidence interval 95%)
        Anti-PT: Pre-vaccination (n=313,313)
    8.46 (7.34 to 9.75)
    9.56 (8.33 to 11.0)
        Anti-PT: 28 days post-vaccination (n=301,311)
    65.0 (57.5 to 73.5)
    76.1 (68.1 to 85.2)
        Anti-FHA: Pre-vaccination (n=310,314)
    19.9 (17.6 to 22.6)
    19.4 (17.1 to 22.1)
        Anti-FHA: 28 days post-vaccination (n=309,315)
    272 (248 to 299)
    266 (240 to 295)
        Anti-PRN: Pre-vaccination (n=314,315)
    3.79 (3.39 to 4.24)
    3.65 (3.25 to 4.10)
        Anti-PRN: 28 days post-vaccination (n=312,315)
    50.6 (41.4 to 61.8)
    45.0 (36.8 to 55.1)
        Anti-FIM2+3: Pre-vaccination (n=297,298)
    15.1 (12.4 to 18.5)
    14.9 (12.2 to 18.1)
        Anti-FIM2+3: 28 days post-vaccination (n=310,313)
    700 (583 to 841)
    642 (537 to 769)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving Serum Antibody Concentration (>=0.1 IU/mL) Against Diphtheria and Tetanus Antigens at Baseline and 28 Days After the Dose of Tdap Vaccine in the Previously Dengue Immune Subjects

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    End point title
    Percentage of Subjects Achieving Serum Antibody Concentration (>=0.1 IU/mL) Against Diphtheria and Tetanus Antigens at Baseline and 28 Days After the Dose of Tdap Vaccine in the Previously Dengue Immune Subjects
    End point description
    The GMC against diphtheria and tetanus antigens was performed by MIT-TNA and ELISA, respectively. Dengue immune subjects at Baseline were defined as subjects with titers >=10 (1/dilution) for at least one serotype with the parental dengue virus strain. Analysis was performed on the subset of FAS population who were immune to dengue at baseline. Here, 'number of subjects analysed'=subjects evaluable for this end-point and ‘n’=subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Pre-vaccination) and 28 days after the dose of Tdap vaccination
    End point values
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects analysed
    314
    315
    Units: percentage of subjects
    number (confidence interval 95%)
        Anti-D: Pre-vaccination (314, 314)
    31.8 (26.7 to 37.3)
    32.8 (27.6 to 38.3)
        Anti-T: Pre-vaccination (314, 313)
    63.7 (58.1 to 69.0)
    69.6 (64.2 to 74.7)
        Anti-D: 28 days post-vaccination (n=313,315)
    90.1 (86.2 to 93.2)
    89.8 (86.0 to 92.9)
        Anti-T: 28 days post-vaccination (n=310,315)
    98.1 (95.8 to 99.3)
    99.0 (97.2 to 99.8)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Immediate Unsolicited Adverse Events (AE) Following Vaccination With Tdap or CYD Dengue Vaccine

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    End point title
    Number of Subjects With Immediate Unsolicited Adverse Events (AE) Following Vaccination With Tdap or CYD Dengue Vaccine
    End point description
    An unsolicited AE was an observed AE that did not fulfill the conditions prelisted in the electronic case report form (eCRF) in terms of diagnosis and/or onset post-vaccination. Any unsolicited systemic AE occurred during first 30 minutes post-vaccination was recorded on the CRF as immediate AE. At Visit 1, subjects of Group 1 received no vaccination and subjects of Group 2 received only Tdap vaccination. At Visit 2, subjects of Group 1 received both CYD and Tdap vaccination and subjects of Group 2 received only CYD vaccination. At Visit 4, subjects of Groups 1 and 2 received CYD vaccination. Analysis was performed on safety analysis set (SafAS) population, which included subjects who received at least one dose of the study vaccines (CYD and Tdap). Here, ‘n’=subjects with available data for each specified category and '99999' was used as a space filler which signifies that the subjects of Group 1 did not receive any vaccination at Visit 1 and therefore were not evaluable.
    End point type
    Secondary
    End point timeframe
    Within 30 minutes after any and each vaccination
    End point values
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects analysed
    338
    342
    Units: subjects
    number (not applicable)
        Post any vaccination(n=338,342)
    0
    0
        Post Tdap vaccination (Visit 1) (n=0,342)
    99999
    0
        Post CYD/Tdap vaccination (Visit 2)(n=338,338)
    0
    0
        Post CYD vaccination (Visit 4) (n=321, 319)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Solicited Injection Site Reactions Following Vaccination With Tdap or CYD Dengue Vaccine

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    End point title
    Number of Subjects With Solicited Injection Site Reactions Following Vaccination With Tdap or CYD Dengue Vaccine
    End point description
    A solicited reaction was an AE observed and reported under the conditions (symptom and onset) prelisted (i.e., solicited) in the eCRF and considered as related to vaccination. Solicited injection site reactions included pain, erythema, and swelling. At Visit 1, subjects of Group 1 received no vaccination and subjects of Group 2 received only Tdap vaccination. At Visit 2, subjects of Group 1 received both CYD and Tdap vaccinations and subjects of Group 2 received only CYD vaccination. At Visit 4, subjects of Groups 1 and 2 received only CYD vaccination. Analysis was performed on SafAS population. Here, ‘n’=subjects with available data for each specified category. Here, '99999' was used as a space filler which signifies that the Group 1 subjects did not receive any vaccination at Visit 1 and therefore were not evaluable.
    End point type
    Secondary
    End point timeframe
    Within 7 days after any and each vaccination
    End point values
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects analysed
    338
    342
    Units: subjects
    number (not applicable)
        Pain: Post any vaccination(n=338,341)
    229
    237
        Pain: Post Tdap vaccination (Visit 1) (n=0,341)
    99999
    212
        Pain:Post CYD/Tdap vaccination(Visit 2)(n=338,338)
    218
    53
        Pain: Post CYD vaccination (Visit 4) (n=320,319)
    61
    55
        Erythema: Post any vaccination(n=338,341)
    14
    17
        Erythema: Post Tdap vaccination (Visit 1)(n=0,341)
    99999
    14
        Erythema:PostCYD/Tdapvaccination(Visit2;n=338,338)
    13
    5
        Erythema: Post CYD vaccination (Visit 4;n=320,319)
    2
    2
        Swelling: Post any vaccination (n=338,341)
    25
    32
        Swelling: Post Tdap vaccination (Visit 1; n=0,341)
    99999
    30
        Swelling:PostCYD/Tdapvaccination(Visit2;n=338,338)
    25
    3
        Swelling: Post CYD vaccination (Visit 4;n=320,319)
    2
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects With Solicited Systemic Reactions Following Vaccination With Tdap or CYD Dengue Vaccine

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    End point title
    Number of Subjects With Solicited Systemic Reactions Following Vaccination With Tdap or CYD Dengue Vaccine
    End point description
    A solicited reaction was an adverse reaction observed and reported under the conditions (symptom and onset) prelisted (i.e., solicited) in the CRF and considered as related to vaccination. Solicited injection site reactions included fever, headache, malaise, myalgia, and asthenia. At Visit 1, subjects of Group 1 received no vaccination and subjects of Group 2 received only Tdap vaccination. At Visit 2, subjects of Group 1 received both CYD and Tdap vaccinations and subjects of Group 2 received only CYD vaccination. At Visit 4, subjects of Groups 1 and 2 received only CYD vaccination. Analysis was performed on SafAS population. Here, ‘n’=subjects with available data for each specified category. Here, '99999' was used as space filler which signifies that Group 1 subjects did not receive any vaccination at Visit 1 and were not evaluable.
    End point type
    Secondary
    End point timeframe
    Within 14 days after any and each vaccination
    End point values
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects analysed
    338
    342
    Units: subjects
    number (not applicable)
        Fever: Post any vaccination (n=338,340)
    21
    30
        Fever: Post Tdap vaccination (Visit 1; n=0,339)
    99999
    15
        Fever:PostCYD/Tdapvaccination(Visit2; n=338,338)
    11
    6
        Fever: Post CYD vaccination (Visit 4; n=320,319)
    10
    9
        Headache: Post any vaccination (n=338,341)
    89
    115
        Headache: Post Tdap vaccination (Visit 1; n=0,341)
    99999
    83
        Headache:PostCYD/Tdapvaccination(Visit2;n=338,338)
    70
    33
        Headache: Post CYD vaccination (Visit 4;n=320,319)
    36
    35
        Malaise: Post any vaccination (n=338,341)
    91
    111
        Malaise: Post Tdap vaccination (Visit 1; n=0,341)
    99999
    81
        Malaise:PostCYD/Tdapvaccination(Visit2; n=338,338)
    74
    28
        Malaise: Post CYD vaccination (Visit 4; n=320,319)
    32
    33
        Myalgia: Post any vaccination (n=338,341)
    74
    100
        Myalgia: Post Tdap vaccination (Visit 1; n=0,341)
    99999
    78
        Myalgia:PostCYD/Tdapvaccination(Visit2; n=338,338)
    67
    30
        Myalgia: Post CYD vaccination (Visit 4; n=320,319)
    26
    22
        Asthenia: Post any vaccination (n=338,341)
    67
    94
        Asthenia: Post Tdap vaccination (Visit 1; n=0,341)
    99999
    69
        Asthenia:PostCYD/Tdapvaccination(Visit2;n=338,338)
    59
    24
        Asthenia: Post CYD vaccination (Visit 4;n=320,319)
    19
    22
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Unsolicited Adverse Events Following Vaccination With Tdap or CYD Dengue Vaccine

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    End point title
    Number of Subjects Reporting Unsolicited Adverse Events Following Vaccination With Tdap or CYD Dengue Vaccine
    End point description
    An unsolicited AE was an observed AE that did not fulfill the conditions prelisted in the eCRF in terms of diagnosis and/or onset post-vaccination. At Visit 1, subjects of Group 1 received no vaccination and subjects of Group 2 received only Tdap vaccination. At Visit 2, subjects of Group 1 received both CYD and Tdap vaccinations and subjects of Group 2 received only CYD vaccination. At Visit 4, subjects of Groups 1 and 2 received CYD vaccination. Analysis was performed on SafAS population. Here, ‘n’=subjects with available data for each specified category and '99999' was used as a space filler which signifies that the subjects from Group 1 did not receive any vaccination at Visit 1 and therefore were not evaluable.
    End point type
    Secondary
    End point timeframe
    Within 28 days after any and each vaccination
    End point values
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects analysed
    338
    342
    Units: subjects
    number (not applicable)
        Post any vaccination (n=338,342)
    56
    70
        Post Tdap vaccination (Visit 1; n=0,342)
    99999
    40
        PostCYD/Tdapvaccination(Visit2; n=338,338)
    37
    20
        Post CYD vaccination (Visit 4; n=321,319)
    28
    26
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Non-serious Adverse Event of Special Interests (AESIs) Following Vaccination With Tdap or CYD Dengue Vaccine

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    End point title
    Number of Subjects Reporting Non-serious Adverse Event of Special Interests (AESIs) Following Vaccination With Tdap or CYD Dengue Vaccine
    End point description
    AESIs were AEs that are considered by the Sponsor to be relevant for the monitoring of the safety profile of the investigational vaccine. At Visit 1, subjects of Group 1 received no vaccination and subjects of Group 2 received only Tdap vaccination. At Visit 2, subjects of Group 1 received both CYD and Tdap vaccinations and subjects of Group 2 received only CYD vaccination. At Visit 4, subjects of Groups 1 and 2 received CYD vaccination. Analysis was performed on SafAS population. Here, ‘n’=subjects with available data for each specified category and '99999' was used as a space filler which signifies that the subjects from Group 1 did not receive any vaccination at Visit 1 and therefore were not evaluable.
    End point type
    Secondary
    End point timeframe
    Within 7 days post any and each vaccination
    End point values
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects analysed
    338
    342
    Units: subjects
    number (not applicable)
        Post any vaccination (n=338,342)
    0
    0
        Post Tdap vaccination (Visit 1; n=0,342)
    99999
    0
        PostCYD/Tdapvaccination(Visit2; n=338,338)
    0
    0
        Post CYD vaccination (Visit 4; n=321,319)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Serious Adverse Events (SAEs) Including Serious AESIs Following Vaccination With Tdap or CYD Dengue Vaccine

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    End point title
    Number of Subjects Reporting Serious Adverse Events (SAEs) Including Serious AESIs Following Vaccination With Tdap or CYD Dengue Vaccine
    End point description
    SAEs were AEs resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening; required hospitalisation or prolonged existing hospitalisation; persistent or significant disability/incapacity; congenital anomaly or a medically important event. AESIs were AEs that were considered by the Sponsor to be relevant for the monitoring of the safety profile of the investigational vaccine. Analysis was performed on SafAS population.
    End point type
    Secondary
    End point timeframe
    From Day 0 up to 6 months after the last Tdap or CYD vaccination
    End point values
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects analysed
    338
    342
    Units: subjects
    number (not applicable)
        SAE
    8
    11
        Serious AESI
    1
    3
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Cases of Virologically Confirmed Dengue (VCD) Hospitalization Following Vaccination With Tdap or CYD Dengue Vaccine

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    End point title
    Number of Subjects Reporting Cases of Virologically Confirmed Dengue (VCD) Hospitalization Following Vaccination With Tdap or CYD Dengue Vaccine
    End point description
    Hospitalised suspected dengue case was defined as an acute febrile illness with diagnosis of dengue requiring hospitalisation (with bed attribution). In such cases, 1 unplanned acute blood sample (within the first 5 days after fever onset) was collected for virological confirmation of hospitalised suspected dengue case. A suspected case was considered VCD if there was a detection of wild type dengue virus by dengue non-structural protein 1 antigen ELISA and/or dengue reverse transcriptase-polymerase chain reactions. Analysis was performed on SafAS population.
    End point type
    Secondary
    End point timeframe
    From Day 0 up to 6 months after the last Tdap or CYD vaccination
    End point values
    CYD Dengue Vaccine + Tdap Vaccine (Concomitant Administration) CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Number of subjects analysed
    338
    342
    Units: subjects
        number (not applicable)
    0
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE data were collected from Day 0 up to Day 28 post any vaccination. SR data were collected from Day 0 up to Day 14 post-vaccination. The SAEs were collected throughout the trial, i.e. 6 months after last Tdap or CYD vaccination.
    Adverse event reporting additional description
    SR was an AE that was prelisted (i.e., solicited) in the eCRF and considered to be related to vaccination (adverse drug reaction). An unsolicited AE was an observed AE that did not fulfill the conditions prelisted in the CRF (i.e., solicited) in terms of symptom and/or onset post-vaccination. Analysis was performed on SafAS population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    CYD Dengue Vaccine + Tdap vaccine (Concomitant Administration)
    Reporting group description
    Subjects received 1 booster dose of Tdap vaccine 0.5 mL IM injection at Month 1, and 2 doses of CYD dengue vaccine 0.5 mL SC injection at Month 1 (concomitantly with Tdap booster dose) and at Month 7.

    Reporting group title
    CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Reporting group description
    Subjects received 1 booster dose of Tdap vaccine 0.5 mL IM injection at Day 0 and 2 doses of CYD dengue vaccine 0.5 mL SC injection at Month 1 (sequentially, one month after the Tdap booster dose) and at Month 7.

    Serious adverse events
    CYD Dengue Vaccine + Tdap vaccine (Concomitant Administration) CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 338 (2.37%)
    11 / 342 (3.22%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Incisional Hernia
         subjects affected / exposed
    0 / 338 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast Cancer
         subjects affected / exposed
    0 / 338 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Hypertensive Heart Disease
         subjects affected / exposed
    0 / 338 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral Infarction
         subjects affected / exposed
    1 / 338 (0.30%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 338 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Complete
         subjects affected / exposed
    1 / 338 (0.30%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    0 / 338 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 338 (0.30%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice Cholestatic
         subjects affected / exposed
    0 / 338 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 338 (0.30%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash Generalised
         subjects affected / exposed
    1 / 338 (0.30%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 338 (0.30%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical Pneumonia
         subjects affected / exposed
    0 / 338 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue Fever
         subjects affected / exposed
    1 / 338 (0.30%)
    3 / 342 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 338 (0.30%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    CYD Dengue Vaccine + Tdap vaccine (Concomitant Administration) CYD Dengue Vaccine + Tdap Vaccine (Sequential Administration)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    248 / 338 (73.37%)
    263 / 342 (76.90%)
    Nervous system disorders
    Headache
    Additional description: Headache event which started on Day 15 post-vaccination was an unsolicited AE.
         subjects affected / exposed
    89 / 338 (26.33%)
    116 / 342 (33.92%)
         occurrences all number
    106
    152
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    67 / 338 (19.82%)
    94 / 342 (27.49%)
         occurrences all number
    78
    115
    Injection Site Pain
         subjects affected / exposed
    229 / 338 (67.75%)
    237 / 342 (69.30%)
         occurrences all number
    376
    320
    Injection Site Swelling
         subjects affected / exposed
    25 / 338 (7.40%)
    32 / 342 (9.36%)
         occurrences all number
    29
    35
    Malaise
         subjects affected / exposed
    91 / 338 (26.92%)
    111 / 342 (32.46%)
         occurrences all number
    106
    142
    Pyrexia
    Additional description: Pyrexia/fever events that occurred after 14 days post-vaccination were considered as unsolicited AEs.
         subjects affected / exposed
    22 / 338 (6.51%)
    32 / 342 (9.36%)
         occurrences all number
    22
    33
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    74 / 338 (21.89%)
    100 / 342 (29.24%)
         occurrences all number
    93
    130
    Infections and infestations
    Upper Respiratory Tract Infection
         subjects affected / exposed
    17 / 338 (5.03%)
    17 / 342 (4.97%)
         occurrences all number
    17
    21

    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? Yes
    Date
    Interruption
    Restart date
    09 Nov 2017
    Given the IDMC recommendations, Sanofi Pasteur has suspended all vaccinations in this study and amended the study protocol, to determine the basal serostatus of the subjects already included in the study and to implement IDMC recommendations. No response was received from Philippines Food and Drug Administration, and therefore the protocol amendment could not be implemented. After having waited for more than 1.5 year, and as the subjects became out of window to complete their immunization schedule and the last safety follow-up call (6 months after the last dose), the Sponsor decided to stop the trial. Subjects only attended a last safety follow-up visit to terminate the study and were informed about the end of the study. As a consequence of the IDMC recommendations, the main immunogenicity analyses were done in dengue immune subjects which is not what was planned in the protocol (and this is why the primary endpoints are not exactly the same as those defined in the protocol as they were finally assessed only in seropositive subjects whereas initially it was planned to be assessed regardless of baseline status).
    02 Oct 2019

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to absence of response of competent authorities from The Philippines on the protocol amendment, the study was prematurely terminated before injection of last dose (3rd dose) of CYD dengue vaccine. Objectives related to 3rd dose was not assessed.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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