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    Clinical Trial Results:
    Study of CYD Dengue Vaccine in Healthy Children and Adolescents in South America

    Summary
    EudraCT number
    2014-001715-39
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    15 May 2012

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Feb 2016
    First version publication date
    29 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CYD30
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01187433
    WHO universal trial number (UTN)
    U1111-1111-6073
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur Inc
    Sponsor organisation address
    1 Discovery Drive, Swiftwater, United States, 18370
    Public contact
    Director, Clinical Development, Sanofi Pasteur Inc, 52 55 5484 4891, enrique.rivas@sanofipasteur.com
    Scientific contact
    Director, Clinical Development, Sanofi Pasteur Inc, 52 55 5484 4891, enrique.rivas@sanofipasteur.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001201-PIP01-11
    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
    12 Oct 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 May 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Humoral immune response to dengue before and after each vaccination with dengue vaccine Safety and reactogenicity
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were randomized and vaccinated in the study. 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
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    20 Aug 2010
    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
    Brazil: 150
    Worldwide total number of subjects
    150
    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)
    59
    Adolescents (12-17 years)
    91
    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
    Study subjects were enrolled from 20 August 2010 to 8 December 2011 at 1 clinical site in Brazil.

    Pre-assignment
    Screening details
    A total of 150 subjects who met all of the inclusion criteria and none of the exclusion criteria were enrolled and randomized.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    An observer-blind procedure was implemented for all three injections. The blind-observer Investigator, Sponsor, and subjects/parents did not know which vaccine was administered. To maintain the blind, the vaccinator prepared and administered the vaccine(s) in a separate room away from the blind-observer Investigator who was in charge of the assessment of safety.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CYD Dengue vaccine group
    Arm description
    Subjects received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.
    Arm type
    Experimental

    Investigational medicinal product name
    CYD Dengue vaccine
    Investigational medicinal product code
    323
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, subcutaneous, 1 injection each at 0, 6, and 12 months.

    Arm title
    Control group
    Arm description
    Subjects received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (NaCl 0.9%)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, subcutaneous, 1 injection each at 0, 6, and 12 months.

    Number of subjects in period 1
    CYD Dengue vaccine group Control group
    Started
    100
    50
    Completed
    89
    46
    Not completed
    11
    4
         Protocol deviation
             6
             2
         Consent withdrawn by subject
             5
             2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CYD Dengue vaccine group
    Reporting group description
    Subjects received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.

    Reporting group title
    Control group
    Reporting group description
    Subjects received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.

    Reporting group values
    CYD Dengue vaccine group Control group Total
    Number of subjects
    100 50 150
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    40 19 59
        Adolescents (12-17 years)
    60 31 91
        Adults (18-64 years)
    0 0 0
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    12.7 ± 2.1 12.7 ± 2.2 -
    Gender categorical
    Units: Subjects
        Female
    59 23 82
        Male
    41 27 68

    End points

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    End points reporting groups
    Reporting group title
    CYD Dengue vaccine group
    Reporting group description
    Subjects received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.

    Reporting group title
    Control group
    Reporting group description
    Subjects received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.

    Primary: Percentage of Subjects With Seropositivity Against Each Serotype with the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Percentage of Subjects With Seropositivity Against Each Serotype with the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [1]
    End point description
    Seropositivity was defined as subjects achieving neutralizing antibody titers ≥10 (1/dil) against each serotype and was assessed using the Dengue Plaque Reduction Neutralization Test (PRNT).
    End point type
    Primary
    End point timeframe
    Pre-Injections 1, 2, and 3 and Post-Injections 1,2, and 3
    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: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    99
    49
    Units: Percentage of subjects
    number (not applicable)
        Serotype 1; Pre-Injection 1
    59.6
    63.3
        Serotype 1; Post-Injection 1
    79.8
    69.4
        Serotype 1; Pre-Injection 2
    80.9
    72.3
        Serotype 1; Post-Injection 2
    95.7
    72.3
        Serotype 1; Pre-Injection 3
    78.9
    69.6
        Serotype 1; Post-Injection 3
    96.6
    69.6
        Serotype 2; Pre-Injection 1
    65.7
    67.3
        Serotype 2; Post-Injection 1
    80.8
    67.3
        Serotype 2; Pre-Injection 2
    80.9
    74.5
        Serotype 2; Post-Injection 2
    98.9
    72.3
        Serotype 2; Pre-Injection 3
    85.6
    76.1
        Serotype 2; Post-Injection 3
    98.9
    76.1
        Serotype 3; Pre-Injection 1
    62.6
    65.3
        Serotype 3; Post-Injection 1
    92.9
    67.3
        Serotype 3; Pre-Injection 2
    89.4
    72.3
        Serotype 3; Post-Injection 2
    100
    72.3
        Serotype 3; Pre-Injection 3
    94.4
    71.7
        Serotype 3; Post-Injection 3
    100
    73.9
        Serotype 4; Pre-Injection 1
    47.5
    51
        Serotype 4; Post-Injection 1
    89.9
    58.3
        Serotype 4; Pre-Injection 2
    92.6
    57.4
        Serotype 4; Post-Injection 2
    100
    59.6
        Serotype 4; Pre-Injection 3
    97.7
    69.6
        Serotype 4; Post-Injection 3
    100
    73.9
    No statistical analyses for this end point

    Primary: Percentage of Flavivirus-immune Subjects With Seropositivity Against Each Serotype with the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Percentage of Flavivirus-immune Subjects With Seropositivity Against Each Serotype with the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [2]
    End point description
    Seropositivity was defined as subjects achieving neutralizing antibody titers ≥10 (1/dil) against each serotype and was assessed using the Dengue Plaque Reduction Neutralization Test (PRNT). Flavivirus-immune subjects at baseline are defined as those subjects with ≥10 (1/dil) for at least 1 serotype with the parental dengue virus strain or for the yellow fever titer.
    End point type
    Primary
    End point timeframe
    Pre-Injections 1, 2, and 3 and Post-Injections 1, 2, and 3
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    80
    41
    Units: Percentage of subjects
    number (not applicable)
        Serotype 1; Pre-Injection 1
    73.8
    75.6
        Serotype 1; Post-Injection 1
    88.8
    82.9
        Serotype 1; Pre-Injection 2
    91
    87.2
        Serotype 1; Post-Injection 2
    100
    87.2
        Serotype 1; Pre-Injection 3
    87.8
    81.6
        Serotype 1; Post-Injection 3
    98.6
    81.6
        Serotype 2; Pre-Injection 1
    81.3
    80.5
        Serotype 2; Post-Injection 1
    93.8
    80.5
        Serotype 2; Pre-Injection 2
    92.3
    89.7
        Serotype 2; Post-Injection 2
    100
    87.2
        Serotype 2; Pre-Injection 3
    91.9
    89.5
        Serotype 2; Post-Injection 3
    100
    89.5
        Serotype 3; Pre-Injection 1
    77.5
    78
        Serotype 3; Post-Injection 1
    95
    80.5
        Serotype 3; Pre-Injection 2
    93.6
    87.2
        Serotype 3; Post-Injection 2
    100
    87.2
        Serotype 3; Pre-Injection 3
    97.3
    84.2
        Serotype 3; Post-Injection 3
    100
    86.8
        Serotype 4; Pre-Injection 1
    58.8
    61
        Serotype 4; Post-Injection 1
    95
    70
        Serotype 4; Pre-Injection 2
    94.9
    69.2
        Serotype 4; Post-Injection 2
    100
    71.8
        Serotype 4; Pre-Injection 3
    98.6
    81.6
        Serotype 4; Post-Injection 3
    100
    84.2
    No statistical analyses for this end point

    Primary: Percentage of Flavivirus-naïve Subjects With Seropositivity Against Each Serotype with the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Percentage of Flavivirus-naïve Subjects With Seropositivity Against Each Serotype with the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [3]
    End point description
    Seropositivity was defined as subjects achieving neutralizing antibody titers ≥10 (1/dil) against each serotype and was assessed using the Dengue Plaque Reduction Neutralization Test (PRNT). Flavivirus-naïve subjects at baseline are defined as those subjects with <10 (1/dil) for all serotypes with parental dengue virus strains and for yellow fever titer.
    End point type
    Primary
    End point timeframe
    Pre-Injections 1, 2, and 3 and Post-Injections 1, 2, and 3
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    19
    8
    Units: Percentage of subjects
    number (not applicable)
        Serotype 1; Pre-Injection 1
    0
    0
        Serotype 1; Post-Injection 1
    42.1
    0
        Serotype 1; Pre-Injection 2
    31.3
    0
        Serotype 1; Post-Injection 2
    75
    0
        Serotype 1; Pre-Injection 3
    37.5
    12.5
        Serotype 1; Post-Injection 3
    87.5
    12.5
        Serotype 2; Pre-Injection 1
    0
    0
        Serotype 2; Post-Injection 1
    26.3
    0
        Serotype 2; Pre-Injection 2
    25
    0
        Serotype 2; Post-Injection 2
    93.8
    0
        Serotype 2; Pre-Injection 3
    56.3
    12.5
        Serotype 2; Post-Injection 3
    93.8
    12.5
        Serotype 3; Pre-Injection 1
    0
    0
        Serotype 3; Post-Injection 1
    84.2
    0
        Serotype 3; Pre-Injection 2
    68.8
    0
        Serotype 3; Post-Injection 2
    100
    0
        Serotype 3; Pre-Injection 3
    80
    12.5
        Serotype 3; Post-Injection 3
    100
    12.5
        Serotype 4; Pre-Injection 1
    0
    0
        Serotype 4; Post-Injection 1
    68.4
    0
        Serotype 4; Pre-Injection 2
    81.3
    0
        Serotype 4; Post-Injection 2
    100
    0
        Serotype 4; Pre-Injection 3
    93.3
    12.5
        Serotype 4; Post-Injection 3
    100
    25
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Seropositivity Against At Least 1, 2, 3, or 4 Parental Dengue Virus Serotypes Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo

    Close Top of page
    End point title
    Percentage of Subjects With Seropositivity Against At Least 1, 2, 3, or 4 Parental Dengue Virus Serotypes Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [4]
    End point description
    Seropositivity was defined as subjects achieving neutralizing antibody titers ≥10 (1/dil) against each serotype and was assessed using the Dengue Plaque Reduction Neutralization Test (PRNT).
    End point type
    Primary
    End point timeframe
    Pre-Injections 1, 2, and 3 and Post-Injections 1, 2, and 3
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    99
    49
    Units: Percentage of subjects
    number (not applicable)
        At least 1 serotype; Pre-Injection 1
    68.7
    71.4
        At least 1 serotype; Post-Injection 1
    97
    71.4
        At least 1 serotype; Pre-Injection 2
    94.7
    74.5
        At least 1 serotype; Post-Injection 2
    100
    74.5
        At least 1 serotype; Pre-Injection 3
    98.9
    78.3
        At least 1 serotype; Post-Injection 3
    100
    78.3
        At least 2 serotypes; Pre-Injection 1
    62.6
    67.3
        At least 2 serotypes; Post-Injection 1
    91.9
    71.4
        At least 2 serotypes; Pre-Injection 2
    92.6
    74.5
        At least 2 serotypes; Post-Injection 2
    100
    72.3
        At least 2 serotypes; Pre-Injection 3
    91.1
    73.9
        At least 2 serotypes; Post-Injection 3
    100
    76.1
        At least 3 serotypes; Pre-Injection 1
    56.6
    61.2
        At least 3 serotypes; Post-Injection 1
    81.8
    65.3
        At least 3 serotypes; Pre-Injection 2
    81.9
    72.3
        At least 3 serotypes; Post-Injection 2
    98.9
    70.2
        At least 3 serotypes; Pre-Injection 3
    86.7
    71.7
        At least 3 serotypes; Post-Injection 3
    98.9
    71.7
        All 4 serotypes; Pre-Injection 1
    47.5
    46.9
        All 4 serotypes; Post-Injection 1
    72.7
    53.1
        All 4 serotypes; Pre-Injection 2
    74.5
    55.3
        All 4 serotypes; Post-Injection 2
    95.7
    59.6
        All 4 serotypes; Pre-Injection 3
    76.7
    63
        All 4 serotypes; Post-Injection 3
    96.6
    67.4
    No statistical analyses for this end point

    Primary: Percentage of Flavivirus-immune Subjects With Seropositivity Against At Least 1, 2, 3, or 4 Parental Dengue Virus Serotypes Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo

    Close Top of page
    End point title
    Percentage of Flavivirus-immune Subjects With Seropositivity Against At Least 1, 2, 3, or 4 Parental Dengue Virus Serotypes Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [5]
    End point description
    Seropositivity was defined as subjects achieving neutralizing antibody titers ≥10 (1/dil) against each serotype and was assessed using the Dengue Plaque Reduction Neutralization Test (PRNT). Flavivirus-immune subjects at baseline are defined as those subjects with ≥10 (1/dil) for at least 1 serotype with the parental dengue virus strain or for the yellow fever titer.
    End point type
    Primary
    End point timeframe
    Pre-Injections 1, 2, and 3 and Post-Injections 1, 2, and 3
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    80
    41
    Units: Percentage of subjects
    number (not applicable)
        At least 1 serotype; Pre-Injection 1
    85
    85.4
        At least 1 serotype; Post-Injection 1
    97.5
    85.4
        At least 1 serotype; Pre-Injection 2
    97.4
    89.7
        At least 1 serotype; Post-Injection 2
    100
    89.7
        At least 1 serotype; Pre-Injection 3
    100
    92.1
        At least 1 serotype; Post-Injection 3
    100
    89.5
        At least 2 serotypes; Pre-Injection 1
    77.5
    80.5
        At least 2 serotypes; Post-Injection 1
    95
    85.4
        At least 2 serotypes; Pre-Injection 2
    97.4
    89.7
        At least 2 serotypes; Post-Injection 2
    100
    87.2
        At least 2 serotypes; Pre-Injection 3
    95.9
    86.8
        At least 2 serotypes; Post-Injection 3
    100
    89.5
        At least 3 serotypes; Pre-Injection 1
    70
    73.2
        At least 3 serotypes; Post-Injection 1
    92.5
    78
        At least 3 serotypes; Pre-Injection 2
    91
    87.2
        At least 3 serotypes; Post-Injection 2
    100
    84.6
        At least 3 serotypes; Pre-Injection 3
    93.2
    84.2
        At least 3 serotypes; Post-Injection 3
    100
    84.2
        All 4 serotypes; Pre-Injection 1
    58.8
    56.1
        All 4 serotypes; Post-Injection 1
    87.5
    63.4
        All 4 serotypes; Pre-Injection 2
    85.9
    66.7
        All 4 serotypes; Post-Injection 2
    100
    71.8
        All 4 serotypes; Pre-Injection 3
    85.1
    73.7
        All 4 serotypes; Post-Injection 3
    98.6
    78.9
    No statistical analyses for this end point

    Primary: Percentage of Flavivirus-naïve Subjects With Seropositivity Against At Least 1, 2, 3, or 4 Parental Dengue Virus Serotypes Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Percentage of Flavivirus-naïve Subjects With Seropositivity Against At Least 1, 2, 3, or 4 Parental Dengue Virus Serotypes Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [6]
    End point description
    Seropositivity was defined as subjects achieving neutralizing antibody titers ≥10 (1/dil) against each serotype and was assessed using the Dengue Plaque Reduction Neutralization Test (PRNT). Flavivirus-naïve subjects at baseline are defined as those subjects with <10 (1/dil) for all serotypes with parental dengue virus strains and for yellow fever titer.
    End point type
    Primary
    End point timeframe
    Pre-Injections 1, 2, and 3 and Post-Injections 1, 2, and 3
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    19
    8
    Units: Percentage of subjects
    number (not applicable)
        At least 1 serotype; Pre-Injection 1
    0
    0
        At least 1 serotype; Post-Injection 1
    94.7
    0
        At least 1 serotype; Pre-Injection 2
    81.3
    0
        At least 1 serotype; Post-Injection 2
    100
    0
        At least 1 serotype; Pre-Injection 3
    93.8
    12.5
        At least 1 serotype; Post-Injection 3
    100
    25
        At least 2 serotypes; Pre-Injection 1
    0
    0
        At least 2 serotypes; Post-Injection 1
    78.9
    0
        At least 2 serotypes; Pre-Injection 2
    68.8
    0
        At least 2 serotypes; Post-Injection 2
    100
    0
        At least 2 serotypes; Pre-Injection 3
    68.8
    12.5
        At least 2 serotypes; Post-Injection 3
    100
    12.5
        At least 3 serotypes; Pre-Injection 1
    0
    0
        At least 3 serotypes; Post-Injection 1
    36.8
    0
        At least 3 serotypes; Pre-Injection 2
    37.5
    0
        At least 3 serotypes; Post-Injection 2
    93.8
    0
        At least 3 serotypes; Pre-Injection 3
    56.3
    12.5
        At least 3 serotypes; Post-Injection 3
    93.8
    12.5
        All 4 serotypes; Pre-Injection 1
    0
    0
        All 4 serotypes; Post-Injection 1
    10.5
    0
        All 4 serotypes; Pre-Injection 2
    18.8
    0
        All 4 serotypes; Post-Injection 2
    75
    0
        All 4 serotypes; Pre-Injection 3
    37.5
    12.5
        All 4 serotypes; Post-Injection 3
    87.5
    12.5
    No statistical analyses for this end point

    Primary: Geometric Mean Titer Ratios (GMTRs) Against Each Serotype with the Parental of Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Geometric Mean Titer Ratios (GMTRs) Against Each Serotype with the Parental of Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [7]
    End point description
    Geometric mean titer ratios of antibodies against the dengue virus serotypes were assessed using the Dengue Plaque Reduction Neutralization Test (PRNT).
    End point type
    Primary
    End point timeframe
    Pre-Injections 1, 2, and 3 and Post-Injections 1, 2, and 3
    Notes
    [7] - 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: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    99
    49
    Units: Titer ratios
    geometric mean (confidence interval 95%)
        Serotype 1; Post-Injection 1/Pre-Injection 1
    4.67 (3.37 to 6.47)
    0.834 (0.699 to 0.994)
        Serotype 1; Post-Injection 2/Pre-Injection 1
    7.26 (5.51 to 9.57)
    2.11 (1.12 to 4)
        Serotype 1; Post-Injection 2/Pre-Injection 2
    1.66 (1.31 to 2.1)
    1.25 (0.801 to 1.94)
        Serotype 1; Post-Injection 3/Pre-Injection 1
    4.92 (3.71 to 6.52)
    1.36 (0.797 to 2.31)
        Serotype 1; Post-Injection 3/Pre-Injection 2
    1.07 (0.828 to 1.39)
    0.793 (0.508 to 1.24)
        Serotype 1; Post-Injection 3/Pre-Injection 3
    1.48 (1.25 to 1.74)
    0.706 (0.607 to 0.821)
        Serotype 2; Post-Injection 1/Pre-Injection 1
    4.15 (3.07 to 5.59)
    0.733 (0.639 to 0.84)
        Serotype 2; Post-Injection 2/Pre-Injection 1
    6.8 (5.46 to 8.45)
    1.75 (0.956 to 3.21)
        Serotype 2; Post-Injection 2/Pre-Injection 2
    1.97 (1.56 to 2.5)
    0.981 (0.66 to 1.46)
        Serotype 2; Post-Injection 3/Pre-Injection 1
    6.21 (4.96 to 7.78)
    1.68 (1.06 to 2.66)
        Serotype 2; Post-Injection 3/Pre-Injection 2
    1.78 (1.39 to 2.28)
    0.944 (0.646 to 1.38)
        Serotype 2; Post-Injection 3/Pre-Injection 3
    1.4 (1.16 to 1.69)
    0.851 (0.734 to 0.986)
        Serotype 3; Post-Injection 1/Pre-Injection 1
    6.5 (5.01 to 8.45)
    0.916 (0.673 to 1.25)
        Serotype 3; Post-Injection 2/Pre-Injection 1
    8.57 (6.79 to 10.8)
    1.85 (1.03 to 3.32)
        Serotype 3; Post-Injection 2/Pre-Injection 2
    2.03 (1.58 to 2.61)
    1.02 (0.701 to 1.47)
        Serotype 3; Post-Injection 3/Pre-Injection 1
    6.26 (4.82 to 8.13)
    1.24 (0.815 to 1.9)
        Serotype 3; Post-Injection 3/Pre-Injection 2
    1.46 (1.11 to 1.91)
    0.673 (0.489 to 0.925)
        Serotype 3; Post-Injection 3/Pre-Injection 3
    1.53 (1.27 to 1.86)
    0.8 (0.681 to 0.94)
        Serotype 4; Post-Injection 1/Pre-Injection 1
    17.7 (12.1 to 26)
    0.806 (0.665 to 0.976)
        Serotype 4; Post-Injection 2/Pre-Injection 1
    15.4 (12.3 to 19.2)
    1.27 (0.795 to 2.04)
        Serotype 4; Post-Injection 2/Pre-Injection 2
    1.84 (1.5 to 2.26)
    0.835 (0.587 to 1.19)
        Serotype 4; Post-Injection 3/Pre-Injection 1
    20.2 (15.4 to 26.3)
    1.4 (0.939 to 2.1)
        Serotype 4; Post-Injection 3/Pre-Injection 2
    2.26 (1.74 to 2.93)
    0.912 (0.606 to 1.37)
        Serotype 4; Post-Injection 3/Pre-Injection 3
    1.68 (1.38 to 2.05)
    0.723 (0.564 to 0.927)
    No statistical analyses for this end point

    Primary: Geometric Mean Titers (GMTs) of Flavivirus-immune Subjects Against Each Serotype with the Parental of Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Geometric Mean Titers (GMTs) of Flavivirus-immune Subjects Against Each Serotype with the Parental of Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [8]
    End point description
    Geometric mean titers of antibodies against the dengue virus serotypes were assessed using the Dengue Plaque Reduction Neutralization Test (PRNT). Flavivirus-immune subjects at baseline are defined as those subjects with ≥10 (1/dil) for at least 1 serotype with the parental dengue virus strain or for the yellow fever titer.
    End point type
    Primary
    End point timeframe
    Pre-Injections 1, 2, and 3 and Post-Injections 1, 2, and 3
    Notes
    [8] - 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: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    80
    41
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Serotype 1; Pre-Injection 1
    68.5 (44.5 to 105)
    73.1 (40.9 to 131)
        Serotype 1; Post-Injection 1
    549 (328 to 918)
    79.8 (46.1 to 138)
        Serotype 1; Pre-Injection 2
    430 (261 to 709)
    154 (78.5 to 303)
        Serotype 1; Post-Injection 2
    661 (442 to 987)
    253 (116 to 553)
        Serotype 1; Pre-Injection 3
    268 (164 to 435)
    143 (73.7 to 278)
        Serotype 1; Post-Injection 3
    381 (256 to 566)
    126 (67.6 to 236)
        Serotype 2; Pre-Injection 1
    124 (81.9 to 188)
    114 (59.7 to 217)
        Serotype 2; Post-Injection 1
    816 (517 to 1290)
    103 (54.8 to 193)
        Serotype 2; Pre-Injection 2
    591 (376 to 928)
    224 (112 to 446)
        Serotype 2; Post-Injection 2
    978 (697 to 1374)
    271 (120 to 610)
        Serotype 2; Pre-Injection 3
    648 (400 to 1048)
    240 (122 to 471)
        Serotype 2; Post-Injection 3
    835 (584 to 1193)
    242 (126 to 463)
        Serotype 3; Pre-Injection 1
    159 (93.5 to 271)
    168 (74.3 to 380)
        Serotype 3; Post-Injection 1
    1263 (764 to 2088)
    202 (89.3 to 455)
        Serotype 3; Pre-Injection 2
    879 (531 to 1455)
    387 (170 to 878)
        Serotype 3; Post-Injection 2
    1426 (950 to 2141)
    497 (204 to 1210)
        Serotype 3; Pre-Injection 3
    776 (481 to 1251)
    272 (122 to 606)
        Serotype 3; Post-Injection 3
    1031 (700 to 1519)
    266 (125 to 566)
        Serotype 4; Pre-Injection 1
    19.5 (14.6 to 26.1)
    22.4 (14.6 to 34.3)
        Serotype 4; Post-Injection 1
    467 (325 to 672)
    25.2 (17.1 to 37.1)
        Serotype 4; Pre-Injection 2
    220 (164 to 295)
    39.5 (23.1 to 67.6)
        Serotype 4; Post-Injection 2
    377 (303 to 470)
    45.3 (25.1 to 81.8)
        Serotype 4; Pre-Injection 3
    313 (231 to 424)
    53.9 (31.7 to 91.8)
        Serotype 4; Post-Injection 3
    485 (374 to 628)
    46.5 (29.3 to 73.6)
    No statistical analyses for this end point

    Primary: Geometric Mean Titer Ratios (GMTRs) of Flavivirus-naïve Subjects Against Each Serotype with the Parental of Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Geometric Mean Titer Ratios (GMTRs) of Flavivirus-naïve Subjects Against Each Serotype with the Parental of Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [9]
    End point description
    Geometric mean titer ratios of antibodies against the dengue virus serotypes were assessed using the Dengue Plaque Reduction Neutralization Test (PRNT). Flavivirus-naïve subjects at baseline are defined as those subjects with <10 (1/dil) for all serotypes with parental dengue virus strains and for yellow fever titer.
    End point type
    Primary
    End point timeframe
    Pre-Injections 1, 2, and 3 and Post-Injections 1, 2, and 3
    Notes
    [9] - 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: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    19
    8
    Units: Titer ratios
    geometric mean (confidence interval 95%)
        Serotype 1; Post-Injection 1/Pre-Injection 1
    1.03 (0.639 to 1.67)
    0.5 (0.5 to 0.5)
        Serotype 1; Post-Injection 2/Pre-Injection 1
    5.73 (1.89 to 17.3)
    0.5 (0.5 to 0.5)
        Serotype 1; Post-Injection 2/Pre-Injection 2
    3.25 (1.18 to 8.93)
    0.5 (0.5 to 0.5)
        Serotype 1; Post-Injection 3/Pre-Injection 1
    5.34 (2.25 to 12.7)
    0.861 (0.238 to 3.11)
        Serotype 1; Post-Injection 3/Pre-Injection 2
    3.03 (1.35 to 6.8)
    0.861 (0.238 to 3.11)
        Serotype 1; Post-Injection 3/Pre-Injection 3
    2.19 (1.37 to 3.48)
    0.446 (0.342 to 0.584)
        Serotype 2; Post-Injection 1/Pre-Injection 1
    1.02 (0.527 to 1.99)
    0.5 (0.5 to 0.5)
        Serotype 2; Post-Injection 2/Pre-Injection 1
    8.62 (3.49 to 21.3)
    0.5 (0.5 to 0.5)
        Serotype 2; Post-Injection 2/Pre-Injection 2
    6.02 (2.37 to 15.3)
    0.5 (0.5 to 0.5)
        Serotype 2; Post-Injection 3/Pre-Injection 1
    7.67 (4.19 to 14)
    0.737 (0.294 to 1.85)
        Serotype 2; Post-Injection 3/Pre-Injection 2
    5.36 (2.73 to 10.5)
    0.737 (0.294 to 1.85)
        Serotype 2; Post-Injection 3/Pre-Injection 3
    2.37 (1.35 to 4.17)
    0.538 (0.453 to 0.639)
        Serotype 3; Post-Injection 1/Pre-Injection 1
    5.41 (2.8 to 10.5)
    0.5 (0.5 to 0.5)
        Serotype 3; Post-Injection 2/Pre-Injection 1
    21.2 (10.5 to 42.9)
    0.5 (0.5 to 0.5)
        Serotype 3; Post-Injection 2/Pre-Injection 2
    7.58 (3.12 to 18.4)
    0.5 (0.5 to 0.5)
        Serotype 3; Post-Injection 3/Pre-Injection 1
    16.3 (9.65 to 27.7)
    0.678 (0.33 to 1.39)
        Serotype 3; Post-Injection 3/Pre-Injection 2
    5.83 (3.17 to 10.7)
    0.678 (0.33 to 1.39)
        Serotype 3; Post-Injection 3/Pre-Injection 3
    3.35 (1.92 to 5.84)
    0.524 (0.469 to 0.587)
        Serotype 4; Post-Injection 1/Pre-Injection 1
    16.5 (4.58 to 59.1)
    0.5 (0.5 to 0.5)
        Serotype 4; Post-Injection 2/Pre-Injection 1
    22.7 (12.8 to 40.3)
    0.5 (0.5 to 0.5)
        Serotype 4; Post-Injection 2/Pre-Injection 2
    3.15 (1.63 to 6.09)
    0.5 (0.5 to 0.5)
        Serotype 4; Post-Injection 3/Pre-Injection 1
    25.5 (11.6 to 55.9)
    0.701 (0.414 to 1.19)
        Serotype 4; Post-Injection 3/Pre-Injection 2
    3.53 (1.71 to 7.26)
    0.701 (0.414 to 1.19)
        Serotype 4; Post-Injection 3/Pre-Injection 3
    2.55 (1.37 to 4.75)
    0.578 (0.401 to 0.832)
    No statistical analyses for this end point

    Primary: Percentage of Subjects Reporting Solicited Injection-site and Systemic Reactions Following Any and Each Vaccination With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Percentage of Subjects Reporting Solicited Injection-site and Systemic Reactions Following Any and Each Vaccination With Either CYD Dengue Vaccine or a Placebo [10]
    End point description
    Injection site reactions: Pain, Erythema, and Swelling. Systemic reactions: Fever, Headache, Malaise, Myalgia, and Asthenia. Grade 3 Injection site reactions (9-11 yrs): Pain, Incapacitating, unable to perform usual activities; Erythema and Swelling, ≥5 cm. Grade 3 Injection site reactions (≥12 yrs): Pain, Significant; prevents daily activity; Erythema and Swelling, >10 cm. Grade 3 Systemic reactions: Fever, ≥39°C; Headache, Malaise, Myalgia, and Asthenia, Significant; prevents daily activity.
    End point type
    Primary
    End point timeframe
    Day 0 up to Day 14 post-any and each vaccination
    Notes
    [10] - 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: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    100
    50
    Units: Percentage of subjects
    number (not applicable)
        Injection site Pain; Post-Any Injection
    40
    40.8
        Gr 3 Injection site Pain; Post-Any Injection
    0
    4.1
        Injection site Erythema; Post-Any Injection
    4
    2
        Gr 3 Injection site Erythema; Post-Any Injection
    0
    0
        Injection site Swelling; Post-Any Injection
    5
    4.1
        Gr 3 Injection site Swelling; Post-Any Injection
    0
    0
        Injection site Pain; Post-Injection 1
    26.3
    30.6
        Gr 3 Injection site Pain; Post-Injection 1
    0
    2
        Injection site Erythema; Post-Injection 1
    1
    2
        Gr 3 Injection site Erythema; Post-Injection 1
    0
    0
        Injection site Swelling; Post-Injection 1
    2
    4.1
        Gr 3 Injection site Swelling; Post-Injection 1
    0
    0
        Injection site Pain; Post-Injection 2
    21.5
    14.9
        Gr 3 Injection site Pain; Post-Injection 2
    0
    2.1
        Injection site Erythema; Post-Injection 2
    3.2
    0
        Gr 3 Injection site Erythema; Post-Injection 2
    0
    0
        Injection site Swelling; Post-Injection 2
    2.2
    0
        Gr 3 Injection site Swelling; Post-Injection 2
    0
    0
        Injection site Pain; Post-Injection 3
    16.9
    15.6
        Gr 3 Injection site Pain; Post-Injection 3
    0
    2.2
        Injection site Erythema; Post-Injection 3
    0
    0
        Gr 3 Injection site Erythema; Post-Injection 3
    0
    0
        Injection site Swelling; Post-Injection 3
    1.1
    0
        Gr 3 Injection site Swelling; Post-Injection 3
    0
    0
        Fever; Post-Any Injection
    30
    18.4
        Gr 3 Fever; Post-Any Injection
    8
    6.1
        Headache; Post-Any Injection
    61
    51
        Gr 3 Headache; Post-Any Injection
    15
    20.4
        Malaise; Post-Any Injection
    40
    32.7
        Gr 3 Malaise; Post-Any Injection
    11
    6.1
        Myalgia; Post-Any Injection
    42
    42.9
        Gr 3 Myalgia; Post-Any Injection
    6
    8.2
        Asthenia; Post-Any Injection
    35
    20.4
        Gr 3 Asthenia; Post-Any Injection
    8
    4.1
        Fever; Post-Injection 1
    15.3
    10.4
        Gr 3 Fever; Post-Injection 1
    3.1
    2.1
        Headache; Post-Injection 1
    48.5
    40.8
        Gr 3 Headache; Post-Injection 1
    8.1
    10.2
        Malaise; Post-Injection 1
    31.3
    18.4
        Gr 3 Malaise; Post-Injection 1
    3
    2
        Myalgia; Post-Injection 1
    32.3
    30.6
        Gr 3 Myalgia; Post-Injection 1
    2
    6.1
        Asthenia; Post-Injection 1
    22.2
    10.2
        Gr 3 Asthenia; Post-Injection 1
    4
    4.1
        Fever; Post-Injection 2
    8.7
    4.3
        Gr 3 Fever; Post-Injection 2
    2.2
    0
        Headache; Post-Injection 2
    28.7
    34
        Gr 3 Headache; Post-Injection 2
    5.3
    6.4
        Malaise; Post-Injection 2
    18.1
    17
        Gr 3 Malaise; Post-Injection 2
    6.4
    4.3
        Myalgia; Post-Injection 2
    20.2
    21.3
        Gr 3 Myalgia; Post-Injection 2
    3.2
    4.3
        Asthenia; Post-Injection 2
    12.8
    14.9
        Gr 3 Asthenia; Post-Injection 2
    3.2
    0
        Fever; Post-Injection 3
    11
    7
        Gr 3 Fever; Post-Injection 3
    3.7
    7
        Headache; Post-Injection 3
    27
    20
        Gr 3 Headache; Post-Injection 3
    5.6
    8.9
        Malaise; Post-Injection 3
    15.7
    11.1
        Gr 3 Malaise; Post-Injection 3
    2.2
    0
        Myalgia; Post-Injection 3
    20.2
    11.1
        Gr 3 Myalgia; Post-Injection 3
    2.2
    0
        Asthenia; Post-Injection 3
    14.6
    4.4
        Gr 3 Asthenia; Post-Injection 3
    2.2
    0
    No statistical analyses for this end point

    Primary: Geometric Mean Titers (GMTs) Against Each Serotype with the Parental of Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Geometric Mean Titers (GMTs) Against Each Serotype with the Parental of Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [11]
    End point description
    Geometric mean titers of antibodies against the dengue virus serotypes were assessed using the Dengue Plaque Reduction Neutralization Test (PRNT).
    End point type
    Primary
    End point timeframe
    Pre-Injections 1, 2, and 3 and Post-Injections 1, 2, and 3
    Notes
    [11] - 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: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    99
    49
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Serotype 1; Pre-Injection 1
    41.4 (27.7 to 62.1)
    47.2 (26.9 to 82.7)
        Serotype 1; Post-Injection 1
    256 (151 to 433)
    50.7 (29.5 to 87.3)
        Serotype 1; Pre-Injection 2
    230 (138 to 384)
    86 (43.8 to 169)
        Serotype 1; Post-Injection 2
    436 (287 to 662)
    130 (59.7 to 283)
        Serotype 1; Pre-Injection 3
    162 (99.8 to 262)
    90.8 (46.6 to 177)
        Serotype 1; Post-Injection 3
    267 (181 to 394)
    79.2 (42.4 to 148)
        Serotype 2; Pre-Injection 1
    67 (44 to 102)
    68.3 (36.3 to 129)
        Serotype 2; Post-Injection 1
    352 (210 to 592)
    62.8 (33.9 to 116)
        Serotype 2; Pre-Injection 2
    287 (173 to 475)
    117 (57.6 to 238)
        Serotype 2; Post-Injection 2
    647 (449 to 932)
    137 (61.4 to 306)
        Serotype 2; Pre-Injection 3
    360 (219 to 592)
    131 (65.7 to 262)
        Serotype 2; Post-Injection 3
    544 (378 to 782)
    132 (67 to 259)
        Serotype 3; Pre-Injection 1
    81.9 (49.3 to 136)
    94.7 (43.6 to 206)
        Serotype 3; Post-Injection 1
    690 (423 to 1125)
    110 (50.3 to 242)
        Serotype 3; Pre-Injection 2
    471 (282 to 787)
    184 (80.3 to 424)
        Serotype 3; Post-Injection 2
    1031 (704 to 1512)
    227 (92.8 to 556)
        Serotype 3; Pre-Injection 3
    481 (300 to 772)
    144 (65.8 to 316)
        Serotype 3; Post-Injection 3
    741 (516 to 1062)
    140 (66 to 298)
        Serotype 4; Pre-Injection 1
    15 (11.6 to 19.4)
    17.5 (11.9 to 25.8)
        Serotype 4; Post-Injection 1
    383 (262 to 559)
    19.2 (13.3 to 27.7)
        Serotype 4; Pre-Injection 2
    178 (134 to 238)
    27.8 (16.9 to 45.8)
        Serotype 4; Post-Injection 2
    346 (281 to 425)
    31.2 (18.1 to 53.7)
        Serotype 4; Pre-Injection 3
    258 (192 to 347)
    37.4 (22.6 to 62.1)
        Serotype 4; Post-Injection 3
    432 (335 to 556)
    33.4 (21.5 to 51.9)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from Day 0 (post-vaccination) up to Day 14 post-Injection 3.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    CYD Dengue vaccine group
    Reporting group description
    Subjects received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.

    Reporting group title
    Control group
    Reporting group description
    Subjects received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.

    Serious adverse events
    CYD Dengue vaccine group Control group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 100 (5.00%)
    3 / 50 (6.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Multiple injuries
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 50 (2.00%)
         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
    Intra-uterine death
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 50 (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
    Abdominal wall abscess
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 50 (2.00%)
         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: 5%
    Non-serious adverse events
    CYD Dengue vaccine group Control group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    61 / 100 (61.00%)
    25 / 50 (50.00%)
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    6 / 100 (6.00%)
    4 / 50 (8.00%)
         occurrences all number
    6
    4
    Wound
         subjects affected / exposed
    0 / 100 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 100 (6.00%)
    4 / 50 (8.00%)
         occurrences all number
    7
    4
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    9 / 100 (9.00%)
    1 / 50 (2.00%)
         occurrences all number
    9
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 100 (6.00%)
    7 / 50 (14.00%)
         occurrences all number
    7
    8
    Headache; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [1]
    61 / 100 (61.00%)
    25 / 49 (51.02%)
         occurrences all number
    61
    25
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    11 / 100 (11.00%)
    7 / 50 (14.00%)
         occurrences all number
    11
    7
    General disorders and administration site conditions
    Injection site Pain; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [2]
    40 / 100 (40.00%)
    20 / 49 (40.82%)
         occurrences all number
    40
    20
    Injection site Swelling; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    5 / 100 (5.00%)
    2 / 49 (4.08%)
         occurrences all number
    5
    2
    Fever; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    30 / 100 (30.00%)
    9 / 49 (18.37%)
         occurrences all number
    30
    9
    Malaise; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    40 / 100 (40.00%)
    16 / 49 (32.65%)
         occurrences all number
    40
    16
    Asthenia; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    35 / 100 (35.00%)
    10 / 49 (20.41%)
         occurrences all number
    35
    10
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    12 / 100 (12.00%)
    4 / 50 (8.00%)
         occurrences all number
    16
    6
    Nausea
         subjects affected / exposed
    8 / 100 (8.00%)
    0 / 50 (0.00%)
         occurrences all number
    11
    0
    Vomiting
         subjects affected / exposed
    7 / 100 (7.00%)
    2 / 50 (4.00%)
         occurrences all number
    7
    2
    Musculoskeletal and connective tissue disorders
    Myalgia; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    42 / 100 (42.00%)
    21 / 49 (42.86%)
         occurrences all number
    42
    21
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    12 / 100 (12.00%)
    6 / 50 (12.00%)
         occurrences all number
    12
    6
    Rhinitis
         subjects affected / exposed
    6 / 100 (6.00%)
    2 / 50 (4.00%)
         occurrences all number
    7
    2
    Tonsillitis
         subjects affected / exposed
    5 / 100 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    5
    0
    Upper respiratory tract infection
         subjects affected / exposed
    18 / 100 (18.00%)
    3 / 50 (6.00%)
         occurrences all number
    19
    3
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 14 days after any injection; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days after any injection; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days after any injection; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 14 days after any injection; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days after any injection; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 14 days after any injection; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 14 days after any injection; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Sep 2009
    Replaced Principal Investigators and Sponsor's Regional Clinical Trial Managers in Venezuela as well as updated the site name.
    15 Nov 2009
    Revised trial dates, replaced the meningococcal A+C vaccine (in Brazil) or ADACEL (in Venezuela) as third vaccination by placebo injection, updated the "Product Logistics" section accordingly, clarified the minimum timeline between two febrile episodes to consider two separate episodes, replaced control products 2 and 3 with placebo, modified the inclusion and exclusion criteria, offered a licensed, commercial vaccine meningococcal A+C vaccine for Brazil and ADACEL for Brazil after the completion of the safety surveillance period, implemented a temperature monitoring card, adapted a second temporary contraindication in the context of future pandemic influenza vaccination campaigns, revised contraindications accordingly, modified the text describing blood collection, revised the text regarding the use of unused stored serum samples, added a full description of the enzyme-linked immunosorbent assay with all acute samples collected from suspected dengue cases having been tested with the wild-type dengue reverse transcriptase-polymerase chain reaction.
    31 Mar 2010
    Updated the trial personnel (including the Principal Investigator in Brazil and Sanofi Pasteur personnel)
    22 Jul 2010
    Reworded to confirm that it was a monocenter trial conducted in Brazil, updated number of enrolled subjects to 150 instead of 300, statistical methods were revised, updated the methodology to the dengue screen reverse transcriptase-polymerase chain reaction assay and dengue plaque reduction neutralization test.
    09 Feb 2011
    Expanded the description of events to be reviewed by the Independent Data Monitoring Committee, increased the number of visits to 10, changed the last study contact to a clinic visit to allow for the optional administration of the vaccine, clarified subject benefits, quantity of blood drawn was no longer specified to give more flexibility due to differences in the amount of blood collected, added a description of the optional administration of the vaccine at the last study contact, reworded clinical supplies section, revised text in the assessment method section in addition to updating text to wild-type dengue reverse transcriptase-polymerase chain reaction for technical accuracy, modified the interim analysis and statistical methods, revised the immunogenicity methods, modified the description of the flavivirus serology, updated study violations, and reworded the description of the handling of missing data and outliers.
    20 Oct 2011
    Updated the study design such that it clarified all three vaccinations were handled in the same way, updated personnel information on the cover page, updated the statistical analyses sections, updated text regarding the status of the phase II trials at the time of the writing of this amendment, updated the date and version number of the Investigator's Brochure, updated text regarding the current status of the clinical trials and current available document, replaced meningococcal A+C vaccine with influenza vaccine since meningococcal A+C vaccine was no longer licensed in Brazil, updated current information on Principal Investigator, updated text to delete the interim analysis after the second vaccination, modified the description of the yellow fever dengue plaque reduction neutralization test assay, updated the description of the Per Protocol Analysis Set, Full Analysis Set, and Safety Analysis Set, and revised the handling of missing data and outliers section to incorporate statistical standard text.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/24189367
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