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    Clinical Trial Results:
    Long-Term Safety Follow-Up of Thai Children Who Were Included in an Efficacy Study of a Tetravalent Dengue Vaccine

    Summary
    EudraCT number
    2014-001737-88
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    19 Feb 2016

    Results information
    Results version number
    v2(current)
    This version publication date
    23 Aug 2018
    First version publication date
    19 May 2016
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Follow-up data up to Year 4 were added to the full data set

    Trial information

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    Trial identification
    Sponsor protocol code
    CYD57
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01983553
    WHO universal trial number (UTN)
    U1111-1127-7380
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur SA
    Sponsor organisation address
    14 Espace Henry Vallée, Lyon, France, 69007
    Public contact
    Trial Transparency, Sanofi Pasteur, RegistryContactUs@sanofipasteur.com
    Scientific contact
    Trial Transparency, Sanofi Pasteur, RegistryContactUs@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
    20 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study is to evaluate the continuous long-term follow-up of hospitalized dengue and safety of subjects who received CYD dengue vaccine in study CYD23 (EudraCT No. 2014-001710-25) including retrospective data collection (i.e., including the blood samples collected from March 05th, 2012 to September 9th, 2013) and prospective data collection from CYD57 study start (September 10th, 2013) until the end of the study, and the following activities will be performed. 1) To describe the incidence of virologically-confirmed hospitalized dengue cases. 2) To characterize hospitalized dengue cases. 3) To evaluate the occurrence of related and fatal serious adverse events (SAEs).
    Protection of trial subjects
    Subjects were vaccinated in a previous study, CYD23. No vaccination was administered as part of this study.
    Background therapy
    In study CYD23, subjects age 4 to 11 were randomized to receive 3 injections of either CYD dengue vaccine or control, 1 each at 0, 6, and 12 months. Those that received at least one injection were eligible to be included in this follow-up study.
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    10 Sep 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    4 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Thailand: 3203
    Worldwide total number of subjects
    3203
    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)
    3203
    Adolescents (12-17 years)
    0
    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 in the original study CYD23 from 10 September 2013 to 29 November 2013 at 1 clinic center in Thailand.

    Pre-assignment
    Screening details
    Of the 3997 subjects who were treated in the original study CYD23, a total of 3203 subjects were included in the 4-year safety follow-up CYD57 study.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    Subjects and site staff remained blinded to the treatment allocation in CYD23 until the end of the study (CYD57) to avoid any bias in the safety follow-up (detection of dengue cases). In the event of an emergency (i.e., serious adverse event), the code of CYD57 could be broken by the Investigator as explained in the code-breaking procedures described in the Operating Guidelines.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CYD Dengue Vaccine Group
    Arm description
    Subjects received 3 injections of CYD dengue vaccine, 1 injection each at 0, 6, and 12 months in study CYD23.
    Arm type
    Experimental

    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, subcutaneous, 1 injection each at 0, 6, and 12 months in the initial CYD23 study.

    Arm title
    Control Group
    Arm description
    Subjects received either Rabies vaccine (Verorab®) or placebo control as a first injection on Day 0, placebo for second and third injections at 6 and 12 months, respectively, in the original CYD23 study.
    Arm type
    Active comparator

    Investigational medicinal product name
    Placebo (sodium chloride)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, subcutaneous, 1 injection of either Verorab or placebo as a first injection on Day 0, placebo for second and third injections at 6 and 12 months, respectively, in the original CYD23 study.

    Investigational medicinal product name
    Rabies vaccine (Verorab®)
    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, subcutaneous, 1 injection of either Verorab or placebo as a first injection on Day 0, placebo for second and third injections at 6 and 12 months, respectively, in the original CYD23 study.

    Number of subjects in period 1
    CYD Dengue Vaccine Group Control Group
    Started
    2131
    1072
    Completed
    2131
    1072

    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 CYD dengue vaccine, 1 injection each at 0, 6, and 12 months in study CYD23.

    Reporting group title
    Control Group
    Reporting group description
    Subjects received either Rabies vaccine (Verorab®) or placebo control as a first injection on Day 0, placebo for second and third injections at 6 and 12 months, respectively, in the original CYD23 study.

    Reporting group values
    CYD Dengue Vaccine Group Control Group Total
    Number of subjects
    2131 1072 3203
    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)
    2131 1072 3203
        Adolescents (12-17 years)
    0 0 0
        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)
    8.11 ± 2.02 8.15 ± 2.06 -
    Gender categorical
    Units: Subjects
        Female
    1118 579 1697
        Male
    1013 493 1506

    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 CYD dengue vaccine, 1 injection each at 0, 6, and 12 months in study CYD23.

    Reporting group title
    Control Group
    Reporting group description
    Subjects received either Rabies vaccine (Verorab®) or placebo control as a first injection on Day 0, placebo for second and third injections at 6 and 12 months, respectively, in the original CYD23 study.

    Primary: Annual Incidence of Hospitalized Virologically-Confirmed Dengue Due to Any and Each Serotype Following Vaccination with Either CYD Dengue Vaccine or a Placebo in a Previous Study

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    End point title
    Annual Incidence of Hospitalized Virologically-Confirmed Dengue Due to Any and Each Serotype Following Vaccination with Either CYD Dengue Vaccine or a Placebo in a Previous Study
    End point description
    Annual incidence rate was defined as the cases among the number of subjects present at the beginning of each period (M) multiplied by 100 converted in annual rate (Annual incidence rate = Cases among M*100). Analysis was performed on Follow-up Analysis Set (FupAS) which included all subjects who were included in study CYD57.
    End point type
    Primary
    End point timeframe
    Year 1 to Year 4 post-vaccination
    End point values
    CYD Dengue Vaccine Group Control Group
    Number of subjects analysed
    2131
    1072
    Units: Annual incidence rate
    number (confidence interval 95%)
        Any of the 4 Serotypes
    1.0 (0.8 to 1.2)
    1.1 (0.8 to 1.4)
        Serotype 1
    0.2 (0.2 to 0.4)
    0.3 (0.1 to 0.5)
        Serotype 2
    0.3 (0.2 to 0.5)
    0.3 (0.1 to 0.5)
        Serotype 3
    0.2 (0.2 to 0.4)
    0.2 (0.1 to 0.4)
        Serotype 4
    0.2 (0.1 to 0.3)
    0.3 (0.1 to 0.5)
        Unserotyped
    0.0 (0.0 to 0.0)
    0.1 (0.0 to 0.2)
    Statistical analysis title
    Relative risk; Any of the 4 Serotypes
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Any of the 4 Serotypes between the CYD Dengue vaccine group and the Control group.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    Method
    Parameter type
    Relative Risk
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    1.36
    Notes
    [1] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative risk; Serotype 1
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 1 between the CYD Dengue vaccine group and the Control group.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    Method
    Parameter type
    Relative Risk
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    2.21
    Notes
    [2] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative risk; Serotype 2
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 2 between the CYD Dengue vaccine group and the Control group.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    Method
    Parameter type
    Relative Risk
    Point estimate
    1.326
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    2.94
    Notes
    [3] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative risk; Serotype 3
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 3 between the CYD Dengue vaccine group and the Control group.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [4]
    Method
    Parameter type
    Relative Risk
    Point estimate
    1.056
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    2.51
    Notes
    [4] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative risk; Serotype 4
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 4 between the CYD Dengue vaccine group and the Control group.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    Method
    Parameter type
    Relative Risk
    Point estimate
    0.629
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.27
         upper limit
    1.47
    Notes
    [5] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative risk; Unserotyped
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Unserotyped between the CYD Dengue vaccine group and the Control group.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    Method
    Parameter type
    Relative Risk
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    1.22
    Notes
    [6] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.

    Primary: Number of Cases and Episodes of Hospitalized Virologically-Confirmed Dengue Due to Any and Each Serotype Following Vaccination with Either CYD Dengue Vaccine or a Placebo in a Previous Study

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    End point title
    Number of Cases and Episodes of Hospitalized Virologically-Confirmed Dengue Due to Any and Each Serotype Following Vaccination with Either CYD Dengue Vaccine or a Placebo in a Previous Study [7]
    End point description
    Cases were defined as the number of subjects with at least one hospitalized virologically-confirmed dengue episode. Episodes were defined as the number of hospitalized virologically-confirmed dengue episodes. Analysis was performed on FupAS.
    End point type
    Primary
    End point timeframe
    Year 1 to Year 4 post-vaccination
    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
    2131
    1072
    Units: Number of cases and episodes of dengue
    number (not applicable)
        Cases; Any of the 4 Serotypes
    85
    46
        Episodes; Any of the 4 Serotypes
    85
    46
        Cases; Serotype 1
    21
    11
        Episodes; Serotype 1
    21
    11
        Cases; Serotype 2
    29
    11
        Episodes; Serotype 2
    29
    11
        Cases; Serotype 3
    21
    10
        Episodes; Serotype 3
    21
    10
        Cases; Serotype 4
    15
    12
        Episodes; Serotype 4
    15
    12
        Cases; Unserotyped
    0
    3
        Episodes; Unserotyped
    0
    3
    No statistical analyses for this end point

    Primary: Annual Incidence of Hospitalized Virologically-Confirmed Dengue Due to Any and Each Serotype Collected By Age Group Following Vaccination with Either CYD Dengue Vaccine or a Placebo in a Previous Study

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    End point title
    Annual Incidence of Hospitalized Virologically-Confirmed Dengue Due to Any and Each Serotype Collected By Age Group Following Vaccination with Either CYD Dengue Vaccine or a Placebo in a Previous Study
    End point description
    Annual incidence rate was defined as the cases among the number of subjects present at the beginning of each period (M) multiplied by 100 converted in annual rate (Annual incidence rate = Cases among M*100). Analysis was performed on FupAS. Here, “n” signifies number of subjects evaluable for each specified category. Endpoint values <0.1 were rounded to 0.1.
    End point type
    Primary
    End point timeframe
    Year 1 to Year 4 post-vaccination
    End point values
    CYD Dengue Vaccine Group Control Group
    Number of subjects analysed
    2131
    1072
    Units: Incidence rate
    number (confidence interval 95%)
        4 to 5 Years: Any of the 4 Serotypes (n=393, 192)
    1.7 (1.1 to 2.4)
    1.2 (0.5 to 2.2)
        6 to 11 Years: Any of the 4 Serotypes(n=1738, 880)
    0.8 (0.6 to 1.1)
    1.1 (0.7 to 1.4)
        4 to 5 Years: Serotype 1 (n=393, 192)
    0.6 (0.3 to 1.2)
    0.1 (0.0 to 0.7)
        6 to 11 Years: Serotype 1 (n=1738, 880)
    0.2 (0.1 to 0.3)
    0.3 (0.1 to 0.5)
        4 to 5 Years: Serotype 2 (n=393, 192)
    0.4 (0.1 to 0.8)
    0.1 (0.0 to 0.7)
        6 to 11 Years: Serotype 2 (n=1738, 880)
    0.3 (0.2 to 0.5)
    0.3 (0.1 to 0.5)
        4 to 5 Years: Serotype 3 (n=393, 192)
    0.3 (0.1 to 0.7)
    0.3 (0.0 to 0.9)
        6 to 11 Years: Serotype 3 (n=1738, 880)
    0.2 (0.1 to 0.4)
    0.2 (0.1 to 0.4)
        4 to 5 Years: Serotype 4 (n=393, 192)
    0.4 (0.1 to 0.8)
    0.4 (0.1 to 1.1)
        6 to 11 Years: Serotype 4 (n=1738, 880)
    0.1 (0.1 to 0.2)
    0.3 (0.1 to 0.5)
        4 to 5 Years: Unserotyped (n=393, 192)
    0.0 (0.0 to 0.2)
    0.3 (0.0 to 0.9)
        6 to 11 Years: Unserotyped (n=1738, 880)
    0.0 (0.0 to 0.1)
    0.1 (0.0 to 0.2)
    Statistical analysis title
    Relative Risk; 4 to 5 years; Any Serotype
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Any of the 4 Serotypes (4 to 5 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 525 instead of 3203.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [8]
    Method
    Parameter type
    Relative Risk
    Point estimate
    1.411
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    3.42
    Notes
    [8] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative Risk; 6 to 11 years; Any Serotype
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Any of the 4 Serotypes (6 to 11 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 2618 instead of 3203.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [9]
    Method
    Parameter type
    Relative Risk
    Point estimate
    0.807
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    1.25
    Notes
    [9] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative Risk; 4 to 5 years; Serotype 1
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 1 (4 to 5 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 525 instead of 3203.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [10]
    Method
    Parameter type
    Relative Risk
    Point estimate
    4.885
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    212.02
    Notes
    [10] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative Risk; 6 to 11 years; Serotype 1
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 1 (6 to 11 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 2618 instead of 3203.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [11]
    Method
    Parameter type
    Relative Risk
    Point estimate
    0.557
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.21
         upper limit
    1.46
    Notes
    [11] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative Risk; 4 to 5 years; Serotype 2
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 2 (4 to 5 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 525 instead of 3203.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [12]
    Method
    Parameter type
    Relative Risk
    Point estimate
    2.931
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.36
         upper limit
    134.83
    Notes
    [12] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative Risk; 6 to 11 years; Serotype 2
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 2 (6 to 11 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 2618 instead of 3203.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [13]
    Method
    Parameter type
    Relative Risk
    Point estimate
    1.165
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    2.74
    Notes
    [13] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative Risk; 4 to 5 years; Serotype 3
    Statistical analysis description
    Relative risk analysis of the annual incidence rate at Year 1 for Serotype 3 (4 to 5 year) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 525 instead of 3203.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [14]
    Method
    Parameter type
    Relative Risk
    Point estimate
    1.221
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2
         upper limit
    12.83
    Notes
    [14] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative Risk; 6 to 11 years; Serotype 3
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 3 (6 to 11 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 2618 instead of 3203.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [15]
    Method
    Parameter type
    Relative Risk
    Point estimate
    1.013
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.41
         upper limit
    2.73
    Notes
    [15] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative Risk; 4 to 5 years; Serotype 4
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 4 (4 to 5 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 525 instead of 3203.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [16]
    Method
    Parameter type
    Relative Risk
    Point estimate
    0.977
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.21
         upper limit
    6.04
    Notes
    [16] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative Risk; 6 to 11 years; Serotype 4
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 4 (6 to 11 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 2618 instead of 3203.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [17]
    Method
    Parameter type
    Relative Risk
    Point estimate
    0.506
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.18
         upper limit
    1.44
    Notes
    [17] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative Risk; 4 to 5 years; Unserotyped
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Unserotyped (4 to 5 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 525 instead of 3203.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [18]
    Method
    Parameter type
    Relative Risk
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    2.6
    Notes
    [18] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative Risk; 6 to 11 years; Unserotyped
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Unserotyped (6 to 11 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 2618 instead of 3203.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [19]
    Method
    Parameter type
    Relative Risk
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    19.75
    Notes
    [19] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.

    Primary: Number of Cases and Episodes of Hospitalized Virologically-Confirmed Dengue Due to Any and Each Serotype Collected By Age Group Following Vaccination with Either CYD Dengue Vaccine or a Placebo in a Previous Study

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    End point title
    Number of Cases and Episodes of Hospitalized Virologically-Confirmed Dengue Due to Any and Each Serotype Collected By Age Group Following Vaccination with Either CYD Dengue Vaccine or a Placebo in a Previous Study [20]
    End point description
    Cases were defined as the number of subjects with at least one hospitalized virologically-confirmed dengue episode. Episodes were defined as the number of hospitalized virologically-confirmed dengue episodes. Analysis was performed on FupAS. Here, “n” signifies number of subjects evaluable for each specified category.
    End point type
    Primary
    End point timeframe
    Year 1 to Year 4 post-vaccination
    Notes
    [20] - 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
    2131
    1072
    Units: Number of cases and episodes of dengue
    number (not applicable)
        4to5 years cases:Any of the 4 Serotypes(n=393,192)
    26
    9
        4to5 years episodes: Any of 4 Serotypes(n=393,192)
    26
    9
        6to11years cases:Any of the 4Serotypes(n=1738,880)
    59
    37
        6to11years episodes:Any of 4 Serotypes(n=1738,880)
    59
    37
        4 to 5 years cases: Serotype 1 (n=393, 192)
    10
    1
        4 to 5 years episodes: Serotype 1 (n=393, 192)
    10
    1
        6 to 11 years cases: Serotype 1 (n=1738,880)
    11
    10
        6 to 11 years episodes: Serotype 1 (n=1738,880)
    11
    10
        4 to 5 years cases: Serotype 2 (n=393, 192)
    6
    1
        4 to 5 years episodes: Serotype 2 (n=393, 192)
    6
    1
        6 to 11 years cases: Serotype 2 (n=1738,880)
    23
    10
        6 to 11 years episodes: Serotype 2 (n=1738,880)
    23
    10
        4 to 5 years cases: Serotype 3 (n=393, 192)
    5
    2
        4 to 5 years episodes: Serotype 3 (n=393, 192)
    5
    2
        6 to 11 years cases: Serotype 3 (n=1738,880)
    16
    8
        6 to 11 years episodes: Serotype 3 (n=1738,880)
    16
    8
        4 to 5 years cases: Serotype 4 (n=393, 192)
    6
    3
        4 to 5 years episodes: Serotype 4 (n=393, 192)
    6
    3
        6 to 11 years cases: Serotype 4 (n=1738,880)
    9
    9
        6 to 11 years episodes: Serotype 4 (n=1738,880)
    9
    9
        4 to 5 years cases: Unserotyped (n=393, 192)
    0
    2
        4 to 5 years episodes: Unserotyped (n=393, 192)
    0
    2
        6 to 11 years cases: Unserotyped (n=1738,880)
    0
    1
        6 to 11 years episodes: Unserotyped (n=1738,880)
    0
    1
    No statistical analyses for this end point

    Primary: Annual Incidence of Clinically Severe Hospitalized Virologically-Confirmed Dengue Due to Any and Each Serotype Following Vaccination with Either CYD Dengue Vaccine or a Placebo in a Previous Study

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    End point title
    Annual Incidence of Clinically Severe Hospitalized Virologically-Confirmed Dengue Due to Any and Each Serotype Following Vaccination with Either CYD Dengue Vaccine or a Placebo in a Previous Study [21]
    End point description
    Annual incidence rate was defined as the cases among the number of subjects present at the beginning of each period (M) multiplied by 100 converted in annual rate (Annual incidence rate = Cases among M*100). Analysis was performed on FupAS. Endpoint values <0.1 were rounded to 0.1.
    End point type
    Primary
    End point timeframe
    Year 1 to Year 4 post-vaccination
    Notes
    [21] - 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
    2131
    1072
    Units: Annual incidence rate
    number (confidence interval 95%)
        Any of the 4 Serotypes
    0.1 (0.0 to 0.2)
    0.1 (0.0 to 0.2)
        Serotype 1
    0.1 (0.0 to 0.2)
    0.0 (0.0 to 0.1)
        Serotype 2
    0.1 (0.0 to 0.1)
    0.1 (0.0 to 0.1)
        Serotype 3
    0.1 (0.0 to 0.1)
    0.0 (0.0 to 0.1)
        Serotype 4
    0.1 (0.0 to 0.1)
    0.1 (0.0 to 0.2)
        Unserotyped
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.1)
    No statistical analyses for this end point

    Primary: Number of Cases and Episodes of Clinically Severe Hospitalized Virologically-Confirmed Dengue Due to Any and Each Serotype Following Vaccination with CYD Dengue Vaccine or Placebo in a Previous Study

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    End point title
    Number of Cases and Episodes of Clinically Severe Hospitalized Virologically-Confirmed Dengue Due to Any and Each Serotype Following Vaccination with CYD Dengue Vaccine or Placebo in a Previous Study [22]
    End point description
    Cases were defined as the number of subjects with at least one hospitalized virologically-confirmed dengue episode. Episodes were defined as the number of hospitalized virologically-confirmed dengue episodes. Analysis was performed on FupAS.
    End point type
    Primary
    End point timeframe
    Year 1 to Year 4 post-vaccination
    Notes
    [22] - 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
    2131
    1072
    Units: Number of cases and episodes
    number (not applicable)
        Cases: Any of the 4 Serotypes
    8
    3
        Episodes: Any of the 4 Serotypes
    8
    3
        Cases: Serotype 1
    6
    0
        Episodes: Serotype 1
    6
    0
        Cases: Serotype 2
    1
    1
        Episodes: Serotype 2
    1
    1
        Cases: Serotype 3
    1
    0
        Episodes: Serotype 3
    1
    0
        Cases: Serotype 4
    1
    2
        Episodes: Serotype 4
    1
    2
        Cases: Unserotyped
    0
    0
        Episodes: Unserotyped
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects with Non-Serotype Specific Dengue Viremia Among Hospitalized Virologically-Confirmed Dengue Cases Following Vaccination with CYD Dengue Vaccine or Placebo in a Previous Study

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    End point title
    Number of Subjects with Non-Serotype Specific Dengue Viremia Among Hospitalized Virologically-Confirmed Dengue Cases Following Vaccination with CYD Dengue Vaccine or Placebo in a Previous Study [23]
    End point description
    Quantified viremia was defined as >= lower limit of quantitation (log10 plaque forming unit [pfu]/mL). Analysis was performed on FupAS.
    End point type
    Primary
    End point timeframe
    Year 1 to Year 4 post-vaccination at each of the following time points: Anytime, 0-3 days, 4-7 days, 0-7 days, After 7 days.
    Notes
    [23] - 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
    2131
    1072
    Units: Number of subjects
    number (not applicable)
        Cases - Anytime
    78
    42
        Mean Viremia - Anytime
    3.64
    3.38
        Cases - 0-3 days
    25
    12
        Mean Viremia - 0-3 days
    4.35
    3.83
        Cases - 4-7 days
    53
    27
        Mean Viremia - 4-7 days
    3.31
    3.12
        Cases - 0-7 days
    78
    39
        Mean Viremia - 0-7 days
    3.64
    3.34
        Cases - After 7 days
    0
    3
        Mean Viremia - After 7 days
    0
    3.88
    No statistical analyses for this end point

    Primary: Annual Incidence of Hospitalized Virologically-Confirmed Dengue Cases Due to Any and Each Serotype and Meeting WHO 1997 Criteria Collected During Entire Passive Surveillance After Previous Vaccination with Either CYD Dengue Vaccine or Placebo

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    End point title
    Annual Incidence of Hospitalized Virologically-Confirmed Dengue Cases Due to Any and Each Serotype and Meeting WHO 1997 Criteria Collected During Entire Passive Surveillance After Previous Vaccination with Either CYD Dengue Vaccine or Placebo
    End point description
    Annual incidence rate was defined as the cases among the number of subjects present at the beginning of each period (M) multiplied by 100 converted in annual rate (Annual incidence rate = Cases among M*100). Analysis was performed on FupAS. Endpoint values <0.1 were rounded to 0.1.
    End point type
    Primary
    End point timeframe
    Year 1 to Year 4 post-vaccination
    End point values
    CYD Dengue Vaccine Group Control Group
    Number of subjects analysed
    2131
    1072
    Units: Annual incidence rate
    number (confidence interval 95%)
        Any of the 4 Serotypes Any grade
    0.1 (0.0 to 0.2)
    0.1 (0.0 to 0.2)
        Any of the 4 Serotypes Grade I
    0.1 (0.0 to 0.1)
    0.1 (0.0 to 0.2)
        Any of the 4 Serotypes Grade II
    0.1 (0.0 to 0.1)
    0.1 (0.0 to 0.1)
        Any of the 4 Serotypes Grade III
    0.1 (0.0 to 0.1)
    0.0 (0.0 to 0.1)
        Any of the 4 Serotypes Grade IV
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.1)
        Serotype 1 Any grade
    0.1 (0.0 to 0.1)
    0.0 (0.0 to 0.1)
        Serotype 1 Grade I
    0.1 (0.0 to 0.1)
    0.0 (0.0 to 0.1)
        Serotype 1 Grade II
    0.1 (0.0 to 0.1)
    0.0 (0.0 to 0.1)
        Serotype 1 Grade III
    0.1 (0.0 to 0.1)
    0.0 (0.0 to 0.1)
        Serotype 1 Grade IV
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.1)
        Serotype 2 Any grade
    0.1 (0.0 to 0.1)
    0.1 (0.0 to 0.1)
        Serotype 2 Grade I
    0.1 (0.0 to 0.1)
    0.1 (0.0 to 0.1)
        Serotype 2 Grade II
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.1)
        Serotype 2 Grade III
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.1)
        Serotype 2 Grade IV
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.1)
        Serotype 3 Any grade
    0.1 (0.0 to 0.1)
    0.0 (0.0 to 0.1)
        Serotype 3 Grade I
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.1)
        Serotype 3 Grade II
    0.1 (0.0 to 0.1)
    0.0 (0.0 to 0.1)
        Serotype 3 Grade III
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.1)
        Serotype 3 Grade IV
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.1)
        Serotype 4 Any grade
    0.1 (0.0 to 0.1)
    0.1 (0.0 to 0.2)
        Serotype 4 Grade I
    0.0 (0.0 to 0.0)
    0.1 (0.0 to 0.1)
        Serotype 4 Grade II
    0.1 (0.0 to 0.1)
    0.1 (0.0 to 0.1)
        Serotype 4 Grade III
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.1)
        Serotype 4 Grade IV
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.1)
        Unserotyped Any grade
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.1)
        Unserotyped Grade I
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.1)
        Unserotyped Grade II
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.1)
        Unserotyped Grade III
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.1)
        Unserotyped Grade IV
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.1)
    Statistical analysis title
    Relative Risk; Any serotype; Any grade
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Any of the 4 Serotypes Any grade between the CYD Dengue vaccine group and the Control group.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [24]
    Method
    Parameter type
    Relative Risk
    Point estimate
    1.174
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.27
         upper limit
    7.03
    Notes
    [24] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative Risk; Any serotype; Grade I
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Any of the 4 Serotypes Grade I between the CYD Dengue vaccine group and the Control group.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [25]
    Method
    Parameter type
    Relative Risk
    Point estimate
    0.252
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    4.83
    Notes
    [25] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative Risk; Any serotype; Grade II
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Any of the 4 Serotypes Grade II between the CYD Dengue vaccine group and the Control group.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [26]
    Method
    Parameter type
    Relative Risk
    Point estimate
    2.012
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2
         upper limit
    99.1
    Notes
    [26] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative Risk; Serotype 2; Any grade
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 2 Any grade between the CYD Dengue vaccine group and the Control group.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [27]
    Method
    Parameter type
    Relative Risk
    Point estimate
    0.503
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.01
         upper limit
    39.49
    Notes
    [27] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative Risk; Serotype 2; Grade I
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 2 Grade I between the CYD Dengue vaccine group and the Control group.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [28]
    Method
    Parameter type
    Relative Risk
    Point estimate
    0.503
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.01
         upper limit
    39.49
    Notes
    [28] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative Risk; Serotype 4; Any grade
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 4 Any grade between the CYD Dengue vaccine group and the Control group.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [29]
    Method
    Parameter type
    Relative Risk
    Point estimate
    0.252
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    4.83
    Notes
    [29] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative Risk; Serotype 4; Grade I
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 4 Grade I between the CYD Dengue vaccine group and the Control group.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [30]
    Method
    Parameter type
    Relative Risk
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    19.62
    Notes
    [30] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.
    Statistical analysis title
    Relative Risk; Serotype 4; Grade II
    Statistical analysis description
    Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 4 Grade II between the CYD Dengue vaccine group and the Control group.
    Comparison groups
    CYD Dengue Vaccine Group v Control Group
    Number of subjects included in analysis
    3203
    Analysis specification
    Pre-specified
    Analysis type
    other [31]
    Method
    Parameter type
    Relative Risk
    Point estimate
    0.503
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.01
         upper limit
    39.49
    Notes
    [31] - The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day.

    Primary: Number of Cases and Episodes of Hospitalized Virologically-Confirmed Dengue Cases Due to Any and Each Serotype and Meeting WHO 1997 Criteria Following Vaccination with CYD Dengue Vaccine or Placebo in a Previous Study

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    End point title
    Number of Cases and Episodes of Hospitalized Virologically-Confirmed Dengue Cases Due to Any and Each Serotype and Meeting WHO 1997 Criteria Following Vaccination with CYD Dengue Vaccine or Placebo in a Previous Study [32]
    End point description
    Cases were defined as the number of subjects with at least one hospitalized virologically-confirmed dengue episode meeting WHO criteria. Episodes are defined as the number of hospitalized virologically-confirmed dengue episodes meeting WHO criteria. Grade I: Fever accompanied by non-specific constitutional symptoms; the only hemorrhagic manifestation is a positive tourniquet test. Grade II: Spontaneous bleeding in addition to the manifestations of Grade I subjects, usually in the form of skin and/or other hemorrhages. Grade III: Circulatory failure manifested by rapid and weak pulse, narrowing of pulse pressure (20 mmHg or less) or hypotension, with the presence of cold clammy skin and restlessness. Grade IV: Profound shock with undetectable blood pressure and pulse. Analysis was performed on FupAS.
    End point type
    Primary
    End point timeframe
    Year 1 to Year 4 post-vaccination
    Notes
    [32] - 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
    2131
    1072
    Units: Number of cases and episodes
    number (not applicable)
        Cases: Any of the 4 Serotypes Any grade
    7
    3
        Episodes: Any of the 4 Serotypes Any grade
    7
    3
        Cases: Any of the 4 Serotypes Grade I
    1
    2
        Episodes: Any of the 4 Serotypes Grade I
    1
    2
        Cases: Any of the 4 Serotypes Grade II
    4
    1
        Episodes: Any of the 4 Serotypes Grade II
    4
    1
        Cases: Any of the 4 Serotypes Grade III
    2
    0
        Episodes: Any of the 4 Serotypes Grade III
    2
    0
        Cases: Any of the 4 Serotypes Grade IV
    0
    0
        Episodes: Any of the 4 Serotypes Grade IV
    0
    0
        Cases: Serotype 1 Any grade
    5
    0
        Episodes: Serotype 1 Any grade
    5
    0
        Cases: Serotype 1 Grade I
    1
    0
        Episodes: Serotype 1 Grade I
    1
    0
        Cases: Serotype 1 Grade II
    2
    0
        Episodes: Serotype 1 Grade II
    2
    0
        Cases: Serotype 1 Grade III
    2
    0
        Episodes: Serotype 1 Grade III
    2
    0
        Cases: Serotype 1 Grade IV
    0
    0
        Episodes: Serotype 1 Grade IV
    0
    0
        Cases: Serotype 2 Any grade
    1
    1
        Episodes: Serotype 2 Any grade
    1
    1
        Cases: Serotype 2 Grade I
    1
    1
        Episodes: Serotype 2 Grade I
    1
    1
        Cases: Serotype 2 Grade II
    0
    0
        Episodes: Serotype 2 Grade II
    0
    0
        Cases: Serotype 2 Grade III
    0
    0
        Episodes: Serotype 2 Grade III
    0
    0
        Cases: Serotype 2 Grade IV
    0
    0
        Episodes: Serotype 2 Grade IV
    0
    0
        Cases: Serotype 3 Any grade
    1
    0
        Episodes: Serotype 3 Any grade
    1
    0
        Cases: Serotype 3 Grade I
    0
    0
        Episodes: Serotype 3 Grade I
    0
    0
        Cases: Serotype 3 Grade II
    1
    0
        Episodes: Serotype 3 Grade II
    1
    0
        Cases: Serotype 3 Grade III
    0
    0
        Episodes: Serotype 3 Grade III
    0
    0
        Cases: Serotype 3 Grade IV
    0
    0
        Episodes: Serotype 3 Grade IV
    0
    0
        Cases: Serotype 4 Any grade
    1
    2
        Episodes: Serotype 4 Any grade
    1
    2
        Cases: Serotype 4 Grade I
    0
    1
        Episodes: Serotype 4 Grade I
    0
    1
        Cases: Serotype 4 Grade II
    1
    1
        Episodes: Serotype 4 Grade II
    1
    1
        Cases: Serotype 4 Grade III
    0
    0
        Episodes: Serotype 4 Grade III
    0
    0
        Cases: Serotype 4 Grade IV
    0
    0
        Episodes: Serotype 4 Grade IV
    0
    0
        Cases: Unserotyped Any grade
    0
    0
        Episodes: Unserotyped Any grade
    0
    0
        Cases: Unserotyped Grade I
    0
    0
        Episodes: Unserotyped Grade I
    0
    0
        Cases: Unserotyped Grade II
    0
    0
        Episodes: Unserotyped Grade II
    0
    0
        Cases: Unserotyped Grade III
    0
    0
        Episodes: Unserotyped Grade III
    0
    0
        Cases: Unserotyped Grade IV
    0
    0
        Episodes: Unserotyped Grade IV
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Throughout the study period (Year 1 to Year 4)
    Adverse event reporting additional description
    This study involved a passive surveillance of hospitalized dengue cases and related and fatal SAEs in subjects that participated in a previous study. Non-serious adverse event data was not collected since no vaccine was administered in the present study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Control Group
    Reporting group description
    Subjects received either Rabies vaccine (Verorab®) or placebo control as a first injection on Day 0, placebo for second and third injections at 6 and 12 months, respectively, in the original CYD23 study.

    Reporting group title
    CYD Dengue Vaccine Group
    Reporting group description
    Subjects received 3 injections of CYD dengue vaccine, 1 injection each at 0, 6, and 12 months in study CYD23.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: This was a long-term immunogenicity follow-up study of subjects who participated in the primary study. No vaccines were administered in the follow-up study and non-SAE data was also not collected.
    Serious adverse events
    Control Group CYD Dengue Vaccine Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 1072 (0.19%)
    3 / 2131 (0.14%)
         number of deaths (all causes)
    2
    3
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Gun-shot wound
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 1072 (0.00%)
    2 / 2131 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Road traffic accident
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 1072 (0.09%)
    1 / 2131 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    General disorders and administration site conditions
    Drowning
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 1072 (0.09%)
    0 / 2131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Control Group CYD Dengue Vaccine Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 1072 (0.00%)
    0 / 2131 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jan 2014
    Additional clarifications were added to the study objectives.
    17 Feb 2014
    Study objectives were further updated and statistical analyses were revised.

    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/22975340
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