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    Clinical Trial Results:
    Efficacy and Safety of a Novel Tetravalent Dengue Vaccine in Healthy Children and Adolescents Aged 9 to 16 Years in Latin America

    Summary
    EudraCT number
    2014-001716-19
    Trial protocol
    Outside EU/EEA  
    Global end of trial date

    Results information
    Results version number
    v1
    This version publication date
    08 Feb 2016
    First version publication date
    02 Aug 2015
    Other versions
    v2

    Trial information

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    Trial identification
    Sponsor protocol code
    CYD15
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01374516
    WHO universal trial number (UTN)
    U1111-1116-4986
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur SA
    Sponsor organisation address
    2, avenue Pont Pasteur, Lyon Cedex 07, France, 69367
    Public contact
    Senior Director, Clinical Development, Sanofi Pasteur SA, 33 4 37 65 60 60, eric.plennevaux@sanofipasteur.com
    Scientific contact
    Senior Director, Clinical Development, Sanofi Pasteur SA, 33 4 37 65 60 60, eric.plennevaux@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
    Interim
    Date of interim/final analysis
    09 Sep 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Apr 2014
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    Efficacy of CYD dengue vaccine after 3 vaccinations (one each at 0, 6 and 12 months) in preventing symptomatic virologically-confirmed dengue cases, regardless of the severity, due to any of the four serotypes
    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
    08 Jun 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    47 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 3548
    Country: Number of subjects enrolled
    Colombia: 9743
    Country: Number of subjects enrolled
    Honduras: 2799
    Country: Number of subjects enrolled
    Mexico: 3464
    Country: Number of subjects enrolled
    Puerto Rico: 1315
    Worldwide total number of subjects
    20869
    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)
    9458
    Adolescents (12-17 years)
    11411
    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 08 June 2011 to 16 March 2012 at 5 clinical sites in Brazil, 9 in Colombia, 1 in Honduras, 5 in Mexico, and 2 in Puerto Rico.

    Pre-assignment
    Screening details
    A total of 20869 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
    The observer-blind design was chosen since the products have different aspects and could be recognized. The person who performed vaccinations knew which product was administered while neither the subject nor the Investigator in charge of safety evaluation knew which product was injected. To maintain the blind and minimize any potential bias, the control group used the same route and schedule as the study vaccine.

    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 months, 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, 3 injections. One 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)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, subcutaneous, 3 injections. One each at 0, 6, and 12 months.

    Number of subjects in period 1
    CYD Dengue vaccine group Control group
    Started
    13920
    6949
    Completed
    13281
    6640
    Not completed
    639
    309
         Protocol deviation
    43
    14
         Adverse event, non-fatal
    3
    -
         Consent withdrawn by subject
    480
    240
         Serious adverse event
    7
    9
         Lost to follow-up
    106
    46

    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 months, 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
    13920 6949 20869
    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)
    6307 3151 9458
        Adolescents (12-17 years)
    7613 3798 11411
        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)
    12.5 ± 2.14 12.5 ± 2.13 -
    Gender categorical
    Units: Subjects
        Female
    7042 3531 10573
        Male
    6878 3418 10296

    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 months, 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: Vaccine Efficacy Against Symptomatic Virologically-confirmed Dengue Cases During the Active Phase Post-dose 3 Injection with CYD Dengue Vaccine

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    End point title
    Vaccine Efficacy Against Symptomatic Virologically-confirmed Dengue Cases During the Active Phase Post-dose 3 Injection with CYD Dengue Vaccine
    End point description
    Symptomatic virologically-confirmed dengue (VCD) cases were defined as acute febrile illness (temperature ≥38°C on at least 2 consecutive days) and confirmed by dengue reverse transcriptase-polymerase chain reaction (RT-PCR) and/or dengue NS1 enzyme-linked immunosorbent assay (ELISA). Cases: number of subjects with at least one symptomatic VCD episode from 28 days post-injection 3 to the end of the Active Phase. Vaccine efficacy was reported as density incidence (cases/100 person-years at risk). The person-years at risk was the cumulative time (in years) until the subject was diagnosed with VCD or until the end of the active period, whichever came first. Density incidence: number of VCD cases divided by the cumulative person-years at risk. The vaccine efficacy is considered significant if the lower bound of its 95% CI was greater than 25%.
    End point type
    Primary
    End point timeframe
    28 days post-injection 3 to the end of the Active Phase (13 months post-injection 3)
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    12574
    6261
    Units: Cases
    number (not applicable)
        Symptomatic virologically-confirmed dengue cases
    176
    221
        Person-years at risk
    11793
    5809
        Density incidence
    1.5
    3.8
    Statistical analysis title
    Vaccine efficacy of the CYD dengue vaccine
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    18835
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    60.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    52
         upper limit
    68

    Primary: Vaccine Efficacy Against Symptomatic Virologically-confirmed Dengue Cases Due to Any and Each Serotype Post-dose 3 Injection with CYD Dengue Vaccine

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    End point title
    Vaccine Efficacy Against Symptomatic Virologically-confirmed Dengue Cases Due to Any and Each Serotype Post-dose 3 Injection with CYD Dengue Vaccine
    End point description
    Symptomatic virologically-confirmed dengue (VCD) cases were defined as acute febrile illness (temperature ≥38°C on at least 2 consecutive days) and confirmed by dengue reverse transcriptase-polymerase chain reaction (RT-PCR) and/or dengue NS1 enzyme-linked immunosorbent assay (ELISA). Outcome assessed in modified full analysis set for efficacy. Cases: number of subjects with at least one symptomatic VCD episode from 28 days post-injection 3 to the end of the Active Phase. Vaccine efficacy was reported as density incidence (cases/100 person-years at risk). The person-years at risk was the cumulative time (in years) until the subject was diagnosed with VCD or until the end of the active period, whichever came first. Density incidence: number of VCD cases divided by the cumulative person-years at risk. The vaccine efficacy is considered significant if the lower bound of its 95% CI was greater than 25%.
    End point type
    Primary
    End point timeframe
    28 days post-injection 3 to the end of the Active Phase (13 months post-injection 3)
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    13288
    6643
    Units: Cases
    number (not applicable)
        Cases; Due to any of the 4 serotypes
    185
    236
        Cases; Serotype 1
    66
    66
        Cases; Serotype 2
    58
    50
        Cases; Serotype 3
    43
    82
        Cases; Serotype 4
    18
    40
        Cases; Unserotyped
    6
    3
        Person-years at risk;Due to any of the 4 serotypes
    12458
    6157
        Person-years at risk; Serotype 1
    12478
    6196
        Person-years at risk; Serotype 2
    12495
    6219
        Person-years at risk; Serotype 3
    12514
    6213
        Person-years at risk; Serotype 4
    12522
    6206
        Person-years at risk; Unserotyped
    12540
    6268
        Density incidence; Due to any of the 4 serotypes
    1.5
    3.8
        Density incidence; Serotype 1
    0.5
    1.1
        Density incidence; Serotype 2
    0.5
    0.8
        Density incidence; Serotype 3
    0.3
    1.3
        Density incidence; Serotype 4
    0.1
    0.6
        Density incidence; Unserotyped
    0.1
    0.1
    Statistical analysis title
    Vaccine efficacy of CYD dengue (Any serotype)
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%. The point estimate (CI) reported corresponds to the vaccine efficacy due to any of the 4 serotypes.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    19931
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    61.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    52.8
         upper limit
    68.2
    Statistical analysis title
    Vaccine efficacy of CYD dengue (Serotype 1)
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%. The point estimate (CI) reported corresponds to the vaccine efficacy of Serotype 1.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    19931
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    50.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    29.1
         upper limit
    65.2
    Statistical analysis title
    Vaccine efficacy of CYD dengue (Serotype 2)
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%. The point estimate (CI) reported corresponds to the vaccine efficacy of Serotype 2.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    19931
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    42.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    14
         upper limit
    61.1
    Statistical analysis title
    Vaccine efficacy of CYD dengue (Serotype 3)
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%. The point estimate (CI) reported corresponds to the vaccine efficacy of Serotype 3.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    19931
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    61.9
         upper limit
    82.4
    Statistical analysis title
    Vaccine efficacy of CYD dengue (Serotype 4)
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%. The point estimate (CI) reported corresponds to the vaccine efficacy of Serotype 4.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    19931
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    77.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    60.2
         upper limit
    88
    Statistical analysis title
    Vaccine efficacy of CYD dengue (Unserotyped)
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%. The point estimate (CI) reported corresponds to the vaccine efficacy of unserotyped.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    19931
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -517.8
         upper limit
    78.6

    Secondary: Vaccine Efficacy Against Symptomatic Virologically-confirmed Dengue Cases Due to At Least Three Serotypes Post-dose 3 Injection with CYD Dengue Vaccine

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    End point title
    Vaccine Efficacy Against Symptomatic Virologically-confirmed Dengue Cases Due to At Least Three Serotypes Post-dose 3 Injection with CYD Dengue Vaccine
    End point description
    Symptomatic virologically-confirmed dengue (VCD) cases were defined as acute febrile illness (temperature ≥38°C on at least 2 consecutive days) and confirmed by dengue reverse transcriptase-polymerase chain reaction (RT-PCR) and/or dengue NS1 enzyme-linked immunosorbent assay (ELISA). Cases: number of subjects with at least one symptomatic VCD episode from 28 days post-injection 3 to the end of the Active Phase. Vaccine efficacy was reported as density incidence (cases/100 person-years at risk). The person-years at risk was the cumulative time (in years) until the subject was diagnosed with VCD or until the end of the active period, whichever came first. Density incidence: number of VCD cases divided by the cumulative person-years at risk. The vaccine efficacy is considered significant if the lower bound of its 95% CI was greater than 25%.
    End point type
    Secondary
    End point timeframe
    28 days post-injection 3 to the end of the Active Phase (13 months post-injection 3)
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    13288
    6643
    Units: Cases
    number (not applicable)
        Cases; Serotypes 1 or 2 or 3
    161
    193
        Cases; Serotypes 1 or 2 or 4
    139
    154
        Cases; Serotypes 2 or 3 or 4
    118
    171
        Cases; Serotypes 1 or 3 or 4
    125
    186
        Person-years at risk; Serotypes 1 or 2 or 3
    12470
    6183
        Person-years at risk; Serotypes 1 or 2 or 4
    12477
    6194
        Person-years at risk; Serotypes 2 or 3 or 4
    12492
    6189
        Person-years at risk; Serotypes 1 or 3 or 4
    12481
    6177
        Density incidence; Serotypes 1 or 2 or 3
    1.3
    3.1
        Density incidence; Serotypes 1 or 2 or 4
    1.1
    2.5
        Density incidence; Serotypes 2 or 3 or 4
    0.9
    2.8
        Density incidence; Serotypes 1 or 3 or 4
    1
    3
    Statistical analysis title
    Vaccine efficacy; Serotype 1 or 2 or 3
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    19931
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    58.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    48.7
         upper limit
    66.7
    Statistical analysis title
    Vaccine efficacy; Serotype 1 or 2 or 4
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    19931
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    55.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    43.3
         upper limit
    64.6
    Statistical analysis title
    Vaccine efficacy; Serotype 2 or 3 or 4
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    19931
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    65.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    56.5
         upper limit
    73.2
    Statistical analysis title
    Vaccine efficacy; Serotype 1 or 3 or 4
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    Control group v CYD Dengue vaccine group
    Number of subjects included in analysis
    19931
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    66.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    58.1
         upper limit
    73.7

    Secondary: Vaccine Efficacy Against Symptomatic Virologically-confirmed Dengue Cases During the Active Phase Injection with CYD Dengue Vaccine

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    End point title
    Vaccine Efficacy Against Symptomatic Virologically-confirmed Dengue Cases During the Active Phase Injection with CYD Dengue Vaccine
    End point description
    Symptomatic virologically-confirmed dengue (VCD) cases were defined as acute febrile illness (temperature ≥38°C on at least 2 consecutive days) and confirmed by dengue reverse transcriptase-polymerase chain reaction (RT-PCR) and/or dengue NS1 enzyme-linked immunosorbent assay (ELISA). Outcome assessed in full analysis set for efficacy. Cases: number of subjects with at least one symptomatic VCD episode from Day 0 to the end of the Active Phase. Vaccine efficacy was reported as density incidence (cases/100 person-years at risk). The person-years at risk was the cumulative time (in years) until the subject was diagnosed with VCD or until the end of the active period, whichever came first. Density incidence: number of VCD cases divided by the cumulative person-years at risk. The vaccine efficacy is considered significant if the lower bound of its 95% CI was greater than 25%.
    End point type
    Secondary
    End point timeframe
    Day 0 to the end of the Active Phase (13 months post-injection 3)
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    13914
    6940
    Units: Cases
    number (not applicable)
        Symptomatic virologically-confirmed dengue cases
    277
    385
        Person-years at risk
    26883
    13204
        Density incidence
    1
    2.9
    Statistical analysis title
    Vaccine efficacy of CYD dengue vaccine
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20854
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    64.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    58.7
         upper limit
    69.8

    Secondary: Vaccine Efficacy Against Symptomatic Virologically-confirmed Dengue Cases Due to Each Serotype During the Active Phase After at Least One Injection with CYD Dengue Vaccine

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    End point title
    Vaccine Efficacy Against Symptomatic Virologically-confirmed Dengue Cases Due to Each Serotype During the Active Phase After at Least One Injection with CYD Dengue Vaccine
    End point description
    Symptomatic virologically-confirmed dengue (VCD) cases were defined as acute febrile illness (temperature ≥38°C on at least 2 consecutive days) and confirmed by dengue reverse transcriptase-polymerase chain reaction (RT-PCR) and/or dengue NS1 enzyme-linked immunosorbent assay (ELISA). Cases: number of subjects with at least one symptomatic VCD episode from Day 0 to the end of the Active Phase. Vaccine efficacy was reported as density incidence (cases/100 person-years at risk). The person-years at risk was the cumulative time (in years) until the subject was diagnosed with VCD or until the end of the active period, whichever came first. Density incidence: number of VCD cases divided by the cumulative person-years at risk. The vaccine efficacy is considered significant if the lower bound of its 95% CI was greater than 25%.
    End point type
    Secondary
    End point timeframe
    Day 0 to the end of the Active Phase (13 months post-injection 3)
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    13914
    6940
    Units: Cases
    number (not applicable)
        Cases; Serotype 1
    99
    109
        Cases; Serotype 2
    84
    84
        Cases; Serotype 3
    55
    106
        Cases; Serotype 4
    32
    83
        Cases; Unserotyped
    15
    14
        Person-years at risk; Serotype 1
    27016
    13434
        Person-years at risk; Serotype 2
    27035
    13461
        Person-years at risk; Serotype 3
    27060
    13459
        Person-years at risk; Serotype 4
    27063
    13442
        Person-years at risk; Unserotyped
    27079
    13514
        Density incidence; Serotype 1
    0.4
    0.8
        Density incidence; Serotype 2
    0.3
    0.6
        Density incidence; Serotype 3
    0.2
    0.8
        Density incidence; Serotype 4
    0.1
    0.6
        Density incidence; Unserotyped
    0.1
    0.1
    Statistical analysis title
    Vaccine efficacy of CYD dengue (Serotype 1)
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20854
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    54.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    40.2
         upper limit
    65.9
    Statistical analysis title
    Vaccine efficacy of CYD dengue (Serotype 2)
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20854
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    50.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    31.8
         upper limit
    63.6
    Statistical analysis title
    Vaccine efficacy of CYD dengue (Serotype 3)
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20854
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    74.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    63.9
         upper limit
    81.7
    Statistical analysis title
    Vaccine efficacy of CYD dengue (Serotype 4)
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    Control group v CYD Dengue vaccine group
    Number of subjects included in analysis
    20854
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    80.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    70.9
         upper limit
    87.7
    Statistical analysis title
    Vaccine efficacy of CYD dengue (Unserotyped)
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20854
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    46.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -19.6
         upper limit
    75.9

    Secondary: Vaccine Efficacy Against Symptomatic Virologically-confirmed Dengue Cases During the Active Phase Post-dose 2 Injection with CYD Dengue Vaccine

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    End point title
    Vaccine Efficacy Against Symptomatic Virologically-confirmed Dengue Cases During the Active Phase Post-dose 2 Injection with CYD Dengue Vaccine
    End point description
    Symptomatic virologically-confirmed dengue (VCD) cases were defined as acute febrile illness (temperature ≥38°C on at least 2 consecutive days) and confirmed by dengue reverse transcriptase-polymerase chain reaction (RT-PCR) and/or dengue NS1 enzyme-linked immunosorbent assay (ELISA). Cases: number of subjects with at least one symptomatic VCD episode from 28 days post-injection 2 to the end of the Active Phase. Vaccine efficacy was reported as density incidence (cases/100 person-years at risk). The person-years at risk was the cumulative time (in years) until the subject was diagnosed with VCD or until the end of the active period, whichever came first. Density incidence: number of VCD cases divided by the cumulative person-years at risk. The vaccine efficacy is considered significant if the lower bound of its 95% CI was greater than 25%.
    End point type
    Secondary
    End point timeframe
    28 days post-injection 2 to the end of the Active Phase (13 months post-injection 3)
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    13506
    6765
    Units: Cases
    number (not applicable)
        Symptomatic virologically-confirmed dengue cases
    236
    306
        Person-years at risk
    19133
    9443
        Density incidence
    1.2
    3.2
    Statistical analysis title
    Vaccine efficacy of CYD dengue vaccine
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20271
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    61.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    54.7
         upper limit
    68

    Secondary: Vaccine Efficacy Against Symptomatic Virologically-confirmed Dengue Cases Due to Any and Each Serotype Post-dose 2 Injection with CYD Dengue Vaccine

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    End point title
    Vaccine Efficacy Against Symptomatic Virologically-confirmed Dengue Cases Due to Any and Each Serotype Post-dose 2 Injection with CYD Dengue Vaccine
    End point description
    Symptomatic virologically-confirmed dengue (VCD) cases were defined as acute febrile illness (temperature ≥38°C on at least 2 consecutive days) and confirmed by dengue reverse transcriptase-polymerase chain reaction (RT-PCR) and/or dengue NS1 enzyme-linked immunosorbent assay (ELISA). Outcome in Other Efficacy Analysis Set. Cases: number of subjects with at least one symptomatic VCD episode from 28 days post-injection 2 to the end of the Active Phase. Vaccine efficacy was reported as density incidence (cases/100 person-years at risk). The person-years at risk was the cumulative time (in years) until the subject was diagnosed with VCD or until the end of the active period, whichever came first. Density incidence: number of VCD cases divided by the cumulative person-years at risk. The vaccine efficacy is considered significant if the lower bound of its 95% CI was greater than 25%.
    End point type
    Secondary
    End point timeframe
    28 days post-injection 2 to the end of the Active Phase.
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    13506
    6765
    Units: Cases
    number (not applicable)
        Cases; Serotype 1
    86
    87
        Cases; Serotype 2
    73
    67
        Cases; Serotype 3
    50
    93
        Cases; Serotype 4
    20
    55
        Cases; Unserotyped
    14
    13
        Person-years at risk; Serotype 1
    19203
    9551
        Person-years at risk; Serotype 2
    19222
    9577
        Person-years at risk; Serotype 3
    19245
    9574
        Person-years at risk; Serotype 4
    19250
    9558
        Person-years at risk; Unserotyped
    19265
    9267
        Density incidence; Serotype 1
    0.4
    0.9
        Density incidence; Serotype 2
    0.4
    0.7
        Density incidence; Serotype 3
    0.3
    1
        Density incidence; Serotype 4
    0.1
    0.6
        Density incidence; Unserotyped
    0.1
    0.1
    Statistical analysis title
    Vaccine efficacy of CYD dengue (Serotype 1)
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20271
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    50.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    33
         upper limit
    63.9
    Statistical analysis title
    Vaccine efficacy of CYD dengue (Serotype 2)
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20271
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    45.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    23.2
         upper limit
    61.6
    Statistical analysis title
    Vaccine efficacy of CYD dengue (Serotype 3)
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20271
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    73.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    61.9
         upper limit
    81.4
    Statistical analysis title
    Vaccine efficacy of CYD dengue (Serotype 4)
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20271
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    81.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    69.4
         upper limit
    89.8
    Statistical analysis title
    Vaccine efficacy of CYD dengue (Unserotyped)
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20271
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    46.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -24.3
         upper limit
    76.5

    Secondary: Vaccine Efficacy Against Symptomatic Virologically-confirmed Dengue Cases Due to At Least Three Serotypes Post-dose 2 Injection with CYD Dengue Vaccine

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    End point title
    Vaccine Efficacy Against Symptomatic Virologically-confirmed Dengue Cases Due to At Least Three Serotypes Post-dose 2 Injection with CYD Dengue Vaccine
    End point description
    Symptomatic virologically-confirmed dengue (VCD) cases were defined as acute febrile illness (temperature ≥38°C on at least 2 consecutive days) and confirmed by dengue reverse transcriptase-polymerase chain reaction (RT-PCR) and/or dengue NS1 enzyme-linked immunosorbent assay (ELISA). Outcome assessed in the Other Efficacy Analysis Set. Cases: number of subjects with at least one symptomatic VCD episode from 28 days post-injection 2 to the end of the Active Phase. Vaccine efficacy was reported as density incidence (cases/100 person-years at risk). The person-years at risk was the cumulative time (in years) until the subject was diagnosed with VCD or until the end of the active period, whichever came first. Density incidence: number of VCD cases divided by the cumulative person-years at risk. The vaccine efficacy is considered significant if the lower bound of its 95% CI was greater than 25%.
    End point type
    Secondary
    End point timeframe
    28 days post-injection 2 to the end of the Active Phase (13 months post-injection 3)
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    13506
    6765
    Units: Cases
    number (not applicable)
        Cases; Serotype 1 or 2 or 3
    202
    240
        Cases; Serotype 1 or 2 or 4
    175
    206
        Cases; Serotype 2 or 3 or 4
    142
    214
        Cases; Serotype 1 or 3 or 4
    154
    232
        Person-years at risk; Serotype 1 or 2 or 3
    19157
    9498
        Person-years at risk; Serotype 1 or 2 or 4
    19170
    9503
        Person-years at risk; Serotype 2 or 3 or 4
    19199
    9509
        Person-years at risk; Serotype 1 or 3 or 4
    19183
    9494
        Density incidence; Serotype 1 or 2 or 3
    1.1
    2.5
        Density incidence; Serotype 1 or 2 or 4
    0.9
    2.2
        Density incidence; Serotype 2 or 3 or 4
    0.7
    2.3
        Density incidence; Serotype 1 or 3 or 4
    0.8
    2.4
    Statistical analysis title
    Vaccine efficacy; Serotype 1 or 2 or 3
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20271
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    58.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    49.5
         upper limit
    65.6
    Statistical analysis title
    Vaccine efficacy; Serotype 1 or 2 or 4
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20271
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    57.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    48.2
         upper limit
    65.8
    Statistical analysis title
    Vaccine efficacy; Serotype 2 or 3 or 4
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20271
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    67.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    59.2
         upper limit
    73.6
    Statistical analysis title
    Vaccine efficacy; Serotype 1 or 3 or 4
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20271
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    67.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    59.6
         upper limit
    73.4

    Secondary: Number of Subjects With at Least One Symptomatic Virologically-confirmed Dengue Case Meeting DHF WHO Criteria During the Active Phase Due to Any and Each Serotype Post Injection with CYD Dengue Vaccine

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    End point title
    Number of Subjects With at Least One Symptomatic Virologically-confirmed Dengue Case Meeting DHF WHO Criteria During the Active Phase Due to Any and Each Serotype Post Injection with CYD Dengue Vaccine
    End point description
    Symptomatic virologically-confirmed dengue cases were defined by dengue hemorrhagic fever (DHF) World Health Organization (WHO) as temperature ≥38°C lasting 2 to 7 days, hemorrhagic manifestations, thrombocytopenia, and plasma leakage and confirmed by dengue RT-PCR and/or dengue NS1 ELISA. DHF WHO cases were subjects with at least one symptomatic virologically-confirmed dengue episode meeting DHF WHO criteria from Day 0 to the end of the Active Phase (13 months post-injection 3). DHF Grade I, Fever with non-specific constitutional symptoms and positive tourniquet test as hemorrhagic manifestation; Grade II, Spontaneous bleeding plus Grade I manifestations, usually in the form of skin and/or hemorrhages; Grade III, Circulatory failure manifested by rapid and weak pulse, narrowing of pulse pressure (≤20 mmHg) or hypotension, with clammy skin and restlessness; Grade IV, profound shock with undetectable blood pressure and pulse.
    End point type
    Secondary
    End point timeframe
    Day 0 to the end of the Active Phase (13 months post-injection 3)
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    13914
    6940
    Units: Number of subjects
    number (not applicable)
        Due to any of the 4 serotypes; Any grade
    1
    10
        Due to any of the 4 serotypes; Grade I
    0
    2
        Due to any of the 4 serotypes; Grade II
    1
    8
        Due to any of the 4 serotypes; Grade III
    0
    0
        Due to any of the 4 serotypes; Grade IV
    0
    0
        Serotype 1; Any grade
    1
    3
        Serotype 2; Any grade
    0
    3
        Serotype 3; Any grade
    0
    3
        Serotype 4; Any grade
    0
    1
        Unserotyped; Any grade
    0
    0
    No statistical analyses for this end point

    Secondary: The Ratio Convalescent/Acute IgM and IgG ELISA Results for All Suspected Dengue Cases During the Active Phase Due to Any and Each Serotype Post Injection with CYD Dengue Vaccine

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    End point title
    The Ratio Convalescent/Acute IgM and IgG ELISA Results for All Suspected Dengue Cases During the Active Phase Due to Any and Each Serotype Post Injection with CYD Dengue Vaccine
    End point description
    The ratio of convalescent/acute is computed if acute and convalescent values are > 0. The ratios of virologically-confirmed dengue (VCD) and non-VCD cases are reported for IgM and IgG.
    End point type
    Secondary
    End point timeframe
    Day 0 to the end of the Active Phase (13 months post-injection 3)
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    252
    328
    Units: Ratio (Convalescent/Acute)
    arithmetic mean (confidence interval 95%)
        IgM; VCD
    8 (6.72 to 9.28)
    9.81 (8.47 to 11.1)
        IgM; Non-VCD
    1.06 (1.03 to 1.08)
    1.07 (1.03 to 1.1)
        IgG; VCD
    2.16 (1.91 to 2.41)
    4.96 (4.1 to 5.82)
        IgG; Non-VCD
    1.05 (1.04 to 1.06)
    1.17 (1.11 to 1.23)
    No statistical analyses for this end point

    Secondary: Number of Subjects By Country with at Least One Symptomatic Virologically-confirmed Dengue Case Due to Any Serotype During the Active Phase and Post-dose 3 Injection with CYD Dengue Vaccine

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    End point title
    Number of Subjects By Country with at Least One Symptomatic Virologically-confirmed Dengue Case Due to Any Serotype During the Active Phase and Post-dose 3 Injection with CYD Dengue Vaccine
    End point description
    Symptomatic virologically-confirmed dengue cases were defined as acute febrile illness (temperature ≥38°C on at least 2 consecutive days) and confirmed by dengue reverse transcriptase-polymerase chain reaction and/or dengue NS1 enzyme-linked immunosorbent assay. Cases were defined as the number of subjects with at least one symptomatic virologically-confirmed dengue episode from 28 days post-injection 3 to the end of Active Phase (post-dose 3) or during the Active Phase.
    End point type
    Secondary
    End point timeframe
    28 days post-injection 3 to the Active Phase (post-dose 3) or during the Active Phase
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    13920
    6949
    Units: Number of subjects
    number (not applicable)
        Active phase; Brazil
    38
    81
        Active phase; Colombia
    108
    164
        Active phase; Honduras
    42
    71
        Active phase; Mexico
    78
    56
        Active phase; Puerto Rico
    11
    13
        Post-dose 3; Brazil
    14
    33
        Post-dose 3; Colombia
    74
    108
        Post-dose 3; Honduras
    37
    59
        Post-dose 3; Mexico
    51
    28
        Post-dose 3; Puerto Rico
    9
    8
    No statistical analyses for this end point

    Secondary: Vaccine Efficacy By Country Against Symptomatic Virologically-confirmed Dengue Case During the Active Phase and Post-dose 3 Injection with CYD Dengue Vaccine

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    End point title
    Vaccine Efficacy By Country Against Symptomatic Virologically-confirmed Dengue Case During the Active Phase and Post-dose 3 Injection with CYD Dengue Vaccine
    End point description
    Symptomatic virologically-confirmed dengue cases were defined as acute febrile illness (temperature ≥38°C on at least 2 consecutive days) and confirmed by dengue reverse transcriptase-polymerase chain reaction and/or dengue NS1 enzyme-linked immunosorbent assay. Vaccine efficacy was reported as density incidence (cases/100 person-years at risk). Density incidence was calculated as the number of virologically-confirmed dengue cases divided by the cumulative person-years at risk, where the person-years at risk was defined as the sum of individual units of time for which the subjects contributed to the analyses.
    End point type
    Secondary
    End point timeframe
    28 days post-injection 3 to the Active Phase (post-dose 3) or during the Active Phase
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    13920
    6949
    Units: Density incidence
    number (confidence interval 95%)
        Active phase; Brazil
    0.8 (0.6 to 1.1)
    3.7 (2.9 to 4.6)
        Active phase; Colombia
    0.9 (0.7 to 1)
    2.7 (2.3 to 3.1)
        Active phase; Honduras
    1.2 (0.8 to 1.6)
    4 (3.2 to 5)
        Active phase; Mexico
    1.7 (1.4 to 2.1)
    2.5 (1.9 to 3.2)
        Active phase; Puerto Rico
    0.7 (0.3 to 1.2)
    1.6 (0.8 to 2.6)
        Post-dose 3; Brazil
    0.7 (0.4 to 1.1)
    3.3 (2.2 to 4.5)
        Post-dose 3; Colombia
    1.3 (1 to 1.6)
    3.8 (3.1 to 4.5)
        Post-dose 3; Honduras
    2.2 (1.5 to 3)
    7.2 (5.5 to 9.1)
        Post-dose 3; Mexico
    2.4 (1.8 to 3.1)
    2.6 (1.8 to 3.8)
        Post-dose 3; Puerto Rico
    1.2 (0.5 to 2.2)
    2.1 (0.9 to 4.1)
    Statistical analysis title
    Vaccine efficacy; Active phase; Brazil
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20869
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    77.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    66.5
         upper limit
    85.1
    Statistical analysis title
    Vaccine efficacy; Active phase; Colombia
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    Control group v CYD Dengue vaccine group
    Number of subjects included in analysis
    20869
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    67.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    58.3
         upper limit
    74.7
    Statistical analysis title
    Vaccine efficacy; Active phase; Honduras
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20869
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    71.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    57
         upper limit
    80.7
    Statistical analysis title
    Vaccine efficacy; Active phase; Mexico
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20869
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    31.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.3
         upper limit
    51.9
    Statistical analysis title
    Vaccine efficacy; Active phase; Puerto Rico
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20869
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    57.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.5
         upper limit
    82.8
    Statistical analysis title
    Vaccine efficacy; Post-dose 3; Brazil
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20869
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    79.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    60.4
         upper limit
    89.8
    Statistical analysis title
    Vaccine efficacy; Post-dose 3; Colombia
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20869
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    53.9
         upper limit
    75.1
    Statistical analysis title
    Vaccine efficacy; Post-dose 3; Honduras
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20869
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    69.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    53.3
         upper limit
    80.4
    Statistical analysis title
    Vaccine efficacy; Post-dose 3; Mexico
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20869
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    8.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -50.3
         upper limit
    43.5
    Statistical analysis title
    Vaccine efficacy; Post-dose 3; Puerto Rico
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% confidence interval (CI) of the vaccine efficacy. The CI was calculated using the exact method conditional on the total number of cases in both groups. The vaccine efficacy of the CYD dengue vaccine was considered significant if the lower bound of its 95% CI was greater than 25%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20869
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    43.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -68.5
         upper limit
    80.6

    Secondary: Incidence of Hospitalized Virologically-confirmed Dengue By Country During the Active Phase Due to Any Serotype Post-injection with CYD Dengue Vaccine

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    End point title
    Incidence of Hospitalized Virologically-confirmed Dengue By Country During the Active Phase Due to Any Serotype Post-injection with CYD Dengue Vaccine
    End point description
    Cases were defined as the number of subjects with at least one hospitalized virologically-confirmed dengue episode, where episodes were defined as the number of hospitalized virologically-confirmed dengue episodes. The annual incidence rate is reported and was calculated based on the cases among the subjects present at the beginning of each year or mean of number of subjects followed during the years included in the considered period x 100 converted in annual rate.
    End point type
    Secondary
    End point timeframe
    Day 0 to the end of the Active Phase (13 months post-injection 3)
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    13915
    6939
    Units: Incidence
    number (confidence interval 95%)
        Brazil
    0.1 (0 to 0.1)
    0.2 (0 to 0.4)
        Colombia
    0.1 (0 to 0.1)
    0.4 (0.3 to 0.6)
        Honduras
    0.1 (0 to 0.3)
    0.4 (0.1 to 0.8)
        Mexico
    0.1 (0 to 0.2)
    0.1 (0 to 0.4)
        Puerto Rico
    0.1 (0 to 0.4)
    0.1 (0 to 0.6)
    Statistical analysis title
    Incidence of hospitalized dengue; Brazil
    Statistical analysis description
    The relative risk (RR) was calculated for each country to assess the reduction of the incidence of hospitalized cases due to any serotype in subjects receiving at least 1 dose CYD dengue vaccine compared with control. A RR <1 indicates a reduction in incidence in the CYD dengue vaccine group.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20854
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.124
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    1.25
    Statistical analysis title
    Incidence of hospitalized dengue; Colombia
    Statistical analysis description
    The relative risk (RR) was calculated for each country to assess the reduction of the incidence of hospitalized cases due to any serotype in subjects receiving at least 1 dose CYD dengue vaccine compared with control. A RR <1 indicates a reduction in incidence in the CYD dengue vaccine group.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20854
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.125
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.05
         upper limit
    0.29
    Statistical analysis title
    Incidence of hospitalized dengue; Honduras
    Statistical analysis description
    The relative risk (RR) was calculated for each country to assess the reduction of the incidence of hospitalized cases due to any serotype in subjects receiving at least 1 dose CYD dengue vaccine compared with control. A RR <1 indicates a reduction in incidence in the CYD dengue vaccine group.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20854
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.285
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.06
         upper limit
    1.12
    Statistical analysis title
    Incidence of hospitalized dengue; Mexico
    Statistical analysis description
    The relative risk (RR) was calculated for each country to assess the reduction of the incidence of hospitalized cases due to any serotype in subjects receiving at least 1 dose CYD dengue vaccine compared with control. A RR <1 indicates a reduction in incidence in the CYD dengue vaccine group.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20854
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.498
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.07
         upper limit
    3.72
    Statistical analysis title
    Incidence of hospitalized dengue; Puerto Rico
    Statistical analysis description
    The relative risk (RR) was calculated for each country to assess the reduction of the incidence of hospitalized cases due to any serotype in subjects receiving at least 1 dose CYD dengue vaccine compared with control. A RR <1 indicates a reduction in incidence in the CYD dengue vaccine group.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    20854
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.009
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.05
         upper limit
    59.55

    Secondary: Percentage of Subjects with Antibody Titer ≥ 10 (1/dil) Against Each Serotype with the Parental Dengue Virus Strains Before and Post-injection with CYD Dengue Tetravalent Vaccine

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    End point title
    Percentage of Subjects with Antibody Titer ≥ 10 (1/dil) Against Each Serotype with the Parental Dengue Virus Strains Before and Post-injection with CYD Dengue Tetravalent Vaccine
    End point description
    Dengue neutralizing antibody levels were measured by the plaque reduction neutralization test (PRNT).
    End point type
    Secondary
    End point timeframe
    Pre-Injection 1 and Post-Injection 2, Post-Injection 3, and 1 year follow up Post-Injection 3
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    1301
    643
    Units: Percentage of subjects
    number (not applicable)
        Serotype 1; Pre-Injection 1
    72.8
    70.5
        Serotype 1; Post-Injection 2
    92.7
    71.8
        Serotype 1; Post-Injection 3
    94.9
    74.2
        Serotype 1; 1 year follow up Post-Injection 3
    85.6
    73.6
        Serotype 2; Pre-Injection 1
    76.1
    73.8
        Serotype 2; Post-Injection 2
    97.5
    75.1
        Serotype 2; Post-Injection 3
    98.5
    77.2
        Serotype 2; 1 year follow up Post-Injection 3
    94.1
    78.8
        Serotype 3; Pre-Injection 1
    76.5
    73.6
        Serotype 3; Post-Injection 2
    98.5
    75.7
        Serotype 3; Post-Injection 3
    98.4
    78
        Serotype 3; 1 year follow up Post-Injection 3
    92.7
    76.1
        Serotype 4; Pre-Injection 1
    68.2
    65
        Serotype 4; Post-Injection 2
    96.9
    67
        Serotype 4; Post-Injection 3
    98.1
    68.9
        Serotype 4; 1 year follow up Post-Injection 3
    94.9
    68.9
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Antibody Titer ≥ 10 (1/dil) Against At Least 1, 2, 3, or 4 Serotypes with the Parental Dengue Virus Strains Before and Post-injection with CYD Dengue Tetravalent Vaccine

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    End point title
    Percentage of Subjects with Antibody Titer ≥ 10 (1/dil) Against At Least 1, 2, 3, or 4 Serotypes with the Parental Dengue Virus Strains Before and Post-injection with CYD Dengue Tetravalent Vaccine
    End point description
    Dengue neutralizing antibody levels were measured by the plaque reduction neutralization test (PRNT).
    End point type
    Secondary
    End point timeframe
    Pre-Injection 1 and Post-Injection 2, Post-Injection 3, and 1 year follow up Post-Injection 3
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    1301
    643
    Units: Percentage of subjects
    number (not applicable)
        At least 1 serotype; Pre-Injection 1
    80.6
    77.2
        At least 1 serotype; Post-Injection 2
    99.8
    80.8
        At least 1 serotype; Post-Injection 3
    99.8
    84.1
        At least 1 serotype; 1 yr follow up Post-Inj. 3
    99
    81.2
        At least 2 serotypes; Pre-Injection 1
    75.6
    73.5
        At least 2 serotypes; Post-Injection 2
    98.8
    74.6
        At least 2 serotypes; Post-Injection 3
    99.5
    76.9
        At least 2 serotypes; 1 yr follow up Post-Inj. 3
    95.3
    77.2
        At least 3 serotypes; Pre-Injection 1
    72.7
    70.7
        At least 3 serotypes; Post-Injection 2
    96.5
    71.8
        At least 3 serotypes; Post-Injection 3
    98.1
    73
        At least 3 serotypes; 1 yr follow up Post-Inj. 3
    90.4
    74
        All 4 serotypes; Pre-Injection 1
    64.3
    61
        All 4 serotypes; Post-Injection 2
    90.4
    62.1
        All 4 serotypes; Post-Injection 3
    92.6
    64.4
        All 4 serotypes; 1 yr follow up Post-Inj. 3
    81.8
    64.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Solicited Injection-site and Systemic Reactions Following Each Injection with CYD Dengue Tetravalent Vaccine

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    End point title
    Percentage of Subjects with Solicited Injection-site and Systemic Reactions Following Each Injection with CYD Dengue Tetravalent Vaccine
    End point description
    Solicited injection site reactions: Pain, Erythema, and Swelling. Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Asthenia. Grade 3 Solicited injection site reactions (9-11 years): Pain, Incapacitating, unable to perform usual activities; Erythema and Swelling, ≥50 mm. Grade 3 Solicited injection site reactions (12-16 years): Pain, Significant, prevents daily activity; Erythema and Swelling, >100 mm. Grade 3 Solicited injection site reactions: Fever, ≥39°C; Headache, Malaise, Myalgia, and Asthenia, Significant, prevents daily activity.
    End point type
    Secondary
    End point timeframe
    Day 0 up to Day 14 post-each injection
    End point values
    CYD Dengue vaccine group Control group
    Number of subjects analysed
    1326
    657
    Units: Percentage of subjects
    number (not applicable)
        Injection site Pain; Post-Injection 1
    32.4
    26.3
        Injection site Pain; Post-Injection 2
    25.6
    16.4
        Injection site Pain; Post-Injection 3
    22.5
    16.5
        Grade 3 Injection site Pain; Post-Injection 1
    0.8
    0.9
        Grade 3 Injection site Pain; Post-Injection 2
    0.5
    0
        Grade 3 Injection site Pain; Post-Injection 3
    0.9
    0.3
        Injection site Erythema; Post-Injection 1
    4.1
    4.7
        Injection site Erythema; Post-Injection 2
    1.9
    1.7
        Injection site Erythema; Post-Injection 3
    1.5
    1.6
        Grade 3 Injection site Erythema; Post-Injection 1
    0
    0.2
        Grade 3 Injection site Erythema; Post-Injection 2
    0.1
    0
        Grade 3 Injection site Erythema; Post-Injection 3
    0
    0
        Injection site Swelling; Post-Injection 1
    3.5
    2.7
        Injection site Swelling; Post-Injection 2
    1.9
    0.9
        Injection site Swelling; Post-Injection 3
    1.6
    1.3
        Grade 3 Injection site Swelling; Post-Injection 1
    0
    0.2
        Grade 3 Injection site Swelling; Post-Injection 2
    0
    0
        Grade 3 Injection site Swelling; Post-Injection 3
    0
    0
        Fever; Post-Injection 1
    6.8
    6.6
        Fever; Post-Injection 2
    5.9
    7.1
        Fever; Post-Injection 3
    7.3
    8.7
        Grade 3 Fever; Post-Injection 1
    1.7
    1.1
        Grade 3 Fever; Post-Injection 2
    0.8
    1.2
        Grade 3 Fever; Post-Injection 3
    1.1
    0.8
        Headache; Post-Injection 1
    39.9
    41.6
        Headache; Post-Injection 2
    29.8
    28.5
        Headache; Post-Injection 3
    29.6
    25
        Grade 3 Headache; Post-Injection 1
    5.1
    4.1
        Grade 3 Headache; Post-Injection 2
    2.1
    2.3
        Grade 3 Headache; Post-Injection 3
    2.6
    1.9
        Malaise; Post-Injection 1
    24.5
    25.9
        Malaise; Post-Injection 2
    20.8
    16.6
        Malaise; Post-Injection 3
    19.3
    15.2
        Grade 3 Malaise; Post-Injection 1
    2.4
    2.3
        Grade 3 Malaise; Post-Injection 2
    1.3
    1.3
        Grade 3 Malaise; Post-Injection 3
    1.4
    1.1
        Myalgia; Post-Injection 1
    29.2
    27.4
        Myalgia; Post-Injection 2
    21
    15.8
        Myalgia; Post-Injection 3
    20
    18.4
        Grade 3 Myalgia; Post-Injection 1
    2.2
    1.5
        Grade 3 Myalgia; Post-Injection 2
    1.6
    0.8
        Grade 3 Myalgia; Post-Injection 3
    1.5
    0.8
        Asthenia; Post-Injection 1
    24.6
    22.5
        Asthenia; Post-Injection 2
    17.8
    16.4
        Asthenia; Post-Injection 3
    16.3
    17.4
        Grade 3 Asthenia; Post-Injection 1
    2.7
    2.6
        Grade 3 Asthenia; Post-Injection 2
    1.8
    1.1
        Grade 3 Asthenia; Post-Injection 3
    1.3
    1.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data were collected from Day 0 (post-vaccination) up to 13 months post-Injection 3.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14
    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 months, 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
    565 / 13915 (4.06%)
    308 / 6939 (4.44%)
         number of deaths (all causes)
    6
    6
         number of deaths resulting from adverse events
    0
    0
    Surgical and medical procedures
    Caesarean section
         subjects affected / exposed
    2 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgery
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Fibroadenoma of breast
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoma
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian germ cell teratoma benign
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteosarcoma metastatic
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Allergy to arthropod sting
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anti-neutrophil cytoplasmic antibody positive vasculitis
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Food allergy
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    6 / 13915 (0.04%)
    4 / 6939 (0.06%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    False labour
         subjects affected / exposed
    5 / 13915 (0.04%)
    3 / 6939 (0.04%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pre-eclampsia
         subjects affected / exposed
    5 / 13915 (0.04%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gestational hypertension
         subjects affected / exposed
    4 / 13915 (0.03%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion
         subjects affected / exposed
    3 / 13915 (0.02%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion spontaneous incomplete
         subjects affected / exposed
    2 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion threatened
         subjects affected / exposed
    2 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stillbirth
         subjects affected / exposed
    2 / 13915 (0.01%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion complete
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion incomplete
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion incomplete complicated
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion missed
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion spontaneous complete
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blighted ovum
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complication of delivery
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature labour
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature rupture of membranes
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retained products of conception
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Threatened labour
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foetal distress syndrome
         subjects affected / exposed
    0 / 13915 (0.00%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oligohydramnios
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postpartum haemorrhage
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prolonged labour
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 13915 (0.04%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue inflammation
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drowning
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malaise
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    7 / 13915 (0.05%)
    4 / 6939 (0.06%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    5 / 13915 (0.04%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute psychosis
         subjects affected / exposed
    2 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    2 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Substance abuse
         subjects affected / exposed
    2 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute stress disorder
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adjustment disorder
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorexia nervosa
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety disorder
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conversion disorder
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dissociative disorder
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug abuse
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional drug misuse
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somatoform disorder
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression suicidal
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional self-injury
         subjects affected / exposed
    0 / 13915 (0.00%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obsessive rumination
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    4 / 13915 (0.03%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Testicular torsion
         subjects affected / exposed
    2 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bartholinitis
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysfunctional uterine bleeding
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematocolpos
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicocele
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gynaecomastia
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Forearm fracture
         subjects affected / exposed
    18 / 13915 (0.13%)
    5 / 6939 (0.07%)
         occurrences causally related to treatment / all
    0 / 18
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    9 / 13915 (0.06%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Head injury
         subjects affected / exposed
    7 / 13915 (0.05%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Femur fracture
         subjects affected / exposed
    5 / 13915 (0.04%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    5 / 13915 (0.04%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    5 / 13915 (0.04%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    4 / 13915 (0.03%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    4 / 13915 (0.03%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    4 / 13915 (0.03%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burns second degree
         subjects affected / exposed
    3 / 13915 (0.02%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    3 / 13915 (0.02%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    3 / 13915 (0.02%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    3 / 13915 (0.02%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tibia fracture
         subjects affected / exposed
    3 / 13915 (0.02%)
    3 / 6939 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burns third degree
         subjects affected / exposed
    2 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gun shot wound
         subjects affected / exposed
    2 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Poisoning deliberate
         subjects affected / exposed
    2 / 13915 (0.01%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tendon rupture
         subjects affected / exposed
    2 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    2 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal injury
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Avulsion fracture
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epiphyseal fracture
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foreign body
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital injury
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb crushing injury
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 13915 (0.01%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord injury cervical
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Stab wound
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic brain injury
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Animal bite
         subjects affected / exposed
    0 / 13915 (0.00%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthropod sting
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 13915 (0.00%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle injury
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord injury
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Antepartum haemorrhage
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cryptorchism
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phimosis
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenitis
         subjects affected / exposed
    3 / 13915 (0.02%)
    3 / 6939 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic thrombocytopenic purpora
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    7 / 13915 (0.05%)
    8 / 6939 (0.12%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthmatic crisis
         subjects affected / exposed
    3 / 13915 (0.02%)
    3 / 6939 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status asthmaticus
         subjects affected / exposed
    2 / 13915 (0.01%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Asphyxia
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary artery stenosis
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Epistaxis
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal septum deviation
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    9 / 13915 (0.06%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    4 / 13915 (0.03%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    3 / 13915 (0.02%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    2 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute polyneuropathy
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complicated migraine
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic cerebral infarction
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute disseminated encephalomyelitis
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersomnia
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic generalised epilepsy
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine with aura
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (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
    10 / 13915 (0.07%)
    4 / 6939 (0.06%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    5 / 13915 (0.04%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    3 / 13915 (0.02%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    3 / 13915 (0.02%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    2 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 13915 (0.01%)
    3 / 6939 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingivitis
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia, obstructive
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal functional disorder
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia, obstructive
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    3 / 13915 (0.02%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    3 / 13915 (0.02%)
    4 / 6939 (0.06%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder disorder
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    5 / 13915 (0.04%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephritic syndrome
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerulonephritis
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lupus nephritis
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal colic
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    4 / 13915 (0.03%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Henoch-Schonlein purpura
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mechanical urticaria
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash erythematous
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthropathy
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epiphysiolysis
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Knee deformity
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatic fever
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sacroiliitis
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Juvenile arthritis
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    94 / 13915 (0.68%)
    52 / 6939 (0.75%)
         occurrences causally related to treatment / all
    0 / 94
    0 / 52
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    41 / 13915 (0.29%)
    48 / 6939 (0.69%)
         occurrences causally related to treatment / all
    0 / 41
    0 / 48
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    32 / 13915 (0.23%)
    14 / 6939 (0.20%)
         occurrences causally related to treatment / all
    0 / 33
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    17 / 13915 (0.12%)
    19 / 6939 (0.27%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    15 / 13915 (0.11%)
    12 / 6939 (0.17%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    7 / 13915 (0.05%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    6 / 13915 (0.04%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 13915 (0.04%)
    11 / 6939 (0.16%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    5 / 13915 (0.04%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    4 / 13915 (0.03%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 13915 (0.02%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis A
         subjects affected / exposed
    3 / 13915 (0.02%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    3 / 13915 (0.02%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    3 / 13915 (0.02%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    3 / 13915 (0.02%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    3 / 13915 (0.02%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    3 / 13915 (0.02%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    2 / 13915 (0.01%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    2 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    2 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    2 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis bacterial
         subjects affected / exposed
    2 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    2 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis viral
         subjects affected / exposed
    2 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leptospirosis
         subjects affected / exposed
    2 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    2 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    2 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    2 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    2 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    2 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 13915 (0.01%)
    3 / 6939 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    2 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amoebic dysentery
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chorioamnionitis
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometritis decidual
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    External ear cellulitis
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital infection female
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Helminthic infection
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious mononucleosis
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastoiditis
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    1 / 13915 (0.01%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mononucleosis syndrome
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 13915 (0.01%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis chronic
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syphilis
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis bacterial
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Typhoid fever
         subjects affected / exposed
    1 / 13915 (0.01%)
    0 / 6939 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion infected
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess neck
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess of salivary gland
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute tonsillitis
         subjects affected / exposed
    0 / 13915 (0.00%)
    2 / 6939 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amoebiasis
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bartholin's abscess
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genitourinary tract infection
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mumps
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scarlet fever
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 13915 (0.00%)
    1 / 6939 (0.01%)
         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
    528 / 13915 (3.79%)
    273 / 6939 (3.93%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed [1]
    55 / 1333 (4.13%)
    33 / 664 (4.97%)
         occurrences all number
    60
    35
    Nervous system disorders
    Headache
         subjects affected / exposed [2]
    84 / 1333 (6.30%)
    36 / 664 (5.42%)
         occurrences all number
    93
    39
    Headache; Post-Injection 1
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    528 / 1324 (39.88%)
    273 / 657 (41.55%)
         occurrences all number
    528
    273
    Headache; Post-Injection 2
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    386 / 1297 (29.76%)
    182 / 639 (28.48%)
         occurrences all number
    386
    182
    Headache; Post-Injection 3
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    378 / 1277 (29.60%)
    158 / 631 (25.04%)
         occurrences all number
    378
    158
    General disorders and administration site conditions
    Injection site Pain; Post-Injection 1
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    430 / 1326 (32.43%)
    173 / 657 (26.33%)
         occurrences all number
    430
    173
    Injection site Pain; Post-Injection 2
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    332 / 1297 (25.60%)
    105 / 639 (16.43%)
         occurrences all number
    332
    105
    Injection site Pain; Post-Injection 3
    alternative assessment type: Systematic
         subjects affected / exposed [8]
    288 / 1279 (22.52%)
    104 / 630 (16.51%)
         occurrences all number
    288
    104
    Fever; Post-Injection 1
    alternative assessment type: Systematic
         subjects affected / exposed [9]
    86 / 1264 (6.80%)
    42 / 635 (6.61%)
         occurrences all number
    86
    42
    Fever; Post-Injection 2
    alternative assessment type: Systematic
         subjects affected / exposed [10]
    72 / 1228 (5.86%)
    42 / 594 (7.07%)
         occurrences all number
    72
    42
    Fever; Post-Injection 3
    alternative assessment type: Systematic
         subjects affected / exposed [11]
    89 / 1215 (7.33%)
    52 / 597 (8.71%)
         occurrences all number
    89
    52
    Malaise; Post-Injection 1
    alternative assessment type: Systematic
         subjects affected / exposed [12]
    324 / 1323 (24.49%)
    170 / 657 (25.88%)
         occurrences all number
    324
    170
    Malaise; Post-Injection 2
    alternative assessment type: Systematic
         subjects affected / exposed [13]
    270 / 1298 (20.80%)
    106 / 639 (16.59%)
         occurrences all number
    270
    106
    Malaise; Post-Injection 3
    alternative assessment type: Systematic
         subjects affected / exposed [14]
    246 / 1277 (19.26%)
    96 / 631 (15.21%)
         occurrences all number
    246
    96
    Myalgia; Post-Injection 2
    alternative assessment type: Systematic
         subjects affected / exposed [15]
    273 / 1298 (21.03%)
    101 / 639 (15.81%)
         occurrences all number
    273
    101
    Myalgia; Post-Injection 3
    alternative assessment type: Systematic
         subjects affected / exposed [16]
    255 / 1277 (19.97%)
    116 / 631 (18.38%)
         occurrences all number
    255
    116
    Asthenia; Post-Injection 1
    alternative assessment type: Systematic
         subjects affected / exposed [17]
    326 / 1323 (24.64%)
    148 / 657 (22.53%)
         occurrences all number
    326
    148
    Asthenia; Post-Injection 2
    alternative assessment type: Systematic
         subjects affected / exposed [18]
    231 / 1298 (17.80%)
    105 / 639 (16.43%)
         occurrences all number
    231
    105
    Asthenia; Post-Injection 3
    alternative assessment type: Systematic
         subjects affected / exposed [19]
    208 / 1277 (16.29%)
    110 / 631 (17.43%)
         occurrences all number
    208
    110
    Musculoskeletal and connective tissue disorders
    Myalgia; Post-Injection 1
    alternative assessment type: Systematic
         subjects affected / exposed [20]
    386 / 1323 (29.18%)
    180 / 657 (27.40%)
         occurrences all number
    386
    180
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed [21]
    150 / 1333 (11.25%)
    60 / 664 (9.04%)
         occurrences all number
    163
    70
    Influenza
         subjects affected / exposed [22]
    76 / 1333 (5.70%)
    37 / 664 (5.57%)
         occurrences all number
    80
    40
    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 an unsolicited adverse event recorded in a diary card within 28 days after any vaccination; 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 an unsolicited adverse event recorded in a diary card within 28 days after any vaccination; 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 14 days after each vaccination; 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 each vaccination; 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 14 days after each vaccination; 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 7 days after each vaccination; 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 7 days after each vaccination; 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.
    [8] - 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 each vaccination; 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.
    [9] - 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 each vaccination; 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.
    [10] - 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 each vaccination; 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.
    [11] - 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 each vaccination; 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.
    [12] - 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 each vaccination; 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.
    [13] - 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 each vaccination; 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.
    [14] - 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 each vaccination; 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.
    [15] - 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 each vaccination; 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.
    [16] - 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 each vaccination; 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.
    [17] - 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 each vaccination; 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.
    [18] - 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 each vaccination; 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.
    [19] - 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 each vaccination; 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.
    [20] - 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 each vaccination; 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.
    [21] - 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 an unsolicited adverse event recorded in a diary card within 28 days after any vaccination; 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.
    [22] - 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 an unsolicited adverse event recorded in a diary card within 28 days after any vaccination; 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
    21 Jan 2011
    Major modifications included Venezuela declined its participation, clarified efficacy during the Active Phase, end of febrile episode was further clarified, frequency of contact during the Hospital Phase was increased to 1 every 3 months, potential manifestations of severity were updated, clarified that the safety surveillance was conducted by the Principal Investigators, transaminases were available to add in the assessment of the severity of confirmed dengue cases, clarification on the reporting of SAEs during the Active Phase and the Hospital Phase, and clarification on subjects who discontinued from vaccination or trial and their continuation in the study for surveillance purposes.
    03 Aug 2011
    Clarified collection periods of acute and convalescent samples, SAE reporting period was extended throughout the entire study, clarified that laboratory staff was blinded to treatment allocation, age stratification was clarified (9 to 11 years and 12 to 16 years), updated time window of assessment of serious viscerotropic disease, and introduced the use of the World Health Organization Verbal Autopsy Questionnaire.
    29 May 2013
    Modified the testing algorithm for the virological-confirmation of dengue cases to maximize the likelihood of detecting dengue cases, updated and clarified text of secondary objectives as it relates to the assessment of the CYD dengue vaccine in preventing symptomatic virologically-confirmed cases, Hospital Phase was extended by 2 years to allow a 5 year follow-up period after the last vaccination, "Other Objectives" section was added, and included re-consenting of subjects for the 2-year extension and for additional testing to identify the dengue virus.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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