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    Clinical Trial Results:
    Efficacy and Safety of Dengue Vaccine in Healthy Children Aged 4 to 11 Years in Thailand

    Summary
    EudraCT number
    		 2014-001710-25
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    10 Sep 2013

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CYD23
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00842530
    WHO universal trial number (UTN)
    		 U1111-1127-6970
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur SA
    Sponsor organisation address
    2, avenue Pont Pasteur, Lyon Cedex 07, France, 69367
    Public contact
    Director, Clinical Development, Sanofi Pasteur SA, 65 6431 2359, anh.wartel-tram@sanofipasteur.com
    Scientific contact
    Director, Clinical Development, Sanofi Pasteur SA, 65 6431 2359, anh.wartel-tram@sanofipasteur.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001201-PIP01-11
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Dec 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Sep 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Efficacy of dengue vaccine after three injections 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
    05 Feb 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Thailand: 4002
    Worldwide total number of subjects
    4002
    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)
    4002
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study subjects were enrolled from 05 February 2009 to 05 February 2010 at 1 clinical site in Thailand.

    Pre-assignment
    Screening details
    		 A total of 4002 subjects who met all of the inclusion criteria and none of the exclusion criteria were enrolled and randomized; however, only 3997 subjects received the first vaccination.

    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 appearances 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 the 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 (Cohort 1, n=100 and Cohort 2, n=2568).
    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 1 injection of rabies vaccine (Day 0) and 1 injection of placebo each at 6 and 12 months (Cohort 1; n=50) or 1 injection each of placebo at 0, 6, and 12 months (Cohort 2; n=1284)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rabies vaccine (Verorab®)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, subcutaneous, 1 injection on Day 0 for subjects in Cohort 1.

    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, 1 injection each at 6 and 12 months (Cohort 1) or 1 injection each at 0, 6, and 12 months (Cohort 2).

    Number of subjects in period 1 [1]
    		CYD Dengue vaccine group Control group
    Started
    2666
    1331
    Completed
    2552
    1276
    Not completed
    114
    55
         Consent withdrawn by subject
    73
    28
         Adverse event, non-fatal
    6
    1
         Serious adverse event
    -
    6
         Lost to follow-up
    6
    8
         Protocol deviation
    29
    12
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects reported in the baseline period were based on the total number of subjects who received the first vaccine. A total of 5 subjects (3 in the CYD Dengue vaccine group and 2 in the control group) did not receive the first vaccination.

    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 (Cohort 1, n=100 and Cohort 2, n=2568).

    Reporting group title
    Control group
    Reporting group description
    		 Subjects received 1 injection of rabies vaccine (Day 0) and 1 injection of placebo each at 6 and 12 months (Cohort 1; n=50) or 1 injection each of placebo at 0, 6, and 12 months (Cohort 2; n=1284)

    Reporting group values
    		 CYD Dengue vaccine group Control group Total
    Number of subjects
    		 2666 1331 3997
    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)
    		 2666 1331 3997
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.16 ± 2.03 8.2 ± 2.05 -
    Gender categorical
    Units: Subjects
        Female
    		 1376 696 2072
        Male
    		 1290 635 1925

    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 (Cohort 1, n=100 and Cohort 2, n=2568).

    Reporting group title
    Control group
    Reporting group description
    		 Subjects received 1 injection of rabies vaccine (Day 0) and 1 injection of placebo each at 6 and 12 months (Cohort 1; n=50) or 1 injection each of placebo at 0, 6, and 12 months (Cohort 2; n=1284)

    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 with fever lasting for at least 1 day (temperature ≥37.5°C measured at least twice with an interval of at least 4 hours), confirmed by dengue reverse transcriptase-polymerase chain reaction and/or dengue non-structural protein 1 (NS1) enzyme-linked immunosorbent assay, and occurring >28 days after the third injection. 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 participant 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 0%.
    End point type
    Primary
    End point timeframe
    28 days post-injection 3 up 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
    2452
    1221
    Units: Density incidence
    number (not applicable)
        Virologically-confirmed dengue cases
    45
    32
        Person-years at risk
    2522
    1251
        Density incidence
    1.8
    2.6
    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.
    Comparison groups
    Control group v CYD Dengue vaccine group
    Number of subjects included in analysis
    3673
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    Method
    Parameter type
    		 Vaccine efficacy (%)
    Point estimate
    30.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.4
         upper limit
    		 56.6
    Notes
    [1] - Superiority significance was not achieved. The vaccine efficacy of the CYD dengue vaccine against severe VCD cases was considered significant only if the lower bound of its 95% CI was greater than 0%.

    Secondary: Vaccine Efficacy Against Severe Virologically-confirmed Dengue Cases Post-dose 3 Injection with CYD Dengue Vaccine

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    End point title
    		 Vaccine Efficacy Against Severe Virologically-confirmed Dengue Cases Post-dose 3 Injection with CYD Dengue Vaccine
    End point description
    Symptomatic virologically-confirmed dengue (VCD) cases were defined as acute febrile illness with fever lasting for at least 1 day (temperature ≥37.5°C measured at least twice with an interval of at least 4 hours), confirmed by dengue reverse transcriptase-polymerase chain reaction and/or dengue non-structural protein 1 (NS1) enzyme-linked immunosorbent assay, and occurring >28 days after the third injection. 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 participant 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 0%.
    End point type
    Secondary
    End point timeframe
    28 days post-injection 3 up 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
    2452
    1221
    Units: Density incidence
    number (not applicable)
        Severe VCD cases (IDMC clinical assessment)
    1
    2
        Severe VCD cases (WHO 1999 severity assessment)
    2
    2
        Person-years at risk; Severe VCD cases (IDMC)
    2543
    1263
        Person-years at risk; Severe VCD cases (WHO 1999)
    2543
    1263
        Density incidence; Severe VCD cases (IDMC)
    0.1
    0.2
        Density incidence; Severe VCD cases (WHO 1999)
    0.1
    0.2
    Statistical analysis title
    		 Vaccine efficacy of against severe VCD (IDMC)
    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 against severe VCD cases was considered significant if the lower bound of its 95% CI was greater than 0%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    3673
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Vaccine efficacy (%)
    Point estimate
    75.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -377
         upper limit
    		 99.6
    Statistical analysis title
    		 Vaccine efficacy of against severe VCD (WHO 1999)
    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 against severe VCD cases was considered significant if the lower bound of its 95% CI was greater than 0%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    3673
    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
    		 -585
         upper limit
    		 96.4

    Secondary: Vaccine Efficacy Against Virologically-confirmed Dengue Cases Following at Least Two Injections with CYD Dengue Vaccine

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    End point title
    		 Vaccine Efficacy Against Virologically-confirmed Dengue Cases Following at Least Two Injections with CYD Dengue Vaccine
    End point description
    Symptomatic virologically-confirmed dengue (VCD) cases were defined as acute febrile illness with fever lasting for at least 1 day (temperature ≥37.5°C measured at least twice with an interval of at least 4 hours), confirmed by dengue reverse transcriptase-polymerase chain reaction and/or dengue non-structural protein 1 (NS1) enzyme-linked immunosorbent assay, and occurring >28 days after the third injection. 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 participant 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 0%.
    End point type
    Secondary
    End point timeframe
    28 days post-injection 2 up 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
    2584
    1300
    Units: Density incidence
    number (not applicable)
        Cases; 28 days Post-Inj. 2 to Inj. 3
    14
    12
        Cases; 28 days Post-Inj. 2–Active Phase
    61
    47
        Person-years; 28 days Post-Inj. 2–Inj. 3
    1017
    509
        Person-years; 28 days Post-Inj. 2–Active Phase
    3824
    1905
        Density incidence; 28 days Post-Inj. 2–Inj. 3
    1.4
    2.4
        Density incidence;28 days Post-Inj. 2–Active Phase
    1.6
    2.5
    Statistical analysis title
    		 Vaccine efficacy; 28 days Post-Inj. 2-Inj. 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.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    3884
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    Method
    Parameter type
    		 Vaccine efficacy (%)
    Point estimate
    41.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -38.4
         upper limit
    		 74.9
    Notes
    [2] - Superiority significance was not achieved. The vaccine efficacy of the CYD dengue vaccine against severe VCD cases was considered significant only if the lower bound of its 95% CI was greater than 0%.
    Statistical analysis title
    		 Vaccine efficacy; 28 days Post-Inj. 2-Active Phase
    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.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    3884
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    Method
    Parameter type
    		 Vaccine efficacy (%)
    Point estimate
    35.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.3
         upper limit
    		 56.5
    Notes
    [3] - Superiority significance was achieved. The vaccine efficacy of the CYD dengue vaccine against severe VCD cases was considered significant only if the lower bound of its 95% CI was greater than 0%.

    Other pre-specified: Vaccine Efficacy Against Virologically-confirmed Dengue Cases Following at Least One Injection with CYD Dengue Vaccine

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    End point title
    		 Vaccine Efficacy Against Virologically-confirmed Dengue Cases Following at Least One Injection with CYD Dengue Vaccine
    End point description
    Symptomatic virologically-confirmed dengue (VCD) cases were defined as acute febrile illness with fever lasting for at least 1 day (temperature ≥37.5°C measured at least twice with an interval of at least 4 hours), confirmed by dengue reverse transcriptase-polymerase chain reaction and/or dengue non-structural protein 1 (NS1) enzyme-linked immunosorbent assay, and occurring >28 days after the third injection. Cases: number of subjects with at least one symptomatic VCD episode from Day 0 up 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 participant 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 0%.
    End point type
    Other pre-specified
    End point timeframe
    Day 0 up 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
    2666
    1331
    Units: Density incidence
    number (not applicable)
        Cases; 28 days Post-Inj. 1–Active Phase
    75
    56
        Cases; Day 0–Active Phase
    76
    58
        Person-years: 28 days Post-Inj. 1–Active Phase
    5089
    2532
        Person-years: Day 0–Active Phase
    5292
    2630
        Density incidence;28 days Post-Inj. 1–Active Phase
    1.5
    2.2
        Density incidence; Day 0–Active Phase
    1.4
    2.2
    Statistical analysis title
    		 Vaccine efficacy; 28 days Post-Inj. 1-Active Phase
    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 against severe VCD cases was considered significant if the lower bound of its 95% CI was greater than 0%.
    Comparison groups
    Control group v CYD Dengue vaccine group
    Number of subjects included in analysis
    3997
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Vaccine efficacy (%)
    Point estimate
    33.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.1
         upper limit
    		 53.5
    Statistical analysis title
    		 Vaccine efficacy; Day 0-Active Phase
    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 against severe VCD cases was considered significant if the lower bound of its 95% CI was greater than 0%.
    Comparison groups
    CYD Dengue vaccine group v Control group
    Number of subjects included in analysis
    3997
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Vaccine efficacy (%)
    Point estimate
    34.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.7
         upper limit
    		 54.3

    Other pre-specified: Number of Subjects with One Virologically-confirmed Dengue Episode During the Active Phase Due to Each Serotypes Post-dose 3 Injection with CYD Dengue Vaccine

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    End point title
    		 Number of Subjects with One Virologically-confirmed Dengue Episode During the Active Phase Due to Each Serotypes Post-dose 3 Injection with CYD Dengue Vaccine
    End point description
    Symptomatic virologically-confirmed dengue cases were defined as acute febrile illness with fever lasting for at least 1 day (temperature ≥37.5°C measured at least twice with an interval of at least 4 hours), confirmed by dengue reverse transcriptase-polymerase chain reaction and/or dengue non-structural protein 1 (NS1) enzyme-linked immunosorbent assay, and occurring >28 days after the third injection. Virologically-confirmed dengue cases confirmed only by NS1 method were classified in the Not Identified category. Cases were defined as the number of subjects with at least one symptomatic virologically-confirmed dengue episode >28 days after 3 injections (during the Active Phase).
    End point type
    Other pre-specified
    End point timeframe
    >28 days after 3 injections (during the Active Phase)
    End point values
    		 CYD Dengue vaccine group Control group
    Number of subjects analysed
    2666
    1331
    Units: Number of subjects
    number (not applicable)
        Dengue Virus Serotype 1
    14
    18
        Dengue Virus Serotype 2
    52
    27
        Dengue Virus Serotype 3
    4
    11
        Dengue Virus Serotype 4
    1
    5
        Not Identified
    5
    1
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects with Clinical Signs and Symptoms for Virologically-confirmed Dengue During the Trial

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    End point title
    		 Number of Subjects with Clinical Signs and Symptoms for Virologically-confirmed Dengue During the Trial
    End point description
    End point type
    Other pre-specified
    End point timeframe
    >28 days after 3 injections (during the Active Phase)
    End point values
    		 CYD Dengue vaccine group Control group
    Number of subjects analysed
    76 [4]
    62 [5]
    Units: Number of subjects
    number (not applicable)
        Mean number of days of fever
    4.13
    4.4
        Mean number of days of clinical syndrome
    5.39
    5.84
        Hospitalization; No
    44
    32
        Hospitalization; Yes
    32
    30
        Mean duration of hospitalization (days)
    4.91
    5.17
    Notes
    [4] - Number of virologically-confirmed dengue cases with available data in the specified category
    [5] - Number of virologically-confirmed dengue cases with available data in the specified category
    No statistical analyses for this end point

    Other pre-specified: Geometric Mean Titers (GMTs) of Antibodies Against Each Serotype with the Parental Dengue Virus Strain Before and Following Injection with CYD Dengue Vaccine

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    End point title
    		 Geometric Mean Titers (GMTs) of Antibodies Against Each Serotype with the Parental Dengue Virus Strain Before and Following Injection with CYD Dengue Vaccine
    End point description
    Geometric mean titers of antibodies against each serotype with the parental dengue virus strain were assessed by the plaque reduction neutralization test (PRNT).
    End point type
    Other pre-specified
    End point timeframe
    Pre-Injection 1 up to 1 year Post-Injection 3
    End point values
    		 CYD Dengue vaccine group Control group
    Number of subjects analysed
    197
    99
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Dengue Virus Serotype 1; Pre-Inj. 1
    42.8 (30.7 to 59.6)
    26.6 (17.6 to 40.2)
        Dengue Virus Serotype 1; Post-Inj. 1
    94.4 (66.4 to 134)
    27.7 (18.1 to 42.3)
        Dengue Virus Serotype 1; Pre-Inj. 2
    78 (54.4 to 112)
    30.5 (19.8 to 47.1)
        Dengue Virus Serotype 1; Post-Inj. 2
    184 (137 to 247)
    28.3 (18.2 to 43.8)
        Dengue Virus Serotype 1; Pre-Inj. 3
    116 (84.8 to 160)
    26.4 (17.1 to 40.8)
        Dengue Virus Serotype 1; Post-Inj. 3
    155 (116 to 207)
    27.8 (18.3 to 42.2)
        Dengue Virus Serotype 1; 1 year Post-Inj. 3
    120 (87 to 166)
    35.8 (23.1 to 55.4)
        Dengue Virus Serotype 2; Pre-Inj. 1
    56.8 (40.3 to 80.1)
    43.7 (27.8 to 68.7)
        Dengue Virus Serotype 2; Post-Inj. 1
    195 (143 to 266)
    42.9 (27.2 to 67.6)
        Dengue Virus Serotype 2; Pre-Inj. 2
    152 (109 to 210)
    50.5 (31.9 to 79.9)
        Dengue Virus Serotype 2; Post-Inj. 2
    351 (274 to 449)
    44.6 (28.5 to 69.8)
        Dengue Virus Serotype 2; Pre-Inj. 3
    239 (184 to 311)
    54.8 (34.3 to 87.4)
        Dengue Virus Serotype 2; Post-Inj. 3
    358 (283 to 453)
    52.2 (32.3 to 84.4)
        Dengue Virus Serotype 2; 1 year Post-Inj. 3
    158 (117 to 213)
    46.1 (29.4 to 72.4)
        Dengue Virus Serotype 3; Pre-Inj. 1
    31.5 (24.2 to 41)
    28.7 (19.3 to 42.6)
        Dengue Virus Serotype 3; Post-Inj. 1
    112 (85.8 to 146)
    27 (18.3 to 39.8)
        Dengue Virus Serotype 3; Pre-Inj. 2
    81.3 (61.6 to 107)
    31.1 (20.6 to 46.9)
        Dengue Virus Serotype 3; Post-Inj. 2
    218 (178 to 267)
    26.9 (18.2 to 39.8)
        Dengue Virus Serotype 3; Pre-Inj. 3
    240 (193 to 299)
    50.3 (32.1 to 78.9)
        Dengue Virus Serotype 3; Post-Inj. 3
    351 (289 to 428)
    46.2 (29.9 to 71.4)
        Dengue Virus Serotype 3; 1 year Post-Inj. 3
    125 (97.2 to 161)
    35.1 (23 to 53.6)
        Dengue Virus Serotype 4; Pre-Inj. 1
    28.1 (21.7 to 36.4)
    23.2 (15.6 to 34.6)
        Dengue Virus Serotype 4; Post-Inj. 1
    138 (106 to 178)
    24.2 (16.4 to 35.8)
        Dengue Virus Serotype 4; Pre-Inj. 2
    74 (57.2 to 95.7)
    25.6 (16.9 to 38.8)
        Dengue Virus Serotype 4; Post-Inj. 2
    183 (151 to 220)
    25.3 (17 to 37.5)
        Dengue Virus Serotype 4; Pre-Inj. 3
    110 (89.3 to 136)
    24.4 (16.7 to 35.8)
        Dengue Virus Serotype 4; Post-Inj. 3
    151 (128 to 178)
    22.1 (15.3 to 32)
        Dengue Virus Serotype 4; 1 year Post-Inj. 3
    152 (120 to 192)
    45.9 (30.4 to 69.3)
    No statistical analyses for this end point

    Other pre-specified: Geometric Mean Titers (GMTs) of Antibodies Against Each Serotype with the Parental Dengue Virus Strain in Dengue-immune Subjects Before and Following Injection with CYD Dengue Vaccine

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    End point title
    		 Geometric Mean Titers (GMTs) of Antibodies Against Each Serotype with the Parental Dengue Virus Strain in Dengue-immune Subjects Before and Following Injection with CYD Dengue Vaccine
    End point description
    Geometric mean titers of antibodies against each serotype with the parental dengue virus strain were assessed by the plaque reduction neutralization test (PRNT).
    End point type
    Other pre-specified
    End point timeframe
    Pre-Injection 1 up to 1 year Post-Injection 3
    End point values
    		 CYD Dengue vaccine group Control group
    Number of subjects analysed
    138
    68
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Dengue Virus Serotype 1; Pre-Inj. 1
    107 (73.1 to 157)
    57 (34.3 to 94.7)
        Dengue Virus Serotype 1; Post-Inj. 1
    235 (158 to 349)
    59.7 (35.3 to 101)
        Dengue Virus Serotype 1; Pre-Inj. 2
    193 (130 to 287)
    68.4 (40.4 to 116)
        Dengue Virus Serotype 1; Post-Inj. 2
    371 (269 to 511)
    58.9 (34 to 102)
        Dengue Virus Serotype 1; Pre-Inj. 3
    254 (180 to 360)
    49.3 (28.2 to 86.1)
        Dengue Virus Serotype 1; Post-Inj. 3
    283 (202 to 397)
    50.6 (29.8 to 85.6)
        Dengue Virus Serotype 1; 1 year Post-Inj. 3
    262 (185 to 371)
    67 (39.9 to 113)
        Dengue Virus Serotype 2; Pre-Inj. 1
    161 (111 to 233)
    119 (72.3 to 197)
        Dengue Virus Serotype 2; Post-Inj. 1
    449 (324 to 623)
    112 (67 to 188)
        Dengue Virus Serotype 2; Pre-Inj. 2
    340 (240 to 481)
    139 (84.8 to 229)
        Dengue Virus Serotype 2; Post-Inj. 2
    619 (471 to 813)
    117 (71.2 to 191)
        Dengue Virus Serotype 2; Pre-Inj. 3
    413 (308 to 555)
    132 (78.4 to 223)
        Dengue Virus Serotype 2; Post-Inj. 3
    562 (427 to 741)
    118 (68 to 206)
        Dengue Virus Serotype 2; 1 year Post-Inj. 3
    332 (246 to 450)
    99.1 (59.5 to 165)
        Dengue Virus Serotype 3; Pre-Inj. 1
    69.2 (51.8 to 92.5)
    63.7 (40.1 to 101)
        Dengue Virus Serotype 3; Post-Inj. 1
    216 (163 to 287)
    56.1 (35.2 to 89.5)
        Dengue Virus Serotype 3; Pre-Inj. 2
    152 (113 to 205)
    66.1 (40.2 to 109)
        Dengue Virus Serotype 3; Post-Inj. 2
    308 (245 to 389)
    52.3 (32.3 to 84.6)
        Dengue Virus Serotype 3; Pre-Inj. 3
    361 (285 to 457)
    107 (64.7 to 178)
        Dengue Virus Serotype 3; Post-Inj. 3
    469 (368 to 599)
    91.7 (55.7 to 151)
        Dengue Virus Serotype 3; 1 year Post-Inj. 3
    213 (162 to 280)
    61.8 (37.7 to 101)
        Dengue Virus Serotype 4; Pre-Inj. 1
    58.8 (43.9 to 78.7)
    46.8 (28.3 to 77.2)
        Dengue Virus Serotype 4; Post-Inj. 1
    212 (162 to 277)
    49.7 (30.7 to 80.5)
        Dengue Virus Serotype 4; Pre-Inj. 2
    121 (90.5 to 163)
    53.2 (31.7 to 89.3)
        Dengue Virus Serotype 4; Post-Inj. 2
    266 (216 to 327)
    51.8 (32 to 84)
        Dengue Virus Serotype 4; Pre-Inj. 3
    170 (137 to 212)
    45.3 (28.3 to 72.6)
        Dengue Virus Serotype 4; Post-Inj. 3
    198 (164 to 239)
    40.1 (25.3 to 63.3)
        Dengue Virus Serotype 4; 1 year Post-Inj. 3
    234 (179 to 305)
    89.6 (56 to 143)
    No statistical analyses for this end point

    Other pre-specified: Geometric Mean Titers (GMTs) of Antibodies Against Each Serotype with the Parental Dengue Virus Strain in Dengue Non-immune Subjects Before and Following Injection with CYD Dengue Vaccine

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    End point title
    		 Geometric Mean Titers (GMTs) of Antibodies Against Each Serotype with the Parental Dengue Virus Strain in Dengue Non-immune Subjects Before and Following Injection with CYD Dengue Vaccine
    End point description
    Geometric mean titers of antibodies against each serotype with the parental dengue virus strain were assessed by the plaque reduction neutralization test (PRNT).
    End point type
    Other pre-specified
    End point timeframe
    Pre-Injection 1 up to 1 year Post-Injection 3
    End point values
    		 CYD Dengue vaccine group Control group
    Number of subjects analysed
    59
    31
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Dengue Virus Serotype 1; Pre-Inj. 1
    5 (5 to 5)
    5 (5 to 5)
        Dengue Virus Serotype 1; Post-Inj. 1
    11.2 (8.04 to 15.5)
    5.24 (4.76 to 5.76)
        Dengue Virus Serotype 1; Pre-Inj. 2
    8.72 (6.07 to 12.5)
    5.31 (4.87 to 5.8)
        Dengue Virus Serotype 1; Post-Inj. 2
    33.3 (22.7 to 49)
    5.62 (4.76 to 6.64)
        Dengue Virus Serotype 1; Pre-Inj. 3
    17.6 (12.3 to 25.3)
    6.86 (4.89 to 9.61)
        Dengue Virus Serotype 1; Post-Inj. 3
    35.8 (25.4 to 50.5)
    7.47 (5.18 to 10.8)
        Dengue Virus Serotype 1; 1 year Post-Inj. 3
    17.6 (12 to 25.8)
    8.76 (5.01 to 15.3)
        Dengue Virus Serotype 2; Pre-Inj. 1
    5 (5 to 5)
    5 (5 to 5)
        Dengue Virus Serotype 2; Post-Inj. 1
    27.7 (18.6 to 41.1)
    5.19 (4.81 to 5.6)
        Dengue Virus Serotype 2; Pre-Inj. 2
    21.3 (14.1 to 32.1)
    5.41 (4.83 to 6.05)
        Dengue Virus Serotype 2; Post-Inj. 2
    88.3 (65.3 to 119)
    5.38 (4.63 to 6.26)
        Dengue Virus Serotype 2; Pre-Inj. 3
    63.7 (43.8 to 92.5)
    8.12 (4.93 to 13.4)
        Dengue Virus Serotype 2; Post-Inj. 3
    120 (89.7 to 162)
    8.64 (4.96 to 15)
        Dengue Virus Serotype 2; 1 year Post-Inj. 3
    25.2 (16.1 to 39.4)
    8.31 (4.85 to 14.2)
        Dengue Virus Serotype 3; Pre-Inj. 1
    5 (5 to 5)
    5 (5 to 5)
        Dengue Virus Serotype 3; Post-Inj. 1
    23.9 (16.6 to 34.4)
    5.43 (4.59 to 6.42)
        Dengue Virus Serotype 3; Pre-Inj. 2
    17.7 (11.8 to 26.5)
    6.05 (5 to 7.33)
        Dengue Virus Serotype 3; Post-Inj. 2
    93.6 (68.7 to 128)
    6.23 (4.94 to 7.85)
        Dengue Virus Serotype 3; Pre-Inj. 3
    89.3 (61.3 to 130)
    9.78 (5.41 to 17.7)
        Dengue Virus Serotype 3; Post-Inj. 3
    174 (137 to 223)
    10.2 (5.67 to 18.3)
        Dengue Virus Serotype 3; 1 year Post-Inj. 3
    33.9 (23.2 to 49.5)
    9.89 (5.35 to 18.3)
        Dengue Virus Serotype 4; Pre-Inj. 1
    5 (5 to 5)
    5 (5 to 5)
        Dengue Virus Serotype 4; Post-Inj. 1
    50 (29.6 to 84.4)
    5 (5 to 5)
        Dengue Virus Serotype 4; Pre-Inj. 2
    22.2 (15.3 to 32.2)
    5.26 (4.74 to 5.84)
        Dengue Virus Serotype 4; Post-Inj. 2
    73 (55.1 to 96.8)
    5.2 (4.8 to 5.63)
        Dengue Virus Serotype 4; Pre-Inj. 3
    38.8 (26.5 to 56.7)
    6.41 (4.66 to 8.82)
        Dengue Virus Serotype 4; Post-Inj. 3
    78.1 (59.7 to 102)
    5.98 (4.64 to 7.71)
        Dengue Virus Serotype 4; 1 year Post-Inj. 3
    52.3 (36.7 to 74.5)
    10.3 (6.11 to 17.2)
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects with Solicited Injection-site and Systemic Reactions Following Any and 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 Any and 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: Pain, Incapacitating, unable to perform usual activities; Erythema and Swelling, ≥5 cm. Grade 3 Solicited systemic reactions: Fever, >39°C; Headache, Malaise, Myalgia, and Asthenia, Prevents daily activity.
    End point type
    Other pre-specified
    End point timeframe
    Day 0 up to Day 14 post-any and each injection
    End point values
    		 CYD Dengue vaccine group Control group
    Number of subjects analysed
    697
    350
    Units: Percentage of subjects
    number (not applicable)
        Inj. site Pain; Post-Any Inj.
    57.7
    57.6
        Grade 3 Inj. site Pain; Post-Any Inj.
    0.1
    0
        Inj. site Erythema; Post-Any Inj.
    28.6
    30.7
        Grade 3 Inj. site Erythema; Post-Any Inj.
    0
    0
        Inj. site Swelling; Post-Any Inj.
    21.4
    22.1
        Grade 3 Inj. site Swelling; Post-Any Inj.
    0.3
    0.3
        Inj. site Pain; Post-Inj. 1
    33.5
    30.9
        Grade 3 Inj. site Pain; Post-Inj. 1
    0
    0
        Inj. site Erythema; Post-Inj. 1
    13.3
    16.3
        Grade 3 Inj. site Erythema; Post-Inj. 1
    0
    0
        Inj. site Swelling; Post-Inj. 1
    9
    9.2
        Grade 3 Inj. site Swelling; Post-Inj. 1
    0.3
    0.3
        Inj. site Pain; Post-Inj. 2
    35
    32.2
        Grade 3 Inj. site Pain; Post-Inj. 2
    0.1
    0
        Inj. site Erythema; Post-Inj. 2
    13
    14.6
        Grade 3 Inj. site Erythema; Post-Inj. 2
    0
    0
        Inj. site Swelling; Post-Inj. 2
    11.1
    11.1
        Grade 3 Inj. site Swelling; Post-Inj. 2
    0
    0
        Inj. site Pain; Post-Inj. 3
    33
    30.5
        Grade 3 Inj. site Pain; Post-Inj. 3
    0
    0
        Inj. site Erythema; Post-Inj. 3
    13.7
    14.5
        Grade 3 Inj. site Erythema; Post-Inj. 3
    0
    0
        Inj. site Swelling; Post-Inj. 3
    10.4
    10.9
        Grade 3 Inj. site Swelling; Post-Inj. 3
    0
    0
        Fever; Post-Any Inj.
    32.2
    34.3
        Grade 3 Fever; Post-Any Inj.
    1.9
    4
        Headache; Post-Any Inj.
    60
    59.3
        Grade 3 Headache; Post-Any Inj.
    2.2
    2.6
        Malaise; Post-Any Inj.
    53.6
    50.7
        Grade 3 Malaise; Post-Any Inj.
    1.6
    2.3
        Myalgia; Post-Any Inj.
    50.3
    47
        Grade 3 Myalgia; Post-Any Inj.
    1.2
    2.9
        Asthenia; Post-Any Inj.
    43.5
    41.8
        Grade 3 Asthenia; Post-Any Inj.
    1.2
    2.6
        Fever; Post-Inj. 1
    13.8
    14.7
        Grade 3 Fever; Post-Inj. 1
    1.3
    1.8
        Headache; Post-Inj. 1
    39.6
    35.2
        Grade 3 Headache; Post-Inj. 1
    1.3
    1.7
        Malaise; Post-Inj. 1
    32.4
    29.5
        Grade 3 Malaise; Post-Inj. 1
    0.9
    1.1
        Myalgia; Post-Inj. 1
    30.2
    24.9
        Grade 3 Myalgia; Post-Inj. 1
    0.4
    2
        Asthenia; Post-Inj. 1
    25.3
    23.5
        Grade 3 Asthenia; Post-Inj. 1
    0.6
    1.1
        Fever; Post-Inj. 2
    14.5
    16.7
        Grade 3 Fever; Post-Inj. 2
    0.5
    1.2
        Headache; Post-Inj. 2
    31.1
    29.8
        Grade 3 Headache; Post-Inj. 2
    0.6
    0.3
        Malaise; Post-Inj. 2
    27.7
    24.9
        Grade 3 Malaise; Post-Inj. 2
    0.7
    0.6
        Myalgia; Post-Inj. 2
    28.6
    25.1
        Grade 3 Myalgia; Post-Inj. 2
    0.3
    0.6
        Asthenia; Post-Inj. 2
    21.7
    21.3
        Grade 3 Asthenia; Post-Inj. 2
    0.4
    0.3
        Fever; Post-Inj. 3
    11.3
    12.9
        Grade 3 Fever; Post-Inj. 3
    0.2
    1.5
        Headache; Post-Inj. 3
    27
    32.5
        Grade 3 Headache; Post-Inj. 3
    0.6
    0.9
        Malaise; Post-Inj. 3
    25.3
    24.3
        Grade 3 Malaise; Post-Inj. 3
    0.2
    0.9
        Myalgia; Post-Inj. 3
    26.4
    24.9
        Grade 3 Myalgia; Post-Inj. 3
    0.5
    0.3
        Asthenia; Post-Inj. 3
    19.9
    23.4
        Grade 3 Asthenia; Post-Inj. 3
    0.2
    1.2
    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
    11.0
    Reporting groups
    Reporting group title
    CYD Dengue vaccine group
    Reporting group description
    		 Subjects received 3 injections of the CYD Dengue vaccine, 1 injection each at 0, 6 months, and 12 months (Cohort 1, n=100 and Cohort 2, n=2568).

    Reporting group title
    Control group
    Reporting group description
    		 Subjects received 1 injection of rabies vaccine (Day 0) and 1 injection of placebo each at 6 and 12 months (Cohort 1; n=50) or 1 injection each of placebo at 0, 6, and 12 months (Cohort 2; n=1284)

    Serious adverse events
    		 CYD Dengue vaccine group Control group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    315 / 2666 (11.82%)
    176 / 1331 (13.22%)
         number of deaths (all causes)
    1
    4
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Ovarian cancer
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    T-cell lymphoma
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Surgical and medical procedures
    Tonsillectomy
         subjects affected / exposed
    2 / 2666 (0.08%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Perineal laceration
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         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
    Chest pain
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drowning
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Influenza like illness
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 2666 (0.08%)
    2 / 1331 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergy to arthropod sting
         subjects affected / exposed
    2 / 2666 (0.08%)
    3 / 1331 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Balanitis
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (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 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal perforation
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         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
    4 / 2666 (0.15%)
    5 / 1331 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         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
    Accidental exposure
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Animal bite
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthropod bite
         subjects affected / exposed
    1 / 2666 (0.04%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blast injury
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burns second degree
         subjects affected / exposed
    1 / 2666 (0.04%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    2 / 2666 (0.08%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epiphyseal injury
         subjects affected / exposed
    2 / 2666 (0.08%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye injury
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 2666 (0.04%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    2 / 2666 (0.08%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foreign body trauma
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 2666 (0.00%)
    2 / 1331 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Humerus fracture
         subjects affected / exposed
    1 / 2666 (0.04%)
    3 / 1331 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (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 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus lesion
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle rupture
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    2 / 2666 (0.08%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 2666 (0.04%)
    2 / 1331 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Snake bite
         subjects affected / exposed
    5 / 2666 (0.19%)
    2 / 1331 (0.15%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon injury
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic haemorrhage
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulva injury
         subjects affected / exposed
    1 / 2666 (0.04%)
    2 / 1331 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    3 / 2666 (0.11%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (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
    Phimosis
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 2666 (0.04%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile convulsion
         subjects affected / exposed
    3 / 2666 (0.11%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 2666 (0.08%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         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
    Idiopathic thrombocytopenic purpura
         subjects affected / exposed
    0 / 2666 (0.00%)
    2 / 1331 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    5 / 2666 (0.19%)
    5 / 1331 (0.38%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphthous stomatitis
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    2 / 2666 (0.08%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 2666 (0.08%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 2666 (0.15%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    2 / 2666 (0.08%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    5 / 2666 (0.19%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    45 / 2666 (1.69%)
    22 / 1331 (1.65%)
         occurrences causally related to treatment / all
    0 / 49
    0 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth cyst
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    2 / 2666 (0.08%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytoclastic vasculitis
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Cystitis haemorrhagic
         subjects affected / exposed
    1 / 2666 (0.04%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post streptococcal glomerulonephritis
         subjects affected / exposed
    3 / 2666 (0.11%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    3 / 2666 (0.11%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess of eyelid
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    1 / 2666 (0.04%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute tonsillitis
         subjects affected / exposed
    8 / 2666 (0.30%)
    2 / 1331 (0.15%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    8 / 2666 (0.30%)
    4 / 1331 (0.30%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    28 / 2666 (1.05%)
    14 / 1331 (1.05%)
         occurrences causally related to treatment / all
    0 / 28
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    5 / 2666 (0.19%)
    4 / 1331 (0.30%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis of male external genital organ
         subjects affected / exposed
    2 / 2666 (0.08%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis staphylococcal
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Croup infectious
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (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 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    19 / 2666 (0.71%)
    19 / 1331 (1.43%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    8 / 2666 (0.30%)
    5 / 1331 (0.38%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysentery
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exanthema subitum
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    44 / 2666 (1.65%)
    20 / 1331 (1.50%)
         occurrences causally related to treatment / all
    0 / 46
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious mononucleosis
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    4 / 2666 (0.15%)
    5 / 1331 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaria
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mumps
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    4 / 2666 (0.15%)
    2 / 1331 (0.15%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 2666 (0.04%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    1 / 2666 (0.04%)
    2 / 1331 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perianal abscess
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    44 / 2666 (1.65%)
    18 / 1331 (1.35%)
         occurrences causally related to treatment / all
    0 / 46
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    8 / 2666 (0.30%)
    8 / 1331 (0.60%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 2666 (0.11%)
    2 / 1331 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyoderma
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         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 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 2666 (0.04%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    3 / 2666 (0.11%)
    3 / 1331 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Typhus
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 2666 (0.04%)
    0 / 1331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 2666 (0.11%)
    0 / 1331 (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
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    9 / 2666 (0.34%)
    7 / 1331 (0.53%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral myositis
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemic seizure
         subjects affected / exposed
    0 / 2666 (0.00%)
    1 / 1331 (0.08%)
         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
    415 / 2666 (15.57%)
    207 / 1331 (15.55%)
    Nervous system disorders
    Headache; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [1]
    415 / 692 (59.97%)
    207 / 349 (59.31%)
         occurrences all number
    661
    335
    General disorders and administration site conditions
    Injection site Pain; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [2]
    399 / 692 (57.66%)
    201 / 349 (57.59%)
         occurrences all number
    685
    321
    Injection site Erythema; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    198 / 692 (28.61%)
    107 / 349 (30.66%)
         occurrences all number
    270
    156
    Injection site Swelling; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    148 / 692 (21.39%)
    77 / 349 (22.06%)
         occurrences all number
    205
    107
    Fever; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    223 / 692 (32.23%)
    120 / 350 (34.29%)
         occurrences all number
    262
    148
    Malaise; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    371 / 692 (53.61%)
    177 / 349 (50.72%)
         occurrences all number
    577
    270
    Asthenia; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    301 / 692 (43.50%)
    146 / 349 (41.83%)
         occurrences all number
    452
    234
    Musculoskeletal and connective tissue disorders
    Myalgia; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [8]
    348 / 692 (50.29%)
    164 / 349 (46.99%)
         occurrences all number
    575
    257
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed [9]
    37 / 697 (5.31%)
    18 / 350 (5.14%)
         occurrences all number
    38
    22
    Pharyngitis
         subjects affected / exposed [10]
    61 / 697 (8.75%)
    32 / 350 (9.14%)
         occurrences all number
    66
    33
    Upper respiratory tract infection
         subjects affected / exposed [11]
    78 / 697 (11.19%)
    47 / 350 (13.43%)
         occurrences all number
    93
    56
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 14 days after any 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 a solicited adverse event recorded in a diary card within 7 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 7 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.
    [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 7 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.
    [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 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.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 14 days after any 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 14 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.
    [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 14 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.
    [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 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.
    [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 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.
    [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 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
    05 Jun 2009
    Rabies vaccine was replaced by placebo (sodium chloride) as the control product which was applicable for the second and third vaccinations for Cohort 1 and all 3 vaccinations for Cohort 2 and clarified when the code could be broken due to the change in control product.
    05 Aug 2009
    Clarified that subjects were assigned to 1 of 4 subsets (biological safety and vaccine viremia; immunogenicity; reactogenicity; and subjects with only efficacy evaluation), informed consent forms were updated to reflect assignment of subjects to subsets, and clarified that blood samples need to be taken in all subjects (including control subjects) and a blood sample post-injection 3 was required to evaluate the relationship between neutralizing antibodies and subsequent cases of dengue.
    24 Sep 2009
    Specified that unblinded subjects were to be followed for 6 months following the first dose of study vaccine to enable collection of serious adverse events and then withdrawn and also specified that all subjects should follow the Thai recommendation for post-exposure treatment in the event of a bite (the code was no longer to be broken following animal bites).
    01 Jul 2010
    PRNT assay replaced the microneutralization assay to determine dengue neutralizing antibodies to serotypes 1, 2, 3, and 4 and the dengue screen reverse transcriptase-polymerase chain reaction (RT-PCR) assay replaced the Pan flavivirus RT-PCR to screen for dengue positive samples.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    18 May 2012
    The CYD23 study was initially planned to include an Active Phase (from the start of the trial to 13 months after the third injection) followed by a Passive Phase (from 13 months after the third injection to 3 years after the third injection). Due to a request from the Ministry of Public Health Ethical Review Committee for Research in Human Subjects, the CYD23 study was stopped at the beginning of the Passive Phase and the 3-year immunogenicity and safety follow up were not done as initially planned in the CYD23 approved protocol. All subjects included in the CYD23 study were asked to participate in a separate long-term safety follow-up study (CYD57 study).
    -

    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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