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    Clinical Trial Results:
    Efficacy and Safety of a Novel Tetravalent Dengue Vaccine in Healthy Children Aged 2 to 14 Years in Asia

    Summary
    EudraCT number
    2014-001708-24
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    21 Nov 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    07 Dec 2018
    First version publication date
    17 Apr 2015
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CYD14
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01373281
    WHO universal trial number (UTN)
    U1111-1116-4957
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur
    Sponsor organisation address
    14 Espace Henry Vallée, Lyon, France, 69007
    Public contact
    Trial Transparency Team, Sanofi Pasteur, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi Pasteur, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    11 Jul 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Efficacy of CYD dengue vaccine after 3 vaccinations at 0, 6 and 12 months in preventing symptomatic virologically-confirmed dengue cases, regardless of the severity, due to any of the four serotypes in children aged 2 to 14 years at the time of inclusion.
    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 equipments were 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
    03 Jun 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    4 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Philippines: 3501
    Country: Number of subjects enrolled
    Malaysia: 1401
    Country: Number of subjects enrolled
    Vietnam: 2333
    Country: Number of subjects enrolled
    Thailand: 1170
    Country: Number of subjects enrolled
    Indonesia: 1870
    Worldwide total number of subjects
    10275
    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)
    7946
    Adolescents (12-17 years)
    2329
    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 03 June 2011 to 01 December 2011 at 9 sites in Indonesia, 5 in Malaysia, 3 in Thailand, 5 in Philippines, and 2 in Vietnam.

    Pre-assignment
    Screening details
    A total of 10275 subjects were enrolled; all but one met all of the inclusion criteria and none of the exclusion criteria. Three subjects were not vaccinated and were excluded from the Full Analysis Set for Efficacy and the Safety Analysis Set.

    Period 1
    Period 1 title
    Vaccination Phase (up to 25 Months)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    An observer-blind procedure was followed for the 3 CYD dengue vaccine or placebo injections. The 'vaccinator' in charge of preparing and administering the vaccines was not authorized to collect safety data and also ensured that the documents on randomization were stored in a secure place with no unauthorized access.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CYD Dengue Vaccine Group
    Arm description
    Subjects received 3 doses of CYD dengue vaccine; one each at 0, 6, and 12 months and were followed up to 60 months after last vaccination (for a total duration of up to 72 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 doses at 0, 6, and 12 months.

    Arm title
    Placebo Group
    Arm description
    Subjects received 3 doses of placebo matched to vaccine; one each at 0, 6, and 12 months and were followed up to 60 months after last vaccination (for a total duration of up to 72 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 doses at 0, 6, and 12 months.

    Number of subjects in period 1
    CYD Dengue Vaccine Group Placebo Group
    Started
    6851
    3424
    Completed
    6797
    3397
    Not completed
    54
    27
         Protocol deviation
             5
             2
         Consent withdrawn by subject
             40
             23
         Serious adverse event
             4
             1
         Lost to follow-up
             5
             1
    Period 2
    Period 2 title
    Surveillance Expansion Period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    An observer-blind procedure was followed for the 3 CYD dengue vaccine or placebo injections. The 'vaccinator' in charge of preparing and administering the vaccines was not authorized to collect safety data and also ensured that the documents on randomization were stored in a secure place with no unauthorized access

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CYD Dengue Vaccine Group
    Arm description
    Subjects received 3 doses of CYD dengue vaccine; one each at 0, 6, and 12 months and were followed up to 60 months after last vaccination (for a total duration of up to 72 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 doses at 0, 6, and 12 months.

    Arm title
    Placebo Group
    Arm description
    Subjects received 3 doses of placebo matched to vaccine; one each at 0, 6, and 12 months and were followed up to 60 months after last vaccination (for a total duration of up to 72 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 doses at 0, 6, and 12 months.

    Number of subjects in period 2
    CYD Dengue Vaccine Group Placebo Group
    Started
    6797
    3397
    Completed
    6595
    3279
    Not completed
    202
    118
         Protocol deviation
             9
             1
         Consent withdrawn by subject
             180
             105
         Serious adverse event
             3
             4
         Lost to follow-up
             10
             8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CYD Dengue Vaccine Group
    Reporting group description
    Subjects received 3 doses of CYD dengue vaccine; one each at 0, 6, and 12 months and were followed up to 60 months after last vaccination (for a total duration of up to 72 months).

    Reporting group title
    Placebo Group
    Reporting group description
    Subjects received 3 doses of placebo matched to vaccine; one each at 0, 6, and 12 months and were followed up to 60 months after last vaccination (for a total duration of up to 72 months).

    Reporting group values
    CYD Dengue Vaccine Group Placebo Group Total
    Number of subjects
    6851 3424 10275
    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)
    5296 2650 7946
        Adolescents (12-17 years)
    1555 774 2329
        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)
    8.8 ± 3.45 8.8 ± 3.42 -
    Gender categorical
    Units: Subjects
        Female
    3524 1767 5291
        Male
    3327 1657 4984

    End points

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    End points reporting groups
    Reporting group title
    CYD Dengue Vaccine Group
    Reporting group description
    Subjects received 3 doses of CYD dengue vaccine; one each at 0, 6, and 12 months and were followed up to 60 months after last vaccination (for a total duration of up to 72 months).

    Reporting group title
    Placebo Group
    Reporting group description
    Subjects received 3 doses of placebo matched to vaccine; one each at 0, 6, and 12 months and were followed up to 60 months after last vaccination (for a total duration of up to 72 months).
    Reporting group title
    CYD Dengue Vaccine Group
    Reporting group description
    Subjects received 3 doses of CYD dengue vaccine; one each at 0, 6, and 12 months and were followed up to 60 months after last vaccination (for a total duration of up to 72 months).

    Reporting group title
    Placebo Group
    Reporting group description
    Subjects received 3 doses of placebo matched to vaccine; one each at 0, 6, and 12 months and were followed up to 60 months after last vaccination (for a total duration of up to 72 months).

    Primary: Number of Symptomatic Virologically Confirmed Dengue (VCD) Cases Due to Any Serotype During the Active Phase Post-Dose 3 Following Injection (Inj.) With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Number of Symptomatic Virologically Confirmed Dengue (VCD) Cases Due to Any Serotype During the Active Phase Post-Dose 3 Following Injection (Inj.) With Either CYD Dengue Vaccine or a Placebo
    End point description
    Symptomatic VCD cases were defined as occurrence of acute febrile illness (temperature >= 38°C on at least 2 consecutive days) and confirmation of dengue virus infection by dengue reverse transcriptase polymerase chain reaction (RT-PCR) and/or dengue non-structural protein (NS) 1 antigen enzyme-linked immunosorbent assay (ELISA). Vaccine efficacy was defined as 1 minus the ratio of density incidence due to any serotype after at least 1 dose in the CYD Dengue Vaccine Group over the density incidence of the Placebo Vaccine Group. Number of symptomatic VCD cases were assessed in the Per-Protocol Analysis Set for Efficacy which included subjects who did not meet at least one of the protocol-specified inclusion/exclusion criteria.
    End point type
    Primary
    End point timeframe
    28 days post-dose 3 and up to 13 months post-dose 3
    End point values
    CYD Dengue Vaccine Group Placebo Group
    Number of subjects analysed
    6709
    3350
    Units: Cases
    number (not applicable)
        Symptomatic virologicaly-confirmed dengue cases
    117
    133
    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 (expressed in %). The CI was calculated using the exact method conditional on the total number of cases in both groups (exact method by Breslow & Day). 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 Placebo Group
    Number of subjects included in analysis
    10059
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    56.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    43.8
         upper limit
    66.4

    Secondary: Geometric Mean Titers of Antibodies Against Each Serotype With the Parental Dengue Virus Strain Before and Following Inj. With Either CYD Dengue Tetravalent Vaccine or a Placebo

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    End point title
    Geometric Mean Titers of Antibodies Against Each Serotype With the Parental Dengue Virus Strain Before and Following Inj. With Either CYD Dengue Tetravalent Vaccine or a Placebo
    End point description
    Geometric mean titers against each of the 4 serotypes of dengue virus strains were assessed using the plaque reduction neutralization test (PRNT) in a pre-defined subset of subjects. Antibody titers against each dengue virus serotype strain were assessed in Full Analysis Set for Immunogenicity (FASI),which included a subset of subjects who received at least one dose of vaccine and had a blood sample drawn and result available after the dose. Here, ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-injection 1, 28 days post Injections 2 and 3, 13 months (Visit 07) and 60 months (Visit 12) post-injection 3
    End point values
    CYD Dengue Vaccine Group Placebo Group
    Number of subjects analysed
    1323
    660
    Units: Titers 1/Dilution (1/dil)
    geometric mean (confidence interval 95%)
        Dengue virus Serotype 1; Pre-Inj. 1(n=1309,655)
    38.3 (33.8 to 43.5)
    42.1 (35 to 50.6)
        Dengue virus Serotype 1; Post Inj. 2 (n=1317,654)
    153 (137 to 170)
    46.1 (38.2 to 55.7)
        Dengue virus Serotype 1; Post Inj. 3 (n=1316,657)
    166 (150 to 183)
    46.6 (38.7 to 56.1)
        Serotype 1;Year 1 Post Inj.3(V 07) (n=1290,634)
    105 (92.8 to 119)
    57.2 (46.9 to 69.8)
        Serotype 1; Year 5 Post Inj. 3 (V 12) (n=1275,640)
    81.2 (72.5 to 91.0)
    77.6 (65.4 to 92.2)
        Dengue virus Serotype 2; Pre-Inj. 1 (n=1313,654)
    55.3 (48.7 to 62.9)
    62.1 (51.7 to 74.7)
        Dengue virus Serotype 2; Post Inj. 2 (n=1316,655)
    360 (329 to 394)
    69.5 (57.7 to 83.6)
        Dengue virus Serotype 2; Post Inj. 3 (n=1314, 657)
    355 (327 to 386)
    68.5 (57.1 to 82.2)
        Serotype 2; Year 1 Post-Inj. 3 (V 07) (n=1298,640)
    194 (175 to 214)
    78.1 (64.8 to 94.0)
        Serotype 2; Year 5 Post-Inj. 3 (V 12) (n=1275,640)
    144 (130 to 160)
    102 (86.8 to 120)
        Dengue virus Serotype 3; Pre-Inj. 1 (n=1307,650)
    40.1 (35.6 to 45.1)
    40.7 (34.5 to 48)
        Dengue virus Serotype 3; Post Inj. 2 (n=1313,656)
    203 (184 to 223)
    40.8 (34.6 to 48.1)
        Dengue virus Serotype 3; Post Inj. 3 (n=1314,657)
    207 (189 to 226)
    42.5 (36.2 to 49.9)
        Serotype 3; Year 1 Post Inj. 3 (V 07) (n=1298,639)
    186 (168 to 206)
    62.1 (51.8 to 74.6)
        Serotype 3; Year 5 Post Inj. 3 (V 12) (n=1275,640)
    120 (108 to 133)
    76.2 (65.3 to 89.0)
        Dengue virus Serotype 4; Pre Inj. 1 (n=1313,653)
    25.3 (22.9 to 28)
    26.2 (22.6 to 30.3)
        Dengue virus Serotype 4; Post Inj. 2 (n=1318,655)
    151 (139 to 163)
    24.4 (21.3 to 28.1)
        Dengue virus Serotype 4; Post Inj. 3 (n=1315,657)
    151 (141 to 162)
    26 (22.6 to 29.8)
        Serotype 4; Year 1 Post Inj. 3 (V 07) (n=1293,621)
    85.5 (78.5 to 93)
    26.0 (22.4 to 30.3)
        Serotype 4; Year 5 Post Inj. 3 (V 12) (n=1275,640)
    65.7 (60.3 to 71.6)
    40.1 (34.8 to 46.1)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Antibody Titers >= 10 1/Dil Against Each Dengue Virus Serotype Strain Before and Following Inj. With CYD Dengue Vaccine or Placebo

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    End point title
    Percentage of Subjects With Antibody Titers >= 10 1/Dil Against Each Dengue Virus Serotype Strain Before and Following Inj. With CYD Dengue Vaccine or Placebo
    End point description
    Percentage of subjects with antibody titers≥10 (1/dil) against each serotypes of the dengue virus strains were assessed using PRNT in a pre-defined subset of subjects. Antibody titers against each dengue virus serotype strain were assessed in FASI. Here, ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-injection 1, 28 days post Injections 2 and 3, 13 months (V 07) and 60 months (V 12) post-injection 3
    End point values
    CYD Dengue Vaccine Group Placebo Group
    Number of subjects analysed
    1323
    660
    Units: Percentage of subjects
    number (not applicable)
        Dengue virus Serotype 1; Pre-Inj. 1 (n=1309,655)
    52.0
    51.3
        Dengue virus Serotype 1; Post Inj. 2 (n=1317,654)
    88.9
    54.4
        Dengue virus Serotype 1; Post-Inj. 3 (n=1316,657)
    94.0
    55.4
        Serotype 1; Year 1 Post-Inj. 3 (V 07) (n=1290,634)
    79.8
    55.7
        Serotype 1; Year 5 Post-Inj 3 (V 12) (n=1275,640)
    76.2
    70.0
        Dengue virus Serotype 2; Pre-Inj. 1 (n=1313,654)
    58.0
    59.3
        Dengue virus Serotype 2; Post-Inj. 2 (n=1316,655)
    97.3
    62.4
        Dengue virus Serotype 2; Post-Inj. 3 (n=1314,657)
    98.7
    61.8
        Serotype 2; Year 1 Post-Inj. 3 (V 07) (n=1298,640)
    92.0
    65.8
        Serotype 2; Year 5 Post-inj 3 (V 12) (n=1275,640)
    86.0
    75.2
        Dengue virus Serotype 3; Pre-Inj. 1 (n=1307,650)
    56.8
    59.4
        Dengue virus Serotype 3; Post-Inj. 2 (n=1313,656)
    95.7
    60.2
        Dengue virus Serotype 3; Post-Inj. 3 (n=1314,657)
    97.0
    61.0
        Serotype 3; Year 1 Post-Inj. 3 (V 07) (n=1298,639)
    93.6
    62.6
        Serotype 3; Year5 Post-Inj. 3 (V 12) (n=1275,640)
    87.4
    75.6
        Dengue virus Serotype 4; Pre-Inj. 1 (n=1313,653)
    51.6
    50.7
        Dengue virus Serotype 4; Post-Inj. 2 (n=1318,655)
    95.1
    51.8
        Dengue virus Serotype 4; Post-Inj. 3 (n=1315,657)
    97.0
    53.9
        Serotype 4; Year 1 Post-Inj 3 (V 07) (n=1293,621)
    89.4
    50.6
        Serotype 4; Year 5 Post-Inj 3 (V 12) (n=1275,640)
    83.8
    65.0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Solicited Injection Site Reactions Following Any and Each Inj. With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Number of Subjects With Solicited Injection Site Reactions Following Any and Each Inj. With Either CYD Dengue Vaccine or a Placebo
    End point description
    Solicited injection site reactions: Pain, Erythema, and Swelling. Grade 3 reactions (2-11 years) - Pain: incapacitating, unable to perform usual activities; Erythema and Swelling, >= 50 mm. Grade 3 Solicited injection site reactions (12-14 years): Pain, Significant, prevents daily activity; Erythema and Swelling, >100 mm. Solicited injection site reactions were assessed in a subset of the Safety Analysis Set, which included all subjects who received at least one dose of study vaccine. Here, ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Within 7 days after injection
    End point values
    CYD Dengue Vaccine Group Placebo Group
    Number of subjects analysed
    1334
    663
    Units: Number of subjects
    number (not applicable)
        Inj. site Pain (Post any Inj.) (n=1332,663)
    614
    275
        Inj. site Erythema (Post-any Inj.) (n=1332,663)
    107
    52
        Inj. site Swelling (Post any Inj.) (n=1332,663)
    68
    33
        Inj. site Pain (Post-Inj. 1) (n=1332,663)
    406
    196
        Grade 3 Inj. site Pain (Post- Inj. 1)(n=1332,663)
    1
    0
        Inj. site Erythema (Post Inj. 1) (n=1332,663)
    63
    35
        Grade 3 Inj. site Erythema(Post Inj.1)(n=1332,663)
    0
    0
        Inj. site Swelling (Post Inj.1)(n=1332,663)
    40
    19
        Grade 3 Inj. site Swelling(Post Inj.1)(n=1332,663)
    0
    0
        Inj. site Pain (Post Inj.2)(n=1319,658)
    303
    135
        Grade 3 Inj. site Pain (Post-Inj.2)(n=1319,658)
    0
    0
        Inj. site Erythema (Post Inj.2)(n=1319,658)
    43
    20
        Grade 3 Inj. site Erythema(Post Inj.2)(n=1319,658)
    0
    0
        Inj. site Swelling (Post Inj.2)(n=1319,658)
    25
    7
        Grade 3 Inj. site Swelling(Post Inj.2)(n=1319,658)
    0
    0
        Inj. site Pain (Post Inj. 3)(n=1313,654)
    283
    118
        Grade 3 Inj. site Pain (Post Inj. 3)(n=1313,654)
    0
    0
        Inj. site Erythema (Post Inj.3)(n=1313,654)
    36
    16
        Grade 3 Inj. site Erythema(Post Inj.3)(n=1313,654)
    0
    1
        Inj. site Swelling (Post Inj.3)(n=1313,654)
    19
    10
        Grade 3 Inj. site Swelling(Post Inj.3)(n=1313,654)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Symptomatic VCD Cases Due to Any Serotype Occurring 28 Days Post-Dose 1 Following Inj. With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Number of Symptomatic VCD Cases Due to Any Serotype Occurring 28 Days Post-Dose 1 Following Inj. With Either CYD Dengue Vaccine or a Placebo
    End point description
    Symptomatic VCD cases were defined as occurrence of acute febrile illness (temperature >= 38°C on at least 2 consecutive days) and confirmation of dengue virus infection by dengue RT-PCR and/or dengue NS1 ELISA. Vaccine efficacy was defined as 1 minus the ratio of density incidence due to any serotype after at least 1 dose in the CYD Dengue Vaccine Group over the density incidence of the Placebo Vaccine Group. Number of symptomatic VCD cases were assessed in the Full Analysis Set for Efficacy, which included subjects who received at least 1 dose of study vaccine.
    End point type
    Secondary
    End point timeframe
    28 days post-injection 1 and up to 13 months post-injection 3
    End point values
    CYD Dengue Vaccine Group Placebo Group
    Number of subjects analysed
    6848
    3424
    Units: Cases
        number (not applicable)
    276
    302
    Statistical analysis title
    CYD Dengue Vaccine Group, Placebo Group
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% CI of the vaccine efficacy (expressed in %) calculated using the exact method conditional on the total number of cases in both groups.
    Comparison groups
    CYD Dengue Vaccine Group v Placebo Group
    Number of subjects included in analysis
    10272
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Vaccine Efficacy
    Point estimate
    55.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    47.3
         upper limit
    62.3

    Secondary: Number of Symptomatic VCD Cases Meeting 1997 World Health Organization (WHO) Criteria During the Surveillance Expansion Period Due to Any Serotype Following Inj. With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Number of Symptomatic VCD Cases Meeting 1997 World Health Organization (WHO) Criteria During the Surveillance Expansion Period Due to Any Serotype Following Inj. With Either CYD Dengue Vaccine or a Placebo
    End point description
    The 1997 WHO criteria are: a) Fever: acute onset, high (>=38°C) and continuous, for 2 to 7 days and (b) any of the following: thrombocytopenia (platelet<=100x109/L) and plasma leakage as shown by hematocrit increased by 20% or more or pleural effusion and/or ascites and/or hypoaluminemia. The first two clinical criteria plus thrombocytopenia and signs of plasma leakage are enough to establish diagnosis of Dengue hemorrhagic fever (DHF). DHF was graded as follows: Grade I: Fever accompanied by non-specific constitutional symptoms; the only hemorrhagic manifestation is a positive tourniquet test; Grade II: Spontaneous bleeding in addition to the manifestations of Grade I subjects, usually in the form of skin and/or other hemorrhages; Grade III: Circulatory failure manifested by rapid and weak pulse, narrowing of pulse pressure (20mmHg or less) or hypotension, with the presence of cold clammy skin and restlessness; and Grade IV: Profound shock with undetectable blood pressure and pulse.
    End point type
    Secondary
    End point timeframe
    From consent to participate in Surveillance Expansion Period to 60 months post-injection 3 (up to Month 72)
    End point values
    CYD Dengue Vaccine Group Placebo Group
    Number of subjects analysed
    6327
    3138
    Units: Cases
    number (not applicable)
        Due to Any of the 4 Serotypes: Any Grade
    19
    12
        Due to Any of the 4 Serotypes: Grade I
    5
    3
        Due to Any of the 4 Serotypes: Grade II
    11
    8
        Due to Any of the 4 Serotypes: Grade III
    3
    1
        Due to Any of the 4 Serotypes: Grade IV
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Clinically Severe VCD Cases During the Surveillance Expansion Period Due to Any Serotype Following Inj. With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Number of Clinically Severe VCD Cases During the Surveillance Expansion Period Due to Any Serotype Following Inj. With Either CYD Dengue Vaccine or a Placebo
    End point description
    The severity of VCD cases was assessed by an IDMC based on a medical review of cases and any of the following criteria:1) Platelet count<=100000μl and bleeding (tourniquet, petechiae or any bleeding) plus plasma leakage 2) Shock (pulse pressure<=20mmHg in a child, or hypotension [<=90 mmHg] with tachycardia, weak pulse and poor perfusion) 3) Bleeding requiring blood transfusion 4)Encephalopathy i.e. Unconsciousness or poor conscious state or fitting not attributable to simple febrile convulsion or focal neurological signs. Poor conscious state or unconsciousness must be supported by Glasgow Coma Scale (GCS) score. 5)Liver impairment (AST1000IU/L or prothrombin time [PT] International normalized ratio [INR] >1.5) excluding other causes of viral hepatitis 6)Impaired kidney function (serum creatinine ≥ 1.5mg/dL) 7)Myocarditis, pericarditis or clinical heart failure supported by Chest X-Ray (CXR), echocardiography, electrocardiogram (ECG) or cardiac enzymes. Full Analysis Set for SEP.
    End point type
    Secondary
    End point timeframe
    From consent to participate in the Surveillance Expansion Period to 60 months post-injection 3 (up to Month 72)
    End point values
    CYD Dengue Vaccine Group Placebo Group
    Number of subjects analysed
    6327
    3138
    Units: Cases
        number (not applicable)
    21
    12
    No statistical analyses for this end point

    Secondary: Number of Symptomatic VCD Cases Due to Any Serotype 28 Days Post-Dose 2 Following Inj. With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Number of Symptomatic VCD Cases Due to Any Serotype 28 Days Post-Dose 2 Following Inj. With Either CYD Dengue Vaccine or a Placebo
    End point description
    Symptomatic VCD cases were defined as occurrence of acute febrile illness (temperature ≥38°C on at least 2 consecutive days) and confirmation of dengue virus infection by dengue RT-PCR and/or dengue NS1 ELISA. Vaccine efficacy was defined as 1 minus the ratio of density incidence due to any serotype after at least 1 dose in the CYD Dengue Vaccine Group over the density incidence of the Placebo Vaccine Group. Number of symptomatic VCD cases were assessed in the Other Efficacy Analysis Set, which included subjects who received at least 2 doses of study vaccine.
    End point type
    Secondary
    End point timeframe
    28 days post-injection 2 and up to 13 months post-injection 3
    End point values
    CYD Dengue Vaccine Group Placebo Group
    Number of subjects analysed
    6793
    3397
    Units: Cases
        number (not applicable)
    205
    238
    Statistical analysis title
    CYD Dengue Vaccine Group, Placebo Group
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% CI of the vaccine efficacy (expressed in %) calculated using the exact method conditional on the total number of cases in both groups.
    Comparison groups
    CYD Dengue Vaccine Group v Placebo Group
    Number of subjects included in analysis
    10190
    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
    49
         upper limit
    65.2

    Secondary: Number of Symptomatic VCD Cases Due to Any Serotype During the Active Phase in Either CYD Dengue Vaccine or Placebo Group

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    End point title
    Number of Symptomatic VCD Cases Due to Any Serotype During the Active Phase in Either CYD Dengue Vaccine or Placebo Group
    End point description
    Symptomatic VCD cases were defined as occurrence of acute febrile illness (temperature >= 38°C on at least 2 consecutive days) and confirmation of dengue virus infection by dengue RT-PCR and/or dengue NS1 ELISA. Vaccine efficacy was defined as 1 minus the ratio of density incidence due to any serotype after at least 1 dose in the CYD Dengue Vaccine Group over the density incidence of the Placebo Vaccine Group. Number of symptomatic VCD cases were assessed in the Full Analysis Set for Efficacy, which included all subjects who received at least 1 injection.
    End point type
    Secondary
    End point timeframe
    Day 0 up to 13 months post-injection 3
    End point values
    CYD Dengue Vaccine Group Placebo Group
    Number of subjects analysed
    6848
    3424
    Units: Cases
        number (not applicable)
    286
    309
    Statistical analysis title
    CYD Dengue Vaccine Group, Placebo Group
    Statistical analysis description
    The statistical methodology was based on the use of the two-sided 95% CI of the vaccine efficacy (expressed in %) calculated using the exact method conditional on the total number of cases in both groups.
    Comparison groups
    CYD Dengue Vaccine Group v Placebo Group
    Number of subjects included in analysis
    10272
    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
    46.8
         upper limit
    61.7

    Secondary: Number of Clinically Severe VCD Cases Throughout the Trial Due to Any Serotype Following Inj. With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Number of Clinically Severe VCD Cases Throughout the Trial Due to Any Serotype Following Inj. With Either CYD Dengue Vaccine or a Placebo
    End point description
    The severity of VCD cases was assessed by an IDMC based on a medical review of cases and any of the following criteria:1) Platelet count <= 100000μl and bleeding (tourniquet, petechiae or any bleeding) plus plasma leakage 2) Shock (pulse pressure <= 20mmHg in a child, or hypotension [<= 90 mmHg] with tachycardia, weak pulse and poor perfusion) 3)Bleeding requiring blood transfusion 4) Encephalopathy i.e. Unconsciousness or poor conscious state or fitting not attributable to simple febrile convulsion or focal neurological signs. Poor conscious state or unconsciousness must be supported by GCS score. 5) Liver impairment (AST >1000IU/L or PT International normalized ratio [INR] >1.5) excluding other causes of viral hepatitis 6) Impaired kidney function (serum creatinine >= 1.5mg/dL) 7) Myocarditis, pericarditis or clinical heart failure supported by CXR, echocardiography, ECG or cardiac enzymes. Number of clinically severe VCD cases were assessed in the Safety Analysis Set.
    End point type
    Secondary
    End point timeframe
    Day 0 to the end of study (up to 72 months)
    End point values
    CYD Dengue Vaccine Group Placebo Group
    Number of subjects analysed
    6745
    3369
    Units: Cases
        number (not applicable)
    61
    41
    No statistical analyses for this end point

    Secondary: Number of Subjects With Systemic Reactions Following Any and Each Inj. With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Number of Subjects With Systemic Reactions Following Any and Each Inj. With Either CYD Dengue Vaccine or a Placebo
    End point description
    Solicited systemic reactions: Fever (Temperature), Headache, Malaise, Myalgia, and Asthenia. Grade 3 reactions- Fever: >=39°C; Headache, Malaise, Myalgia, and Asthenia, Significant, prevents daily activity. Solicited systemic reactions were assessed in a subset of the Safety Analysis Set, which included all subjects who received at least one dose of study vaccine. Here, ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Within 14 days after injection
    End point values
    CYD Dengue Vaccine Group Placebo Group
    Number of subjects analysed
    1334
    663
    Units: Number of subjects
    number (not applicable)
        Fever (Post any injection) (n=1332,663)
    248
    118
        Headache (Post any injection) (n=1332,663)
    562
    259
        Malaise (Post any injection) (n=1332,663)
    476
    239
        Myalgia (Post any injection) (n=1332,663)
    414
    197
        Asthenia (Post any injection) (n=1332,663)
    378
    167
        Fever (Post-injection 1) (n=1330,663)
    103
    45
        Grade 3 Fever (Post-injection 1) (n=1330,663)
    18
    7
        Headache (Post-injection 1) (n=1332,663)
    387
    168
        Grade 3 Headache (Post-injection 1) (n=1332,663)
    7
    6
        Malaise (Post-injection 1) (n=1332,663)
    312
    148
        Grade 3 Malaise (Post-injection 1) (n=1332,663)
    7
    4
        Myalgia (Post-injection 1) (n=1332,663)
    255
    124
        Grade 3 Myalgia (Post-injection 1) (n=1332,663)
    2
    2
        Asthenia (Post-injection 1) (n=1332,663)
    229
    97
        Grade 3 Asthenia (Post-injection 1) (n=1332,663)
    5
    5
        Fever (Post-injection 2) (n=1320,657)
    90
    44
        Grade 3 Fever (Post-injection 2) (n=1320,657)
    19
    9
        Headache (Post-injection 2) (n=1319,658)
    247
    118
        Grade 3 Headache (Post-injection 2) (n=1319,658)
    12
    3
        Malaise (Post-injection 2) (n=1319,658)
    192
    100
        Grade 3 Malaise (Post-injection 2) (n=1319,658)
    6
    4
        Myalgia (Post-injection 2) (n=1319,658)
    174
    92
        Grade 3 Myalgia (Post-injection 2) (n=1319,658)
    3
    0
        Asthenia (Post-injection 2) (n=1319,658)
    158
    74
        Grade 3 Asthenia (Post-injection 2) (n=1319,658)
    5
    6
        Fever (Post-injection 3) (n=1309,654)
    76
    39
        Grade 3 Fever (Post-injection 3) (n=1309,654)
    16
    2
        Headache (Post-injection 3) (n=1313,654)
    219
    113
        Grade 3 Headache (Post-injection 3) (n=1313,654)
    6
    1
        Malaise (Post-injection 3) (n=1313,654)
    183
    104
        Grade 3 Malaise (Post-injection 3) (n=1313,654)
    7
    1
        Myalgia (Post-injection 3) (n=1313,654)
    156
    76
        Grade 3 Myalgia (Post-injection 3) (n=1313,654)
    3
    0
        Asthenia (Post-injection 3) (n=1313,654)
    142
    73
        Grade 3 Asthenia (Post-injection 3) (n=1313,654)
    4
    2
    No statistical analyses for this end point

    Secondary: Number of Hospitalized VCD Cases During the Surveillance Expansion Period Due to Any Serotype Following Inj. With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Number of Hospitalized VCD Cases During the Surveillance Expansion Period Due to Any Serotype Following Inj. With Either CYD Dengue Vaccine or a Placebo
    End point description
    Hospitalized VCD cases were defined as VCD confirmed by dengue RT –PCR and/or dengue NS1 ELISA in subjects with acute febrile illness (temperature >= 38°C on at least 2 consecutive days) requiring hospitalization. Number of hospitalized VCD cases were assessed in the Safety Analysis Set.
    End point type
    Secondary
    End point timeframe
    From consent to participate in the Surveillance Expansion Period to 60 months post-injection 3 (up to Month 72)
    End point values
    CYD Dengue Vaccine Group Placebo Group
    Number of subjects analysed
    6848
    3424
    Units: Cases
        number (not applicable)
    74
    48
    No statistical analyses for this end point

    Secondary: Number of Hospitalized VCD Cases Throughout the Trial Due to Any Serotype Following Inj. With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Number of Hospitalized VCD Cases Throughout the Trial Due to Any Serotype Following Inj. With Either CYD Dengue Vaccine or a Placebo
    End point description
    Hospitalized VCD cases were defined as VCD confirmed by dengue RT –PCR and/or dengue NS1 ELISA in subjects with acute febrile illness (temperature >= 38°C on at least 2 consecutive days) requiring hospitalization. Number of VCD cases were assessed in the Safety Analysis Set.
    End point type
    Secondary
    End point timeframe
    Day 0 to the end of study (up to 72 months)
    End point values
    CYD Dengue Vaccine Group Placebo Group
    Number of subjects analysed
    6745
    3369
    Units: Cases
        number (not applicable)
    210
    154
    No statistical analyses for this end point

    Secondary: Number of Symptomatic VCD Cases Meeting 1997 WHO Criteria Throughout the Trial Due to Any Serotype Following Inj. With Either CYD Dengue Vaccine or a Placebo

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    End point title
    Number of Symptomatic VCD Cases Meeting 1997 WHO Criteria Throughout the Trial Due to Any Serotype Following Inj. With Either CYD Dengue Vaccine or a Placebo
    End point description
    The 1997 WHO criteria are: a) Fever: acute onset, high (>=38°C) and continuous, for 2 to 7 days and (b) any of the following: thrombocytopenia (platelet<=100x109/L) and plasma leakage as shown by hematocrit increased by 20% or more or pleural effusion and/or ascites and/or hypoaluminemia. The first two clinical criteria plus thrombocytopenia and signs of plasma leakage are enough to establish diagnosis of DHF.DHF was graded as follows: Grade I: Fever accompanied by non-specific constitutional symptoms; the only hemorrhagic manifestation is a positive tourniquet test; Grade II: Spontaneous bleeding in addition to the manifestations of Grade I subjects, usually in the form of skin and/or other hemorrhages; Grade III: Circulatory failure manifested by rapid and weak pulse, narrowing of pulse pressure (20 mmHg or less) or hypotension, with the presence of cold clammy skin and restlessness; and Grade IV: Profound shock with undetectable blood pressure and pulse. Full Analysis Set for SEP.
    End point type
    Secondary
    End point timeframe
    Day 0 to the end of study (up to 72 months)
    End point values
    CYD Dengue Vaccine Group Placebo Group
    Number of subjects analysed
    6745
    3369
    Units: Cases
    number (not applicable)
        Due to Any of the 4 Serotypes: Any Grade
    55
    41
        Due to Any of the 4 Serotypes: Grade I
    14
    9
        Due to Any of the 4 Serotypes: Grade II
    37
    29
        Due to Any of the 4 Serotypes: Grade III
    4
    3
        Due to Any of the 4 Serotypes: Grade IV
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE data were collected from Day 0 (post-vaccination) up to 60 months post-injection 3 (up to 72 months).
    Adverse event reporting additional description
    All vaccinated subjects were assessed for serious AEs during the trial. Non-serious AEs were assessed in a subset of subjects from each group, and included solicited injection site and systemic reactions (within 7 and 14 days after injection), as well as unsolicited non-serious AEs (28 days after injection).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    CYD Dengue Vaccine Group
    Reporting group description
    Subjects received 3 doses of CYD dengue vaccine; one each at 0, 6, and 12 months and were followed up to 60 months after last vaccination (for a total duration of up to 72 months).

    Reporting group title
    Placebo Group
    Reporting group description
    Subjects received 3 doses of placebo matched to vaccine; one each at 0, 6, and 12 months and were followed up to 60 months after last vaccination (for a total duration of up to 72 months).

    Serious adverse events
    CYD Dengue Vaccine Group Placebo Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    947 / 6848 (13.83%)
    552 / 3424 (16.12%)
         number of deaths (all causes)
    10
    4
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    4 / 6848 (0.06%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adverse Event Following Immunisation
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (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
    2 / 6848 (0.03%)
    4 / 3424 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthropod Bite
         subjects affected / exposed
    3 / 6848 (0.04%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burns Second Degree
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chemical Poisoning
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Injury
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle Fracture
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    7 / 6848 (0.10%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear Injury
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrical Burn
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Excoriation
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye Injury
         subjects affected / exposed
    2 / 6848 (0.03%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eyeball Rupture
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial Bones Fracture
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    15 / 6848 (0.22%)
    6 / 3424 (0.18%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula Fracture
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         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
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         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
    9 / 6848 (0.13%)
    4 / 3424 (0.12%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foreign Body
         subjects affected / exposed
    5 / 6848 (0.07%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foreign Body In Eye
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital Injury
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gun Shot Wound
         subjects affected / exposed
    2 / 6848 (0.03%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand Fracture
         subjects affected / exposed
    3 / 6848 (0.04%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head Injury
         subjects affected / exposed
    5 / 6848 (0.07%)
    4 / 3424 (0.12%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    9 / 6848 (0.13%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impacted Fracture
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    1 / 6848 (0.01%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional Overdose
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint Dislocation
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint Injury
         subjects affected / exposed
    2 / 6848 (0.03%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    2 / 6848 (0.03%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament Sprain
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb Injury
         subjects affected / exposed
    1 / 6848 (0.01%)
    3 / 3424 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Limb Fracture
         subjects affected / exposed
    1 / 6848 (0.01%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple Fractures
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple Injuries
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle Strain
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Near Drowning
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Open Wound
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Poisoning Deliberate
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative Adhesion
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative Ileus
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius Fracture
         subjects affected / exposed
    6 / 6848 (0.09%)
    5 / 3424 (0.15%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    71 / 6848 (1.04%)
    38 / 3424 (1.11%)
         occurrences causally related to treatment / all
    0 / 75
    0 / 39
         deaths causally related to treatment / all
    0 / 6
    0 / 0
    Scrotal Haematoma
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Snake Bite
         subjects affected / exposed
    4 / 6848 (0.06%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft Tissue Injury
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sports Injury
         subjects affected / exposed
    5 / 6848 (0.07%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stab Wound
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon Rupture
         subjects affected / exposed
    3 / 6848 (0.04%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal Burn
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia Fracture
         subjects affected / exposed
    1 / 6848 (0.01%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity To Various Agents
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal Injury
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Traumatic Brain Injury
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic Intracranial Haemorrhage
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (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
    3 / 6848 (0.04%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac Failure Congestive
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic Shock
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Rheumatic Heart Disease
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular Tachycardia
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (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 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duchenne Muscular Dystrophy
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Familial Periodic Paralysis
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrous Dysplasia Of Bone
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Odontogenic Cyst
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phimosis
         subjects affected / exposed
    0 / 6848 (0.00%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia Of Pregnancy
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic Anaemia
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron Deficiency Anaemia
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Acute Disseminated Encephalomyelitis
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autonomic Neuropathy
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Venous Thrombosis
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complex Partial Seizures
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    4 / 6848 (0.06%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsions Local
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Epilepsy
         subjects affected / exposed
    8 / 6848 (0.12%)
    4 / 3424 (0.12%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extrapyramidal Disorder
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         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
    13 / 6848 (0.19%)
    7 / 3424 (0.20%)
         occurrences causally related to treatment / all
    0 / 23
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Grand Mal Convulsion
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Guillain-Barre Syndrome
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intercostal Neuralgia
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine Without Aura
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (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
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status Epilepticus
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tension Headache
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonic Convulsion
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (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
    3 / 6848 (0.04%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Chalazion
         subjects affected / exposed
    3 / 6848 (0.04%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Choroidal Dystrophy
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corneal Oedema
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Middle Ear Effusion
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo Positional
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular Disorder
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (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
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain Lower
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal Fistula
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Caecitis
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dental Caries
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (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
    6 / 6848 (0.09%)
    6 / 3424 (0.18%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    8 / 6848 (0.12%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    5 / 6848 (0.07%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food Poisoning
         subjects affected / exposed
    9 / 6848 (0.13%)
    3 / 3424 (0.09%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    31 / 6848 (0.45%)
    14 / 3424 (0.41%)
         occurrences causally related to treatment / all
    0 / 32
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Disorder
         subjects affected / exposed
    9 / 6848 (0.13%)
    5 / 3424 (0.15%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Inflammation
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (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
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis Chronic
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salivary Gland Calculus
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salivary Gland Mucocoele
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth Development Disorder
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth Impacted
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toothache
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus Ureteric
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerulonephritis Acute
         subjects affected / exposed
    3 / 6848 (0.04%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic Syndrome
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurogenic Bladder
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post Streptococcal Glomerulonephritis
         subjects affected / exposed
    9 / 6848 (0.13%)
    3 / 3424 (0.09%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure Acute
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Tubular Acidosis
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    2 / 6848 (0.03%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermal Cyst
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Henoch-Schonlein Purpura
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Hypertrophy
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 6848 (0.01%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone Cyst
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exostosis
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fasciitis
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture Malunion
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaw Cyst
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle Spasms
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (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
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial Cyst
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Calcium Deficiency
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    2 / 6848 (0.03%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 6848 (0.03%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess Limb
         subjects affected / exposed
    4 / 6848 (0.06%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess Neck
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess Of External Auditory Meatus
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acinetobacter Bacteraemia
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (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 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Tonsillitis
         subjects affected / exposed
    7 / 6848 (0.10%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenoiditis
         subjects affected / exposed
    4 / 6848 (0.06%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amoebiasis
         subjects affected / exposed
    9 / 6848 (0.13%)
    4 / 3424 (0.12%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amoebic Dysentery
         subjects affected / exposed
    3 / 6848 (0.04%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal Abscess
         subjects affected / exposed
    0 / 6848 (0.00%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendiceal Abscess
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    33 / 6848 (0.48%)
    27 / 3424 (0.79%)
         occurrences causally related to treatment / all
    0 / 33
    0 / 27
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis Perforated
         subjects affected / exposed
    5 / 6848 (0.07%)
    4 / 3424 (0.12%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial Diarrhoea
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial Infection
         subjects affected / exposed
    2 / 6848 (0.03%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bartholin's Abscess
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    16 / 6848 (0.23%)
    6 / 3424 (0.18%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis Bacterial
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (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
    8 / 6848 (0.12%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brucellosis
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (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
    7 / 6848 (0.10%)
    3 / 3424 (0.09%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chikungunya Virus Infection
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Tonsillitis
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conjunctivitis Infective
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (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
    3 / 6848 (0.04%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue Fever
         subjects affected / exposed
    238 / 6848 (3.48%)
    158 / 3424 (4.61%)
         occurrences causally related to treatment / all
    0 / 241
    0 / 167
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea Infectious
         subjects affected / exposed
    3 / 6848 (0.04%)
    5 / 3424 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated Tuberculosis
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis Viral
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Furuncle
         subjects affected / exposed
    3 / 6848 (0.04%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis Bacterial
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    53 / 6848 (0.77%)
    40 / 3424 (1.17%)
         occurrences causally related to treatment / all
    0 / 64
    0 / 43
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Bacterial
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    3 / 6848 (0.04%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Bacterial Infection
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Infection
         subjects affected / exposed
    6 / 6848 (0.09%)
    5 / 3424 (0.15%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin Abscess
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiv Infection
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand-Foot-And-Mouth Disease
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis A
         subjects affected / exposed
    2 / 6848 (0.03%)
    1 / 3424 (0.03%)
         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
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpangina
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hordeolum
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection In An Immunocompromised Host
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    9 / 6848 (0.13%)
    3 / 3424 (0.09%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leptospirosis
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar Pneumonia
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis Bacterial
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaria
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Measles
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis Aseptic
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis Bacterial
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (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
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral Herpes
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis Externa
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis Media
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis Media Chronic
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paratyphoid Fever
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital Cellulitis
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         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
    1 / 6848 (0.01%)
    0 / 3424 (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
    32 / 6848 (0.47%)
    19 / 3424 (0.55%)
         occurrences causally related to treatment / all
    0 / 35
    0 / 25
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis Bacterial
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis Streptococcal
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (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
    15 / 6848 (0.22%)
    4 / 3424 (0.12%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasmodium Falciparum Infection
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    33 / 6848 (0.48%)
    12 / 3424 (0.35%)
         occurrences causally related to treatment / all
    0 / 37
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Bacterial
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Measles
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Primary Atypical
         subjects affected / exposed
    2 / 6848 (0.03%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Viral
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative Wound Infection
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Tuberculosis
         subjects affected / exposed
    5 / 6848 (0.07%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    4 / 6848 (0.06%)
    3 / 3424 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         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
    2 / 6848 (0.03%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 6848 (0.03%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sinusitis
         subjects affected / exposed
    4 / 6848 (0.06%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal Sepsis
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal Infection
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    12 / 6848 (0.18%)
    4 / 3424 (0.12%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis Bacterial
         subjects affected / exposed
    2 / 6848 (0.03%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth Abscess
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculous Pleurisy
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Typhoid Fever
         subjects affected / exposed
    15 / 6848 (0.22%)
    13 / 3424 (0.38%)
         occurrences causally related to treatment / all
    0 / 18
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Typhus
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         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
    11 / 6848 (0.16%)
    5 / 3424 (0.15%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethritis
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (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
    22 / 6848 (0.32%)
    14 / 3424 (0.41%)
         occurrences causally related to treatment / all
    0 / 23
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    32 / 6848 (0.47%)
    29 / 3424 (0.85%)
         occurrences causally related to treatment / all
    0 / 35
    0 / 29
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Pharyngitis
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Rash
         subjects affected / exposed
    0 / 6848 (0.00%)
    3 / 3424 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 6848 (0.03%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval Abscess
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound Infection
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aneurysm Ruptured
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haematoma
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion Induced
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute Lymphocytic Leukaemia
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angiofibroma
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign Neoplasm Of Skin
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign Soft Tissue Neoplasm
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone Giant Cell Tumour Benign
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone Sarcoma
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast Neoplasm
         subjects affected / exposed
    3 / 6848 (0.04%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear Neoplasm
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibroadenoma Of Breast
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrous Histiocytoma
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemangioma
         subjects affected / exposed
    2 / 6848 (0.03%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lip Neoplasm Benign
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    0 / 6848 (0.00%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangioma
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Papilloma
         subjects affected / exposed
    0 / 6848 (0.00%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft Tissue Neoplasm
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Teratoma
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergy To Arthropod Bite
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Allergy To Arthropod Sting
         subjects affected / exposed
    4 / 6848 (0.06%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic Reaction
         subjects affected / exposed
    3 / 6848 (0.04%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic Shock
         subjects affected / exposed
    1 / 6848 (0.01%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug Hypersensitivity
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food Allergy
         subjects affected / exposed
    5 / 6848 (0.07%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    2 / 6848 (0.03%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Child Abuse
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Physical Assault
         subjects affected / exposed
    4 / 6848 (0.06%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Victim Of Child Abuse
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Victim Of Crime
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Victim Of Sexual Abuse
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Complete
         subjects affected / exposed
    3 / 6848 (0.04%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion Incomplete
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion Spontaneous
         subjects affected / exposed
    2 / 6848 (0.03%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion Spontaneous Incomplete
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion Threatened
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breech Presentation
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cephalo-Pelvic Disproportion
         subjects affected / exposed
    3 / 6848 (0.04%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eclampsia
         subjects affected / exposed
    3 / 6848 (0.04%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ectopic Pregnancy
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    False Labour
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foetal Distress Syndrome
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oligohydramnios
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postpartum Haemorrhage
         subjects affected / exposed
    0 / 6848 (0.00%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature Labour
         subjects affected / exposed
    4 / 6848 (0.06%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Puerperal Pyrexia
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stillbirth
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         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
    Drowning
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hernia Obstructive
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (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 / 6848 (0.03%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal Behaviour
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Psychosis
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bipolar I Disorder
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bipolar Disorder
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental Disorder
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychosomatic Disease
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic Disorder
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    2 / 6848 (0.03%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somatoform Disorder
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    1 / 6848 (0.01%)
    2 / 3424 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Acquired Phimosis
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast Mass
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (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 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic Ovarian Cyst
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian Cyst
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian Haemorrhage
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine Cervical Erosion
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine Haemorrhage
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal Haematoma
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Adenoidal Hypertrophy
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asphyxia
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    12 / 6848 (0.18%)
    9 / 3424 (0.26%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial Hyperreactivity
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal Polyps
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         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 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neonatal Asphyxia
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Acidosis
         subjects affected / exposed
    0 / 6848 (0.00%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep Apnoea Syndrome
         subjects affected / exposed
    1 / 6848 (0.01%)
    1 / 3424 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Inflammation
         subjects affected / exposed
    2 / 6848 (0.03%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    1 / 6848 (0.01%)
    0 / 3424 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         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 Placebo Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    942 / 6848 (13.76%)
    453 / 3424 (13.23%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed [1]
    63 / 1334 (4.72%)
    48 / 663 (7.24%)
         occurrences all number
    69
    61
    Rhinorrhoea
         subjects affected / exposed [2]
    46 / 1334 (3.45%)
    36 / 663 (5.43%)
         occurrences all number
    48
    43
    Nervous system disorders
    Headache
         subjects affected / exposed [3]
    567 / 1334 (42.50%)
    264 / 663 (39.82%)
         occurrences all number
    866
    409
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed [4]
    378 / 1334 (28.34%)
    167 / 663 (25.19%)
         occurrences all number
    530
    244
    Injection Site Erythema
         subjects affected / exposed [5]
    107 / 1334 (8.02%)
    52 / 663 (7.84%)
         occurrences all number
    142
    71
    Injection Site Pain
         subjects affected / exposed [6]
    616 / 1334 (46.18%)
    275 / 663 (41.48%)
         occurrences all number
    994
    449
    Injection Site Swelling
         subjects affected / exposed [7]
    68 / 1334 (5.10%)
    33 / 663 (4.98%)
         occurrences all number
    84
    36
    Malaise
         subjects affected / exposed [8]
    476 / 1334 (35.68%)
    239 / 663 (36.05%)
         occurrences all number
    689
    352
    Pyrexia
         subjects affected / exposed [9]
    267 / 1334 (20.01%)
    125 / 663 (18.85%)
         occurrences all number
    291
    137
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed [10]
    414 / 1334 (31.03%)
    197 / 663 (29.71%)
         occurrences all number
    585
    296
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed [11]
    85 / 1334 (6.37%)
    45 / 663 (6.79%)
         occurrences all number
    113
    61
    Upper Respiratory Tract Infection
         subjects affected / exposed [12]
    95 / 1334 (7.12%)
    54 / 663 (8.14%)
         occurrences all number
    104
    62
    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: Non-serious adverse events were assessed in a subset of subjects in each group, in accordance with the protocol.
    [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: Non-serious adverse events were assessed in a subset of subjects in each group, in accordance with the protocol.
    [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: Non-serious adverse events were assessed in a subset of subjects in each group, in accordance with the protocol.
    [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: Non-serious adverse events were assessed in a subset of subjects in each group, in accordance with the protocol.
    [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: Non-serious adverse events were assessed in a subset of subjects in each group, in accordance with the protocol.
    [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: Non-serious adverse events were assessed in a subset of subjects in each group, in accordance with the protocol.
    [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: Non-serious adverse events were assessed in a subset of subjects in each group, in accordance with the protocol.
    [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: Non-serious adverse events were assessed in a subset of subjects in each group, in accordance with the protocol.
    [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: Non-serious adverse events were assessed in a subset of subjects in each group, in accordance with the protocol.
    [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: Non-serious adverse events were assessed in a subset of subjects in each group, in accordance with the protocol.
    [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: Non-serious adverse events were assessed in a subset of subjects in each group, in accordance with the protocol.
    [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: Non-serious adverse events were assessed in a subset of subjects in each group, in accordance with the protocol.

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jan 2011
    The ‘Other Objectives’ section was revised to improve specificity of confirmation of dengue in line with the non-primary endpoint suggested in the WHO guidelines (version 2.0); It was also specified that the safety surveillance will be conducted by the Principal Investigators.
    03 Aug 2011
    Clarified the issue of sample collection times and the reporting period; Extended the collection of all SAEs to the entire study period; Noted that laboratory staff is blinded to treatment allocation and also the stratification by age as (2 to 5 years, 6 to 11 years, and 12 to 14 years); and updated the time window for assessment of serious viscerotropic disease in-line with the update of the Guidelines for Assessing Viscerotropic and Neurotropic Adverse Events, and introduced the use of the WHO Verbal Autopsy Questionnaire.
    29 May 2013
    Modified the testing algorithm for the virological-confirmation by adding the dengue screen RT-PCR and the Simplexa RT-PCR, assessment of the CYD dengue vaccine in preventing symptomatic virologically-confirmed dengue cases; The study objectives was revised along with the addition of ‘Other Objectives’; The Hospital Phase was extended by 2 years to allow a 5-year follow-up period after the last vaccination; and the addition of use of neutralization antibody assays and analyses in addition to PRNT to characterize the immune response.
    25 Jan 2015
    Enhanced the surveillance system also known as the Surveillance Expansion Phase (SEP). The subjects who consented to SEP were actively followed for dengue case detection, and an additional visit (Vse) and blood sample at SEP requested . The trial objectives were modified to add other objectives and endpoints; to describe the occurrence of hospitalized VCD cases and severe VCD throughout SEP and entire trial duration and correlate immunogenicity profile as assessed by PRNT at post-dose 3 and/or at the time of SEP enrollment

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/25018116
    http://www.ncbi.nlm.nih.gov/pubmed/26614588
    http://www.ncbi.nlm.nih.gov/pubmed/26214039
    http://www.ncbi.nlm.nih.gov/pubmed/26639777
    http://www.ncbi.nlm.nih.gov/pubmed/27007959
    http://www.ncbi.nlm.nih.gov/pubmed/27414655
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