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    Clinical Trial Results:
    A Double-Blind, Efficacy and Safety Study of Duloxetine versus Placebo in the Treatment of Children and Adolescents with Generalized Anxiety Disorder

    Summary
    EudraCT number
    		 2017-001599-46
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    03 Jun 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Dec 2017
    First version publication date
    24 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    F1J-MC-HMGI
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01226511
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Eli Lilly and Company: 12929
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly,
    Scientific contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐285‐4559,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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
    03 Jun 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jun 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to find out if duloxetine [30-120 milligrams (mg)] given once a day by mouth for 10 weeks to children and adolescents, is better than placebo when treating Generalized Anxiety Disorder (GAD).
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Jun 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 206
    Country: Number of subjects enrolled
    Mexico: 52
    Country: Number of subjects enrolled
    South Africa: 23
    Worldwide total number of subjects
    281
    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)
    128
    Adolescents (12-17 years)
    144
    Adults (18-64 years)
    9
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All Randomized participants from one site were excluded from this results record. All randomized participants from this site were not considered as part of the ITT population & were excluded from Subject Disposition, Baseline characteristics, efficacy and safety analyses due to major quality issues at that site.

    Pre-assignment
    Screening details
    		 This study had 4 periods: Screening period (1-week), acute treatment period (10-week, double-blind period with flexible duloxetine dosing), extension treatment (18-week period, of which 16 weeks were open-label treatment with flexible duloxetine dosing), and a taper period (2 weeks recommended at discontinuation from study any point after Week 2).

    Period 1
    Period 1 title
    Acute Treatment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Duloxetine/Duloxetine
    Arm description
    		 Participants received flexible doses of duloxetine 30 to 120 milligrams (mg) orally, once daily (QD) for 10 weeks during the acute treatment period and flexible doses of duloxetine 30 to 120 mg orally, QD for 18 weeks during the optional extension treatment period. Duloxetine was provided in 30-mg capsules. Participants who received higher doses of duloxetine at the end of treatment period participation received gradually lower doses of duloxetine over the 2-week recommended tapering period, and participants who received the lowest dose of duloxetine or placebo at the end of treatment period participation received placebo over the 2-week recommended tapering period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Duloxetine
    Investigational medicinal product code
    Other name
    LY248686, Cymbalta
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    30 to 120 Duloxetine mg administered orally.

    Arm title
    		 Placebo/Duloxetine
    Arm description
    		 Participants received placebo capsules orally, QD for 10 weeks during the acute treatment period and flexible doses of duloxetine 30 to 120 mg orally, QD for 18 weeks during the optional extension treatment period. Duloxetine was provided in 30-mg capsules. Participants who received higher doses of duloxetine at the end of treatment period participation received gradually lower doses of duloxetine over the 2-week recommended tapering period, and participants who received the lowest dose of duloxetine or placebo at the end of treatment period participation received placebo over the 2-week recommended tapering period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo administered orally.

    Number of subjects in period 1 [1]
    		Duloxetine/Duloxetine Placebo/Duloxetine
    Started
    135
    137
    Completed
    104
    106
    Not completed
    31
    31
         Parent/Caregiver Decision
    4
    7
         Consent withdrawn by subject
    10
    6
         Adverse event, non-fatal
    7
    6
         Lost to follow-up
    3
    6
         Lack of efficacy
    2
    1
         Protocol deviation
    5
    5
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 39 in Duloxetine/Duloxetine group & 35 Participants in Placebo/Duloxetine group who completed extension treatment period did not enter the taper period.
    Period 2
    Period 2 title
    Extension Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    18-week treatment period of which 16 weeks were open-label.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Duloxetine/Duloxetine
    Arm description
    		 Participants received flexible doses of duloxetine 30 to 120 milligrams (mg) orally, once daily (QD) for 10 weeks during the acute treatment period and flexible doses of duloxetine 30 to 120 mg orally, QD for 18 weeks during the optional extension treatment period. Duloxetine was provided in 30-mg capsules. Participants who received higher doses of duloxetine at the end of treatment period participation received gradually lower doses of duloxetine over the 2-week recommended tapering period, and participants who received the lowest dose of duloxetine or placebo at the end of treatment period participation received placebo over the 2-week recommended tapering period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Duloxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    30 to 120 mg administered orally.

    Arm title
    		 Placebo/Duloxetine
    Arm description
    		 Participants received placebo capsules orally, QD for 10 weeks during the acute treatment period and flexible doses of duloxetine 30 to 120 mg orally, QD for 18 weeks during the optional extension treatment period. Duloxetine was provided in 30-mg capsules. Participants who received higher doses of duloxetine at the end of treatment period participation received gradually lower doses of duloxetine over the 2-week recommended tapering period, and participants who received the lowest dose of duloxetine or placebo at the end of treatment period participation received placebo over the 2-week recommended tapering period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Duloxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    30 to 120 mg administered orally.

    Number of subjects in period 2
    		Duloxetine/Duloxetine Placebo/Duloxetine
    Started
    104
    106
    Completed
    79
    81
    Not completed
    25
    25
         Parent/Caregiver Decision
    7
    8
         Consent withdrawn by subject
    1
    3
         Adverse event, non-fatal
    8
    7
         Lost to follow-up
    4
    3
         Lack of efficacy
    3
    2
         Protocol deviation
    2
    2
    Period 3
    Period 3 title
    Taper Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Duloxetine/Duloxetine
    Arm description
    		 Participants received flexible doses of duloxetine 30 to 120 milligrams (mg) orally, once daily (QD) for 10 weeks during the acute treatment period and flexible doses of duloxetine 30 to 120 mg orally, QD for 18 weeks during the optional extension treatment period. Duloxetine was provided in 30-mg capsules. Participants who received higher doses of duloxetine at the end of treatment period participation received gradually lower doses of duloxetine over the 2-week recommended tapering period, and participants who received the lowest dose of duloxetine or placebo at the end of treatment period participation received placebo over the 2-week recommended tapering period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Duloxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    30 to 120 mg administered orally.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo administered orally.

    Arm title
    		 Placebo/Duloxetine
    Arm description
    		 Participants received placebo capsules orally, QD for 10 weeks during the acute treatment period and flexible doses of duloxetine 30 to 120 mg orally, QD for 18 weeks during the optional extension treatment period. Duloxetine was provided in 30-mg capsules. Participants who received higher doses of duloxetine at the end of treatment period participation received gradually lower doses of duloxetine over the 2-week recommended tapering period, and participants who received the lowest dose of duloxetine or placebo at the end of treatment period participation received placebo over the 2-week recommended tapering period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Duloxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    30 to 120 mg administered orally.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo administered orally.

    Number of subjects in period 3 [2]
    		Duloxetine/Duloxetine Placebo/Duloxetine
    Started
    49
    55
    Completed
    44
    52
    Not completed
    5
    3
         Parent/Caregiver Decision
    1
    1
         Adverse event, non-fatal
    1
    -
         Lost to follow-up
    2
    2
         Protocol deviation
    1
    -
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 39 in Duloxetine/Duloxetine group & 35 Participants in Placebo/Duloxetine group who completed extension treatment period did not enter the taper period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Duloxetine/Duloxetine
    Reporting group description
    		 Participants received flexible doses of duloxetine 30 to 120 milligrams (mg) orally, once daily (QD) for 10 weeks during the acute treatment period and flexible doses of duloxetine 30 to 120 mg orally, QD for 18 weeks during the optional extension treatment period. Duloxetine was provided in 30-mg capsules. Participants who received higher doses of duloxetine at the end of treatment period participation received gradually lower doses of duloxetine over the 2-week recommended tapering period, and participants who received the lowest dose of duloxetine or placebo at the end of treatment period participation received placebo over the 2-week recommended tapering period.

    Reporting group title
    Placebo/Duloxetine
    Reporting group description
    		 Participants received placebo capsules orally, QD for 10 weeks during the acute treatment period and flexible doses of duloxetine 30 to 120 mg orally, QD for 18 weeks during the optional extension treatment period. Duloxetine was provided in 30-mg capsules. Participants who received higher doses of duloxetine at the end of treatment period participation received gradually lower doses of duloxetine over the 2-week recommended tapering period, and participants who received the lowest dose of duloxetine or placebo at the end of treatment period participation received placebo over the 2-week recommended tapering period.

    Reporting group values
    		 Duloxetine/Duloxetine Placebo/Duloxetine Total
    Number of subjects
    		 135 137 272
    Age, Customized
    Units: participants
        7 - 11 Years
    		 62 66 128
        12 - 17 Years
    		 73 71 144
    Age continuous
    Units:
        
    		12.55 ( 2.596 ) 12.2 ( 2.904 ) -
    Gender, Male/Female
    Units:
        Male
    		 65 62 127
        Female
    		 70 75 145
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 7 6 13
        Asian
    		 1 1 2
        Black or African American
    		 9 10 19
        White
    		 112 111 223
        More than one race
    		 6 9 15
    Region of Enrollment
    Units: Subjects
        United States
    		 98 99 197
        Mexico
    		 26 26 52
        South Africa
    		 11 12 23

    End points

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    End points reporting groups
    Reporting group title
    Duloxetine/Duloxetine
    Reporting group description
    		 Participants received flexible doses of duloxetine 30 to 120 milligrams (mg) orally, once daily (QD) for 10 weeks during the acute treatment period and flexible doses of duloxetine 30 to 120 mg orally, QD for 18 weeks during the optional extension treatment period. Duloxetine was provided in 30-mg capsules. Participants who received higher doses of duloxetine at the end of treatment period participation received gradually lower doses of duloxetine over the 2-week recommended tapering period, and participants who received the lowest dose of duloxetine or placebo at the end of treatment period participation received placebo over the 2-week recommended tapering period.

    Reporting group title
    Placebo/Duloxetine
    Reporting group description
    		 Participants received placebo capsules orally, QD for 10 weeks during the acute treatment period and flexible doses of duloxetine 30 to 120 mg orally, QD for 18 weeks during the optional extension treatment period. Duloxetine was provided in 30-mg capsules. Participants who received higher doses of duloxetine at the end of treatment period participation received gradually lower doses of duloxetine over the 2-week recommended tapering period, and participants who received the lowest dose of duloxetine or placebo at the end of treatment period participation received placebo over the 2-week recommended tapering period.
    Reporting group title
    Duloxetine/Duloxetine
    Reporting group description
    		 Participants received flexible doses of duloxetine 30 to 120 milligrams (mg) orally, once daily (QD) for 10 weeks during the acute treatment period and flexible doses of duloxetine 30 to 120 mg orally, QD for 18 weeks during the optional extension treatment period. Duloxetine was provided in 30-mg capsules. Participants who received higher doses of duloxetine at the end of treatment period participation received gradually lower doses of duloxetine over the 2-week recommended tapering period, and participants who received the lowest dose of duloxetine or placebo at the end of treatment period participation received placebo over the 2-week recommended tapering period.

    Reporting group title
    Placebo/Duloxetine
    Reporting group description
    		 Participants received placebo capsules orally, QD for 10 weeks during the acute treatment period and flexible doses of duloxetine 30 to 120 mg orally, QD for 18 weeks during the optional extension treatment period. Duloxetine was provided in 30-mg capsules. Participants who received higher doses of duloxetine at the end of treatment period participation received gradually lower doses of duloxetine over the 2-week recommended tapering period, and participants who received the lowest dose of duloxetine or placebo at the end of treatment period participation received placebo over the 2-week recommended tapering period.
    Reporting group title
    Duloxetine/Duloxetine
    Reporting group description
    		 Participants received flexible doses of duloxetine 30 to 120 milligrams (mg) orally, once daily (QD) for 10 weeks during the acute treatment period and flexible doses of duloxetine 30 to 120 mg orally, QD for 18 weeks during the optional extension treatment period. Duloxetine was provided in 30-mg capsules. Participants who received higher doses of duloxetine at the end of treatment period participation received gradually lower doses of duloxetine over the 2-week recommended tapering period, and participants who received the lowest dose of duloxetine or placebo at the end of treatment period participation received placebo over the 2-week recommended tapering period.

    Reporting group title
    Placebo/Duloxetine
    Reporting group description
    		 Participants received placebo capsules orally, QD for 10 weeks during the acute treatment period and flexible doses of duloxetine 30 to 120 mg orally, QD for 18 weeks during the optional extension treatment period. Duloxetine was provided in 30-mg capsules. Participants who received higher doses of duloxetine at the end of treatment period participation received gradually lower doses of duloxetine over the 2-week recommended tapering period, and participants who received the lowest dose of duloxetine or placebo at the end of treatment period participation received placebo over the 2-week recommended tapering period.

    Subject analysis set title
    Duloxetine (Acute Treatment)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received flexible doses of duloxetine 30 to 120 milligrams (mg) orally, once daily (QD) for 10 weeks during the acute treatment period.

    Subject analysis set title
    Placebo (Acute Treatment)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received placebo capsules orally, QD for 10 weeks during the acute treatment period.

    Subject analysis set title
    Duloxetine (Acute Treatment)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received flexible doses of duloxetine 30 to 120 milligrams (mg) orally, once daily (QD) for 10 weeks during the acute treatment period.

    Subject analysis set title
    Placebo (Acute Treatment)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received placebo capsules orally, QD for 10 weeks during the acute treatment period.

    Subject analysis set title
    Placebo (Acute Treatment)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received placebo capsules orally, QD for 10 weeks during the acute treatment period.

    Subject analysis set title
    Duloxetine/Duloxetine (Extension Treatment)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received flexible doses of duloxetine 30 to 120 milligrams (mg) orally, once daily (QD) for 10 weeks during the acute treatment period and flexible doses of duloxetine 30 to 120 mg orally, QD for 18 weeks during the optional extension treatment period.

    Subject analysis set title
    Placebo/Duloxetine (Extension Treatment)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received placebo capsules orally, QD for 10 weeks during the acute treatment period and flexible doses of duloxetine 30 to 120 mg orally, QD for 18 weeks during the optional extension treatment period.

    Subject analysis set title
    Duloxetine/Duloxetine (Extension Treatment)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received flexible doses of duloxetine 30 to 120 milligrams (mg) orally, once daily (QD) for 10 weeks during the acute treatment period and flexible doses of duloxetine 30 to 120 mg orally, QD for 18 weeks during the optional extension treatment period.

    Primary: Change from Baseline to 10-Week Endpoint in the Pediatric Anxiety Rating Scale (PARS) Severity Score Evaluated for Symptoms Identified on the Generalized Anxiety Subsection of the PARS Symptom Checklist

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    End point title
    		 Change from Baseline to 10-Week Endpoint in the Pediatric Anxiety Rating Scale (PARS) Severity Score Evaluated for Symptoms Identified on the Generalized Anxiety Subsection of the PARS Symptom Checklist
    End point description
    PARS severity score for GAD was assessed for all symptoms identified in the generalized anxiety section of the PARS symptom checklist. PARS severity score for GAD was derived by summing 5 of 7 severity/impairment/interference items (2, 3, 5, 6, 7); each item ranged from 0 (none) to 5 (extreme severity/impairment/interference). PARS severity scores for GAD ranged from 0 (none) to 25 (extreme severity), with a score of 15 indicating moderate illness severity. Least squares (LS) mean was calculated using a mixed-effects model repeated measures (MMRM) approach adjusted for baseline, pooled investigator, age category, visit, treatment, treatment*visit, age category*visit, and baseline*visit. Analysis Population Description: Randomized participants with a baseline and at least 1 post-baseline PARS severity score for GAD during the acute treatment period, excluding 9 participants from 1 site with major quality issues.
    End point type
    Primary
    End point timeframe
    Baseline, 10 weeks
    End point values
    		 Duloxetine (Acute Treatment) Placebo (Acute Treatment)
    Number of subjects analysed
    135
    133
    Units: units on a scale
        least squares mean (standard error)
    -9.7 ( 0.502 )
    -7.05 ( 0.5 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Duloxetine (Acute Treatment) v Placebo (Acute Treatment)
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    -2.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.03
         upper limit
    		 -1.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.7

    Secondary: Response Rate at Endpoint for Generalized Anxiety Disorder (GAD) Using Pediatric Anxiety Rating Scale (PARS) Severity Score for GAD

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    End point title
    		 Response Rate at Endpoint for Generalized Anxiety Disorder (GAD) Using Pediatric Anxiety Rating Scale (PARS) Severity Score for GAD
    End point description
    Response rate was defined as the percentage of participants having a 50% improvement from baseline to endpoint on the PARS severity score for GAD. PARS severity score for GAD was assessed for all symptoms identified in the generalized anxiety section of the PARS symptom checklist. PARS severity score for GAD was derived by summing 5 of 7 severity/impairment/interference items (2, 3, 5, 6, 7); each item ranged from 0 (none) to 5 (extreme severity/impairment/interference). PARS severity scores for GAD ranged from 0 (none) to 25 (extreme severity), with a score of 15 indicating moderate illness severity. Analysis Population Description: Randomized participants with a baseline and at least 1 post-baseline PARS severity score for GAD [last observation carried forward (LOCF)] during the acute treatment period, excluding 9 participants from 1 site with major quality issues.
    End point type
    Secondary
    End point timeframe
    Baseline, 10 weeks
    End point values
    		 Duloxetine (Acute Treatment) Placebo (Acute Treatment)
    Number of subjects analysed
    135
    133
    Units: percentage of participants
        number (not applicable)
    51
    37
    No statistical analyses for this end point

    Secondary: Change from Baseline to 10-Week Endpoint on the Pediatric Anxiety Rating Scale (PARS) Severity Total Score Evaluated for All Symptoms Identified on the PARS Symptom Checklist

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    End point title
    		 Change from Baseline to 10-Week Endpoint on the Pediatric Anxiety Rating Scale (PARS) Severity Total Score Evaluated for All Symptoms Identified on the PARS Symptom Checklist
    End point description
    PARS severity total score was assessed for all symptoms identified on the PARS symptom checklist. PARS severity total score was derived by summing 5 of 7 severity/impairment/interference items (2, 3, 5, 6, 7); each item ranged from 0 (none) to 5 (extreme severity/impairment/interference). PARS severity total scores ranged from 0 (none) to 25 (extreme severity), with a score of 15 indicating moderate illness severity. Least squares (LS) mean was calculated using a mixed-effects model repeated measures (MMRM) approach adjusted for treatment, pooled investigator, visit, baseline, age category, treatment*visit, baseline*visit, and age category*visit. Analysis Population Description: Randomized participants with a baseline and at least 1 post-baseline PARS severity total score during the acute treatment period, excluding 9 participants from 1 site with major quality issues.
    End point type
    Secondary
    End point timeframe
    Baseline, 10 weeks
    End point values
    		 Duloxetine (Acute Treatment) Placebo (Acute Treatment)
    Number of subjects analysed
    135
    133
    Units: units on a scale
        least squares mean (standard error)
    -9.15 ( 0.479 )
    -6.36 ( 0.477 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to 10-Week Endpoint on the Clinical Global Impression of Severity (CGI-S) Scale

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    End point title
    		 Change from Baseline to 10-Week Endpoint on the Clinical Global Impression of Severity (CGI-S) Scale
    End point description
    The CGI-S scale evaluated the severity of illness at the time of assessment. Scores ranged from 1 (normal, not at all ill) to 7 (among the most extremely ill). Higher scores indicated a greater severity of illness. Least squares (LS) mean was calculated using a mixed-effects model repeated measures (MMRM) approach adjusted for treatment, pooled investigator, visit, baseline, age category, treatment*visit, baseline*visit, and age category*visit. Analysis Population Description: Randomized participants with a baseline and at least 1 post-baseline CGI-S score during the acute treatment period, excluding 9 participants from 1 site with major quality issues.
    End point type
    Secondary
    End point timeframe
    Baseline, 10 weeks
    End point values
    		 Duloxetine (Acute Treatment) Placebo (Acute Treatment)
    Number of subjects analysed
    135
    133
    Units: units on a scale
        least squares mean (standard error)
    -1.93 ( 0.114 )
    -1.38 ( 0.113 )
    No statistical analyses for this end point

    Secondary: Remission Rate at Endpoint for generalized anxiety disorder (GAD) Using Clinical Global Impressions of Severity (CGI-S) Scale

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    End point title
    		 Remission Rate at Endpoint for generalized anxiety disorder (GAD) Using Clinical Global Impressions of Severity (CGI-S) Scale
    End point description
    Remission rate was defined as the percentage of participants having a CGI-S score ≤2 at endpoint. The CGI-S scale evaluated the severity of illness at the time of assessment. Scores ranged from 1 (normal, not at all ill) to 7 (among the most extremely ill). Higher scores indicated a greater severity of illness. Analysis Population Description: Randomized participants with at least 1 post-baseline CGI-S score [last observation carried forward (LOCF)] during the acute treatment period, excluding 9 participants from 1 site with major quality issues.
    End point type
    Secondary
    End point timeframe
    10 weeks
    End point values
    		 Duloxetine (Acute Treatment) Placebo (Acute Treatment)
    Number of subjects analysed
    135
    133
    Units: percentage of participants
        number (not applicable)
    45
    30
    No statistical analyses for this end point

    Secondary: Change from Baseline to 10-Week Endpoint in the Children's Global Assessment Scale (CGAS)

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    End point title
    		 Change from Baseline to 10-Week Endpoint in the Children's Global Assessment Scale (CGAS)
    End point description
    The CGAS was a clinician-rated assessment of general functioning. CGAS raw scores ranged from 1 (greatest impairment) to 100 (superior functioning). Lower scores indicated a lower level of functioning and greater impairment. Least squares (LS) mean from an analysis of covariance (ANCOVA) was adjusted for treatment, pooled investigator, baseline, and age category. Analysis Population Description: Randomized participants with a baseline and at least 1 post-baseline [last observation carried forward (LOCF)] CGAS score during the acute treatment period, excluding 9 participants from 1 site with major quality issues.
    End point type
    Secondary
    End point timeframe
    Baseline, 10 weeks
    End point values
    		 Duloxetine (Acute Treatment) Placebo (Acute Treatment)
    Number of subjects analysed
    123
    124
    Units: units on a scale
        least squares mean (standard error)
    17.14 ( 1.232 )
    12.16 ( 1.219 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants During the 10-Week Period with Treatment-Emergent (New or Worsening) Suicidal Ideation as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)

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    End point title
    		 Percentage of Participants During the 10-Week Period with Treatment-Emergent (New or Worsening) Suicidal Ideation as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)
    End point description
    The C-SSRS captured occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation: a "yes" answer to any 1 of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation. Results reported as percentage of participants with treatment-emergent (new or worsening) suicidal ideation from baseline=(number of participants with changes compared to baseline/total number of participants at risk)*100. Analysis Population Description: Randomized participants with a baseline and at least 1 post-baseline C-SSRS suicidal ideation score during the acute treatment period, whose baseline maximum C-SSRS suicidal ideation score was <5. Nine (9) participants from 1 site with major quality issues were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline up to 10 weeks
    End point values
    		 Duloxetine (Acute Treatment) Placebo (Acute Treatment)
    Number of subjects analysed
    135
    134
    Units: percentage of participants
        number (not applicable)
    5.9
    5.2
    No statistical analyses for this end point

    Secondary: Percentage of Participants During the 10-Week Period with Treatment-Emergent (New or Worsening) Suicidal Behavior as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)

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    End point title
    		 Percentage of Participants During the 10-Week Period with Treatment-Emergent (New or Worsening) Suicidal Behavior as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)
    End point description
    The C-SSRS captured occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal behavior: a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Reported as percentage of participants with treatment-emergent (new or worsening) suicidal behavior from baseline=(number of participants with changes compared to baseline/total number of participants at risk)*100. Analysis Population Description: Randomized participants with a baseline and at least 1 post-baseline C-SSRS suicidal behavior score during the acute treatment period, excluding 9 participants from 1 site with major quality issues.
    End point type
    Secondary
    End point timeframe
    Baseline up to 10 weeks
    End point values
    		 Duloxetine (Acute Treatment) Placebo (Acute Treatment)
    Number of subjects analysed
    135
    134
    Units: percentage of participants
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Change from 10-Week to 28-Week Endpoint in the Pediatric Anxiety Rating Scale (PARS) Severity Score Evaluated for Symptoms Identified on the Generalized Anxiety Subsection of the PARS Symptom Checklist

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    End point title
    		 Change from 10-Week to 28-Week Endpoint in the Pediatric Anxiety Rating Scale (PARS) Severity Score Evaluated for Symptoms Identified on the Generalized Anxiety Subsection of the PARS Symptom Checklist
    End point description
    PARS severity score for GAD was assessed for all symptoms identified in the generalized anxiety section of the PARS symptom checklist. PARS severity score for GAD was derived by summing 5 of 7 severity/impairment/interference items (2, 3, 5, 6, 7); each item ranged from 0 (none) to 5 (extreme severity/impairment/interference). PARS severity scores for GAD ranged from 0 (none) to 25 (extreme severity), with a score of 15 indicating moderate illness severity. Least squares (LS) mean was calculated using a mixed-effects model repeated measures (MMRM) approach adjusted for pooled investigator, visit, baseline, age category, baseline*visit, and age category*visit within reporting groups. Analysis Population Description: Randomized participants with a PARS severity score for GAD during the acute treatment period and at least 1 PARS severity score for GAD during the extension treatment period, excluding 9 participants from 1 site with major quality issues.
    End point type
    Secondary
    End point timeframe
    10 weeks, 28 weeks
    End point values
    		 Duloxetine/Duloxetine Placebo/Duloxetine
    Number of subjects analysed
    104
    105
    Units: units on a scale
        least squares mean (standard error)
    -3.33 ( 0.352 )
    -5.15 ( 0.452 )
    No statistical analyses for this end point

    Secondary: Change from 10-Week to 28-Week Endpoint on the Pediatric Anxiety Rating Scale (PARS) Severity Total Score Evaluated for All Symptoms Identified on the PARS Symptom ChecklistSymptoms

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    End point title
    		 Change from 10-Week to 28-Week Endpoint on the Pediatric Anxiety Rating Scale (PARS) Severity Total Score Evaluated for All Symptoms Identified on the PARS Symptom ChecklistSymptoms
    End point description
    PARS severity total score was assessed for all symptoms identified on the PARS symptom checklist. PARS severity total score was derived by summing 5 of 7 severity/impairment/interference items (2, 3, 5, 6, 7); each item ranged from 0 (none) to 5 (extreme severity/impairment/interference). PARS severity total scores ranged from 0 (none) to 25 (extreme severity), with a score of 15 indicating moderate illness severity. Least squares (LS) mean was calculated using a mixed-effects model repeated measures (MMRM) approach adjusted for pooled investigator, visit, baseline, age category, baseline*visit, and age category*visit within reporting groups. Analysis Population Description: Randomized participants with a PARS severity total score during the acute treatment period and at least 1 PARS severity total score during the extension treatment period, excluding 9 participants from 1 site with major quality issues.
    End point type
    Secondary
    End point timeframe
    10 weeks, 28 weeks
    End point values
    		 Duloxetine/Duloxetine Placebo/Duloxetine
    Number of subjects analysed
    104
    105
    Units: units on a scale
        least squares mean (standard error)
    -3.32 ( 0.357 )
    -5.26 ( 0.432 )
    No statistical analyses for this end point

    Secondary: Change from 10-Week to 28-Week Endpoint on the Clinical Global Impression of Severity (CGI-S) Scale

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    End point title
    		 Change from 10-Week to 28-Week Endpoint on the Clinical Global Impression of Severity (CGI-S) Scale
    End point description
    The CGI-S scale evaluated the severity of mental illness at the time of assessment. Scores ranged from 1 (normal, not at all ill) to 7 (among the most extremely ill). Higher scores indicated a greater severity of illness. Least squares (LS) mean was calculated using a mixed-effects model repeated measures (MMRM) approach adjusted for pooled investigator, visit, baseline, age category, baseline*visit, and age category*visit within reporting groups. Analysis Population Description: Randomized participants with a CGI-S score during the acute treatment period and at least 1 CGI-S score during the extension treatment period, excluding 9 participants from 1 site with major quality issues.
    End point type
    Secondary
    End point timeframe
    10 weeks, 28 weeks
    End point values
    		 Duloxetine/Duloxetine Placebo/Duloxetine
    Number of subjects analysed
    104
    105
    Units: units on a scale
        least squares mean (standard error)
    -0.76 ( 0.093 )
    -1.17 ( 0.088 )
    No statistical analyses for this end point

    Secondary: Change from 10-Week to 28-Week Endpoint in the Children's Global Assessment Scale (CGAS)

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    End point title
    		 Change from 10-Week to 28-Week Endpoint in the Children's Global Assessment Scale (CGAS)
    End point description
    The CGAS was a clinician-rated assessment of general functioning. CGAS raw scores ranged from 1 (greatest impairment) to 100 (superior functioning). Lower scores indicated a lower level of functioning and greater impairment. Least squares (LS) mean from an analysis of covariance (ANCOVA) was adjusted for pooled investigator, baseline, and age category within reporting groups. Analysis Population Description: Randomized participants with a CGAS score during the acute treatment period and at least 1 CGAS score during the extension treatment period [last observation carried forward (LOCF)], excluding 9 participants from 1 site with major quality issues.
    End point type
    Secondary
    End point timeframe
    10 weeks, 28 weeks
    End point values
    		 Duloxetine/Duloxetine Placebo/Duloxetine
    Number of subjects analysed
    103
    105
    Units: units on a scale
        least squares mean (standard error)
    7.32 ( 1.19 )
    10.48 ( 1.03 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants During the 18-Week Extension Period with Treatment-Emergent (New or Worsening) Suicidal Ideation as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)

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    End point title
    		 Percentage of Participants During the 18-Week Extension Period with Treatment-Emergent (New or Worsening) Suicidal Ideation as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)
    End point description
    The C-SSRS captured occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation: a "yes" answer to any 1 of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation. Results reported as percentage of participants with treatment-emergent (new or worsening) suicidal ideation from baseline=(number of participants with changes compared to baseline/total number of participants at risk)*100. Analysis Population Description: Randomized participants with a C-SSRS suicidal ideation score <5 at the last 2 visits in the acute treatment period and at least 1 C-SSRS suicidal ideation score during the extension treatment period. Nine (9) participants from 1 site with major quality issues were excluded.
    End point type
    Secondary
    End point timeframe
    10 weeks up to 28 weeks
    End point values
    		 Duloxetine/Duloxetine Placebo/Duloxetine
    Number of subjects analysed
    104
    105
    Units: percentage of participants
        number (not applicable)
    3
    3
    No statistical analyses for this end point

    Secondary: Percentage of Participants During the 18-Week Extension Period with Treatment-Emergent (New or Worsening) Suicidal Behavior as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)

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    End point title
    		 Percentage of Participants During the 18-Week Extension Period with Treatment-Emergent (New or Worsening) Suicidal Behavior as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)
    End point description
    The C-SSRS captured occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal behavior: a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Reported as percentage of participants with treatment-emergent (new or worsening) suicidal behavior from baseline=(number of participants with changes compared to baseline/total number of participants at risk)*100. Analysis Population Description: Randomized participants with a C-SSRS suicidal behavior score at the last 2 visits in the acute treatment period and at least 1 C-SSRS suicidal behavior score during the extension treatment period, excluding 9 participants from 1 site with major quality issues.
    End point type
    Secondary
    End point timeframe
    10 weeks up to 28 weeks
    End point values
    		 Duloxetine/Duloxetine Placebo/Duloxetine
    Number of subjects analysed
    104
    105
    Units: percentage of participants
        number (not applicable)
    0
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire Study
    Adverse event reporting additional description
    F1J-MC-HMGI
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Duloxetine-Acute
    Reporting group description
    		 Adverse events (AEs) during the acute treatment period for participants who received flexible doses of duloxetine 30 to 120 milligrams (mg) orally, once daily (QD) for 10 weeks.

    Reporting group title
    Placebo-Acute
    Reporting group description
    		 AEs during the acute treatment period for participants who received placebo capsules orally, QD for 10 weeks.

    Reporting group title
    Duloxetine-Extension
    Reporting group description
    		 AEs during the extension treatment period for participants who received flexible doses of duloxetine 30 to 120 mg orally, QD during both the acute and extension treatment periods (up to 28 weeks).

    Reporting group title
    Placebo/Duloxetine-Extension
    Reporting group description
    		 AEs during the extension treatment period for participants who received placebo capsules orally, QD during the acute treatment period (10 weeks) and flexible doses of duloxetine 30 to 120 mg orally, QD during the extension treatment period (up to 18 weeks).

    Reporting group title
    Duloxetine-Taper
    Reporting group description
    		 AEs during the taper period for participants who were dispensed duloxetine prior to entering the taper phase. Participants who received higher doses of duloxetine at the end of treatment period participation received gradually lower doses of duloxetine over the 2-week recommended tapering period.

    Reporting group title
    Placebo-Taper
    Reporting group description
    		 AEs during the taper period for participants who were dispensed placebo prior to entering the taper phase. Participants who received the lowest dose of duloxetine or placebo at the end of treatment period participation received placebo over the 2-week recommended tapering period.

    Serious adverse events
    		 Duloxetine-Acute Placebo-Acute Duloxetine-Extension Placebo/Duloxetine-Extension Duloxetine-Taper Placebo-Taper
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    2 / 104 (1.92%)
    2 / 106 (1.89%)
    1 / 97 (1.03%)
    1 / 7 (14.29%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    acute psychosis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    bipolar disorder
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    self-injurious ideation
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    suicidal ideation
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    1 / 97 (1.03%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    adenoiditis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    tonsillitis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Duloxetine-Acute Placebo-Acute Duloxetine-Extension Placebo/Duloxetine-Extension Duloxetine-Taper Placebo-Taper
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    106 / 135 (78.52%)
    90 / 137 (65.69%)
    73 / 104 (70.19%)
    73 / 106 (68.87%)
    12 / 97 (12.37%)
    1 / 7 (14.29%)
    Vascular disorders
    hot flush
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    3 / 106 (2.83%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    1
    0
    3
    0
    0
    hypotension
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    pallor
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Surgical and medical procedures
    tooth extraction
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    1 / 97 (1.03%)
    0 / 7 (0.00%)
         occurrences all number
    2
    1
    0
    0
    1
    0
    chest discomfort
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    1 / 104 (0.96%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    chest pain
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    3 / 135 (2.22%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    3
    0
    1
    0
    0
    0
    crying
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    1 / 97 (1.03%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    fatigue
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    11 / 135 (8.15%)
    6 / 137 (4.38%)
    4 / 104 (3.85%)
    9 / 106 (8.49%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    11
    6
    4
    9
    0
    0
    feeling abnormal
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    feeling cold
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    inflammation
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    inflammatory pain
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    influenza like illness
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    irritability
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    4 / 135 (2.96%)
    6 / 137 (4.38%)
    4 / 104 (3.85%)
    3 / 106 (2.83%)
    1 / 97 (1.03%)
    0 / 7 (0.00%)
         occurrences all number
    4
    6
    4
    3
    1
    0
    malaise
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    medical device pain
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    non-cardiac chest pain
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    oedema peripheral
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    pain
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    1 / 104 (0.96%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    pyrexia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    4 / 137 (2.92%)
    2 / 104 (1.92%)
    2 / 106 (1.89%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    5
    2
    2
    0
    0
    temperature intolerance
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    thirst
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Immune system disorders
    multiple allergies
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    seasonal allergy
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    2 / 104 (1.92%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Social circumstances
    educational problem
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Reproductive system and breast disorders
    breast mass
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    dysmenorrhoea
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed [1]
    2 / 70 (2.86%)
    2 / 75 (2.67%)
    0 / 104 (0.00%)
    2 / 59 (3.39%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    3
    2
    0
    2
    0
    0
    orchitis noninfective
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed [2]
    0 / 135 (0.00%)
    1 / 62 (1.61%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    ovarian cyst
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed [3]
    1 / 70 (1.43%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    vaginal haemorrhage
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed [4]
    1 / 70 (1.43%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    asthma
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    cough
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    6 / 135 (4.44%)
    0 / 137 (0.00%)
    4 / 104 (3.85%)
    5 / 106 (4.72%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    6
    0
    4
    5
    0
    0
    dyspnoea
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    3 / 135 (2.22%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    epistaxis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    1 / 137 (0.73%)
    2 / 104 (1.92%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    4
    1
    2
    0
    0
    0
    nasal congestion
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 137 (0.73%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    oropharyngeal pain
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    10 / 135 (7.41%)
    3 / 137 (2.19%)
    1 / 104 (0.96%)
    7 / 106 (6.60%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    10
    3
    1
    7
    0
    0
    pharyngeal inflammation
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    productive cough
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    respiratory tract congestion
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    rhinitis allergic
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    rhinorrhoea
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    sinus congestion
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    2 / 106 (1.89%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    2
    0
    0
    yawning
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    2 / 106 (1.89%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    Psychiatric disorders
    abnormal behaviour
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    0
    abnormal dreams
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    activation syndrome
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    affect lability
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    aggression
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    2 / 137 (1.46%)
    1 / 104 (0.96%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    1
    1
    0
    0
    agitation
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    1 / 97 (1.03%)
    0 / 7 (0.00%)
         occurrences all number
    2
    1
    0
    1
    1
    0
    anger
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    2 / 106 (1.89%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    2
    0
    0
    anxiety
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    apathy
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    attention deficit/hyperactivity disorder
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    bruxism
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    compulsive handwashing
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    depression
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    distractibility
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    fear
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    flat affect
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    impulsive behaviour
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    2 / 104 (1.92%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    initial insomnia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    insomnia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    12 / 135 (8.89%)
    7 / 137 (5.11%)
    1 / 104 (0.96%)
    3 / 106 (2.83%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    13
    8
    1
    3
    0
    0
    intentional self-injury
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 137 (0.73%)
    3 / 104 (2.88%)
    2 / 106 (1.89%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    3
    2
    0
    0
    Major depression
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    middle insomnia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    negativism
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    nervousness
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    nightmare
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    obsessive thoughts
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    onychophagia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    oppositional defiant disorder
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    panic attack
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    phobia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    psychotic disorder
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    self injurious behaviour
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    sexually inappropriate behaviour
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    sleep disorder
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    2 / 137 (1.46%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    sleep terror
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    suicidal ideation
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 137 (0.73%)
    2 / 104 (1.92%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    3
    1
    0
    0
    tic
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    withdrawal syndrome
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Investigations
    blood pressure increased
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    blood triglycerides increased
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    electrocardiogram qt prolonged
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    heart rate increased
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    neutrophil count increased
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    weight decreased
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    5 / 135 (3.70%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    2 / 106 (1.89%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    5
    1
    0
    2
    0
    0
    weight increased
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    3 / 137 (2.19%)
    2 / 104 (1.92%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    3
    2
    0
    0
    0
    white blood cell count increased
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    animal bite
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    ankle fracture
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    arthropod bite
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    arthropod sting
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    2 / 106 (1.89%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    bone contusion
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    burns first degree
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    1 / 97 (1.03%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    concussion
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    fall
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    fibula fracture
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    head injury
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    human bite
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    humerus fracture
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    joint dislocation
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    laceration
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    ligament sprain
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    2 / 104 (1.92%)
    2 / 106 (1.89%)
    1 / 97 (1.03%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    2
    1
    0
    limb injury
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    1 / 137 (0.73%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    1
    1
    0
    0
    0
    lip injury
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    muscle rupture
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    muscle strain
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 137 (0.73%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    post procedural swelling
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    procedural pain
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    road traffic accident
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    scratch
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    sunburn
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    tendon injury
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    thermal burn
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    upper limb fracture
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Cardiac disorders
    bundle branch block right
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    palpitations
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    6 / 135 (4.44%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    6
    0
    0
    0
    0
    0
    sinus arrhythmia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    sinus tachycardia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    tachycardia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Nervous system disorders
    disturbance in attention
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    1 / 137 (0.73%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    1
    1
    0
    0
    0
    dizziness
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    10 / 135 (7.41%)
    2 / 137 (1.46%)
    5 / 104 (4.81%)
    7 / 106 (6.60%)
    1 / 97 (1.03%)
    0 / 7 (0.00%)
         occurrences all number
    10
    2
    5
    9
    1
    0
    dizziness postural
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    dysgeusia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    dyskinesia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    headache
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    27 / 135 (20.00%)
    23 / 137 (16.79%)
    13 / 104 (12.50%)
    11 / 106 (10.38%)
    3 / 97 (3.09%)
    0 / 7 (0.00%)
         occurrences all number
    37
    29
    17
    13
    3
    0
    hypersomnia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 137 (0.73%)
    1 / 104 (0.96%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    1
    1
    0
    0
    hypoaesthesia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    2 / 104 (1.92%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    migraine
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    2 / 137 (1.46%)
    1 / 104 (0.96%)
    2 / 106 (1.89%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    1
    2
    0
    0
    myoclonus
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    paraesthesia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    3 / 137 (2.19%)
    0 / 104 (0.00%)
    2 / 106 (1.89%)
    1 / 97 (1.03%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    2
    1
    0
    poor quality sleep
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    post-traumatic headache
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    psychomotor hyperactivity
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    3 / 135 (2.22%)
    2 / 137 (1.46%)
    1 / 104 (0.96%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    3
    2
    1
    1
    0
    0
    sedation
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    3 / 135 (2.22%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    2 / 106 (1.89%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    3
    0
    0
    2
    0
    0
    somnolence
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    16 / 135 (11.85%)
    9 / 137 (6.57%)
    3 / 104 (2.88%)
    8 / 106 (7.55%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    16
    9
    4
    11
    0
    0
    tremor
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    4 / 135 (2.96%)
    1 / 137 (0.73%)
    2 / 104 (1.92%)
    2 / 106 (1.89%)
    1 / 97 (1.03%)
    0 / 7 (0.00%)
         occurrences all number
    4
    1
    2
    2
    1
    0
    Ear and labyrinth disorders
    ear pain
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    2 / 137 (1.46%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    0
    1
    0
    0
    motion sickness
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    tinnitus
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    vertigo
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    2 / 106 (1.89%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Eye disorders
    blepharospasm
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    blindness
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    conjunctival haemorrhage
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    eye pain
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    mydriasis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    strabismus
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    vision blurred
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    abdominal discomfort
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    3 / 135 (2.22%)
    4 / 137 (2.92%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    1 / 97 (1.03%)
    0 / 7 (0.00%)
         occurrences all number
    3
    4
    0
    0
    2
    0
    abdominal distension
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 137 (0.73%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    1
    0
    0
    0
    abdominal pain
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 137 (0.00%)
    2 / 104 (1.92%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    2
    2
    0
    0
    abdominal pain lower
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    2 / 137 (1.46%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    abdominal pain upper
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    13 / 135 (9.63%)
    9 / 137 (6.57%)
    5 / 104 (4.81%)
    7 / 106 (6.60%)
    2 / 97 (2.06%)
    0 / 7 (0.00%)
         occurrences all number
    15
    10
    6
    7
    2
    0
    aphthous stomatitis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    chapped lips
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    colitis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    2 / 106 (1.89%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    constipation
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    5 / 135 (3.70%)
    4 / 137 (2.92%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    6
    4
    0
    1
    0
    0
    diarrhoea
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    9 / 135 (6.67%)
    6 / 137 (4.38%)
    1 / 104 (0.96%)
    5 / 106 (4.72%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    10
    6
    3
    6
    0
    0
    dry mouth
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    1 / 137 (0.73%)
    1 / 104 (0.96%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    2
    1
    1
    0
    0
    dyspepsia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    2 / 104 (1.92%)
    1 / 106 (0.94%)
    1 / 97 (1.03%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    1
    1
    0
    eructation
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 137 (0.73%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    flatulence
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    food poisoning
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    frequent bowel movements
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    gastritis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    gingival pain
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    lip dry
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    mouth ulceration
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    nausea
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    28 / 135 (20.74%)
    8 / 137 (5.84%)
    10 / 104 (9.62%)
    13 / 106 (12.26%)
    1 / 97 (1.03%)
    0 / 7 (0.00%)
         occurrences all number
    35
    8
    10
    16
    1
    0
    odynophagia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    oral mucosal blistering
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    toothache
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    2 / 104 (1.92%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    0
    vomiting
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    22 / 135 (16.30%)
    10 / 137 (7.30%)
    5 / 104 (4.81%)
    6 / 106 (5.66%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    23
    10
    7
    6
    0
    0
    Skin and subcutaneous tissue disorders
    acne
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    alopecia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    dermatitis allergic
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    dermatitis contact
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 137 (0.00%)
    2 / 104 (1.92%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    0
    dry skin
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    erythema
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    hyperhidrosis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    3 / 135 (2.22%)
    1 / 137 (0.73%)
    1 / 104 (0.96%)
    2 / 106 (1.89%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    4
    2
    1
    4
    0
    0
    night sweats
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    petechiae
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    pruritus
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    1 / 104 (0.96%)
    2 / 106 (1.89%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    1
    4
    0
    0
    rash
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    2 / 137 (1.46%)
    1 / 104 (0.96%)
    4 / 106 (3.77%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    1
    4
    0
    0
    rash maculo-papular
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    rash papular
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    rash pruritic
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    urticaria
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    2 / 106 (1.89%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    0
    Renal and urinary disorders
    enuresis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    5
    0
    0
    hypertonic bladder
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    pollakiuria
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    urinary hesitation
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Endocrine disorders
    hypothyroidism
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    2 / 106 (1.89%)
    1 / 97 (1.03%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    2
    2
    0
    back pain
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    2 / 106 (1.89%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    2
    0
    0
    bone pain
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    flank pain
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    muscle spasms
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    muscle twitching
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    musculoskeletal pain
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    myalgia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    1 / 97 (1.03%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    neck pain
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    pain in extremity
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 137 (0.73%)
    2 / 104 (1.92%)
    2 / 106 (1.89%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    2
    2
    0
    0
    synovial cyst
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    temporomandibular joint syndrome
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Infections and infestations
    bronchitis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    4 / 135 (2.96%)
    4 / 137 (2.92%)
    2 / 104 (1.92%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    4
    4
    2
    1
    0
    0
    conjunctivitis infective
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    1 / 97 (1.03%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    ear infection
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    2 / 137 (1.46%)
    3 / 104 (2.88%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    3
    1
    0
    0
    fungal infection
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    gastroenteritis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 137 (0.73%)
    1 / 104 (0.96%)
    3 / 106 (2.83%)
    1 / 97 (1.03%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    1
    3
    1
    0
    gastroenteritis viral
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    4 / 135 (2.96%)
    2 / 137 (1.46%)
    1 / 104 (0.96%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    4
    2
    1
    1
    0
    0
    gastrointestinal infection
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    gastrointestinal viral infection
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    genital candidiasis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    hand-foot-and-mouth disease
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    herpes simplex
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    hordeolum
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    influenza
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    4 / 135 (2.96%)
    3 / 137 (2.19%)
    6 / 104 (5.77%)
    4 / 106 (3.77%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    4
    3
    6
    4
    0
    0
    labyrinthitis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    lower respiratory tract infection
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    nasopharyngitis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    4 / 135 (2.96%)
    12 / 137 (8.76%)
    4 / 104 (3.85%)
    5 / 106 (4.72%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    4
    13
    4
    5
    0
    0
    oral herpes
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    otitis externa
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    otitis media
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    pharyngitis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    3 / 135 (2.22%)
    1 / 137 (0.73%)
    2 / 104 (1.92%)
    2 / 106 (1.89%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    3
    1
    2
    2
    0
    0
    pharyngitis streptococcal
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    2 / 137 (1.46%)
    3 / 104 (2.88%)
    2 / 106 (1.89%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    3
    2
    0
    0
    pharyngotonsillitis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    2 / 137 (1.46%)
    1 / 104 (0.96%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    1
    1
    0
    0
    pneumonia
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    rhinitis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 137 (0.73%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    sinusitis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    4 / 137 (2.92%)
    6 / 104 (5.77%)
    5 / 106 (4.72%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    4
    6
    5
    0
    0
    skin infection
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    staphylococcal infection
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    tonsillitis
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    tooth infection
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    upper respiratory tract infection
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    4 / 137 (2.92%)
    3 / 104 (2.88%)
    2 / 106 (1.89%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    4
    4
    2
    0
    0
    urinary tract infection
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    2 / 137 (1.46%)
    3 / 104 (2.88%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    3
    0
    0
    0
    vaginitis bacterial
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed [5]
    1 / 70 (1.43%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    viral infection
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    2 / 137 (1.46%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    0
    1
    0
    0
    viral upper respiratory tract infection
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 137 (0.00%)
    0 / 104 (0.00%)
    1 / 106 (0.94%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    20 / 135 (14.81%)
    7 / 137 (5.11%)
    1 / 104 (0.96%)
    9 / 106 (8.49%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    21
    7
    1
    10
    0
    0
    dehydration
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 137 (0.00%)
    1 / 104 (0.96%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    increased appetite
    alternative dictionary used: MedDRA 16.0
         subjects affected / exposed
    2 / 135 (1.48%)
    4 / 137 (2.92%)
    0 / 104 (0.00%)
    0 / 106 (0.00%)
    0 / 97 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    4
    0
    0
    0
    0
    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: Gender specific event, total number exposed corresponds to only female subjects.
    [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: Gender specific event, total number exposed corresponds to only male subjects.
    [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: Gender specific event, total number exposed corresponds to only female subjects.
    [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: Gender specific event, total number exposed corresponds to only female subjects.
    [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: Gender specific event, total number exposed corresponds to only female subjects.

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Feb 2011
    Dose range was changed based on health authority recommendation.
    31 Jul 2012
    Statistical analysis sample size was changed.

    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.
    All Randomized participants from one site were excluded due to major quality issues at site; they were not considered part of ITT population and were excluded from the subject disposition, baseline characteristics, efficacy and safety analyses.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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