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    Clinical Trial Results:
    Phase I/IIa, 2-Part, Multi-Center, Single-Arm, Open-Label Study to Determine the Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib in Children and Adolescent Subjects with Advanced BRAF V600-Mutation Positive Solid Tumors

    Summary
    EudraCT number
    		 2012-001499-12
    Trial protocol
    		 GB   Outside EU/EEA   ES   DE   DK   IT  
    Global end of trial date
    04 Dec 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    26 Dec 2021
    First version publication date
    20 Jun 2021
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    116013
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01677741
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Novartis: CDRB436A2102
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001147-PIP01-11
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Dec 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Dec 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to determine the safe and tolerable dabrafenib dose(s) for chronic dosing in pediatric subjects (infants, children, and adolescents) that achieves similar exposures to the dabrafenib adult dose, in subjects with BRAF V600 mutation positive tumors
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 May 2013
    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
    Australia: 4
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 18
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United States: 31
    Worldwide total number of subjects
    85
    EEA total number of subjects
    27
    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)
    3
    Children (2-11 years)
    47
    Adolescents (12-17 years)
    35
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This study was conducted in 19 centers in eight participating countries: Australia (1), Canada (1), Denmark (1), Germany (1), France (4), Spain (1), United Kingdom (2), and United States (8).

    Pre-assignment
    Screening details
    		 Patients participated in only either Part 1 (Dose Escalation) or Part 2 (Tumor specific expansion) of the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg)
    Arm description
    		 Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    DRB436
    Pharmaceutical forms
    Dispersible tablet, Capsule, Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The study used both oral solid dose formulations as well as oral liquid dose formulations. The oral solid dose forms used were the approved adult formulations, dabrafenib 50 mg and 75 mg capsules, for children who were able to swallow capsules. Two lower strength capsules (10 mg and 25 mg) were also used initially but were discontinued during the course of the study. The total daily dose was not to exceed 300 mg (150 mg BID). The oral liquid formulation was initially a powder for oral suspension (stick pack) and was replaced by dispersible tablets for oral suspension during the course of the study. The oral liquid formulations were to be used by all subjects with difficulty swallowing solid dose forms or were at risk of choking.

    Arm title
    		 Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg)
    Arm description
    		 Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    DRB436
    Pharmaceutical forms
    Dispersible tablet, Capsule, Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The study used both oral solid dose formulations as well as oral liquid dose formulations. The oral solid dose forms used were the approved adult formulations, dabrafenib 50 mg and 75 mg capsules, for children who were able to swallow capsules. Two lower strength capsules (10 mg and 25 mg) were also used initially but were discontinued during the course of the study. The total daily dose was not to exceed 300 mg (150 mg BID). The oral liquid formulation was initially a powder for oral suspension (stick pack) and was replaced by dispersible tablets for oral suspension during the course of the study. The oral liquid formulations were to be used by all subjects with difficulty swallowing solid dose forms or were at risk of choking.

    Arm title
    		 Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg)
    Arm description
    		 Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    DRB436
    Pharmaceutical forms
    Dispersible tablet, Capsule, Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The study used both oral solid dose formulations as well as oral liquid dose formulations. The oral solid dose forms used were the approved adult formulations, dabrafenib 50 mg and 75 mg capsules, for children who were able to swallow capsules. Two lower strength capsules (10 mg and 25 mg) were also used initially but were discontinued during the course of the study. The total daily dose was not to exceed 300 mg (150 mg BID). The oral liquid formulation was initially a powder for oral suspension (stick pack) and was replaced by dispersible tablets for oral suspension during the course of the study. The oral liquid formulations were to be used by all subjects with difficulty swallowing solid dose forms or were at risk of choking.

    Arm title
    		 Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg)
    Arm description
    		 Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    DRB436
    Pharmaceutical forms
    Dispersible tablet, Capsule, Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The study used both oral solid dose formulations as well as oral liquid dose formulations. The oral solid dose forms used were the approved adult formulations, dabrafenib 50 mg and 75 mg capsules, for children who were able to swallow capsules. Two lower strength capsules (10 mg and 25 mg) were also used initially but were discontinued during the course of the study. The total daily dose was not to exceed 300 mg (150 mg BID). The oral liquid formulation was initially a powder for oral suspension (stick pack) and was replaced by dispersible tablets for oral suspension during the course of the study. The oral liquid formulations were to be used by all subjects with difficulty swallowing solid dose forms or were at risk of choking.

    Arm title
    		 Part 2 (Tumor specific expansion): Cohort 1 (LGG)
    Arm description
    		 Subjects with low-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    DRB436
    Pharmaceutical forms
    Dispersible tablet, Capsule, Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The study used both oral solid dose formulations as well as oral liquid dose formulations. The oral solid dose forms used were the approved adult formulations, dabrafenib 50 mg and 75 mg capsules, for children who were able to swallow capsules. Two lower strength capsules (10 mg and 25 mg) were also used initially but were discontinued during the course of the study. The total daily dose was not to exceed 300 mg (150 mg BID). The oral liquid formulation was initially a powder for oral suspension (stick pack) and was replaced by dispersible tablets for oral suspension during the course of the study. The oral liquid formulations were to be used by all subjects with difficulty swallowing solid dose forms or were at risk of choking.

    Arm title
    		 Part 2 (Tumor specific expansion): Cohort 2 (HGG)
    Arm description
    		 Subjects with high-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    DRB436
    Pharmaceutical forms
    Dispersible tablet, Capsule, Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The study used both oral solid dose formulations as well as oral liquid dose formulations. The oral solid dose forms used were the approved adult formulations, dabrafenib 50 mg and 75 mg capsules, for children who were able to swallow capsules. Two lower strength capsules (10 mg and 25 mg) were also used initially but were discontinued during the course of the study. The total daily dose was not to exceed 300 mg (150 mg BID). The oral liquid formulation was initially a powder for oral suspension (stick pack) and was replaced by dispersible tablets for oral suspension during the course of the study. The oral liquid formulations were to be used by all subjects with difficulty swallowing solid dose forms or were at risk of choking.

    Arm title
    		 Part 2 (Tumor specific expansion): Cohort 3 (LCH)
    Arm description
    		 Subjects with LCH with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    DRB436
    Pharmaceutical forms
    Dispersible tablet, Capsule, Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The study used both oral solid dose formulations as well as oral liquid dose formulations. The oral solid dose forms used were the approved adult formulations, dabrafenib 50 mg and 75 mg capsules, for children who were able to swallow capsules. Two lower strength capsules (10 mg and 25 mg) were also used initially but were discontinued during the course of the study. The total daily dose was not to exceed 300 mg (150 mg BID). The oral liquid formulation was initially a powder for oral suspension (stick pack) and was replaced by dispersible tablets for oral suspension during the course of the study. The oral liquid formulations were to be used by all subjects with difficulty swallowing solid dose forms or were at risk of choking.

    Arm title
    		 Part 2 (Tumor specific expansion): Cohort 4 (Other)
    Arm description
    		 Subjects with other tumors with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    DRB436
    Pharmaceutical forms
    Dispersible tablet, Capsule, Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The study used both oral solid dose formulations as well as oral liquid dose formulations. The oral solid dose forms used were the approved adult formulations, dabrafenib 50 mg and 75 mg capsules, for children who were able to swallow capsules. Two lower strength capsules (10 mg and 25 mg) were also used initially but were discontinued during the course of the study. The total daily dose was not to exceed 300 mg (150 mg BID). The oral liquid formulation was initially a powder for oral suspension (stick pack) and was replaced by dispersible tablets for oral suspension during the course of the study. The oral liquid formulations were to be used by all subjects with difficulty swallowing solid dose forms or were at risk of choking.

    Number of subjects in period 1
    		Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg) Part 2 (Tumor specific expansion): Cohort 1 (LGG) Part 2 (Tumor specific expansion): Cohort 2 (HGG) Part 2 (Tumor specific expansion): Cohort 3 (LCH) Part 2 (Tumor specific expansion): Cohort 4 (Other)
    Started
    3
    10
    8
    6
    17
    28
    11
    2
    DLT evaluable population
    3
    10
    8
    6
    0
    0
    0
    0
    PK population
    3
    10
    8
    6
    17
    28
    11
    2
    Completed
    0
    0
    0
    0
    0
    0
    0
    0
    Not completed
    3
    10
    8
    6
    17
    28
    11
    2
         Adverse event, serious fatal
    -
    -
    -
    1
    -
    1
    -
    -
         Consent withdrawn by subject
    2
    7
    5
    4
    11
    20
    4
    2
         Enrolled in a rollover study
    -
    3
    2
    1
    6
    6
    7
    -
         Progressive disease
    1
    -
    1
    -
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg)
    Reporting group description
    		 Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.

    Reporting group title
    Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg)
    Reporting group description
    		 Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.

    Reporting group title
    Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg)
    Reporting group description
    		 Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.

    Reporting group title
    Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg)
    Reporting group description
    		 Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.

    Reporting group title
    Part 2 (Tumor specific expansion): Cohort 1 (LGG)
    Reporting group description
    		 Subjects with low-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

    Reporting group title
    Part 2 (Tumor specific expansion): Cohort 2 (HGG)
    Reporting group description
    		 Subjects with high-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

    Reporting group title
    Part 2 (Tumor specific expansion): Cohort 3 (LCH)
    Reporting group description
    		 Subjects with LCH with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

    Reporting group title
    Part 2 (Tumor specific expansion): Cohort 4 (Other)
    Reporting group description
    		 Subjects with other tumors with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

    Reporting group values
    		 Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg) Part 2 (Tumor specific expansion): Cohort 1 (LGG) Part 2 (Tumor specific expansion): Cohort 2 (HGG) Part 2 (Tumor specific expansion): Cohort 3 (LCH) Part 2 (Tumor specific expansion): Cohort 4 (Other) Total
    Number of subjects
    		 3 10 8 6 17 28 11 2 85
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 1 0 0 0 2 0 3
        Children (2-11 years)
    		 2 4 6 6 9 10 9 1 47
        Adolescents (12-17 years)
    		 1 6 1 0 8 18 0 1 35
        Adults (18-64 years)
    		 0 0 0 0 0 0 0 0 0
        From 65-84 years
    		 0 0 0 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 9.33 ( 5.132 ) 11.30 ( 5.355 ) 6.58 ( 5.445 ) 7.17 ( 3.189 ) 9.65 ( 5.195 ) 12.32 ( 3.692 ) 5.52 ( 3.390 ) 9.50 ( 10.607 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 1 5 3 3 8 11 4 0 35
        Male
    		 2 5 5 3 9 17 7 2 50
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0 0 0 0
        Asian
    		 0 2 0 0 2 3 0 0 7
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 1 0 0 1
        Black or African American
    		 0 0 1 0 2 1 0 0 4
        White
    		 3 8 7 6 13 22 11 2 72
        More than one race
    		 0 0 0 0 0 1 0 0 1
        Unknown or Not Reported
    		 0 0 0 0 0 0 0 0 0
    Subject analysis sets

    Subject analysis set title
    Part 2 (Tumor Expansion): All patients at RP2D of 4,5 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients at recommended dose phase 2 (RP2D) of 4,5 mg/kg in Part 2 study cohorts (Cohort 1 Low-Grade Gliomas (LGG), Cohort 2 High-Grade Gliomas (HGG), Cohort 3 Langerhans cell histiocytosis (LCH) and Cohort 4 Miscellaneous tumors including melanoma and papillary thyroid carcinoma (Other)) were pooled together.

    Subject analysis set title
    Part 2 (Tumor Expansion): All patients at RP2D of 5.25 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients at recommended dose phase 2 (RP2D) of 5.25 mg/kg in Part 2 study cohorts (Cohort 1 Low-Grade Gliomas (LGG), Cohort 2 High-Grade Gliomas (HGG), Cohort 3 Langerhans cell histiocytosis (LCH) and Cohort 4 Miscellaneous tumors including melanoma and papillary thyroid carcinoma (Other)) were pooled together.

    Subject analysis set title
    Part 2 (Tumor Expansion): All patients at RP2D of 4,5 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients at recommended dose phase 2 (RP2D) of 4,5 mg/kg in Part 2 study cohorts (Cohort 1 Low-Grade Gliomas (LGG), Cohort 2 High-Grade Gliomas (HGG), Cohort 3 Langerhans cell histiocytosis (LCH) and Cohort 4 Miscellaneous tumors including melanoma and papillary thyroid carcinoma (Other)) were pooled together.

    Subject analysis set title
    Part 2 (Tumor Expansion): All patients at RP2D of 5.25 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients at recommended dose phase 2 (RP2D) of 5.25 mg/kg in Part 2 study cohorts (Cohort 1 Low-Grade Gliomas (LGG), Cohort 2 High-Grade Gliomas (HGG), Cohort 3 Langerhans cell histiocytosis (LCH) and Cohort 4 Miscellaneous tumors including melanoma and papillary thyroid carcinoma (Other)) were pooled together.

    Subject analysis set title
    Part 2 (Tumor Expansion): All patients at RP2D of 4,5 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients at recommended dose phase 2 (RP2D) of 4,5 mg/kg in Part 2 study cohorts (Cohort 1 Low-Grade Gliomas (LGG), Cohort 2 High-Grade Gliomas (HGG), Cohort 3 Langerhans cell histiocytosis (LCH) and Cohort 4 Miscellaneous tumors including melanoma and papillary thyroid carcinoma (Other)) were pooled together.

    Subject analysis set title
    All LGG subjects at Recommended Phase 2 dose (RP2D)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All LGG patients who have been assigned to Recommended Phase II Dose (RP2D) across Part 1 and Part 2.

    Subject analysis set title
    All LGG subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All LGG subjects in the study

    Subject analysis set title
    All HGG subjects at Recommended Phase 2 dose (RP2D)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All HGG patients who have been assigned to Recommended Phase II Dose (RP2D) across Part 1 and Part 2.

    Subject analysis set title
    All HGG subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All HGG subjects in the study

    Subject analysis set title
    Part 1 and Part 2 – All participants with PK data
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the study (all doses and all tumor types) with available pharmacokinetic data

    Subject analysis sets values
    		 Part 2 (Tumor Expansion): All patients at RP2D of 4,5 mg/kg Part 2 (Tumor Expansion): All patients at RP2D of 5.25 mg/kg Part 2 (Tumor Expansion): All patients at RP2D of 4,5 mg/kg Part 2 (Tumor Expansion): All patients at RP2D of 5.25 mg/kg Part 2 (Tumor Expansion): All patients at RP2D of 4,5 mg/kg All LGG subjects at Recommended Phase 2 dose (RP2D) All LGG subjects All HGG subjects at Recommended Phase 2 dose (RP2D) All HGG subjects Part 1 and Part 2 – All participants with PK data
    Number of subjects
    27
    31
    26
    29
    25
    24
    33
    28
    35
    85
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    17 ( )
    24 ( )
    7 ( )
    10 ( )
    0.223 ( )
    Sex: Female, Male
    Units: Participants
        Female
        Male
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
        Asian
        Native Hawaiian or Other Pacific Islander
        Black or African American
        White
        More than one race
        Unknown or Not Reported

    End points

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    End points reporting groups
    Reporting group title
    Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg)
    Reporting group description
    		 Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.

    Reporting group title
    Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg)
    Reporting group description
    		 Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.

    Reporting group title
    Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg)
    Reporting group description
    		 Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.

    Reporting group title
    Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg)
    Reporting group description
    		 Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.

    Reporting group title
    Part 2 (Tumor specific expansion): Cohort 1 (LGG)
    Reporting group description
    		 Subjects with low-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

    Reporting group title
    Part 2 (Tumor specific expansion): Cohort 2 (HGG)
    Reporting group description
    		 Subjects with high-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

    Reporting group title
    Part 2 (Tumor specific expansion): Cohort 3 (LCH)
    Reporting group description
    		 Subjects with LCH with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

    Reporting group title
    Part 2 (Tumor specific expansion): Cohort 4 (Other)
    Reporting group description
    		 Subjects with other tumors with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

    Subject analysis set title
    Part 2 (Tumor Expansion): All patients at RP2D of 4,5 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients at recommended dose phase 2 (RP2D) of 4,5 mg/kg in Part 2 study cohorts (Cohort 1 Low-Grade Gliomas (LGG), Cohort 2 High-Grade Gliomas (HGG), Cohort 3 Langerhans cell histiocytosis (LCH) and Cohort 4 Miscellaneous tumors including melanoma and papillary thyroid carcinoma (Other)) were pooled together.

    Subject analysis set title
    Part 2 (Tumor Expansion): All patients at RP2D of 5.25 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients at recommended dose phase 2 (RP2D) of 5.25 mg/kg in Part 2 study cohorts (Cohort 1 Low-Grade Gliomas (LGG), Cohort 2 High-Grade Gliomas (HGG), Cohort 3 Langerhans cell histiocytosis (LCH) and Cohort 4 Miscellaneous tumors including melanoma and papillary thyroid carcinoma (Other)) were pooled together.

    Subject analysis set title
    Part 2 (Tumor Expansion): All patients at RP2D of 4,5 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients at recommended dose phase 2 (RP2D) of 4,5 mg/kg in Part 2 study cohorts (Cohort 1 Low-Grade Gliomas (LGG), Cohort 2 High-Grade Gliomas (HGG), Cohort 3 Langerhans cell histiocytosis (LCH) and Cohort 4 Miscellaneous tumors including melanoma and papillary thyroid carcinoma (Other)) were pooled together.

    Subject analysis set title
    Part 2 (Tumor Expansion): All patients at RP2D of 5.25 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients at recommended dose phase 2 (RP2D) of 5.25 mg/kg in Part 2 study cohorts (Cohort 1 Low-Grade Gliomas (LGG), Cohort 2 High-Grade Gliomas (HGG), Cohort 3 Langerhans cell histiocytosis (LCH) and Cohort 4 Miscellaneous tumors including melanoma and papillary thyroid carcinoma (Other)) were pooled together.

    Subject analysis set title
    Part 2 (Tumor Expansion): All patients at RP2D of 4,5 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients at recommended dose phase 2 (RP2D) of 4,5 mg/kg in Part 2 study cohorts (Cohort 1 Low-Grade Gliomas (LGG), Cohort 2 High-Grade Gliomas (HGG), Cohort 3 Langerhans cell histiocytosis (LCH) and Cohort 4 Miscellaneous tumors including melanoma and papillary thyroid carcinoma (Other)) were pooled together.

    Subject analysis set title
    All LGG subjects at Recommended Phase 2 dose (RP2D)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All LGG patients who have been assigned to Recommended Phase II Dose (RP2D) across Part 1 and Part 2.

    Subject analysis set title
    All LGG subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All LGG subjects in the study

    Subject analysis set title
    All HGG subjects at Recommended Phase 2 dose (RP2D)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All HGG patients who have been assigned to Recommended Phase II Dose (RP2D) across Part 1 and Part 2.

    Subject analysis set title
    All HGG subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All HGG subjects in the study

    Subject analysis set title
    Part 1 and Part 2 – All participants with PK data
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the study (all doses and all tumor types) with available pharmacokinetic data

    Primary: Incidence of treatment emergent Adverse Events (AEs) in Part 1 (Dose Escalation)

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    End point title
    		 Incidence of treatment emergent Adverse Events (AEs) in Part 1 (Dose Escalation) [1] [2]
    End point description
    The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Events, Serious Adverse Events and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.
    End point type
    Primary
    End point timeframe
    From study treatment start date till 28 days safety follow-up, assessed up to approximately 90 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis performed
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Primary endpoint "Incidence of treatment emergent Adverse Events (AEs) in Part 1 (Dose Escalation)" only apply to Part 1.
    End point values
    		 Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg)
    Number of subjects analysed
    3
    10
    8
    6
    Units: Participants
        All deaths
    0
    0
    0
    1
        On-treatment deaths
    0
    0
    0
    1
        Adverse Events (AEs)
    3
    10
    8
    6
        AEs suspected to be drug related
    3
    10
    8
    5
        Serious Adverse Events (SAEs)
    0
    5
    5
    3
        SAEs suspected to be drug related
    0
    2
    2
    1
        Fatal SAEs
    0
    0
    0
    1
        Fatal SAEs suspected to be drug related
    0
    0
    0
    0
        AEs leading to discontinuation
    0
    0
    1
    0
        AEs requiring dose interruptions
    1
    5
    6
    5
        AEs requiring dose reductions
    0
    2
    3
    1
        AEs requiring dose reductions or interruptions
    1
    5
    6
    5
    No statistical analyses for this end point

    Primary: Maximum concentration (Cmax) of dabrafenib

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    End point title
    		 Maximum concentration (Cmax) of dabrafenib [3] [4]
    End point description
    Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Cmax of dabrafenib was listed and summarized using descriptive statistics.
    End point type
    Primary
    End point timeframe
    Week 1 Day 1, Week 3 Day 15
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis performed
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only apply to Part 1 (Dose Escalation)
    End point values
    		 Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg) Part 2 (Tumor Expansion): All patients at RP2D of 4,5 mg/kg Part 2 (Tumor Expansion): All patients at RP2D of 5.25 mg/kg
    Number of subjects analysed
    3
    10
    8
    6
    27
    31
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Week 1 Day 1
    1820 ( 38.0 )
    1250 ( 61.5 )
    1250 ( 529.9 )
    1900 ( 45.0 )
    1340 ( 82.6 )
    1550 ( 56.8 )
        Week 3 Day 15
    1470 ( 37.7 )
    1260 ( 48.1 )
    1580 ( 49.2 )
    1710 ( 56.4 )
    1450 ( 57.8 )
    1310 ( 49.4 )
    No statistical analyses for this end point

    Primary: Area under the concentration-time curve over the dosing interval (AUC(0-τ)) and AUC from zero to infinity (AUC(0-inf)) of dabrafenib

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    End point title
    		 Area under the concentration-time curve over the dosing interval (AUC(0-τ)) and AUC from zero to infinity (AUC(0-inf)) of dabrafenib [5] [6]
    End point description
    Venous whole blood samples were collected for activity-based pharmacokinetics characterization. AUC(0-τ) and AUC(0-inf) of dabrafenib were to be listed and summarized using descriptive statistics.
    End point type
    Primary
    End point timeframe
    Week 1 Day 1
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only apply to Part 1 (Dose Escalation)
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only apply to Part 1 (Dose Escalation)
    End point values
    		 Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg)
    Number of subjects analysed
    0 [7]
    0 [8]
    0 [9]
    0 [10]
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    ( )
    ( )
    Notes
    [7] - No reliable AUC(0-t) and AUC (0-inf) PK parameters were collected/calculated.
    [8] - No reliable AUC(0-t) and AUC (0-inf) PK parameters were collected/calculated.
    [9] - No reliable AUC(0-t) and AUC (0-inf) PK parameters were collected/calculated.
    [10] - No reliable AUC(0-t) and AUC (0-inf) PK parameters were collected/calculated.
    No statistical analyses for this end point

    Secondary: Pre-dose (trough) concentration (C tau) of dabrafenib and its metabolites

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    End point title
    		 Pre-dose (trough) concentration (C tau) of dabrafenib and its metabolites [11]
    End point description
    Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Pre-dose (trough) concentration (C tau) was to be listed and summarized using descriptive statistics for dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
    End point type
    Secondary
    End point timeframe
    Week 3 Day 15
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only apply to Part 1 (Dose Escalation)
    End point values
    		 Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg) Part 2 (Tumor Expansion): All patients at RP2D of 4,5 mg/kg Part 2 (Tumor Expansion): All patients at RP2D of 5.25 mg/kg
    Number of subjects analysed
    3
    10
    8
    6
    26
    29
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        dabrafenib
    11.9 ( 276.5 )
    39.8 ( 176.1 )
    50.7 ( 121.0 )
    11.0 ( 67.5 )
    42.7 ( 135.9 )
    22.8 ( 209.5 )
        hydroxy-dabrafenib
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
        carboxy-dabrafenib
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
        desmethyl-dabrafenib
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: The AUC(0-t) of dabrafenib metabolites

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    End point title
    		 The AUC(0-t) of dabrafenib metabolites [12]
    End point description
    Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC[0-t]) dabrafenib metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]) were to be listed and summarized using descriptive statistics.
    End point type
    Secondary
    End point timeframe
    Week 1 Day 1, Week 3 Day 15
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only apply to Part 1 (Dose Escalation)
    End point values
    		 Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg)
    Number of subjects analysed
    0 [13]
    0 [14]
    0 [15]
    0 [16]
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    ( )
    ( )
    Notes
    [13] - No reliable AUC(0-t) PK parameters were collected/calculated.
    [14] - No reliable AUC(0-t) PK parameters were collected/calculated.
    [15] - No reliable AUC(0-t) PK parameters were collected/calculated.
    [16] - No reliable AUC(0-t) PK parameters were collected/calculated.
    No statistical analyses for this end point

    Secondary: The AUC(0-tau) of dabrafenib and its metabolites

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    End point title
    		 The AUC(0-tau) of dabrafenib and its metabolites [17]
    End point description
    Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC(0-tau) of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]) were to be listed and summarized using descriptive statistics.
    End point type
    Secondary
    End point timeframe
    Week 1 Day 1, Week 3 Day 15
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only apply to Part 1 (Dose Escalation)
    End point values
    		 Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg)
    Number of subjects analysed
    0 [18]
    0 [19]
    0 [20]
    0 [21]
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    ( )
    ( )
    Notes
    [18] - No reliable AUC(0-tau) PK parameters were collected/calculated.
    [19] - No reliable AUC(0-tau) PK parameters were collected/calculated.
    [20] - No reliable AUC(0-tau) PK parameters were collected/calculated.
    [21] - No reliable AUC(0-tau) PK parameters were collected/calculated.
    No statistical analyses for this end point

    Secondary: Apparent total clearance of the drug from plasma after oral administration (CL/F) of dabrafenib

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    End point title
    		 Apparent total clearance of the drug from plasma after oral administration (CL/F) of dabrafenib [22]
    End point description
    Venous whole blood samples were collected for activity-based pharmacokinetics characterization. CL/F of dabrafenib was to be listed and summarized using descriptive statistics.
    End point type
    Secondary
    End point timeframe
    Week 1 Day 1, Week 3 Day 15
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only apply to Part 1 (Dose Escalation)
    End point values
    		 Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg)
    Number of subjects analysed
    0 [23]
    0 [24]
    0 [25]
    0 [26]
    Units: mL/hr
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    ( )
    ( )
    Notes
    [23] - No reliable CL/F PK parameters were collected/calculated.
    [24] - No reliable CL/F PK parameters were collected/calculated.
    [25] - No reliable CL/F PK parameters were collected/calculated.
    [26] - No reliable CL/F PK parameters were collected/calculated.
    No statistical analyses for this end point

    Secondary: Maximum concentration (Cmax) of dabrafenib metabolites

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    End point title
    		 Maximum concentration (Cmax) of dabrafenib metabolites [27]
    End point description
    Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Cmax of dabrafenib metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]) were listed and summarized using descriptive statistics.
    End point type
    Secondary
    End point timeframe
    Week 1 Day 1, Week 3 Day 15
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only apply to Part 1 (Dose Escalation)
    End point values
    		 Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg) Part 2 (Tumor Expansion): All patients at RP2D of 4,5 mg/kg Part 2 (Tumor Expansion): All patients at RP2D of 5.25 mg/kg
    Number of subjects analysed
    3
    10
    8
    6
    27
    31
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        hydroxy-dabrafenib @ Week 1 Day 1
    811 ( 24.7 )
    662 ( 66.7 )
    473 ( 1643.7 )
    1370 ( 43.9 )
    694 ( 77.9 )
    894 ( 58.2 )
        hydroxy-dabrafenib @ Week 3 Day 15
    673 ( 62.8 )
    726 ( 37.6 )
    752 ( 32.8 )
    1010 ( 51.5 )
    772 ( 50.1 )
    711 ( 43.4 )
        carboxy-dabrafenib @ Week 1 Day 1
    1720 ( 90.6 )
    1300 ( 55.7 )
    824 ( 291.3 )
    4250 ( 67.0 )
    1650 ( 161.2 )
    2330 ( 97.6 )
        carboxy-dabrafenib @ Week 3 Day 15
    4700 ( 51.7 )
    6410 ( 28.0 )
    9650 ( 35.9 )
    11200 ( 28.4 )
    8280 ( 45.9 )
    7970 ( 30.0 )
        desmethyl-dabrafenib @ Week 1 Day 1
    13.0 ( 27.3 )
    6.55 ( 80.5 )
    15.4 ( 103.9 )
    23.7 ( 53.8 )
    10.7 ( 159.4 )
    10.1 ( 88.7 )
        desmethyl-dabrafenib @ Week 3 Day 15
    194 ( 219.4 )
    311 ( 78.9 )
    317 ( 324.9 )
    238 ( 45.6 )
    328 ( 38.8 )
    274 ( 77.4 )
    No statistical analyses for this end point

    Secondary: Time to reach maximum (peak) plasma concentration following drug administration (Tmax) of dabrafenib and its metabolites

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    End point title
    		 Time to reach maximum (peak) plasma concentration following drug administration (Tmax) of dabrafenib and its metabolites [28]
    End point description
    Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Tmax was listed and summarized using descriptive statistics for dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
    End point type
    Secondary
    End point timeframe
    Week 1 Day 1, Week 3 Day 15
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only apply to Part 1 (Dose Escalation)
    End point values
    		 Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg) Part 2 (Tumor Expansion): All patients at RP2D of 4,5 mg/kg Part 2 (Tumor Expansion): All patients at RP2D of 5.25 mg/kg
    Number of subjects analysed
    3
    10
    8
    6
    27
    31
    Units: Hour (hr)
    median (full range (min-max))
        dabrafenib @ Week 1 Day 1
    2.00 (2.00 to 2.00)
    2.00 (2.00 to 4.00)
    2.00 (0.50 to 4.00)
    2.00 (2.00 to 4.00)
    2.00 (0.50 to 4.00)
    2.00 (0.50 to 4.00)
        dabrafenib @ Week 3 Day 15
    1.00 (1.00 to 2.00)
    2.00 (0.50 to 4.00)
    2.00 (1.00 to 3.00)
    2.00 (1.00 to 3.00)
    2.00 (1.00 to 6.00)
    2.00 (1.00 to 4.00)
        hydroxy-dabrafenib @ Week 1 Day 1
    4.00 (4.00 to 4.00)
    4.00 (2.00 to 4.00)
    3.00 (0.50 to 4.00)
    3.00 (2.00 to 4.00)
    4.00 (2.00 to 4.00)
    4.00 (2.00 to 4.00)
        hydroxy-dabrafenib @ Week 3 Day 15
    2.00 (1.00 to 3.00)
    2.50 (1.00 to 4.00)
    2.00 (1.00 to 4.00)
    2.00 (1.00 to 3.00)
    2.00 (1.00 to 6.00)
    2.00 (1.00 to 4.00)
        carboxy-dabrafenib @ Week 1 Day 1
    4.00 (4.00 to 4.00)
    4.00 (4.00 to 4.00)
    4.00 (4.00 to 4.00)
    4.00 (4.00 to 4.00)
    4.00 (0.50 to 4.00)
    4.00 (4.00 to 4.00)
        carboxy-dabrafenib @ Week 3 Day 15
    6.00 (4.00 to 8.00)
    4.00 (3.00 to 8.00)
    4.00 (3.00 to 8.00)
    4.00 (3.00 to 4.00)
    4.00 (0.00 to 8.00)
    4.00 (2.00 to 8.00)
        desmethyl-dabrafenib @ Week 1 Day 1
    4.00 (4.00 to 4.00)
    4.00 (4.00 to 4.00)
    4.00 (4.00 to 4.00)
    4.00 (4.00 to 4.00)
    4.00 (0.50 to 4.00)
    4.00 (4.00 to 4.00)
        desmethyl-dabrafenib @ Week 3 Day 15
    2.00 (0.00 to 8.00)
    2.00 (0.50 to 8.00)
    1.50 (0.00 to 8.00)
    1.50 (0.00 to 3.00)
    2.00 (0.00 to 8.00)
    1.00 (0.00 to 8.00)
    No statistical analyses for this end point

    Secondary: Elimination half life (T½) of dabrafenib and its metabolites

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    End point title
    		 Elimination half life (T½) of dabrafenib and its metabolites [29]
    End point description
    Venous whole blood samples were collected for activity-based pharmacokinetics characterization. T1/2 of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]) was listed and summarized using descriptive statistics.
    End point type
    Secondary
    End point timeframe
    Week 3 Day 15
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only apply to Part 1 (Dose Escalation)
    End point values
    		 Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg) Part 2 (Tumor Expansion): All patients at RP2D of 5.25 mg/kg Part 2 (Tumor Expansion): All patients at RP2D of 4,5 mg/kg
    Number of subjects analysed
    3
    10
    8
    6
    29
    25
    Units: Hour (hr)
    arithmetic mean (standard deviation)
        dabrafenib
    1.98 ( 0.687 )
    2.85 ( 1.58 )
    2.74 ( 0.840 )
    1.56 ( 0.359 )
    2.54 ( 2.44 )
    3.03 ( 2.27 )
        hydroxy-dabrafenib
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
        carboxy-dabrafenib
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
        desmethyl-dabrafenib
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: Incidence of treatment emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)

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    End point title
    		 Incidence of treatment emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion) [30]
    End point description
    The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Events, Serious Adverse Event and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.
    End point type
    Secondary
    End point timeframe
    From study treatment start date till 28 days safety follow-up, assessed up to approximately 90 months
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Secondary endpoint "Incidence of treatment emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)" only apply to Part 2.
    End point values
    		 Part 2 (Tumor specific expansion): Cohort 1 (LGG) Part 2 (Tumor specific expansion): Cohort 2 (HGG) Part 2 (Tumor specific expansion): Cohort 3 (LCH) Part 2 (Tumor specific expansion): Cohort 4 (Other)
    Number of subjects analysed
    17
    28
    11
    2
    Units: Participants
        All deaths
    0
    1
    0
    0
        On-treatment deaths
    0
    0
    0
    0
        Adverse Events (AEs)
    17
    26
    11
    2
        AEs suspected to be drug related
    16
    26
    11
    0
        Serious Adverse Events (SAEs)
    7
    13
    6
    0
        SAEs suspected to be drug related
    1
    3
    2
    0
        Fatal SAEs
    0
    1
    0
    0
        Fatal SAEs suspected to be drug related
    0
    0
    0
    0
        AEs leading to discontinuation
    2
    1
    1
    0
        AEs requiring dose interruptions
    10
    13
    7
    2
        AEs requiring dose reductions
    2
    4
    2
    1
        AEs requiring dose reductions or interruptions
    10
    13
    7
    2
    No statistical analyses for this end point

    Secondary: Best overall response based on investigator assessment per Response Assessment in Neuro-Oncology (RANO) criteria for Low Grade Glioma (LLG) subjects

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    End point title
    		 Best overall response based on investigator assessment per Response Assessment in Neuro-Oncology (RANO) criteria for Low Grade Glioma (LLG) subjects [31]
    End point description
    Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR).based on Response Assessment in Neuro-Oncology (RANO) criteria for Low Grade Glioma (LLG) and High Grade Glioma (HGG) subjects.
    End point type
    Secondary
    End point timeframe
    Up to 6 months
    Notes
    [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only apply to Low Grade Glioma (LLG) subset of subjects
    End point values
    		 Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg) Part 2 (Tumor specific expansion): Cohort 1 (LGG) All LGG subjects at Recommended Phase 2 dose (RP2D) All LGG subjects
    Number of subjects analysed
    4
    6
    6
    17
    24
    33
    Units: Participants
    3
    5
    4
    12
    17
    24
    No statistical analyses for this end point

    Secondary: Best overall response based on investigator assessment per Response Assessment in Neuro-Oncology (RANO) criteria for High Grade Glioma (HGG) subjects

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    End point title
    		 Best overall response based on investigator assessment per Response Assessment in Neuro-Oncology (RANO) criteria for High Grade Glioma (HGG) subjects [32]
    End point description
    Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR).based on Response Assessment in Neuro-Oncology (RANO) criteria for Low Grade Glioma (LLG) and High Grade Glioma (HGG) subjects.
    End point type
    Secondary
    End point timeframe
    Up to 6 months
    Notes
    [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only apply to High Grade Glioma (HGG) subset of subjects
    End point values
    		 Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg) Part 2 (Tumor specific expansion): Cohort 2 (HGG) All HGG subjects at Recommended Phase 2 dose (RP2D) All HGG subjects
    Number of subjects analysed
    3
    4
    28
    28
    35
    Units: Participants
    2
    1
    7
    7
    10
    No statistical analyses for this end point

    Secondary: Effect of weight on total apparent clearance (CL/F) of dabrafenib estimated with a PopPK model

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    End point title
    		 Effect of weight on total apparent clearance (CL/F) of dabrafenib estimated with a PopPK model
    End point description
    The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on total apparent clearance (CL/F) of dabrafenib estimated with the PopPK model is summarized in this record.
    End point type
    Secondary
    End point timeframe
    Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.
    End point values
    		 Part 1 and Part 2 – All participants with PK data
    Number of subjects analysed
    85
    Units: coefficient
        number (not applicable)
    0.223
    No statistical analyses for this end point

    Secondary: Effect of weight on volume of distribution (V/F) of dabrafenib estimated with a PopPK model

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    End point title
    		 Effect of weight on volume of distribution (V/F) of dabrafenib estimated with a PopPK model
    End point description
    The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on volume of distribution (V/F) of dabrafenib estimated with the PopPK model is summarized in this record.
    End point type
    Secondary
    End point timeframe
    Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.
    End point values
    		 Part 1 and Part 2 – All participants with PK data
    Number of subjects analysed
    85
    Units: coefficient
        number (not applicable)
    0.593
    No statistical analyses for this end point

    Secondary: Effect of weight on absorption rate (ka) of dabrafenib estimated with a PopPK model

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    End point title
    		 Effect of weight on absorption rate (ka) of dabrafenib estimated with a PopPK model
    End point description
    The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on absorption rate (ka) of dabrafenib estimated with a PopPK model is summarized in this record.
    End point type
    Secondary
    End point timeframe
    Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.
    End point values
    		 Part 1 and Part 2 – All participants with PK data
    Number of subjects analysed
    85
    Units: coefficient
    999
    No statistical analyses for this end point

    Secondary: Effect of weight on coefficients for significant covariates of dabrafenib estimated with a PopPK model

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    End point title
    		 Effect of weight on coefficients for significant covariates of dabrafenib estimated with a PopPK model
    End point description
    The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on coefficients for significant covariates of dabrafenib estimated with a PopPK model is summarized in this record.
    End point type
    Secondary
    End point timeframe
    Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.
    End point values
    		 Part 1 and Part 2 – All participants with PK data
    Number of subjects analysed
    85
    Units: coefficient
    999
    No statistical analyses for this end point

    Post-hoc: All collected deaths in Parts I and II

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    End point title
    		 All collected deaths in Parts I and II
    End point description
    On treatment deaths were collected from FPFT up to 28 days after study drug discontinuation, for a maximum duration of 360 weeks in Part I (treatment duration ranged from 5.6 to 356.0 weeks) and a maximum duration of 300 weeks in Part II (treatment duration ranged from 0.3 to 296.0 weeks). Deaths post treatment survival follow up were collected after the on- treatment period, up to approximately 7 years. Patients who didn’t die during the on-treatment period and had not stopped study participation at the time of data cut-off (end of study) were censored.
    End point type
    Post-hoc
    End point timeframe
    up to 360 weeks (on-treatment in Part I), up to 300 weeks (on-treatment in Part II), up to approximately 7 years (study duration)
    End point values
    		 Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg) Part 2 (Tumor specific expansion): Cohort 1 (LGG) Part 2 (Tumor specific expansion): Cohort 2 (HGG) Part 2 (Tumor specific expansion): Cohort 3 (LCH) Part 2 (Tumor specific expansion): Cohort 4 (Other)
    Number of subjects analysed
    3
    10
    8
    6
    17
    28
    11
    2
    Units: Participants
        On-treatment deaths
    0
    0
    0
    1
    0
    0
    0
    0
        Post-treatment deaths
    0
    0
    0
    0
    0
    1
    0
    0
        All deaths
    0
    0
    0
    1
    0
    1
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment up to 28 days after the last dose, assessed up to approximately 90 months
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg)
    Reporting group description
    		 Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.

    Reporting group title
    Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg)
    Reporting group description
    		 Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.

    Reporting group title
    Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg)
    Reporting group description
    		 Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.

    Reporting group title
    Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg)
    Reporting group description
    		 Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.

    Reporting group title
    Part 2 (Tumor expansion): Cohort 3 (LCH)
    Reporting group description
    		 Subjects with Langerhans cell histiocytosis (LCH) with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

    Reporting group title
    Part 2 (Tumor expansion): Cohort 2 High-Grade Gliomas (HGG)
    Reporting group description
    		 Subjects with high-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

    Reporting group title
    Part 2 (Tumor expansion): Cohort 1 Low-Grade Gliomas (LGG)
    Reporting group description
    		 Subjects with low-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

    Reporting group title
    Part 2 (Tumor expansion): Cohort 4 Miscellaneous tumors
    Reporting group description
    		 Subjects with other tumors with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

    Serious adverse events
    		 Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg) Part 2 (Tumor expansion): Cohort 3 (LCH) Part 2 (Tumor expansion): Cohort 2 High-Grade Gliomas (HGG) Part 2 (Tumor expansion): Cohort 1 Low-Grade Gliomas (LGG) Part 2 (Tumor expansion): Cohort 4 Miscellaneous tumors
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 10 (50.00%)
    0 / 3 (0.00%)
    5 / 8 (62.50%)
    3 / 6 (50.00%)
    6 / 11 (54.55%)
    13 / 28 (46.43%)
    7 / 17 (41.18%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    1
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Epstein-Barr virus associated lymphoma
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    5 / 11 (45.45%)
    4 / 28 (14.29%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 1
    0 / 1
    1 / 8
    1 / 6
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood culture positive
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Shunt malfunction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Stroke-like migraine attacks after radiation therapy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    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
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    3 / 28 (10.71%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Meningeal disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis bullous
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pityriasis rosea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    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
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    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
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Corynebacterium infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Croup infectious
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal bacteraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg) Part 2 (Tumor expansion): Cohort 3 (LCH) Part 2 (Tumor expansion): Cohort 2 High-Grade Gliomas (HGG) Part 2 (Tumor expansion): Cohort 1 Low-Grade Gliomas (LGG) Part 2 (Tumor expansion): Cohort 4 Miscellaneous tumors
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    3 / 3 (100.00%)
    8 / 8 (100.00%)
    6 / 6 (100.00%)
    11 / 11 (100.00%)
    26 / 28 (92.86%)
    17 / 17 (100.00%)
    2 / 2 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    4 / 11 (36.36%)
    8 / 28 (28.57%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    4
    1
    6
    2
    9
    11
    7
    0
    Skin papilloma
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    0
    1
    1
    2
    0
    0
    Acrochordon
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    Lip neoplasm
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Neoplasm skin
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Xanthogranuloma
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    1
    1
    3
    0
    Hypertension
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    1 / 11 (9.09%)
    4 / 28 (14.29%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    1
    2
    1
    5
    3
    0
    Hypotension
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    3 / 11 (27.27%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    2
    0
    4
    0
    5
    0
    Haematoma
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    Hot flush
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    2
    0
    Venous thrombosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Surgical and medical procedures
    Steroid therapy
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    6 / 28 (21.43%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    6
    0
    0
    Chills
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    2
    1
    0
    1
    0
    0
    Complication associated with device
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    2
    1
    0
    0
    0
    0
    Face oedema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    6 / 10 (60.00%)
    2 / 3 (66.67%)
    2 / 8 (25.00%)
    3 / 6 (50.00%)
    3 / 11 (27.27%)
    11 / 28 (39.29%)
    6 / 17 (35.29%)
    0 / 2 (0.00%)
         occurrences all number
    13
    2
    2
    7
    6
    13
    7
    0
    Gait disturbance
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    1
    0
    0
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    2 / 11 (18.18%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    2
    1
    2
    1
    0
    0
    Pain
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    1
    1
    0
    1
    1
    0
    Pyrexia
         subjects affected / exposed
    5 / 10 (50.00%)
    3 / 3 (100.00%)
    7 / 8 (87.50%)
    5 / 6 (83.33%)
    4 / 11 (36.36%)
    10 / 28 (35.71%)
    11 / 17 (64.71%)
    2 / 2 (100.00%)
         occurrences all number
    25
    6
    20
    12
    10
    103
    23
    2
    Xerosis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    0
    0
    Catheter site erythema
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    0
    Catheter site extravasation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Chest pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    Facial pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Feeling hot
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Localised oedema
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    0
    0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Hypersensitivity
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    2
    0
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Dysmenorrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Testicular pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 10 (50.00%)
    1 / 3 (33.33%)
    4 / 8 (50.00%)
    3 / 6 (50.00%)
    6 / 11 (54.55%)
    8 / 28 (28.57%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    8
    14
    6
    10
    17
    11
    4
    0
    Epistaxis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    2
    3
    0
    Nasal congestion
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    3 / 11 (27.27%)
    1 / 28 (3.57%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    5
    6
    7
    3
    5
    1
    3
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    7
    1
    1
    3
    1
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    3
    0
    2
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    3 / 6 (50.00%)
    3 / 11 (27.27%)
    4 / 28 (14.29%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    2
    6
    3
    4
    3
    0
    Wheezing
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    1
    0
    Adenoidal hypertrophy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Catarrh
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Hypocapnia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    Laryngeal inflammation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Productive cough
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Respiratory acidosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Respiratory tract congestion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Restrictive pulmonary disease
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    Sneezing
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Tachypnoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    0
    0
    0
    Anxiety
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    3 / 11 (27.27%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    2
    4
    3
    1
    1
    0
    Depression
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    3
    2
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    0
    Mood altered
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    Affect lability
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    Aggression
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Anger
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    Attention deficit hyperactivity disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Dysphemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    Emotional disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Hallucination
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Irritability
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    1
    0
    Middle insomnia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Suicidal ideation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    3 / 11 (27.27%)
    0 / 28 (0.00%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    11
    1
    2
    4
    5
    0
    8
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    3 / 8 (37.50%)
    2 / 6 (33.33%)
    3 / 11 (27.27%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    4
    1
    3
    4
    4
    2
    0
    0
    Blood alkaline phosphatase decreased
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    2
    1
    1
    1
    0
    Blood creatinine decreased
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    0
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    5 / 11 (45.45%)
    5 / 28 (17.86%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    4
    3
    13
    9
    3
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    2 / 28 (7.14%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    3
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    1
    1
    0
    1
    0
    Haemoglobin increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    1 / 11 (9.09%)
    2 / 28 (7.14%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    6
    1
    2
    2
    1
    2
    8
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    8
    2
    1
    8
    0
    2
    0
    Platelet count decreased
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    3 / 8 (37.50%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    2
    5
    3
    2
    0
    1
    1
    0
    Weight decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    2 / 28 (7.14%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    2
    1
    2
    2
    1
    0
    Weight increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    4
    2
    0
    1
    4
    0
    White blood cell count decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    4 / 11 (36.36%)
    2 / 28 (7.14%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    1
    5
    0
    1
    13
    2
    4
    0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Blood albumin decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Blood bilirubin decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    0
    0
    Blood calcium decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Blood chloride increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    1
    0
    Blood fibrinogen decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Blood luteinising hormone increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Blood prolactin abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Blood urea decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Carbon dioxide decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    0
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Creatinine urine decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    Eosinophil count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    International normalised ratio increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Low density lipoprotein increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    Platelet count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Protein total increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    0
    Protein urine present
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    0
    Red blood cell count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    Respiratory rate decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Urine albumin/creatinine ratio increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    Urine analysis abnormal
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Urine protein/creatinine ratio increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    3
    2
    3
    0
    1
    0
    Contusion
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    4
    2
    0
    1
    0
    Fall
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    3 / 8 (37.50%)
    2 / 6 (33.33%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    3
    2
    4
    0
    1
    0
    Gastrostomy tube site complication
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    0
    0
    0
    Animal bite
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Animal scratch
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Clavicle fracture
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Foot fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Hand fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Ligament sprain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Nail avulsion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Overdose
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Radius fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Scar
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    Skin laceration
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Sunburn
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    Upper limb fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Wound
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    3
    0
    2
    6
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    4
    2
    1
    2
    1
    0
    Bradycardia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    Cardiac disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Palpitations
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    0
    Tricuspid valve disease
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    2 / 28 (7.14%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    5
    3
    8
    1
    2
    2
    3
    0
    Headache
         subjects affected / exposed
    8 / 10 (80.00%)
    1 / 3 (33.33%)
    3 / 8 (37.50%)
    2 / 6 (33.33%)
    4 / 11 (36.36%)
    10 / 28 (35.71%)
    8 / 17 (47.06%)
    0 / 2 (0.00%)
         occurrences all number
    17
    10
    14
    11
    6
    14
    18
    0
    Paraesthesia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2
    0
    Seizure
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    4 / 28 (14.29%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    6
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    Syncope
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    2
    0
    0
    Altered state of consciousness
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Ataxia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    1
    0
    Dysaesthesia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Dysarthria
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    Dysmetria
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    Facial nerve disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Hemianopia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Hypersomnia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    Migraine
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Muscle spasticity
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Nervous system disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Nystagmus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Oculofacial paralysis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Partial seizures
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Periodic limb movement disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Tremor
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    VIth nerve paralysis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Visual field defect
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 3 (66.67%)
    2 / 8 (25.00%)
    3 / 6 (50.00%)
    3 / 11 (27.27%)
    4 / 28 (14.29%)
    5 / 17 (29.41%)
    0 / 2 (0.00%)
         occurrences all number
    3
    3
    2
    4
    4
    5
    9
    0
    Leukocytosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    2
    2
    1
    0
    0
    Leukopenia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    2
    2
    0
    0
    Lymphopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    2
    0
    Neutropenia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    3 / 28 (10.71%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    2
    1
    3
    8
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    1
    2
    1
    1
    0
    Monocytosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    0
    0
    Neutrophilia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Thrombocytosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    4
    0
    1
    1
    0
    0
    0
    Cerumen impaction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Deafness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Excessive cerumen production
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    External ear inflammation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    0
    0
    Eye pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    1
    0
    2
    0
    Blepharospasm
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Dark circles under eyes
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Dry eye
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    0
    Eye pruritus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Hypermetropia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Keratitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Myopia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    Optic nerve disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Papilloedema
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Periorbital swelling
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Photophobia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Retinal exudates
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Scleral disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Uveitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Vernal keratoconjunctivitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    0
    0
    Visual acuity reduced
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    1 / 11 (9.09%)
    3 / 28 (10.71%)
    4 / 17 (23.53%)
    0 / 2 (0.00%)
         occurrences all number
    5
    2
    1
    13
    3
    5
    7
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    5
    1
    5
    2
    0
    1
    0
    0
    Constipation
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    3 / 8 (37.50%)
    1 / 6 (16.67%)
    4 / 11 (36.36%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    9
    1
    6
    2
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    4 / 8 (50.00%)
    3 / 6 (50.00%)
    4 / 11 (36.36%)
    4 / 28 (14.29%)
    6 / 17 (35.29%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    8
    8
    10
    4
    12
    0
    Dyspepsia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    0
    0
    1
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    2
    0
    0
    Nausea
         subjects affected / exposed
    5 / 10 (50.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    4 / 11 (36.36%)
    7 / 28 (25.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    7
    2
    8
    9
    8
    8
    3
    0
    Oral disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    2 / 6 (33.33%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    2
    0
    Oral pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    0
    Toothache
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    5 / 10 (50.00%)
    2 / 3 (66.67%)
    5 / 8 (62.50%)
    4 / 6 (66.67%)
    9 / 11 (81.82%)
    10 / 28 (35.71%)
    6 / 17 (35.29%)
    0 / 2 (0.00%)
         occurrences all number
    15
    5
    11
    20
    20
    17
    17
    0
    Angular cheilitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Chapped lips
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Cheilitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Cheilosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Chronic gastritis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Dental caries
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Duodenal ulcer
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Duodenitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Glossodynia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    Mouth ulceration
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Odynophagia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    0
    0
    Oesophagitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Oral mucosal eruption
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Paraesthesia oral
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Stomatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    1
    0
    Tongue ulceration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    2 / 28 (7.14%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    3
    1
    0
    Alopecia
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    3 / 11 (27.27%)
    3 / 28 (10.71%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    4
    1
    0
    0
    3
    3
    3
    0
    Blister
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    4 / 17 (23.53%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    5
    0
    Dermatitis acneiform
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    4 / 17 (23.53%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    1
    0
    0
    0
    4
    0
    Dermatitis exfoliative generalised
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    1
    0
    Dry skin
         subjects affected / exposed
    6 / 10 (60.00%)
    1 / 3 (33.33%)
    3 / 8 (37.50%)
    4 / 6 (66.67%)
    5 / 11 (45.45%)
    9 / 28 (32.14%)
    7 / 17 (41.18%)
    0 / 2 (0.00%)
         occurrences all number
    7
    1
    4
    8
    8
    9
    10
    0
    Eczema
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    1
    2
    1
    1
    5
    0
    Erythema
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    3 / 11 (27.27%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    9
    0
    2
    1
    3
    4
    0
    0
    Erythema nodosum
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    3 / 11 (27.27%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    1
    2
    0
    Hair texture abnormal
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    3 / 11 (27.27%)
    1 / 28 (3.57%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    3
    1
    3
    1
    2
    0
    Hyperkeratosis
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 3 (0.00%)
    3 / 8 (37.50%)
    2 / 6 (33.33%)
    3 / 11 (27.27%)
    4 / 28 (14.29%)
    4 / 17 (23.53%)
    0 / 2 (0.00%)
         occurrences all number
    7
    0
    3
    2
    5
    4
    7
    0
    Keratosis pilaris
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 3 (33.33%)
    3 / 8 (37.50%)
    2 / 6 (33.33%)
    0 / 11 (0.00%)
    4 / 28 (14.29%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    1
    5
    2
    0
    4
    0
    0
    Macule
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    2
    0
    1
    0
    1
    0
    Pain of skin
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    3
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    4
    1
    1
    0
    Palmoplantar keratoderma
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    1
    3
    1
    0
    0
    Panniculitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    5
    0
    Papule
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    2 / 6 (33.33%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    5 / 17 (29.41%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    3
    2
    2
    1
    6
    0
    Rash
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    3 / 6 (50.00%)
    3 / 11 (27.27%)
    8 / 28 (28.57%)
    6 / 17 (35.29%)
    0 / 2 (0.00%)
         occurrences all number
    11
    1
    4
    4
    4
    11
    11
    0
    Rash macular
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    1
    0
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 3 (33.33%)
    3 / 8 (37.50%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    3 / 28 (10.71%)
    5 / 17 (29.41%)
    0 / 2 (0.00%)
         occurrences all number
    3
    5
    5
    1
    1
    3
    10
    0
    Rash papular
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    4 / 8 (50.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    7
    0
    1
    0
    2
    0
    Rash pruritic
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    0
    0
    Skin discolouration
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    1
    0
    0
    0
    Skin disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2
    0
    Skin exfoliation
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    4
    0
    4
    1
    1
    0
    3
    0
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    4 / 17 (23.53%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    2
    1
    1
    2
    5
    0
    Skin hypertrophy
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    0
    0
    Skin lesion
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    3 / 6 (50.00%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    4
    0
    3
    4
    1
    1
    3
    0
    Skin mass
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Urticaria
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    1
    1
    0
    Yellow skin
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    0
    0
    Cafe au lait spots
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Dermal cyst
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Dermatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Dermatitis bullous
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    3
    0
    0
    0
    Dermatitis diaper
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    0
    0
    Ecchymosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    Eczema asteatotic
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Ephelides
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Hair colour changes
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Hidradenitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    Ingrown hair
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Intertrigo
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Keloid scar
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Lentigo
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    Miliaria
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Nail discolouration
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Nail disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Nail pigmentation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Neurodermatitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Night sweats
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Onychomadesis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Rash erythematous
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    Rash vesicular
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Scab
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Seborrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Skin fissures
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Skin induration
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    Skin odour abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Xeroderma
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    Haematuria
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    0
    0
    Proteinuria
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    4 / 8 (50.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    4 / 28 (14.29%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    4
    4
    2
    10
    7
    0
    Haemoglobinuria
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Microalbuminuria
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Polyuria
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Renal tubular disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    Urinary tract pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    2 / 28 (7.14%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    2
    6
    0
    Adrenal insufficiency
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Precocious puberty
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    1 / 11 (9.09%)
    4 / 28 (14.29%)
    4 / 17 (23.53%)
    0 / 2 (0.00%)
         occurrences all number
    7
    1
    5
    2
    1
    7
    8
    0
    Back pain
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    3 / 28 (10.71%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    2
    1
    0
    3
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    6
    0
    Muscular weakness
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    0
    1
    0
    0
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    4
    0
    0
    2
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    1
    1
    1
    0
    2
    0
    Neck pain
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    4
    0
    0
    1
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    4 / 10 (40.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    3 / 11 (27.27%)
    4 / 28 (14.29%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    12
    0
    7
    2
    5
    5
    6
    0
    Flank pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Ligament pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Limb mass
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Muscle contracture
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Musculoskeletal deformity
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    4 / 11 (36.36%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    5
    2
    0
    0
    Ear infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    4
    1
    0
    1
    1
    1
    Folliculitis
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    5
    0
    2
    0
    1
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    1
    1
    0
    0
    Herpes zoster
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    2 / 28 (7.14%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    0
    1
    0
    2
    3
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    3 / 28 (10.71%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    5
    2
    0
    Otitis media
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    3 / 8 (37.50%)
    2 / 6 (33.33%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    2
    4
    2
    0
    1
    1
    0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    1
    0
    Pharyngitis
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 3 (66.67%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    2
    0
    4
    0
    4
    0
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    1
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    1
    0
    Rash pustular
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    2
    0
    1
    0
    1
    0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    3 / 11 (27.27%)
    4 / 28 (14.29%)
    2 / 17 (11.76%)
    1 / 2 (50.00%)
         occurrences all number
    2
    0
    2
    2
    12
    7
    2
    1
    Rhinovirus infection
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    1
    3
    0
    0
    1
    0
    Skin infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    3 / 28 (10.71%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    3
    0
    1
    5
    8
    0
    Tinea pedis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    5 / 8 (62.50%)
    2 / 6 (33.33%)
    4 / 11 (36.36%)
    4 / 28 (14.29%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    4
    7
    10
    2
    4
    6
    0
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    4 / 17 (23.53%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    1
    1
    0
    4
    0
    Viral infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    1
    2
    0
    COVID-19
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Candida infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    Carbuncle
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Coronavirus infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Croup infectious
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    0
    0
    Enterobiasis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Enterovirus infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Eye infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Fungal infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Fungal skin infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    Furuncle
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Gastritis viral
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Groin abscess
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Impetigo
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Metapneumovirus infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Onychomycosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Otitis externa
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Otitis media acute
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    Paronychia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Pertussis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Pitted keratolysis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Pustule
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Sinusitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    1
    0
    Skin bacterial infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Staphylococcal infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Streptococcal infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Tinea cruris
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Tinea infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Tonsillitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    0
    0
    Tooth infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Tracheostomy infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Varicella
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    Vascular device infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Viral rash
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Vulval abscess
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    3 / 8 (37.50%)
    4 / 6 (66.67%)
    2 / 11 (18.18%)
    6 / 28 (21.43%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    3
    6
    2
    6
    1
    0
    Dehydration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    1
    1
    0
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    7
    0
    1
    0
    0
    0
    4
    0
    Hyperglycaemia
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 3 (33.33%)
    3 / 8 (37.50%)
    1 / 6 (16.67%)
    3 / 11 (27.27%)
    3 / 28 (10.71%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    8
    1
    5
    1
    6
    3
    6
    0
    Hyperkalaemia
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    5
    0
    1
    0
    4
    0
    1
    0
    Hypermagnesaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    1 / 28 (3.57%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    1
    2
    0
    Hypernatraemia
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    12
    0
    3
    0
    0
    1
    6
    0
    Hyperuricaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    2 / 6 (33.33%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    0
    5
    3
    0
    2
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    2
    0
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    2
    0
    3
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    3 / 6 (50.00%)
    2 / 11 (18.18%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    2
    5
    2
    1
    1
    0
    Hypomagnesaemia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    3 / 6 (50.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    6
    0
    0
    4
    0
    1
    8
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    3
    0
    0
    0
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 3 (66.67%)
    4 / 8 (50.00%)
    3 / 6 (50.00%)
    5 / 11 (45.45%)
    4 / 28 (14.29%)
    3 / 17 (17.65%)
    1 / 2 (50.00%)
         occurrences all number
    3
    2
    5
    5
    9
    4
    3
    1
    Folate deficiency
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Hyperchloraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Hyperlipidaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Hyperphosphataemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    Iron deficiency
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    Metabolic acidosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    Polydipsia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    Vitamin B12 deficiency
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Oct 2012
    1.0, 19-Oct-2012: Corrected Inclusion Criteria #6 to ensure consistency with the contraception requirements as outlined in Section 7.1.1; the requirement for male contraception was deleted since the risk of embryofetal developmental toxicity as a consequence of exposure to female pregnant partners is very low. In addition, the dose escalation procedure table provided in Appendix 1 was changed to ensure that escalation of dose when 6 subjects are enrolled occurs only if there are ≤1 subject with a DLT and no subject data pending, and to fix the reference and formatting
    13 Dec 2012
    2.0, 13-Dec-2012: Amendment No. 02 is a country-specific amendment for France which prohibits children younger than 6 years and children older than 6 years with a risk of choking when swallowing capsules from inclusion in the study in France (pending availability of an oral suspension formulation); changes the QTc stopping criteria to 500 msec for French subjects (as compared to 530 msec); adds cardiac monitoring by echocardiogram (ECHO) at Week 4; and highlights that ECHOs are to be performed by the same operator throughout the study, where possible.
    28 Mar 2013
    3.0, 28-Mar-2013: To take into account potential renal effects, Amendment 03 changed the lower age limit of inclusion criterion #2 from subjects 1 month old to ≥12 months old, adjusted criteria for adequate renal function in inclusion criterion #7, added guidelines for renal insufficiency and additional laboratory testing. Information on the new suspension formulation was incorporated. The section on dose modification was re-organized for consistency. The Time and Events Table was adjusted to include assessments on Day 22, Week 4 was clarified to be Day 29, and increased chemistry and urinalysis evaluations were added.
    19 Jun 2013
    4.0, 19-Jun-2013: Expanded eligibility to subjects with refractory disease, and allows for BID dosing on Day 1. Clarifications made to glioma scan requirements and BRAF mutation testing timing. Pyrexia management guidelines updated and Prohibited and Cautionary medication section updated.
    25 Jul 2013
    5.0, 25-Jul-2013: to clarify the dose escalation rules to allow selection of the appropriate dose by age group in the absence of MTD; to include 2 additional dose levels; to clarify that at least 5 subjects less than 6 years old will be enrolled to be consistent with the binding elements of the Pediatric Investigation Plan (PIP); to clarify the general dose modification guidelines; to clarify the DLT evaluable population and PK population; to update the T&E table to specify that ECHOs will be collected for all subjects; to correct Appendix 1.
    30 Jul 2014
    6.0, 30-Jul-2014: Title changed to specify children and adolescents instead of specific years. Lower age range increased to ≥12 months from >1 month. Study rationale updated to specify refractory disease. Clarification of the dose escalation rules for selection of the appropriate dose by age group in the absence of MTD. Addition of LCH assessments to the time and events schedule, and addition of the LCH scoring system. Overdose section updated in accordance with the most recent information available for dabrafenib. SAE definition of protocol-specific SAEs updated for clarity and modified based on additional understanding of the compound.
    15 Sep 2016
    7.0, 15-Sep-2016: References to GSK or its staff were deleted and replaced with those of Novartis/Novartis and its authorized agents. Administrative changes to align with Novartis processes and procedures were made.
    19 May 2017
    8.0, 19-May-2017: To allow the enrollment of additional subjects in the HGG cohort of Part 2 of the study. This cohort was originally planned to include approximately 10 subjects and has enrolled 21 subjects in Part 2 to date. In view of the promising efficacy in this otherwise very poor prognosis disease, enrollment will remain open until another pediatric HGG study is open for enrollment of this population across all age groups in the same countries (expected by the end of 2018 and no later than mid 2019). Enrollment into the LGG and LCH cohorts have not been extended as subjects may be able to enroll into another pediatric study (MEK116540). The data analysis and statistical consideration was updated to align the analysis populations with the statistical analysis plan. Two interim analyses were added to explain a past unplanned interim analysis and a future interim analysis for decision making of development options. Independent review of HGG tumor histology was clarified in the protocol. It has been shown that LGG can be misdiagnosed for HGG, so the independent review was to ensure consistent application of the WHO glioma classification scale to allow for more reliable comparison to historical studies. As a sensitivity analysis, the efficacy data was to be analyzed including only subjects with centrally confirmed HGG.
    17 Sep 2018
    9.0, 17-Sep-2018: The purpose of this amendment was: i) Addition of a new pediatric formulation dosage form of dabrafenib 10mg as dispersible tablets. ii) Update the withdrawal of consent language to align with the new Global Data Protection Requirements.
    04 Apr 2019
    10.0, 04-Apr-2019: The purpose of this amendment was to add additional interim analyses of data to support a regulatory submission
    21 Aug 2020
    11.0, 21-Aug-2020: The purpose of this amendment was to change the target subject enrollment number for the miscellaneous tumor cohort. The trial has enrolled only four subjects with miscellaneous tumor types (those that are BRAFV600 mutant but are not HGG, LGG, or LCH); two in the dose finding portion, two in the dedicated miscellaneous cohort, over the more than 5 years of enrollment. The miscellaneous cohort was not required for regulatory obligations, and was not required to meet the aims of the clinical trial. Hence, the proposed enrollment target for the miscellaneous cohort was modified from ‘at least 10 subjects’ to ‘up to ten subjects.’ The protocol was also amended to add updated RANO criteria specifically for low grade glioma (RANO-LGG; Wen 2017) as the basis for independent review.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
    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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