Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43692   clinical trials with a EudraCT protocol, of which   7246   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    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
    		 v1
    This version publication date
    20 Jun 2021
    First version publication date
    20 Jun 2021
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    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
    CH-4002, 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
    United States: 31
    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
    Spain: 5
    Country: Number of subjects enrolled
    United Kingdom: 10
    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 expansion): Cohort 1 Low-Grade Gliomas (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 expansion): Cohort 2 High-Grade Gliomas (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 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.
    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 expansion): Cohort 1 Low-Grade Gliomas (LGG) Part 2 (Tumor expansion): Cohort 2 High-Grade Gliomas (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

    		 Close Top of page
    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 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 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 specific 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 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 expansion): Cohort 1 Low-Grade Gliomas (LGG) Part 2 (Tumor expansion): Cohort 2 High-Grade Gliomas (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 1 (Dose Escalation): Dabrafenib treatment (All Patients)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from all dose levels (3 mg/kg, 3.75 mg/kg, 4.5 mg/kg and 5.25 mg/kg) were pooled together

    Subject analysis set title
    Part 2 (Tumor Specific Expansion): All patients (4.5 mg/kg)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in all 4 tumor-specific pediatric populations (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 and 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 Specific Expansion): All patients (5.25 mg/kg)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in all 4 tumor-specific pediatric populations (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 and 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 Specific Expansion): All patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in all 4 tumor-specific pediatric populations (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 subjects who have been assigned to 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 across Part 1 and Part 2

    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 subjects who have been assigned to 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 across Part 1 and Part 2

    Subject analysis set title
    All enrolled participants
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who received at least one dose of study treatment across Part 1 and Part 2 were pooled together

    Subject analysis set title
    Part 2 (Tumor Specific Expansion): All patients (5.25 mg/kg)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from in all 4 tumor-specific pediatric populations (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 and 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 sets values
    		 Part 1 (Dose Escalation): Dabrafenib treatment (All Patients) Part 2 (Tumor Specific Expansion): All patients (4.5 mg/kg) Part 2 (Tumor Specific Expansion): All patients (5.25 mg/kg) Part 2 (Tumor Specific Expansion): All patients All LGG subjects at Recommended Phase 2 dose (RP2D) All LGG subjects All HGG subjects at Recommended Phase 2 dose (RP2D) All HGG subjects All enrolled participants Part 2 (Tumor Specific Expansion): All patients (5.25 mg/kg)
    Number of subjects
    27
    27
    31
    58
    24
    33
    28
    35
    85
    31
    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

    		 Close Top of page
    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 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 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 specific 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 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 1 (Dose Escalation): Dabrafenib treatment (All Patients)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from all dose levels (3 mg/kg, 3.75 mg/kg, 4.5 mg/kg and 5.25 mg/kg) were pooled together

    Subject analysis set title
    Part 2 (Tumor Specific Expansion): All patients (4.5 mg/kg)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in all 4 tumor-specific pediatric populations (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 and 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 Specific Expansion): All patients (5.25 mg/kg)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in all 4 tumor-specific pediatric populations (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 and 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 Specific Expansion): All patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in all 4 tumor-specific pediatric populations (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 subjects who have been assigned to 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 across Part 1 and Part 2

    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 subjects who have been assigned to 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 across Part 1 and Part 2

    Subject analysis set title
    All enrolled participants
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who received at least one dose of study treatment across Part 1 and Part 2 were pooled together

    Subject analysis set title
    Part 2 (Tumor Specific Expansion): All patients (5.25 mg/kg)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from in all 4 tumor-specific pediatric populations (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 and 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.

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

    		 Close Top of page
    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 will be 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 30 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: Only applicable 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) Part 1 (Dose Escalation): Dabrafenib treatment (All Patients)
    Number of subjects analysed
    3
    10
    8
    6
    27
    Units: Participants
        All deaths (All grades)
    0
    0
    0
    1
    1
        All deaths (Grades 3/4/5)
    0
    0
    0
    1
    1
        On-treatment deaths (All grades)
    0
    0
    0
    1
    1
        On-treatment deaths (Grades 3/4/5)
    0
    0
    0
    1
    1
        Adverse Events (AEs) (All grades)
    3
    10
    8
    6
    27
        Adverse Events (AEs) (Grades 3/4/5)
    1
    6
    5
    5
    17
        AEs suspected to be drug related (All grades)
    3
    10
    8
    5
    26
        AEs suspected to be drug related (Grades 3/4/5)
    0
    3
    2
    3
    8
        Serious Adverse Events (SAEs) (All grades)
    0
    5
    5
    3
    13
        Serious Adverse Events (SAEs) (Grades 3/4/5)
    0
    4
    4
    3
    11
        SAEs suspected to be drug related (All grades)
    0
    2
    2
    1
    5
        SAEs suspected to be drug related (Grades 3/4/5)
    0
    2
    1
    1
    4
        Fatal SAEs (All grades)
    0
    0
    0
    1
    1
        Fatal SAEs (Grades 3/4/5)
    0
    0
    0
    1
    1
        AEs leading to discontinuation (All grades)
    0
    0
    1
    0
    1
        AEs leading to discontinuation (Grades 3/4/5)
    0
    0
    1
    0
    1
        AEs requiring dose interruptions (All grades)
    1
    5
    6
    5
    17
        AEs requiring dose interruptions (Grades 3/4/5)
    1
    4
    3
    4
    12
        AEs requiring dose reductions (All grades)
    0
    2
    3
    1
    6
        AEs requiring dose reductions (Grades 3/4/5)
    0
    2
    2
    1
    5
    No statistical analyses for this end point

    Primary: Maximum concentration (Cmax) of dabrafenib

    		 Close Top of page
    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 applicable 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) Part 2 (Tumor Specific Expansion): All patients (4.5 mg/kg) Part 2 (Tumor Specific Expansion): All patients (5.25 mg/kg)
    Number of subjects analysed
    3
    10
    8
    6
    27
    31
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 1 Day 1 (n=2,10,8,6,27,31)
    1890 ± 678
    1440 ± 787
    2200 ± 1210
    2070 ± 1120
    1640 ± 922
    1740 ± 806
        Week 3 Day 15 (n=3,10,8,6,26,29)
    1530 ± 526
    1390 ± 721
    1760 ± 1010
    1920 ± 1030
    1640 ± 763
    1440 ± 580
    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

    		 Close Top of page
    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. Due to limited dabrafenib PK data collected for Day 1 (up to 4 hours post-dose PK data only), no reliable AUC(0-t) and AUC (0-inf) PK parameters were collected/calculated.
    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: No reliable AUC(0-t) and AUC (0-inf) PK parameters were collected/calculated.
    [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 applicable 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
    0 [7]
    0 [8]
    0 [9]
    0 [10]
    Units: hr*ng/mL
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    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

    		 Close Top of page
    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 applicable 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) Part 2 (Tumor Specific Expansion): All patients (4.5 mg/kg) Part 2 (Tumor Specific Expansion): All patients (5.25 mg/kg)
    Number of subjects analysed
    3
    10
    8
    6
    27
    31
    Units: ng/mL
    arithmetic mean (standard deviation)
        dabrafenib (n=3,10,8,6,26,29)
    22.1 ± 26.0
    82.1 ± 115.0
    76.6 ± 86.0
    12.6 ± 6.48
    71.4 ± 83.2
    54.7 ± 97.4
        hydroxy-dabrafenib (n=0,0,0,0,0,0)
    999 ± 999
    999 ± 999
    999 ± 999
    999 ± 999
    999 ± 999
    999 ± 999
        carboxy-dabrafenib (n=0,0,0,0,0,0)
    999 ± 999
    999 ± 999
    999 ± 999
    999 ± 999
    999 ± 999
    999 ± 999
        desmethyl-dabrafenib (n=0,0,0,0,0,0)
    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

    		 Close Top of page
    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. Due to limited dabrafenib PK data collected for Day 1 (up to 4 hours post-dose PK data only), no reliable AUC(0-t) PK parameters were collected/calculated.
    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 applicable 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
    0 [13]
    0 [14]
    0 [15]
    0 [16]
    Units: hr*ng/mL
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    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

    		 Close Top of page
    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. Due to limited dabrafenib PK data collected for Day 1 (up to 4 hours post-dose PK data only), no reliable AUC(0-t) PK parameters were collected/calculated.
    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 applicable 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
    0 [18]
    0 [19]
    0 [20]
    0 [21]
    Units: hr*ng/mL
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    Notes
    [18] - No reliable AUC(0-t) PK parameters were collected/calculated.
    [19] - No reliable AUC(0-t) PK parameters were collected/calculated.
    [20] - No reliable AUC(0-t) PK parameters were collected/calculated.
    [21] - No reliable AUC(0-t) 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

    		 Close Top of page
    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. Due to limited dabrafenib PK data collected for Day 1 (up to 4 hours post-dose PK data only), no reliable CL/F PK parameters were collected/calculated.
    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 applicable 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
    0 [23]
    0 [24]
    0 [25]
    0 [26]
    Units: mL/hr
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    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

    		 Close Top of page
    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 applicable 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) Part 2 (Tumor Specific Expansion): All patients (4.5 mg/kg) Part 2 (Tumor Specific Expansion): All patients (5.25 mg/kg)
    Number of subjects analysed
    3
    10
    8
    6
    27
    31
    Units: ng/mL
    arithmetic mean (standard deviation)
        hydroxy-dabrafenib @ Wk1D1 (n=2,10,8,6,26,31)
    823 ± 199
    765 ± 398
    1060 ± 670
    1470 ± 597
    828 ± 422
    1010 ± 475
        hydroxy-dabrafenib @ Wk3D15 (n=3,10,8,6,26,29)
    743 ± 362
    764 ± 225
    787 ± 263
    1120 ± 565
    851 ± 356
    767 ± 278
        carboxy-dabrafenib @ Wk1D1 (n=3,10,8,6,27,31)
    1980 ± 1400
    1440 ± 637
    1550 ± 1370
    5040 ± 3630
    2520 ± 1960
    2980 ± 1760
        carboxy-dabrafenib @ Wk3D15 (n=3,10,8,6,26,29)
    5120 ± 2700
    6630 ± 1800
    10200 ± 3990
    11600 ± 3070
    9070 ± 3990
    8320 ± 2570
        desmethyl-dabrafenib @ Wk1D1 (n=3,10,8,6,21,27)
    13.3 ± 3.53
    8.06 ± 5.11
    20.2 ± 14.6
    26.0 ± 11.3
    28.9 ± 77.0
    13.5 ± 11.3
        desmethyl-dabrafenib @ Wk3D15 (n=3,10,8,6,24,29)
    356 ± 455
    399 ± 370
    730 ± 841
    256 ± 98.0
    350 ± 125
    333 ± 207
    No statistical analyses for this end point

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

    		 Close Top of page
    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 applicable 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) Part 2 (Tumor Specific Expansion): All patients (4.5 mg/kg) Part 2 (Tumor Specific Expansion): All patients (5.25 mg/kg)
    Number of subjects analysed
    3
    10
    8
    6
    27
    31
    Units: Hour (hr)
    median (full range (min-max))
        dabrafenib @ Wk1D1 (n=2,10,8,6,27,31)
    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 @ Wk3D15 (n=3,10,8,6,26,29)
    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 @ Wk1D1 (n=2,10,8,6,26,31)
    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 @ Wk3D15 (n=3,10,8,6,26,29)
    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 @ Wk1D1 (n=2,10,7,6,27,31)
    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 @ Wk3D15 (n=3,10,8,6,26,29)
    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 @ Wk1D1 (n=2,10,6,6,21,27)
    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 @ Wk3D15 (n=3,10,8,6,24,29)
    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

    		 Close Top of page
    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 applicable 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) Part 2 (Tumor Specific Expansion): All patients (4.5 mg/kg) Part 2 (Tumor Specific Expansion): All patients (5.25 mg/kg)
    Number of subjects analysed
    3
    10
    8
    6
    27
    31
    Units: Hour (hr)
    arithmetic mean (standard deviation)
        dabrafenib (n=3,10,8,6,25,29)
    1.98 ± 0.687
    2.85 ± 1.58
    2.74 ± 0.840
    1.56 ± 0.359
    3.03 ± 2.27
    2.54 ± 2.44
        hydroxy-dabrafenib (n=0,0,0,0,0,0)
    999 ± 999
    999 ± 999
    999 ± 999
    999 ± 999
    999 ± 999
    999 ± 999
        carboxy-dabrafenib (n=0,0,0,0,0,0)
    999 ± 999
    999 ± 999
    999 ± 999
    999 ± 999
    999 ± 999
    999 ± 999
        desmethyl-dabrafenib (n=0,0,0,0,0,0)
    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)

    		 Close Top of page
    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 will be 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 30 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: Only applicable to Part 2
    End point values
    		 Part 2 (Tumor expansion): Cohort 1 Low-Grade Gliomas (LGG) Part 2 (Tumor expansion): Cohort 2 High-Grade Gliomas (HGG) Part 2 (Tumor specific expansion): Cohort 3 (LCH) Part 2 (Tumor specific expansion): Cohort 4 (Other) Part 2 (Tumor Specific Expansion): All patients
    Number of subjects analysed
    17
    28
    11
    2
    58
    Units: Participants
        All deaths (All grades)
    0
    1
    0
    0
    1
        All deaths (Grades 3/4/5)
    0
    1
    0
    0
    1
        On-treatment deaths (All grades)
    0
    0
    0
    0
    0
        On-treatment deaths (Grades 3/4/5)
    0
    0
    0
    0
    0
        Adverse Events (AEs) (All grades)
    17
    26
    11
    2
    56
        Adverse Events (AEs) (Grades 3/4/5)
    10
    13
    9
    2
    34
        AEs suspected to be drug related (All grades)
    16
    26
    11
    0
    53
        AEs suspected to be drug related (Grades 3/4/5)
    4
    5
    2
    0
    11
        Serious Adverse Events (SAEs) (All grades)
    7
    13
    6
    0
    26
        Serious Adverse Events (SAEs) (Grades 3/4/5)
    5
    8
    3
    0
    16
        SAEs suspected to be drug related (All grades)
    1
    3
    2
    0
    6
        SAEs suspected to be drug related (Grades 3/4/5)
    0
    1
    0
    0
    1
        Fatal SAEs (All grades)
    0
    1
    0
    0
    1
        Fatal SAEs (Grades 3/4/5)
    0
    1
    0
    0
    1
        AEs leading to discontinuation (All grades)
    2
    1
    1
    0
    4
        AEs leading to discontinuation (Grades 3/4/5)
    0
    1
    0
    0
    1
        AEs requiring dose interruptions (All grades)
    10
    13
    7
    2
    32
        AEs requiring dose interruptions (Grades 3/4/5)
    3
    6
    3
    1
    13
        AEs requiring dose reductions (All grades)
    2
    4
    2
    1
    9
        AEs requiring dose reductions (Grades 3/4/5)
    1
    0
    0
    1
    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

    		 Close Top of page
    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 applicable to Low Grade Glioma (LLG) and High Grade Glioma (HGG) 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 expansion): Cohort 1 Low-Grade Gliomas (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

    		 Close Top of page
    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 applicable to Low Grade Glioma (LLG) and High Grade Glioma (HGG) 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 expansion): Cohort 2 High-Grade Gliomas (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 age and weight on CL/F of dabrafenib

    		 Close Top of page
    End point title
    		 Effect of age and weight on CL/F of dabrafenib
    End point description
    The CL/F data with the effect of age and weight using a population pharmacokinetic approach was to be evaluated. The effect of age was not incorporated in the PopPK model, as body weight and age are correlated, and body-weight is a more informative to be used.
    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
    		 All enrolled participants
    Number of subjects analysed
    85
    Units: No unit of measure
        number (not applicable)
    0.223
    No statistical analyses for this end point

    Secondary: Effect of age and weight on volume of distribution (V/F) of dabrafenib

    		 Close Top of page
    End point title
    		 Effect of age and weight on volume of distribution (V/F) of dabrafenib
    End point description
    The V/F data with the effect of age and weight using a population pharmacokinetic approach was to be evaluated. The effect of age was not incorporated in the PopPK model, as body weight and age are correlated, and body-weight is a more informative to be used.
    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
    		 All enrolled participants
    Number of subjects analysed
    85
    Units: No unit of measure
        number (not applicable)
    0.593
    No statistical analyses for this end point

    Secondary: Effect of age and weight on absorption rate (ka) of dabrafenib

    		 Close Top of page
    End point title
    		 Effect of age and weight on absorption rate (ka) of dabrafenib
    End point description
    The ka data with the effect of age and weight using a population pharmacokinetic approach was to be evaluated. The effect of age was not incorporated in the PopPK model, as body weight and age are correlated, and body-weight is a more informative to be used.
    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
    		 All enrolled participants
    Number of subjects analysed
    85 [33]
    Units: No unit of measure
    999
    Notes
    [33] - No covariate on KA parameter analyzed
    No statistical analyses for this end point

    Secondary: Effect of age and weight on coefficients for significant covariates of dabrafenib

    		 Close Top of page
    End point title
    		 Effect of age and weight on coefficients for significant covariates of dabrafenib
    End point description
    The coefficients for significant covariates data with the effect of age and weight using a population pharmacokinetic approach was to be evaluated. The effect of age was not incorporated in the PopPK model, as body weight and age are correlated, and body-weight is a more informative to be used.
    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
    		 All enrolled participants
    Number of subjects analysed
    85 [34]
    Units: No unit of measure
    999
    Notes
    [34] - No coefficients for significant covariates of dabrafenib
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    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 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 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 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 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 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): Cohort 2 High-Grade Gliomas (HGG) Part 2 (Tumor expansion): Cohort 1 Low-Grade Gliomas (LGG) Part 2 (Tumor expansion): Cohort 3 (LCH) Part 2 (Tumor expansion): Cohort 4 Miscellaneous tumors
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 10 (50.00%)
    5 / 8 (62.50%)
    3 / 6 (50.00%)
    7 / 17 (41.18%)
    13 / 28 (46.43%)
    6 / 11 (54.55%)
    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 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (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
    Metastases to meninges
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    0 / 11 (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
    Tumour haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 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
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    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 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    0 / 11 (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
    General physical health deterioration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 10 (20.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    4 / 28 (14.29%)
    5 / 11 (45.45%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
    0 / 2
    0 / 2
    0 / 2
    2 / 12
    2 / 16
    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
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 2
    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
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    Investigations
    Blood culture positive
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 4
    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 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    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
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    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
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (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
    Stroke-like migraine attacks after radiation therapy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    0 / 11 (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
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    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
    Depressed level of consciousness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    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
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    3 / 28 (10.71%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 2
    0 / 6
    2 / 2
    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 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    2 / 28 (7.14%)
    0 / 11 (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
    Intracranial pressure increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (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
    Meningeal disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 8
    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 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    Presyncope
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    Seizure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    2 / 28 (7.14%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 2
    0 / 0
    0 / 6
    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
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    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
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    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 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 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
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (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
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    2 / 28 (7.14%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    2 / 2
    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 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    Pityriasis rosea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    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 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 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
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 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
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    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
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    0 / 11 (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
    Bacteraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    0 / 11 (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
    Catheter site infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (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
    Device related infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 4
    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 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    0 / 11 (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
    Herpes zoster
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    Infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (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
    Influenza
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    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 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 4
    0 / 2
    0 / 2
    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
    Pseudomonal bacteraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (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
    Respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 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
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    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 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    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 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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 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): Cohort 2 High-Grade Gliomas (HGG) Part 2 (Tumor expansion): Cohort 1 Low-Grade Gliomas (LGG) Part 2 (Tumor expansion): Cohort 3 (LCH) Part 2 (Tumor expansion): Cohort 4 Miscellaneous tumors
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    10 / 10 (100.00%)
    8 / 8 (100.00%)
    6 / 6 (100.00%)
    17 / 17 (100.00%)
    26 / 28 (92.86%)
    11 / 11 (100.00%)
    2 / 2 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 10 (20.00%)
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    3 / 17 (17.65%)
    8 / 28 (28.57%)
    4 / 11 (36.36%)
    0 / 2 (0.00%)
         occurrences all number
    2
    8
    12
    4
    14
    22
    18
    0
    Skin papilloma
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 10 (20.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    2 / 28 (7.14%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    2
    4
    0
    2
    0
    4
    2
    0
    Acrochordon
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    2
    0
    Lip neoplasm
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Neoplasm skin
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Xanthogranuloma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    2 / 17 (11.76%)
    1 / 28 (3.57%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    2
    6
    2
    2
    0
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 10 (20.00%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    2 / 17 (11.76%)
    4 / 28 (14.29%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    6
    2
    4
    6
    10
    2
    0
    Hypotension
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 10 (10.00%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    3 / 11 (27.27%)
    0 / 2 (0.00%)
         occurrences all number
    2
    2
    4
    0
    10
    0
    8
    0
    Haematoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    0
    0
    Hot flush
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 17 (11.76%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    4
    0
    0
    0
    Venous thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Surgical and medical procedures
    Steroid therapy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    6 / 28 (21.43%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    12
    0
    0
    Chills
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 10 (10.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    4
    4
    2
    0
    2
    0
    0
    Complication associated with device
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    4
    2
    0
    0
    0
    0
    Face oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    0
    2
    0
    Fatigue
         subjects affected / exposed
    2 / 3 (66.67%)
    6 / 10 (60.00%)
    2 / 8 (25.00%)
    3 / 6 (50.00%)
    6 / 17 (35.29%)
    11 / 28 (39.29%)
    3 / 11 (27.27%)
    0 / 2 (0.00%)
         occurrences all number
    4
    26
    4
    14
    14
    26
    12
    0
    Gait disturbance
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 10 (20.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    6
    2
    0
    0
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
         occurrences all number
    0
    4
    4
    2
    0
    2
    4
    0
    Pain
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 10 (10.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    2
    2
    2
    2
    2
    0
    0
    Pyrexia
         subjects affected / exposed
    3 / 3 (100.00%)
    5 / 10 (50.00%)
    7 / 8 (87.50%)
    5 / 6 (83.33%)
    11 / 17 (64.71%)
    10 / 28 (35.71%)
    4 / 11 (36.36%)
    2 / 2 (100.00%)
         occurrences all number
    12
    50
    40
    24
    46
    206
    20
    4
    Xerosis
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 10 (10.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    2
    2
    0
    0
    0
    0
    0
    Catheter site erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    4
    0
    Catheter site extravasation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    2
    0
    0
    Facial pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Feeling hot
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Localised oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    2
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    4
    2
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    4
    0
    0
    0
    0
    0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    Hypersensitivity
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 17 (11.76%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    4
    0
    0
    0
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Dysmenorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Testicular pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 3 (33.33%)
    5 / 10 (50.00%)
    4 / 8 (50.00%)
    3 / 6 (50.00%)
    3 / 17 (17.65%)
    8 / 28 (28.57%)
    6 / 11 (54.55%)
    0 / 2 (0.00%)
         occurrences all number
    28
    16
    12
    20
    8
    22
    34
    0
    Epistaxis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    3 / 17 (17.65%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    4
    2
    6
    4
    0
    0
    Nasal congestion
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 10 (20.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    2 / 17 (11.76%)
    1 / 28 (3.57%)
    3 / 11 (27.27%)
    0 / 2 (0.00%)
         occurrences all number
    12
    10
    14
    6
    6
    2
    10
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 10 (30.00%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    2
    14
    2
    6
    0
    2
    2
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    6
    0
    0
    2
    4
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    2 / 8 (25.00%)
    3 / 6 (50.00%)
    3 / 17 (17.65%)
    4 / 28 (14.29%)
    3 / 11 (27.27%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    4
    12
    6
    8
    6
    0
    Wheezing
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    2
    0
    0
    2
    0
    0
    0
    Adenoidal hypertrophy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Catarrh
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Hypocapnia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    2
    0
    0
    0
    Laryngeal inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 17 (11.76%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Respiratory acidosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Respiratory tract congestion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Restrictive pulmonary disease
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    2
    0
    0
    0
    Sneezing
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Tachypnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    2
    0
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 10 (0.00%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    4
    0
    0
    0
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 10 (20.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    1 / 28 (3.57%)
    3 / 11 (27.27%)
    0 / 2 (0.00%)
         occurrences all number
    0
    4
    4
    8
    2
    2
    6
    0
    Depression
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    6
    0
    0
    4
    0
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    0
    0
    0
    Mood altered
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    0
    0
    0
    Affect lability
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    0
    0
    Aggression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Anger
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    2
    0
    0
    0
    Attention deficit hyperactivity disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Dysphemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    2
    0
    Emotional disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    Hallucination
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    Irritability
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    4
    2
    0
    0
    0
    Middle insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Suicidal ideation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 10 (40.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    3 / 17 (17.65%)
    0 / 28 (0.00%)
    3 / 11 (27.27%)
    0 / 2 (0.00%)
         occurrences all number
    2
    22
    4
    8
    16
    0
    10
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 10 (20.00%)
    3 / 8 (37.50%)
    2 / 6 (33.33%)
    0 / 17 (0.00%)
    2 / 28 (7.14%)
    3 / 11 (27.27%)
    0 / 2 (0.00%)
         occurrences all number
    2
    8
    6
    8
    0
    4
    8
    0
    Blood alkaline phosphatase decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 10 (20.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    0
    2
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    1 / 28 (3.57%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    4
    2
    2
    2
    0
    Blood creatinine decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 10 (20.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    4
    0
    2
    2
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    3 / 17 (17.65%)
    5 / 28 (17.86%)
    5 / 11 (45.45%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    8
    6
    6
    18
    26
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    2 / 28 (7.14%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    2
    2
    6
    2
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 10 (20.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    4
    0
    2
    2
    0
    2
    0
    Haemoglobin increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    6
    0
    0
    0
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 10 (20.00%)
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    3 / 17 (17.65%)
    2 / 28 (7.14%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    2
    12
    4
    4
    16
    4
    2
    0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
         occurrences all number
    16
    0
    4
    2
    4
    0
    16
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 10 (20.00%)
    3 / 8 (37.50%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    10
    4
    6
    4
    2
    2
    0
    0
    Weight decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 10 (0.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    2 / 28 (7.14%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    4
    2
    2
    4
    4
    0
    Weight increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    3 / 17 (17.65%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    8
    4
    8
    2
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    2 / 17 (11.76%)
    2 / 28 (7.14%)
    4 / 11 (36.36%)
    0 / 2 (0.00%)
         occurrences all number
    10
    2
    0
    2
    8
    4
    26
    0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Blood albumin decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Blood bilirubin decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    4
    0
    Blood calcium decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Blood chloride increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    4
    0
    0
    Blood fibrinogen decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Blood luteinising hormone increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    Blood prolactin abnormal
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Blood urea decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    0
    2
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Carbon dioxide decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    4
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Creatinine urine decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    2
    0
    Eosinophil count increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Low density lipoprotein increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    2
    0
    0
    0
    Platelet count increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Protein total increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 17 (11.76%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    6
    0
    0
    0
    Protein urine present
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    6
    0
    0
    0
    Red blood cell count increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    0
    0
    Respiratory rate decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Transaminases increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    Urine albumin/creatinine ratio increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    2
    0
    Urine analysis abnormal
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    0
    0
    0
    Urine protein/creatinine ratio increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    0
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 10 (20.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
         occurrences all number
    0
    6
    6
    4
    2
    0
    6
    0
    Contusion
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
         occurrences all number
    2
    2
    0
    8
    2
    0
    4
    0
    Fall
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 10 (0.00%)
    3 / 8 (37.50%)
    2 / 6 (33.33%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    6
    4
    2
    0
    8
    0
    Gastrostomy tube site complication
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    4
    4
    0
    0
    0
    0
    0
    Animal bite
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Animal scratch
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Clavicle fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Foot fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    0
    0
    Fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    0
    0
    0
    Hand fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Nail avulsion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Overdose
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Radius fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    Scar
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    0
    0
    Skin laceration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Sunburn
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    2
    0
    Upper limb fracture
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Wound
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
         occurrences all number
    6
    2
    0
    4
    0
    0
    12
    0
    Tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    1 / 28 (3.57%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    8
    4
    2
    4
    2
    0
    Bradycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    2
    0
    0
    Cardiac disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    0
    Palpitations
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    0
    0
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    4
    0
    Tricuspid valve disease
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    6
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 10 (20.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 10 (30.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    2 / 17 (11.76%)
    2 / 28 (7.14%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
         occurrences all number
    6
    10
    16
    2
    6
    4
    4
    0
    Headache
         subjects affected / exposed
    1 / 3 (33.33%)
    8 / 10 (80.00%)
    3 / 8 (37.50%)
    2 / 6 (33.33%)
    8 / 17 (47.06%)
    10 / 28 (35.71%)
    4 / 11 (36.36%)
    0 / 2 (0.00%)
         occurrences all number
    20
    34
    28
    22
    36
    28
    12
    0
    Paraesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 17 (11.76%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    2
    0
    0
    Seizure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    4 / 28 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    12
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    2 / 28 (7.14%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    4
    4
    0
    Altered state of consciousness
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Ataxia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    2
    2
    0
    0
    Dysaesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 28 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Dysarthria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 28 (3.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0