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

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

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

    Trial information

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    Trial identification
    Sponsor protocol code
    116013
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01677741
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Novartis: CDRB436A2102
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001147-PIP01-11
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Dec 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Dec 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to determine the safe and tolerable dabrafenib dose(s) for chronic dosing in pediatric subjects (infants, children, and adolescents) that achieves similar exposures to the dabrafenib adult dose, in subjects with BRAF V600 mutation positive tumors
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 May 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 18
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United States: 31
    Worldwide total number of subjects
    85
    EEA total number of subjects
    27
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    3
    Children (2-11 years)
    47
    Adolescents (12-17 years)
    35
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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

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

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

    Arms
    Are arms mutually exclusive
    Yes

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    Baseline characteristics

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    End points

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    Primary: Maximum concentration (Cmax) of dabrafenib

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

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

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

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

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

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

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

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

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

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

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

    Secondary: Maximum concentration (Cmax) of dabrafenib metabolites

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    Adverse events

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

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

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

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

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

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

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

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

    Serious adverse events
    Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg) Part 2 (Tumor expansion): Cohort 3 (LCH) Part 2 (Tumor expansion): Cohort 2 High-Grade Gliomas (HGG) Part 2 (Tumor expansion): Cohort 1 Low-Grade Gliomas (LGG) Part 2 (Tumor expansion): Cohort 4 Miscellaneous tumors
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 10 (50.00%)
    0 / 3 (0.00%)
    5 / 8 (62.50%)
    3 / 6 (50.00%)
    6 / 11 (54.55%)
    13 / 28 (46.43%)
    7 / 17 (41.18%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    1
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Epstein-Barr virus associated lymphoma
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    5 / 11 (45.45%)
    4 / 28 (14.29%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 1
    0 / 1
    1 / 8
    1 / 6
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood culture positive
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shunt malfunction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stroke-like migraine attacks after radiation therapy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    3 / 28 (10.71%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningeal disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis bullous
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pityriasis rosea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Corynebacterium infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Croup infectious
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal bacteraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Part 1 (Dose Escalation): Dabrafenib treatment (3.75 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (3 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (4.5 mg/kg) Part 1 (Dose Escalation): Dabrafenib treatment (5.25 mg/kg) Part 2 (Tumor expansion): Cohort 3 (LCH) Part 2 (Tumor expansion): Cohort 2 High-Grade Gliomas (HGG) Part 2 (Tumor expansion): Cohort 1 Low-Grade Gliomas (LGG) Part 2 (Tumor expansion): Cohort 4 Miscellaneous tumors
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    3 / 3 (100.00%)
    8 / 8 (100.00%)
    6 / 6 (100.00%)
    11 / 11 (100.00%)
    26 / 28 (92.86%)
    17 / 17 (100.00%)
    2 / 2 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    4 / 11 (36.36%)
    8 / 28 (28.57%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    4
    1
    6
    2
    9
    11
    7
    0
    Skin papilloma
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    0
    1
    1
    2
    0
    0
    Acrochordon
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    Lip neoplasm
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Neoplasm skin
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Xanthogranuloma
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    1
    1
    3
    0
    Hypertension
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    1 / 11 (9.09%)
    4 / 28 (14.29%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    1
    2
    1
    5
    3
    0
    Hypotension
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    3 / 11 (27.27%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    2
    0
    4
    0
    5
    0
    Haematoma
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    Hot flush
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    2
    0
    Venous thrombosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Surgical and medical procedures
    Steroid therapy
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    6 / 28 (21.43%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    6
    0
    0
    Chills
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    2
    1
    0
    1
    0
    0
    Complication associated with device
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    2
    1
    0
    0
    0
    0
    Face oedema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    6 / 10 (60.00%)
    2 / 3 (66.67%)
    2 / 8 (25.00%)
    3 / 6 (50.00%)
    3 / 11 (27.27%)
    11 / 28 (39.29%)
    6 / 17 (35.29%)
    0 / 2 (0.00%)
         occurrences all number
    13
    2
    2
    7
    6
    13
    7
    0
    Gait disturbance
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    1
    0
    0
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    2 / 11 (18.18%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    2
    1
    2
    1
    0
    0
    Pain
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    1
    1
    0
    1
    1
    0
    Pyrexia
         subjects affected / exposed
    5 / 10 (50.00%)
    3 / 3 (100.00%)
    7 / 8 (87.50%)
    5 / 6 (83.33%)
    4 / 11 (36.36%)
    10 / 28 (35.71%)
    11 / 17 (64.71%)
    2 / 2 (100.00%)
         occurrences all number
    25
    6
    20
    12
    10
    103
    23
    2
    Xerosis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    0
    0
    Catheter site erythema
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    0
    Catheter site extravasation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Chest pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    Facial pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Feeling hot
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Localised oedema
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    0
    0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Hypersensitivity
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    2
    0
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Dysmenorrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Testicular pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 10 (50.00%)
    1 / 3 (33.33%)
    4 / 8 (50.00%)
    3 / 6 (50.00%)
    6 / 11 (54.55%)
    8 / 28 (28.57%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    8
    14
    6
    10
    17
    11
    4
    0
    Epistaxis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    2
    3
    0
    Nasal congestion
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    3 / 11 (27.27%)
    1 / 28 (3.57%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    5
    6
    7
    3
    5
    1
    3
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    7
    1
    1
    3
    1
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    3
    0
    2
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    3 / 6 (50.00%)
    3 / 11 (27.27%)
    4 / 28 (14.29%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    2
    6
    3
    4
    3
    0
    Wheezing
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    1
    0
    Adenoidal hypertrophy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Catarrh
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Hypocapnia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    Laryngeal inflammation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Productive cough
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Respiratory acidosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Respiratory tract congestion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Restrictive pulmonary disease
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    Sneezing
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Tachypnoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    0
    0
    0
    Anxiety
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    3 / 11 (27.27%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    2
    4
    3
    1
    1
    0
    Depression
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    3
    2
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    0
    Mood altered
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    Affect lability
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    Aggression
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Anger
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    Attention deficit hyperactivity disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Dysphemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    Emotional disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Hallucination
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Irritability
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    1
    0
    Middle insomnia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Suicidal ideation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    3 / 11 (27.27%)
    0 / 28 (0.00%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    11
    1
    2
    4
    5
    0
    8
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    3 / 8 (37.50%)
    2 / 6 (33.33%)
    3 / 11 (27.27%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    4
    1
    3
    4
    4
    2
    0
    0
    Blood alkaline phosphatase decreased
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    2
    1
    1
    1
    0
    Blood creatinine decreased
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    0
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    5 / 11 (45.45%)
    5 / 28 (17.86%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    4
    3
    13
    9
    3
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    2 / 28 (7.14%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    3
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    1
    1
    0
    1
    0
    Haemoglobin increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    1 / 11 (9.09%)
    2 / 28 (7.14%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    6
    1
    2
    2
    1
    2
    8
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    8
    2
    1
    8
    0
    2
    0
    Platelet count decreased
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    3 / 8 (37.50%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    2
    5
    3
    2
    0
    1
    1
    0
    Weight decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    2 / 28 (7.14%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    2
    1
    2
    2
    1
    0
    Weight increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    4
    2
    0
    1
    4
    0
    White blood cell count decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    4 / 11 (36.36%)
    2 / 28 (7.14%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    1
    5
    0
    1
    13
    2
    4
    0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Blood albumin decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Blood bilirubin decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    0
    0
    Blood calcium decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Blood chloride increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    1
    0
    Blood fibrinogen decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Blood luteinising hormone increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Blood prolactin abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Blood urea decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Carbon dioxide decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    0
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Creatinine urine decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    Eosinophil count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    International normalised ratio increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Low density lipoprotein increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    Platelet count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Protein total increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    0
    Protein urine present
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    0
    Red blood cell count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    Respiratory rate decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Urine albumin/creatinine ratio increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    Urine analysis abnormal
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Urine protein/creatinine ratio increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    3
    2
    3
    0
    1
    0
    Contusion
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    4
    2
    0
    1
    0
    Fall
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    3 / 8 (37.50%)
    2 / 6 (33.33%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    3
    2
    4
    0
    1
    0
    Gastrostomy tube site complication
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    0
    0
    0
    Animal bite
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Animal scratch
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Clavicle fracture
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Foot fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Hand fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Ligament sprain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Nail avulsion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Overdose
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Radius fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Scar
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    Skin laceration
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Sunburn
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    Upper limb fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Wound
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    2 / 11 (18.18%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    3
    0
    2
    6
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    4
    2
    1
    2
    1
    0
    Bradycardia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    Cardiac disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Palpitations
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    0
    Tricuspid valve disease
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    2 / 28 (7.14%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    5
    3
    8
    1
    2
    2
    3
    0
    Headache
         subjects affected / exposed
    8 / 10 (80.00%)
    1 / 3 (33.33%)
    3 / 8 (37.50%)
    2 / 6 (33.33%)
    4 / 11 (36.36%)
    10 / 28 (35.71%)
    8 / 17 (47.06%)
    0 / 2 (0.00%)
         occurrences all number
    17
    10
    14
    11
    6
    14
    18
    0
    Paraesthesia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2
    0
    Seizure
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    4 / 28 (14.29%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    6
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    Syncope
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    2
    0
    0
    Altered state of consciousness
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Ataxia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    1
    0
    Dysaesthesia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Dysarthria
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    Dysmetria
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)<