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    Clinical Trial Results:
    A Phase I, open-label, dose escalation study of ceritinib in pediatric patients with malignancies that have a genetic alteration in anaplastic lymphoma kinase (ALK) Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

    Summary
    EudraCT number
    2012-002074-31
    Trial protocol
    DE   NL   GB   IT   FR   ES  
    Global end of trial date
    26 Apr 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Nov 2019
    First version publication date
    11 Nov 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLDK378X2103
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01742286
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, +41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, +41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Apr 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Estimate the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of ceritinib as a single agent when administered orally to pediatric patients with ALK-activated tumors in fasting and fed states. Fasted cohort: each daily dose of LDK378 (including days which involved PK blood sampling) was taken at least 2 hours after last meal & subjects did not eat until 1 hour after LDK378 was taken. Each daily dose of LDK378 was taken with 1-2 tablespoons (15-30 mL) of an appropriate food (such as applesauce or non-fat yogurt) & a glass of water Fed cohort: each daily dose of LDK378 (including days which involved PK blood sampling) was taken with, or within 30 minutes after finishing a low-fat light snack containing 100-300 calories & 1.5-2 grams of fat.
    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
    12 Feb 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: 6
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 30
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    83
    EEA total number of subjects
    67
    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)
    5
    Children (2-11 years)
    48
    Adolescents (12-17 years)
    30
    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
    Eighty-three subjects were treated at different dose levels in both fasted and fed states dose escalation and expansion groups. Forty subjects were treated with ceritinib in the dose escalation phase of the study. Twenty-five subjects were treated with ceritinib in fasted condition in dose escalation.

    Pre-assignment
    Screening details
    At least 15 subjects for the fasted dose escalation & 12 subjects for the fed dose escalation were expected to be treated. During the expansion part, approx. 45 subjects were planned to be treated on the preferred regimen, approx. 25 in group 1 (ALK-activated neuroblastoma) & approx. 20 in group 2 (other ALK-activated tumor such as IMT or ALCL).

    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
    Fasted: Ceritinib 300 mg/m2
    Arm description
    Participants in the fasted group who took 300 mg of ceritinib
    Arm type
    Experimental

    Investigational medicinal product name
    Ceritinib
    Investigational medicinal product code
    LDK378
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use, Nasogastric use , Gastric use
    Dosage and administration details
    300 mg/m2 Ceritinib was administered once daily by mouth, or by nasogastric tube or gastric tube.

    Arm title
    Fasted: Ceritinib 450 mg/m2
    Arm description
    Participants in the fasted group who took 450 mg of ceritinib
    Arm type
    Experimental

    Investigational medicinal product name
    Ceritinib
    Investigational medicinal product code
    LDK378
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use, Nasogastric use , Gastric use
    Dosage and administration details
    450 mg/m2 Ceritinib was administered once daily by mouth, or by nasogastric tube or gastric tube.

    Arm title
    Fasted: Ceritinib 510 mg/m2
    Arm description
    Participants in the fasted group who took 510 mg of ceritinib
    Arm type
    Experimental

    Investigational medicinal product name
    Ceritinib
    Investigational medicinal product code
    LDK378
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use, Nasogastric use , Gastric use
    Dosage and administration details
    510 mg/m2 Ceritinib was administered once daily by mouth, or by nasogastric tube or gastric tube.

    Arm title
    Fasted: Ceritinib 560 mg/m2
    Arm description
    Participants in the fasted group who took 560 mg of ceritinib
    Arm type
    Experimental

    Investigational medicinal product name
    Ceritinib
    Investigational medicinal product code
    LDK378
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use, Nasogastric use , Gastric use
    Dosage and administration details
    560 mg/m2 Ceritinib was administered once daily by mouth, or by nasogastric tube or gastric tube.

    Arm title
    Fed: Ceritinib 320 mg/m2
    Arm description
    Participants in the fed group who took 320 mg of ceritinib
    Arm type
    Experimental

    Investigational medicinal product name
    Ceritinib
    Investigational medicinal product code
    LDK378
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use, Nasogastric use , Gastric use
    Dosage and administration details
    320 mg/m2 Ceritinib was administered once daily by mouth, or by nasogastric tube or gastric tube.

    Arm title
    Fed: Ceritinib 400 mg/m2
    Arm description
    Participants in the fed group who took 400 mg of ceritinib
    Arm type
    Experimental

    Investigational medicinal product name
    Ceritinib
    Investigational medicinal product code
    LDK378
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use, Nasogastric use , Gastric use
    Dosage and administration details
    400 mg/m2 Ceritinib was administered once daily by mouth, or by nasogastric tube or gastric tube.

    Arm title
    Fed: Ceritinib 500 mg/m2
    Arm description
    Participants in the fed group who took 500 mg of ceritinib
    Arm type
    Experimental

    Investigational medicinal product name
    Ceritinib
    Investigational medicinal product code
    LDK378
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use, Nasogastric use , Gastric use
    Dosage and administration details
    500 mg/m2 Ceritinib was administered once daily by mouth, or by nasogastric tube or gastric tube.

    Number of subjects in period 1
    Fasted: Ceritinib 300 mg/m2 Fasted: Ceritinib 450 mg/m2 Fasted: Ceritinib 510 mg/m2 Fasted: Ceritinib 560 mg/m2 Fed: Ceritinib 320 mg/m2 Fed: Ceritinib 400 mg/m2 Fed: Ceritinib 500 mg/m2
    Started
    5
    12
    13
    2
    4
    5
    42
    Ended Treatment = Not Completed)
    5
    12
    13
    2
    4
    5
    42
    Completed
    0
    0
    0
    0
    0
    0
    0
    Not completed
    5
    12
    13
    2
    4
    5
    42
         Adverse event, serious fatal
    -
    -
    -
    -
    -
    1
    -
         Physician decision
    -
    3
    4
    1
    -
    -
    11
         Consent withdrawn by subject
    -
    -
    -
    -
    -
    -
    1
         Disease progression
    3
    7
    7
    1
    4
    3
    17
         Adverse event, non-fatal
    -
    1
    2
    -
    -
    1
    6
         Administrative problems
    1
    1
    -
    -
    -
    -
    7
         Patient/guardian decision
    1
    -
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fasted: Ceritinib 300 mg/m2
    Reporting group description
    Participants in the fasted group who took 300 mg of ceritinib

    Reporting group title
    Fasted: Ceritinib 450 mg/m2
    Reporting group description
    Participants in the fasted group who took 450 mg of ceritinib

    Reporting group title
    Fasted: Ceritinib 510 mg/m2
    Reporting group description
    Participants in the fasted group who took 510 mg of ceritinib

    Reporting group title
    Fasted: Ceritinib 560 mg/m2
    Reporting group description
    Participants in the fasted group who took 560 mg of ceritinib

    Reporting group title
    Fed: Ceritinib 320 mg/m2
    Reporting group description
    Participants in the fed group who took 320 mg of ceritinib

    Reporting group title
    Fed: Ceritinib 400 mg/m2
    Reporting group description
    Participants in the fed group who took 400 mg of ceritinib

    Reporting group title
    Fed: Ceritinib 500 mg/m2
    Reporting group description
    Participants in the fed group who took 500 mg of ceritinib

    Reporting group values
    Fasted: Ceritinib 300 mg/m2 Fasted: Ceritinib 450 mg/m2 Fasted: Ceritinib 510 mg/m2 Fasted: Ceritinib 560 mg/m2 Fed: Ceritinib 320 mg/m2 Fed: Ceritinib 400 mg/m2 Fed: Ceritinib 500 mg/m2 Total
    Number of subjects
    5 12 13 2 4 5 42 83
    Age, Customized
    Units: Subjects
        1 - < 7 yrs
    1 4 6 1 2 2 21 37
        7 - < 12 yrs
    2 2 1 0 0 1 10 16
        12 - < 18 yrs
    2 6 6 1 2 2 11 30
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    11.6 ± 5.27 10.0 ± 4.94 9.2 ± 5.34 9.0 ± 9.90 8.8 ± 4.99 9.2 ± 4.02 7.3 ± 4.73 -
    Sex: Female, Male
    Units: Subjects
        Female
    3 3 5 1 1 3 14 30
        Male
    2 9 8 1 3 2 28 53
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    0 1 1 0 0 0 3 5
        Black
    0 1 0 0 0 0 0 1
        Caucasian
    5 7 11 2 4 3 33 65
        Other
    0 3 1 0 0 2 5 11
        Native American
    0 0 0 0 0 0 1 1
    Subject analysis sets

    Subject analysis set title
    ALK-activated Neuroblastoma
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with ALK-activated neuroblstoma enrolled in the expansion part of the study and were given ceritinib once daily, continuously

    Subject analysis set title
    ALK-activated Inflammatory myofibroblastic tumors (IMT)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with ALK-activated IMT enrolled in the expansion part of the study who were given ceritinib once daily, continuously

    Subject analysis set title
    ALK-activated Anaplastic large cell lymphoma (ALCL)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with ALK-activated ALCL enrolled in the expansion part of the study who were given ceritinib once daily, continuously

    Subject analysis set title
    ALK-activated Other
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with other ALK-activated tumors enrolled in the expansion part of the study who were given ceritinib once daily, continuously

    Subject analysis set title
    ALK-activated Neuroblastoma
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with ALK-activated neuroblstoma enrolled in the expansion part of the study and were given ceritinib once daily, continuously

    Subject analysis set title
    ALK-activated Inflammatory myofibroblastic tumors (IMT)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with ALK-activated IMT enrolled in the expansion part of the study who were given ceritinib once daily, continuously

    Subject analysis set title
    ALK-activated Anaplastic large cell lymphoma (ALCL)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with ALK-activated ALCL enrolled in the expansion part of the study who were given ceritinib once daily, continuously

    Subject analysis set title
    ALK-activated Other
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with other ALK-activated tumors enrolled in the expansion part of the study who were given ceritinib once daily, continuously

    Subject analysis sets values
    ALK-activated Neuroblastoma ALK-activated Inflammatory myofibroblastic tumors (IMT) ALK-activated Anaplastic large cell lymphoma (ALCL) ALK-activated Other ALK-activated Neuroblastoma ALK-activated Inflammatory myofibroblastic tumors (IMT) ALK-activated Anaplastic large cell lymphoma (ALCL) ALK-activated Other
    Number of subjects
    30
    10
    8
    7
    6
    7
    6
    1
    Age, Customized
    Units: Subjects
        1 - < 7 yrs
        7 - < 12 yrs
        12 - < 18 yrs
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    20.0 ±
    70.0 ±
    75.0 ±
    14.3 ±
    15.0 ±
    99.99 ±
    99.99 ±
    99.99 ±
    Sex: Female, Male
    Units: Subjects
        Female
        Male
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
        Black
        Caucasian
        Other
        Native American

    End points

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    End points reporting groups
    Reporting group title
    Fasted: Ceritinib 300 mg/m2
    Reporting group description
    Participants in the fasted group who took 300 mg of ceritinib

    Reporting group title
    Fasted: Ceritinib 450 mg/m2
    Reporting group description
    Participants in the fasted group who took 450 mg of ceritinib

    Reporting group title
    Fasted: Ceritinib 510 mg/m2
    Reporting group description
    Participants in the fasted group who took 510 mg of ceritinib

    Reporting group title
    Fasted: Ceritinib 560 mg/m2
    Reporting group description
    Participants in the fasted group who took 560 mg of ceritinib

    Reporting group title
    Fed: Ceritinib 320 mg/m2
    Reporting group description
    Participants in the fed group who took 320 mg of ceritinib

    Reporting group title
    Fed: Ceritinib 400 mg/m2
    Reporting group description
    Participants in the fed group who took 400 mg of ceritinib

    Reporting group title
    Fed: Ceritinib 500 mg/m2
    Reporting group description
    Participants in the fed group who took 500 mg of ceritinib

    Subject analysis set title
    ALK-activated Neuroblastoma
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with ALK-activated neuroblstoma enrolled in the expansion part of the study and were given ceritinib once daily, continuously

    Subject analysis set title
    ALK-activated Inflammatory myofibroblastic tumors (IMT)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with ALK-activated IMT enrolled in the expansion part of the study who were given ceritinib once daily, continuously

    Subject analysis set title
    ALK-activated Anaplastic large cell lymphoma (ALCL)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with ALK-activated ALCL enrolled in the expansion part of the study who were given ceritinib once daily, continuously

    Subject analysis set title
    ALK-activated Other
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with other ALK-activated tumors enrolled in the expansion part of the study who were given ceritinib once daily, continuously

    Subject analysis set title
    ALK-activated Neuroblastoma
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with ALK-activated neuroblstoma enrolled in the expansion part of the study and were given ceritinib once daily, continuously

    Subject analysis set title
    ALK-activated Inflammatory myofibroblastic tumors (IMT)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with ALK-activated IMT enrolled in the expansion part of the study who were given ceritinib once daily, continuously

    Subject analysis set title
    ALK-activated Anaplastic large cell lymphoma (ALCL)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with ALK-activated ALCL enrolled in the expansion part of the study who were given ceritinib once daily, continuously

    Subject analysis set title
    ALK-activated Other
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with other ALK-activated tumors enrolled in the expansion part of the study who were given ceritinib once daily, continuously

    Primary: Incidence rate of Dose Limiting Toxicities (DLTs) occurring during first cycle of treatment

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    End point title
    Incidence rate of Dose Limiting Toxicities (DLTs) occurring during first cycle of treatment [1]
    End point description
    A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant therapies that occurs within the first 21 days of treatment with LDK378 and meets a specified defined criteria. A participant with multiple occurrences of DLTs under one treatment is counted only once in the Adverse Event category for that treatment. A participant with multiple DLTs within a primary system organ class is counted only once in the total row.
    End point type
    Primary
    End point timeframe
    up to day 21 after the patient's first dose; cycle = within the first 21 days of patient's first dose
    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: No statistical analysis was planned for this endpoint
    End point values
    Fasted: Ceritinib 300 mg/m2 Fasted: Ceritinib 450 mg/m2 Fasted: Ceritinib 510 mg/m2 Fasted: Ceritinib 560 mg/m2 Fed: Ceritinib 320 mg/m2 Fed: Ceritinib 400 mg/m2 Fed: Ceritinib 500 mg/m2
    Number of subjects analysed
    4
    12
    6
    2
    4
    4
    5
    Units: Participants
        Investigations: Alanine aminotransferase incr.
    0
    0
    0
    1
    0
    1
    0
        Gastrointestinal disorders: abdominal pain
    0
    0
    0
    1
    0
    0
    0
        Gastrointestinal disorders: Influenza
    0
    0
    0
    0
    0
    0
    1
        Total DLTs
    0
    0
    0
    2
    0
    1
    1
    No statistical analyses for this end point

    Secondary: Summary of best overall response by Overall response Rate (ORR) per Investigator assessment

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    End point title
    Summary of best overall response by Overall response Rate (ORR) per Investigator assessment
    End point description
    Assessed the anti-tumor activity of LDK378 per investigator assessment of disease status using RECIST 1.1 by treatment group.
    End point type
    Secondary
    End point timeframe
    30 months
    End point values
    ALK-activated Neuroblastoma ALK-activated Inflammatory myofibroblastic tumors (IMT) ALK-activated Anaplastic large cell lymphoma (ALCL) ALK-activated Other
    Number of subjects analysed
    30
    10
    8
    7
    Units: percentage of participants
        number (confidence interval 95%)
    20.0 (7.7 to 38.6)
    70.0 (34.8 to 93.3)
    75.0 (34.9 to 96.8)
    14.3 (0.4 to 57.9)
    No statistical analyses for this end point

    Secondary: Duration of response (DoR) per investigator assessment

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    End point title
    Duration of response (DoR) per investigator assessment
    End point description
    Assess the anti-tumor activity of LDK378 per DOR by primary diagnosis of tumor
    End point type
    Secondary
    End point timeframe
    30 months
    End point values
    ALK-activated Neuroblastoma ALK-activated Inflammatory myofibroblastic tumors (IMT) ALK-activated Anaplastic large cell lymphoma (ALCL) ALK-activated Other
    Number of subjects analysed
    6
    7
    6
    1
    Units: months
        median (confidence interval 95%)
    15.0 (5.8 to 22.2)
    999 (3.5 to 999)
    999 (2.8 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Progression free survival (PFS) based on investigator assessment

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    End point title
    Progression free survival (PFS) based on investigator assessment
    End point description
    Assess the anti-tumor activity of LDK378 as per RECIST 1.1 by PFS by primary diagnosis of tumor
    End point type
    Secondary
    End point timeframe
    30 months
    End point values
    ALK-activated Neuroblastoma ALK-activated Inflammatory myofibroblastic tumors (IMT) ALK-activated Anaplastic large cell lymphoma (ALCL) ALK-activated Other
    Number of subjects analysed
    30
    10
    6
    1
    Units: months
        median (confidence interval 95%)
    2.4 (1.2 to 6.8)
    999 (1.2 to 999)
    999 (4.1 to 999)
    1.9 (1.2 to 999)
    No statistical analyses for this end point

    Secondary: Plasma concentration time profiles by treatment group in escalation phase

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    End point title
    Plasma concentration time profiles by treatment group in escalation phase
    End point description
    Characterize single and multiple-dose PK of LDK378 in pediatric patients. Only PK plasma concentrations with non-missing sampling date and time, and for which the last dose date and time prior to the PK sample draw are non-missing, were included in the PK analysis.
    End point type
    Secondary
    End point timeframe
    0hr pre-dose, 2hrs post-dose, 4hrs post-dose, 6hrs post-dose & 24hrs post-dose in Cycle1 Day1 & Cycle 2 day 1; 0hr pre-dose in Cycle 1 Day 15, Cycle 2 Day1, Cycle 2 Day 2, Cycle 3 day 1 & Cycle 4 Day 1
    End point values
    Fasted: Ceritinib 300 mg/m2 Fasted: Ceritinib 450 mg/m2 Fasted: Ceritinib 510 mg/m2 Fasted: Ceritinib 560 mg/m2 Fed: Ceritinib 320 mg/m2 Fed: Ceritinib 400 mg/m2 Fed: Ceritinib 500 mg/m2
    Number of subjects analysed
    5
    12
    13
    2
    4
    5
    21
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle1 Day1 (C1D1) 0 hr pre-dose(n=5,12,6,2,4,5,5)
    0.0 ± 0.0
    0.0 ± 0.0
    0.0 ± 0.0
    0.0 ± 0.0
    0.0 ± 0.0
    0.0 ± 0.0
    0.0 ± 0.0
        C1D1 2 hrs post-dose(n=5,11,6,2,4,5,5)
    104 ± 97.9
    99.0 ± 94.7
    112 ± 90.6
    126 ± 0.6
    52.4 ± 138.1
    197 ± 58.3
    72.5 ± 82.3
        C1D1 4 hrs post-dose(n=5,11,6,2,4,5,5)
    216 ± 39.6
    233 ± 69.0
    250 ± 93.5
    350 ± 54.7
    166 ± 92.8
    311 ± 28.1
    153 ± 34.1
        C1D1 6 hrs post-dose(n=5,11,6,2,4,5,4)
    227 ± 33.8
    245 ± 78.1
    245 ± 97.2
    423 ± 74.2
    275 ± 35.3
    318 ± 36.7
    168 ± 68.9
        C1D1 24 hrs post-dose(n=5,11,6,2,4,5,4)
    130 ± 66.3
    141 ± 89.9
    86.4 ± 117.2
    268 ± 73.6
    98.5 ± 63.7
    126 ± 107.7
    161 ± 111.3
        C1D2 0 hr pre-dose(n=5,11,6,2,4,5,4)
    130 ± 66.3
    141 ± 89.9
    86.4 ± 117.2
    268 ± 73.6
    98.5 ± 63.7
    126 ± 107.7
    161 ± 111.3
        C1D15 0 hr pre-dose(n=5,12,6,2,3,4,5)
    193 ± 99.6
    618 ± 64.6
    537 ± 49.9
    942 ± 5.1
    262 ± 118.4
    379 ± 119.2
    461 ± 76.3
        C2D1 0 hr pre-dose(n=5,12,5,2,3,4,3)
    169 ± 299.5
    661 ± 53.5
    672 ± 45.4
    695 ± 152.7
    218 ± 103.7
    429 ± 73.8
    655 ± 12.4
        C2D1 2 hrs post-dose(n=5,12,5,2,3,4,3)
    287 ± 85.4
    687 ± 61.6
    801 ± 45.9
    662 ± 99.6
    196 ± 112.4
    475 ± 96.6
    718 ± 21.1
        C2D1 4 hrs post-dose(n=5,12,5,2,3,4,3)
    386 ± 47.6
    810 ± 51.9
    1000 ± 30.4
    1230 ± 30.1
    262 ± 133.9
    631 ± 86.6
    744 ± 13.2
        C2D1 6 hrs post-dose(n=5,12,5,2,3,4,2)
    426 ± 38.4
    852 ± 47.8
    898 ± 37.6
    1260 ± 16.4
    300 ± 130.3
    648 ± 105.5
    786 ± 7.7
        C2D1 24 hrs post-dose(n=5,12,5,2,3,4,5)
    247 ± 46.9
    651 ± 53.7
    714 ± 40.8
    847 ± 72.2
    194 ± 106.5
    411 ± 147.3
    448 ± 43.9
        C2D2 0 hr pre-dose(n=5,12,5,2,3,4,5)
    247 ± 46.9
    651 ± 53.7
    714 ± 40.8
    847 ± 72.2
    194 ± 106.5
    411 ± 147.3
    448 ± 43.9
        C3D1 0 hr pre-dose(n=2,8,4,1,2,1,5)
    399 ± 94.4
    810 ± 34.3
    415 ± 117.7
    1320 ± 0.0
    167 ± 218.3
    328 ± 0.0
    433 ± 128.5
        C4D1 0 hr pre-dose(n=2,8,4,1,1,1,3)
    503 ± 35.1
    960 ± 36.2
    321 ± 874.8
    857 ± 0.0
    403 ± 0.0
    1320 ± 0.0
    658 ± 27.0
    No statistical analyses for this end point

    Secondary: Plasma concentration time profiles by treatment group in expansion phase

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    End point title
    Plasma concentration time profiles by treatment group in expansion phase
    End point description
    Characterize single and multiple-dose PK of LDK378 in pediatric patients. Only PK plasma concentrations with non-missing sampling date and time, and for which thelast dose date and time prior to the PK sample draw are non-missing, were included in the PK analysis.
    End point type
    Secondary
    End point timeframe
    0hr pre-dose Cycle 1 Day 1, cycle 1 Day 15; 0hr pre-dose, 2hrs post-dose, 4hrs post-dose, 6hrs post-dose & 24hrs post-dose in Cycle2 Day1; 0hr pre-dose in Cycle2 Day2, Cycle 3 Day 1 & Cycle 4 Day 1
    End point values
    Fasted: Ceritinib 300 mg/m2 Fasted: Ceritinib 450 mg/m2 Fasted: Ceritinib 510 mg/m2 Fasted: Ceritinib 560 mg/m2 Fed: Ceritinib 320 mg/m2 Fed: Ceritinib 400 mg/m2 Fed: Ceritinib 500 mg/m2
    Number of subjects analysed
    5
    12
    13
    2
    4
    5
    21
    Units: mg/mg^2
    geometric mean (geometric coefficient of variation)
        C1D1 0 hr pre-dose(n=0,0,6,0,0,0,9)
    999 ± 999
    999 ± 999
    0.0 ± 0.0
    999 ± 999
    999 ± 999
    999 ± 999
    0.0 ± 0.0
        C1D15 0 hr post-dose(n=0,0,1,0,0,0,0)
    999 ± 999
    999 ± 999
    1190 ± 0.0
    999 ± 999
    999 ± 999
    999 ± 999
    999 ± 999
        C2D1 0 hr pre-dose(n=0,0,7,0,0,0,16)
    999 ± 999
    999 ± 999
    529 ± 365.4
    999 ± 999
    999 ± 999
    999 ± 999
    627 ± 93.6
        C2D1 2 hrs post-dose(n=0,0,7,0,0,0,15)
    999 ± 999
    999 ± 999
    798 ± 69.0
    999 ± 999
    999 ± 999
    999 ± 999
    729 ± 72.3
        C2D1 4 hrs post-dose(n=0,0,7,0,0,0,4)
    999 ± 999
    999 ± 999
    863 ± 65.2
    999 ± 999
    999 ± 999
    999 ± 999
    828 ± 47.9
        C2D1 6 hrs post-dose(n=0,0,7,0,0,0,15)
    999 ± 999
    999 ± 999
    939 ± 71.4
    999 ± 999
    999 ± 999
    999 ± 999
    870 ± 52.6
        C2D1 24 hrs post-dose(n=0,0,6,0,0,0,14)
    999 ± 999
    999 ± 999
    615 ± 119.9
    999 ± 999
    999 ± 999
    999 ± 999
    596 ± 75.5
        C2D2 0 hr pre-dose(n=0,0,6,0,0,0,14)
    999 ± 999
    999 ± 999
    615 ± 119.9
    999 ± 999
    999 ± 999
    999 ± 999
    596 ± 75.5
        C3D1 0 hr pre-dose(n=0,0,5,0,0,0,14)
    999 ± 999
    999 ± 999
    836 ± 60.4
    999 ± 999
    999 ± 999
    999 ± 999
    573 ± 134.2
        C4D1 0 hr pre-dose(n=0,0,5,0,0,0,12)
    999 ± 999
    999 ± 999
    834 ± 78.8
    999 ± 999
    999 ± 999
    999 ± 999
    622 ± 96.5
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK) parameters: AUC0 - 24h & AUClast in Cycle 1 Day 1 - Dose escalation phase (single dose)

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    End point title
    Pharmacokinetics (PK) parameters: AUC0 - 24h & AUClast in Cycle 1 Day 1 - Dose escalation phase (single dose)
    End point description
    Characterize single and multiple-dose PK of LDK378 in pediatric patients. AUC: Area under the plasma (serum, or blood) concentration versus time curve AUClast: Area under the plasma (serum, or blood) concentration versus time curverea under the concentration-time curve from time zero to the last measureable concentration time AUC0-24h: AUC0-24h Area under the plasma concentration-time curve t=0-24 h
    End point type
    Secondary
    End point timeframe
    0hr pre-dose, 2, 4, 6 & 24hrs post-dose
    End point values
    Fasted: Ceritinib 300 mg/m2 Fasted: Ceritinib 450 mg/m2 Fasted: Ceritinib 510 mg/m2 Fasted: Ceritinib 560 mg/m2 Fed: Ceritinib 320 mg/m2 Fed: Ceritinib 400 mg/m2 Fed: Ceritinib 500 mg/m2
    Number of subjects analysed
    5
    12
    10
    2
    3
    4
    18
    Units: hr*ng/mL
    geometric mean (geometric coefficient of variation)
        AUC0-24h (n=4,3,2,0,1,1,2)
    3920 ± 39.9
    5220 ± 58.0
    8750 ± 11.1
    999 ± 999
    5720 ± 0.0
    7272 ± 0.0
    4730 ± 59.4
        AUClast (n= 5,9,3,1,3,4,3)
    4260 ± 39.3
    4350 ± 91.8
    7670 ± 24.5
    4860 ± 0.0
    3730 ± 48.6
    5760 ± 49.1
    4940 ± 32.6
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK) parameters: AUC0 - 24h & AUClast in Cycle 2 Day 1 - Dose escalation phase (single dose)

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    End point title
    Pharmacokinetics (PK) parameters: AUC0 - 24h & AUClast in Cycle 2 Day 1 - Dose escalation phase (single dose)
    End point description
    Characterize single and multiple-dose PK of LDK378 in pediatric patients. AUC: Area under the plasma (serum, or blood) concentration versus time curve AUClast: Area under the plasma (serum, or blood) concentration versus time curverea under the concentration-time curve from time zero to the last measureable concentration time AUC0-24h: AUC0-24h Area under the plasma concentration-time curve t=0-24 h
    End point type
    Secondary
    End point timeframe
    0hr pre-dose, 2, 4, 6 & 24hrs post-dose
    End point values
    Fasted: Ceritinib 300 mg/m2 Fasted: Ceritinib 450 mg/m2 Fasted: Ceritinib 510 mg/m2 Fasted: Ceritinib 560 mg/m2 Fed: Ceritinib 320 mg/m2 Fed: Ceritinib 400 mg/m2 Fed: Ceritinib 500 mg/m2
    Number of subjects analysed
    5
    12
    10
    2
    3
    4
    18
    Units: hr*ng/mL
    geometric mean (geometric coefficient of variation)
        AUC0-24h (n=5,7,2,2,1,1,1)
    8160 ± 44.0
    16900 ± 59.1
    21000 ± 20.8
    25300 ± 39.2
    2100 ± 0.0
    30500 ± 0.0
    16500 ± 0.0
        AUClast (n= 5,12,5,2,3,4,2)
    8210 ± 44.3
    18000 ± 50.0
    17200 ± 51.2
    25600 ± 39.0
    5840 ± 118.4
    125000 ± 113.2
    16700 ± 1.8
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK) parameters: AUC0 - 24h & AUClast in Cycle 2 Day 1 - Dose expansion phase (multiple dose)

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    End point title
    Pharmacokinetics (PK) parameters: AUC0 - 24h & AUClast in Cycle 2 Day 1 - Dose expansion phase (multiple dose) [2]
    End point description
    Characterize single and multiple-dose PK of LDK378 in pediatric patients. In this phase ceritinib was expanded at 500mg/m2 fed and 510mg/m2 fasted administered orally once daily and was assessed only at steady state, Cycle 2 Day 1. AUC: Area under the plasma (serum, or blood) concentration versus time curve AUClast: Area under the plasma (serum, or blood) concentration versus time curverea under the concentration-time curve from time zero to the last measureable concentration time AUC0-24h: AUC0-24h Area under the plasma concentration-time curve t=0-24 h
    End point type
    Secondary
    End point timeframe
    0hr pre-dose, 2, 4, 6 & 24hrs post-dose
    Notes
    [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: No statistical analysis was planned for this endpoint
    End point values
    Fasted: Ceritinib 510 mg/m2 Fed: Ceritinib 500 mg/m2
    Number of subjects analysed
    10
    18
    Units: hr*ng/mL
    geometric mean (geometric coefficient of variation)
        AUC0-24h (n = 0, 6)
    999 ± 999
    15900 ± 93.8
        AUClast (n = 4, 14)
    24100 ± 38.9
    16100 ± 61.2
    No statistical analyses for this end point

    Secondary: PK parameter: Cmax in Cycle 1 Day 1 - Dose escalation phase (single dose)

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    End point title
    PK parameter: Cmax in Cycle 1 Day 1 - Dose escalation phase (single dose)
    End point description
    Characterize single and multiple-dose PK of LDK378 in pediatric patients. Cmax: Maximum (peak) concentration of drug
    End point type
    Secondary
    End point timeframe
    0hr pre-dose, 2, 4, 6 & 24hrs post-dose
    End point values
    Fasted: Ceritinib 300 mg/m2 Fasted: Ceritinib 450 mg/m2 Fasted: Ceritinib 510 mg/m2 Fasted: Ceritinib 560 mg/m2 Fed: Ceritinib 320 mg/m2 Fed: Ceritinib 400 mg/m2 Fed: Ceritinib 500 mg/m2
    Number of subjects analysed
    5
    12
    10
    2
    3
    4
    18
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    258 ± 39.0
    270 ± 82.1
    537 ± 22.2
    265 ± 0.0
    251 ± 37.0
    341 ± 34.2
    204 ± 54.6
    No statistical analyses for this end point

    Secondary: PK parameter: Cmax in Cycle 2 Day 1 - Dose escalation phase (single dose)

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    End point title
    PK parameter: Cmax in Cycle 2 Day 1 - Dose escalation phase (single dose)
    End point description
    Characterize single and multiple-dose PK of LDK378 in pediatric patients. Cmax: Maximum (peak) concentration of drug.
    End point type
    Secondary
    End point timeframe
    0hr pre-dose, 2, 4, 6 & 24hrs post-dose
    End point values
    Fasted: Ceritinib 300 mg/m2 Fasted: Ceritinib 450 mg/m2 Fasted: Ceritinib 510 mg/m2 Fasted: Ceritinib 560 mg/m2 Fed: Ceritinib 320 mg/m2 Fed: Ceritinib 400 mg/m2 Fed: Ceritinib 500 mg/m2
    Number of subjects analysed
    5
    12
    10
    2
    3
    4
    18
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    427 ± 38.5
    870 ± 48.7
    1020 ± 32.1
    1300 ± 21.4
    300 ± 130.3
    674 ± 93.8
    804 ± 10.4
    No statistical analyses for this end point

    Secondary: PK parameter: Cmax in Cycle 2 Day 1 - Dose expansion phase (multiple dose)

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    End point title
    PK parameter: Cmax in Cycle 2 Day 1 - Dose expansion phase (multiple dose) [3]
    End point description
    Characterize single and multiple-dose PK of LDK378 in pediatric patients. In this phase ceritinib was expanded at 500mg/m2 fed and 510mg/m2 fasted administered orally once daily and was assessed only at steady state, Cycle 2 Day 1. Cmax: Maximum (peak) concentration of drug
    End point type
    Secondary
    End point timeframe
    0hr pre-dose, 2, 4, 6 & 24hrs post-dose
    Notes
    [3] - 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: No statistical analysis was planned for this endpoint
    End point values
    Fasted: Ceritinib 510 mg/m2 Fed: Ceritinib 500 mg/m2
    Number of subjects analysed
    10
    18
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    1220 ± 40.2
    890 ± 50.9
    No statistical analyses for this end point

    Secondary: PK parameter: Tmax in Cycle 1 Day 1 - Dose escalation phase (single dose)

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    End point title
    PK parameter: Tmax in Cycle 1 Day 1 - Dose escalation phase (single dose)
    End point description
    Characterize single and multiple-dose PK of LDK378 in pediatric patients. Tmax: The time to reach maximum plasma concentration
    End point type
    Secondary
    End point timeframe
    0hr pre-dose, 2, 4, 6 & 24hrs post-dose
    End point values
    Fasted: Ceritinib 300 mg/m2 Fasted: Ceritinib 450 mg/m2 Fasted: Ceritinib 510 mg/m2 Fasted: Ceritinib 560 mg/m2 Fed: Ceritinib 320 mg/m2 Fed: Ceritinib 400 mg/m2 Fed: Ceritinib 500 mg/m2
    Number of subjects analysed
    5
    12
    10
    2
    3
    4
    18
    Units: hour (hr)
        median (full range (min-max))
    4.20 (1.90 to 24.0)
    4.25 (0.00 to 6.10)
    4.30 (4.10 to 6.00)
    6.10 (6.10 to 6.10)
    6.10 (5.70 to 6.30)
    6.00 (4.30 to 6.20)
    5.80 (4.10 to 6.10)
    No statistical analyses for this end point

    Secondary: PK parameter: Tmax in Cycle 2 Day 1 - Dose escalation phase (single dose)

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    End point title
    PK parameter: Tmax in Cycle 2 Day 1 - Dose escalation phase (single dose)
    End point description
    Characterize single and multiple-dose PK of LDK378 in pediatric patients. Tmax: The time to reach maximum plasma concentration
    End point type
    Secondary
    End point timeframe
    0hr pre-dose, 2, 4, 6 & 24hrs post-dose
    End point values
    Fasted: Ceritinib 300 mg/m2 Fasted: Ceritinib 450 mg/m2 Fasted: Ceritinib 510 mg/m2 Fasted: Ceritinib 560 mg/m2 Fed: Ceritinib 320 mg/m2 Fed: Ceritinib 400 mg/m2 Fed: Ceritinib 500 mg/m2
    Number of subjects analysed
    5
    12
    10
    2
    3
    4
    18
    Units: hour (hr)
        median (full range (min-max))
    6.00 (4.10 to 6.70)
    5.10 (2.00 to 6.60)
    4.00 (2.10 to 6.00)
    3.95 (0.00 to 6.70)
    5.90 (5.80 to 6.10)
    6.00 (4.00 to 6.10)
    2.20 (2.00 to 2.40)
    No statistical analyses for this end point

    Secondary: PK parameter: Tmax in Cycle 2 Day 1 - Dose expansion phase (multiple dose)

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    End point title
    PK parameter: Tmax in Cycle 2 Day 1 - Dose expansion phase (multiple dose) [4]
    End point description
    Characterize single and multiple-dose PK of LDK378 in pediatric patients. In this phase ceritinib was expanded at 500mg/m2 fed and 510mg/m2 fasted administered orally once daily and was assessed only at steady state, Cycle 2 Day 1. Characterize single and multiple-dose PK of LDK378 in pediatric patients. Tmax: The time to reach maximum plasma concentration
    End point type
    Secondary
    End point timeframe
    0hr pre-dose, 2, 4, 6 & 24hrs post-dose
    Notes
    [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: No statistical analysis was planned for this endpoint
    End point values
    Fasted: Ceritinib 510 mg/m2 Fed: Ceritinib 500 mg/m2
    Number of subjects analysed
    10
    18
    Units: hour (hr)
        median (full range (min-max))
    6.20 (3.80 to 23.8)
    5.90 (1.90 to 23.6)
    No statistical analyses for this end point

    Secondary: PK parameter: Racc in Dose escalation phase Cycle 2 Day 1

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    End point title
    PK parameter: Racc in Dose escalation phase Cycle 2 Day 1
    End point description
    Characterize single and multiple-dose PK of LDK378 in pediatric patients. Racc: Accumulation ratio
    End point type
    Secondary
    End point timeframe
    0hr pre-dose, 2, 4, 6 & 24hrs post-dose
    End point values
    Fasted: Ceritinib 300 mg/m2 Fasted: Ceritinib 450 mg/m2 Fasted: Ceritinib 510 mg/m2 Fasted: Ceritinib 560 mg/m2 Fed: Ceritinib 320 mg/m2 Fed: Ceritinib 400 mg/m2 Fed: Ceritinib 500 mg/m2
    Number of subjects analysed
    5
    12
    10
    2
    3
    4
    18
    Units: ratio
        geometric mean (geometric coefficient of variation)
    41.6 ± 80.7
    30.3 ± 116.3
    22.8 ± 71.6
    15.5 ± 0.0
    95.0 ± 0.0
    9.83 ± 0.0
    19.3 ± 118.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of 63.7 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
    21.0
    Reporting groups
    Reporting group title
    Ceritinib@300 mg/m2
    Reporting group description
    Ceritinib@300 mg/m2

    Reporting group title
    Ceritinib@450 mg/m2
    Reporting group description
    Ceritinib@450 mg/m2

    Reporting group title
    Ceritinib@510 mg/m2
    Reporting group description
    Ceritinib@510 mg/m2

    Reporting group title
    Ceritinib@560 mg/m2
    Reporting group description
    Ceritinib@560 mg/m2

    Reporting group title
    Ceritinib@320 mg/m2
    Reporting group description
    Ceritinib@320 mg/m2

    Reporting group title
    Ceritinib@400 mg/m2
    Reporting group description
    Ceritinib@400 mg/m2

    Reporting group title
    Ceritinib@500 mg/m2
    Reporting group description
    Ceritinib@500 mg/m2

    Reporting group title
    Fasted+Fed All Subjects
    Reporting group description
    All participants in the Fasted and Fed groups

    Serious adverse events
    Ceritinib@300 mg/m2 Ceritinib@450 mg/m2 Ceritinib@510 mg/m2 Ceritinib@560 mg/m2 Ceritinib@320 mg/m2 Ceritinib@400 mg/m2 Ceritinib@500 mg/m2 Fasted+Fed All Subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 5 (20.00%)
    4 / 12 (33.33%)
    8 / 13 (61.54%)
    2 / 2 (100.00%)
    3 / 4 (75.00%)
    1 / 5 (20.00%)
    21 / 42 (50.00%)
    40 / 83 (48.19%)
         number of deaths (all causes)
    1
    1
    2
    0
    2
    1
    5
    12
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 42 (0.00%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    2 / 2
         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 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         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
    1 / 5 (20.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    6 / 83 (7.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 7
    1 / 10
         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
    Bronchopleural fistula
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    4 / 83 (4.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amylase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    2 / 13 (15.38%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    4 / 83 (4.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    2 / 13 (15.38%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         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
    Hemiplegia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         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
    Anaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         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 / 5 (0.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    1 / 2 (50.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    5 / 83 (6.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 2
    0 / 1
    1 / 1
    0 / 0
    1 / 1
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dental caries
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         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 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         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
    Acute kidney injury
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         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
    Bone pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         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 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         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 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    4 / 42 (9.52%)
    4 / 83 (4.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         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 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    1 / 2
         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 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         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 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    3 / 83 (3.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    3 / 83 (3.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Septic shock
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         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 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         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 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         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
    Ceritinib@300 mg/m2 Ceritinib@450 mg/m2 Ceritinib@510 mg/m2 Ceritinib@560 mg/m2 Ceritinib@320 mg/m2 Ceritinib@400 mg/m2 Ceritinib@500 mg/m2 Fasted+Fed All Subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    12 / 12 (100.00%)
    13 / 13 (100.00%)
    2 / 2 (100.00%)
    4 / 4 (100.00%)
    5 / 5 (100.00%)
    42 / 42 (100.00%)
    83 / 83 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Tumour pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Haematoma
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    2
    Hypertension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    2 / 83 (2.41%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    2
    Hypotension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Pallor
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    3 / 83 (3.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    9 / 42 (21.43%)
    10 / 83 (12.05%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    11
    12
    Catheter site pain
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 12 (16.67%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    3 / 83 (3.61%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    0
    3
    Chest pain
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 12 (16.67%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    6 / 42 (14.29%)
    11 / 83 (13.25%)
         occurrences all number
    0
    2
    1
    0
    1
    3
    6
    13
    Fatigue
         subjects affected / exposed
    3 / 5 (60.00%)
    4 / 12 (33.33%)
    3 / 13 (23.08%)
    2 / 2 (100.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    9 / 42 (21.43%)
    22 / 83 (26.51%)
         occurrences all number
    3
    6
    4
    2
    2
    0
    14
    31
    Gait disturbance
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    General physical health deterioration
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    2
    Influenza like illness
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    2 / 83 (2.41%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    2
    3
    Malaise
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    2 / 83 (2.41%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    2
    Oedema peripheral
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    2 / 4 (50.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    4 / 83 (4.82%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    3
    5
    Pyrexia
         subjects affected / exposed
    3 / 5 (60.00%)
    4 / 12 (33.33%)
    6 / 13 (46.15%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    20 / 42 (47.62%)
    35 / 83 (42.17%)
         occurrences all number
    5
    6
    15
    1
    0
    1
    49
    77
    Secretion discharge
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    3 / 83 (3.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    3
    Ulcer
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Cough
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 12 (8.33%)
    2 / 13 (15.38%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    8 / 42 (19.05%)
    13 / 83 (15.66%)
         occurrences all number
    1
    2
    7
    1
    0
    0
    16
    27
    Dyspnoea
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    4 / 42 (9.52%)
    6 / 83 (7.23%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    5
    7
    Dyspnoea exertional
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Emphysema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    4 / 83 (4.82%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    3
    5
    Nasal congestion
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    3 / 83 (3.61%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    1
    3
    Oropharyngeal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    5 / 83 (6.02%)
         occurrences all number
    0
    1
    2
    0
    0
    0
    4
    7
    Pleural effusion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    3 / 83 (3.61%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    2
    3
    Pleuritic pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    2 / 83 (2.41%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    2
    Rhinorrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    4 / 83 (4.82%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    5
    8
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    3 / 83 (3.61%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    2
    4
    Irritability
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Mental disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Restlessness
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Sleep disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 5 (20.00%)
    8 / 12 (66.67%)
    8 / 13 (61.54%)
    2 / 2 (100.00%)
    3 / 4 (75.00%)
    2 / 5 (40.00%)
    30 / 42 (71.43%)
    54 / 83 (65.06%)
         occurrences all number
    3
    13
    18
    2
    5
    2
    72
    115
    Amylase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    3 / 42 (7.14%)
    6 / 83 (7.23%)
         occurrences all number
    0
    4
    1
    0
    0
    1
    5
    11
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 5 (20.00%)
    6 / 12 (50.00%)
    7 / 13 (53.85%)
    2 / 2 (100.00%)
    3 / 4 (75.00%)
    1 / 5 (20.00%)
    28 / 42 (66.67%)
    48 / 83 (57.83%)
         occurrences all number
    3
    10
    21
    2
    3
    1
    74
    114
    Blood albumin decreased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 5 (20.00%)
    4 / 12 (33.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    4 / 42 (9.52%)
    10 / 83 (12.05%)
         occurrences all number
    1
    4
    0
    0
    1
    0
    4
    10
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    2 / 83 (2.41%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    2
    Blood bilirubin increased
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 12 (16.67%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    5 / 42 (11.90%)
    8 / 83 (9.64%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    9
    12
    Blood creatine increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    3 / 83 (3.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    4
    Blood creatine phosphokinase MB increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    2 / 5 (40.00%)
    4 / 12 (33.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    11 / 42 (26.19%)
    18 / 83 (21.69%)
         occurrences all number
    5
    5
    1
    0
    0
    0
    17
    28
    Blood glucose increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 12 (16.67%)
    3 / 13 (23.08%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    5 / 42 (11.90%)
    11 / 83 (13.25%)
         occurrences all number
    0
    3
    4
    0
    0
    1
    5
    13
    Blood magnesium increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    3 / 83 (3.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    4
    Blood pressure increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Blood urea increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    3 / 83 (3.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    6
    6
    Blood uric acid increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    4 / 83 (4.82%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    3
    4
    C-reactive protein increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    4 / 42 (9.52%)
    6 / 83 (7.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    4
    6
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 12 (16.67%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    3 / 83 (3.61%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    1
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 12 (25.00%)
    3 / 13 (23.08%)
    1 / 2 (50.00%)
    2 / 4 (50.00%)
    3 / 5 (60.00%)
    14 / 42 (33.33%)
    26 / 83 (31.33%)
         occurrences all number
    0
    3
    4
    1
    2
    3
    21
    34
    Haemoglobin decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    3 / 83 (3.61%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    2
    3
    Lipase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    2 / 13 (15.38%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    6 / 42 (14.29%)
    9 / 83 (10.84%)
         occurrences all number
    0
    0
    2
    0
    0
    1
    9
    12
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    4 / 83 (4.82%)
         occurrences all number
    0
    4
    1
    0
    0
    0
    5
    10
    Neutrophil count decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    5 / 83 (6.02%)
         occurrences all number
    0
    2
    1
    0
    1
    0
    2
    6
    Platelet count decreased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    3 / 83 (3.61%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    1
    4
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Prothrombin time shortened
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Troponin increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    2
    Tumour marker increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 12 (16.67%)
    3 / 13 (23.08%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    6 / 42 (14.29%)
    13 / 83 (15.66%)
         occurrences all number
    1
    2
    3
    1
    0
    0
    7
    14
    White blood cell count decreased
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    4 / 83 (4.82%)
         occurrences all number
    1
    2
    0
    1
    0
    0
    1
    5
    White blood cell count increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    2
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    2 / 83 (2.41%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    2
    Hand fracture
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Muscle injury
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    2 / 83 (2.41%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    2
    Pericardial effusion
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    2 / 83 (2.41%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    2
    Tachycardia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    4 / 83 (4.82%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    2
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 12 (16.67%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    5 / 83 (6.02%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    3
    6
    Dysaesthesia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    2 / 83 (2.41%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    2
    Dysgeusia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Headache
         subjects affected / exposed
    3 / 5 (60.00%)
    4 / 12 (33.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    2 / 4 (50.00%)
    1 / 5 (20.00%)
    8 / 42 (19.05%)
    19 / 83 (22.89%)
         occurrences all number
    3
    8
    1
    0
    2
    1
    20
    35
    Hypertonia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    2
    Lethargy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Migraine
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Neuralgia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Somnolence
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Tremor
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    3 / 83 (3.61%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    1
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 12 (25.00%)
    3 / 13 (23.08%)
    1 / 2 (50.00%)
    3 / 4 (75.00%)
    0 / 5 (0.00%)
    11 / 42 (26.19%)
    22 / 83 (26.51%)
         occurrences all number
    2
    4
    5
    1
    5
    0
    14
    31
    Bone marrow disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Leukocytosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    2
    Leukopenia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    2 / 13 (15.38%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    5 / 42 (11.90%)
    8 / 83 (9.64%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    7
    10
    Lymphadenopathy
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Neutropenia
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 12 (8.33%)
    3 / 13 (23.08%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    5 / 42 (11.90%)
    10 / 83 (12.05%)
         occurrences all number
    14
    2
    6
    0
    0
    0
    23
    45
    Thrombocytopenia
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 12 (16.67%)
    2 / 13 (15.38%)
    2 / 2 (100.00%)
    2 / 4 (50.00%)
    0 / 5 (0.00%)
    11 / 42 (26.19%)
    19 / 83 (22.89%)
         occurrences all number
    0
    3
    2
    2
    3
    0
    16
    26
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    4 / 83 (4.82%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    4
    5
    External ear inflammation
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Hypoacusis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Eye disorders
    Eye pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Eye swelling
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Ocular discomfort
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    5
    1
    0
    0
    0
    0
    0
    6
    Abdominal pain
         subjects affected / exposed
    3 / 5 (60.00%)
    6 / 12 (50.00%)
    6 / 13 (46.15%)
    2 / 2 (100.00%)
    2 / 4 (50.00%)
    1 / 5 (20.00%)
    22 / 42 (52.38%)
    42 / 83 (50.60%)
         occurrences all number
    6
    17
    12
    2
    7
    1
    56
    101
    Abdominal pain upper
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 12 (16.67%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    3 / 42 (7.14%)
    7 / 83 (8.43%)
         occurrences all number
    0
    2
    0
    0
    2
    1
    3
    8
    Anal fissure
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Anal incontinence
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Anal inflammation
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Constipation
         subjects affected / exposed
    3 / 5 (60.00%)
    2 / 12 (16.67%)
    2 / 13 (15.38%)
    1 / 2 (50.00%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    4 / 42 (9.52%)
    14 / 83 (16.87%)
         occurrences all number
    4
    3
    2
    2
    2
    1
    4
    18
    Diarrhoea
         subjects affected / exposed
    4 / 5 (80.00%)
    12 / 12 (100.00%)
    10 / 13 (76.92%)
    2 / 2 (100.00%)
    2 / 4 (50.00%)
    3 / 5 (60.00%)
    32 / 42 (76.19%)
    65 / 83 (78.31%)
         occurrences all number
    11
    30
    21
    4
    7
    3
    93
    169
    Dyspepsia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    4 / 42 (9.52%)
    6 / 83 (7.23%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    6
    8
    Flatulence
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    1 / 42 (2.38%)
    4 / 83 (4.82%)
         occurrences all number
    1
    0
    1
    0
    0
    1
    1
    4
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Gingival pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Haematemesis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Haematochezia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    2
    Nausea
         subjects affected / exposed
    2 / 5 (40.00%)
    8 / 12 (66.67%)
    10 / 13 (76.92%)
    1 / 2 (50.00%)
    2 / 4 (50.00%)
    3 / 5 (60.00%)
    21 / 42 (50.00%)
    47 / 83 (56.63%)
         occurrences all number
    3
    8
    20
    3
    4
    3
    32
    73
    Odynophagia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    3 / 83 (3.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    3
    Proctalgia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    5
    0
    0
    0
    0
    0
    5
    Stomatitis
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    6 / 83 (7.23%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    3
    6
    Vomiting
         subjects affected / exposed
    4 / 5 (80.00%)
    10 / 12 (83.33%)
    13 / 13 (100.00%)
    2 / 2 (100.00%)
    4 / 4 (100.00%)
    3 / 5 (60.00%)
    36 / 42 (85.71%)
    72 / 83 (86.75%)
         occurrences all number
    11
    25
    33
    4
    7
    3
    72
    155
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    2 / 83 (2.41%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    2
    4
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    4 / 83 (4.82%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    2
    4
    Alopecia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    3 / 83 (3.61%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    1
    3
    Eczema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    3 / 83 (3.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    5
    5
    Erythema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    4 / 42 (9.52%)
    4 / 83 (4.82%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    6
    6
    Night sweats
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    3 / 83 (3.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    3
    Pain of skin
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 12 (16.67%)
    2 / 13 (15.38%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    1 / 42 (2.38%)
    7 / 83 (8.43%)
         occurrences all number
    0
    2
    2
    1
    0
    1
    1
    7
    Rash
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 12 (16.67%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    6 / 42 (14.29%)
    8 / 83 (9.64%)
         occurrences all number
    0
    5
    0
    0
    0
    0
    10
    15
    Rash erythematous
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 12 (25.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    5 / 83 (6.02%)
         occurrences all number
    0
    3
    1
    0
    0
    0
    1
    5
    Skin exfoliation
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 12 (16.67%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    2
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Skin irritation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Skin lesion
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Swelling face
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    2
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    2
    Micturition urgency
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Pollakiuria
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Endocrine disorders
    Delayed puberty
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Hypothyroidism
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    2 / 13 (15.38%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    4 / 83 (4.82%)
         occurrences all number
    0
    2
    1
    0
    1
    0
    1
    5
    Back pain
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    4 / 42 (9.52%)
    6 / 83 (7.23%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    4
    6
    Bone pain
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 12 (16.67%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    6 / 83 (7.23%)
         occurrences all number
    1
    3
    0
    0
    1
    0
    2
    7
    Groin pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    3 / 83 (3.61%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    1
    3
    Joint range of motion decreased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    2 / 83 (2.41%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    2
    Muscular weakness
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    3 / 83 (3.61%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    2
    3
    Musculoskeletal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 12 (16.67%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    5 / 83 (6.02%)
         occurrences all number
    0
    4
    1
    0
    0
    0
    3
    8
    Neck pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    3 / 83 (3.61%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    2
    4
    Pain in extremity
         subjects affected / exposed
    1 / 5 (20.00%)
    5 / 12 (41.67%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    5 / 42 (11.90%)
    13 / 83 (15.66%)
         occurrences all number
    1
    6
    0
    0
    1
    1
    5
    14
    Torticollis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Bacterial vulvovaginitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    3 / 83 (3.61%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    2
    3
    Conjunctivitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    5 / 83 (6.02%)
         occurrences all number
    0
    3
    1
    0
    0
    0
    3
    7
    Device related infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    3 / 83 (3.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    5
    5
    Ear infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    3 / 83 (3.61%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    2
    3
    Gastroenteritis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    4 / 42 (9.52%)
    4 / 83 (4.82%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    5
    5
    Genital candidiasis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    2
    Human herpesvirus 6 infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Influenza
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    4 / 83 (4.82%)
         occurrences all number
    5
    1
    0
    0
    0
    0
    2
    8
    Molluscum contagiosum
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Mycoplasma infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 12 (8.33%)
    2 / 13 (15.38%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    4 / 42 (9.52%)
    10 / 83 (12.05%)
         occurrences all number
    6
    1
    3
    0
    2
    0
    4
    16
    Oral herpes
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    2 / 83 (2.41%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    2
    Pneumonia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    3 / 83 (3.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    5
    5
    Rhinitis
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 12 (16.67%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    8 / 42 (19.05%)
    11 / 83 (13.25%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    12
    15
    Sinusitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 12 (16.67%)
    3 / 13 (23.08%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    8 / 42 (19.05%)
    15 / 83 (18.07%)
         occurrences all number
    2
    3
    8
    1
    0
    0
    20
    34
    Urinary tract infection
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 42 (0.00%)
    3 / 83 (3.61%)
         occurrences all number
    3
    1
    0
    0
    0
    1
    0
    5
    Varicella
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    2 / 83 (2.41%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    2
    Viral infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    2 / 83 (2.41%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    2
    Wound infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 5 (60.00%)
    4 / 12 (33.33%)
    0 / 13 (0.00%)
    2 / 2 (100.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    16 / 42 (38.10%)
    26 / 83 (31.33%)
         occurrences all number
    3
    5
    0
    3
    1
    0
    17
    29
    Dehydration
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    0
    3
    Electrolyte imbalance
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    2
    Fluid retention
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    2 / 83 (2.41%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    1
    4
    Hypermagnesaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    4 / 42 (9.52%)
    5 / 83 (6.02%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    4
    5
    Hypocalcaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 42 (2.38%)
    4 / 83 (4.82%)
         occurrences all number
    1
    2
    1
    0
    0
    0
    1
    5
    Hypokalaemia
         subjects affected / exposed
    3 / 5 (60.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    7 / 42 (16.67%)
    12 / 83 (14.46%)
         occurrences all number
    6
    2
    0
    0
    0
    2
    9
    19
    Hypomagnesaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    5 / 83 (6.02%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    4
    6
    Hyponatraemia
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 42 (7.14%)
    7 / 83 (8.43%)
         occurrences all number
    2
    2
    1
    0
    0
    0
    3
    8
    Hypophosphataemia
         subjects affected / exposed
    2 / 5 (40.00%)
    2 / 12 (16.67%)
    1 / 13 (7.69%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    2 / 42 (4.76%)
    8 / 83 (9.64%)
         occurrences all number
    4
    2
    1
    0
    1
    0
    4
    12
    Obesity
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 42 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Mar 2013
    The following changes were requested by a Health Authority: In order to clarify the eligibility criteria in the protocol, a detailed definition of “a genetic alteration of ALK” has been added to the inclusion criteria. Due to the observation that ceritinib use is sometimes associated with hypophosphatemia, patients with abnormalities of phosphate as well as potassium, calcium or magnesium > CTCAE grade 1 are excluded from the study. The table defining dose-limiting toxicities was reorganized to clarify that any adverse event of CTCAE grade 3 or higher is a DLT, except as noted in the table. Due to the possibility that taking ceritinib mixed with a small amount of food may affect its bioavailability, the protocol has been modified to require that all patients take ceritinib with a small amount of food. If patients can swallow intact capsules, they must eat 1-2 tablespoons (15-30 mL) of food, such as apple sauce or non-fat yogurt at the time that they take ceritinib. If patients open the capsules, the contents are mixed with a food carrier, such as apple sauce or non-fat yogurt (or other carriers as defined in the separate instructions for patients who cannot swallow capsules). This prevented unexpected differences in bioavailability between those patients who swallow intact capsules and those who opened the capsules.
    27 Sep 2013
    The following changes were requested by Health Authorities: To address the management of QTc prolongation separately from the broader array of DLTs a specific approach including a detailed monitoring plan, need for physician evaluation, and recommendations for dose reduction or permanent discontinuation. Cases of pneumonitis/interstitial lung disease (ILD) have been reported with ceritinib in patients treated at the 750 mg dose level. Most cases improved or resolved with interruption of ceritinib and treatment with antibiotics and/or steroids. Fatal outcome of treatment-related pneumonitis was reported. Exclusion criteria, the definition of dose limiting toxicity, and the guidance for dose modification have been amended to address this newly observed risk
    15 Jul 2014
    The protocol was modified to include a fed state (low-fat light snack) dose escalation part following the determination of the fasted MTD/RDE. Further expansion at the fed MTD/RDE was allowed if the safety, PK or efficacy suggested that administering ceritinib with food was preferred. The age range in the inclusion criteria has been changed to ‘up to 18’ to make it clear that patients were eligible until they turn18 years of age.
    13 May 2015
    A consistent approach was implemented across ongoing studies with ceritinib to monitor and manage safety signals identified as the clinical experience with ceritinib has grown. Specifically, changes were made that addressed hepatic toxicity, pancreatitis and pneumonitis.
    26 Feb 2016
    The primary purpose of this amendment was to clarify the ceritinib dose modification recommendations, the guidelines for follow up of toxicities to ceritinib (including follow up evaluations for hepatic toxicities and work up guidelines for potential drug induced liver injury (DILI) cases) and the use of concomitant medications in order to optimize the patient safety. Furthermore, this amendment provided updated parameters for study visits for patients who were on study drug for more than 14 cycles. This was done in an effort to decrease the burden on the patient after a set number of cycles on study drug. In addition, the definition of highly effective contraception and the time period for using it have been updated, as well as the reporting period for pregnancy that has been revised to 3 months.
    30 Sep 2016
    The primary purpose of this amendment was to revise the dose reduction steps for The primary purpose of this amendment was to revise the dose reduction steps for ceritinib. Considering the recommended doses established for fed and fasted state were similar, the dose reduction schedule was revised to be applicable for both states. In addition, the schedule of assessments was revised to reduce frequency of on-site visits after cycle 16: on-site visits on day 1 of odd numbered cycles are replaced by phone calls and local laboratory tests for safety assessments Moreover, the pre-dose PK sample and the post-dose ECGs collection at Cycle 1 Day 1 have been removed in the expansion phase as they were no longer required at this time point as no correlation is planned in the expansion.
    24 Jan 2017
    The primary purpose of this amendment was to address Health Authorities’ concerns regarding the cardiac safety monitoring conducted until Cycle 6 only and not afterwards for patient who remain on treatment, and the recent changes at Cycle 1 Day 1 (ECG monitoring at 4 and 6 hours post first dose of study drug) for the patients to be treated in the expansion phase of the study. Novartis decided to strengthen the cardiac safety monitoring: all patients were monitored with an ECG at Cycle 1 Day 1 (4-h post dose and 6-h post dose), and at each first day of every cycle of treatment. The ECG collection was expanded throughout the entire treatment duration. This was done in alignment with the ceritinib cardiovascular safety monitoring recommendations. In addition, guidelines for dose modification in case of Grade 3 transaminases elevation are clarified, allowing patients to stay in the study in case of a re-occurrence of Grade 3 ALT or AST elevation after a dose reduction as allowed across the ceritinib development program in adults patients. This was to avoid unnecessary withdrawal of patients who continued to derive clinical benefit from ceritinib. The guidelines in relation to concomitant medications use are also clarified to optimize the patient’s safety. Moreover, ALK status inclusion criterion was clarified and it was specified that 15% threshold for rearrangement was applicable only when assessed by FISH. Furthermore the ALK tyrosine kinase domain (TKD) mutation inclusion criterion was simplified.
    18 May 2018
    The main purpose of this global amendment was to allow patients who were still deriving clinical benefit from study treatment as per the investigator to be transitioned to a separate rollover study or another option for continued treatment with ceritinib (i.e. managed access program), as soon as they become available. The end of study would occur once: All patients have discontinued study treatment and completed the required Study Evaluation Completion follow-up visit, or All patients have died, been lost to follow-up, have withdrawn consent, or the last patient has been enrolled into a separate rollover study (or other option for continued study treatment), whichever comes first As per original protocol, a primary analysis and CSR were planned after all patients had completed at least 6 cycles of treatment or discontinued the study. Given interim data presented previously, and at the time of this amendment all patients already completed at least 6 cycles of treatment and were allowed to transition into a separate rollover study (or other options for continued study treatment access), a single final analysis/CSR was planned once the end of study criteria are met.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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