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    Clinical Trial Results:
    A Phase 1/2, Open-Label, Dose-Escalation, Safety and Tolerability Study of INCAGN01949 in Subjects With Advanced or Metastatic Solid Tumors

    Summary
    EudraCT number
    		 2016-002079-93
    Trial protocol
    		 GB  
    Global end of trial date
    26 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Apr 2020
    First version publication date
    10 Apr 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    INCAGN 1949-101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02923349
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Incyte Biosciences International Sàrl
    Sponsor organisation address
    1110 Morges, , Rue Docteur-Yersin , Switzerland, 10
    Public contact
    call centre, Incyte Corporation, 1 8554633463, RA@INCYTE.COM
    Scientific contact
    call centre, Incyte Corporation, 1 8554633463, RA@INCYTE.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 Mar 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Mar 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the safety, tolerability, and DLTs of INCAGN01949 and to define a MTD or PAD of INCAGN01949 in subjects with metastatic or advanced solid tumors.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles of Good Clinical Practice, according to the International Conference on Harmonisation Guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Oct 2016
    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
    Spain: 10
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    United States: 55
    Country: Number of subjects enrolled
    Switzerland: 5
    Worldwide total number of subjects
    87
    EEA total number of subjects
    27
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    59
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 4 different sites in US, 1 site in Switzerland, Spain and 2 sites in the United Kingdom

    Pre-assignment
    Screening details
    		 A total of 129 participants were screened for this study, of which 42 participants were screen failures and 87 participants were randomized to treatment.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort1 - INCAGN1949 7mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    INCAGN01949
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    7mg of ICAGN 1949 is dosed as an IV infusion over 30minutes on Day 1 of each cycle

    Arm title
    		 Cohort2 - INCAGN1949 20mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    INCAGN01949
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    20mg of ICAGN 1949 is dosed as an IV infusion over 30minutes on Day 1 of each cycle

    Arm title
    		 Cohort3 - INCAGN1949 70mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    INCAGN01949
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    70mg of ICAGN 1949 is dosed as an IV infusion over 30minutes on Day 1 of each cycle

    Arm title
    		 Cohort4 - INCAGN1949 200 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    INCAGN01949
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    200mg of ICAGN 1949 is dosed as an IV infusion over 30minutes on Day 1 of each cycle

    Arm title
    		 Cohort5 - INCAGN1949 350mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    INCAGN01949
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    350mg of ICAGN 1949 is dosed as an IV infusion over 30minutes on Day 1 of each cycle

    Arm title
    		 Cohort6 - INCAGN1949 700mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    INCAGN01949
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    700mg of ICAGN 1949 is dosed as an IV infusion over 30minutes on Day 1 of each cycle

    Arm title
    		 Cohort7 - INCAGN1949 1400mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    INCAGN01949
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1400mg of ICAGN 1949 is dosed as an IV infusion over 30minutes on Day 1 of each cycle

    Number of subjects in period 1
    		Cohort1 - INCAGN1949 7mg Cohort2 - INCAGN1949 20mg Cohort3 - INCAGN1949 70mg Cohort4 - INCAGN1949 200 mg Cohort5 - INCAGN1949 350mg Cohort6 - INCAGN1949 700mg Cohort7 - INCAGN1949 1400mg
    Started
    4
    4
    22
    18
    23
    12
    4
    Completed
    0
    0
    5
    2
    4
    5
    1
    Not completed
    4
    4
    17
    16
    19
    7
    3
         Physician decision
    -
    -
    -
    1
    1
    -
    2
         Death
    1
    -
    2
    4
    2
    3
    -
         Unknown
    1
    2
    4
    1
    3
    -
    1
         Lost to follow-up
    -
    -
    3
    -
    1
    1
    -
         Withdrawal by subject
    2
    2
    8
    10
    12
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort1 - INCAGN1949 7mg
    Reporting group description
    		 -

    Reporting group title
    Cohort2 - INCAGN1949 20mg
    Reporting group description
    		 -

    Reporting group title
    Cohort3 - INCAGN1949 70mg
    Reporting group description
    		 -

    Reporting group title
    Cohort4 - INCAGN1949 200 mg
    Reporting group description
    		 -

    Reporting group title
    Cohort5 - INCAGN1949 350mg
    Reporting group description
    		 -

    Reporting group title
    Cohort6 - INCAGN1949 700mg
    Reporting group description
    		 -

    Reporting group title
    Cohort7 - INCAGN1949 1400mg
    Reporting group description
    		 -

    Reporting group values
    		 Cohort1 - INCAGN1949 7mg Cohort2 - INCAGN1949 20mg Cohort3 - INCAGN1949 70mg Cohort4 - INCAGN1949 200 mg Cohort5 - INCAGN1949 350mg Cohort6 - INCAGN1949 700mg Cohort7 - INCAGN1949 1400mg Total
    Number of subjects
    		 4 4 22 18 23 12 4 87
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 3 2 14 12 17 8 3 59
        From 65-84 years
    		 1 2 8 6 6 4 1 28
        85 years and over
    		 0 0 0 0 0 0 0 0
    Age continuous
    Units: years
        geometric mean (standard deviation)
    		 54.3 ± 16.24 63.8 ± 12.63 56.8 ± 14.27 58.9 ± 12.78 58.1 ± 12.44 61.3 ± 9.93 52.8 ± 24.50 -
    Gender categorical
    Units: Subjects
        Female
    		 2 3 14 12 17 3 2 53
        Male
    		 2 1 8 6 6 9 2 34
    Race
    Units: Subjects
        White/Caucasian
    		 4 3 19 17 23 9 4 79
        Asian
    		 0 1 2 0 0 1 0 4
        Other
    		 0 0 1 1 0 0 0 2
        Black/African American
    		 0 0 0 0 0 2 0 2
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0 1 1 0 1 1 4
        Not Hispanic or Latino
    		 4 4 19 16 22 11 2 78
        Not Reported
    		 0 0 1 1 1 0 1 4
        Other
    		 0 0 1 0 0 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Cohort1 - INCAGN1949 7mg
    Reporting group description
    		 -

    Reporting group title
    Cohort2 - INCAGN1949 20mg
    Reporting group description
    		 -

    Reporting group title
    Cohort3 - INCAGN1949 70mg
    Reporting group description
    		 -

    Reporting group title
    Cohort4 - INCAGN1949 200 mg
    Reporting group description
    		 -

    Reporting group title
    Cohort5 - INCAGN1949 350mg
    Reporting group description
    		 -

    Reporting group title
    Cohort6 - INCAGN1949 700mg
    Reporting group description
    		 -

    Reporting group title
    Cohort7 - INCAGN1949 1400mg
    Reporting group description
    		 -

    Primary: To evaluate the safety, tolerability, and DLTs of INCAGN01949 and to define a MTD or PAD of INCAGN01949 in subjects with metastatic or advanced solid tumors

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    End point title
    		 To evaluate the safety, tolerability, and DLTs of INCAGN01949 and to define a MTD or PAD of INCAGN01949 in subjects with metastatic or advanced solid tumors [1]
    End point description
    To evaluate the safety, tolerability, and DLTs of INCAGN01949 and to define a MTD or PAD of INCAGN01949 in subjects with metastatic or advanced solid tumors
    End point type
    Primary
    End point timeframe
    From screening through 60 days after end of treatment, up to 11 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There is no hypothesis testing for this endpoint , descriptive analysis is provided.
    End point values
    		 Cohort1 - INCAGN1949 7mg Cohort2 - INCAGN1949 20mg Cohort3 - INCAGN1949 70mg Cohort4 - INCAGN1949 200 mg Cohort5 - INCAGN1949 350mg Cohort6 - INCAGN1949 700mg Cohort7 - INCAGN1949 1400mg
    Number of subjects analysed
    4
    4
    22
    18
    23
    12
    4
    Units: participants
    4
    4
    21
    17
    22
    11
    4
    No statistical analyses for this end point

    Secondary: To evaluate the preliminary efficacy of INCAGN01949 by assessing the objective response rate per RECIST v1.1 and mRECIST v1.1.

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    End point title
    		 To evaluate the preliminary efficacy of INCAGN01949 by assessing the objective response rate per RECIST v1.1 and mRECIST v1.1.
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and every 8 weeks, up to 11 months
    End point values
    		 Cohort1 - INCAGN1949 7mg Cohort2 - INCAGN1949 20mg Cohort3 - INCAGN1949 70mg Cohort4 - INCAGN1949 200 mg Cohort5 - INCAGN1949 350mg Cohort6 - INCAGN1949 700mg Cohort7 - INCAGN1949 1400mg
    Number of subjects analysed
    4
    4
    22
    18
    23
    12
    4
    Units: participants
    0
    0
    0
    0
    0
    1
    0
    No statistical analyses for this end point

    Secondary: To evaluate the preliminary efficacy of INCAGN01949 by assessing the duration of response per RECIST v1.1 and mRECIST v1.1.

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    End point title
    		 To evaluate the preliminary efficacy of INCAGN01949 by assessing the duration of response per RECIST v1.1 and mRECIST v1.1.
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and every 8 weeks , up to 11 months
    End point values
    		 Cohort1 - INCAGN1949 7mg Cohort2 - INCAGN1949 20mg Cohort3 - INCAGN1949 70mg Cohort4 - INCAGN1949 200 mg Cohort5 - INCAGN1949 350mg Cohort6 - INCAGN1949 700mg Cohort7 - INCAGN1949 1400mg
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    0 [5]
    0 [6]
    1
    0 [7]
    Units: days
        median (full range (min-max))
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    192 (192 to 192)
    ( to )
    Notes
    [2] - There were no responders in this group
    [3] - There were no responders in this group
    [4] - There were no responders in this group
    [5] - There were no responders in this group
    [6] - There were no responders in this group
    [7] - There were no responders in this group
    No statistical analyses for this end point

    Secondary: To evaluate the preliminary efficacy of INCAGN01949 by assessing the progression free survival per RECIST v1.1 and mRECIST v1.1.

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    End point title
    		 To evaluate the preliminary efficacy of INCAGN01949 by assessing the progression free survival per RECIST v1.1 and mRECIST v1.1.
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and every 8 weeks , up to 11 months
    End point values
    		 Cohort1 - INCAGN1949 7mg Cohort2 - INCAGN1949 20mg Cohort3 - INCAGN1949 70mg Cohort4 - INCAGN1949 200 mg Cohort5 - INCAGN1949 350mg Cohort6 - INCAGN1949 700mg Cohort7 - INCAGN1949 1400mg
    Number of subjects analysed
    4
    4
    22
    18
    23
    12
    4
    Units: days
        median (full range (min-max))
    57 (55 to 59)
    47.5 (29 to 112)
    54 (23 to 216)
    56 (26 to 281)
    52 (1 to 166)
    125 (21 to 298)
    46.5 (42 to 53)
    No statistical analyses for this end point

    Secondary: To evaluate the preliminary efficacy of INCAGN01949 by assessing the duration of disease control per RECIST v1.1 and mRECIST v1.1.

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    End point title
    		 To evaluate the preliminary efficacy of INCAGN01949 by assessing the duration of disease control per RECIST v1.1 and mRECIST v1.1.
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and every 8 weeks , up to 11 months
    End point values
    		 Cohort1 - INCAGN1949 7mg Cohort2 - INCAGN1949 20mg Cohort3 - INCAGN1949 70mg Cohort4 - INCAGN1949 200 mg Cohort5 - INCAGN1949 350mg Cohort6 - INCAGN1949 700mg Cohort7 - INCAGN1949 1400mg
    Number of subjects analysed
    1
    1
    8
    7
    3
    7
    0 [8]
    Units: days
        median (full range (min-max))
    0 (0 to 0)
    57 (57 to 57)
    64 (1 to 160)
    57 (1 to 225)
    0 (0 to 0)
    120 (1 to 249)
    ( to )
    Notes
    [8] - All subjects had a response of progressive disease
    No statistical analyses for this end point

    Secondary: To evaluate the Tmax of INCAGN01949 in subjects with advanced or metastatic solid tumors

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    End point title
    		 To evaluate the Tmax of INCAGN01949 in subjects with advanced or metastatic solid tumors
    End point description
    End point type
    Secondary
    End point timeframe
    cycle 1
    End point values
    		 Cohort1 - INCAGN1949 7mg Cohort2 - INCAGN1949 20mg Cohort3 - INCAGN1949 70mg Cohort4 - INCAGN1949 200 mg Cohort5 - INCAGN1949 350mg Cohort6 - INCAGN1949 700mg Cohort7 - INCAGN1949 1400mg
    Number of subjects analysed
    4
    4
    21
    17
    21
    7
    4
    Units: hr
        median (full range (min-max))
    0.64 (0.6 to 4.4)
    2.53 (0.55 to 4.5)
    4.3 (0.50 to 25.2)
    0.63 (0.5 to 4.5)
    0.6 (0.0 to 194)
    0.7 (0.53 to 4.2)
    0.73 (0.0 to 2.43)
    No statistical analyses for this end point

    Secondary: To evaluate the Cmin of INCAGN01949 in subjects with advanced or metastatic solid tumors. Cmin is the minimum observed concentration of INCAGN1949

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    End point title
    		 To evaluate the Cmin of INCAGN01949 in subjects with advanced or metastatic solid tumors. Cmin is the minimum observed concentration of INCAGN1949
    End point description
    End point type
    Secondary
    End point timeframe
    cycle 1
    End point values
    		 Cohort1 - INCAGN1949 7mg Cohort2 - INCAGN1949 20mg Cohort3 - INCAGN1949 70mg Cohort4 - INCAGN1949 200 mg Cohort5 - INCAGN1949 350mg Cohort6 - INCAGN1949 700mg Cohort7 - INCAGN1949 1400mg
    Number of subjects analysed
    4
    4
    20
    17
    18
    7
    3
    Units: ng/ml
        arithmetic mean (standard deviation)
    303 ± 202
    1890 ± 1570
    3620 ± 1550
    8880 ± 4510
    17000 ± 8040
    41000 ± 13000
    117000 ± 19300
    No statistical analyses for this end point

    Secondary: To evaluate the Cmax of INCAGN01949 in subjects with advanced or metastatic solid tumors.

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    End point title
    		 To evaluate the Cmax of INCAGN01949 in subjects with advanced or metastatic solid tumors.
    End point description
    End point type
    Secondary
    End point timeframe
    cycle 1
    End point values
    		 Cohort1 - INCAGN1949 7mg Cohort2 - INCAGN1949 20mg Cohort3 - INCAGN1949 70mg Cohort4 - INCAGN1949 200 mg Cohort5 - INCAGN1949 350mg Cohort6 - INCAGN1949 700mg Cohort7 - INCAGN1949 1400mg
    Number of subjects analysed
    4
    4
    21
    17
    21
    7
    4
    Units: ng/mL
        arithmetic mean (standard deviation)
    1630 ± 735
    5820 ± 324
    22300 ± 32800
    39200 ± 10300
    84900 ± 76700
    207000 ± 45500
    347000 ± 130000
    No statistical analyses for this end point

    Secondary: To evaluate the AUC0-t of INCAGN01949 in subjects with advanced or metastatic solid tumors

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    End point title
    		 To evaluate the AUC0-t of INCAGN01949 in subjects with advanced or metastatic solid tumors
    End point description
    End point type
    Secondary
    End point timeframe
    cycle 1
    End point values
    		 Cohort1 - INCAGN1949 7mg Cohort2 - INCAGN1949 20mg Cohort3 - INCAGN1949 70mg Cohort4 - INCAGN1949 200 mg Cohort5 - INCAGN1949 350mg Cohort6 - INCAGN1949 700mg Cohort7 - INCAGN1949 1400mg
    Number of subjects analysed
    4
    4
    21
    17
    21
    7
    4
    Units: ug*hr/mL
        arithmetic mean (standard deviation)
    185 ± 81.7
    904 ± 197
    2370 ± 841
    5400 ± 1820
    10000 ± 5600
    28300 ± 7720
    61600 ± 9130
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening through 60 days after end of treatment, up to 11 months
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    PART 1 Dose 1 (7 mg)
    Reporting group description
    		 PART 1 Dose 1 (7 mg)

    Reporting group title
    PART 1 Dose 2 (20 mg)
    Reporting group description
    		 PART 1 Dose 2 (20 mg)

    Reporting group title
    PART 1 Dose 3 (70 mg)
    Reporting group description
    		 PART 1 Dose 3 (70 mg)

    Reporting group title
    PART 1 Dose 4 (200 mg)
    Reporting group description
    		 PART 1 Dose 4 (200 mg)

    Reporting group title
    PART 1 Dose 5 (350 mg)
    Reporting group description
    		 PART 1 Dose 5 (350 mg)

    Reporting group title
    PART 1 Dose 6 (700 mg)
    Reporting group description
    		 PART 1 Dose 6 (700 mg)

    Reporting group title
    PART 1 Dose 7 (1400 mg)
    Reporting group description
    		 PART 1 Dose 7 (1400 mg)

    Serious adverse events
    		 PART 1 Dose 1 (7 mg) PART 1 Dose 2 (20 mg) PART 1 Dose 3 (70 mg) PART 1 Dose 4 (200 mg) PART 1 Dose 5 (350 mg) PART 1 Dose 6 (700 mg) PART 1 Dose 7 (1400 mg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    8 / 22 (36.36%)
    9 / 18 (50.00%)
    9 / 23 (39.13%)
    5 / 12 (41.67%)
    1 / 4 (25.00%)
         number of deaths (all causes)
    1
    0
    2
    4
    2
    3
    0
         number of deaths resulting from adverse events
    1
    0
    1
    1
    2
    3
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    1 / 18 (5.56%)
    2 / 23 (8.70%)
    3 / 12 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 3
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Spinal fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Ventricular tachycardia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cauda equina syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    2 / 18 (11.11%)
    2 / 23 (8.70%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    1 / 18 (5.56%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    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
    Jaundice cholestatic
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PART 1 Dose 1 (7 mg) PART 1 Dose 2 (20 mg) PART 1 Dose 3 (70 mg) PART 1 Dose 4 (200 mg) PART 1 Dose 5 (350 mg) PART 1 Dose 6 (700 mg) PART 1 Dose 7 (1400 mg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    21 / 22 (95.45%)
    17 / 18 (94.44%)
    22 / 23 (95.65%)
    10 / 12 (83.33%)
    4 / 4 (100.00%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Hypertension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 22 (9.09%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    0
    0
    Chills
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 22 (4.55%)
    0 / 18 (0.00%)
    2 / 23 (8.70%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    3
    0
    2
    0
    0
    Early satiety
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 4 (50.00%)
    6 / 22 (27.27%)
    7 / 18 (38.89%)
    8 / 23 (34.78%)
    4 / 12 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    2
    2
    8
    7
    8
    4
    2
    Gait disturbance
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 22 (4.55%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    Nodule
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    3 / 18 (16.67%)
    0 / 23 (0.00%)
    2 / 12 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    3
    0
    2
    1
    Peripheral swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 22 (9.09%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    1 / 22 (4.55%)
    0 / 18 (0.00%)
    2 / 23 (8.70%)
    1 / 12 (8.33%)
    1 / 4 (25.00%)
         occurrences all number
    0
    4
    1
    0
    2
    1
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    2 / 23 (8.70%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    4 / 22 (18.18%)
    5 / 18 (27.78%)
    1 / 23 (4.35%)
    1 / 12 (8.33%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    5
    7
    1
    1
    1
    Dyspnoea
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    2 / 22 (9.09%)
    3 / 18 (16.67%)
    3 / 23 (13.04%)
    2 / 12 (16.67%)
    2 / 4 (50.00%)
         occurrences all number
    1
    2
    2
    3
    3
    2
    2
    Dyspnoea exertional
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    2 / 12 (16.67%)
    2 / 4 (50.00%)
         occurrences all number
    0
    0
    1
    1
    0
    2
    3
    Epistaxis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Haemothorax
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Hypoxia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Pleural effusion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    2 / 23 (8.70%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    Pulmonary embolism
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Wheezing
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 22 (4.55%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    0
    Hallucination
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    2 / 18 (11.11%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    3
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    2 / 12 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    1
    Blood bilirubin increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    2 / 23 (8.70%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    1
    2
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Blood urea increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    1 / 23 (4.35%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    2
    0
    Lymph node palpable
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 22 (9.09%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    1
    Platelet count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    0 / 22 (0.00%)
    2 / 18 (11.11%)
    2 / 23 (8.70%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    0
    2
    2
    0
    0
    Weight increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    1 / 18 (5.56%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    0
    Joint injury
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Meniscus injury
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Rib fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Spinal fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Tooth fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    1 / 18 (5.56%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    0
    Dysgeusia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 22 (9.09%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Spinal cord compression
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Tremor
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    4 / 22 (18.18%)
    2 / 18 (11.11%)
    1 / 23 (4.35%)
    2 / 12 (16.67%)
    2 / 4 (50.00%)
         occurrences all number
    0
    0
    5
    2
    1
    2
    3
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 22 (4.55%)
    3 / 18 (16.67%)
    4 / 23 (17.39%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    3
    4
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    Ascites
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Constipation
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    4 / 22 (18.18%)
    6 / 18 (33.33%)
    4 / 23 (17.39%)
    1 / 12 (8.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    4
    6
    4
    1
    1
    Diarrhoea
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    3 / 22 (13.64%)
    4 / 18 (22.22%)
    3 / 23 (13.04%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    3
    7
    3
    1
    0
    Dry mouth
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Dysphagia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Epigastric discomfort
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    2 / 18 (11.11%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 22 (9.09%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    3 / 22 (13.64%)
    3 / 18 (16.67%)
    6 / 23 (26.09%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    5
    3
    7
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    5 / 22 (22.73%)
    3 / 18 (16.67%)
    4 / 23 (17.39%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    5
    3
    6
    0
    0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Night sweats
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 22 (9.09%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 22 (9.09%)
    2 / 18 (11.11%)
    2 / 23 (8.70%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    2
    2
    0
    0
    Pruritus generalised
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 22 (9.09%)
    2 / 18 (11.11%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    2
    1
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    2 / 18 (11.11%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    0
    Tumour pruritus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    1 / 18 (5.56%)
    1 / 23 (4.35%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    1
    0
    Haemorrhage urinary tract
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Nocturia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Urinary retention
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    2 / 18 (11.11%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 4 (75.00%)
    3 / 22 (13.64%)
    1 / 18 (5.56%)
    1 / 23 (4.35%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    4
    3
    1
    1
    1
    0
    Back pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    3 / 22 (13.64%)
    2 / 18 (11.11%)
    5 / 23 (21.74%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    3
    3
    5
    1
    0
    Bone pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Fistula
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Flank pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Groin pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    2
    0
    1
    0
    2
    0
    Pain in extremity
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 22 (4.55%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Rash pustular
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Skin infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 22 (9.09%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 22 (4.55%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    2 / 18 (11.11%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Wound infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 4 (75.00%)
    6 / 22 (27.27%)
    4 / 18 (22.22%)
    7 / 23 (30.43%)
    3 / 12 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    3
    6
    4
    8
    4
    0
    Dehydration
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 22 (4.55%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    2
    1
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    2
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 22 (0.00%)
    1 / 18 (5.56%)
    1 / 23 (4.35%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    None reported
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    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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