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    Clinical Trial Results:
    A Three-Part Study of Eltrombopag in Thrombocytopenic Subjects with Myelodysplastic Syndromes or Acute Myeloid Leukemia (Part 1: Open-Label, Part 2: Randomized, Double-Blind, Part 3: Extension).

    Summary
    EudraCT number
    		 2011-000114-19
    Trial protocol
    		 BE   DE   CZ   GR   ES   IE   PL   HU   IT   NL  
    Global end of trial date
    21 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jan 2017
    First version publication date
    04 Jan 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CETB115D2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01440374
    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,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    21 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part 1 open-label, 8 week first part of the study are: • To evaluate the safety and tolerability of eltrombopag. • To determine optimal dose escalation scheme for use in Part 2 of the study by assessing the dose of eltrombopag required to achieve platelet count response. • To characterize plasma eltrombopag pharmacokinetics (steady-state plasma eltrombopag Cmax, tmax, AUC(0-τ), CL/F, and half-life). Part 2: • The primary objective of this study is to determine reduction in the number of clinically relevant thrombocytopenic events (CRTE) in subjects with MDS or AML who have Grade 4 thrombocytopenia (<25 Gi/L) and are treated with eltrombopag compared to those treated with placebo. Part 3: The objectives of Part 3 of the study are to evaluate the long-term durability of clinical benefit as well as overall survival, the long-term safety and tolerability of eltrombopag in subjects with MDS and AML.”
    Protection of trial subjects
    The study was in compliance with the ethic 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
    30 Sep 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Czech Republic: 3
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Greece: 13
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Ireland: 11
    Country: Number of subjects enrolled
    Israel: 24
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Korea, Republic of: 7
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    Taiwan: 6
    Country: Number of subjects enrolled
    Thailand: 4
    Country: Number of subjects enrolled
    United States: 8
    Worldwide total number of subjects
    162
    EEA total number of subjects
    89
    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)
    34
    From 65 to 84 years
    120
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 Part 1, 17 subjects received open-label eltrombopag. Part 2, 145 subjects were randomized to receive eltrombopag plus SOC (N=98) or placebo plus SOC (N=47). Part 3, 59 subjects from Part 2 entered Part 3. SOC was allowed as needed throughout the study. Subjects could receive disease-modifying therapy as needed.

    Pre-assignment
    Screening details
    		 Participants with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) and Grade 4 thrombocytopenia due to bone marrow insufficiency and had at least one of the following: platelet count <10 Giga cells per liter, platelet transfusion or symptomatic hemorrhagic event during the 4 weeks prior to enrollment, were enrolled in the study.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    Part 1: Open-label Phase Part 2: Double-blind Phase Part 3: Extension

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Part 1: Eltrombopag
    Arm description
    		 The eltrombopag starting dose the participants received was 100 milligrams (mg) daily (50 mg for participants of East Asian heritage). The dose of eltrombopag was escalated from 100 mg to 200 mg (50 mg to 100 mg for East Asians) and further from 200 mg to 300 mg once daily (100 mg to 150 mg for East Asians) based on the platelet response and safety data after two weeks of current dose level. After all participants finished the 8 week treatment period, platelet response and safety were analyzed before initiating Part 2 of the study. Supportive standard of care was allowed as needed. The duration of Part 1 was 8 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eltrombopag
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Eltrombopag 100 mg once daily was selected as the starting dose for this study (50 mg for East Asian subjects), with subsequent dose adjustments dependent on each subject’s platelet counts. Eltrombopag was to be taken on an empty stomach (1 hour before or 2 hours after a meal) or with food containing little (<50 mg) or preferably no calcium or dairy products. At least a 4-hour interval between eltrombopag and other medications or products containing polyvalent cations.

    Arm title
    		 Part 2: Placebo
    Arm description
    		 Participants received eltrombopag matching placebo once daily (3 tablets). Supportive standard of care was allowed as needed throughout the study.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    In Part 2 of the study, the duration of placebo administration required before dose escalation was based on platelet response and safety assessed during Part 1 of the study. The maximum dose of study medication was 300 mg once daily (150 mg for East Asian subjects). Placebo was to be taken on an empty stomach (1 hour before or 2 hours after a meal) or with food containing little (<50 mg) or preferably no calcium or dairy products. At least a 4-hour interval between placebo and other medications or products containing polyvalent cations (e.g., calcium, magnesium, aluminum, zinc, selenium, or iron), such as antacids, dairy products, and mineral supplements, should be allowed to avoid significant (70% to 75%) reduction in absorption due to chelation.

    Arm title
    		 Part 2: Eltrombopag
    Arm description
    		 The eltrombopag starting dose the participants received was 100 mg daily (50 mg for participants of East Asian heritage). The duration of treatment with the initial dose level prior to first dose escalation was determined based on the platelet response and toxicity observed in Part 1. The dose of eltrombopag was escalated from 100 mg to 200 mg (50 mg to 100 mg for East Asians) and further from 200 mg to 300 mg once daily (100 mg to 150 mg for East Asians) based on the platelet response and safety data after two weeks of current dose level. Supportive standard of care was allowed as needed throughout the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eltrombopag
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    In Part 2 of the study, the duration of eltrombopag administration required before dose escalation was based on platelet response and safety assessed during Part 1 of the study. The maximum dose of study medication was 300 mg once daily (150 mg for East Asian subjects). Eltrombopag was to be taken on an empty stomach (1 hour before or 2 hours after a meal) or with food containing little (<50 mg) or preferably no calcium or dairy products. At least a 4-hour interval between eltrombopag and other medications or products containing polyvalent cations (e.g., calcium, magnesium, aluminum, zinc, selenium, or iron), such as antacids, dairy products, and mineral supplements, should be allowed to avoid significant (70% to 75%) reduction in eltrombopag absorption due to chelation.

    Arm title
    		 Part 3: Eltrombopag
    Arm description
    		 23 subjects of the 47 randomized to the placebo group in Part 2 entered part 3. 36 subjects of the 98 randomized to the Etrombopag group in Part 2 entered part 3. All subjects received eltrombopag. Part 3 subjects could also have received treatment for their disease per local SOC, including azacitidine, decitabine, lenalidomide, and chemotherapy. The duration of Part 3 was to be 10 months for subjects from Part 1and 9 months for subjects from Part 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eltrombopag
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Eltrombopag 100 mg once daily was selected as the starting dose for this study (50 mg for East Asian subjects), with subsequent dose adjustments dependent on each subject’s platelet counts. Eltrombopag was to be taken on an empty stomach (1 hour before or 2 hours after a meal) or with food containing little (<50 mg) or preferably no calcium or dairy products. At least a 4-hour interval between eltrombopag and other medications or products containing polyvalent cations.

    Number of subjects in period 1
    		Part 1: Eltrombopag Part 2: Placebo Part 2: Eltrombopag Part 3: Eltrombopag
    Started
    17
    47
    98
    59
    Completed
    11
    27
    43
    27
    Not completed
    6
    20
    55
    32
         Physician decision
    1
    8
    17
    14
         Consent withdrawn by subject
    -
    4
    5
    5
         Adverse event, non-fatal
    5
    7
    31
    13
         Lack of efficacy
    -
    1
    -
    -
         Not treated
    -
    -
    1
    -
         Protocol deviation
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Eltrombopag
    Reporting group description
    		 The eltrombopag starting dose the participants received was 100 milligrams (mg) daily (50 mg for participants of East Asian heritage). The dose of eltrombopag was escalated from 100 mg to 200 mg (50 mg to 100 mg for East Asians) and further from 200 mg to 300 mg once daily (100 mg to 150 mg for East Asians) based on the platelet response and safety data after two weeks of current dose level. After all participants finished the 8 week treatment period, platelet response and safety were analyzed before initiating Part 2 of the study. Supportive standard of care was allowed as needed. The duration of Part 1 was 8 weeks.

    Reporting group title
    Part 2: Placebo
    Reporting group description
    		 Participants received eltrombopag matching placebo once daily (3 tablets). Supportive standard of care was allowed as needed throughout the study.

    Reporting group title
    Part 2: Eltrombopag
    Reporting group description
    		 The eltrombopag starting dose the participants received was 100 mg daily (50 mg for participants of East Asian heritage). The duration of treatment with the initial dose level prior to first dose escalation was determined based on the platelet response and toxicity observed in Part 1. The dose of eltrombopag was escalated from 100 mg to 200 mg (50 mg to 100 mg for East Asians) and further from 200 mg to 300 mg once daily (100 mg to 150 mg for East Asians) based on the platelet response and safety data after two weeks of current dose level. Supportive standard of care was allowed as needed throughout the study.

    Reporting group title
    Part 3: Eltrombopag
    Reporting group description
    		 23 subjects of the 47 randomized to the placebo group in Part 2 entered part 3. 36 subjects of the 98 randomized to the Etrombopag group in Part 2 entered part 3. All subjects received eltrombopag. Part 3 subjects could also have received treatment for their disease per local SOC, including azacitidine, decitabine, lenalidomide, and chemotherapy. The duration of Part 3 was to be 10 months for subjects from Part 1and 9 months for subjects from Part 2.

    Reporting group values
    		 Part 1: Eltrombopag Part 2: Placebo Part 2: Eltrombopag Part 3: Eltrombopag Total
    Number of subjects
    		 17 47 98 59
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71.5 ( 10.78 ) 70.6 ( 10.72 ) 72.3 ( 8.94 ) 72.2 ( 9.27 ) -
    Gender categorical
    Units: Subjects
        Female
    		 7 16 32 19 74
        Male
    		 10 31 66 40 147
    RaceEthnicityOther
    Units: Subjects
        African American/African Heritage
    		 0 0 1 0 1
        Asian - East Asian Heritage
    		 3 5 9 9 26
        Asian - South East Asian Heritage
    		 0 2 2 0 4
        White - Arabic/North African Heritage
    		 0 1 5 0 6
        White - White/Caucasian/European Heritage
    		 14 39 81 50 184

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Eltrombopag
    Reporting group description
    		 The eltrombopag starting dose the participants received was 100 milligrams (mg) daily (50 mg for participants of East Asian heritage). The dose of eltrombopag was escalated from 100 mg to 200 mg (50 mg to 100 mg for East Asians) and further from 200 mg to 300 mg once daily (100 mg to 150 mg for East Asians) based on the platelet response and safety data after two weeks of current dose level. After all participants finished the 8 week treatment period, platelet response and safety were analyzed before initiating Part 2 of the study. Supportive standard of care was allowed as needed. The duration of Part 1 was 8 weeks.

    Reporting group title
    Part 2: Placebo
    Reporting group description
    		 Participants received eltrombopag matching placebo once daily (3 tablets). Supportive standard of care was allowed as needed throughout the study.

    Reporting group title
    Part 2: Eltrombopag
    Reporting group description
    		 The eltrombopag starting dose the participants received was 100 mg daily (50 mg for participants of East Asian heritage). The duration of treatment with the initial dose level prior to first dose escalation was determined based on the platelet response and toxicity observed in Part 1. The dose of eltrombopag was escalated from 100 mg to 200 mg (50 mg to 100 mg for East Asians) and further from 200 mg to 300 mg once daily (100 mg to 150 mg for East Asians) based on the platelet response and safety data after two weeks of current dose level. Supportive standard of care was allowed as needed throughout the study.

    Reporting group title
    Part 3: Eltrombopag
    Reporting group description
    		 23 subjects of the 47 randomized to the placebo group in Part 2 entered part 3. 36 subjects of the 98 randomized to the Etrombopag group in Part 2 entered part 3. All subjects received eltrombopag. Part 3 subjects could also have received treatment for their disease per local SOC, including azacitidine, decitabine, lenalidomide, and chemotherapy. The duration of Part 3 was to be 10 months for subjects from Part 1and 9 months for subjects from Part 2.

    Primary: Number of participants with platelet response up to Week 8 during Part 1

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    End point title
    		 Number of participants with platelet response up to Week 8 during Part 1 [1] [2]
    End point description
    A participant was considered as a responder if he/she met the following response criteria: a Baseline platelet count <20 Giga cells per liter (Gi/L) and a post-Baseline increased to >20 Gi/L and at least 2 times the Baseline value; or a Baseline platelet count >=20 Gi/L and a post-Baseline absolute platelet count increased to >=50 Gi/L and at least 2 times the Baseline value. The response criteria was evaluated at each visit. Increase in platelet count observed up to 3 days after a platelet transfusion was not considered as a platelet response. The Part 1 Population was comprised of all participants enrolled into Part 1.
    End point type
    Primary
    End point timeframe
    From Baseline up to Week 8 during Part 1
    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: Statistics were not reported for this endpoint.
    [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: Statistics are not reported for all arms in this study.
    End point values
    		 Part 1: Eltrombopag
    Number of subjects analysed
    17
    Units: Participants
    4
    No statistical analyses for this end point

    Primary: Percentage of participants with clinically relevant thrombocytopenic events (CRTE) from Week 5 up to Week 12 during Part 2

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    End point title
    		 Percentage of participants with clinically relevant thrombocytopenic events (CRTE) from Week 5 up to Week 12 during Part 2 [3]
    End point description
    A participant was considered to have a CRTE at a given assessment if he/she had platelet counts <10 Gi/L, or platelet transfusions, or >=Grade 3 hemorrhagic adverse events. CRTEs during Weeks 5 to 12 were compared between treatments using a generalized linear mixed model. Average of weekly proportion of subjects with CRTE during Week 5 to 12 was estimated for each treatment. Intent to Treat (ITT) Population was comprised of all randomized participants during Part 2.
    End point type
    Primary
    End point timeframe
    From Week 5 up to Week 12 during Part 2
    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: Statistics are not reported for all arms in this study.
    End point values
    		 Part 2: Placebo Part 2: Eltrombopag
    Number of subjects analysed
    47
    98
    Units: Percentage
        arithmetic mean (confidence interval 95%)
    69 (57 to 80)
    54 (43 to 64)
    Statistical analysis title
    		 clinically relevant thrombocytopenic events
    Comparison groups
    Part 2: Placebo v Part 2: Eltrombopag
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0315
    Method
    		 Generalized Linear Mixed Models
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.202
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.047
         upper limit
    		 0.868

    Secondary: Plasma Eltrombopag Pharmacokinetic Concentration-Time Data - by Visit (Part 1 Subjects)

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    End point title
    		 Plasma Eltrombopag Pharmacokinetic Concentration-Time Data - by Visit (Part 1 Subjects) [4]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to week 8
    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: Statistics are not reported for all arms in this study.
    End point values
    		 Part 1: Eltrombopag
    Number of subjects analysed
    17
    Units: ug/mL
    arithmetic mean (standard deviation)
        Baseline/day 1 (Pre-dose PK)
    0 ( 0 )
        Day8 week 1 (Pre-dose PK)
    7.7 ( 3.96 )
        Day15 week 2 (Pre-dose PK)
    7.2 ( 5.17 )
        Day22 week 3 (Pre-dose PK)
    14.3 ( 10.63 )
        Day29 week 3 (2-6hrs post-dose PK)
    20.8 ( 14.98 )
        Day36 week 5 (Pre-dose PK)
    20.2 ( 16.37 )
        Day43 week6 (2-6hrs post-dose PK)
    41.2 ( 32.56 )
        Day50 week 7 (Pre-dose PK)
    30.4 ( 27.95 )
        Day57 week 8 (2-6hrs post-dose PK)
    30.1 ( 18.99 )
    No statistical analyses for this end point

    Secondary: Plasma Eltrombopag Pharmacokinetic Concentration-Time Data - by Visit (Part 2 Subjects)

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    End point title
    		 Plasma Eltrombopag Pharmacokinetic Concentration-Time Data - by Visit (Part 2 Subjects) [5]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to week 12
    Notes
    [5] - 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: Statistics are not reported for all arms in this study.
    End point values
    		 Part 2: Eltrombopag
    Number of subjects analysed
    97
    Units: ug/mL
    arithmetic mean (standard deviation)
        Baseline/day 1 (Pre-dose PK)
    0 ( 0 )
        Day15 week 2 (Pre-dose PK)
    10.1 ( 5.54 )
        Day22 week 3 (2-6hrs post-dose PK)
    24 ( 14.6 )
        Day29 week 4 (Pre-dose PK)
    20.2 ( 13.61 )
        Day43 week 6 (Pre-dose PK)
    29 ( 18.13 )
        Day50 week 7 (2-6hrs post-dose PK)
    42.9 ( 22.37 )
        Day57 week8 (Pre-dose PK)
    36.3 ( 20.91 )
        Day71 week 10 (Pre-dose PK)
    33.5 ( 20.4 )
        Day78 week 11 (2-6hrs post-dose PK)
    41.2 ( 24.91 )
        Day85 week12 (Pre-dose PK)
    30.7 ( 18.03 )
    No statistical analyses for this end point

    Secondary: Mean Number of Platelet Transfusions

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    End point title
    		 Mean Number of Platelet Transfusions [6]
    End point description
    End point type
    Secondary
    End point timeframe
    Weeks 5 to 12
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are not reported for all arms in this study.
    End point values
    		 Part 2: Placebo Part 2: Eltrombopag
    Number of subjects analysed
    47
    98
    Units: Number of platelet transfusions
        arithmetic mean (standard deviation)
    15.7 ( 20.36 )
    18.8 ( 18.6 )
    No statistical analyses for this end point

    Secondary: Hematologic Improvement

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    End point title
    		 Hematologic Improvement [7]
    End point description
    End point type
    Secondary
    End point timeframe
    Weeks 5 to 12
    Notes
    [7] - 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: Statistics are not reported for all arms in this study.
    End point values
    		 Part 2: Placebo Part 2: Eltrombopag
    Number of subjects analysed
    47
    98
    Units: Number of subjects
        Any Improvement
    4
    10
        Platelets
    2
    8
        Neutrophils
    4
    4
        Hemoglobin
    0
    0
        Platelets and neutrophils
    2
    2
        Platelets and hemoglobin
    0
    0
        Platelets, hemoglobin and neutrophils
    0
    0
        Neutrophils and hemoglobin
    0
    0
    No statistical analyses for this end point

    Secondary: Change in Mean Platelet Count

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    End point title
    		 Change in Mean Platelet Count [8]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    Notes
    [8] - 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: Statistics are not reported for all arms in this study.
    End point values
    		 Part 2: Placebo Part 2: Eltrombopag
    Number of subjects analysed
    47
    98
    Units: Gi/L
    arithmetic mean (standard deviation)
        Day8 week1
    1.66 ( 6.249 )
    3.36 ( 11.795 )
        Day15 week2
    3.06 ( 9.675 )
    10.41 ( 60.225 )
        Day22 week3
    2.13 ( 9.258 )
    6.23 ( 22.872 )
        Day29 week4
    2.44 ( 11.215 )
    5.63 ( 17.582 )
        Day36 week5
    5.9 ( 16 )
    8.58 ( 22.504 )
        Day43 week6
    5.93 ( 21.96 )
    8.64 ( 19.779 )
        Day50 week7
    6.74 ( 31.074 )
    9.91 ( 25.561 )
        Day57 week8
    7.84 ( 34.213 )
    9.67 ( 23.243 )
        Day64 week9
    6.75 ( 31.709 )
    12.84 ( 27.272 )
        Day71 week10
    6.23 ( 30.941 )
    15.97 ( 33.866 )
        Day78 week11
    6.92 ( 26.906 )
    14.42 ( 36.901 )
        Day 85 week12
    4.85 ( 26.219 )
    9.06 ( 28.259 )
    No statistical analyses for this end point

    Secondary: MeanMaximum Duration of Platelet Transfusion Independence

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    End point title
    		 MeanMaximum Duration of Platelet Transfusion Independence [9]
    End point description
    End point type
    Secondary
    End point timeframe
    Weeks 5 to 12
    Notes
    [9] - 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: Statistics are not reported for all arms in this study.
    End point values
    		 Part 2: Placebo Part 2: Eltrombopag
    Number of subjects analysed
    47
    98
    Units: Number of platelet transfusions
        arithmetic mean (standard deviation)
    25.4 ( 19.7 )
    26.3 ( 21.47 )
    No statistical analyses for this end point

    Secondary: Maximum Bleeding Grade According to World Health Organization on Bleeding Scale

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    End point title
    		 Maximum Bleeding Grade According to World Health Organization on Bleeding Scale [10]
    End point description
    End point type
    Secondary
    End point timeframe
    Weeks 5 to 12
    Notes
    [10] - 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: Statistics are not reported for all arms in this study.
    End point values
    		 Part 2: Placebo Part 2: Eltrombopag
    Number of subjects analysed
    47
    98
    Units: Number of subjects
        Grade 0 (no bleeding)
    4
    15
        Grade 1 (petechiae)
    22
    31
        Grade 2 (mild blood loss)
    14
    41
        Grade 3 (gross blood loss)
    3
    5
        Grade 4 (debilitating blood loss)
    3
    1
        Grades 0 – 1
    26
    46
        Grades 0 – 4
    42
    78
        Grades 2 - 4
    20
    47
    No statistical analyses for this end point

    Secondary: Independent Reviewer-Assessed Best Response

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    End point title
    		 Independent Reviewer-Assessed Best Response [11]
    End point description
    End point type
    Secondary
    End point timeframe
    up to week 12
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are not reported for all arms in this study.
    End point values
    		 Part 2: Placebo Part 2: Eltrombopag
    Number of subjects analysed
    47
    98
    Units: Number of subjects
        Responder
    1
    1
        Complete response (CR)
    0
    0
        Morphologic CR
    1
    0
        Morphologic leukemia-free state
    0
    0
        Marrow CR
    0
    1
        Cytogenetic CR
    0
    0
        Molecular CR
    0
    0
        Non-responder
    46
    97
        Partial response
    0
    0
        Stable disease (non-responder)
    10
    18
        Progressive disease (non-responder)
    28
    41
        Not evaluable (non-responder)
    8
    36
        Missing (non-responder)
    0
    2
    No statistical analyses for this end point

    Secondary: Independent Reviewer Assessed Disease Progression

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    End point title
    		 Independent Reviewer Assessed Disease Progression [12]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to week 12
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are not reported for all arms in this study.
    End point values
    		 Part 2: Placebo Part 2: Eltrombopag
    Number of subjects analysed
    47
    98
    Units: Number of subjects
        Disease progression
    36
    61
        No disease progression
    6
    12
        Not evaluable
    5
    23
        Missing
    0
    2
    No statistical analyses for this end point

    Secondary: Median Overall Survival

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    End point title
    		 Median Overall Survival [13]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to week 12
    Notes
    [13] - 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: Statistics are not reported for all arms in this study.
    End point values
    		 Part 2: Placebo Part 2: Eltrombopag
    Number of subjects analysed
    47
    98
    Units: Months
        median (confidence interval 95%)
    4.6 (3.29 to 7.82)
    4.27 (2.96 to 7.59)
    No statistical analyses for this end point

    Secondary: Summary of Health Outcomes

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    End point title
    		 Summary of Health Outcomes [14]
    End point description
    The number of subject with medical resource utilization (MRU) data are reported in this table. MRU included number of emergency room visits, number of home healthcare visits, number of hospitalization days, number of medication or surgery specialist visits, number of procedures inpatient, number of procedures outpatient, number of non-study radiology visits, number of non-study laboratory visits, number of nurse practitioner/physician assistance/nurse visits, number of primary care physician visits, number of telephone consultations.
    End point type
    Secondary
    End point timeframe
    week 12
    Notes
    [14] - 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: Statistics are not reported for all arms in this study.
    End point values
    		 Part 2: Placebo Part 2: Eltrombopag
    Number of subjects analysed
    47
    98
    Units: week
        Number of emergency room visits (n=17, n=10)
    0
    1
        Number of home healthcare visits (n=17, n=10)
    1
    2
        Number of hospitalization days (n=17, n=10)
    4
    5
        Number of med/surg specialist visits (n=17, n=10)
    3
    1
        Number of procedures inpatient (n=17, n=10)
    1
    2
        Number of procedures outpatient (n=17, n=10)
    1
    1
        Number of non-study radiology visits (n=2, n=2)
    2
    2
        Number of nurse prac/pa/nurse visits (n=17, n=10)
    3
    5
        Number of primary care physician visits (n=17,10)
    1
    7
        Number of telephone consultations (n=17, n=10)
    0
    1
        Number of non-study laboratory visits (n=17, n=10)
    6
    8
    No statistical analyses for this end point

    Secondary: Functional Assessment of Cancer Therapy (FACT)

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    End point title
    		 Functional Assessment of Cancer Therapy (FACT) [15]
    End point description
    FACT-Th-18 questionnaire is the most widely used and accepted tool evaluating health-related quality-of-life outcomes in cancer patients with chronically low platelets (where Th designates thrombocytopenia). The entire FACT-Th-18 was used in this trial, which includes the 18-item thrombocytopenia subscale used to assess the impact of symptoms, signs, and functional consequences of thrombocytopenia in MDS and AML subjects. The FACT-Th-18 is a validated and reliable instrument with known psychometric properties [Cella, 2006]. The core questionnaire measures general health and well-being across 4 dimensions: physical, social and family, emotional, and functional well-being. FACT-Th-18 Trial Outcome Index (TOI) and FACT-G (global) scores.
    End point type
    Secondary
    End point timeframe
    Change from baseline, up to week 12
    Notes
    [15] - 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: Statistics are not reported for all arms in this study.
    End point values
    		 Part 2: Placebo Part 2: Eltrombopag
    Number of subjects analysed
    47
    98
    Units: Adjusted mean change from baseline
    arithmetic mean (standard error)
        FACTG week 5 (n=61. n=34)
    -3.15 ( 2.19 )
    -0.79 ( 1.64 )
        FACTG week 9 (n=46. n=28)
    -2.76 ( 2.34 )
    -4.83 ( 1.82 )
        FACTG week12 (n=37. n=26)
    -4.17 ( 2.39 )
    -3.38 ( 1.94 )
        FACTHTOI week 5 (n=61, n=34)
    -2.28 ( 2.74 )
    0.91 ( 2.04 )
        FACTHTOI week 9 (n=46, n=28)
    0.19 ( 2.89 )
    -1.69 ( 2.24 )
        FACTHTOI week 12 (n=37, n=26)
    -1.56 ( 2.95 )
    -0.26 ( 2.37 )
    No statistical analyses for this end point

    Secondary: EQ-5D Utility Score Analysis

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    End point title
    		 EQ-5D Utility Score Analysis [16]
    End point description
    A summary of the number and percentage of subjects responding at each level for each dimension or item of the EQ-5D was displayed by visit and by treatment group. The EQ-5D measures mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Responses to each of the 5 health states are measured on a 3-point scale.
    End point type
    Secondary
    End point timeframe
    Change from baseline, up to week 12
    Notes
    [16] - 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: Statistics are not reported for all arms in this study.
    End point values
    		 Part 2: Placebo Part 2: Eltrombopag
    Number of subjects analysed
    47
    98
    Units: Adjusted mean change from baseline
    arithmetic mean (standard error)
        Week 5 (n=55. n=34)
    -0.15 ( 0.05 )
    -0.01 ( 0.04 )
        Week 9 (n=43. n=27)
    -0.06 ( 0.05 )
    -0.08 ( 0.04 )
        Week 12 (n=36. n=26)
    -0.11 ( 0.05 )
    -0.09 ( 0.05 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field "number of deaths 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
    18.1
    Reporting groups
    Reporting group title
    Part 1 Eltrombopag
    Reporting group description
    		 Part 1 Eltrombopag

    Reporting group title
    Part 2 Placebo
    Reporting group description
    		 Part 2 Placebo

    Reporting group title
    Part 2 Eltrombopag
    Reporting group description
    		 Part 2 Eltrombopag

    Reporting group title
    Part 2 subjects in Part 3 Eltrombopag
    Reporting group description
    		 Part 2 subjects in Part 3 Eltrombopag

    Serious adverse events
    		 Part 1 Eltrombopag Part 2 Placebo Part 2 Eltrombopag Part 2 subjects in Part 3 Eltrombopag
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 17 (52.94%)
    32 / 47 (68.09%)
    56 / 97 (57.73%)
    39 / 59 (66.10%)
         number of deaths (all causes)
    5
    13
    35
    24
         number of deaths resulting from adverse events
    0
    0
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    2 / 97 (2.06%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Vascular disorders
    Arterial thrombosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 47 (4.26%)
    2 / 97 (2.06%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
    Malaise
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 47 (4.26%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 17 (11.76%)
    6 / 47 (12.77%)
    7 / 97 (7.22%)
    7 / 59 (11.86%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
    1 / 8
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung consolidation
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    2 / 97 (2.06%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Subdural haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    1 / 97 (1.03%)
    3 / 59 (5.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 3
    Myocardial infarction
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Seizure
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    2 / 97 (2.06%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    2 / 97 (2.06%)
    3 / 59 (5.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Febrile neutropenia
         subjects affected / exposed
    0 / 17 (0.00%)
    7 / 47 (14.89%)
    7 / 97 (7.22%)
    6 / 59 (10.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 10
    0 / 10
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    Haemolytic anaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    3 / 59 (5.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Lymphadenopathy
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic artery thrombosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenomegaly
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal vein occlusion
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    2 / 97 (2.06%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    2 / 97 (2.06%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 47 (6.38%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    2 / 97 (2.06%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal hypomotility
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Melaena
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral mucosal blistering
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Haematuria
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal disorder
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess neck
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    4 / 59 (6.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter site cellulitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Enteritis infectious
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    2 / 97 (2.06%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    2 / 97 (2.06%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Lung infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 17 (5.88%)
    5 / 47 (10.64%)
    14 / 97 (14.43%)
    10 / 59 (16.95%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
    0 / 17
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 4
    0 / 5
    Respiratory tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 17 (23.53%)
    5 / 47 (10.64%)
    8 / 97 (8.25%)
    6 / 59 (10.17%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 9
    0 / 15
    0 / 12
         deaths causally related to treatment / all
    0 / 3
    0 / 4
    0 / 7
    0 / 6
    Septic shock
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 47 (2.13%)
    1 / 97 (1.03%)
    3 / 59 (5.08%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 2
    Splenic abscess
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    3 / 97 (3.09%)
    5 / 59 (8.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral oesophagitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1 Eltrombopag Part 2 Placebo Part 2 Eltrombopag Part 2 subjects in Part 3 Eltrombopag
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 17 (100.00%)
    44 / 47 (93.62%)
    89 / 97 (91.75%)
    54 / 59 (91.53%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 17 (0.00%)
    9 / 47 (19.15%)
    7 / 97 (7.22%)
    9 / 59 (15.25%)
         occurrences all number
    0
    12
    7
    10
    Haemorrhage
         subjects affected / exposed
    2 / 17 (11.76%)
    4 / 47 (8.51%)
    4 / 97 (4.12%)
    1 / 59 (1.69%)
         occurrences all number
    2
    4
    7
    1
    Hypertension
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    6 / 97 (6.19%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    7
    0
    Hypotension
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 47 (2.13%)
    3 / 97 (3.09%)
    2 / 59 (3.39%)
         occurrences all number
    1
    1
    3
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 17 (17.65%)
    5 / 47 (10.64%)
    4 / 97 (4.12%)
    6 / 59 (10.17%)
         occurrences all number
    6
    9
    4
    17
    Catheter site related reaction
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 17 (5.88%)
    3 / 47 (6.38%)
    23 / 97 (23.71%)
    9 / 59 (15.25%)
         occurrences all number
    1
    4
    28
    11
    Oedema peripheral
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 47 (6.38%)
    9 / 97 (9.28%)
    7 / 59 (11.86%)
         occurrences all number
    0
    3
    9
    9
    Pain
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 47 (2.13%)
    2 / 97 (2.06%)
    2 / 59 (3.39%)
         occurrences all number
    1
    1
    2
    2
    Pyrexia
         subjects affected / exposed
    4 / 17 (23.53%)
    10 / 47 (21.28%)
    18 / 97 (18.56%)
    12 / 59 (20.34%)
         occurrences all number
    12
    25
    29
    20
    Xerosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    2 / 97 (2.06%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    6
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cough
         subjects affected / exposed
    1 / 17 (5.88%)
    4 / 47 (8.51%)
    13 / 97 (13.40%)
    7 / 59 (11.86%)
         occurrences all number
    1
    5
    16
    8
    Dyspnoea
         subjects affected / exposed
    1 / 17 (5.88%)
    5 / 47 (10.64%)
    9 / 97 (9.28%)
    4 / 59 (6.78%)
         occurrences all number
    1
    6
    10
    6
    Epistaxis
         subjects affected / exposed
    5 / 17 (29.41%)
    11 / 47 (23.40%)
    27 / 97 (27.84%)
    12 / 59 (20.34%)
         occurrences all number
    6
    18
    46
    21
    Haemoptysis
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 47 (6.38%)
    6 / 97 (6.19%)
    2 / 59 (3.39%)
         occurrences all number
    0
    3
    7
    3
    Oropharyngeal pain
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 47 (4.26%)
    0 / 97 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    1
    2
    0
    3
    Productive cough
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences all number
    1
    0
    1
    1
    Rales
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Sputum increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    2 / 97 (2.06%)
    2 / 59 (3.39%)
         occurrences all number
    1
    0
    2
    2
    Confusional state
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    1 / 97 (1.03%)
    3 / 59 (5.08%)
         occurrences all number
    0
    1
    1
    3
    Initial insomnia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    1
    0
    0
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 17 (17.65%)
    5 / 47 (10.64%)
    10 / 97 (10.31%)
    5 / 59 (8.47%)
         occurrences all number
    4
    7
    17
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 17 (5.88%)
    5 / 47 (10.64%)
    3 / 97 (3.09%)
    2 / 59 (3.39%)
         occurrences all number
    1
    7
    3
    2
    Blood albumin decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 47 (2.13%)
    2 / 97 (2.06%)
    1 / 59 (1.69%)
         occurrences all number
    1
    2
    2
    4
    Blood bilirubin increased
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 47 (4.26%)
    6 / 97 (6.19%)
    5 / 59 (8.47%)
         occurrences all number
    3
    3
    9
    7
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood sodium increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    1
    0
    0
    1
    Blood urea increased
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 47 (6.38%)
    2 / 97 (2.06%)
    2 / 59 (3.39%)
         occurrences all number
    0
    3
    2
    3
    Body temperature fluctuation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Liver function test abnormal
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences all number
    2
    0
    1
    1
    Serum ferritin increased
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences all number
    2
    0
    1
    1
    Weight decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 47 (2.13%)
    1 / 97 (1.03%)
    3 / 59 (5.08%)
         occurrences all number
    2
    1
    1
    5
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 17 (5.88%)
    3 / 47 (6.38%)
    4 / 97 (4.12%)
    5 / 59 (8.47%)
         occurrences all number
    2
    17
    7
    12
    Fall
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 47 (2.13%)
    1 / 97 (1.03%)
    3 / 59 (5.08%)
         occurrences all number
    2
    1
    1
    3
    Laceration
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Post procedural haematoma
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Transfusion reaction
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 47 (6.38%)
    2 / 97 (2.06%)
    1 / 59 (1.69%)
         occurrences all number
    0
    4
    2
    1
    Wound
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    0
    3
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Nervous system disorders
    Aphonia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Balance disorder
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    2 / 17 (11.76%)
    4 / 47 (8.51%)
    9 / 97 (9.28%)
    2 / 59 (3.39%)
         occurrences all number
    2
    5
    10
    2
    Headache
         subjects affected / exposed
    3 / 17 (17.65%)
    3 / 47 (6.38%)
    3 / 97 (3.09%)
    1 / 59 (1.69%)
         occurrences all number
    3
    3
    3
    1
    Mental impairment
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    2
    0
    0
    2
    Poor quality sleep
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Syncope
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    2
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 17 (17.65%)
    2 / 47 (4.26%)
    8 / 97 (8.25%)
    2 / 59 (3.39%)
         occurrences all number
    14
    5
    12
    5
    Blood disorder
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Febrile neutropenia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    4 / 97 (4.12%)
    2 / 59 (3.39%)
         occurrences all number
    1
    0
    4
    2
    Haemolysis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Leukocytosis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    3 / 97 (3.09%)
    4 / 59 (6.78%)
         occurrences all number
    0
    1
    4
    11
    Neutropenia
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 47 (4.26%)
    2 / 97 (2.06%)
    3 / 59 (5.08%)
         occurrences all number
    4
    4
    2
    3
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Vertigo
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 47 (4.26%)
    1 / 97 (1.03%)
    2 / 59 (3.39%)
         occurrences all number
    3
    2
    1
    2
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
    4 / 47 (8.51%)
    2 / 97 (2.06%)
    0 / 59 (0.00%)
         occurrences all number
    1
    4
    2
    0
    Eye haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    5 / 97 (5.15%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    5
    0
    Ocular hyperaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Ocular icterus
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    5 / 59 (8.47%)
         occurrences all number
    0
    0
    0
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 17 (5.88%)
    3 / 47 (6.38%)
    6 / 97 (6.19%)
    5 / 59 (8.47%)
         occurrences all number
    1
    4
    8
    5
    Abdominal pain upper
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 47 (4.26%)
    6 / 97 (6.19%)
    2 / 59 (3.39%)
         occurrences all number
    0
    3
    9
    2
    Colitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 47 (0.00%)
    12 / 97 (12.37%)
    7 / 59 (11.86%)
         occurrences all number
    3
    0
    20
    8
    Diarrhoea
         subjects affected / exposed
    4 / 17 (23.53%)
    5 / 47 (10.64%)
    20 / 97 (20.62%)
    11 / 59 (18.64%)
         occurrences all number
    5
    5
    29
    19
    Gingival bleeding
         subjects affected / exposed
    1 / 17 (5.88%)
    8 / 47 (17.02%)
    13 / 97 (13.40%)
    7 / 59 (11.86%)
         occurrences all number
    2
    15
    14
    8
    Gingival swelling
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    7 / 47 (14.89%)
    9 / 97 (9.28%)
    7 / 59 (11.86%)
         occurrences all number
    0
    13
    12
    13
    Nausea
         subjects affected / exposed
    1 / 17 (5.88%)
    8 / 47 (17.02%)
    13 / 97 (13.40%)
    14 / 59 (23.73%)
         occurrences all number
    1
    9
    20
    14
    Vomiting
         subjects affected / exposed
    2 / 17 (11.76%)
    5 / 47 (10.64%)
    6 / 97 (6.19%)
    6 / 59 (10.17%)
         occurrences all number
    2
    6
    8
    7
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    3 / 97 (3.09%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    3
    0
    Skin and subcutaneous tissue disorders
    Blood blister
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    2
    0
    3
    Decubitus ulcer
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences all number
    1
    0
    1
    2
    Dry skin
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    1
    3
    Ecchymosis
         subjects affected / exposed
    2 / 17 (11.76%)
    6 / 47 (12.77%)
    7 / 97 (7.22%)
    6 / 59 (10.17%)
         occurrences all number
    3
    13
    17
    7
    Petechiae
         subjects affected / exposed
    6 / 17 (35.29%)
    11 / 47 (23.40%)
    41 / 97 (42.27%)
    8 / 59 (13.56%)
         occurrences all number
    9
    16
    56
    15
    Pruritus
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 47 (2.13%)
    2 / 97 (2.06%)
    1 / 59 (1.69%)
         occurrences all number
    2
    1
    2
    1
    Purpura
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 47 (4.26%)
    0 / 97 (0.00%)
    2 / 59 (3.39%)
         occurrences all number
    3
    2
    0
    2
    Rash
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    1
    3
    0
    2
    Skin discolouration
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 47 (0.00%)
    2 / 97 (2.06%)
    3 / 59 (5.08%)
         occurrences all number
    2
    0
    2
    3
    Skin haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 47 (6.38%)
    2 / 97 (2.06%)
    0 / 59 (0.00%)
         occurrences all number
    0
    4
    2
    0
    Skin ulcer
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Renal and urinary disorders
    Azotaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urinary incontinence
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urinary retention
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 17 (5.88%)
    4 / 47 (8.51%)
    1 / 97 (1.03%)
    2 / 59 (3.39%)
         occurrences all number
    2
    4
    1
    2
    Back pain
         subjects affected / exposed
    0 / 17 (0.00%)
    4 / 47 (8.51%)
    11 / 97 (11.34%)
    5 / 59 (8.47%)
         occurrences all number
    0
    5
    11
    5
    Pain in extremity
         subjects affected / exposed
    0 / 17 (0.00%)
    5 / 47 (10.64%)
    6 / 97 (6.19%)
    2 / 59 (3.39%)
         occurrences all number
    0
    5
    6
    2
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Arthritis infective
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Bacterial infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cellulitis
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 47 (6.38%)
    2 / 97 (2.06%)
    2 / 59 (3.39%)
         occurrences all number
    0
    3
    2
    2
    Escherichia infection
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 47 (2.13%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    7 / 59 (11.86%)
         occurrences all number
    0
    0
    1
    9
    Otitis externa
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    4 / 17 (23.53%)
    1 / 47 (2.13%)
    3 / 97 (3.09%)
    2 / 59 (3.39%)
         occurrences all number
    4
    1
    3
    2
    Skin infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences all number
    1
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 17 (17.65%)
    2 / 47 (4.26%)
    2 / 97 (2.06%)
    0 / 59 (0.00%)
         occurrences all number
    3
    2
    2
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 47 (4.26%)
    5 / 97 (5.15%)
    3 / 59 (5.08%)
         occurrences all number
    2
    4
    5
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 17 (11.76%)
    7 / 47 (14.89%)
    14 / 97 (14.43%)
    10 / 59 (16.95%)
         occurrences all number
    3
    7
    15
    12
    Dehydration
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 47 (2.13%)
    2 / 97 (2.06%)
    3 / 59 (5.08%)
         occurrences all number
    0
    2
    2
    3
    Hyperkalaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    1 / 97 (1.03%)
    1 / 59 (1.69%)
         occurrences all number
    1
    0
    1
    1
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 47 (4.26%)
    7 / 97 (7.22%)
    0 / 59 (0.00%)
         occurrences all number
    1
    3
    8
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    4 / 97 (4.12%)
    1 / 59 (1.69%)
         occurrences all number
    2
    0
    5
    8
    Hypokalaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 47 (6.38%)
    9 / 97 (9.28%)
    8 / 59 (13.56%)
         occurrences all number
    0
    5
    12
    12
    Hypomagnesaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    5 / 97 (5.15%)
    3 / 59 (5.08%)
         occurrences all number
    2
    0
    5
    3
    Hypophagia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    0 / 97 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 47 (0.00%)
    2 / 97 (2.06%)
    2 / 59 (3.39%)
         occurrences all number
    1
    0
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Dec 2011
    The Czech Republic Regulatory Authority requested revisions to the protocol to comply with local country standards for liver chemistry inclusion criteria and liver chemistry discontinuation/withdrawal criteria.
    25 May 2012
    Selection of dose escalation scheme based on Part 1 results; added secondary endpoint of overall survival and separate endpoints to assess disease progression and response; addition of external adjudication committee to review disease progression and disease response; modifications to simplify dose adjustment guidelines; addition of guidelines to allow rechallenge with study medication after a subject met a liver stopping criteria.
    17 Jan 2013
    Modified to allow continued access to study medication in Part 3 for up to an additional 12 months. The amendment applied only to subjects in Israel.

    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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