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    Clinical Trial Results:
    An Open-Label, Randomized, Multicenter Phase III Trial of Dasatinib (SPRYCEL®) vs. Standard Dose Imatinib (400 mg) in the Treatment of Subjects with Newly Diagnosed Chronic Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia

    Summary
    EudraCT number
    		 2006-005712-27
    Trial protocol
    		 FR   CZ   GR   BE   NL   DE   AT   HU   ES   IT   DK   PL  
    Global end of trial date
    22 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Feb 2017
    First version publication date
    03 Feb 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA180-056
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00481247
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb International Corporation
    Sponsor organisation address
    Chausse de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb Study Director, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Dec 2009
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Dec 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this clinical research study is to compare the confirmed complete cytogenetic response of dasatinib with that of imatinib within 12 months after randomization in patients with newly diagnosed chronic-phase Philadelphia positive chronic myeloid leukemia. The safety of this treatment will also be studied.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Sep 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Poland: 21
    Country: Number of subjects enrolled
    Spain: 30
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Czech Republic: 22
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    France: 42
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Argentina: 28
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    Brazil: 24
    Country: Number of subjects enrolled
    Chile: 11
    Country: Number of subjects enrolled
    China: 37
    Country: Number of subjects enrolled
    Colombia: 5
    Country: Number of subjects enrolled
    India: 111
    Country: Number of subjects enrolled
    Japan: 49
    Country: Number of subjects enrolled
    Korea, Republic of: 14
    Country: Number of subjects enrolled
    Mexico: 40
    Country: Number of subjects enrolled
    Peru: 18
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    Singapore: 11
    Country: Number of subjects enrolled
    Turkey: 6
    Worldwide total number of subjects
    547
    EEA total number of subjects
    172
    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)
    488
    From 65 to 84 years
    59
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in 108 sites in 26 countries.

    Pre-assignment
    Screening details
    		 Of the 547 subjects enrolled, 519 were randomized and 516 received treatment. Of the 28 who were enrolled but not randomized, 20 no longer met study criteria, 3 withdrew consent, 1 was lost to follow-up, and 4 withdrew for other reasons.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dasatinib
    Arm description
    		 Dasatinib 100 mg once daily (QD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dasatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dasatinib: 100 mg orally once daily

    Arm title
    		 Imatinib
    Arm description
    		 Imatinib 400 mg once daily (QD)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Imatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Imatinib: 400 mg orally once daily

    Number of subjects in period 1 [1]
    		Dasatinib Imatinib
    Started
    259
    260
    Received treatment
    258
    258
    Completed
    0
    0
    Not completed
    259
    260
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    8
    13
         Disease progression
    18
    22
         Treatment failure
    10
    14
         Varied
    6
    15
         Poor compliance/noncompliance
    1
    7
         Pregnancy
    2
    1
         AE unrelated to study drug
    13
    4
         Intolerance
    42
    17
         Lost to follow-up
    1
    2
         Did not receive treatment
    1
    2
         Administrative reason by sponsor
    157
    162
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of the 547 patients enrolled, 519 were randomized and 516 received treatment. Of the 28 who were enrolled but not randomized, 20 no longer met study criteria, 3 withdrew consent, 1 was lost to follow-up, and 4 withdrew for other reasons.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dasatinib
    Reporting group description
    		 Dasatinib 100 mg once daily (QD)

    Reporting group title
    Imatinib
    Reporting group description
    		 Imatinib 400 mg once daily (QD)

    Reporting group values
    		 Dasatinib Imatinib Total
    Number of subjects
    		 259 260 519
    Age, Customized
    Units: Subjects
        <20 years
    		 5 9 14
        Between 21 and 45 years
    		 123 102 225
        Between 46 and 65 years
    		 111 125 236
        Between 66 and 75 years
    		 13 20 33
        >75 years
    		 7 4 11
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 46.4 ± 14.6 47.1 ± 13.9 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 115 97 212
        Male
    		 144 163 307
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 132 143 275
        Black/African American
    		 2 1 3
        Asian
    		 108 95 203
        Other
    		 17 21 38
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    ECOG is a 6-item scale used to assess disease progression, daily functioning, and appropriate treatment and prognosis. Performance status is scored on a scale ranging from 0-5, with (best score) 0=fully active and able to carry on all predisease performance without restriction and (worst score) 5=death.
    Units: Subjects
        ECOG score=0
    		 213 205 418
        ECOG score=1
    		 46 53 99
        ECOG score=2
    		 0 2 2

    End points

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    End points reporting groups
    Reporting group title
    Dasatinib
    Reporting group description
    		 Dasatinib 100 mg once daily (QD)

    Reporting group title
    Imatinib
    Reporting group description
    		 Imatinib 400 mg once daily (QD)

    Primary: Number of Subjects with Best Confirmed Complete Cytogenetic Response (cCCyR) Within 12 Months

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    End point title
    		 Number of Subjects with Best Confirmed Complete Cytogenetic Response (cCCyR) Within 12 Months
    End point description
    Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive (Ph+) cells in metaphase from bone marrow (BM) sample. (Ideally, 25 metaphases but at least 20 metaphases from a BM sample were evaluated). Complete Cytogenetic Response (CCyR)=0% Ph+ cells in metaphase in BM. A cCCyR=those in which all measurements up to at least 28 days after the initial response show an equivalent or better CCyR. The analysis population included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Pretreatment, every 3 months up to 12 months
    End point values
    		 Dasatinib Imatinib
    Number of subjects analysed
    259
    260
    Units: Subjects
        number (not applicable)
    204
    177
    Statistical analysis title
    		 Comparison of Daisatinib and Imatinib
    Comparison groups
    Dasatinib v Imatinib
    Number of subjects included in analysis
    519
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0056 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [1] - A priori threshold for statistical significance=0.05.

    Secondary: Percentage of Subjects Remaining in Confirmed Complete Cytogenetic Response (cCCyR)

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    End point title
    		 Percentage of Subjects Remaining in Confirmed Complete Cytogenetic Response (cCCyR)
    End point description
    Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive (Ph+) cells in metaphase from bone marrow (BM) sample. (Ideally, 25 metaphases but at least 20 metaphases from a BM sample were evaluated). Complete Cytogenetic Response (CCyR)=0% Ph+ cells in metaphase in BM. A cCCyR=those in which all measurements up to at least 28 days after the initial response show an equivalent or better CCyR. Percentage of subjects in cCCyR at years 2, 3, 4 and 5 was computed for all randomized subjects who achieved cCCyR as measured from the time of first confirmation until the date of progression or death. Subjects with cCCyR who neither progress nor die are censored on the date of their last cytogenetic assessment. Subjects without cCCyR are considered to have progressed on Day 1. The analysis population included all randomized subjects who achieved cCCyR.
    End point type
    Secondary
    End point timeframe
    Years 2, 3, 4 and 5
    End point values
    		 Dasatinib Imatinib
    Number of subjects analysed
    215
    204
    Units: percentage of subjects
    number (confidence interval 95%)
        At Year 2
    98 (94.7 to 99.2)
    96.9 (93.2 to 98.6)
        At Year 3
    96.9 (93.3 to 98.6)
    95.7 (91.6 to 97.8)
        At Year 4
    95.6 (91.4 to 97.8)
    95.7 (91.6 to 97.8)
        At Year 5
    93.1 (86.5 to 96.5)
    91 (83.6 to 95.2)
    Statistical analysis title
    		 Comparison of Dasatinib and Imatinib
    Comparison groups
    Dasatinib v Imatinib
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.13

    Secondary: Percentage of Subjects with Major Molecular Response (MMR) at Any Time

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    End point title
    		 Percentage of Subjects with Major Molecular Response (MMR) at Any Time
    End point description
    Molecular response was assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. MMR is defined as a ratio BCR-ABL/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value). The analysis population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Planned total follow-up duration of 5 years
    End point values
    		 Dasatinib Imatinib
    Number of subjects analysed
    259
    260
    Units: Percentage of subjects
        number (not applicable)
    76.4
    64.2
    No statistical analyses for this end point

    Secondary: Time to Confirmed Complete Cytogenic Response (cCCyR) Overall

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    End point title
    		 Time to Confirmed Complete Cytogenic Response (cCCyR) Overall
    End point description
    The time to cCCyR for all randomized subjects is defined as the time from the randomization date until criteria are first met for complete cytogenic response (provided it is confirmed later). The time to cCCyR analysis censors nonresponders who do not progress at their last cytogenetic assessments and nonresponders who progress at the maximum time of all randomized subjects. The analysis population included all randomized subjects. .
    End point type
    Secondary
    End point timeframe
    Day 1 to 5 years
    End point values
    		 Dasatinib Imatinib
    Number of subjects analysed
    215
    204
    Units: Months
        median (confidence interval 95%)
    3.1 (3 to 3.1)
    5.8 (5.6 to 6)
    Statistical analysis title
    		 Comparison of Dasatinib and Imatinib
    Statistical analysis description
    Hazard Ratio and Confidence Interval were based on analyses on all randomized subjects
    Comparison groups
    Dasatinib v Imatinib
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Stratified Log-rank Test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 1.77

    Secondary: Time to Major Molecular Response (MMR) Overall

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    End point title
    		 Time to Major Molecular Response (MMR) Overall
    End point description
    The time to MMR for all randomized subjects is defined as the time from randomization date until measurement criteria are first met for MMR. The time to MMR analysis censors nonresponders who do not progress at their last molecular assessments and nonresponders who progress at the maximum time of all randomized subjects. The analysis population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Day 1 to 5 years
    End point values
    		 Dasatinib Imatinib
    Number of subjects analysed
    198
    167
    Units: Months
        median (confidence interval 95%)
    9.3 (8.8 to 11.8)
    15 (12.2 to 18.2)
    Statistical analysis title
    		 Comparison of Dasatinib and Imatinib
    Statistical analysis description
    Hazard Ratio, and Confidence Interval were based on analyses on all randomized subjects
    Comparison groups
    Dasatinib v Imatinib
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Stratified Log-rank Test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.25
         upper limit
    		 1.89

    Secondary: Percentage of Subjects with Progression-free Survival (PFS)

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    End point title
    		 Percentage of Subjects with Progression-free Survival (PFS)
    End point description
    PFS was defined as the time from randomization until progression (any progression/death within 30 days of last dosing date, or between 30-60 days of last dosing prior to start of secondary therapy). Those who did not progress/die or who progressed/died after 60 days of last dose were censored at last on-study hematologic/cytogenetic assessment; those with progression/death 30-60 days of last dosing date and after start date of secondary therapy censored at last on-study hematologic/cytogenetic assessment prior to start of secondary therapy; those who had not received study treatment censored on date randomized. The analysis population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Subjects were followed-up for at least 5 years
    End point values
    		 Dasatinib Imatinib
    Number of subjects analysed
    259
    260
    Units: Percentage of subjects
        number (not applicable)
    88.9
    89.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Overall Survival (OS)

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    End point title
    		 Percentage of Subjects With Overall Survival (OS)
    End point description
    OS was defined as the time from randomization to the date of death. If the subject had not died, survival was censored on last date the subject was known to be alive. The analysis population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Subjects were followed-up for at least 5 years
    End point values
    		 Dasatinib Imatinib
    Number of subjects analysed
    259
    260
    Units: Percentage of subjects
        number (not applicable)
    90.9
    89.6
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects with Adverse Events (AEs), Drug-related AEs, Drug-related Serious Adverse Events (SAEs), Drug-related AEs Leading to Discontinuation, and All Deaths

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    End point title
    		 Number of Subjects with Adverse Events (AEs), Drug-related AEs, Drug-related Serious Adverse Events (SAEs), Drug-related AEs Leading to Discontinuation, and All Deaths
    End point description
    AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. The analysis population included all treated subjects.
    End point type
    Other pre-specified
    End point timeframe
    From date of last person, first visit to date of last person, last visit (approximately 8 years)
    End point values
    		 Dasatinib Imatinib
    Number of subjects analysed
    258
    258
    Units: Subjects
    number (not applicable)
        All AEs
    251
    251
        All Drug-related AEs
    224
    231
        Diarrhea
    100
    91
        Pleural effusion
    74
    3
        Nausea
    40
    74
        Cough
    68
    28
        Muscle spasms
    14
    63
        Thrombocytopenia
    61
    50
        Neutropenia
    60
    49
        Headache
    59
    46
        Pyrexia
    58
    51
        Vomiting
    43
    54
        SAEs
    90
    70
        Drug-related SAEs
    43
    22
        AEs leading to discontinuation
    51
    26
        All deaths
    26
    26
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Grade 3/4 Abnormalities in On-study Laboratory Test Results

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    End point title
    		 Number of Subjects With Grade 3/4 Abnormalities in On-study Laboratory Test Results
    End point description
    ULN=upper limit of normal. Grade 3=Severe AE; Grade 4=Life-threatening or disabling AE. Absolute neutrophil count: Grade 3 <1000-500/mm^3; Grade 4 <500/mm^3. Hemoglobin: Grade 3 <8.0-6.5 g/dL; Grade 4 <6.5 g/dL. Platelets: Grade 3 <50,000-25,000/mm^3; Grade 4 <25,000/mm^3. ALT/AST: Grade 3 >5.0-20*ULN; Grade 4 >20*ULN. Total bilirubin: Grade 3 >3-10*ULN; Grade 4 >10*ULN. Sample normal ranges (may vary by institution): ALT, Female: 7-30 U/L, Male: 10-55 U/L; AST, Female: 9-25 U/L, Male10-40 U/L; Total bilirubin: 0.0-1.0 mg/dL. Creatinine: Grade 3 >3.0–6.0*ULN; Grade 4 >6.0*ULN. Phosphate: Grade 3 <2.0–1.0 mg/dL; Grade 4 <1.0 mg/dL. Calcium: Grade 3 <7.0–6.0 mg/dL; Grade 4 <6.0 mg/dL. Potassium: Grade 3 <3.0–2.5 mmol/L; Grade 4 <2.5 mmol/L. The analysis population included all subjects with laboratory assessments.
    End point type
    Other pre-specified
    End point timeframe
    From date of last person, first visit to date of last person, last visit (approximately 8 years)
    End point values
    		 Dasatinib Imatinib
    Number of subjects analysed
    256
    257
    Units: Subjects
    number (not applicable)
        Grade 3/4 Absolute neutrophil count
    74
    61
        Grade 3/4 Hemoglobin
    35
    23
        Grade 3/4 Platelets
    56
    37
        Grade 3/4 Alanine aminotransferase (ALT)
    2
    4
        Grade 3/4 Aspartate aminotransferase (AST)
    2
    3
        Grade 3/4 Total bilirubin
    3
    0
        Grade 3/4 Creatinine
    3
    2
        Grade 3/4 Phosphate
    19
    79
        Grade 3/4 Calcium
    9
    7
        Grade 3/4 Potassium
    0
    8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug until the last dose of study drug plus 30 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Imatinib
    Reporting group description
    		 Imatinib

    Reporting group title
    Dasatinib
    Reporting group description
    		 Dasatinib

    Serious adverse events
    		 Imatinib Dasatinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    70 / 258 (27.13%)
    90 / 258 (34.88%)
         number of deaths (all causes)
    5
    8
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blast crisis in myelogenous leukaemia
         subjects affected / exposed
    4 / 258 (1.55%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 3
         deaths causally related to treatment / all
    1 / 2
    1 / 1
    Blast cell proliferation
         subjects affected / exposed
    2 / 258 (0.78%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nodal marginal zone b-cell lymphoma
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    3 / 258 (1.16%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectosigmoid cancer
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 258 (0.39%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 258 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pain
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 258 (0.78%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scrotal oedema
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    2 / 258 (0.78%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 258 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 258 (0.39%)
    13 / 258 (5.04%)
         occurrences causally related to treatment / all
    1 / 1
    22 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 258 (0.00%)
    7 / 258 (2.71%)
         occurrences causally related to treatment / all
    0 / 0
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella test positive
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heat stroke
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle rupture
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    2 / 258 (0.78%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin injury
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 258 (0.39%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Angina unstable
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    2 / 258 (0.78%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 258 (0.39%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive cardiomegaly
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 258 (0.39%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinoatrial block
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 258 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 258 (0.39%)
    4 / 258 (1.55%)
         occurrences causally related to treatment / all
    0 / 1
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bicytopenia
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 258 (1.16%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    4 / 258 (1.55%)
    4 / 258 (1.55%)
         occurrences causally related to treatment / all
    4 / 5
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytosis
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 258 (0.78%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scleral haemorrhage
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 258 (0.39%)
    5 / 258 (1.94%)
         occurrences causally related to treatment / all
    0 / 1
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 258 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 258 (1.16%)
    5 / 258 (1.94%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 258 (0.78%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 258 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal ulcer
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic disorder
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Protein-Losing gastroenteropathy
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toothache
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 258 (1.16%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 258 (0.78%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 258 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 258 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder polyp
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urogenital haemorrhage
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibromyalgia
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaw cyst
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in jaw
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 258 (0.39%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 258 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 258 (0.00%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 258 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 258 (0.39%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1n1 influenza
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis viral
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 258 (0.00%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 258 (0.78%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningoencephalitis bacterial
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neutropenic sepsis
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 258 (1.16%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    2 / 4
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subcutaneous abscess
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 258 (0.78%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Imatinib Dasatinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    243 / 258 (94.19%)
    238 / 258 (92.25%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    20 / 258 (7.75%)
    26 / 258 (10.08%)
         occurrences all number
    22
    32
    Pallor
         subjects affected / exposed
    13 / 258 (5.04%)
    7 / 258 (2.71%)
         occurrences all number
    21
    10
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    37 / 258 (14.34%)
    42 / 258 (16.28%)
         occurrences all number
    51
    49
    Chest pain
         subjects affected / exposed
    13 / 258 (5.04%)
    24 / 258 (9.30%)
         occurrences all number
    14
    32
    Face oedema
         subjects affected / exposed
    27 / 258 (10.47%)
    14 / 258 (5.43%)
         occurrences all number
    38
    15
    Fatigue
         subjects affected / exposed
    40 / 258 (15.50%)
    40 / 258 (15.50%)
         occurrences all number
    54
    66
    Influenza like illness
         subjects affected / exposed
    17 / 258 (6.59%)
    23 / 258 (8.91%)
         occurrences all number
    26
    44
    Oedema
         subjects affected / exposed
    24 / 258 (9.30%)
    10 / 258 (3.88%)
         occurrences all number
    38
    11
    Oedema peripheral
         subjects affected / exposed
    32 / 258 (12.40%)
    25 / 258 (9.69%)
         occurrences all number
    38
    47
    Pyrexia
         subjects affected / exposed
    50 / 258 (19.38%)
    58 / 258 (22.48%)
         occurrences all number
    72
    119
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    28 / 258 (10.85%)
    68 / 258 (26.36%)
         occurrences all number
    40
    102
    Dyspnoea
         subjects affected / exposed
    10 / 258 (3.88%)
    36 / 258 (13.95%)
         occurrences all number
    11
    60
    Oropharyngeal pain
         subjects affected / exposed
    11 / 258 (4.26%)
    14 / 258 (5.43%)
         occurrences all number
    15
    14
    Pleural effusion
         subjects affected / exposed
    3 / 258 (1.16%)
    69 / 258 (26.74%)
         occurrences all number
    4
    119
    Psychiatric disorders
    Depression
         subjects affected / exposed
    13 / 258 (5.04%)
    5 / 258 (1.94%)
         occurrences all number
    18
    8
    Insomnia
         subjects affected / exposed
    16 / 258 (6.20%)
    20 / 258 (7.75%)
         occurrences all number
    20
    28
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 258 (2.71%)
    13 / 258 (5.04%)
         occurrences all number
    16
    13
    Haemoglobin decreased
         subjects affected / exposed
    17 / 258 (6.59%)
    30 / 258 (11.63%)
         occurrences all number
    32
    76
    Weight increased
         subjects affected / exposed
    33 / 258 (12.79%)
    25 / 258 (9.69%)
         occurrences all number
    47
    38
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    18 / 258 (6.98%)
    28 / 258 (10.85%)
         occurrences all number
    33
    37
    Headache
         subjects affected / exposed
    46 / 258 (17.83%)
    59 / 258 (22.87%)
         occurrences all number
    73
    99
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    31 / 258 (12.02%)
    38 / 258 (14.73%)
         occurrences all number
    38
    53
    Leukopenia
         subjects affected / exposed
    28 / 258 (10.85%)
    21 / 258 (8.14%)
         occurrences all number
    45
    48
    Neutropenia
         subjects affected / exposed
    49 / 258 (18.99%)
    60 / 258 (23.26%)
         occurrences all number
    101
    124
    Thrombocytopenia
         subjects affected / exposed
    48 / 258 (18.60%)
    59 / 258 (22.87%)
         occurrences all number
    78
    117
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    40 / 258 (15.50%)
    7 / 258 (2.71%)
         occurrences all number
    61
    8
    Periorbital oedema
         subjects affected / exposed
    20 / 258 (7.75%)
    4 / 258 (1.55%)
         occurrences all number
    42
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    28 / 258 (10.85%)
    36 / 258 (13.95%)
         occurrences all number
    37
    60
    Abdominal pain upper
         subjects affected / exposed
    18 / 258 (6.98%)
    22 / 258 (8.53%)
         occurrences all number
    19
    30
    Constipation
         subjects affected / exposed
    7 / 258 (2.71%)
    21 / 258 (8.14%)
         occurrences all number
    10
    26
    Diarrhoea
         subjects affected / exposed
    89 / 258 (34.50%)
    99 / 258 (38.37%)
         occurrences all number
    196
    223
    Dyspepsia
         subjects affected / exposed
    22 / 258 (8.53%)
    17 / 258 (6.59%)
         occurrences all number
    25
    31
    Gastritis
         subjects affected / exposed
    18 / 258 (6.98%)
    23 / 258 (8.91%)
         occurrences all number
    21
    25
    Nausea
         subjects affected / exposed
    74 / 258 (28.68%)
    40 / 258 (15.50%)
         occurrences all number
    106
    54
    Toothache
         subjects affected / exposed
    10 / 258 (3.88%)
    17 / 258 (6.59%)
         occurrences all number
    10
    26
    Vomiting
         subjects affected / exposed
    52 / 258 (20.16%)
    41 / 258 (15.89%)
         occurrences all number
    159
    62
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 258 (0.39%)
    14 / 258 (5.43%)
         occurrences all number
    1
    19
    Pruritus
         subjects affected / exposed
    19 / 258 (7.36%)
    15 / 258 (5.81%)
         occurrences all number
    22
    19
    Rash
         subjects affected / exposed
    44 / 258 (17.05%)
    45 / 258 (17.44%)
         occurrences all number
    59
    74
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    38 / 258 (14.73%)
    34 / 258 (13.18%)
         occurrences all number
    59
    46
    Back pain
         subjects affected / exposed
    44 / 258 (17.05%)
    35 / 258 (13.57%)
         occurrences all number
    57
    59
    Muscle spasms
         subjects affected / exposed
    63 / 258 (24.42%)
    14 / 258 (5.43%)
         occurrences all number
    119
    15
    Musculoskeletal pain
         subjects affected / exposed
    19 / 258 (7.36%)
    22 / 258 (8.53%)
         occurrences all number
    23
    26
    Myalgia
         subjects affected / exposed
    39 / 258 (15.12%)
    36 / 258 (13.95%)
         occurrences all number
    53
    52
    Pain in extremity
         subjects affected / exposed
    39 / 258 (15.12%)
    28 / 258 (10.85%)
         occurrences all number
    50
    39
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    14 / 258 (5.43%)
    20 / 258 (7.75%)
         occurrences all number
    18
    28
    Conjunctivitis
         subjects affected / exposed
    17 / 258 (6.59%)
    10 / 258 (3.88%)
         occurrences all number
    21
    13
    Gastroenteritis
         subjects affected / exposed
    10 / 258 (3.88%)
    19 / 258 (7.36%)
         occurrences all number
    18
    24
    Influenza
         subjects affected / exposed
    12 / 258 (4.65%)
    20 / 258 (7.75%)
         occurrences all number
    15
    22
    Nasopharyngitis
         subjects affected / exposed
    43 / 258 (16.67%)
    32 / 258 (12.40%)
         occurrences all number
    93
    72
    Pharyngitis
         subjects affected / exposed
    10 / 258 (3.88%)
    14 / 258 (5.43%)
         occurrences all number
    15
    15
    Upper respiratory tract infection
         subjects affected / exposed
    28 / 258 (10.85%)
    30 / 258 (11.63%)
         occurrences all number
    43
    55
    Urinary tract infection
         subjects affected / exposed
    13 / 258 (5.04%)
    11 / 258 (4.26%)
         occurrences all number
    19
    17
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    13 / 258 (5.04%)
    23 / 258 (8.91%)
         occurrences all number
    16
    30

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jul 2007
    1. Modification of the definition of PFS to align with the endpoint used in imatinib first-line trial (IRIS) 2. Modification of the definition of time-to treatment failure 3. Inclusion of time-in, time-to and duration of cytogenetic response as secondary endpoints 4. Inclusion of time-to maximum clinical benefit as a tertiary endpoint 5. Removal of the previously permitted prior (up to) 28 days of imatinib from eligibility criteria 6. Inclusion of stem cell transplant as a reason for discontinuation of subjects from treatment
    13 Jun 2008
    1. Clarification of the definition of progression and extramedullary disease 2. Clarification of the definition of intolerance 3. Correction of the formula for Hasford score calculation 4. Clarification of dose reduction guidelines
    21 Jul 2009
    1. Change the rank of the secondary endpoints 2. Clarify the assessment schedule for the primary endpoint (cytogenetic response) 3. Minor clarification in the definition of progression 4. Clarification of reasons for discontinuation of subjects from treatment 5. Update imatinib information regarding subjects with renal impairment 6. Clarifications to the identification of investigational products 7. Clarify that treatment decisions based on major molecular response should be from local laboratory results if available and not from research samples of QRT-PCR drawn for this study 8. Clarification to collection of mutation analysis samples 9. Update the interim analysis section

    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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