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    Clinical Trial Results:
    A Randomized Two-by-Two, Multicenter, Open-Label Phase III Study of BMS-354825 Administered Orally at a Dose of 50 mg or 70 mg Twice Daily or 100 mg or 140 mg Once Daily in Subjects with Chronic Phase Philadelphia Chromosome or BCR-ABL Positive Chronic Myelogenous Leukemia Who are Resistant or Intolerant to Imatinib Mesylate.

    Summary
    EudraCT number
    		 2005-001294-99
    Trial protocol
    		 AT   SE   GB   HU   DK   IE   CZ   FI   IT   EE   ES   DE   BE  
    Global end of trial date
    14 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Apr 2016
    First version publication date
    22 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA180-034
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00123474
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, 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
    14 Jul 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to compare the efficacy of BMS-354825 as defined by major cytogenetic response when administered once daily relative to BMS-354825 administered twice daily in the treatment of chronic phase chronic myelogenous leukemia imatinib-resistant subjects.
    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
    13 Jul 2005
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 7 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 36
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Brazil: 45
    Country: Number of subjects enrolled
    Canada: 14
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    Israel: 5
    Country: Number of subjects enrolled
    Korea, Republic of: 46
    Country: Number of subjects enrolled
    Mexico: 15
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Peru: 2
    Country: Number of subjects enrolled
    Philippines: 7
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Russian Federation: 18
    Country: Number of subjects enrolled
    South Africa: 9
    Country: Number of subjects enrolled
    Singapore: 7
    Country: Number of subjects enrolled
    Switzerland: 11
    Country: Number of subjects enrolled
    Taiwan: 4
    Country: Number of subjects enrolled
    United States: 224
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Sweden: 10
    Country: Number of subjects enrolled
    United Kingdom: 31
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    Denmark: 16
    Country: Number of subjects enrolled
    France: 69
    Country: Number of subjects enrolled
    Germany: 42
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Ireland: 11
    Country: Number of subjects enrolled
    Italy: 19
    Worldwide total number of subjects
    724
    EEA total number of subjects
    263
    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)
    534
    From 65 to 84 years
    190
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study initiated July 2005 and completed July 2014.

    Pre-assignment
    Screening details
    		 724 subjects were enrolled, 670 were randomized, and 662 were treated with study drug. Reasons for non-randomization: 38 no longer met criteria, 8 other reasons, 7 withdrew consent, and 1 death. 1 subject was randomized to 100 mg once daily but received 50 mg twice daily; 1 subject was randomized to 50 mg twice daily but received 100 mg once daily.

    Period 1
    Period 1 title
    As Treated (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 100 mg QD
    Arm description
    		 Subjects received dasatinib 100 mg once daily until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dasatinib
    Investigational medicinal product code
    BMS-354825-03
    Other name
    Sprycel
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 Dasatinib 50-mg tablets were administered once daily until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw.

    Arm title
    		 Dasatinib 140 mg QD
    Arm description
    		 Subjects received dasatinib 140 mg once daily until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dasatinib
    Investigational medicinal product code
    BMS-354825-03
    Other name
    Sprycel
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 Dasatinib 20-mg and 50-mg tablets were administered once daily until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw.

    Arm title
    		 Dasatinib 50 mg BID
    Arm description
    		 Subjects received dasatinib 50 mg twice daily until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, subjects on a twice daily dosing schedule were allowed to switch to a once daily dosing schedule.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dasatinib
    Investigational medicinal product code
    BMS-354825-03
    Other name
    Sprycel
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dasatinib 50-mg tablet was administered twice daily and switching to once daily was allowed after the 2-year analysis, and with protocol amendment 02, until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw.

    Arm title
    		 Dasatinib 70 mg BID
    Arm description
    		 Subjects received dasatinib 70 mg twice daily until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, subjects on a BID dosing schedule were allowed to switch to a QD dosing schedule.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dasatinib
    Investigational medicinal product code
    BMS-354825-03
    Other name
    Sprycel
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dasatinib 50-mg and 20-mg tablets were administered twice daily and switching to once daily was allowed after the 2-year analysis, and with protocol amendment 02, until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw.

    Number of subjects in period 1 [1]
    		Dasatinib 100 mg QD Dasatinib 140 mg QD Dasatinib 50 mg BID Dasatinib 70 mg BID
    Started
    167
    167
    168
    168
    Randomized
    167
    167
    168
    168
    Completed
    0
    0
    0
    0
    Not completed
    167
    167
    168
    168
         Consent withdrawn by subject
    14
    19
    18
    16
         Disease progression
    35
    42
    29
    27
         Adverse event, non-fatal
    10
    4
    10
    8
         Study drug toxicity
    39
    45
    45
    51
         Not reported
    1
    -
    -
    -
         Randomized, never treated
    1
    4
    2
    1
         Treated in 50 mg BID arm
    1
    -
    -
    -
         Other reasons
    54
    47
    57
    60
         Investigator request
    12
    6
    7
    5
    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: 724 subjects were enrolled, 670 were randomized. Reasons for non-randomization: 38 no longer met criteria, 8 other reasons, 7 withdrew consent, and 1 death.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dasatinib 100 mg QD
    Reporting group description
    		 Subjects received dasatinib 100 mg once daily until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw.

    Reporting group title
    Dasatinib 140 mg QD
    Reporting group description
    		 Subjects received dasatinib 140 mg once daily until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw.

    Reporting group title
    Dasatinib 50 mg BID
    Reporting group description
    		 Subjects received dasatinib 50 mg twice daily until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, subjects on a twice daily dosing schedule were allowed to switch to a once daily dosing schedule.

    Reporting group title
    Dasatinib 70 mg BID
    Reporting group description
    		 Subjects received dasatinib 70 mg twice daily until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, subjects on a BID dosing schedule were allowed to switch to a QD dosing schedule.

    Reporting group values
    		 Dasatinib 100 mg QD Dasatinib 140 mg QD Dasatinib 50 mg BID Dasatinib 70 mg BID Total
    Number of subjects
    		 167 167 168 168 670
    Age categorical
    Units: Subjects
        <=65 years
    		 121 128 130 125 504
        >65 years
    		 46 39 38 43 166
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.6 ± 13.6 53.7 ± 15 53.3 ± 14.6 53.7 ± 15 -
    Gender categorical
    Units: Subjects
        Female
    		 83 97 83 91 354
        Male
    		 84 70 85 77 316
    Imatinib status
    Primary Resistance: no decrease in white blood cell count after >=4 weeks imatinib/not achieved a complete hematologic response after 3 months, a major cytogenetic response (MCyR) after 6 months, or a complete cytogenetic response (CCyR) after 12 months. Acquired resistance: achieved MCyR and no longer met the criteria for MCyR. Intolerance: Grade >=3 toxicity considered at least possibly related to imatinib at a dose of <=400 mg/day which led to discontinuation of therapy; tolerated the dose of 400 mg but did not achieve a CCyR and subsequently did not tolerate doses >=600 mg.
    Units: Subjects
        Primary Resistance to Imatinib
    		 75 78 88 81 322
        Acquired Resistance to Imatinib
    		 49 45 36 45 175
        Intolerant to Imatinib
    		 43 44 44 42 173

    End points

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    End points reporting groups
    Reporting group title
    Dasatinib 100 mg QD
    Reporting group description
    		 Subjects received dasatinib 100 mg once daily until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw.

    Reporting group title
    Dasatinib 140 mg QD
    Reporting group description
    		 Subjects received dasatinib 140 mg once daily until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw.

    Reporting group title
    Dasatinib 50 mg BID
    Reporting group description
    		 Subjects received dasatinib 50 mg twice daily until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, subjects on a twice daily dosing schedule were allowed to switch to a once daily dosing schedule.

    Reporting group title
    Dasatinib 70 mg BID
    Reporting group description
    		 Subjects received dasatinib 70 mg twice daily until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, subjects on a BID dosing schedule were allowed to switch to a QD dosing schedule.

    Subject analysis set title
    QD Dasatinib
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received dasatinib either 100 mg or 140 mg once daily until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw.

    Subject analysis set title
    BID Dasatinib
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received dasatinib either 50 mg or 70 mg twice daily until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw.

    Subject analysis set title
    Dasatinib 100 mg Total Daily Dose
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received dasatinib 100 mg as a total daily dose (either 50 mg twice daily or 100 mg once daily) until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw.

    Subject analysis set title
    Dasatinib 140 mg Total Daily Dose
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received dasatinib 140 mg as a total daily dose (either 70 mg twice daily or 140 mg once daily) until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw.

    Subject analysis set title
    Other Treatment Groups
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects participated in all other treatment arms until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw.

    Subject analysis set title
    Total
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received study drug in any schedule or total daily dose until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw.

    Primary: Percentage of Subjects With Major Cytogenetic Response (MCyR) After at Least 6 Months Follow-Up - Imatinib-Resistant Subjects

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    End point title
    		 Percentage of Subjects With Major Cytogenetic Response (MCyR) After at Least 6 Months Follow-Up - Imatinib-Resistant Subjects
    End point description
    Cytogenetic response (CyR) was based on the number of Philadelphia chromosome positive (Ph+) metaphases among cells in metaphase on a Bone Marrow (BM) sample. The criteria for CyR were as follows: Complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM; Partial CyR (PCyR): >0 to 35% Ph+ cells in metaphase in BM; Minor cytogenetic response: >35 to 65% Ph+ cells in metaphase in BM; Minimal cytogenetic response: >65 to 95% Ph+ cells in metaphase in BM; No cytogenetic response: >95 to 100% Ph+ cells in metaphase in BM; Best CyR was defined as the best response obtained at any time during the study; MCyR was defined as a best CyR of CCyR or PCyR. Baseline=closest to, but no later than, the first day of study drug for treated subjects and closest to, but no later than, the date of randomization, for those who were randomized but who never received treatment, unless otherwise specified. All randomized imatinib-resistant subjects with available data were summarized
    End point type
    Primary
    End point timeframe
    Baseline up to at Least 6 Months follow-up
    End point values
    		 QD Dasatinib BID Dasatinib
    Number of subjects analysed
    247
    251
    Units: Percentage of subjects
        number (confidence interval 95%)
    51.8 (45.4 to 58.2)
    49 (42.7 to 55.4)
    Statistical analysis title
    		 MCyR: 6 month follow-up analysis
    Comparison groups
    QD Dasatinib v BID Dasatinib
    Number of subjects included in analysis
    498
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 11.6
    Notes
    [1] - Non-inferiority of the QD schedule relative to the BID schedule was deduced if the lower bound of the 95% confidence interval (CI) for the MCyR QD minus MCyR BID difference was greater than or equal to -15%.

    Secondary: Percentage of Subjects With Major Cytogenetic Response (MCyR) at or Prior to 24 Months Follow-Up - Imatinib-Resistant Subjects

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    End point title
    		 Percentage of Subjects With Major Cytogenetic Response (MCyR) at or Prior to 24 Months Follow-Up - Imatinib-Resistant Subjects
    End point description
    Cytogenetic response (CyR) was based on the number of Philadelphia chromosome positive (Ph+) metaphases among cells in metaphase on a Bone Marrow (BM) sample. The criteria for CyR were as follows: Complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM; Partial CyR (PCyR): >0 to 35% Ph+ cells in metaphase in BM; Minor cytogenetic response: >35 to 65% Ph+ cells in metaphase in BM; Minimal cytogenetic response: >65 to 95% Ph+ cells in metaphase in BM; No cytogenetic response: >95 to 100% Ph+ cells in metaphase in BM; Best CyR was defined as the best response obtained at any time during the study; MCyR was defined as a best CyR of CCyR or PCyR. Baseline=closest to, but no later than, the first day of study drug for treated subjects and closest to, but no later than, the date of randomization, for those who were randomized but who never received treatment, unless otherwise specified. All randomized imatinib-resistant subjects with available data were summarized.
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 Months Follow-Up
    End point values
    		 QD Dasatinib BID Dasatinib Dasatinib 100 mg Total Daily Dose Dasatinib 140 mg Total Daily Dose
    Number of subjects analysed
    247
    250
    248
    249
    Units: Percentage of subjects
        number (confidence interval 95%)
    58.3 (51.9 to 64.5)
    56.4 (50 to 62.6)
    57.3 (50.8 to 63.5)
    57.4 (51 to 63.7)
    Statistical analysis title
    		 MCyR: At or Prior to 24 Months Follow-Up
    Comparison groups
    QD Dasatinib v BID Dasatinib
    Number of subjects included in analysis
    497
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.8
         upper limit
    		 10.6
    Notes
    [2] - Non-inferiority of the QD schedule relative to the BID schedule was deduced if the lower bound of the 95% CI for the MCyRRQD minus MCyRRBID difference was greater than or equal to -15%.
    Statistical analysis title
    		 MCyR: At or Prior to 24 Months Follow-Up
    Comparison groups
    Dasatinib 100 mg Total Daily Dose v Dasatinib 140 mg Total Daily Dose
    Number of subjects included in analysis
    497
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.9
         upper limit
    		 8.5
    Notes
    [3] - Non-inferiority of 100 mg total daily dose relative to 140 mg total daily dose was deduced if the lower bound of the 95% CI for the difference was greater than or equal to -15%.

    Secondary: Percentage of Subjects With Complete Hematologic Response (CHR) After at Least 6 and 24 Months Follow-Up - Imatinib-Resistant Subjects

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    End point title
    		 Percentage of Subjects With Complete Hematologic Response (CHR) After at Least 6 and 24 Months Follow-Up - Imatinib-Resistant Subjects
    End point description
    CHR was obtained when all the following criteria were met: White Blood Cells <= institutional upper limit of normal (ULN); Platelets < 450,000/mm³; No blasts or promyelocytes in peripheral blood (PB); < 5% myelocytes plus metamyelocytes in PB; Basophils in PB < 20%; No extramedullary involvement (including no splenomegaly or hepatomegaly). Hematologic responses were counted anytime following 14 days after the dosing start date. All randomized imatinib-resistant subjects with available data were summarized. Here, ‘n’ signifies evaluable subjects for specified categories in respective treatment arms.
    End point type
    Secondary
    End point timeframe
    Baseline up to at Least 6 and 24 Months Follow-Up
    End point values
    		 Dasatinib 100 mg QD Dasatinib 140 mg QD Dasatinib 50 mg BID Dasatinib 70 mg BID
    Number of subjects analysed
    124
    123
    124
    126
    Units: Percentage of subjects
    number (confidence interval 95%)
        6 Months (n=124, 123, 124, 126)
    86.3 (79 to 91.8)
    85.4 (77.9 to 91.1)
    91.1 (84.7 to 95.5)
    87.4 (80.3 to 92.6)
        24 Months (n=124, 123, 124, 126)
    88.7 (81.8 to 93.7)
    86.2 (78.8 to 91.7)
    91.9 (85.7 to 96.1)
    88.9 (82.1 to 93.8)
    No statistical analyses for this end point

    Secondary: Time to Major Cytogenetic Response (MCyR) in Subjects With MCyR After At Least 24 Months Follow-Up - Imatinib-Resistant Subjects

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    End point title
    		 Time to Major Cytogenetic Response (MCyR) in Subjects With MCyR After At Least 24 Months Follow-Up - Imatinib-Resistant Subjects
    End point description
    Time to MCyR was defined as the time from the first dosing date until criteria were first met for complete cytogenetic response or partial cytogenetic response, whichever occurred first. Non-responders were censored at the maximum time of all subjects in their respective group (that is, maximum between time to MCyR response for responders and time to last cytogenetic assessment for non-responders). All randomized imatinib-resistant subjects with MCyR and available data were summarized.
    End point type
    Secondary
    End point timeframe
    Baseline up to at Least 24 Months Follow-Up
    End point values
    		 Dasatinib 100 mg QD Dasatinib 140 mg QD Dasatinib 50 mg BID Dasatinib 70 mg BID
    Number of subjects analysed
    73
    71
    69
    72
    Units: Months
        median (confidence interval 95%)
    2.9 (2.8 to 3.4)
    2.8 (2.8 to 3)
    2.9 (2.8 to 3.3)
    2.9 (2.8 to 3)
    No statistical analyses for this end point

    Secondary: Time to Complete Hematologic Response (CHR) in Subjects With CHR After at Least 24 Months Follow-Up - Imatinib-Resistant Subjects

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    End point title
    		 Time to Complete Hematologic Response (CHR) in Subjects With CHR After at Least 24 Months Follow-Up - Imatinib-Resistant Subjects
    End point description
    Time to CHR was defined as the time from the first dosing date until criteria are first met for the response. Non-responders were censored at the maximum time of all subjects in their respective group (that is, maximum between time to CHR response for responders and time to last hematologic assessment for non-responders). Cytogenetic assessments were not done after the 2 Year Follow-up. All randomized imatinib-resistant subjects with CHR were summarized.
    End point type
    Secondary
    End point timeframe
    Baseline up to at Least 24 Months Follow-up
    End point values
    		 Dasatinib 100 mg QD Dasatinib 140 mg QD Dasatinib 50 mg BID Dasatinib 70 mg BID
    Number of subjects analysed
    110
    106
    114
    112
    Units: Months
        median (confidence interval 95%)
    0.5 (0.5 to 0.6)
    0.5 (0.5 to 0.7)
    0.6 (0.5 to 0.9)
    0.7 (0.5 to 0.9)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Major Cytogenetic Response (MCyR) Whose Disease Progressed - Imatinib-Resistant Subjects

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    End point title
    		 Number of Subjects With Major Cytogenetic Response (MCyR) Whose Disease Progressed - Imatinib-Resistant Subjects
    End point description
    Progression in a subject=subject achieved a complete hematologic response (CHR) and no longer met the criteria consistently over consecutive 2-weeks after starting their maximum dose; had no CHR after receiving their maximum dose and had a doubling of the white blood cell count from the lowest value to >20,000/mm^3 or an increase by >50,000/mm^3 on two assessments performed at least 2 weeks apart; subject met criteria of accelerated or blast phase chronic myelogenous leukemia at any time; had a MCyR and subsequently no longer met the criteria for MCyR after starting their maximum dose; had a >=30% absolute increase in the number of Philadelphia  chromosome positive metaphases. Medium duration of MCyR could not be estimated because the majority of subjects with MCyR continued to respond, or could not be reliably estimated because of the large number of censored subjects. All imatinib-resistant subjects who had achieved MCyR and experienced disease progression were summarized.
    End point type
    Secondary
    End point timeframe
    Baseline up to at Least 24 Months Follow-Up
    End point values
    		 Dasatinib 100 mg QD Dasatinib 140 mg QD Dasatinib 50 mg BID Dasatinib 70 mg BID
    Number of subjects analysed
    73
    71
    69
    72
    Units: Subjects
    5
    17
    6
    9
    No statistical analyses for this end point

    Secondary: Number of Subjects With Complete Hematologic Response (CHR) Whose Disease Progressed - Imatinib-Resistant Subjects

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    End point title
    		 Number of Subjects With Complete Hematologic Response (CHR) Whose Disease Progressed - Imatinib-Resistant Subjects
    End point description
    Progression in a subject=achieved a CHR and subsequently no longer met the criteria consistently over a consecutive 2-week period after starting their maximum dose; had no CHR after receiving their maximum dose and had a doubling of the white blood cell count from the lowest value to >20,000/mm^3 or an increase by > 50,000/mm^3 on two assessments performed at least 2 weeks apart; met the criteria of accelerated or blast phase chronic myelogenous leukemia at any time; had a major cytogenetic response (MCyR) and subsequently no longer met the criteria for MCyR after starting their maximum dose; had a >= 30% absolute increase in the number of Philadelphia chromosome  positive metaphases. Medium duration of CHR could not be estimated because the majority of subjects with CHR continued to respond, or could not be reliably estimated because of the large number of censored subjects. All imatinib-resistant subjects who achieved CHR and then experienced disease progression were summarized.
    End point type
    Secondary
    End point timeframe
    Baseline up to at Least 24 Months Follow-Up
    End point values
    		 Dasatinib 100 mg QD Dasatinib 140 mg QD Dasatinib 50 mg BID Dasatinib 70 mg BID
    Number of subjects analysed
    110
    106
    114
    112
    Units: Subjects
    18
    28
    22
    24
    No statistical analyses for this end point

    Secondary: Number of Subjects With Major Cytogenetic Response (MCyR) and Baseline BCR-ABL Gene Mutation - All Treated Subjects

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    End point title
    		 Number of Subjects With Major Cytogenetic Response (MCyR) and Baseline BCR-ABL Gene Mutation - All Treated Subjects
    End point description
    BCR-ABL mutations were assessed in subjects prior to the start of study drug (baseline) and at the time of disease progression or at end of therapy. Quantification of BCR-ABL transcripts in peripheral blood was evaluated using quantitative reverse transcriptase polymerase chain reaction (Q-RT-PCR, RT-PCR). All randomized, treated subjects with available mutation data were summarized.
    End point type
    Secondary
    End point timeframe
    Baseline up to 2 Years
    End point values
    		 Dasatinib 100 mg QD Dasatinib 140 mg QD Dasatinib 50 mg BID Dasatinib 70 mg BID
    Number of subjects analysed
    147
    139
    149
    146
    Units: Subjects
        Imatinib-resistant mutations
    49
    49
    62
    48
        Mutations with unknown Imatinib-resistance status
    0
    1
    1
    2
        Imatinib resistant or unknown mutations
    49
    50
    63
    50
        Polymorphisms
    0
    2
    0
    0
        No mutations
    98
    87
    96
    96
    No statistical analyses for this end point

    Secondary: Percentage of Imatinib-Resistant Subjects With Progression Free Survival (PFS) After at Least 24, 36, 48, 60, 72, and 84 Months Follow-Up

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    End point title
    		 Percentage of Imatinib-Resistant Subjects With Progression Free Survival (PFS) After at Least 24, 36, 48, 60, 72, and 84 Months Follow-Up
    End point description
    PFS=time from randomization until: complete hematologic response (CHR) achieved and subject subsequently no longer met criteria for CHR over 2 weeks; no CHR after receiving maximum dose and had a doubling of the white blood cell count from the lowest value to >20,000/mm^3 or an increase by > 50,000/mm^3 on 2 assessments performed 2 weeks apart); subject met criteria of accelerated phase or blast phase chronic myelogenous leukemia; had MCyR and subsequently no longer met criteria for MCyR after starting maximum dose; >=30% absolute increase in number of Philadelphia chromosome positive metaphases. Deaths without a reported prior progression were considered to have progressed on the date of death; those who neither progressed nor died were censored on the date of their last cytogenetic or hematologic assessment. If the first progression reported during follow-up was death, subject considered to have progressed at date of death. All randomized imatinib-resistant subjects were summarized.
    End point type
    Secondary
    End point timeframe
    Baseline up to 84 months follow up
    End point values
    		 Dasatinib 100 mg QD Dasatinib 140 mg QD Dasatinib 50 mg BID Dasatinib 70 mg BID
    Number of subjects analysed
    124
    123
    124
    126
    Units: Percentage of subjects
    number (confidence interval 95%)
        24 Months (n=124, 123, 124, 126)
    75.2 (66.3 to 82.1)
    61.3 (52.7 to 69.6)
    70.3 (60.8 to 77.9)
    70.8 (61.6 to 78.2)
        36 Months (n=124, 123, 124, 126)
    64.8 (55.2 to 72.9)
    47.4 (37.7 to 56.5)
    67.1 (57.3 to 75.1)
    58.2 (48.4 to 66.8)
        48 Months (n=124, 123, 124, 126)
    57.8 (48 to 66.5)
    40 (30.6 to 49.3)
    63.8 (53.7 to 72.2)
    55.1 (45.2 to 64.8)
        60 Months (n=124, 123, 124, 126)
    50.2 (40.2 to 59.3)
    36.4 (27.1 to 45.8)
    57.4 (46.9 to 66.5)
    50.2 (40.2 to 59.4)
        72 Months (n=124, 123, 124, 126)
    44 (34 to 53.6)
    31.4 (22.4 to 40.8)
    50.7 (40 to 60.4)
    45.3 (35.2 to 54.8)
        84 Months (n=124, 123, 124, 126)
    39 (29.2 to 48.7)
    30.2 (21.2 to 39.6)
    42.1 (31.5 to 52.4)
    41.3 (31.3 to 51)
    No statistical analyses for this end point

    Secondary: Percentage of Imatinib-Resistant Subjects With Overall Survival (OS) After at Least 24, 36, 48, 60, 72, and 84 Months Follow-Up

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    End point title
    		 Percentage of Imatinib-Resistant Subjects With Overall Survival (OS) After at Least 24, 36, 48, 60, 72, and 84 Months Follow-Up
    End point description
    OS was defined as the time from randomization until death. Survival data were collected for up to 5 years on subjects who had discontinued dasatinib treatment. Subjects who did not die or who were lost to follow-up were censored on the last date the subject was known to be alive. All randomized imatinib-resistant subjects were summarized. Here, ‘n’ signifies evaluable subjects for specified categories in respective treatment arms.
    End point type
    Secondary
    End point timeframe
    Baseline up to 84 months follow up
    End point values
    		 Dasatinib 100 mg QD Dasatinib 140 mg QD Dasatinib 50 mg BID Dasatinib 70 mg BID
    Number of subjects analysed
    124
    123
    124
    126
    Units: Percentage of Subjects
    number (confidence interval 95%)
        24 Months (n=124, 123, 124, 126)
    90.1 (83.2 to 94.2)
    93.9 (87.6 to 97)
    88.9 (81.6 to 93.4)
    85.1 (77.3 to 90.3)
        36 Months (n=124, 123, 124, 126)
    87.5 (80.2 to 92.3)
    83.8 (75.6 to 89.5)
    83.5 (75.3 to 89.1)
    76.5 (67.7 to 83.1)
        48 Months (n=124, 123, 124, 126)
    79.7 (71.3 to 85.9)
    82 (73.4 to 88)
    80.7 (72.1 to 86.9)
    71.1 (61.9 to 78.4)
        60 Months (n=124, 123, 124, 126)
    75.1 (66.1 to 82)
    78 (68.9 to 84.7)
    73.6 (64.1 to 80.9)
    69.1 (59.8 to 76.7)
        72 Months (n=124, 123, 124, 126)
    67.9 (58.3 to 75.8)
    72.6 (62.9 to 80.1)
    71.4 (61.8 to 79)
    67.1 (57.6 to 74.9)
        84 Months (n=124, 123, 124, 126)
    62.6 (52.6 to 71)
    68.1 (58 to 76.2)
    67.9 (57.9 to 76)
    65 (55.3 to 73)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Intolerant to Imatinib With Major Cytogenetic Response (MCyR) After at Least 6 Months and After at Least 24 Months Follow-Up, by QD and BID Schedules and by Total Daily Dose

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    End point title
    		 Percentage of Subjects Intolerant to Imatinib With Major Cytogenetic Response (MCyR) After at Least 6 Months and After at Least 24 Months Follow-Up, by QD and BID Schedules and by Total Daily Dose
    End point description
    Cytogenetic response (CyR) was based on the number of Philadelphia chromosome positive (Ph+) metaphases among cells in metaphase on a Bone Marrow (BM) sample. The criteria for CyR were as follows: complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM; PCyR: >0 to 35% Ph+ cells in metaphase in BM; Minor cytogenetic response: >35 to 65% Ph+ cells in metaphase in BM; Minimal cytogenetic response: >65 to 95% Ph+ cells in metaphase in BM; No CyR: >95 to 100% Ph+ cells in metaphase in BM; Best CyR was defined as the best response obtained at any time during the study; MCyR was defined as a best CyR of CCyR or PCyR. All randomized imatinib-intolerant subjects with available data were summarized.
    End point type
    Secondary
    End point timeframe
    Baseline up to at least 6 months and 24 months follow-up
    End point values
    		 QD Dasatinib BID Dasatinib Dasatinib 100 mg Total Daily Dose Dasatinib 140 mg Total Daily Dose
    Number of subjects analysed
    87
    85
    87
    86
    Units: Percentage of Subjects
    number (confidence interval 95%)
        6 Month
    72.4 (61.8 to 81.5)
    70.6 (59.7 to 80)
    73.6 (63 to 82.4)
    69.4 (58.5 to 79)
        24 Month
    77 (66.8 to 85.4)
    75.6 (65.1 to 84.2)
    77 (66.8 to 85.4)
    75.6 (65.1 to 84.2)
    Statistical analysis title
    		 Risk difference: QD Dasatinib and BID Dasatinib
    Statistical analysis description
    6 month analysis.
    Comparison groups
    QD Dasatinib v BID Dasatinib
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.7
         upper limit
    		 15.3
    Notes
    [4] - Non-inferiority of the QD schedule relative to the BID schedule was deduced if the lower bound of the 95% CI for the MCyR QD minus MCyR BID difference was greater than or equal to -15%.
    Statistical analysis title
    		 Risk difference:Total Daily Dose 100 mg and 140 mg
    Statistical analysis description
    6 month analysis.
    Comparison groups
    Dasatinib 100 mg Total Daily Dose v Dasatinib 140 mg Total Daily Dose
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    4.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.3
         upper limit
    		 17.6
    Notes
    [5] - Non-inferiority of 100 mg QD Total Daily Dose relative to 140 mg QD Total Daily Dose was deduced if the lower bound of the 95% CI difference was greater than or equal to -15%.
    Statistical analysis title
    		 Risk difference: QD Dasatinib and BID Dasatinib
    Statistical analysis description
    24 month analysis.
    Comparison groups
    QD Dasatinib v BID Dasatinib
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.2
         upper limit
    		 14.1
    Notes
    [6] - Non-inferiority of the QD schedule relative to the BID schedule was deduced if the lower bound of the 95% CI for the MCyR QD minus MCyR BID difference was greater than or equal to -15%.
    Statistical analysis title
    		 Risk difference:Total Daily Dose 100 mg and 140 mg
    Statistical analysis description
    24 month analysis.
    Comparison groups
    Dasatinib 100 mg Total Daily Dose v Dasatinib 140 mg Total Daily Dose
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.2
         upper limit
    		 14.1
    Notes
    [7] - Non-inferiority of 100 mg QD Total Daily Dose relative to 140 mg QD Total Daily Dose was deduced if the lower bound of the 95% CI difference was greater than or equal to -15%.

    Secondary: Percentage of Subjects Intolerant to Imatinib With Complete Hematologic Response (CHR) After at Least 6 Months and After at Least 24 Months Follow-Up

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    End point title
    		 Percentage of Subjects Intolerant to Imatinib With Complete Hematologic Response (CHR) After at Least 6 Months and After at Least 24 Months Follow-Up
    End point description
    A CHR was obtained when all the following criteria were met: white blood cells <= institutional upper limit of normal (ULN); Platelets < 450,000/mm³; No blasts or promyelocytes in peripheral blood (PB); < 5% myelocytes plus metamyelocytes in PB; Basophils in PB <20%; No extramedullary involvement (including no splenomegaly or hepatomegaly). Hematologic responses were counted anytime following 14 days after the dosing start date. All randomized imatinib-intolerant subjects were summarized. Here, ‘n’ signifies evaluable subjects for specified categories in respective treatment arms.
    End point type
    Secondary
    End point timeframe
    Baseline up to at Least 6 months and 24 months follow up
    End point values
    		 Dasatinib 100 mg QD Dasatinib 140 mg QD Dasatinib 50 mg BID Dasatinib 70 mg BID
    Number of subjects analysed
    43
    44
    44
    42
    Units: Percentage of Subjects
    number (not applicable)
        6 Months (n=43, 44, 44, 41)
    100
    86
    93
    85
        24 Months (n=43, 44, 44, 42)
    100
    89
    93
    86
    No statistical analyses for this end point

    Secondary: Percentage of Imatinib Intolerant Subjects With Progression Free Survival (PFS) After 24, 36, 48, 60, 72, and 84 Months of Follow-Up

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    End point title
    		 Percentage of Imatinib Intolerant Subjects With Progression Free Survival (PFS) After 24, 36, 48, 60, 72, and 84 Months of Follow-Up
    End point description
    PFS= From randomization until: complete hematologic response (CHR) achieved and subject subsequently no longer met criteria for CHR over 2 weeks; no CHR after receiving maximum dose and doubling of the white blood cells count from the lowest value to > 20,000/mm^3 or an increase by > 50,000/mm^3 on 2 assessments performed 2 weeks apart; subject met criteria of accelerated phase or blast phase chronic myelogenous leukemia; subject had Major Cytogenetic Response (MCyR) and subsequently no longer met criteria for MCyR after starting maximum dose; >=30% absolute increase in number of Ph+ metaphases. Deaths without a reported prior progression were considered to have progressed on the date of death; those who neither progressed nor died were censored on the date of their last cytogenetic or hematologic assessment. All randomized imatinib-intolerant subjects with available data were summarized. Here, ‘n’ signifies evaluable subjects for specified categories in respective treatment arms.
    End point type
    Secondary
    End point timeframe
    Baseline up to 84 months follow-up
    End point values
    		 Dasatinib 100 mg QD Dasatinib 140 mg QD Dasatinib 50 mg BID Dasatinib 70 mg BID
    Number of subjects analysed
    43
    44
    44
    42
    Units: Percentage of Subjects
    number (confidence interval 95%)
        24 Months (n=43, 44, 44, 42)
    83.6 (67 to 92.3)
    87.7 (72.8 to 94.7)
    77.4 (61 to 87.6)
    83.7 (67.1 to 92.4)
        36 Months (n=43, 44, 44, 42)
    71.7 (53.6 to 83.7)
    76 (58.7 to 86.8)
    68.6 (51.1 to 80.9)
    77.4 (59.6 to 88.1)
        48 Months (n=43, 44, 44, 42)
    62.7 (44.5 to 76.5)
    76 (58.7 to 86.8)
    62 (44.1 to 75.7)
    66.9 (47.8 to 80.4)
        60 Months (n=43, 44, 44, 42)
    59.2 (40.8 to 73.6)
    71.2 (52.1 to 83.8)
    62 (44.1 to 75.7)
    59.5 (40.1 to 74.4)
        72 Months (n=43, 44, 44, 42)
    59.2 (40.8 to 73.6)
    66.5 (46.3 to 80.6)
    58.2 (39.8 to 72.7)
    55.2 (35.7 to 71.1)
        84 Months (n=43, 44, 44, 42)
    50.9 (32.1 to 67)
    66.5 (46.3 to 80.6)
    47.5 (27.4 to 65.2)
    50.2 (30.4 to 67.1)
    No statistical analyses for this end point

    Secondary: Percentage of Imatinib Intolerant Subjects With Overall Survival (OS) After 24, 36, 48, 60, 72, and 84 Months of Follow-up

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    End point title
    		 Percentage of Imatinib Intolerant Subjects With Overall Survival (OS) After 24, 36, 48, 60, 72, and 84 Months of Follow-up
    End point description
    OS was defined as the time from randomization until death. Survival data were collected for up to 5 years on subjects who had discontinued dasatinib treatment. Subjects who did not die or who were lost to follow-up were censored on the last date the subject was known to be alive. All randomized imatinib-intolerant subjects were summarized. Here, ‘n’ signifies evaluable subjects for specified categories in respective treatment arms.
    End point type
    Secondary
    End point timeframe
    Baseline up to 84 months follow-up
    End point values
    		 Dasatinib 100 mg QD Dasatinib 140 mg QD Dasatinib 50 mg BID Dasatinib 70 mg BID
    Number of subjects analysed
    43
    44
    44
    42
    Units: Percentage of subjects
    number (confidence interval 95%)
        24 Months (n=43, 44, 44, 42)
    94.9 (81.2 to 98.7)
    92.8 (79.2 to 97.6)
    95.3 (82.5 to 98.8)
    97.4 (82.8 to 99.6)
        36 Months (n=43, 44, 44, 42)
    89.7 (74.9 to 96)
    92.8 (79.2 to 97.6)
    90.4 (76.4 to 96.3)
    94.7 (80.6 to 98.7)
        48 Months (n=43, 44, 44, 42)
    84.5 (68.6 to 92.7)
    87.5 (72.4 to 94.6)
    85.1 (69.7 to 93)
    86.8 (71.2 to 94.3)
        60 Months (n=43, 44, 44, 42)
    81.8 (65.6 to 90.9)
    87.5 (72.4 to 94.6)
    82.4 (66.6 to 91.2)
    81.1 (64.3 to 90.5)
        72 Months (n=43, 44, 44, 42)
    79 (62.3 to 88.9)
    87.5 (72.4 to 94.6)
    79.6 (63.2 to 89.3)
    81.1 (64.3 to 90.5)
        84 Months (n=43, 44, 44, 42)
    70 (52.2 to 82.2)
    87.5 (72.4 to 94.6)
    76.9 (59.7 to 87.2)
    77.7 (60.1 to 88.2)
    No statistical analyses for this end point

    Secondary: Percentage of All Randomized Subjects With Cytogenic and Hematologic Response by Dosing Schedule (QD or BID) and by Total Daily Dose (100 mg or 140 mg) After at Least 6 Months Follow-Up

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    End point title
    		 Percentage of All Randomized Subjects With Cytogenic and Hematologic Response by Dosing Schedule (QD or BID) and by Total Daily Dose (100 mg or 140 mg) After at Least 6 Months Follow-Up
    End point description
    Complete cytogenetic response (CCyR): 0% Philadelphia chromosome positive cells in metaphase in Bone Marrow (BM). Partial cytogenetic response (PCyR) >0 to 35% Ph+ cells in metaphase in BM. MCyR: best cytogenetic response of CCyR or PCyR. A complete hematologic response (CHR) was obtained when all the following criteria were met: White Blood Cells <=institutional upper limit of normal (ULN); Platelets <450,000/mm³; No blasts or promyelocytes in peripheral blood (PB); <5% myelocytes plus metamyelocytes in PB; Basophils in PB <20%; No extramedullary involvement (including no splenomegaly or hepatomegaly). Hematologic responses were counted anytime following 14 days after the dosing start date. All randomized subjects were summarized. Here, ‘n’ signifies evaluable subjects for specified categories in respective treatment arms.
    End point type
    Secondary
    End point timeframe
    Baseline up to at least 6 months follow-up
    End point values
    		 QD Dasatinib BID Dasatinib Dasatinib 100 mg Total Daily Dose Dasatinib 140 mg Total Daily Dose
    Number of subjects analysed
    334
    336
    335
    335
    Units: Percentage of Subjects
    number (confidence interval 95%)
        MCyR (n=334, 336, 335, 335)
    57.2 (51.7 to 62.6)
    54.5 (49 to 59.9)
    56.1 (50.6 to 61.5)
    55.5 (50 to 60.9)
        CHR (n=334, 336, 335, 335)
    87.7 (83.7 to 91)
    89.3 (85.5 to 92.4)
    90.7 (87.1 to 93.6)
    86.3 (82.1 to 89.8)
    No statistical analyses for this end point

    Secondary: Percentage of All Randomized Subjects With Cytogenic and Hematologic Response by Dosing Schedule (QD or BID) and by Total Daily Dose (100 mg or 140 mg) After at Least 24 Months Follow-Up

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    End point title
    		 Percentage of All Randomized Subjects With Cytogenic and Hematologic Response by Dosing Schedule (QD or BID) and by Total Daily Dose (100 mg or 140 mg) After at Least 24 Months Follow-Up
    End point description
    Complete cytogenetic response (CCyR): 0% Philadelphia chromosome positive cells in metaphase in Bone Marrow (BM). Partial cytogenetic response (PCyR) : >0 to 35% Ph+ cells in metaphase in BM. Major cytogenetic response: best cytogenetic response of CCyR or PCyR. A complete hematologic response was obtained when all the following criteria were met: White Blood Cells <=institutional upper limit of normal (ULN); Platelets <450,000/mm³; No blasts or promyelocytes in peripheral blood (PB); <5% myelocytes plus metamyelocytes in PB; Basophils in PB <20%; No extramedullary involvement (including no splenomegaly or hepatomegaly). Hematologic responses were counted anytime following 14 days after the dosing start date. No cytogenic assessments were made after 2 years of follow-up. All randomized subjects were summarized. Here, ‘n’ signifies evaluable subjects for specified categories in respective treatment arms.
    End point type
    Secondary
    End point timeframe
    Baseline up to at least 24 months follow-up
    End point values
    		 QD Dasatinib BID Dasatinib Dasatinib 100 mg Total Daily Dose Dasatinib 140 mg Total Daily Dose
    Number of subjects analysed
    334
    336
    335
    335
    Units: Percentage of Subjects
    number (confidence interval 95%)
        MCyR (n=334, 336, 335, 335)
    63.2 (57.8 to 68.4)
    61.3 (55.9 to 66.5)
    62.4 (57 to 67.6)
    62.1 (56.7 to 67.3)
        CHR (n=334, 336, 335, 335)
    89.2 (85.4 to 92.3)
    90.2 (86.5 to 93.1)
    91.9 (88.5 to 94.6)
    87.5 (83.4 to 90.8)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Progression Free Survival (PFS) at 24, 36, 48, 60, 72, and 84 Months Follow-Up by Dose Schedule and Total Daily Dose - All Randomized Subjects

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    End point title
    		 Percentage of Subjects With Progression Free Survival (PFS) at 24, 36, 48, 60, 72, and 84 Months Follow-Up by Dose Schedule and Total Daily Dose - All Randomized Subjects
    End point description
    PFS= time from randomization until: complete hematologic response (CHR) achieved and subject subsequently no longer met criteria for CHR over 2 weeks; no CHR after receiving maximum dose and doubling of the white blood cells count from the lowest value to > 20,000/mm^3 or an increase by > 50,000/mm^3 on 2 assessments performed 2 weeks apart); subject met criteria of accelerated phase or blast phase chronic myelogenous leukemia; subject had major cytogenetic response (MCyR) and subsequently no longer met criteria for MCyR after starting maximum dose; >=30% absolute increase in number of Ph+ metaphases. Deaths without a reported prior progression were considered to have progressed on the date of death; those who neither progressed nor died were censored on the date of their last cytogenetic or hematologic assessment. All subjects who were randomized to a treatment arm were summarized. Here, ‘n’ signifies evaluable subjects for specified categories in respective treatment arms.
    End point type
    Secondary
    End point timeframe
    Baseline up to 84 months follow-up
    End point values
    		 Dasatinib 100 mg QD Dasatinib 140 mg QD Dasatinib 50 mg BID Dasatinib 70 mg BID
    Number of subjects analysed
    167
    167
    168
    168
    Units: Percentage of Subjects
    number (confidence interval 95%)
        24 Months (n=167, 167, 168, 168)
    77.4 (69.9 to 83.2)
    67.7 (59.6 to 74.5)
    72.2 (64.3 to 78.7)
    73.9 (66.1 to 80.1)
        36 Months (n=167, 167, 168, 168)
    66.6 (58.3 to 73.6)
    54 (45.4 to 61.8)
    67.5 (59.2 to 74.5)
    62.8 (54.3 to 70.1)
        48 Months (n=167, 167, 168, 168)
    59.1 (50.6 to 66.6)
    48 (39.4 to 56.2)
    63.3 (54.8 to 70.7)
    58.7 (50.1 to 66.3)
        60 Months (n=167, 167, 168, 168)
    52.5 (43.8 to 60.5)
    44.2 (35.5 to 52.5)
    58.7 (49.8 to 66.5)
    52.5 (43.7 to 60.5)
        72 Months (n=167, 167, 168, 168)
    48 (39.2 to 56.2)
    39.2 (30.6 to 47.7)
    52.8 (43.7 to 61.1)
    47.7 (38.7 to 56)
        84 Months (n=167, 167, 168, 168)
    42.1 (33.4 to 50.6)
    38.2 (29.6 to 46.7)
    43.9 (34.5 to 52.9)
    43.5 (34.5 to 52.1)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Overall Survival (OS) at 24, 36, 48, 60, 72, and 84 Months Follow-Up - All Randomized Subjects

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    End point title
    		 Percentage of Subjects With Overall Survival (OS) at 24, 36, 48, 60, 72, and 84 Months Follow-Up - All Randomized Subjects
    End point description
    OS was defined as the time from randomization until death. Survival data were collected for up to 5 years on subjects who had discontinued dasatinib treatment. Subjects who did not die or who were lost to follow-up were censored on the last date the subject was known to be alive. All subjects who were randomized to a treatment arm were summarized. Here, ‘n’ signifies evaluable subjects for specified categories in respective treatment arms.
    End point type
    Secondary
    End point timeframe
    Baseline up to 84 months follow-up
    End point values
    		 Dasatinib 100 mg QD Dasatinib 140 mg QD Dasatinib 50 mg BID Dasatinib 70 mg BID
    Number of subjects analysed
    167
    167
    168
    168
    Units: Percentage of Subjects
    number (confidence interval 95%)
        24 Months (n=167, 167, 168, 168)
    91.3 (85.8 to 94.8)
    93.6 (88.4 to 96.5)
    90.6 (84.9 to 94.2)
    88.1 (81.9 to 92.2)
        36 Months (n=167, 167, 168, 168)
    88.1 (82 to 92.3)
    86.2 (79.6 to 90.8)
    85.3 (78.7 to 90)
    80.9 (73.9 to 86.3)
        48 Months (n=167, 167, 168, 168)
    81 (73.9 to 86.3)
    83.4 (76.4 to 88.5)
    81.8 (74.7 to 87.1)
    74.9 (67.3 to 81)
        60 Months (n=167, 167, 168, 168)
    76.8 (69.4 to 82.7)
    80.5 (73.1 to 86)
    75.9 (68.2 to 82)
    72 (64.1 to 78.4)
        72 Months (n=167, 167, 168, 168)
    70.9 (62.9 to 77.5)
    76.6 (68.7 to 82.7)
    73.6 (65.6 to 80)
    70.5 (62.5 to 77.1)
        84 Months (n=167, 167, 168, 168)
    64.6 (56.1 to 71.8)
    73.4 (65.2 to 79.9)
    70.3 (62 to 77.1)
    68.1 (59.8 to 74.9)
    No statistical analyses for this end point

    Secondary: After 2 Years Follow-Up: Number of Subjects With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) That Led to Treatment Discontinuation

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    End point title
    		 After 2 Years Follow-Up: Number of Subjects With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) That Led to Treatment Discontinuation
    End point description
    AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Baseline=closest to, but no later than, the first day of study drug for treated subjects. All randomized subjects who received at least 1 dose of study drug were summarized.
    End point type
    Secondary
    End point timeframe
    Baseline up to 2 years follow-up
    End point values
    		 Dasatinib 100 mg QD Dasatinib 140 mg QD Dasatinib 50 mg BID Dasatinib 70 mg BID
    Number of subjects analysed
    165
    163
    167
    167
    Units: Subjects
        Any SAEs
    58
    67
    73
    78
        Drug-Related SAEs
    32
    40
    47
    55
        Drug-Related AEs that led to discontinuation
    14
    24
    20
    25
        Death within 30 days of last dose of study drug
    3
    2
    6
    5
    No statistical analyses for this end point

    Secondary: After 7 Years Follow-Up and Study Closure: Number of Subjects With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) That Led to Treatment Discontinuation

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    End point title
    		 After 7 Years Follow-Up and Study Closure: Number of Subjects With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) That Led to Treatment Discontinuation [8]
    End point description
    AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. After the 2-year analysis those on a twice daily dosing schedule were allowed to switch to a once daily dosing schedule. Due to the large number of subjects switching from twice daily dosing to once daily dosing, the overall safety data are presented for the 100 mg once daily group and combined for the other treatment groups. All randomized subjects who received at least 1 dose of study drug were summarized.
    End point type
    Secondary
    End point timeframe
    Baseline to 30 days post last dose; 7 years follow up; study closure July 2014
    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: The endpoint was to be evaluated for the specified arms only.
    End point values
    		 Dasatinib 100 mg QD Other Treatment Groups Total
    Number of subjects analysed
    165
    497
    662
    Units: Subjects
        All Deaths
    51
    133
    184
        Deaths on-study or within 30 days post dose
    11
    15
    26
        SAEs
    75
    259
    334
        AEs Leading to Discontinuation of Treatment
    43
    153
    196
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to 30 days post last dose; 7 years follow up
    Adverse event reporting additional description
    Study closure July 2014.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Dasatinib 100 mg QD
    Reporting group description
    		 Subjects received dasatinib 100 mg once a day (QD) until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw.

    Reporting group title
    Dasatinib 140 mg QD
    Reporting group description
    		 Subjects received dasatinib 140 mg QD until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw.

    Reporting group title
    Dasatinib 50 mg BID
    Reporting group description
    		 Subjects received 50 mg twice a day (BID) until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, subjects on a BID dosing schedule were allowed to switch to a QD dosing schedule.

    Reporting group title
    Dasatinib 70 mg BID
    Reporting group description
    		 Subjects received 70 mg BID until progression of disease, development of intolerable toxicity, or the subject's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, subjects on a BID dosing schedule were allowed to switch to a QD dosing schedule.

    Serious adverse events
    		 Dasatinib 100 mg QD Dasatinib 140 mg QD Dasatinib 50 mg BID Dasatinib 70 mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    75 / 165 (45.45%)
    78 / 163 (47.85%)
    89 / 167 (53.29%)
    92 / 167 (55.09%)
         number of deaths (all causes)
    15
    11
    17
    22
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenoma benign
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Basal cell carcinoma
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    1 / 167 (0.60%)
         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 / 0
    Blast cell crisis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    3 / 167 (1.80%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Blast cell proliferation
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Blast crisis in myelogenous leukaemia
         subjects affected / exposed
    0 / 165 (0.00%)
    2 / 163 (1.23%)
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 165 (0.61%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic myeloid leukaemia transformation
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    2 / 167 (1.20%)
    0 / 167 (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 / 2
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Leukaemia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Lip neoplasm malignant stage unspecified
         subjects affected / exposed
    1 / 165 (0.61%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pituitary tumour
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Prostate cancer
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Skin cancer
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Skin cancer metastatic
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Squamous cell carcinoma
         subjects affected / exposed
    3 / 165 (1.82%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 165 (0.61%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid adenoma
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Tongue neoplasm malignant stage unspecified
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Vulval cancer
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Extremity necrosis
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Haematoma
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Haemorrhage
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    1 / 167 (0.60%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Peripheral ischaemia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Poor peripheral circulation
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Thrombosis
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Chest pain
         subjects affected / exposed
    4 / 165 (2.42%)
    2 / 163 (1.23%)
    3 / 167 (1.80%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    2 / 4
    3 / 3
    2 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Device malfunction
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Fatigue
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Malaise
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Medical device pain
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Oedema peripheral
         subjects affected / exposed
    2 / 165 (1.21%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 165 (1.82%)
    11 / 163 (6.75%)
    6 / 167 (3.59%)
    9 / 167 (5.39%)
         occurrences causally related to treatment / all
    2 / 3
    6 / 13
    4 / 10
    4 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Serositis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Thrombosis in device
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Cholangitis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Cholecystitis acute
         subjects affected / exposed
    1 / 165 (0.61%)
    2 / 163 (1.23%)
    0 / 167 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergy to arthropod sting
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Anaphylactoid reaction
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Hypersensitivity
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometriosis
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Menorrhagia
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Menstrual disorder
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Uterine haemorrhage
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    7 / 165 (4.24%)
    15 / 163 (9.20%)
    14 / 167 (8.38%)
    20 / 167 (11.98%)
         occurrences causally related to treatment / all
    16 / 16
    30 / 30
    23 / 23
    32 / 35
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    4 / 165 (2.42%)
    6 / 163 (3.68%)
    7 / 167 (4.19%)
    9 / 167 (5.39%)
         occurrences causally related to treatment / all
    8 / 8
    4 / 7
    11 / 12
    10 / 14
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 165 (1.21%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    2 / 167 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Alveolar proteinosis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Bronchospasm
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 165 (0.61%)
    1 / 163 (0.61%)
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Interstitial lung disease
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Laryngeal oedema
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Obstructive airways disorder
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Oropharyngeal pain
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Pleurisy
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Pneumothorax
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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 arterial hypertension
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Pulmonary congestion
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    2 / 165 (1.21%)
    2 / 163 (1.23%)
    0 / 167 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Confusional state
         subjects affected / exposed
    3 / 165 (1.82%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed mood
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Depression
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Mental status changes
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Psychotic disorder
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blast cell count increased
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Blood creatinine increased
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Clostridium test positive
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin
         subjects affected / exposed
    3 / 165 (1.82%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    3 / 165 (1.82%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Platelet count increased
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    White blood cell count decreased
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Brain contusion
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Fibula fracture
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Fracture
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Incisional hernia, obstructive
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Injury
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Jaw fracture
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Joint injury
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Ligament sprain
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Muscle strain
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Overdose
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Postoperative thoracic procedure complication
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Procedural intestinal perforation
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Rib fracture
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Road traffic accident
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Spinal compression fracture
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    1 / 165 (0.61%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    2 / 167 (1.20%)
         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
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Atrial fibrillation
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    4 / 167 (2.40%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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 arrest
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Cardiac failure
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    1 / 167 (0.60%)
    1 / 167 (0.60%)
         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
    Cardiac failure acute
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Cardiac failure congestive
         subjects affected / exposed
    0 / 165 (0.00%)
    3 / 163 (1.84%)
    2 / 167 (1.20%)
    5 / 167 (2.99%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    2 / 2
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac valve disease
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 165 (0.00%)
    2 / 163 (1.23%)
    0 / 167 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 165 (1.21%)
    1 / 163 (0.61%)
    2 / 167 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 165 (0.61%)
    2 / 163 (1.23%)
    2 / 167 (1.20%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    2 / 165 (1.21%)
    3 / 163 (1.84%)
    3 / 167 (1.80%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
    2 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 165 (0.61%)
    2 / 163 (1.23%)
    2 / 167 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Restrictive cardiomyopathy
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Tachycardia
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Nervous system disorders
    Central nervous system haemorrhage
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Cerebellar infarction
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Cerebral haematoma
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Cerebral ischaemia
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Cerebrovascular accident
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Dizziness
         subjects affected / exposed
    2 / 165 (1.21%)
    2 / 163 (1.23%)
    0 / 167 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 165 (0.00%)
    2 / 163 (1.23%)
    1 / 167 (0.60%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Myasthenia gravis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Neuropathy peripheral
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Paraesthesia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Syncope
         subjects affected / exposed
    1 / 165 (0.61%)
    2 / 163 (1.23%)
    0 / 167 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 165 (1.21%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 165 (0.61%)
    3 / 163 (1.84%)
    3 / 167 (1.80%)
    5 / 167 (2.99%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
    2 / 3
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 165 (1.21%)
    2 / 163 (1.23%)
    3 / 167 (1.80%)
    6 / 167 (3.59%)
         occurrences causally related to treatment / all
    4 / 4
    3 / 3
    3 / 3
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Lymphadenopathy
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Neutropenia
         subjects affected / exposed
    2 / 165 (1.21%)
    2 / 163 (1.23%)
    2 / 167 (1.20%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
    3 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Thrombocytopenia
         subjects affected / exposed
    2 / 165 (1.21%)
    4 / 163 (2.45%)
    6 / 167 (3.59%)
    9 / 167 (5.39%)
         occurrences causally related to treatment / all
    1 / 2
    4 / 5
    8 / 8
    9 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Amaurosis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Cataract
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Diplopia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Retinal haemorrhage
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 165 (1.21%)
    2 / 163 (1.23%)
    4 / 167 (2.40%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    2 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 165 (0.00%)
    2 / 163 (1.23%)
    1 / 167 (0.60%)
    1 / 167 (0.60%)
         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
    Anal fistula
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Colitis
         subjects affected / exposed
    0 / 165 (0.00%)
    2 / 163 (1.23%)
    0 / 167 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 165 (1.21%)
    1 / 163 (0.61%)
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dental caries
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Diarrhoea
         subjects affected / exposed
    5 / 165 (3.03%)
    12 / 163 (7.36%)
    5 / 167 (2.99%)
    4 / 167 (2.40%)
         occurrences causally related to treatment / all
    3 / 5
    10 / 15
    6 / 8
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    1 / 167 (0.60%)
         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
    Enterocolitis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 165 (0.61%)
    2 / 163 (1.23%)
    1 / 167 (0.60%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 165 (0.61%)
    1 / 163 (0.61%)
    4 / 167 (2.40%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    3 / 4
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Gingival bleeding
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Haemorrhoids
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Ileus
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Inguinal hernia
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Large intestine polyp
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Loose tooth
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 165 (1.21%)
    3 / 163 (1.84%)
    2 / 167 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal pain
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Oesophagitis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Pancreatitis
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Toothache
         subjects affected / exposed
    0 / 165 (0.00%)
    2 / 163 (1.23%)
    0 / 167 (0.00%)
    0 / 167 (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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 165 (1.21%)
    5 / 163 (3.07%)
    6 / 167 (3.59%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 6
    5 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Cholecystitis
         subjects affected / exposed
    1 / 165 (0.61%)
    3 / 163 (1.84%)
    1 / 167 (0.60%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Angioedema
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Decubitus ulcer
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Dermatosis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erythema nodosum
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Exfoliative rash
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyoderma gangrenosum
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    3 / 165 (1.82%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Skin lesion
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Pollakiuria
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Renal failure
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Hypothyroidism
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    2 / 167 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Arthritis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    1 / 167 (0.60%)
         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 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 165 (0.61%)
    1 / 163 (0.61%)
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Muscle spasms
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Myalgia
         subjects affected / exposed
    1 / 165 (0.61%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 165 (0.00%)
    2 / 163 (1.23%)
    0 / 167 (0.00%)
    0 / 167 (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
    Osteonecrosis
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    1 / 167 (0.60%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Anal abscess
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Appendicitis
         subjects affected / exposed
    0 / 165 (0.00%)
    2 / 163 (1.23%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Bronchitis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Campylobacter infection
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    5 / 165 (3.03%)
    2 / 163 (1.23%)
    0 / 167 (0.00%)
    4 / 167 (2.40%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Clostridium difficile infection
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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 / 165 (0.00%)
    0 / 163 (0.00%)
    2 / 167 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis bacterial
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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 enterococcal
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Erysipelas
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    2 / 167 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 165 (0.00%)
    2 / 163 (1.23%)
    1 / 167 (0.60%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis clostridial
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Gastroenteritis viral
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Gastrointestinal infection
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Haematoma infection
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 165 (0.61%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    5 / 165 (3.03%)
    0 / 163 (0.00%)
    2 / 167 (1.20%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    3 / 9
    0 / 0
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Influenza
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Lobar pneumonia
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    1 / 167 (0.60%)
         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
    Lung infection
         subjects affected / exposed
    3 / 165 (1.82%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Neutropenic sepsis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Periodontitis
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Pharyngitis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Pneumonia
         subjects affected / exposed
    4 / 165 (2.42%)
    15 / 163 (9.20%)
    10 / 167 (5.99%)
    8 / 167 (4.79%)
         occurrences causally related to treatment / all
    2 / 5
    6 / 21
    9 / 15
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (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
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Sepsis
         subjects affected / exposed
    1 / 165 (0.61%)
    1 / 163 (0.61%)
    3 / 167 (1.80%)
    4 / 167 (2.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 3
    2 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    1 / 1
    Septic shock
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin bacterial infection
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Skin infection
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    1 / 167 (0.60%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 165 (0.00%)
    2 / 163 (1.23%)
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 167 (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
    Wound infection
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    2 / 167 (1.20%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Fluid overload
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Fluid retention
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 167 (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
    Hyperkalaemia
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Hypokalaemia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         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
    Hyponatraemia
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         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
    		 Dasatinib 100 mg QD Dasatinib 140 mg QD Dasatinib 50 mg BID Dasatinib 70 mg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    160 / 165 (96.97%)
    155 / 163 (95.09%)
    160 / 167 (95.81%)
    165 / 167 (98.80%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    9 / 165 (5.45%)
    5 / 163 (3.07%)
    5 / 167 (2.99%)
    7 / 167 (4.19%)
         occurrences all number
    11
    11
    6
    10
    Hypertension
         subjects affected / exposed
    15 / 165 (9.09%)
    12 / 163 (7.36%)
    13 / 167 (7.78%)
    20 / 167 (11.98%)
         occurrences all number
    17
    14
    15
    20
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    15 / 165 (9.09%)
    16 / 163 (9.82%)
    23 / 167 (13.77%)
    27 / 167 (16.17%)
         occurrences all number
    20
    18
    32
    34
    Chest pain
         subjects affected / exposed
    21 / 165 (12.73%)
    16 / 163 (9.82%)
    19 / 167 (11.38%)
    17 / 167 (10.18%)
         occurrences all number
    27
    19
    21
    31
    Chills
         subjects affected / exposed
    11 / 165 (6.67%)
    11 / 163 (6.75%)
    16 / 167 (9.58%)
    14 / 167 (8.38%)
         occurrences all number
    15
    15
    21
    14
    Fatigue
         subjects affected / exposed
    62 / 165 (37.58%)
    62 / 163 (38.04%)
    56 / 167 (33.53%)
    49 / 167 (29.34%)
         occurrences all number
    80
    77
    71
    74
    Influenza like illness
         subjects affected / exposed
    14 / 165 (8.48%)
    17 / 163 (10.43%)
    9 / 167 (5.39%)
    13 / 167 (7.78%)
         occurrences all number
    21
    29
    14
    16
    Oedema peripheral
         subjects affected / exposed
    30 / 165 (18.18%)
    29 / 163 (17.79%)
    30 / 167 (17.96%)
    36 / 167 (21.56%)
         occurrences all number
    41
    39
    39
    43
    Pain
         subjects affected / exposed
    19 / 165 (11.52%)
    10 / 163 (6.13%)
    12 / 167 (7.19%)
    10 / 167 (5.99%)
         occurrences all number
    28
    11
    14
    12
    Pyrexia
         subjects affected / exposed
    32 / 165 (19.39%)
    40 / 163 (24.54%)
    43 / 167 (25.75%)
    44 / 167 (26.35%)
         occurrences all number
    52
    88
    68
    69
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    53 / 165 (32.12%)
    42 / 163 (25.77%)
    57 / 167 (34.13%)
    54 / 167 (32.34%)
         occurrences all number
    68
    64
    84
    81
    Dyspnoea
         subjects affected / exposed
    49 / 165 (29.70%)
    51 / 163 (31.29%)
    53 / 167 (31.74%)
    43 / 167 (25.75%)
         occurrences all number
    63
    71
    76
    58
    Dyspnoea exertional
         subjects affected / exposed
    11 / 165 (6.67%)
    8 / 163 (4.91%)
    9 / 167 (5.39%)
    2 / 167 (1.20%)
         occurrences all number
    11
    9
    9
    2
    Epistaxis
         subjects affected / exposed
    15 / 165 (9.09%)
    15 / 163 (9.20%)
    7 / 167 (4.19%)
    12 / 167 (7.19%)
         occurrences all number
    17
    28
    9
    13
    Oropharyngeal pain
         subjects affected / exposed
    20 / 165 (12.12%)
    16 / 163 (9.82%)
    19 / 167 (11.38%)
    17 / 167 (10.18%)
         occurrences all number
    24
    20
    27
    16
    Pleural effusion
         subjects affected / exposed
    41 / 165 (24.85%)
    51 / 163 (31.29%)
    54 / 167 (32.34%)
    51 / 167 (30.54%)
         occurrences all number
    56
    68
    71
    73
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    6 / 165 (3.64%)
    9 / 163 (5.52%)
    15 / 167 (8.98%)
    12 / 167 (7.19%)
         occurrences all number
    6
    11
    19
    16
    Depression
         subjects affected / exposed
    16 / 165 (9.70%)
    12 / 163 (7.36%)
    14 / 167 (8.38%)
    11 / 167 (6.59%)
         occurrences all number
    17
    12
    17
    13
    Insomnia
         subjects affected / exposed
    19 / 165 (11.52%)
    20 / 163 (12.27%)
    14 / 167 (8.38%)
    12 / 167 (7.19%)
         occurrences all number
    19
    21
    16
    14
    Investigations
    Weight decreased
         subjects affected / exposed
    14 / 165 (8.48%)
    19 / 163 (11.66%)
    18 / 167 (10.78%)
    27 / 167 (16.17%)
         occurrences all number
    14
    22
    18
    32
    Weight increased
         subjects affected / exposed
    18 / 165 (10.91%)
    8 / 163 (4.91%)
    13 / 167 (7.78%)
    11 / 167 (6.59%)
         occurrences all number
    20
    10
    14
    12
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    4 / 165 (2.42%)
    10 / 163 (6.13%)
    12 / 167 (7.19%)
    3 / 167 (1.80%)
         occurrences all number
    4
    11
    12
    13
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    13 / 165 (7.88%)
    7 / 163 (4.29%)
    8 / 167 (4.79%)
    11 / 167 (6.59%)
         occurrences all number
    16
    8
    9
    12
    Pericardial effusion
         subjects affected / exposed
    3 / 165 (1.82%)
    9 / 163 (5.52%)
    10 / 167 (5.99%)
    7 / 167 (4.19%)
         occurrences all number
    3
    9
    11
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    24 / 165 (14.55%)
    26 / 163 (15.95%)
    25 / 167 (14.97%)
    25 / 167 (14.97%)
         occurrences all number
    30
    35
    33
    28
    Headache
         subjects affected / exposed
    75 / 165 (45.45%)
    73 / 163 (44.79%)
    60 / 167 (35.93%)
    76 / 167 (45.51%)
         occurrences all number
    142
    146
    95
    131
    Paraesthesia
         subjects affected / exposed
    12 / 165 (7.27%)
    11 / 163 (6.75%)
    10 / 167 (5.99%)
    7 / 167 (4.19%)
         occurrences all number
    12
    14
    13
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    23 / 165 (13.94%)
    14 / 163 (8.59%)
    26 / 167 (15.57%)
    23 / 167 (13.77%)
         occurrences all number
    28
    13
    38
    35
    Neutropenia
         subjects affected / exposed
    23 / 165 (13.94%)
    28 / 163 (17.18%)
    29 / 167 (17.37%)
    28 / 167 (16.77%)
         occurrences all number
    71
    70
    68
    61
    Thrombocytopenia
         subjects affected / exposed
    22 / 165 (13.33%)
    38 / 163 (23.31%)
    29 / 167 (17.37%)
    27 / 167 (16.17%)
         occurrences all number
    43
    80
    85
    83
    Eye disorders
    Periorbital oedema
         subjects affected / exposed
    8 / 165 (4.85%)
    4 / 163 (2.45%)
    17 / 167 (10.18%)
    5 / 167 (2.99%)
         occurrences all number
    9
    4
    21
    6
    Vision blurred
         subjects affected / exposed
    11 / 165 (6.67%)
    8 / 163 (4.91%)
    5 / 167 (2.99%)
    5 / 167 (2.99%)
         occurrences all number
    12
    9
    6
    5
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    13 / 165 (7.88%)
    8 / 163 (4.91%)
    9 / 167 (5.39%)
    7 / 167 (4.19%)
         occurrences all number
    16
    9
    11
    10
    Abdominal pain
         subjects affected / exposed
    25 / 165 (15.15%)
    26 / 163 (15.95%)
    24 / 167 (14.37%)
    20 / 167 (11.98%)
         occurrences all number
    31
    39
    36
    24
    Abdominal pain upper
         subjects affected / exposed
    13 / 165 (7.88%)
    24 / 163 (14.72%)
    17 / 167 (10.18%)
    18 / 167 (10.78%)
         occurrences all number
    15
    30
    18
    21
    Constipation
         subjects affected / exposed
    31 / 165 (18.79%)
    20 / 163 (12.27%)
    25 / 167 (14.97%)
    20 / 167 (11.98%)
         occurrences all number
    33
    29
    31
    22
    Diarrhoea
         subjects affected / exposed
    67 / 165 (40.61%)
    70 / 163 (42.94%)
    73 / 167 (43.71%)
    82 / 167 (49.10%)
         occurrences all number
    114
    139
    152
    151
    Dyspepsia
         subjects affected / exposed
    13 / 165 (7.88%)
    25 / 163 (15.34%)
    13 / 167 (7.78%)
    16 / 167 (9.58%)
         occurrences all number
    14
    33
    15
    17
    Flatulence
         subjects affected / exposed
    9 / 165 (5.45%)
    5 / 163 (3.07%)
    6 / 167 (3.59%)
    3 / 167 (1.80%)
         occurrences all number
    10
    5
    6
    3
    Gastritis
         subjects affected / exposed
    4 / 165 (2.42%)
    11 / 163 (6.75%)
    7 / 167 (4.19%)
    7 / 167 (4.19%)
         occurrences all number
    4
    13
    7
    8
    Nausea
         subjects affected / exposed
    37 / 165 (22.42%)
    54 / 163 (33.13%)
    52 / 167 (31.14%)
    69 / 167 (41.32%)
         occurrences all number
    63
    74
    83
    109
    Stomatitis
         subjects affected / exposed
    5 / 165 (3.03%)
    7 / 163 (4.29%)
    12 / 167 (7.19%)
    7 / 167 (4.19%)
         occurrences all number
    6
    9
    16
    10
    Toothache
         subjects affected / exposed
    10 / 165 (6.06%)
    15 / 163 (9.20%)
    8 / 167 (4.79%)
    8 / 167 (4.79%)
         occurrences all number
    15
    17
    13
    10
    Vomiting
         subjects affected / exposed
    23 / 165 (13.94%)
    29 / 163 (17.79%)
    32 / 167 (19.16%)
    52 / 167 (31.14%)
         occurrences all number
    33
    37
    54
    89
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    5 / 165 (3.03%)
    7 / 163 (4.29%)
    7 / 167 (4.19%)
    9 / 167 (5.39%)
         occurrences all number
    5
    9
    9
    12
    Alopecia
         subjects affected / exposed
    13 / 165 (7.88%)
    8 / 163 (4.91%)
    7 / 167 (4.19%)
    13 / 167 (7.78%)
         occurrences all number
    14
    9
    7
    13
    Dermatitis acneiform
         subjects affected / exposed
    4 / 165 (2.42%)
    8 / 163 (4.91%)
    8 / 167 (4.79%)
    11 / 167 (6.59%)
         occurrences all number
    4
    10
    9
    12
    Dry skin
         subjects affected / exposed
    10 / 165 (6.06%)
    8 / 163 (4.91%)
    8 / 167 (4.79%)
    6 / 167 (3.59%)
         occurrences all number
    11
    9
    8
    6
    Erythema
         subjects affected / exposed
    5 / 165 (3.03%)
    7 / 163 (4.29%)
    9 / 167 (5.39%)
    5 / 167 (2.99%)
         occurrences all number
    5
    9
    13
    7
    Hyperhidrosis
         subjects affected / exposed
    11 / 165 (6.67%)
    4 / 163 (2.45%)
    9 / 167 (5.39%)
    1 / 167 (0.60%)
         occurrences all number
    12
    4
    10
    1
    Night sweats
         subjects affected / exposed
    7 / 165 (4.24%)
    10 / 163 (6.13%)
    12 / 167 (7.19%)
    10 / 167 (5.99%)
         occurrences all number
    10
    12
    14
    10
    Petechiae
         subjects affected / exposed
    1 / 165 (0.61%)
    11 / 163 (6.75%)
    4 / 167 (2.40%)
    6 / 167 (3.59%)
         occurrences all number
    1
    11
    4
    6
    Pruritus
         subjects affected / exposed
    24 / 165 (14.55%)
    22 / 163 (13.50%)
    17 / 167 (10.18%)
    23 / 167 (13.77%)
         occurrences all number
    27
    27
    29
    31
    Rash
         subjects affected / exposed
    37 / 165 (22.42%)
    52 / 163 (31.90%)
    43 / 167 (25.75%)
    43 / 167 (25.75%)
         occurrences all number
    50
    83
    59
    63
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    47 / 165 (28.48%)
    39 / 163 (23.93%)
    36 / 167 (21.56%)
    30 / 167 (17.96%)
         occurrences all number
    59
    51
    47
    39
    Back pain
         subjects affected / exposed
    26 / 165 (15.76%)
    29 / 163 (17.79%)
    28 / 167 (16.77%)
    24 / 167 (14.37%)
         occurrences all number
    30
    36
    34
    37
    Bone pain
         subjects affected / exposed
    20 / 165 (12.12%)
    25 / 163 (15.34%)
    15 / 167 (8.98%)
    15 / 167 (8.98%)
         occurrences all number
    26
    31
    18
    19
    Muscle spasms
         subjects affected / exposed
    10 / 165 (6.06%)
    4 / 163 (2.45%)
    14 / 167 (8.38%)
    8 / 167 (4.79%)
         occurrences all number
    14
    4
    20
    8
    Musculoskeletal pain
         subjects affected / exposed
    24 / 165 (14.55%)
    13 / 163 (7.98%)
    15 / 167 (8.98%)
    18 / 167 (10.78%)
         occurrences all number
    31
    14
    16
    20
    Myalgia
         subjects affected / exposed
    27 / 165 (16.36%)
    26 / 163 (15.95%)
    24 / 167 (14.37%)
    22 / 167 (13.17%)
         occurrences all number
    40
    36
    27
    26
    Neck pain
         subjects affected / exposed
    10 / 165 (6.06%)
    6 / 163 (3.68%)
    5 / 167 (2.99%)
    6 / 167 (3.59%)
         occurrences all number
    9
    9
    5
    6
    Pain in extremity
         subjects affected / exposed
    33 / 165 (20.00%)
    29 / 163 (17.79%)
    24 / 167 (14.37%)
    22 / 167 (13.17%)
         occurrences all number
    37
    35
    30
    27
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    14 / 165 (8.48%)
    5 / 163 (3.07%)
    16 / 167 (9.58%)
    11 / 167 (6.59%)
         occurrences all number
    16
    9
    21
    12
    Conjunctivitis
         subjects affected / exposed
    3 / 165 (1.82%)
    11 / 163 (6.75%)
    7 / 167 (4.19%)
    6 / 167 (3.59%)
         occurrences all number
    3
    12
    8
    6
    Infection
         subjects affected / exposed
    9 / 165 (5.45%)
    4 / 163 (2.45%)
    8 / 167 (4.79%)
    2 / 167 (1.20%)
         occurrences all number
    11
    6
    6
    2
    Influenza
         subjects affected / exposed
    13 / 165 (7.88%)
    4 / 163 (2.45%)
    17 / 167 (10.18%)
    11 / 167 (6.59%)
         occurrences all number
    20
    4
    20
    13
    Nasopharyngitis
         subjects affected / exposed
    23 / 165 (13.94%)
    13 / 163 (7.98%)
    22 / 167 (13.17%)
    13 / 167 (7.78%)
         occurrences all number
    26
    21
    37
    16
    Oral herpes
         subjects affected / exposed
    13 / 165 (7.88%)
    5 / 163 (3.07%)
    9 / 167 (5.39%)
    8 / 167 (4.79%)
         occurrences all number
    16
    5
    14
    10
    Pneumonia
         subjects affected / exposed
    5 / 165 (3.03%)
    5 / 163 (3.07%)
    10 / 167 (5.99%)
    13 / 167 (7.78%)
         occurrences all number
    7
    5
    7
    12
    Sinusitis
         subjects affected / exposed
    19 / 165 (11.52%)
    8 / 163 (4.91%)
    17 / 167 (10.18%)
    12 / 167 (7.19%)
         occurrences all number
    29
    11
    22
    15
    Upper respiratory tract infection
         subjects affected / exposed
    28 / 165 (16.97%)
    26 / 163 (15.95%)
    35 / 167 (20.96%)
    23 / 167 (13.77%)
         occurrences all number
    46
    43
    52
    43
    Urinary tract infection
         subjects affected / exposed
    15 / 165 (9.09%)
    13 / 163 (7.98%)
    12 / 167 (7.19%)
    9 / 167 (5.39%)
         occurrences all number
    23
    17
    25
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    16 / 165 (9.70%)
    21 / 163 (12.88%)
    21 / 167 (12.57%)
    24 / 167 (14.37%)
         occurrences all number
    20
    24
    28
    39

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Apr 2006
    The purpose of this amendment was to make minor modifications to the hematologic response criteria and to remove the restriction of concurrent medications that inhibit platelet function.
    08 Mar 2007
    The purpose of this amendment was to allow subjects on the twice daily dosing schedule to switch to once daily dosing, in specific circumstances, to optimize the safety of dasatinib.
    28 Feb 2008
    The purpose of this amendment was to describe the participation requirements and study conduct for subjects who completed 2 years on study: The study will continue until all subjects have discontinued due to death, withdrawn consent or lost to follow up or until all subjects are followed for at least 5 years after study start, whichever occurs first.
    19 Dec 2008
    The purpose of this amendment was to clarify language surrounding study conduct for all enrolled subjects after two years on study in terms of data collection and submission of adverse events.
    14 Sep 2010
    The purpose of this amendment was to extend the duration of the study to subjects who continued to have clinical benefit.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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