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    Clinical Trial Results:
    A Phase III multi-center, open-label, randomized study of imatinib versus nilotinib in adult patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia in chronic phase (CML-CP)

    Summary
    EudraCT number
    		 2007-000208-34
    Trial protocol
    		 SE   CZ   BE   IT   ES   SK   AT   FR   NL   FI   DK   DE   PT   HU   GB  
    Global end of trial date
    21 Aug 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Sep 2020
    First version publication date
    02 Sep 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CAMN107A2303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00471497
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    - To compare the efficacy (major molecular response (MMR) rate at 12 months) of nilotinib at 400 mg bid with that of imatinib 400 mg qd in newly diagnosed, previously untreated Ph+ CML-CP patients. - To compare the efficacy (MMR rate at 12 months) of nilotinib at 300 mg bid with that of imatinib 400 mg qd in newly diagnosed, previously untreated Ph+ CML-CP patients. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jul 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 6
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Brazil: 67
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Colombia: 3
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    Egypt: 8
    Country: Number of subjects enrolled
    Finland: 11
    Country: Number of subjects enrolled
    France: 86
    Country: Number of subjects enrolled
    Germany: 51
    Country: Number of subjects enrolled
    United Kingdom: 32
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Italy: 63
    Country: Number of subjects enrolled
    Japan: 77
    Country: Number of subjects enrolled
    Korea, Republic of: 58
    Country: Number of subjects enrolled
    Malaysia: 1
    Country: Number of subjects enrolled
    Mexico: 6
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Norway: 10
    Country: Number of subjects enrolled
    Poland: 42
    Country: Number of subjects enrolled
    Russian Federation: 13
    Country: Number of subjects enrolled
    Singapore: 18
    Country: Number of subjects enrolled
    Slovakia: 8
    Country: Number of subjects enrolled
    South Africa: 14
    Country: Number of subjects enrolled
    Spain: 40
    Country: Number of subjects enrolled
    Sweden: 27
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Taiwan: 11
    Country: Number of subjects enrolled
    Thailand: 39
    Country: Number of subjects enrolled
    Turkey: 13
    Country: Number of subjects enrolled
    United States: 94
    Country: Number of subjects enrolled
    Venezuela, Bolivarian Republic of: 7
    Worldwide total number of subjects
    846
    EEA total number of subjects
    397
    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)
    748
    From 65 to 84 years
    97
    85 years and over
    1

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study over-enrolled, and 846 patients (283 in the imatinib 400 mg arm, 282 in the nilotinib 300 mg arm and 281 in the nilotinib 400 mg arm) were randomized. DP = disease progression, SOR/TF = Suboptimal response or treatment failure

    Pre-assignment
    Screening details
    		 Randomization was planned for a total of 771 patients.

    Period 1
    Period 1 title
    Core Treatment Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Imatinib 400 mg QD
    Arm description
    		 Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Imatinib
    Investigational medicinal product code
    STI571
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Imatinib was supplied as 100 mg and/or 400 mg tablets. Patients imatinib 400 mg qd orally. If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg bid orally. Imatinib was to be taken with food and a large glass of water.

    Arm title
    		 Nilotinb 300 mg BID
    Arm description
    		 Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nilotinib
    Investigational medicinal product code
    AMN107
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Nilotinib was supplied as 50 mg, 150 mg, or 200 mg hard gelatin capsules and was dosed on a flat scale and not dosed by body weight. Patients were randomized to receive nilotinib 300 mg bid by mouth each morning and evening approximately 12 hours apart.

    Arm title
    		 Nilotinib 400 mg BID
    Arm description
    		 Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nilotinib
    Investigational medicinal product code
    AMN107
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Nilotinib was supplied as 50 mg, 150 mg, or 200 mg hard gelatin capsules and was dosed on a flat scale and not dosed by body weight. Patients were randomized to receive nilotinib 400 mg bid by mouth each morning and evening approximately 12 hours apart.

    Number of subjects in period 1
    		Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Started
    283
    282
    281
    Safety Analysis Set
    280
    279
    277
    Discon. Core/Did not enter Ext.
    235
    256
    278
    Discontinued Core/Entered Ext.
    48 [1]
    26 [2]
    3 [3]
    Completed
    99
    107
    99
    Not completed
    184
    175
    182
         Adverse event, serious fatal
    3
    9
    3
         Sub optimal response or treat. failure
    19
    11
    13
         Abnormal Test Procedures
    1
    -
    1
         Abnormal Laboratory Values
    3
    9
    9
         Administrative problems
    14
    14
    12
         Disc. Core/Entered Ext.- SOR/TF
    46
    26
    3
         Disease Progression
    10
    2
    4
         Consent withdrawn by subject
    31
    29
    34
         Disc. Core/Entered Ext. - DP progression
    2
    -
    -
         Adverse event, non-fatal
    43
    53
    89
         Condition no longer requires study drug
    -
    1
    -
         Lost to follow-up
    6
    6
    3
         Protocol deviation
    6
    15
    11
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Extension period was optional a and so not all who completed Core moved into Extension period.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Extension period was optional a and so not all who completed Core moved into Extension period.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Extension period was optional a and so not all who completed Core moved into Extension period.
    Period 2
    Period 2 title
    Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Imatinib 400 mg QD (Treatment taken during core phase)
    Arm description
    		 Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Imatinib
    Investigational medicinal product code
    STI571
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Imatinib was supplied as 100 mg and/or 400 mg tablets. Patients imatinib 400 mg qd orally. If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg bid orally. Imatinib was to be taken with food and a large glass of water.

    Arm title
    		 Nilotinb 300 mg BID (Treatment taken during core phase)
    Arm description
    		 Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nilotinib
    Investigational medicinal product code
    AMN107
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Nilotinib was supplied as 50 mg, 150 mg, or 200 mg hard gelatin capsules and was dosed on a flat scale and not dosed by body weight. Patients were randomized to receive nilotinib 300 mg bid by mouth each morning and evening approximately 12 hours apart.

    Arm title
    		 Nilotinib 400 mg BID (Treatment taken during core phase)
    Arm description
    		 Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nilotinib
    Investigational medicinal product code
    AMN107
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Nilotinib was supplied as 50 mg, 150 mg, or 200 mg hard gelatin capsules and was dosed on a flat scale and not dosed by body weight. Patients were randomized to receive nilotinib 400 mg bid by mouth each morning and evening approximately 12 hours apart.

    Number of subjects in period 2 [4]
    		Imatinib 400 mg QD (Treatment taken during core phase) Nilotinb 300 mg BID (Treatment taken during core phase) Nilotinib 400 mg BID (Treatment taken during core phase)
    Started
    48
    26
    3
    Completed
    21
    12
    2
    Not completed
    27
    14
    1
         Adverse event, serious fatal
    1
    -
    -
         Consent withdrawn by subject
    3
    1
    -
         Adverse event, non-fatal
    9
    5
    1
         Unsatisfactory therapeutic effect
    8
    6
    -
         Lost to follow-up
    2
    -
    -
         Disease Progression
    2
    -
    -
         Protocol deviation
    2
    2
    -
    Notes
    [4] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Extension period was optional a and so not all who completed Core moved into Extension period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Imatinib 400 mg QD
    Reporting group description
    		 Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated

    Reporting group title
    Nilotinb 300 mg BID
    Reporting group description
    		 Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.

    Reporting group title
    Nilotinib 400 mg BID
    Reporting group description
    		 Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.

    Reporting group values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID Total
    Number of subjects
    		 283 282 281 846
    Age Categorical
    Units: Participants
        <35 years
    		 63 67 65 195
        >= 35 - <45 years
    		 67 50 59 176
        >=45 - <55 years
    		 63 72 65 200
        >=55 - < 65 years
    		 55 57 65 177
        >=65 years
    		 35 36 27 98
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.1 ± 14.34 47.2 ± 14.53 46.7 ± 13.90 -
    Sex: Female, Male
    Units:
        Female
    		 125 124 106 355
        Male
    		 158 158 175 491
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 187 170 185 542
        Black
    		 7 12 11 30
        Asian
    		 71 76 66 213
        Native American
    		 1 0 2 3
        Other
    		 17 24 17 58

    End points

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    End points reporting groups
    Reporting group title
    Imatinib 400 mg QD
    Reporting group description
    		 Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated

    Reporting group title
    Nilotinb 300 mg BID
    Reporting group description
    		 Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.

    Reporting group title
    Nilotinib 400 mg BID
    Reporting group description
    		 Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
    Reporting group title
    Imatinib 400 mg QD (Treatment taken during core phase)
    Reporting group description
    		 Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated

    Reporting group title
    Nilotinb 300 mg BID (Treatment taken during core phase)
    Reporting group description
    		 Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.

    Reporting group title
    Nilotinib 400 mg BID (Treatment taken during core phase)
    Reporting group description
    		 Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.

    Primary: Major molecular response rate (MMR) at 12 months between all 3 arms - with imputation

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    End point title
    		 Major molecular response rate (MMR) at 12 months between all 3 arms - with imputation
    End point description
    MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months.
    End point type
    Primary
    End point timeframe
    Baseline, 12 months
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    283
    282
    281
    Units: Percentage of participants
        number (confidence interval 95%)
    22.3 (17.6 to 27.6)
    44.3 (38.4 to 50.3)
    42.7 (36.8 to 48.7)
    Statistical analysis title
    		 Imatinib 400 mg qd vs nilotinib 300mg bid
    Comparison groups
    Imatinib 400 mg QD v Nilotinb 300 mg BID
    Number of subjects included in analysis
    565
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in response rate
    Point estimate
    22.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.5
         upper limit
    		 29.6
    Statistical analysis title
    		 Imatinib 400 mg qd vs nilotinib 400mg bid
    Comparison groups
    Imatinib 400 mg QD v Nilotinib 400 mg BID
    Number of subjects included in analysis
    564
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in response rate
    Point estimate
    20.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12.9
         upper limit
    		 28

    Primary: MMR rates at 12 months between all 3 arms by Sokal risk group with imputation (Low Sokal risk group)

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    End point title
    		 MMR rates at 12 months between all 3 arms by Sokal risk group with imputation (Low Sokal risk group)
    End point description
    MMR is defined as the proportion of patients in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months.
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    104
    103
    103
    Units: Percentage of participants
    number (confidence interval 95%)
        Sokal risk group = Low (n=104,103,103)
    26.0 (17.9 to 35.5)
    40.8 (31.2 to 50.9)
    53.4 (43.3 to 63.3)
    Statistical analysis title
    		 SS Low: Imatinib 400mg qd vs nilotinib 300mg bid
    Statistical analysis description
    (Low)
    Comparison groups
    Imatinib 400 mg QD v Nilotinb 300 mg BID
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in response rate
    Point estimate
    14.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.1
         upper limit
    		 27.5
    Statistical analysis title
    		 SS Low: Imatinib 400 mg qd vs nilotinib 400mg bid
    Statistical analysis description
    (Low)
    Comparison groups
    Imatinib 400 mg QD v Nilotinib 400 mg BID
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in response rate
    Point estimate
    27.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.6
         upper limit
    		 40.2

    Primary: MMR rates at 12 months between all 3 arms by Sokal risk group with imputation (Intermediate Sokal risk group)

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    End point title
    		 MMR rates at 12 months between all 3 arms by Sokal risk group with imputation (Intermediate Sokal risk group)
    End point description
    MMR is defined as the proportion of patients in MMR reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months.
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    101
    101
    100
    Units: Percentage of participants
        number (confidence interval 95%)
    22.8 (15.0 to 32.2)
    50.5 (40.4 to 60.6)
    40.0 (30.3 to 50.3)
    Statistical analysis title
    		 MMR Inter:Imatinib 400mg qd vs nilotinib
    Statistical analysis description
    (Intermediate)
    Comparison groups
    Imatinib 400 mg QD v Nilotinb 300 mg BID
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in response rate
    Point estimate
    27.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 15
         upper limit
    		 40.4
    Statistical analysis title
    		 MMR Inter:Imatinib 400mg qd vs nilotinib
    Statistical analysis description
    (Intermediate)
    Comparison groups
    Imatinib 400 mg QD v Nilotinib 400 mg BID
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in response rate
    Point estimate
    17.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.6
         upper limit
    		 29.8

    Primary: MMR rates at 12 months between all 3 arms by Sokal risk group with imputation (High Sokal risk group)

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    End point title
    		 MMR rates at 12 months between all 3 arms by Sokal risk group with imputation (High Sokal risk group)
    End point description
    MMR is defined as the proportion of patients in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months.
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    78
    78
    78
    Units: Percentage of participants
        number (confidence interval 95%)
    16.7 (9.2 to 26.8)
    41.0 (30.0 to 52.7)
    32.1 (21.9 to 43.6)
    Statistical analysis title
    		 MMR High:Imatinib 400mg qd vs nilotinib
    Statistical analysis description
    (High)
    Comparison groups
    Imatinib 400 mg QD v Nilotinb 300 mg BID
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in response rate
    Point estimate
    24.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.7
         upper limit
    		 38.1
    Statistical analysis title
    		 MMR High:Imatinib 400mg qd vs nilotinib
    Statistical analysis description
    (High)
    Comparison groups
    Imatinib 400 mg QD v Nilotinib 400 mg BID
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in response rate
    Point estimate
    15.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.1
         upper limit
    		 28.6

    Secondary: Rates of durable MMR at 24 months between all 3 arms

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    End point title
    		 Rates of durable MMR at 24 months between all 3 arms
    End point description
    Durable MMR at 24 months is defined as having MMR both at 12 months and at 24 months, and with no documented loss of MMR between these 12 month and 24 month time points.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    283
    282
    281
    Units: Percentage of participants
        number (confidence interval 95%)
    20.5 (15.9 to 25.7)
    41.8 (36.0 to 47.8)
    39.1 (33.4 to 45.1)
    Statistical analysis title
    		 Dur. MMR: Imatinib 400mg qd vs nilotinib 300mg bid
    Comparison groups
    Imatinib 400 mg QD v Nilotinb 300 mg BID
    Number of subjects included in analysis
    565
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in response rate
    Point estimate
    21.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.9
         upper limit
    		 28.8
    Statistical analysis title
    		 Dur. MMR: Imatinib 400mg qd vs nilotinib 400mg bid
    Comparison groups
    Imatinib 400 mg QD v Nilotinib 400 mg BID
    Number of subjects included in analysis
    564
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in response rate
    Point estimate
    18.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.3
         upper limit
    		 26

    Secondary: Rate of complete cytogenetic response (CCyR) in nilotinib treatment arms with imatinib at 12 months and beyond 12 months

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    End point title
    		 Rate of complete cytogenetic response (CCyR) in nilotinib treatment arms with imatinib at 12 months and beyond 12 months
    End point description
    CCyR is defined as 0% Ph+ metaphases based on at least 20 metaphases from bone marrow cytogenetics. Patients with no CCyR as the best response by any specific time point, all missing cytogenetic evaluations by that time point or Ph- at baseline are combined as “Nocomplete cytogenetic response”.
    End point type
    Secondary
    End point timeframe
    12, 24, 36, 48, 60, 72 months (M)
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    283
    282
    281
    Units: Percentage of participants
    number (not applicable)
        CCyR at M12
    55.5
    70.2
    68.7
        CCyR at M24
    61.5
    66.0
    66.2
        CCyR at M36
    14.1
    9.2
    12.8
        CCyR at M48
    11.3
    8.9
    13.5
        CCyR at M60
    2.5
    2.8
    2.8
        CCyR at M72
    1.8
    1.8
    2.8
    No statistical analyses for this end point

    Secondary: Rate of Major molecular response (MMR) at 12 months between two nilotinib arms

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    End point title
    		 Rate of Major molecular response (MMR) at 12 months between two nilotinib arms [1]
    End point description
    MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months.
    End point type
    Secondary
    End point timeframe
    12 months
    Notes
    [1] - 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: There was no plan to report statistical analysis for this endpoint
    End point values
    		 Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    282
    281
    Units: Percentage of participants
        number (confidence interval 95%)
    44.3 (38.4 to 50.3)
    42.7 (36.8 to 48.7)
    Statistical analysis title
    		 MMR: nilotinib 300mg bid vs nilotinib 400mg bid
    Comparison groups
    Nilotinb 300 mg BID v Nilotinib 400 mg BID
    Number of subjects included in analysis
    563
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6987
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Absolute difference
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.8
         upper limit
    		 6.6

    Secondary: Rate of MMR at 6 months and beyond 12 months in all 3 treatment arms

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    End point title
    		 Rate of MMR at 6 months and beyond 12 months in all 3 treatment arms
    End point description
    MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 6 months and 12 months and beyond 12 months.
    End point type
    Secondary
    End point timeframe
    6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    283
    282
    281
    Units: Percentage of participants
    number (confidence interval 95%)
        MMR at M6
    12.0 (8.5 to 16.4)
    33.0 (27.5 to 38.8)
    29.5 (24.3 to 35.2)
        MMR at M12
    22.3 (17.6 to 27.6)
    44.7 (38.8 to 50.7)
    43.1 (37.2 to 49.1)
        MMR at M24
    37.5 (31.8 to 43.4)
    61.7 (55.8 to 67.4)
    59.1 (53.1 to 64.9)
        MMR at M36
    38.5 (32.8 to 44.5)
    59.2 (53.2 to 65.0)
    57.3 (51.3 to 63.2)
        MMR at M48
    43.8 (38.0 to 49.8)
    59.9 (54.0 to 65.7)
    55.2 (49.1 to 61.1)
        MMR at M60
    49.1 (43.2 to 55.1)
    62.8 (56.8 to 68.4)
    61.2 (55.2 to 66.9)
        MMR at M72
    41.7 (35.9 to 47.7)
    52.5 (46.5 to 58.4)
    57.7 (51.6 to 63.5)
        MMR at M84
    40.3 (34.5 to 46.3)
    50.0 (44.0 to 56.0)
    50.9 (44.9 to 56.9)
        MMR at M96
    37.5 (31.8 to 43.4)
    46.1 (40.2 to 52.1)
    46.3 (40.3 to 52.3)
        MMR at M108
    37.5 (31.8 to 43.4)
    43.3 (37.4 to 49.3)
    40.2 (34.4 to 46.2)
        MMR at M120
    36.4 (30.8 to 42.3)
    37.9 (32.3 to 43.9)
    39.1 (33.4 to 45.1)
    No statistical analyses for this end point

    Secondary: Rate of a ≥ 4 log reduction in BCR-ABL transcripts in nilotinib treatment arms with imatinib

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    End point title
    		 Rate of a ≥ 4 log reduction in BCR-ABL transcripts in nilotinib treatment arms with imatinib
    End point description
    Molecular response of <=0.01% is defined as BCR-ABL ratio (%) on IS <= 0.01% (corresponds to >=4 log reduction of BCR-ABL transcripts from standardized baseline value)
    End point type
    Secondary
    End point timeframe
    at 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    283
    282
    281
    Units: Percentage of participants
    number (confidence interval 95%)
        Molecular response of <=0.01% at 6 months
    1.1 (0.2 to 3.1)
    8.9 (5.8 to 12.8)
    5.7 (3.3 to 9.1)
        Molecular response of <=0.01% at 12 months
    3.9 (2.0 to 6.8)
    12.1 (8.5 to 16.4)
    8.9 (5.8 to 12.9)
        Molecular response of <=0.01% at 24 months
    10.2 (7.0 to 14.4)
    24.5 (19.6 to 29.9)
    22.1 (17.4 to 27.4)
        Molecular response of <=0.01% at 36 months
    14.1 (10.3 to 18.7)
    29.4 (24.2 to 35.1)
    23.8 (19.0 to 29.3)
        Molecular response of <=0.01% at 48 months
    19.8 (15.3 to 24.9)
    33.0 (27.5 to 38.8)
    29.9 (24.6 to 35.6)
        Molecular response of <=0.01% at 60 months
    31.1 (25.7 to 36.8)
    47.9 (41.9 to 53.9)
    43.4 (37.5 to 49.4)
        Molecular response of <=0.01% at 72 months
    27.2 (22.1 to 32.8)
    44.3 (38.4 to 50.3)
    45.2 (39.3 to 51.2)
        Molecular response of <=0.01% at 84 months
    29.0 (23.8 to 34.6)
    42.9 (37.1 to 48.9)
    40.6 (34.8 to 46.6)
        Molecular response of <=0.01% at 96 months
    28.3 (23.1 to 33.9)
    39.7 (34.0 to 45.7)
    38.1 (32.4 to 44.0)
        Molecular response of <=0.01% at 108 months
    32.2 (26.7 to 37.9)
    40.4 (34.6 to 46.4)
    34.9 (29.3 to 40.8)
        Molecular response of <=0.01% at 120 months
    28.3 (23.1 to 33.9)
    35.5 (29.9 to 41.4)
    33.8 (28.3 to 39.7)
    No statistical analyses for this end point

    Secondary: Rate of a ≥ 4.5 log reduction in BCR-ABL transcripts in nilotinib treatment arms with imatinib

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    End point title
    		 Rate of a ≥ 4.5 log reduction in BCR-ABL transcripts in nilotinib treatment arms with imatinib
    End point description
    This is the molecular response of <=0.0032% is defined as BCR-ABL ratio (%) on IS <= 0.0032% (corresponds to >=4.5 log reduction of BCR-ABL transcripts from standardized baseline value)
    End point type
    Secondary
    End point timeframe
    at 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    283
    282
    281
    Units: Percentage of participants
    number (confidence interval 95%)
        Molecular response of <=0.0032% at 6 months
    0.0 (0.0 to 1.3)
    3.5 (1.7 to 6.4)
    1.4 (0.4 to 3.6)
        Molecular response of <=0.0032% at 12 months
    0.4 (0.0 to 2.0)
    4.6 (2.5 to 7.8)
    5.0 (2.8 to 8.2)
        Molecular response of <=0.0032% at 24 months
    2.8 (1.2 to 5.5)
    12.4 (8.8 to 16.8)
    7.8 (5.0 to 11.6)
        Molecular response of <=0.0032% at 36 months
    8.1 (5.2 to 11.9)
    13.8 (10.0 to 18.4)
    12.1 (8.5 to 16.5)
        Molecular response of <=0.01032 at 48 months
    10.2 (7.0 to 14.4)
    16.3 (12.2 to 21.2)
    17.1 (12.9 to 22.0)
        Molecular response of <=0.0032% at 60 months
    19.8 (15.3 to 24.9)
    32.3 (26.8 to 38.1)
    29.5 (24.3 to 35.2)
        Molecular response of <=0.0032% at 72 months
    18.0 (13.7 to 23.0)
    31.2 (25.8 to 37.0)
    28.8 (23.6 to 34.5)
        Molecular response of <=0.0032% at 84 months
    19.1 (14.7 to 24.2)
    31.6 (26.2 to 37.3)
    28.8 (23.6 to 34.5)
        Molecular response of <=0.01% at 96 months
    23.3 (18.5 to 28.7)
    31.9 (26.5 to 37.7)
    32.4 (26.9 to 38.2)
        Molecular response of <=0.0032% at 108 months
    24.0 (19.2 to 29.4)
    31.9 (26.5 to 37.7)
    28.1 (22.9 to 33.8)
        Molecular response of <=0.0032% at 120 months
    21.2 (16.6 to 26.4)
    27.0 (21.9 to 32.5)
    25.6 (20.6 to 31.1)
    No statistical analyses for this end point

    Secondary: Time to first MMR

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    End point title
    		 Time to first MMR
    End point description
    Time to MMR is defined as time from date of randomization to the date of the first documented MMR in nilotinib treatment arms, compared to imatinib in adult patients with Ph+ CML in CP.
    End point type
    Secondary
    End point timeframe
    up to 84 months
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    283
    282
    281
    Units: Months
        median (confidence interval 95%)
    14.13 (11.60 to 17.31)
    8.31 (6.21 to 8.48)
    8.53 (8.31 to 11.07)
    No statistical analyses for this end point

    Secondary: Duration of MMR

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    End point title
    		 Duration of MMR
    End point description
    Duration of MMR for patients with MMR is defined as the time between date of MMR and the earliest of the following: loss of MMR, CML-related death or progression to AP/BC during study treatment The time will be censored at last molecular assessment (PCR) date for patients for whom none of the above events is reported.
    End point type
    Secondary
    End point timeframe
    approx. 12 years
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    283
    282
    281
    Units: Months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Time to both a ≥ 4 and ≥ 4.5 log reduction in BCR-ABL transcripts

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    End point title
    		 Time to both a ≥ 4 and ≥ 4.5 log reduction in BCR-ABL transcripts
    End point description
    Time to BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032% is defined as: date of first BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032% - date of randomization +1.
    End point type
    Secondary
    End point timeframe
    up to 84 months
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    283
    282
    281
    Units: Months
    median (confidence interval 95%)
        time to first molecular response of <=0.01%
    30.46 (24.11 to 36.01)
    19.38 (16.62 to 22.34)
    22.70 (19.48 to 27.63)
        time to first molecular response of <=0.0032%
    37.29 (33.45 to 41.63)
    32.46 (23.23 to 38.67)
    35.94 (30.39 to 41.00)
    No statistical analyses for this end point

    Secondary: Duration of both a ≥ 4 and ≥ 4.5 log reduction in BCR-ABL transcripts

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    End point title
    		 Duration of both a ≥ 4 and ≥ 4.5 log reduction in BCR-ABL transcripts
    End point description
    It is defined as the time from the date of first documented BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032% to the earliest of the following: Loss of BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032%, respectively, CML-related death or progression to AP/BC during study treatment. The time will be censored at last molecular assessment (PCR) date for patients for whom none of the above events is reported.
    End point type
    Secondary
    End point timeframe
    approx. 12 years
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    283
    282
    281
    Units: Months
    median (confidence interval 95%)
        duration of first molecular response of <=0.01%
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
        duration of first molecular response of <=0.0032%
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Rate of hematologic response

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    End point title
    		 Rate of hematologic response
    End point description
    Rate of hematologic response is defined as the percentage of participants in complete hematologic response (defined as the following present for at least 4 weeks: WBC count <10 x 109/L, Platelet count <450 x 109/L, Basophils <5%, No blasts and promyelocytes in peripheral blood, Myelocytes + metamyelocytes < 5% in peripheral blood, No evidence of extramedullary disease, including spleen and liver).
    End point type
    Secondary
    End point timeframe
    12 months, 24 months, Overall (beyond 120 months & up to LPLV)
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    283
    282
    281
    Units: Percentage of participants
    number (confidence interval 95%)
        Complete hematologic response (CHR) by M12
    93.3 (89.7 to 95.9)
    90.1 (86.0 to 93.3)
    89.0 (84.7 to 92.4)
        CHR by M24
    93.6 (90.1 to 96.2)
    90.8 (86.8 to 93.9)
    90.4 (86.3 to 93.6)
        CHR Overall
    94.0 (90.6 to 96.5)
    92.2 (88.4 to 95.0)
    90.7 (86.7 to 93.9)
    No statistical analyses for this end point

    Secondary: Time to Complete cytogenic response (CCyR)

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    End point title
    		 Time to Complete cytogenic response (CCyR)
    End point description
    Time to CCyR is defined as the time from the date of randomization to the date of first documented CCyR
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    283
    282
    281
    Units: Months
        median (confidence interval 95%)
    8.5 (5.8 to 10.9)
    5.7 (5.6 to 5.7)
    5.7 (5.7 to 5.8)
    No statistical analyses for this end point

    Secondary: Duration of CCyR

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    End point title
    		 Duration of CCyR
    End point description
    Duration of CCyR is defined as the time from date of first documented CCyR to the earliest date of loss of CCyR.
    End point type
    Secondary
    End point timeframe
    up to 72 months
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    283
    282
    281
    Units: Months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    Progression-free survival is defined as the time from the date of randomization to the date of event defined as the first documented disease progression to AP/BC or the date of death from any cause occurring in the core or extension study, or during the follow-up period after discontinuation of core or extension study
    End point type
    Secondary
    End point timeframe
    approx. 12 years
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    283
    282
    281
    Units: Months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Event-free survival (EFS)

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    End point title
    		 Event-free survival (EFS)
    End point description
    Event-free survival is defined as the time from the date of randomization to the date of first occurrence of any of the following: death due to any cause (if death is the primary reason for discontinuation), progression to AP or BC, loss of PCyR, loss of CCyR, loss of CHR
    End point type
    Secondary
    End point timeframe
    approx. 12 years
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    283
    282
    281
    Units: Months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS is defined as the time from the date of randomization to the date death. Up to 10 calendar years of follow up from the date when the last patient randomized received the first dose of study drug in all active treatment arms of adult patients with Ph+ CML CP.
    End point type
    Secondary
    End point timeframe
    approx. 12 years
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    283
    282
    281
    Units: Months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Actual dose-intensity

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    End point title
    		 Actual dose-intensity
    End point description
    Actual dose intensity is defined as total dose over time on treatment
    End point type
    Secondary
    End point timeframe
    approx. 12 years
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    280
    279
    277
    Units: mg/day
        median (full range (min-max))
    400.0 (206 to 800)
    591.1 (186 to 699)
    758.9 (232 to 800)
    No statistical analyses for this end point

    Secondary: Time to progression to AP/BC

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    End point title
    		 Time to progression to AP/BC
    End point description
    Time to progression to AP/BC is defined as the time from the date of randomization to the date of event defined as the first documented disease progression to AP/BC or the date of CML related death.
    End point type
    Secondary
    End point timeframe
    approx. 12 years
    End point values
    		 Imatinib 400 mg QD Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    283
    282
    281
    Units: Months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics as per Cmax at 12 months

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    End point title
    		 Pharmacokinetics as per Cmax at 12 months [2]
    End point description
    Cmax is defined as the maximum serum concentration after dose
    End point type
    Secondary
    End point timeframe
    any day after day 8 at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administration
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no plan to report statistical analysis for this endpoint
    End point values
    		 Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    8
    8
    Units: ng/mL
        median (inter-quartile range (Q1-Q3))
    1555 (1340 to 2300)
    1440 (1002 to 2125)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics as per Cmin at 12 months

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    End point title
    		 Pharmacokinetics as per Cmin at 12 months [3]
    End point description
    Cmin is defined as the minimum serum concentration after dose
    End point type
    Secondary
    End point timeframe
    any day after day 8 at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administration
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no plan to report statistical analysis for this endpoint
    End point values
    		 Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    8
    8
    Units: ng/mL
        median (inter-quartile range (Q1-Q3))
    1430 (1250 to 1740)
    915 (752 to 2080)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics as per Tmax at 12 months

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    End point title
    		 Pharmacokinetics as per Tmax at 12 months [4]
    End point description
    Tmax is defined as the sampling time when maximum measured serum concentration occurs
    End point type
    Secondary
    End point timeframe
    any day after day 8 at pre-dose (0 hour), 1 hour, 2 hours, 3 hour
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no plan to report statistical analysis for this endpoint
    End point values
    		 Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    8
    8
    Units: hour (h)
        median (inter-quartile range (Q1-Q3))
    1.47 (0.50 to 2.04)
    1.50 (0.00 to 2.02)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics as per AUC0-last at 12 months

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    End point title
    		 Pharmacokinetics as per AUC0-last at 12 months [5]
    End point description
    AUC0 - last is defined as area under concentration-time curve from time zero to the last measurable sample, calculated by log-linear trapezoidal method
    End point type
    Secondary
    End point timeframe
    any day after day 8 at pre-dose (0 hour), 1 hour, 2 hours, 3 hour
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no plan to report statistical analysis for this endpoint
    End point values
    		 Nilotinb 300 mg BID Nilotinib 400 mg BID
    Number of subjects analysed
    8
    8
    Units: h.ng/mL
        median (inter-quartile range (Q1-Q3))
    14446 (12806 to 17411)
    11689 (7925 to 18678)
    No statistical analyses for this end point

    Secondary: Rate of hematologic response on nilotinib 400 mg BID therapy after insufficient response during core treatment and switch to extension phase (Extension)

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    End point title
    		 Rate of hematologic response on nilotinib 400 mg BID therapy after insufficient response during core treatment and switch to extension phase (Extension)
    End point description
    Rate of hematologic response is defined as the percentage of participants in complete hematologic response (defined as the following present for at least 4 weeks: WBC count <10 x 109/L, Platelet count <450 x 109/L, Basophils <5%, No blasts and promyelocytes in peripheral blood, Myelocytes + metamyelocytes < 5% in peripheral blood, No evidence of extramedullary disease, including spleen and liver).
    End point type
    Secondary
    End point timeframe
    Overall (beyond 120 months and up to LPLV)
    End point values
    		 Imatinib 400 mg QD (Treatment taken during core phase) Nilotinb 300 mg BID (Treatment taken during core phase) Nilotinib 400 mg BID (Treatment taken during core phase)
    Number of subjects analysed
    48
    26
    3
    Units: Percentage of participants
        number (confidence interval 95%)
    83.3 (69.8 to 92.5)
    84.6 (65.1 to 95.6)
    66.7 (9.4 to 99.2)
    No statistical analyses for this end point

    Secondary: Rate of complete cytogenetic response (CCyR) on nilotinib 400 mg BID therapy after insufficient response during core treatment and switch to extension phase (Extension)

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    End point title
    		 Rate of complete cytogenetic response (CCyR) on nilotinib 400 mg BID therapy after insufficient response during core treatment and switch to extension phase (Extension)
    End point description
    Rate of CCyR is defined as the percentage of participants in complete cytogenetic response (CCyR). CcyR is defined as 0% of Ph+ metaphases in the bone marrow.
    End point type
    Secondary
    End point timeframe
    Overall (beyond 120 months and up to LPLV)
    End point values
    		 Imatinib 400 mg QD (Treatment taken during core phase) Nilotinb 300 mg BID (Treatment taken during core phase) Nilotinib 400 mg BID (Treatment taken during core phase)
    Number of subjects analysed
    48
    26
    3
    Units: Percentage of participants
        number (confidence interval 95%)
    72.9 (58.2 to 84.7)
    73.1 (52.2 to 88.4)
    66.7 (9.4 to 99.2)
    No statistical analyses for this end point

    Secondary: Rate of major molecular response (MMR) on nilotinib 400 mg BID therapy after insufficient response during core treatment and switch to extension phase (Extension)

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    End point title
    		 Rate of major molecular response (MMR) on nilotinib 400 mg BID therapy after insufficient response during core treatment and switch to extension phase (Extension)
    End point description
    Rate of MMR is defined as the percentage pf participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR))
    End point type
    Secondary
    End point timeframe
    Overall (beyond 120 months and up to LPLV)
    End point values
    		 Imatinib 400 mg QD (Treatment taken during core phase) Nilotinb 300 mg BID (Treatment taken during core phase) Nilotinib 400 mg BID (Treatment taken during core phase)
    Number of subjects analysed
    48
    26
    3
    Units: Percentage of participants
        number (confidence interval 95%)
    64.6 (49.5 to 77.8)
    73.1 (52.2 to 88.4)
    66.7 (9.4 to 99.2)
    No statistical analyses for this end point

    Secondary: Rate of a ≥ 4 log reduction in BCR-ABL transcripts on nilotinib 400 mg BID therapy after insufficient response during core treatment and switch to extension phase (Extension)

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    End point title
    		 Rate of a ≥ 4 log reduction in BCR-ABL transcripts on nilotinib 400 mg BID therapy after insufficient response during core treatment and switch to extension phase (Extension)
    End point description
    Molecular response of <=0.01% is defined as BCR-ABL ratio (%) on IS <= 0.01% (corresponds to >=4 log reduction of BCR-ABL transcripts from standardized baseline value)
    End point type
    Secondary
    End point timeframe
    Overall (beyond 120 months and up to LPLV)
    End point values
    		 Imatinib 400 mg QD (Treatment taken during core phase) Nilotinb 300 mg BID (Treatment taken during core phase) Nilotinib 400 mg BID (Treatment taken during core phase)
    Number of subjects analysed
    48
    26
    3
    Units: Percentage of participants
        number (confidence interval 95%)
    43.8 (29.5 to 58.8)
    57.7 (36.9 to 76.6)
    33.3 (0.8 to 90.6)
    No statistical analyses for this end point

    Secondary: Rate of ≥ 4.5 log reduction in BCR-ABL transcripts on nilotinib 400 mg BID therapy after insufficient response during core treatment and switch to extension phase (Extension)

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    End point title
    		 Rate of ≥ 4.5 log reduction in BCR-ABL transcripts on nilotinib 400 mg BID therapy after insufficient response during core treatment and switch to extension phase (Extension)
    End point description
    Molecular response of <=0.0032% is defined as BCR-ABL ratio (%) on IS <= 0.0032% (corresponds to >=4.5 log reduction of BCR-ABL transcripts from standardized baseline value)
    End point type
    Secondary
    End point timeframe
    Overall (beyond 120 months and up to LPLV)
    End point values
    		 Imatinib 400 mg QD (Treatment taken during core phase) Nilotinb 300 mg BID (Treatment taken during core phase) Nilotinib 400 mg BID (Treatment taken during core phase)
    Number of subjects analysed
    48
    26
    3
    Units: Percentage of participants
        number (confidence interval 95%)
    35.4 (22.2 to 50.5)
    38.5 (20.2 to 59.4)
    33.3 (0.8 to 90.6)
    No statistical analyses for this end point

    Secondary: Presence of newly observed BCR-ABL mutations in patients post-baseline and correlate with response to treatment with imatinib and nilotinib (Extension)

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    End point title
    		 Presence of newly observed BCR-ABL mutations in patients post-baseline and correlate with response to treatment with imatinib and nilotinib (Extension)
    End point description
    This is the percentage of patients with any emergent mutation on extension treatment. The mutation comprised of T315T, less sensitive to nilotinib, unknown and sensitive to nilotinib.
    End point type
    Secondary
    End point timeframe
    Overall (beyond 120 months and up to LPLV)
    End point values
    		 Imatinib 400 mg QD (Treatment taken during core phase) Nilotinb 300 mg BID (Treatment taken during core phase) Nilotinib 400 mg BID (Treatment taken during core phase)
    Number of subjects analysed
    48
    26
    3
    Units: Percentage of participants
        number (not applicable)
    20.8
    11.5
    33.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Event (AE) timeframe: Adverse events were collected from first dose of study treatment until end of study treatment plus 28 days post treatment, up to maximum duration of 136.6 months in the Core phase and 121.9 months in the Extension phase.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Imatinib 400 mg QD
    Reporting group description
    		 Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated.

    Reporting group title
    Nilotinib 300 mg BID
    Reporting group description
    		 Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.

    Reporting group title
    Nilotinib 400 mg BID
    Reporting group description
    		 Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.

    Reporting group title
    All Patients
    Reporting group description
    		 All patients randomized in the study to all 3 arms and received at lease one dose of study drug.

    Serious adverse events
    		 Imatinib 400 mg QD Nilotinib 300 mg BID Nilotinib 400 mg BID All Patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    81 / 280 (28.93%)
    106 / 279 (37.99%)
    124 / 277 (44.77%)
    311 / 836 (37.20%)
         number of deaths (all causes)
    3
    10
    5
    18
         number of deaths resulting from adverse events
    0
    0
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign uterine neoplasm
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blast crisis in myelogenous leukaemia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chloroma
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    2 / 280 (0.71%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 10
    0 / 0
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal stromal tumour
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glioblastoma
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Histiocytosis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leiomyoma
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukaemic retinopathy
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liposarcoma
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to abdominal wall
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian epithelial cancer
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic neuroendocrine tumour
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papilloma
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraproteinaemia
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Plasmacytoma
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    3 / 280 (1.07%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    5 / 836 (0.60%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 2
    0 / 2
    2 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rosai-Dorfman syndrome
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superficial spreading melanoma stage III
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 280 (0.00%)
    2 / 279 (0.72%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Angiopathy
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arterial occlusive disease
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arterial stenosis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    2 / 277 (0.72%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    2 / 4
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    0 / 280 (0.00%)
    2 / 279 (0.72%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 280 (0.00%)
    3 / 279 (1.08%)
    5 / 277 (1.81%)
    8 / 836 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    8 / 8
    6 / 10
    14 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    8 / 8
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    4 / 277 (1.44%)
    5 / 836 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    8 / 10
    8 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Retained products of conception
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 280 (0.00%)
    2 / 279 (0.72%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    2 / 277 (0.72%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    2 / 4
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
    1 / 3
    Drug interaction
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
    2 / 2
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    3 / 277 (1.08%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 12
    2 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 280 (0.71%)
    6 / 279 (2.15%)
    5 / 277 (1.81%)
    13 / 836 (1.56%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 12
    2 / 12
    6 / 28
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular stent stenosis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adenomyosis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adnexa uteri pain
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    2 / 277 (0.72%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast swelling
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gynaecomastia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Menstruation irregular
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 280 (0.00%)
    2 / 279 (0.72%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst ruptured
         subjects affected / exposed
    2 / 280 (0.71%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 0
    0 / 0
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scrotal swelling
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 280 (0.00%)
    5 / 279 (1.79%)
    2 / 277 (0.72%)
    7 / 836 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 10
    4 / 4
    4 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mediastinal cyst
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal septum deviation
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Painful respiration
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal oedema
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 280 (0.71%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 2
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol abuse
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alcohol withdrawal syndrome
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Confusional state
         subjects affected / exposed
    0 / 280 (0.00%)
    2 / 279 (0.72%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    2 / 280 (0.71%)
    3 / 279 (1.08%)
    2 / 277 (0.72%)
    7 / 836 (0.84%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    0 / 4
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somatic symptom disorder
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Thrombosis in device
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amylase increased
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blast cell count increased
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase MB increased
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardioactive drug level increased
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    3 / 277 (1.08%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 6
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin I increased
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    2 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin T increased
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urine output decreased
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal injury
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac valve replacement complication
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest injury
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    2 / 280 (0.71%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    2 / 277 (0.72%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gun shot wound
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    2 / 280 (0.71%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 2
    0 / 0
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Heat illness
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incorrect dose administered
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kidney contusion
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament injury
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle rupture
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    3 / 280 (1.07%)
    0 / 279 (0.00%)
    2 / 277 (0.72%)
    5 / 836 (0.60%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 4
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skeletal injury
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord injury cervical
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic haemothorax
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular graft occlusion
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Trisomy 8
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 280 (0.00%)
    2 / 279 (0.72%)
    5 / 277 (1.81%)
    7 / 836 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    4 / 10
    8 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 280 (0.36%)
    3 / 279 (1.08%)
    10 / 277 (3.61%)
    14 / 836 (1.67%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 10
    8 / 30
    10 / 42
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    2 / 280 (0.71%)
    1 / 279 (0.36%)
    2 / 277 (0.72%)
    5 / 836 (0.60%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 2
    0 / 4
    2 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    4 / 277 (1.44%)
    5 / 836 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    4 / 12
    6 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brugada syndrome
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 280 (0.36%)
    2 / 279 (0.72%)
    0 / 277 (0.00%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 3
    Cardiac failure congestive
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 2
    0 / 2
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 280 (0.36%)
    3 / 279 (1.08%)
    10 / 277 (3.61%)
    14 / 836 (1.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
    14 / 22
    14 / 30
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    3 / 277 (1.08%)
    4 / 836 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    6 / 14
    6 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 280 (0.00%)
    2 / 279 (0.72%)
    1 / 277 (0.36%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    2 / 2
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 280 (0.71%)
    2 / 279 (0.72%)
    6 / 277 (2.17%)
    10 / 836 (1.20%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    6 / 12
    6 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    2 / 280 (0.71%)
    1 / 279 (0.36%)
    2 / 277 (0.72%)
    5 / 836 (0.60%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    2 / 4
    2 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    2 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis constrictive
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Basilar artery stenosis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid arteriosclerosis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    4 / 277 (1.44%)
    4 / 836 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    8 / 8
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebellar stroke
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral artery stenosis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    2 / 277 (0.72%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 280 (0.36%)
    2 / 279 (0.72%)
    0 / 277 (0.00%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 4
    0 / 0
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 280 (0.00%)
    2 / 279 (0.72%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 280 (0.00%)
    2 / 279 (0.72%)
    3 / 277 (1.08%)
    5 / 836 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
    2 / 6
    4 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Cerebrovascular disorder
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical radiculopathy
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Demyelination
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Essential tremor
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Focal dyscognitive seizures
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head discomfort
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 280 (0.36%)
    3 / 279 (1.08%)
    1 / 277 (0.36%)
    5 / 836 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 6
    0 / 2
    2 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 280 (0.00%)
    2 / 279 (0.72%)
    3 / 277 (1.08%)
    5 / 836 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    2 / 10
    2 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    2 / 277 (0.72%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 4
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Miller Fisher syndrome
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    2 / 277 (0.72%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parkinsonism
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 280 (0.71%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 280 (0.00%)
    2 / 279 (0.72%)
    4 / 277 (1.44%)
    6 / 836 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    6 / 8
    6 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertebral artery stenosis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 280 (1.07%)
    2 / 279 (0.72%)
    5 / 277 (1.81%)
    10 / 836 (1.20%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
    0 / 10
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia macrocytic
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    2 / 277 (0.72%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    4 / 4
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoplastic anaemia
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 280 (0.71%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    4 / 4
    2 / 2
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 280 (0.36%)
    3 / 279 (1.08%)
    4 / 277 (1.44%)
    8 / 836 (0.96%)
         occurrences causally related to treatment / all
    2 / 2
    6 / 6
    10 / 10
    18 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 280 (0.71%)
    4 / 279 (1.43%)
    4 / 277 (1.44%)
    10 / 836 (1.20%)
         occurrences causally related to treatment / all
    4 / 4
    8 / 8
    8 / 8
    20 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Otosclerosis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 280 (0.00%)
    2 / 279 (0.72%)
    2 / 277 (0.72%)
    4 / 836 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
    0 / 4
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Amaurosis fugax
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blindness unilateral
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 280 (0.00%)
    2 / 279 (0.72%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Macular fibrosis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Photophobia
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinopathy
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 280 (0.71%)
    5 / 279 (1.79%)
    6 / 277 (2.17%)
    13 / 836 (1.56%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 12
    4 / 12
    4 / 28
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    3 / 280 (1.07%)
    1 / 279 (0.36%)
    4 / 277 (1.44%)
    8 / 836 (0.96%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
    0 / 8
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal inflammation
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 280 (0.00%)
    2 / 279 (0.72%)
    1 / 277 (0.36%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
    0 / 2
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecal vomiting
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric mucosa erythema
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 279 (0.36%)
    2 / 277 (0.72%)
    4 / 836 (0.48%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    0 / 6
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    2 / 277 (0.72%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    3 / 277 (1.08%)
    4 / 836 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 6
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Intestinal perforation
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal stenosis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 280 (0.36%)
    2 / 279 (0.72%)
    2 / 277 (0.72%)
    5 / 836 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    4 / 4
    4 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic fistula
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 280 (0.00%)
    2 / 279 (0.72%)
    3 / 277 (1.08%)
    5 / 836 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 6
    4 / 6
    8 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    3 / 277 (1.08%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    6 / 6
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periodontal disease
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritoneal haematoma
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 280 (0.00%)
    3 / 279 (1.08%)
    1 / 277 (0.36%)
    4 / 836 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 18
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toothache
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 280 (0.71%)
    3 / 279 (1.08%)
    4 / 277 (1.44%)
    9 / 836 (1.08%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 6
    8 / 10
    10 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    2 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 280 (0.00%)
    2 / 279 (0.72%)
    1 / 277 (0.36%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    2 / 2
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    3 / 277 (1.08%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 6
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic steatosis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    2 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psoriasis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 280 (1.07%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    4 / 836 (0.48%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
    0 / 2
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anuria
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Azotaemia
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    2 / 277 (0.72%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder obstruction
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvi-ureteric obstruction
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 280 (0.71%)
    1 / 279 (0.36%)
    2 / 277 (0.72%)
    5 / 836 (0.60%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 4
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal infarct
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    2 / 277 (0.72%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 280 (0.71%)
    2 / 279 (0.72%)
    6 / 277 (2.17%)
    10 / 836 (1.20%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 6
    0 / 12
    2 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma muscle
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    4 / 280 (1.43%)
    6 / 279 (2.15%)
    0 / 277 (0.00%)
    10 / 836 (1.20%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 14
    0 / 0
    0 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myofascial pain syndrome
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 280 (0.36%)
    2 / 279 (0.72%)
    1 / 277 (0.36%)
    4 / 836 (0.48%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 4
    0 / 2
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal ligament ossification
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondyloarthropathy
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 280 (0.00%)
    2 / 279 (0.72%)
    1 / 277 (0.36%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal infection
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 280 (0.36%)
    2 / 279 (0.72%)
    0 / 277 (0.00%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 280 (0.71%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    4 / 280 (1.43%)
    1 / 279 (0.36%)
    2 / 277 (0.72%)
    7 / 836 (0.84%)
         occurrences causally related to treatment / all
    2 / 10
    0 / 2
    0 / 4
    2 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 280 (1.07%)
    0 / 279 (0.00%)
    2 / 277 (0.72%)
    5 / 836 (0.60%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 0
    0 / 4
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Measles
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral infection
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis chronic
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perihepatic abscess
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    2 / 280 (0.71%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    2 / 277 (0.72%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 280 (2.50%)
    6 / 279 (2.15%)
    6 / 277 (2.17%)
    19 / 836 (2.27%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 12
    0 / 16
    0 / 44
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 3
    Pneumonia legionella
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulpitis dental
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salpingitis
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    2 / 277 (0.72%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Septic shock
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 279 (0.36%)
    1 / 277 (0.36%)
    3 / 836 (0.36%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    2 / 2
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 280 (0.71%)
    1 / 279 (0.36%)
    2 / 277 (0.72%)
    5 / 836 (0.60%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 4
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 280 (0.00%)
    2 / 279 (0.72%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral rash
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 280 (0.71%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 279 (0.36%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    2 / 836 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 279 (0.00%)
    1 / 277 (0.36%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 279 (0.00%)
    0 / 277 (0.00%)
    1 / 836 (0.12%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
    4 / 4
         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
    		 Imatinib 400 mg QD Nilotinib 300 mg BID Nilotinib 400 mg BID All Patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    274 / 280 (97.86%)
    276 / 279 (98.92%)
    271 / 277 (97.83%)
    821 / 836 (98.21%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    17 / 280 (6.07%)
    44 / 279 (15.77%)
    55 / 277 (19.86%)
    116 / 836 (13.88%)
         occurrences all number
    34
    92
    122
    248
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    40 / 280 (14.29%)
    38 / 279 (13.62%)
    29 / 277 (10.47%)
    107 / 836 (12.80%)
         occurrences all number
    138
    98
    84
    320
    Chills
         subjects affected / exposed
    9 / 280 (3.21%)
    11 / 279 (3.94%)
    14 / 277 (5.05%)
    34 / 836 (4.07%)
         occurrences all number
    22
    24
    28
    74
    Face oedema
         subjects affected / exposed
    40 / 280 (14.29%)
    2 / 279 (0.72%)
    7 / 277 (2.53%)
    49 / 836 (5.86%)
         occurrences all number
    114
    4
    14
    132
    Fatigue
         subjects affected / exposed
    57 / 280 (20.36%)
    68 / 279 (24.37%)
    56 / 277 (20.22%)
    181 / 836 (21.65%)
         occurrences all number
    136
    182
    176
    494
    Influenza like illness
         subjects affected / exposed
    14 / 280 (5.00%)
    15 / 279 (5.38%)
    14 / 277 (5.05%)
    43 / 836 (5.14%)
         occurrences all number
    42
    62
    50
    154
    Non-cardiac chest pain
         subjects affected / exposed
    16 / 280 (5.71%)
    16 / 279 (5.73%)
    24 / 277 (8.66%)
    56 / 836 (6.70%)
         occurrences all number
    38
    40
    58
    136
    Oedema peripheral
         subjects affected / exposed
    63 / 280 (22.50%)
    32 / 279 (11.47%)
    43 / 277 (15.52%)
    138 / 836 (16.51%)
         occurrences all number
    188
    82
    130
    400
    Pyrexia
         subjects affected / exposed
    38 / 280 (13.57%)
    42 / 279 (15.05%)
    49 / 277 (17.69%)
    129 / 836 (15.43%)
         occurrences all number
    110
    138
    154
    402
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    41 / 280 (14.64%)
    55 / 279 (19.71%)
    61 / 277 (22.02%)
    157 / 836 (18.78%)
         occurrences all number
    136
    176
    180
    492
    Dyspnoea
         subjects affected / exposed
    21 / 280 (7.50%)
    33 / 279 (11.83%)
    30 / 277 (10.83%)
    84 / 836 (10.05%)
         occurrences all number
    52
    82
    80
    214
    Oropharyngeal pain
         subjects affected / exposed
    21 / 280 (7.50%)
    34 / 279 (12.19%)
    29 / 277 (10.47%)
    84 / 836 (10.05%)
         occurrences all number
    72
    90
    66
    228
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    26 / 280 (9.29%)
    23 / 279 (8.24%)
    22 / 277 (7.94%)
    71 / 836 (8.49%)
         occurrences all number
    60
    60
    52
    172
    Depression
         subjects affected / exposed
    20 / 280 (7.14%)
    18 / 279 (6.45%)
    18 / 277 (6.50%)
    56 / 836 (6.70%)
         occurrences all number
    50
    38
    42
    130
    Insomnia
         subjects affected / exposed
    26 / 280 (9.29%)
    38 / 279 (13.62%)
    37 / 277 (13.36%)
    101 / 836 (12.08%)
         occurrences all number
    60
    100
    92
    252
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    25 / 280 (8.93%)
    80 / 279 (28.67%)
    87 / 277 (31.41%)
    192 / 836 (22.97%)
         occurrences all number
    58
    292
    364
    714
    Amylase increased
         subjects affected / exposed
    10 / 280 (3.57%)
    22 / 279 (7.89%)
    23 / 277 (8.30%)
    55 / 836 (6.58%)
         occurrences all number
    34
    70
    86
    190
    Aspartate aminotransferase increased
         subjects affected / exposed
    20 / 280 (7.14%)
    48 / 279 (17.20%)
    44 / 277 (15.88%)
    112 / 836 (13.40%)
         occurrences all number
    50
    158
    148
    356
    Blood alkaline phosphatase increased
         subjects affected / exposed
    12 / 280 (4.29%)
    8 / 279 (2.87%)
    16 / 277 (5.78%)
    36 / 836 (4.31%)
         occurrences all number
    30
    22
    40
    92
    Blood bilirubin increased
         subjects affected / exposed
    4 / 280 (1.43%)
    36 / 279 (12.90%)
    41 / 277 (14.80%)
    81 / 836 (9.69%)
         occurrences all number
    10
    176
    202
    388
    Blood cholesterol increased
         subjects affected / exposed
    1 / 280 (0.36%)
    15 / 279 (5.38%)
    15 / 277 (5.42%)
    31 / 836 (3.71%)
         occurrences all number
    2
    34
    40
    76
    Blood creatinine increased
         subjects affected / exposed
    21 / 280 (7.50%)
    4 / 279 (1.43%)
    10 / 277 (3.61%)
    35 / 836 (4.19%)
         occurrences all number
    58
    14
    32
    104
    Blood phosphorus decreased
         subjects affected / exposed
    6 / 280 (2.14%)
    9 / 279 (3.23%)
    14 / 277 (5.05%)
    29 / 836 (3.47%)
         occurrences all number
    32
    28
    54
    114
    Haemoglobin decreased
         subjects affected / exposed
    14 / 280 (5.00%)
    7 / 279 (2.51%)
    15 / 277 (5.42%)
    36 / 836 (4.31%)
         occurrences all number
    46
    18
    42
    106
    Lipase increased
         subjects affected / exposed
    14 / 280 (5.00%)
    37 / 279 (13.26%)
    38 / 277 (13.72%)
    89 / 836 (10.65%)
         occurrences all number
    36
    114
    188
    338
    Weight decreased
         subjects affected / exposed
    8 / 280 (2.86%)
    15 / 279 (5.38%)
    13 / 277 (4.69%)
    36 / 836 (4.31%)
         occurrences all number
    16
    38
    28
    82
    Weight increased
         subjects affected / exposed
    27 / 280 (9.64%)
    24 / 279 (8.60%)
    22 / 277 (7.94%)
    73 / 836 (8.73%)
         occurrences all number
    66
    72
    62
    200
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    4 / 280 (1.43%)
    12 / 279 (4.30%)
    14 / 277 (5.05%)
    30 / 836 (3.59%)
         occurrences all number
    8
    38
    28
    74
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    11 / 280 (3.93%)
    18 / 279 (6.45%)
    19 / 277 (6.86%)
    48 / 836 (5.74%)
         occurrences all number
    38
    40
    48
    126
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    31 / 280 (11.07%)
    34 / 279 (12.19%)
    34 / 277 (12.27%)
    99 / 836 (11.84%)
         occurrences all number
    94
    94
    82
    270
    Headache
         subjects affected / exposed
    67 / 280 (23.93%)
    93 / 279 (33.33%)
    105 / 277 (37.91%)
    265 / 836 (31.70%)
         occurrences all number
    224
    392
    436
    1052
    Hypoaesthesia
         subjects affected / exposed
    7 / 280 (2.50%)
    15 / 279 (5.38%)
    10 / 277 (3.61%)
    32 / 836 (3.83%)
         occurrences all number
    18
    32
    20
    70
    Paraesthesia
         subjects affected / exposed
    12 / 280 (4.29%)
    14 / 279 (5.02%)
    11 / 277 (3.97%)
    37 / 836 (4.43%)
         occurrences all number
    32
    34
    28
    94
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    67 / 280 (23.93%)
    38 / 279 (13.62%)
    45 / 277 (16.25%)
    150 / 836 (17.94%)
         occurrences all number
    188
    150
    132
    470
    Leukopenia
         subjects affected / exposed
    47 / 280 (16.79%)
    23 / 279 (8.24%)
    22 / 277 (7.94%)
    92 / 836 (11.00%)
         occurrences all number
    198
    62
    66
    326
    Neutropenia
         subjects affected / exposed
    58 / 280 (20.71%)
    44 / 279 (15.77%)
    30 / 277 (10.83%)
    132 / 836 (15.79%)
         occurrences all number
    258
    134
    92
    484
    Thrombocytopenia
         subjects affected / exposed
    53 / 280 (18.93%)
    54 / 279 (19.35%)
    57 / 277 (20.58%)
    164 / 836 (19.62%)
         occurrences all number
    174
    162
    180
    516
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    11 / 280 (3.93%)
    13 / 279 (4.66%)
    14 / 277 (5.05%)
    38 / 836 (4.55%)
         occurrences all number
    34
    40
    44
    118
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    25 / 280 (8.93%)
    3 / 279 (1.08%)
    5 / 277 (1.81%)
    33 / 836 (3.95%)
         occurrences all number
    80
    8
    10
    98
    Dry eye
         subjects affected / exposed
    20 / 280 (7.14%)
    20 / 279 (7.17%)
    21 / 277 (7.58%)
    61 / 836 (7.30%)
         occurrences all number
    44
    44
    42
    130
    Eyelid oedema
         subjects affected / exposed
    43 / 280 (15.36%)
    3 / 279 (1.08%)
    5 / 277 (1.81%)
    51 / 836 (6.10%)
         occurrences all number
    114
    6
    12
    132
    Periorbital oedema
         subjects affected / exposed
    44 / 280 (15.71%)
    1 / 279 (0.36%)
    4 / 277 (1.44%)
    49 / 836 (5.86%)
         occurrences all number
    106
    2
    8
    116
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    13 / 280 (4.64%)
    12 / 279 (4.30%)
    15 / 277 (5.42%)
    40 / 836 (4.78%)
         occurrences all number
    34
    24
    36
    94
    Abdominal pain
         subjects affected / exposed
    37 / 280 (13.21%)
    43 / 279 (15.41%)
    48 / 277 (17.33%)
    128 / 836 (15.31%)
         occurrences all number
    92
    128
    116
    336
    Abdominal pain upper
         subjects affected / exposed
    41 / 280 (14.64%)
    51 / 279 (18.28%)
    61 / 277 (22.02%)
    153 / 836 (18.30%)
         occurrences all number
    130
    170
    178
    478
    Constipation
         subjects affected / exposed
    26 / 280 (9.29%)
    63 / 279 (22.58%)
    52 / 277 (18.77%)
    141 / 836 (16.87%)
         occurrences all number
    56
    168
    160
    384
    Diarrhoea
         subjects affected / exposed
    133 / 280 (47.50%)
    58 / 279 (20.79%)
    67 / 277 (24.19%)
    258 / 836 (30.86%)
         occurrences all number
    552
    202
    216
    970
    Dyspepsia
         subjects affected / exposed
    37 / 280 (13.21%)
    32 / 279 (11.47%)
    36 / 277 (13.00%)
    105 / 836 (12.56%)
         occurrences all number
    98
    90
    92
    280
    Flatulence
         subjects affected / exposed
    12 / 280 (4.29%)
    12 / 279 (4.30%)
    15 / 277 (5.42%)
    39 / 836 (4.67%)
         occurrences all number
    24
    30
    34
    88
    Gastritis
         subjects affected / exposed
    11 / 280 (3.93%)
    9 / 279 (3.23%)
    18 / 277 (6.50%)
    38 / 836 (4.55%)
         occurrences all number
    26
    20
    42
    88
    Gastrooesophageal reflux disease
         subjects affected / exposed
    20 / 280 (7.14%)
    15 / 279 (5.38%)
    17 / 277 (6.14%)
    52 / 836 (6.22%)
         occurrences all number
    50
    36
    46
    132
    Haemorrhoids
         subjects affected / exposed
    18 / 280 (6.43%)
    9 / 279 (3.23%)
    19 / 277 (6.86%)
    46 / 836 (5.50%)
         occurrences all number
    48
    20
    40
    108
    Nausea
         subjects affected / exposed
    118 / 280 (42.14%)
    61 / 279 (21.86%)
    88 / 277 (31.77%)
    267 / 836 (31.94%)
         occurrences all number
    436
    290
    264
    990
    Toothache
         subjects affected / exposed
    18 / 280 (6.43%)
    13 / 279 (4.66%)
    11 / 277 (3.97%)
    42 / 836 (5.02%)
         occurrences all number
    36
    36
    26
    98
    Vomiting
         subjects affected / exposed
    79 / 280 (28.21%)
    45 / 279 (16.13%)
    60 / 277 (21.66%)
    184 / 836 (22.01%)
         occurrences all number
    344
    210
    204
    758
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    5 / 280 (1.79%)
    53 / 279 (19.00%)
    53 / 277 (19.13%)
    111 / 836 (13.28%)
         occurrences all number
    20
    218
    218
    456
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    21 / 280 (7.50%)
    41 / 279 (14.70%)
    58 / 277 (20.94%)
    120 / 836 (14.35%)
         occurrences all number
    42
    88
    140
    270
    Dry skin
         subjects affected / exposed
    17 / 280 (6.07%)
    34 / 279 (12.19%)
    40 / 277 (14.44%)
    91 / 836 (10.89%)
         occurrences all number
    36
    92
    102
    230
    Eczema
         subjects affected / exposed
    10 / 280 (3.57%)
    16 / 279 (5.73%)
    11 / 277 (3.97%)
    37 / 836 (4.43%)
         occurrences all number
    28
    42
    34
    104
    Erythema
         subjects affected / exposed
    10 / 280 (3.57%)
    15 / 279 (5.38%)
    18 / 277 (6.50%)
    43 / 836 (5.14%)
         occurrences all number
    20
    32
    44
    96
    Hyperhidrosis
         subjects affected / exposed
    4 / 280 (1.43%)
    13 / 279 (4.66%)
    16 / 277 (5.78%)
    33 / 836 (3.95%)
         occurrences all number
    10
    36
    36
    82
    Night sweats
         subjects affected / exposed
    8 / 280 (2.86%)
    10 / 279 (3.58%)
    18 / 277 (6.50%)
    36 / 836 (4.31%)
         occurrences all number
    20
    28
    44
    92
    Pruritus
         subjects affected / exposed
    20 / 280 (7.14%)
    61 / 279 (21.86%)
    56 / 277 (20.22%)
    137 / 836 (16.39%)
         occurrences all number
    46
    178
    162
    386
    Rash
         subjects affected / exposed
    57 / 280 (20.36%)
    110 / 279 (39.43%)
    124 / 277 (44.77%)
    291 / 836 (34.81%)
         occurrences all number
    186
    378
    480
    1044
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    60 / 280 (21.43%)
    72 / 279 (25.81%)
    65 / 277 (23.47%)
    197 / 836 (23.56%)
         occurrences all number
    158
    220
    180
    558
    Back pain
         subjects affected / exposed
    54 / 280 (19.29%)
    64 / 279 (22.94%)
    65 / 277 (23.47%)
    183 / 836 (21.89%)
         occurrences all number
    178
    194
    178
    550
    Bone pain
         subjects affected / exposed
    16 / 280 (5.71%)
    21 / 279 (7.53%)
    29 / 277 (10.47%)
    66 / 836 (7.89%)
         occurrences all number
    36
    60
    60
    156
    Muscle spasms
         subjects affected / exposed
    97 / 280 (34.64%)
    38 / 279 (13.62%)
    37 / 277 (13.36%)
    172 / 836 (20.57%)
         occurrences all number
    370
    104
    118
    592
    Musculoskeletal pain
         subjects affected / exposed
    24 / 280 (8.57%)
    27 / 279 (9.68%)
    38 / 277 (13.72%)
    89 / 836 (10.65%)
         occurrences all number
    66
    78
    96
    240
    Myalgia
         subjects affected / exposed
    56 / 280 (20.00%)
    57 / 279 (20.43%)
    55 / 277 (19.86%)
    168 / 836 (20.10%)
         occurrences all number
    152
    146
    166
    464
    Neck pain
         subjects affected / exposed
    8 / 280 (2.86%)
    19 / 279 (6.81%)
    11 / 277 (3.97%)
    38 / 836 (4.55%)
         occurrences all number
    18
    44
    24
    86
    Pain in extremity
         subjects affected / exposed
    47 / 280 (16.79%)
    47 / 279 (16.85%)
    52 / 277 (18.77%)
    146 / 836 (17.46%)
         occurrences all number
    122
    154
    162
    438
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    27 / 280 (9.64%)
    27 / 279 (9.68%)
    19 / 277 (6.86%)
    73 / 836 (8.73%)
         occurrences all number
    82
    94
    56
    232
    Conjunctivitis
         subjects affected / exposed
    20 / 280 (7.14%)
    21 / 279 (7.53%)
    18 / 277 (6.50%)
    59 / 836 (7.06%)
         occurrences all number
    50
    48
    42
    140
    Folliculitis
         subjects affected / exposed
    3 / 280 (1.07%)
    15 / 279 (5.38%)
    17 / 277 (6.14%)
    35 / 836 (4.19%)
         occurrences all number
    6
    34
    60
    100
    Gastroenteritis
         subjects affected / exposed
    30 / 280 (10.71%)
    24 / 279 (8.60%)
    21 / 277 (7.58%)
    75 / 836 (8.97%)
         occurrences all number
    76
    56
    56
    188
    Herpes zoster
         subjects affected / exposed
    13 / 280 (4.64%)
    14 / 279 (5.02%)
    8 / 277 (2.89%)
    35 / 836 (4.19%)
         occurrences all number
    28
    28
    16
    72
    Influenza
         subjects affected / exposed
    36 / 280 (12.86%)
    45 / 279 (16.13%)
    51 / 277 (18.41%)
    132 / 836 (15.79%)
         occurrences all number
    132
    140
    154
    426
    Nasopharyngitis
         subjects affected / exposed
    65 / 280 (23.21%)
    81 / 279 (29.03%)
    67 / 277 (24.19%)
    213 / 836 (25.48%)
         occurrences all number
    298
    536
    396
    1230
    Pharyngitis
         subjects affected / exposed
    15 / 280 (5.36%)
    16 / 279 (5.73%)
    17 / 277 (6.14%)
    48 / 836 (5.74%)
         occurrences all number
    46
    44
    42
    132
    Sinusitis
         subjects affected / exposed
    20 / 280 (7.14%)
    23 / 279 (8.24%)
    29 / 277 (10.47%)
    72 / 836 (8.61%)
         occurrences all number
    72
    72
    104
    248
    Upper respiratory tract infection
         subjects affected / exposed
    44 / 280 (15.71%)
    56 / 279 (20.07%)
    67 / 277 (24.19%)
    167 / 836 (19.98%)
         occurrences all number
    152
    226
    248
    626
    Urinary tract infection
         subjects affected / exposed
    12 / 280 (4.29%)
    16 / 279 (5.73%)
    27 / 277 (9.75%)
    55 / 836 (6.58%)
         occurrences all number
    54
    46
    102
    202
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    13 / 280 (4.64%)
    28 / 279 (10.04%)
    22 / 277 (7.94%)
    63 / 836 (7.54%)
         occurrences all number
    32
    76
    54
    162
    Hypercholesterolaemia
         subjects affected / exposed
    3 / 280 (1.07%)
    33 / 279 (11.83%)
    39 / 277 (14.08%)
    75 / 836 (8.97%)
         occurrences all number
    8
    78
    98
    184
    Hyperglycaemia
         subjects affected / exposed
    8 / 280 (2.86%)
    28 / 279 (10.04%)
    28 / 277 (10.11%)
    64 / 836 (7.66%)
         occurrences all number
    24
    92
    122
    238
    Hyperlipidaemia
         subjects affected / exposed
    1 / 280 (0.36%)
    19 / 279 (6.81%)
    15 / 277 (5.42%)
    35 / 836 (4.19%)
         occurrences all number
    2
    46
    40
    88
    Hyperuricaemia
         subjects affected / exposed
    5 / 280 (1.79%)
    12 / 279 (4.30%)
    15 / 277 (5.42%)
    32 / 836 (3.83%)
         occurrences all number
    12
    32
    38
    82
    Hypokalaemia
         subjects affected / exposed
    15 / 280 (5.36%)
    19 / 279 (6.81%)
    11 / 277 (3.97%)
    45 / 836 (5.38%)
         occurrences all number
    40
    50
    40
    130
    Hypophosphataemia
         subjects affected / exposed
    50 / 280 (17.86%)
    45 / 279 (16.13%)
    55 / 277 (19.86%)
    150 / 836 (17.94%)
         occurrences all number
    220
    166
    202
    588

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Mar 2007
    Amendment 1 (released 20 weeks before first patient first visit on 31-Jul-2007) was a local, country-specific amendment for Japan. The modifications to the protocol were made in order to allow patients in Japan to participate in this global study. Specifically, this study clarified the tablet strength for imatinib and stated that PK parameters in Japanese patients would be investigated more thoroughly. This amendment also indicated that Japan would not be participating in the pharmacogenetic, pharmacogenomic, and biomarker portions of the study. Additionally, changes were made to align study procedures in data review/management and safety monitoring/reporting with Japanese standards of practice.
    09 Jun 2007
    Amendment 2 (released seven weeks before first patient first visit on 31-Jul-2007) was a global amendment to reflect newly available data in support of an alternate nilotinib lower dose and regimen (300 mg bid replaced 600 mg qd). This amendment re moved (1) the dose escalation in the nilotinib 300 mg bid arm and (2) the crossover regimens for all arms, while establishing an extension protocol (Protocol post-text supplement 4) to allow for continuation of therapy after patients had demonstrated lack of response to their assigned treatment regimen. Clarifications of the dose escalation in the imatinib arm and the use and definition of MMR in the clinical conduct of the study were also made. Statistically, the protocol was amended to include the following: "durable" MMR to be measured at 24 months, patients with missing data were to be considered as non-responders, confirmed responses for MMR, and the presentation of ≥ 4.5 log reduction in BCR-ABL transcripts.
    29 Nov 2007
    Amendment 3 (released on 29-Nov-2007 after 69 patients were enrolled into the study) was a global amendment. The major changes in this amendment included: -The dosage form of nilotinib (50 mg capsules) was replaced with 150 mg capsules in the nilotinib 300 mg treatment arm; - Clarifications were made to the dose reduction guidelines for study drug related non-hematological toxicities; - The restriction of using Erythropoiesis Stimulating Agents was removed from the protocol, the use of leukapheresis and hydroxyurea and/or anagrelide was to be permitted during the first month of treatment; - The frequency of the patients’ reported outcome assessment was reduced; - The entrance criteria to the extension study were clarified; - The PCR committee was removed from the protocol. Additionally, the ECHO and ECG review processes were clarified as follows: (1). ECHOs were to be reviewed both locally and centrally. Study eligibility and all clinical decisions (including dose-adjustments) were to be based on local ECHO reads. Centrally read ECHO results were to be used for the data analyses; (2) the enrollment of patients had to be based on centrally assessed QTcF time. If one of the three serial ECGs prior to dosing on Day 1 of Cycle 1 showed a QTcF >450 ms by automated reading, an immediate manual central reading had to be requested by calling CRO. The patient was not to be dosed if the average of the manually read ECGs confirmed a QTcF >450 ms.
    21 Oct 2008
    Amendment 4 (released on 21-Oct-2008, following completion of enrolment on 30-Sep-2008, total 846 patients were enrolled into the study) was a global amendment. Some of th major changes in this amendment included: - Cardiac troponin was assessed whenever clinically indicated; - “No MMR at 18 months” and “loss of MMR at any time” were moved from the list of definitions of “treatment failures” to the list of definition of “suboptimal responses”; - “Evidence of clonal evolution” was deleted from the list of AP defining criteria; - The dose reduction guidelines for hypophosphatemia, pancreatitis and QTc prolongation were clarified; - For patients who achieved undetectable BCR-ABL by RQ-PCR due to variability in sample quality and blood cell counts, a repeat assay using more than 10 mL of blood may have been needed to determine whether a ≤ 0.01% and ≤ 0.0032% BCR-ABL/ABL% level was reached. Therefore, collection of 20 mL of blood from these patients for PCR analysis was permitted; - The measurement frequency of glucose, insulin, C-peptide, glycosylated hemoglobin A1c (HbA1c) and lipid panel was modified; - Time to event CRF page was removed from CRF binder since the information on this page can be derived from data collected; - The time points of mandatory manual differential counts were clarified; - The time points of evaluation of cytogenetic response were clarified, bone marrow aspirates and/or biopsies were to be performed at the end of every six cycles until Month 24; - Full PK blood samples could be drawn any day after Day 8 at protocol-defined time points; - The definition of a molecular or cytogenetic response duration, and the definition of loss of a molecular or cytogenetic response were clarified;
    08 Jun 2009
    Amendment 5 (released on 08-Jun-2009) was a local, country-specific amendment for Sweden. This amendment includes all changes introduced with global Amendment 4, except the “evidence of clonal evolution” which remains in the list of AP defining criteria upon request from the Swedish medical products agency. The amendments described above (all introduced before primary analysis database lock on 08-Oct-2009) are not considered to affect the interpretation of study results, as most changes were made to enhance safety monitoring. No changes were made to study end points; however, a sensitivity analysis was added to the planned analyses for progression to AP/BC including clonal evolution as a progression criterion
    30 Jul 2010
    Amendment 6 (released on 30-Jul-2010) was a global amendment. The purpose of this amendment was to: remove the comparison of MMR rates at 12 months between studies CAMN107A2303 and CSTI571K2301 from exploratory objectives, modify the decision algorithm for patients insufficiently responding to their assigned core study treatments, amend the schedule of cytogenetic bone marrow assessments, allow patients who have been dose escalated from imatinib 400 mg QD and did not tolerate 400 mg BID imatinib or reduced dose levels of 600 mg QD imatinib, further dose de-escalation to highest tolerable dose. Patients who do not tolerate 300 mg QD must discontinue treatment, removal of the prohibition on the concurrent use of nilotinib with warfarin or other coumarin derivatives, extend biomarker test sample collection beyond Cycle 12, add ECG with central reading after month 12, remove requirements of collecting pregnancy outcomes from female partners of male patients, integrate into the protocol clarifications from the RAP , implement additional changes in the extension protocol.
    11 Jul 2011
    Amendment 7 (released on 11-July-2011) was a global amendment. The purpose of this amendment was to: modify decision algorithm, combine safety analyses with the annual analyses of the study after the Month 24 analysis time point and to disband DMC if there are no significant new safety findings in the Month 36 analysis, remove PK sample collection at the end of core study visit or early discontinuation visit, to remove time-off data collection at cycle 36 and 48, remove treatment options in the event of early termination of nilotinib 300mg BID arm.
    31 Jan 2012
    Amendment 8 (released on 31-Jan-2012) was a global amendment and major changes included: - the duration of the study was extended to 10 calendar years from 15-Oct-2008: date when the last patient randomized to the core study received the first dose of study drug. Therefore, the end of study date or Last Patient Last Visit is projected to be 15-Oct-2018. All end-of-study evaluations for ongoing patients must be completed by this date. This includes survival information follow-up on those patients who have discontinued for reasons other than death. By the end of the study, all patients would have received at least 10 calendar years of treatment or discontinued from the study; - remove the option for patients treated with nilotinib in the core study and experiencing unsatisfactory therapeutic effect to enter the extension study to receive imatinib - the current visit frequency after End of Cycle 60 was revised from every 3 months to every six months for patients in MMR; - Bone marrow biopsy for cytogenetics was no longer required to evaluate response; - Vital sign parameters were reduced to assessments of blood pressure and body weight at each visit; cardiac safety monitoring and laboratory safety assessments were modified, collection of the SF-36 and Fact-Leu questionnaires was extended.
    09 Aug 2013
    Amendment 9 (released on 09-Aug-2013) was a global amendment. The purpose of this amendment was to 1) provide additional guidance for the management of ischemic vascular or ischemic cardiovascular events, 2) outlined acceptable contraception methods for female patients of childbearing potential and revised pregnancy testing and reporting processes and 3) clarified the use of commercial drug supply of imatinib and nilotinib.
    03 Nov 2014
    Amendment 10 (released on 03-Nov-2014) was a global amendment. The purpose of this amendment was to: - modify treatment guidelines for patients on the nilotinib 400 mg BID treatment arm in the context of ischemic cardio/vascular events - eliminate the Ischemic Vascular or Ischemic Cardiovascular AE Fax alert form - incorporate nilotinib program-wide language regarding monitoring and treatment of glucose and cholesterol as well as dose reduction guidelines - emphasize the importance of monitoring glucose levels in patients and - provide a harmonization on dose reductions guidelines across Novartis-sponsored Tasigna study protocols
    18 Apr 2016
    Amendment 11 (released on 18-Apr-2016) was a global amendment. The purpose of this amendment was to include hepatitis B virus testing as one of the study procedures, to identify study patients who may be at risk of hepatitis B virus reactivation. Reactivation of hepatitis B virus infection could occur in patients who were chronic carriers of this virus and were receiving a drug of the BCR-ABL TKI class such as nilotinib/imatinib. Some cases involving BCR-ABL TKI resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome.
    30 Mar 2017
    Amendment 12 (released on 30-Mar-2017) was a global amendment. The main purpose for the amendment was: - To change the source of the Reference Safety Information for Glivec® (imatinib), Novartis has taken the decision to discontinue the use of the Investigator´s Brochure for Glivec® (imatinib), since Glivec has been on the market for more than 15 years (first registered in 2001) and has a well-established efficacy/safety profile. The Glivec IB version 19 (dated 21-Jun-2016) is the final IB for the compound. As of the dispatch of the Glivec DSUR 006 in July 2017, the latest approved national/regional product information (e.g. in the EU Summary of Product Characteristics) will serve as the reference safety information (RSI) for the compound. In addition, there is no further global clinical development planned for the compound. - After Cycle 60, all ECG assessments were to be performed and assessed locally. The reference to the central evaluation via vendor (eRT) has been removed from the toxicity guidelines for study drug-related non-hematologic toxicity.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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

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