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    Clinical Trial Results:
    A prospective, randomized, open-label, two-arm Phase III study to evaluate treatment-free remission (TFR) rate in patients with Philadelphia chromosome-positive CML after two different durations of consolidation treatment with nilotinib 300 mg BID

    Summary
    EudraCT number
    		 2012-005124-15
    Trial protocol
    		 AT   SK   SE   HU   IT   DE   NO   PT   FI   ES   IE   CZ   BG   BE   GR   DK   SI   HR  
    Global end of trial date
    08 Jul 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Jul 2021
    First version publication date
    09 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CAMN107AIC05
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01743989
    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
    08 Jul 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to assess the optimal duration of consolidation treatment with nilotinib 300 mg twice daily (BID) in order that patients remained in treatment free remission (TFR) (≥MR4.0) without molecular relapse 12 months after entering the TFR phase.
    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
    15 Apr 2013
    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
    Austria: 15
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Bulgaria: 17
    Country: Number of subjects enrolled
    Czechia: 9
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    France: 54
    Country: Number of subjects enrolled
    Germany: 65
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Greece: 14
    Country: Number of subjects enrolled
    Hungary: 17
    Country: Number of subjects enrolled
    Italy: 182
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Poland: 54
    Country: Number of subjects enrolled
    Portugal: 27
    Country: Number of subjects enrolled
    Romania: 19
    Country: Number of subjects enrolled
    Serbia: 27
    Country: Number of subjects enrolled
    Slovakia: 6
    Country: Number of subjects enrolled
    Slovenia: 2
    Country: Number of subjects enrolled
    Spain: 85
    Country: Number of subjects enrolled
    Sweden: 4
    Worldwide total number of subjects
    620
    EEA total number of subjects
    585
    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)
    512
    From 65 to 84 years
    108
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 For one participant randomized to Nilotinib 36-month treatment arm, the informed consent was not obtained prior to any study specific procedure. This participant discontinued the study before entering the TFR phase.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nilotinib 24-month treatment
    Arm description
    		 Participants were treated with nilotinib 300mg BID for 24 months and, thereafter, entered the 36-month TFR phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nilotinib
    Investigational medicinal product code
    AMN107
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Nilotinib daily oral dose of 300 mg BID, supplied as 150 mg hard gelatin capsules.

    Arm title
    		 Nilotinib 36-month treatment
    Arm description
    		 Participants were treated with nilotinib 300mg BID for 36 months and, thereafter, entered the 24-month TFR phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nilotinib
    Investigational medicinal product code
    AMN107
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Nilotinib daily oral dose of 300 mg BID, supplied as 150 mg hard gelatin capsules.

    Arm title
    		 Not randomized
    Arm description
    		 Participants were treated with nilotinib 300mg BID for 24 months, but did not achieve a sustained molecular response after 24 months of treatment and were not randomized.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nilotinib
    Investigational medicinal product code
    AMN107
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Nilotinib daily oral dose of 300 mg BID, supplied as 150 mg hard gelatin capsules.

    Number of subjects in period 1
    		Nilotinib 24-month treatment Nilotinib 36-month treatment Not randomized
    Started
    120
    119
    381
    Participants who signed informed consent
    120
    118
    381
    Completed
    119
    104
    0
    Not completed
    1
    15
    381
         Adverse event, serious fatal
    -
    1
    3
         New cancer (CML) therapy
    -
    1
    -
         Abnormal laboratory value(s)
    -
    -
    3
         Physician decision
    -
    -
    3
         Unstable MR4.0
    -
    6
    263
         Patient non-compliance to treatment
    -
    -
    3
         Not randomized by mistake
    -
    -
    1
         Administrative problems
    -
    -
    1
         Abnormal test procedure result(s)
    -
    -
    1
         Included by mistake
    -
    -
    1
         Consent withdrawn by subject
    1
    3
    28
         Adverse event, non-fatal
    -
    4
    67
         Protocol deviation
    -
    -
    3
         Pregnancy
    -
    -
    2
         Lost to follow-up
    -
    -
    2
    Period 2
    Period 2 title
    TFR phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nilotinib 24-month treatment
    Arm description
    		 Participants were treated with nilotinib 300mg BID for 24 months and, thereafter, entered the 36-month TFR phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nilotinib
    Investigational medicinal product code
    AMN107
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Nilotinib daily oral dose of 300 mg BID, supplied as 150 mg hard gelatin capsules.

    Arm title
    		 Nilotinib 36-month treatment
    Arm description
    		 Participants were treated with nilotinib 300mg BID for 36 months and, thereafter, entered the 24-month TFR phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nilotinib
    Investigational medicinal product code
    AMN107
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Nilotinib daily oral dose of 300 mg BID, supplied as 150 mg hard gelatin capsules.

    Number of subjects in period 2
    		Nilotinib 24-month treatment Nilotinib 36-month treatment
    Started
    119
    104
    Participants who were re-treated
    74
    55
    Completed
    37
    36
    Not completed
    82
    68
         Consent withdrawn by subject
    -
    2
         Physician decision
    -
    1
         Logistical problems
    -
    2
         Adverse event, non-fatal
    -
    1
         Relapse (Loss of MMR/Confirmed loss of MR4.0)
    82
    59
         Protocol deviation
    -
    1
         Lost to follow-up
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nilotinib 24-month treatment
    Reporting group description
    		 Participants were treated with nilotinib 300mg BID for 24 months and, thereafter, entered the 36-month TFR phase

    Reporting group title
    Nilotinib 36-month treatment
    Reporting group description
    		 Participants were treated with nilotinib 300mg BID for 36 months and, thereafter, entered the 24-month TFR phase

    Reporting group title
    Not randomized
    Reporting group description
    		 Participants were treated with nilotinib 300mg BID for 24 months, but did not achieve a sustained molecular response after 24 months of treatment and were not randomized.

    Reporting group values
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment Not randomized Total
    Number of subjects
    		 120 119 381 620
    Age Categorical
    Units: Participants
        <=18 years
    		 0 0 0 0
        Between 18 and 65 years
    		 106 98 308 512
        >=65 years
    		 14 21 73 108
    Sex: Female, Male
    Units: Participants
        Female
    		 48 49 129 226
        Male
    		 72 70 252 394
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 114 112 355 581
        Black
    		 0 1 4 5
        Asian
    		 0 0 2 2
        Native American
    		 0 1 1 2
        North African descent
    		 1 0 1 2
        Unknown
    		 0 1 5 6
        Other
    		 5 4 13 22

    End points

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    End points reporting groups
    Reporting group title
    Nilotinib 24-month treatment
    Reporting group description
    		 Participants were treated with nilotinib 300mg BID for 24 months and, thereafter, entered the 36-month TFR phase

    Reporting group title
    Nilotinib 36-month treatment
    Reporting group description
    		 Participants were treated with nilotinib 300mg BID for 36 months and, thereafter, entered the 24-month TFR phase

    Reporting group title
    Not randomized
    Reporting group description
    		 Participants were treated with nilotinib 300mg BID for 24 months, but did not achieve a sustained molecular response after 24 months of treatment and were not randomized.
    Reporting group title
    Nilotinib 24-month treatment
    Reporting group description
    		 Participants were treated with nilotinib 300mg BID for 24 months and, thereafter, entered the 36-month TFR phase

    Reporting group title
    Nilotinib 36-month treatment
    Reporting group description
    		 Participants were treated with nilotinib 300mg BID for 36 months and, thereafter, entered the 24-month TFR phase

    Primary: Percentage of participants who remained in treatment free remission (TFR) without molecular relapse 12 months after entering the TFR phase

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    End point title
    		 Percentage of participants who remained in treatment free remission (TFR) without molecular relapse 12 months after entering the TFR phase
    End point description
    Number of participants who remained in TFR (≥molecular response (MR) 4.0) without molecular relapse 12 months after entering the TFR phase (without re-starting nilotinib therapy) divided by the number of participants who entered the TFR phase and multiplied by 100. Molecular relapse during TFR is defined as the loss of major molecular response (MMR), or the confirmed loss of MR4.0 (defined by 3 consecutive tests less than MR4.0 assessed at 3 consecutive visits during TFR phase). Participants dropping out early from the study during the TFR phase were considered as unsuccessful TFR. Confidence intervals were calculated based on the Exact Clopper-Pearson method. MMR is defined as≥3.0 log reduction in BCR-ABL transcripts compared to the standardized baseline or ≤0.1% BCR-ABL. MR4.0 is defined as either detectable disease≤0.01% BCR-ABL or undetectable disease in cDNA with≥10,000 ABL transcripts
    End point type
    Primary
    End point timeframe
    12 months after entering the TFR phase, which is after 36 months from study treatment start for Nilotinib 24-month treatment arm and after 48 months from study treatment start for Nilotinib 36-month treatment arm
    End point values
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment
    Number of subjects analysed
    119
    104
    Units: Percentage of participants
        number (confidence interval 95%)
    31.9 (23.7 to 41.1)
    37.5 (28.2 to 47.5)
    Statistical analysis title
    		 Nilotinib 24-month vs Nilotinib 36-month treatment
    Comparison groups
    Nilotinib 24-month treatment v Nilotinib 36-month treatment
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.383
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Cumulative incidence of MMR during the pre-randomization induction/consolidation phase among participants without that response at study entry

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    End point title
    		 Cumulative incidence of MMR during the pre-randomization induction/consolidation phase among participants without that response at study entry
    End point description
    Number of participants who were in MMR during pre-randomization induction/consolidation phase divided by the number of participants without that response at baseline and multiplied by 100. Confidence intervals were calculated based on the Exact Clopper-Pearson method. MMR is defined as ≥3.0 log reduction in BCR-ABL transcripts compared to the standardized baseline or ≤0.1% BCR-ABL.
    End point type
    Secondary
    End point timeframe
    From baseline up to 24 months after study treatment start
    End point values
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment Not randomized
    Number of subjects analysed
    23
    16
    98
    Units: Percentage of participants
    number (confidence interval 95%)
        Up to 3 months after study treatment start
    69.6 (47.1 to 86.8)
    37.5 (15.2 to 64.6)
    29.6 (20.8 to 39.7)
        Up to 6 months after study treatment start
    100 (85.2 to 100.0)
    100.0 (79.4 to 100.0)
    64.3 (54.0 to 73.7)
        Up to 9 months after study treatment start
    100 (85.2 to 100.0)
    100.0 (79.4 to 100.0)
    71.4 (61.4 to 80.1)
        Up to 12 months after study treatment start
    100 (85.2 to 100.0)
    100.0 (79.4 to 100.0)
    77.6 (68.0 to 85.4)
        Up to 15 months after study treatment start
    100 (85.2 to 100.0)
    100.0 (79.4 to 100.0)
    80.6 (71.4 to 87.9)
        Up to 18 months after study treatment start
    100 (85.2 to 100.0)
    100.0 (79.4 to 100.0)
    82.7 (73.7 to 89.6)
        Up to 21 months after study treatment start
    100 (85.2 to 100.0)
    100.0 (79.4 to 100.0)
    85.7 (77.2 to 92.0)
        Up to 24 months after study treatment start
    100 (85.2 to 100.0)
    100.0 (79.4 to 100.0)
    86.7 (78.4 to 92.7)
    No statistical analyses for this end point

    Secondary: Cumulative incidence of MMR during the post-randomization consolidation phase among participants without that response at study entry

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    End point title
    		 Cumulative incidence of MMR during the post-randomization consolidation phase among participants without that response at study entry [1]
    End point description
    Number of participants who were in MMR during post-randomization consolidation phase divided by the number of participants without that response at baseline and multiplied by 100. Post-randomization consolidation phase corresponded to the 12-month additional treatment (after randomization) for Nilotinib 36-month treatment arm. Confidence intervals were calculated based on the Exact Clopper-Pearson method. MMR is defined as ≥3.0 log reduction in BCR-ABL transcripts compared to the standardized baseline or ≤0.1% BCR-ABL.
    End point type
    Secondary
    End point timeframe
    From randomization (month 24 after study treatment start) up to 36 months after study treatment start
    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: Only participants randomized to Nilotinib 36-month treatment arm entered the post-randomization consolidation phase.
    End point values
    		 Nilotinib 36-month treatment
    Number of subjects analysed
    16
    Units: Percentage of participants
    number (confidence interval 95%)
        Up to 27 months after study treatment start
    100.0 (79.4 to 100.0)
        Up to 30 months after study treatment start
    100.0 (79.4 to 100.0)
        Up to 33 months after study treatment start
    100.0 (79.4 to 100.0)
        Up to 36 months after study treatment start
    100.0 (79.4 to 100.0)
    No statistical analyses for this end point

    Secondary: Cumulative incidence of MR4.0 during the pre-randomization induction/consolidation phase among participants without that response at study entry

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    End point title
    		 Cumulative incidence of MR4.0 during the pre-randomization induction/consolidation phase among participants without that response at study entry
    End point description
    Number of participants who were in MR4.0 during the pre-randomization induction/consolidation phase divided by the number of participants without that response at baseline and multiplied by 100. Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.0 is defined as either detectable disease ≤0.01% BCR-ABL IS or undetectable disease in cDNA with ≥10,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)
    End point type
    Secondary
    End point timeframe
    From baseline up to 24 months after study treatment start
    End point values
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment Not randomized
    Number of subjects analysed
    92
    94
    357
    Units: Percentage of participants
    number (confidence interval 95%)
        Up to 3 months after study treatment start
    48.9 (38.3 to 59.6)
    38.3 (28.5 to 48.9)
    12.9 (9.6 to 16.8)
        Up to 6 months after study treatment start
    85.9 (77.1 to 92.3)
    81.9 (72.6 to 89.1)
    26.6 (22.1 to 31.5)
        Up to 9 months after study treatment start
    94.6 (87.8 to 98.2)
    92.6 (85.3 to 97.0)
    34.5 (29.5 to 39.6)
        Up to 12 months after study treatment start
    96.7 (90.8 to 99.3)
    98.9 (94.2 to 100.0)
    39.2 (34.1 to 44.5)
        Up to 15 months after study treatment start
    100.0 (96.1 to 100.0)
    98.9 (94.2 to 100.0)
    42.0 (36.8 to 47.3)
        Up to 18 months after study treatment start
    100.0 (96.1 to 100.0)
    100.0 (96.2 to 100.0)
    45.1 (39.9 to 50.4)
        Up to 21 months after study treatment start
    100.0 (96.1 to 100.0)
    100.0 (96.2 to 100.0)
    48.7 (43.4 to 54.1)
        Up to 24 months after study treatment start
    100.0 (96.1 to 100.0)
    100.0 (96.2 to 100.0)
    52.1 (46.8 to 57.4)
    No statistical analyses for this end point

    Secondary: Cumulative incidence of MR4.0 during the post-randomization consolidation phase among participants without that response at study entry

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    End point title
    		 Cumulative incidence of MR4.0 during the post-randomization consolidation phase among participants without that response at study entry [2]
    End point description
    Number of participants who were in MR4.0 during the post-randomization consolidation phase divided by the number of participants without that response at baseline and multiplied by 100. Post-randomization consolidation phase corresponded to the 12-month additional treatment (after randomization) for Nilotinib 36-month treatment arm. Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.0 is defined as either detectable disease ≤0.01% BCR-ABL IS or undetectable disease in cDNA with ≥10,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)
    End point type
    Secondary
    End point timeframe
    From randomization (month 24 after study treatment start) up to 36 months after study treatment start
    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: Only participants randomized to Nilotinib 36-month treatment arm entered the post-randomization consolidation phase.
    End point values
    		 Nilotinib 36-month treatment
    Number of subjects analysed
    94
    Units: Percentage of participants
    number (confidence interval 95%)
        Up to 27 months after study treatment start
    97.9 (92.5 to 99.7)
        Up to 30 months after study treatment start
    97.9 (92.5 to 99.7)
        Up to 33 months after study treatment start
    97.9 (92.5 to 99.7)
        Up to 36 months after study treatment start
    97.9 (92.5 to 99.7)
    No statistical analyses for this end point

    Secondary: Cumulative incidence of MR4.5 during the pre-randomization induction/consolidation phase among participants without that response at study entry

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    End point title
    		 Cumulative incidence of MR4.5 during the pre-randomization induction/consolidation phase among participants without that response at study entry
    End point description
    Number of participants who were in MR4.5 during the pre-randomization induction/consolidation phase divided by the number of participants without that response at baseline and multiplied by 100. Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.5 is defined as either detectable disease ≤ 0.0032% BCR-ABL IS; or undetectable disease within cDNA with ≥ 32,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)
    End point type
    Secondary
    End point timeframe
    From baseline up to 24 months after study treatment start
    End point values
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment Not randomized
    Number of subjects analysed
    109
    109
    374
    Units: Percentage of participants
    number (confidence interval 95%)
        Up to 3 months after study treatment start
    21.1 (13.9 to 30.0)
    17.4 (10.8 to 25.9)
    4.0 (2.3 to 6.5)
        Up to 6 months after study treatment start
    38.5 (29.4 to 48.3)
    38.5 (29.4 to 48.3)
    8.6 (5.9 to 11.9)
        Up to 9 months after study treatment start
    57.8 (48.0 to 67.2)
    54.1 (44.3 to 63.7)
    10.7 (7.8 to 14.3)
        Up to 12 months after study treatment start
    70.6 (61.2 to 79.0)
    65.1 (55.4 to 74.0)
    14.2 (10.8 to 18.1)
        Up to 15 months after study treatment start
    79.8 (71.1 to 86.9)
    76.1 (67.0 to 83.8)
    15.2 (11.8 to 19.3)
        Up to 18 months after study treatment start
    83.5 (75.2 to 89.9)
    80.7 (72.1 to 87.7)
    16.6 (13.0 to 20.7)
        Up to 21 months after study treatment start
    85.3 (77.3 to 91.4)
    84.4 (76.2 to 90.6)
    18.4 (14.7 to 22.8)
        Up to 24 months after study treatment start
    89.0 (81.6 to 94.2)
    89.0 (81.6 to 94.2)
    20.3 (16.4 to 24.8)
    No statistical analyses for this end point

    Secondary: Cumulative incidence of MR4.5 during the post-randomization consolidation phase among participants without that response at study entry

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    End point title
    		 Cumulative incidence of MR4.5 during the post-randomization consolidation phase among participants without that response at study entry [3]
    End point description
    Number of participants who were in MR4.5 during the post-randomization consolidation phase divided by the number of participants without that response at baseline and multiplied by 100. Post-randomization consolidation phase corresponded to the 12-month additional treatment (after randomization) for Nilotinib 36-month treatment arm. Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.5 is defined as either detectable disease ≤ 0.0032% BCR-ABL IS; or undetectable disease within cDNA with ≥ 32,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)
    End point type
    Secondary
    End point timeframe
    From randomization (month 24 after study treatment start) up to 36 months after study treatment start
    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: Only participants randomized to Nilotinib 36-month treatment arm entered the post-randomization consolidation phase.
    End point values
    		 Nilotinib 36-month treatment
    Number of subjects analysed
    109
    Units: Percentage of participants
    number (confidence interval 95%)
        Up to 27 months after study treatment start
    70.6 (61.2 to 79.0)
        Up to 30 months after study treatment start
    76.1 (67.0 to 83.8)
        Up to 33 months after study treatment start
    84.4 (76.2 to 90.6)
        Up to 36 months after study treatment start
    87.2 (79.4 to 92.8)
    No statistical analyses for this end point

    Secondary: Cumulative incidence of MMR during the pre-randomization induction/consolidation phase

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    End point title
    		 Cumulative incidence of MMR during the pre-randomization induction/consolidation phase
    End point description
    Number of participants who were in MMR during the pre-randomization induction/consolidation phase divided by the number of enrolled participants and multiplied by 100. Confidence intervals were calculated based on the Exact Clopper-Pearson method. MMR is defined as ≥3.0 log reduction in BCR-ABL transcripts compared to the standardized baseline or ≤0.1% BCR-ABL.
    End point type
    Secondary
    End point timeframe
    From baseline up to 24 months after study treatment start
    End point values
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment Not randomized
    Number of subjects analysed
    120
    118
    381
    Units: Percentage of participants
    number (confidence interval 95%)
        Baseline
    80.8 (72.6 to 87.4)
    86.4 (78.9 to 92.1)
    74.3 (69.6 to 78.6)
        Up to 3 months after study treatment start
    94.2 (88.4 to 97.6)
    91.5 (85.0 to 95.9)
    81.9 (77.7 to 85.6)
        Up to 6 months after study treatment start
    100.0 (97.0 to 100.0)
    100.0 (96.9 to 100.0)
    90.8 (87.5 to 93.5)
        Up to 9 months after study treatment start
    100.0 (97.0 to 100.0)
    100.0 (96.9 to 100.0)
    92.7 (89.6 to 95.1)
        Up to 12 months after study treatment start
    100.0 (97.0 to 100.0)
    100.0 (96.9 to 100.0)
    94.2 (91.4 to 96.4)
        Up to 15 months after study treatment start
    100.0 (97.0 to 100.0)
    100.0 (96.9 to 100.0)
    95.0 (92.3 to 97.0)
        Up to 18 months after study treatment start
    100.0 (97.0 to 100.0)
    100.0 (96.9 to 100.0)
    95.5 (93.0 to 97.4)
        Up to 21 months after study treatment start
    100.0 (97.0 to 100.0)
    100.0 (96.9 to 100.0)
    96.3 (93.9 to 98.0)
        Up to 24 months after study treatment start
    100.0 (97.0 to 100.0)
    100.0 (96.9 to 100.0)
    96.6 (94.2 to 98.2)
    No statistical analyses for this end point

    Secondary: Cumulative incidence of MMR during the post-randomization consolidation phase

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    End point title
    		 Cumulative incidence of MMR during the post-randomization consolidation phase [4]
    End point description
    Number of participants who were in MMR during the post-randomization consolidation phase divided by the number of enrolled participants and multiplied by 100. Post-randomization consolidation phase corresponded to the 12-month additional treatment (after randomization) for Nilotinib 36-month treatment arm. Confidence intervals were calculated based on the Exact Clopper-Pearson method. MMR is defined as ≥3.0 log reduction in BCR-ABL transcripts compared to the standardized baseline or ≤0.1% BCR-ABL.
    End point type
    Secondary
    End point timeframe
    From randomization (month 24 after study treatment start) up to 36 months after study treatment start
    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: Only participants randomized to Nilotinib 36-month treatment arm entered the post-randomization consolidation phase.
    End point values
    		 Nilotinib 36-month treatment
    Number of subjects analysed
    118
    Units: Percentage of participants
    number (confidence interval 95%)
        Up to 27 months after study treatment start
    98.3 (94.0 to 99.8)
        Up to 30 months after study treatment start
    98.3 (94.0 to 99.8)
        Up to 33 months after study treatment start
    98.3 (94.0 to 99.8)
        Up to 36 months after study treatment start
    98.3 (94.0 to 99.8)
    No statistical analyses for this end point

    Secondary: Cumulative incidence of MR4.0 during the pre-randomization induction/consolidation phase

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    End point title
    		 Cumulative incidence of MR4.0 during the pre-randomization induction/consolidation phase
    End point description
    Number of participants who were in MR4.0 during the pre-randomization induction/consolidation phase divided by the number of enrolled participants and multiplied by 100. Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.0 is defined as either detectable disease ≤0.01% BCR-ABL IS or undetectable disease in cDNA with ≥10,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)
    End point type
    Secondary
    End point timeframe
    From baseline up to 24 months after study treatment start
    End point values
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment Not randomized
    Number of subjects analysed
    120
    118
    381
    Units: Percentage of participants
    number (confidence interval 95%)
        Baseline
    23.3 (16.1 to 31.9)
    20.3 (13.5 to 28.7)
    6.3 (4.1 to 9.2)
        Up to 3 months after study treatment start
    60.8 (51.5 to 69.6)
    50.8 (41.5 to 60.2)
    18.4 (14.6 to 22.6)
        Up to 6 months after study treatment start
    89.2 (82.2 to 94.1)
    85.6 (77.9 to 91.4)
    31.2 (26.6 to 36.2)
        Up to 9 months after study treatment start
    95.8 (90.5 to 98.6)
    94.1 (88.2 to 97.6)
    38.6 (33.7 to 43.7)
        Up to 12 months after study treatment start
    97.5 (92.9 to 99.5)
    99.2 (95.4 to 100.0)
    43.0 (38.0 to 48.2)
        Up to 15 months after study treatment start
    100.0 (97.0 to 100.0)
    99.2 (95.4 to 100.0)
    45.7 (40.6 to 50.8)
        Up to 18 months after study treatment start
    100.0 (97.0 to 100.0)
    100.0 (96.9 to 100.0)
    48.6 (43.4 to 53.7)
        Up to 21 months after study treatment start
    100.0 (97.0 to 100.0)
    100.0 (96.9 to 100.0)
    52.0 (46.8 to 57.1)
        Up to 24 months after study treatment start
    100.0 (97.0 to 100.0)
    100.0 (96.9 to 100.0)
    55.1 (50.0 to 60.2)
    No statistical analyses for this end point

    Secondary: Cumulative incidence of MR4.0 during the post-randomization consolidation phase

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    End point title
    		 Cumulative incidence of MR4.0 during the post-randomization consolidation phase [5]
    End point description
    Number of participants who were in MR4.0 during the post-randomization consolidation phase divided by the number of enrolled participants and multiplied by 100. Post-randomization consolidation phase corresponded to the 12-month additional treatment (after randomization) for Nilotinib 36-month treatment arm. Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.0 is defined as either detectable disease ≤0.01% BCR-ABL IS or undetectable disease in cDNA with ≥10,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)
    End point type
    Secondary
    End point timeframe
    From randomization (month 24 after study treatment start) up to 36 months after study treatment start
    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: Only participants randomized to Nilotinib 36-month treatment arm entered the post-randomization consolidation phase.
    End point values
    		 Nilotinib 36-month treatment
    Number of subjects analysed
    118
    Units: Percentage of participants
    number (confidence interval 95%)
        Up to 27 months after study treatment start
    98.3 (94.0 to 99.8)
        Up to 30 months after study treatment start
    98.3 (94.0 to 99.8)
        Up to 33 months after study treatment start
    98.3 (94.0 to 99.8)
        Up to 36 months after study treatment start
    98.3 (94.0 to 99.8)
    No statistical analyses for this end point

    Secondary: Cumulative incidence of MR4.5 during the pre-randomization induction/consolidation phase

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    End point title
    		 Cumulative incidence of MR4.5 during the pre-randomization induction/consolidation phase
    End point description
    Number of participants who were in MR4.5 during the pre-randomization induction/consolidation phase divided by the number of enrolled participants and multiplied by 100. Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.5 is defined as either detectable disease ≤ 0.0032% BCR-ABL IS; or undetectable disease within cDNA with ≥ 32,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)
    End point type
    Secondary
    End point timeframe
    From baseline up to 24 months after study treatment start
    End point values
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment Not randomized
    Number of subjects analysed
    120
    118
    381
    Units: Percentage of participants
    number (confidence interval 95%)
        Baseline
    9.2 (4.7 to 15.8)
    7.6 (3.6 to 14.0)
    1.8 (0.7 to 3.8)
        Up to 3 months after study treatment start
    28.3 (20.5 to 37.3)
    23.7 (16.4 to 32.4)
    5.8 (3.7 to 8.6)
        Up to 6 months after study treatment start
    44.2 (35.1 to 53.5)
    43.2 (34.1 to 52.7)
    10.2 (7.4 to 13.7)
        Up to 9 months after study treatment start
    61.7 (52.4 to 70.4)
    57.6 (48.2 to 66.7)
    12.3 (9.2 to 16.1)
        Up to 12 months after study treatment start
    73.3 (64.5 to 81.0)
    67.8 (58.6 to 76.1)
    15.7 (12.2 to 19.8)
        Up to 15 months after study treatment start
    81.7 (73.6 to 88.1)
    78.0 (69.4 to 85.1)
    16.8 (13.2 to 20.9)
        Up to 18 months after study treatment start
    85.0 (77.3 to 90.9)
    82.2 (74.1 to 88.6)
    18.1 (14.4 to 22.4)
        Up to 21 months after study treatment start
    86.7 (79.3 to 92.2)
    85.6 (77.9 to 91.4)
    19.9 (16.1 to 24.3)
        Up to 24 months after study treatment start
    90.0 (83.2 to 94.7)
    89.8 (82.9 to 94.6)
    21.8 (17.7 to 26.3)
    No statistical analyses for this end point

    Secondary: Cumulative incidence of MR4.5 during the post-randomization consolidation phase

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    End point title
    		 Cumulative incidence of MR4.5 during the post-randomization consolidation phase [6]
    End point description
    Number of participants who were in MR4.5 during the post-randomization consolidation phase divided by the number of enrolled participants and multiplied by 100. Post-randomization consolidation phase corresponded to the 12-month additional treatment (after randomization) for Nilotinib 36-month treatment arm. Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.5 is defined as either detectable disease ≤ 0.0032% BCR-ABL IS; or undetectable disease within cDNA with ≥ 32,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)
    End point type
    Secondary
    End point timeframe
    From randomization (month 24 after study treatment start) up to 36 months after study treatment start
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants randomized to Nilotinib 36-month treatment arm entered the post-randomization consolidation phase.
    End point values
    		 Nilotinib 36-month treatment
    Number of subjects analysed
    118
    Units: Percentage of participants
    number (confidence interval 95%)
        Up to 27 months after study treatment start
    72.9 (63.9 to 80.7)
        Up to 30 months after study treatment start
    78.0 (69.4 to 85.1)
        Up to 33 months after study treatment start
    85.6 (77.9 to 91.4)
        Up to 36 months after study treatment start
    88.1 (80.9 to 93.4)
    No statistical analyses for this end point

    Secondary: Percentage of participants who were in MMR during TFR phase

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    End point title
    		 Percentage of participants who were in MMR during TFR phase
    End point description
    Number of participants who were in MMR at selected timepoints divided by the number of participants in the TFR phase and multiplied by 100. Participants randomized in Nilotinib 36-month treatment arm had a maximum of 24 months of TFR phase, whereas participants randomized in Nilotinib 24-month treatment arm had a maximum of 36 months of TFR phase. Confidence intervals were calculated based on the Exact Clopper-Pearson method. MMR is defined as ≥3.0 log reduction in BCR-ABL transcripts compared to the standardized baseline or ≤0.1% BCR-ABL. Note: 999 indicates value is not applicable.
    End point type
    Secondary
    End point timeframe
    From Month 1 after entering TFR phase up to 24 months after entering TFR phase for Nilotinib 36-month treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-month treatment arm
    End point values
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment
    Number of subjects analysed
    119
    104
    Units: Percentage of participants
    number (confidence interval 95%)
        Month 1 after entering TFR phase
    97.5 (92.8 to 99.5)
    94.2 (87.9 to 97.9)
        Month 2 after entering TFR phase
    84.9 (77.2 to 90.8)
    80.8 (71.9 to 87.8)
        Month 3 after entering TFR phase
    62.2 (52.8 to 70.9)
    61.5 (51.5 to 70.9)
        Month 4 after entering TFR phase
    51.3 (41.9 to 60.5)
    53.8 (43.8 to 63.7)
        Month 5 after entering TFR phase
    45.4 (36.2 to 54.8)
    46.2 (36.3 to 56.2)
        Month 6 after entering TFR phase
    42.9 (33.8 to 52.3)
    43.3 (33.6 to 53.4)
        Month 8 after entering TFR phase
    40.3 (31.5 to 49.7)
    43.3 (33.6 to 53.4)
        Month 10 after entering TFR phase
    38.7 (29.9 to 48.0)
    42.3 (32.7 to 52.4)
        Month 12 after entering TFR phase
    36.1 (27.5 to 45.5)
    39.4 (30.0 to 49.5)
        Month 15 after entering TFR phase
    35.3 (26.8 to 44.6)
    39.4 (30.0 to 49.5)
        Month 18 after entering TFR phase
    35.3 (26.8 to 44.6)
    39.4 (30.0 to 49.5)
        Month 21 after entering TFR phase
    34.5 (26.0 to 43.7)
    38.5 (29.1 to 48.5)
        Month 24 after entering TFR phase
    31.9 (23.7 to 41.1)
    35.6 (26.4 to 45.6)
        Month 27 after entering TFR phase
    31.9 (23.7 to 41.1)
    999 (999 to 999)
        Month 30 after entering TFR phase
    31.9 (23.7 to 41.1)
    999 (999 to 999)
        Month 33 after entering TFR phase
    30.3 (22.2 to 39.4)
    999 (999 to 999)
        Month 36 after entering TFR phase
    23.5 (16.2 to 32.2)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Percentage of participants who were in MR4.0 during the TFR phase

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    End point title
    		 Percentage of participants who were in MR4.0 during the TFR phase
    End point description
    Number of participants who were in MR4.0 at selected timepoints divided by the number of participants in the TFR phase and multiplied by 100. Participants randomized in Nilotinib 36-month treatment arm had a maximum of 24 months of TFR phase, whereas participants randomized in Nilotinib 24-month treatment arm had a maximum of 36 months of TFR phase. Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.0 is defined as either detectable disease ≤0.01% BCR-ABL IS or undetectable disease in cDNA with ≥10,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL). Note: 999 indicates value is not applicable.
    End point type
    Secondary
    End point timeframe
    From Month 1 after entering TFR phase up to 24 months after entering TFR phase for Nilotinib 36-month treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-month treatment arm
    End point values
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment
    Number of subjects analysed
    119
    104
    Units: Percentage of participants
    number (confidence interval 95%)
        Month 1 after entering TFR phase
    87.4 (80.1 to 92.8)
    83.7 (75.1 to 90.2)
        Month 2 after entering TFR phase
    58.0 (48.6 to 67.0)
    56.7 (46.7 to 66.4)
        Month 3 after entering TFR phase
    39.5 (30.7 to 48.9)
    42.3 (32.7 to 52.4)
        Month 4 after entering TFR phase
    36.1 (27.5 to 45.5)
    42.3 (32.7 to 52.4)
        Month 5 after entering TFR phase
    32.8 (24.5 to 42.0)
    41.3 (31.8 to 51.4)
        Month 6 after entering TFR phase
    33.6 (25.2 to 42.9)
    38.5 (29.1 to 48.5)
        Month 8 after entering TFR phase
    34.5 (26.0 to 43.7)
    40.4 (30.9 to 50.5)
        Month 10 after entering TFR phase
    35.3 (26.8 to 44.6)
    38.5 (29.1 to 48.5)
        Month 12 after entering TFR phase
    31.9 (23.7 to 41.1)
    37.5 (28.2 to 47.5)
        Month 15 after entering TFR phase
    34.5 (26.0 to 43.7)
    34.6 (25.6 to 44.6)
        Month 18 after entering TFR phase
    33.6 (25.2 to 42.9)
    38.5 (29.1 to 48.5)
        Month 21 after entering TFR phase
    30.3 (22.2 to 39.4)
    32.7 (23.8 to 42.6)
        Month 24 after entering TFR phase
    29.4 (21.4 to 38.5)
    30.8 (22.1 to 40.6)
        Month 27 after entering TFR phase
    31.1 (22.9 to 40.2)
    999 (999 to 999)
        Month 30 after entering TFR phase
    30.3 (22.2 to 39.4)
    999 (999 to 999)
        Month 33 after entering TFR phase
    27.7 (19.9 to 36.7)
    999 (999 to 999)
        Month 36 after entering TFR phase
    26.1 (18.4 to 34.9)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Percentage of participants who were in MR4.5 during the TFR phase

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    End point title
    		 Percentage of participants who were in MR4.5 during the TFR phase
    End point description
    Number of participants who were in MR4.5 at selected timepoints divided by the number of participants in the TFR phase and multiplied by 100. Participants randomized in Nilotinib 36-month treatment arm had a maximum of 24 months of TFR phase, whereas participants randomized in Nilotinib 24-month treatment arm had a maximum of 36 months of TFR phase. Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.5 is defined as either detectable disease ≤ 0.0032% BCR-ABL IS; or undetectable disease within cDNA with ≥ 32,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL). Note: 999 indicates value is not applicable.
    End point type
    Secondary
    End point timeframe
    From Month 1 after entering TFR phase up to 24 months after entering TFR phase for Nilotinib 36-month treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-month treatment arm
    End point values
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment
    Number of subjects analysed
    119
    104
    Units: Percentage of participants
    number (confidence interval 95%)
        Month 3 after entering TFR phase
    21.8 (14.8 to 30.4)
    26.9 (18.7 to 36.5)
        Month 6 after entering TFR phase
    17.6 (11.3 to 25.7)
    28.8 (20.4 to 38.6)
        Month 12 after entering TFR phase
    20.2 (13.4 to 28.5)
    26.9 (18.7 to 36.5)
        Month 15 after entering TFR phase
    18.5 (12.0 to 26.6)
    23.1 (15.4 to 32.4)
        Month 18 after entering TFR phase
    25.2 (17.7 to 34.0)
    26.9 (18.7 to 36.5)
        Month 21 after entering TFR phase
    22.7 (15.5 to 31.3)
    22.1 (14.6 to 31.3)
        Month 24 after entering TFR phase
    24.4 (17.0 to 33.1)
    20.2 (13.0 to 29.2)
        Month 27 after entering TFR phase
    21.8 (14.8 to 30.4)
    999 (999 to 999)
        Month 30 after entering TFR phase
    22.7 (15.5 to 31.3)
    999 (999 to 999)
        Month 33 after entering TFR phase
    19.3 (12.7 to 27.6)
    999 (999 to 999)
        Month 36 after entering TFR phase
    16.8 (10.6 to 24.8)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: BCR-ABL ratio (expressed as a percentage) during the induction/consolidation phase

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    End point title
    		 BCR-ABL ratio (expressed as a percentage) during the induction/consolidation phase
    End point description
    BCR-ABL transcript ratio by international scale (IS) (expressed as a percentage) during the induction/consolidation phase. Participants randomized to Nilotinib 36-month treatment arm had 12-month additional consolidation phase (post-randomization).Only those participants with evaluable data at the specified time points for this outcome measure were analyzed (represented by n=X / Y / Z in the category titles). Note: 999 indicates value is not applicable.
    End point type
    Secondary
    End point timeframe
    From baseline up to 24 months after study treatment start for Nilotinib 24-month treatment arm and Not randomized participants; and up to 36 months after study treatment start for Nilotinib 36-month treatment arm.
    End point values
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment Not randomized
    Number of subjects analysed
    120
    118
    381
    Units: Percentage
    arithmetic mean (standard deviation)
        Baseline (n= 120/ 117/ 380)
    0.1367 ± 0.55144
    0.0633 ± 0.12790
    0.5509 ± 3.94256
        Month 3 after treatment start(n=117/117/343)
    0.0106 ± 0.02660
    0.0086 ± 0.01155
    0.0728 ± 0.22537
        Month 6 after treatment start (n=118/115/327)
    0.0052 ± 0.00631
    0.0124 ± 0.05508
    0.0530 ± 0.09587
        Month 9 after treatment start (n=116/117/312)
    0.0049 ± 0.00809
    0.0046 ± 0.00544
    0.0573 ± 0.13905
        Month 12 after treatment start (n=117/117/298)
    0.0044 ± 0.00611
    0.0037 ± 0.00440
    0.0772 ± 0.56398
        Month 15 after treatment start (n=117/116/286)
    0.0035 ± 0.00591
    0.0034 ± 0.00389
    0.0669 ± 0.37209
        Month 18 after treatment start (n=117/115/269)
    0.0029 ± 0.00354
    0.0034 ± 0.00409
    0.0462 ± 0.12284
        Month 21 after treatment start (n=115/114/246)
    0.0028 ± 0.00319
    0.0031 ± 0.00288
    0.0390 ± 0.08271
        Month 24 after treatment start (n=113/113/153)
    0.0027 ± 0.00424
    0.0029 ± 0.00319
    0.0325 ± 0.05140
        Month 27 after treatment start (n=0/112/0)
    999 ± 999
    0.0089 ± 0.06119
    999 ± 999
        Month 30 after treatment start (n=0/112/0)
    999 ± 999
    0.0111 ± 0.08672
    999 ± 999
        Month 33 after treatment start (n=0/111/0)
    999 ± 999
    0.0025 ± 0.00439
    999 ± 999
        Month 36 after treatment start (n=0/103/0)
    999 ± 999
    0.0025 ± 0.00338
    999 ± 999
    No statistical analyses for this end point

    Secondary: BCR-ABL ratio (expressed as a percentage) during the TFR phase

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    End point title
    		 BCR-ABL ratio (expressed as a percentage) during the TFR phase
    End point description
    BCR-ABL/control gene (ABL) transcript ratio by international scale (IS) (expressed as a percentage) during the TFR phase. BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. Participants randomized in Nilotinib 36-month treatment arm had a maximum of 24 months of TFR phase, whereas participants randomized in Nilotinib 24-month treatment arm had a maximum of 36 months of TFR phase. Only those participants with evaluable data at the specified time points for this outcome measure were analyzed (represented by n=X / Y in the category titles). Note: 999 indicates value is not applicable.
    End point type
    Secondary
    End point timeframe
    From Month 1 after entering TFR phase up to 24 months after entering TFR phase for Nilotinib 36-month treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-month treatment arm
    End point values
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment
    Number of subjects analysed
    119
    104
    Units: Percentage
    arithmetic mean (standard deviation)
        Month 1 after entering the TFR phase (n=116/ 99)
    0.0042 ± 0.00621
    0.0074 ± 0.02130
        Month 2 after entering the TFR phase (n=112/ 100)
    0.1162 ± 0.35606
    0.2122 ± 0.99372
        Month 3 after entering the TFR phase (n=81/ 64)
    1.3774 ± 9.71909
    0.4754 ± 1.84649
        Month 4 after entering the TFR phase (n=112/ 100)
    0.2667 ± 0.80336
    0.2506 ± 0.91197
        Month 5 after entering the TFR phase (n=62/ 52)
    0.1740 ± 0.76123
    0.0801 ± 0.26739
        Month 6 after entering the TFR phase (n=51/ 43)
    0.2219 ± 1.51808
    0.1095 ± 0.66322
        Month 8 after entering the TFR phase (n=47/ 42)
    0.0075 ± 0.01403
    0.0042 ± 0.00742
        Month 10 after entering the TFR phase (n=45/ 43)
    0.0062 ± 0.01295
    0.0039 ± 0.00680
        Month 12 after entering the TFR phase (n=41/ 39)
    0.0047 ± 0.00665
    0.0027 ± 0.00357
        Month 15 after entering the TFR phase (n=42/ 39)
    0.0030 ± 0.00317
    0.0043 ± 0.00555
        Month 18 after entering the TFR phase (n=40/ 40)
    0.0030 ± 0.00384
    0.0027 ± 0.00330
        Month 21 after entering the TFR phase (n=38/ 40)
    0.0036 ± 0.00484
    0.0041 ± 0.00495
        Month 24 after entering the TFR phase (n=38/ 35)
    0.0077 ± 0.02910
    0.0047 ± 0.00691
        Month 27 after entering the TFR phase (n=112/ 100)
    0.0024 ± 0.00246
    999 ± 999
        Month 30 after entering the TFR phase (n=36/ 0)
    0.0023 ± 0.00281
    999 ± 999
        Month 33 after entering the TFR phase (n=35/ 0)
    0.0079 ± 0.02376
    999 ± 999
        Month 36 after entering the TFR phase (n=28/ 0)
    0.0041 ± 0.00767
    999 ± 999
    No statistical analyses for this end point

    Secondary: BCR-ABL ratio (expressed as a percentage) during the nilotinib re-treatment phase

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    End point title
    		 BCR-ABL ratio (expressed as a percentage) during the nilotinib re-treatment phase
    End point description
    BCR-ABL/control gene (ABL) transcript ratio by international scale (IS) (expressed as a percentage) during the nilotinib re-treatment phase. BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. Only those participants who entered the re-treatment phase with evaluable data at the specified time points for this outcome measure were analyzed (represented by n=X / Y in the category titles). Note: 999 indicates value is not applicable.
    End point type
    Secondary
    End point timeframe
    From Day 1 after entering the re-treatment phase up to 24 months after entering re-treatment phase for Nilotinib 36-month treatment arm and 36 months after entering the re-treatment phase for Nilotinib 24-month treatment arm
    End point values
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment
    Number of subjects analysed
    74
    55
    Units: Percentage
    arithmetic mean (standard deviation)
        Day 1 re-treatment phase (n=2/ 2)
    2.8246 ± 2.39596
    0.6301 ± 0.74388
        Week 6 re-treatment phase (n=70/ 54)
    0.6276 ± 2.34231
    0.3112 ± 0.60279
        Month 3 re-treatment phase (n=70/ 52)
    0.0311 ± 0.07265
    0.0131 ± 0.02359
        Month 6 re-treatment phase (n=70/ 53)
    0.0095 ± 0.03296
    0.0070 ± 0.01330
        Month 9 re-treatment phase (n=71/ 51)
    0.0259 ± 0.17766
    0.0065 ± 0.01099
        Month 12 re-treatment phase (n=64/ 45)
    0.0088 ± 0.03190
    0.0047 ± 0.00839
        Month 15 re-treatment phase (n=64/ 48)
    0.0061 ± 0.01322
    0.0045 ± 0.01176
        Month 18 re-treatment phase (n=64/ 48)
    0.0105 ± 0.05205
    0.0039 ± 0.00581
        Month 21 re-treatment phase (n=59/ 21)
    0.0051 ± 0.01699
    0.0031 ± 0.00342
        Month 24 re-treatment phase (n=55/ 2)
    0.0038 ± 0.00756
    0.0014 ± 0.00197
        Month 27 re-treatment phase (n=52/ 0)
    0.0033 ± 0.00439
    999 ± 999
        Month 30 re-treatment phase (n=43/ 0)
    0.0113 ± 0.04446
    999 ± 999
        Month 33 re-treatment phase (n=11/ 0)
    0.0029 ± 0.00541
    999 ± 999
        Month 36 re-treatment phase (n=1/ 0)
    0.0005 ± 999
    999 ± 999
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS) during the TFR phase of the study.

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    End point title
    		 Progression-free survival (PFS) during the TFR phase of the study.
    End point description
    PFS is defined as the time from the date of start of the nilotinib TFR phase to the date of acelerated phase/blast crisis (AP/BC) or death, whichever came first. Participants randomized in Nilotinib 36-month treatment arm had a maximum of 24 months of TFR phase, whereas participants randomized in Nilotinib 24-month treatment arm had a maximum of 36 months of TFR phase. Patients not known to have recurred or died on or before the cut-off date for PFS analysis were censored at the date of their last assessment (cytogenetic, hematology or extramedullary) for patients who were on study, and at the date of last contact for patients who were in follow-up. Note: 999 indicates value is not applicable.
    End point type
    Secondary
    End point timeframe
    From the start of the TFR phase to progression to AP/BC or death up to 24 months after entering TFR phase for Nilotininb 36-month treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-month treatment arm
    End point values
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment
    Number of subjects analysed
    119
    104
    Units: Months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Treatment -free survival (TFS) during the TFR phase of the study

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    End point title
    		 Treatment -free survival (TFS) during the TFR phase of the study
    End point description
    TFS is defined as the time from the start of the TFR phase to the date of the earliest of the following: loss of MMR, confirmed loss of MR4.0, re-start of nilotinib treatment, progression to AP/BC,or death from any cause. Patients not known to have had any of the events on or before the cut-off date were censored at the earlier of the date of their last assessment for patients who were still on study and the date of last contact for patients who were in follow-up. Participants randomized in Nilotinib 36-month treatment arm had a maximum of 24 months of TFR phase, whereas participants randomized in Nilotinib 24-month treatment arm had a maximum of 36 months of TFR phase. MMR is defined as ≥3.0 log reduction in BCR-ABL transcripts compared to the standardized baseline or ≤0.1%BCR-ABL. MR4.0 is defined as either detectable disease ≤0.01%BCR-ABL IS or undetectable disease in cDNA with ≥10,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)
    End point type
    Secondary
    End point timeframe
    From the start of the TFR phase to the date of occurrence of treatment-free survival event, up to 24 months after entering TFR phase for Nilotinib 36-month treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-month treatment arm
    End point values
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment
    Number of subjects analysed
    119
    104
    Units: Months
        median (confidence interval 95%)
    4.1 (3.7 to 5.5)
    4.2 (3.7 to 19.7)
    No statistical analyses for this end point

    Secondary: Overall survival (OS) rate during the TFR phase of the study.

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    End point title
    		 Overall survival (OS) rate during the TFR phase of the study. [7]
    End point description
    OS is defined as the time from start of the TFR phase to the time of death due to any cause. Participants randomized in Nilotinib 36-month treatment arm had a maximum of 24 months of TFR phase, whereas participants randomized in Nilotinib 24-month treatment arm had a maximum of 36 months of TFR phase. For participants without any event on or before the cut-off date, survival time will be censored at the date of their last assessment for patients who are still on study, and at the date of last contact for patients who are in follow-up. Note: 999 indicates value is not applicable.
    End point type
    Secondary
    End point timeframe
    From the start of the TFR phase to death due to any cause, assessed up to 24 months after entering TFR phase for Nilotinib 36-month treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-month treatment arm
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint refers to TFR phase not the baseline period
    End point values
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment
    Number of subjects analysed
    120
    119
    Units: Months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Post-hoc: All Collected Deaths

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    End point title
    		 All Collected Deaths
    End point description
    Deaths on-treatment were collected during the induction/consolidation phase (from the first dose of study drug to 30 days after study treatment discontinuation, assessed up to 24 months for Nilotinib 24-month treatment arm and Not randomized, and up to 36 months for Nilotinib 36-month treatment arm) and during the re-treatment phase (from the start date of the re-treatment phase to 30 days after study treatment discontinuation, assessed up to 36 months for Nilotinib 24-month treatment arm and up to 24 months for Nilotinib 36-month treatment arm). Total deaths were collected from first dose of study drug until end of study, up to maximum duration of 5 years
    End point type
    Post-hoc
    End point timeframe
    On-treatment deaths: induction/consolidation phase (up to 24 months or 36 months from treatment start, depending on arm) and re-treatment phase (up to 36 months or up to 24 months from re-treatment start, depending on arm). All deaths: up to 5 years
    End point values
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment Not randomized
    Number of subjects analysed
    120
    118
    381
    Units: Participants
        On-treatment deaths
    1
    1
    3
        Total deaths
    1
    3
    10
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected during: -Induction/consolidation phase, up to 24 months (or 36 months for Nilotinib 36-month treatment arm) -Re-treatment phase, up to 36 months for Nilotinib 24-month treatment arm (or 24 months for Nilotinib 36-month treatment arm)
    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
    23.1
    Reporting groups
    Reporting group title
    Nilotinib 24-month treatment
    Reporting group description
    		 Participants were treated with nilotinib 300mg BID for 24 months and, thereafter, entered the 36-month TFR phase

    Reporting group title
    Nilotinib 36-month treatment
    Reporting group description
    		 Participants were treated with nilotinib 300mg BID for 36 months and, thereafter, entered the 24-month TFR phase

    Reporting group title
    Not Randomized
    Reporting group description
    		 Participants were treated with nilotinib 300mg BID for 24 months, but did not achieve a sustained molecular response after 24 months of treatment and were not randomized

    Reporting group title
    Total
    Reporting group description
    		 Total

    Serious adverse events
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment Not Randomized Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 120 (27.50%)
    27 / 118 (22.88%)
    76 / 381 (19.95%)
    136 / 619 (21.97%)
         number of deaths (all causes)
    1
    1
    3
    5
         number of deaths resulting from adverse events
    0
    0
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glioblastoma
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelofibrosis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Arterial disorder
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arterial occlusive disease
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemia
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    2 / 381 (0.52%)
    3 / 619 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thromboangiitis obliterans
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         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
    Peripheral artery occlusion
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Hyperplasia
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrosis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         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
    Sudden death
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Sarcoidosis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Acquired hydrocele
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adnexa uteri mass
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    2 / 381 (0.52%)
    2 / 619 (0.32%)
         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 embolism
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment disorder
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Amylase increased
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    2 / 381 (0.52%)
    2 / 619 (0.32%)
         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
    Troponin increased
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye contusion
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    3 / 619 (0.48%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    2 / 381 (0.52%)
    3 / 619 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    5 / 381 (1.31%)
    5 / 619 (0.81%)
         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
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 120 (2.50%)
    2 / 118 (1.69%)
    4 / 381 (1.05%)
    9 / 619 (1.45%)
         occurrences causally related to treatment / all
    3 / 5
    2 / 2
    3 / 5
    8 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    1 / 381 (0.26%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    Coronary artery disease
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    4 / 381 (1.05%)
    4 / 619 (0.65%)
         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
    Coronary artery stenosis
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    3 / 381 (0.79%)
    3 / 619 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive cardiomyopathy
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 118 (0.00%)
    4 / 381 (1.05%)
    6 / 619 (0.97%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    4 / 5
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    2 / 381 (0.52%)
    3 / 619 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral artery thrombosis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    3 / 381 (0.79%)
    4 / 619 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    3 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    2 / 381 (0.52%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mononeuropathy
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         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
    Syncope
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 118 (0.85%)
    2 / 381 (0.52%)
    4 / 619 (0.65%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    0 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy mediastinal
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    1 / 381 (0.26%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    2 / 381 (0.52%)
    2 / 619 (0.32%)
         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
    Anal fissure
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    2 / 381 (0.52%)
    2 / 619 (0.32%)
         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
    Anal fistula
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         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
    Constipation
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         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
    Inguinal hernia
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar hernia
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    3 / 381 (0.79%)
    3 / 619 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    2 / 381 (0.52%)
    2 / 619 (0.32%)
         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
    Umbilical hernia
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    1 / 381 (0.26%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    1 / 381 (0.26%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperhidrosis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkeratosis
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    2 / 381 (0.52%)
    2 / 619 (0.32%)
         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
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthropathy
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    2 / 381 (0.52%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    2 / 381 (0.52%)
    3 / 619 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metatarsalgia
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    2 / 619 (0.32%)
         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
    Pain in extremity
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylitis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 120 (0.83%)
    2 / 118 (1.69%)
    0 / 381 (0.00%)
    3 / 619 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder empyema
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    1 / 381 (0.26%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuroborreliosis
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    1 / 381 (0.26%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 118 (0.00%)
    1 / 381 (0.26%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 118 (0.00%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         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
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 118 (0.85%)
    0 / 381 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Nilotinib 24-month treatment Nilotinib 36-month treatment Not Randomized Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    97 / 120 (80.83%)
    104 / 118 (88.14%)
    280 / 381 (73.49%)
    481 / 619 (77.71%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    10 / 120 (8.33%)
    18 / 118 (15.25%)
    27 / 381 (7.09%)
    55 / 619 (8.89%)
         occurrences all number
    14
    29
    32
    75
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 120 (6.67%)
    12 / 118 (10.17%)
    11 / 381 (2.89%)
    31 / 619 (5.01%)
         occurrences all number
    13
    18
    15
    46
    Blood bilirubin increased
         subjects affected / exposed
    8 / 120 (6.67%)
    13 / 118 (11.02%)
    30 / 381 (7.87%)
    51 / 619 (8.24%)
         occurrences all number
    12
    20
    48
    80
    Blood cholesterol increased
         subjects affected / exposed
    15 / 120 (12.50%)
    14 / 118 (11.86%)
    24 / 381 (6.30%)
    53 / 619 (8.56%)
         occurrences all number
    17
    26
    26
    69
    Blood triglycerides increased
         subjects affected / exposed
    3 / 120 (2.50%)
    8 / 118 (6.78%)
    6 / 381 (1.57%)
    17 / 619 (2.75%)
         occurrences all number
    3
    13
    7
    23
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 120 (3.33%)
    6 / 118 (5.08%)
    9 / 381 (2.36%)
    19 / 619 (3.07%)
         occurrences all number
    5
    6
    10
    21
    Lipase increased
         subjects affected / exposed
    21 / 120 (17.50%)
    10 / 118 (8.47%)
    34 / 381 (8.92%)
    65 / 619 (10.50%)
         occurrences all number
    31
    20
    56
    107
    Weight increased
         subjects affected / exposed
    5 / 120 (4.17%)
    6 / 118 (5.08%)
    3 / 381 (0.79%)
    14 / 619 (2.26%)
         occurrences all number
    7
    8
    3
    18
    Vascular disorders
    Hypertension
         subjects affected / exposed
    20 / 120 (16.67%)
    25 / 118 (21.19%)
    27 / 381 (7.09%)
    72 / 619 (11.63%)
         occurrences all number
    21
    30
    27
    78
    Nervous system disorders
    Headache
         subjects affected / exposed
    17 / 120 (14.17%)
    12 / 118 (10.17%)
    34 / 381 (8.92%)
    63 / 619 (10.18%)
         occurrences all number
    25
    12
    39
    76
    Sciatica
         subjects affected / exposed
    5 / 120 (4.17%)
    7 / 118 (5.93%)
    9 / 381 (2.36%)
    21 / 619 (3.39%)
         occurrences all number
    5
    9
    10
    24
    Paraesthesia
         subjects affected / exposed
    6 / 120 (5.00%)
    4 / 118 (3.39%)
    9 / 381 (2.36%)
    19 / 619 (3.07%)
         occurrences all number
    7
    4
    9
    20
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    16 / 120 (13.33%)
    14 / 118 (11.86%)
    27 / 381 (7.09%)
    57 / 619 (9.21%)
         occurrences all number
    20
    18
    28
    66
    Fatigue
         subjects affected / exposed
    13 / 120 (10.83%)
    7 / 118 (5.93%)
    17 / 381 (4.46%)
    37 / 619 (5.98%)
         occurrences all number
    15
    8
    17
    40
    Pyrexia
         subjects affected / exposed
    5 / 120 (4.17%)
    10 / 118 (8.47%)
    23 / 381 (6.04%)
    38 / 619 (6.14%)
         occurrences all number
    8
    11
    26
    45
    Influenza like illness
         subjects affected / exposed
    2 / 120 (1.67%)
    6 / 118 (5.08%)
    2 / 381 (0.52%)
    10 / 619 (1.62%)
         occurrences all number
    2
    6
    2
    10
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 120 (5.83%)
    6 / 118 (5.08%)
    15 / 381 (3.94%)
    28 / 619 (4.52%)
         occurrences all number
    8
    7
    16
    31
    Abdominal pain upper
         subjects affected / exposed
    12 / 120 (10.00%)
    14 / 118 (11.86%)
    19 / 381 (4.99%)
    45 / 619 (7.27%)
         occurrences all number
    14
    17
    22
    53
    Constipation
         subjects affected / exposed
    19 / 120 (15.83%)
    14 / 118 (11.86%)
    25 / 381 (6.56%)
    58 / 619 (9.37%)
         occurrences all number
    21
    16
    26
    63
    Dyspepsia
         subjects affected / exposed
    4 / 120 (3.33%)
    7 / 118 (5.93%)
    6 / 381 (1.57%)
    17 / 619 (2.75%)
         occurrences all number
    5
    7
    7
    19
    Nausea
         subjects affected / exposed
    13 / 120 (10.83%)
    5 / 118 (4.24%)
    11 / 381 (2.89%)
    29 / 619 (4.68%)
         occurrences all number
    17
    8
    13
    38
    Vomiting
         subjects affected / exposed
    10 / 120 (8.33%)
    3 / 118 (2.54%)
    9 / 381 (2.36%)
    22 / 619 (3.55%)
         occurrences all number
    10
    3
    9
    22
    Diarrhoea
         subjects affected / exposed
    6 / 120 (5.00%)
    5 / 118 (4.24%)
    11 / 381 (2.89%)
    22 / 619 (3.55%)
         occurrences all number
    6
    5
    13
    24
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 120 (7.50%)
    15 / 118 (12.71%)
    13 / 381 (3.41%)
    37 / 619 (5.98%)
         occurrences all number
    11
    18
    15
    44
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    6 / 120 (5.00%)
    9 / 118 (7.63%)
    18 / 381 (4.72%)
    33 / 619 (5.33%)
         occurrences all number
    6
    9
    18
    33
    Dry skin
         subjects affected / exposed
    9 / 120 (7.50%)
    15 / 118 (12.71%)
    17 / 381 (4.46%)
    41 / 619 (6.62%)
         occurrences all number
    13
    22
    19
    54
    Pruritus
         subjects affected / exposed
    15 / 120 (12.50%)
    23 / 118 (19.49%)
    57 / 381 (14.96%)
    95 / 619 (15.35%)
         occurrences all number
    20
    28
    66
    114
    Rash
         subjects affected / exposed
    21 / 120 (17.50%)
    10 / 118 (8.47%)
    41 / 381 (10.76%)
    72 / 619 (11.63%)
         occurrences all number
    26
    12
    46
    84
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 120 (3.33%)
    6 / 118 (5.08%)
    3 / 381 (0.79%)
    13 / 619 (2.10%)
         occurrences all number
    4
    7
    3
    14
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    17 / 120 (14.17%)
    18 / 118 (15.25%)
    27 / 381 (7.09%)
    62 / 619 (10.02%)
         occurrences all number
    21
    23
    33
    77
    Back pain
         subjects affected / exposed
    16 / 120 (13.33%)
    11 / 118 (9.32%)
    21 / 381 (5.51%)
    48 / 619 (7.75%)
         occurrences all number
    19
    12
    23
    54
    Muscle spasms
         subjects affected / exposed
    10 / 120 (8.33%)
    16 / 118 (13.56%)
    12 / 381 (3.15%)
    38 / 619 (6.14%)
         occurrences all number
    12
    18
    13
    43
    Musculoskeletal pain
         subjects affected / exposed
    4 / 120 (3.33%)
    11 / 118 (9.32%)
    6 / 381 (1.57%)
    21 / 619 (3.39%)
         occurrences all number
    4
    13
    7
    24
    Myalgia
         subjects affected / exposed
    12 / 120 (10.00%)
    15 / 118 (12.71%)
    26 / 381 (6.82%)
    53 / 619 (8.56%)
         occurrences all number
    14
    20
    31
    65
    Pain in extremity
         subjects affected / exposed
    12 / 120 (10.00%)
    21 / 118 (17.80%)
    26 / 381 (6.82%)
    59 / 619 (9.53%)
         occurrences all number
    14
    30
    30
    74
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    8 / 120 (6.67%)
    9 / 118 (7.63%)
    14 / 381 (3.67%)
    31 / 619 (5.01%)
         occurrences all number
    11
    11
    15
    37
    Gastroenteritis
         subjects affected / exposed
    10 / 120 (8.33%)
    3 / 118 (2.54%)
    4 / 381 (1.05%)
    17 / 619 (2.75%)
         occurrences all number
    10
    6
    4
    20
    Influenza
         subjects affected / exposed
    6 / 120 (5.00%)
    9 / 118 (7.63%)
    15 / 381 (3.94%)
    30 / 619 (4.85%)
         occurrences all number
    6
    9
    16
    31
    Nasopharyngitis
         subjects affected / exposed
    4 / 120 (3.33%)
    12 / 118 (10.17%)
    14 / 381 (3.67%)
    30 / 619 (4.85%)
         occurrences all number
    5
    17
    15
    37
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 120 (6.67%)
    8 / 118 (6.78%)
    11 / 381 (2.89%)
    27 / 619 (4.36%)
         occurrences all number
    8
    13
    16
    37
    Folliculitis
         subjects affected / exposed
    6 / 120 (5.00%)
    4 / 118 (3.39%)
    4 / 381 (1.05%)
    14 / 619 (2.26%)
         occurrences all number
    7
    4
    5
    16
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    0 / 120 (0.00%)
    7 / 118 (5.93%)
    5 / 381 (1.31%)
    12 / 619 (1.94%)
         occurrences all number
    0
    10
    5
    15
    Hypercholesterolaemia
         subjects affected / exposed
    23 / 120 (19.17%)
    20 / 118 (16.95%)
    65 / 381 (17.06%)
    108 / 619 (17.45%)
         occurrences all number
    26
    26
    74
    126
    Hyperglycaemia
         subjects affected / exposed
    5 / 120 (4.17%)
    16 / 118 (13.56%)
    16 / 381 (4.20%)
    37 / 619 (5.98%)
         occurrences all number
    8
    23
    22
    53
    Hypertriglyceridaemia
         subjects affected / exposed
    10 / 120 (8.33%)
    2 / 118 (1.69%)
    14 / 381 (3.67%)
    26 / 619 (4.20%)
         occurrences all number
    16
    2
    15
    33
    Hypophosphataemia
         subjects affected / exposed
    7 / 120 (5.83%)
    13 / 118 (11.02%)
    13 / 381 (3.41%)
    33 / 619 (5.33%)
         occurrences all number
    15
    22
    17
    54
    Decreased appetite
         subjects affected / exposed
    6 / 120 (5.00%)
    1 / 118 (0.85%)
    5 / 381 (1.31%)
    12 / 619 (1.94%)
         occurrences all number
    7
    1
    5
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Apr 2014
    The main purpose for this substantial amendment was the inclusion of the optional Stem cells ENESTpath substudy “Leukemic stem cells quantification in patients with chronic myeloid leukemia included in the ENESTpath trial”; the purpose of this substudy was to evaluate the importance of leukemic stem cells (LSC) in the long-term maintenance of the disease and their role in the relapse of patients during the TFR phase.
    10 Feb 2015
    The main purposes for this substantial amendment were: 1. To modify the study sample size based on new data from the ENESTcmr and STIM studies and a number of published clinical trials 2. To amend the secondary objectives of the study and related endpoints 3. To incorporate the safety recommendations provided by the DMC on patients with severe cardiovascular ischemic events experienced before entering the study or while on study
    23 Sep 2015
    To update the protocol including the ‘CML patient’s voice’ Italian substudy to evaluate the emotional aspects in patients participating to a nilotinib Treatment-free remission (TFR) trial. This substudy aims to examine patients’ psycho-emotional characteristics, quality of life and experiences of being involved in CAMN107AIC05 trial and its discontinuation using a qualitative-quantitative mixed method. The ‘CML patient’s voice’ Italian substudy will be conducted in Italy only.
    01 Jun 2016
    To include hepatitis B virus testing as one of the study procedures, to identify study patients who may be at risk of hepatitis B reactivation. Reactivation of hepatitis B virus can occur in patients who are chronic carriers of this virus and are receiving a drug of the BCR-ABL TKI class such as nilotinib. Some cases involving BCR-ABL TKI resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome.

    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/ 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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