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    Clinical Trial Results:
    An Open Label, Randomized Study of Nilotinib vs. Standard Imatinib (400/600 mg QD) Comparing the Kinetics of Complete Molecular Response for CML-CP Patients With Evidence of Persistent Leukemia by RQ-PCR. Due to EudraCT system limitations, which EMA is aware of, results of crossover studies and data using 999 as data points are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results

    Summary
    EudraCT number
    		 2009-012616-40
    Trial protocol
    		 FR   GB   ES  
    Global end of trial date
    03 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jul 2018
    First version publication date
    06 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CAMN107A2405
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00760877
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to compare the rate of confirmed best cumulative response (CMR) within the first year of study therapy with nilotinib or imatinib (for a definition of confirmed CMR.
    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
    12 Jun 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Australia: 48
    Country: Number of subjects enrolled
    Brazil: 82
    Country: Number of subjects enrolled
    Canada: 36
    Country: Number of subjects enrolled
    France: 31
    Country: Number of subjects enrolled
    Spain: 9
    Worldwide total number of subjects
    207
    EEA total number of subjects
    40
    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)
    179
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were randomized 1:1 to either nilotinib or imatinib. Participants in the imatinib arm were permitted to cross-over to nilotinib after 2 years on study if CMR was not achieved, or at any time during the study if participants experienced treatment failure, had confirmed loss of major molecular response (MMR) or had confirmed loss of CMR.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nilotinib
    Arm description
    		 Participants received Nilotinib 400 mg orally twice daily (bid) for 48 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nilotinib
    Investigational medicinal product code
    AMN107
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Nilotinib 400 mg orally twice daily (bid) for 48 months.

    Arm title
    		 Imatinib
    Arm description
    		 Participants received Imatinib 400 mg or 600 mg once daily (qd) (based on the participant\'s dose prior to randomization) for 48 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Imatinib
    Investigational medicinal product code
    Other name
    Glivec/Gleevec
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Imatinib 400 mg or 600 mg once daily (qd) (based on the participant's dose prior to randomization) for 48 months. Participants were permitted to cross over to Nilotinib at 2 years if participants had not achieved CMR or at any time during the study if participants experienced treatment failure, had confirmed loss of MMR or confirmed loss of CMR.

    Number of subjects in period 1
    		Nilotinib Imatinib
    Started
    104
    103
    Cross-over to Nilotinib
    0 [1]
    46 [2]
    Safety set
    101
    103
    Completed
    59
    77
    Not completed
    45
    26
         Adverse event, serious fatal
    2
    1
         Consent withdrawn by subject
    7
    3
         Physician decision
    1
    2
         Non-compliance with protocol treatment
    2
    1
         Treatment failure
    1
    -
         Adverse event, non-fatal
    19
    12
         Participants transferred to AMN107A2408
    11
    1
         Participant diagnosed with AML
    -
    1
         Pregnancy
    1
    4
         Participant not eligible to cross-over
    -
    1
         Protocol deviation
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: As this was a crossover study, only 46 patients crossed over to the Nilotinib Arm. This is why the numbers are different in Period 2.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: As this was a crossover study, only 46 patients crossed over to the Nilotinib Arm. This is why the numbers are different in Period 2.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nilotinib
    Reporting group description
    		 Participants received Nilotinib 400 mg orally twice daily (bid) for 48 months.

    Reporting group title
    Imatinib
    Reporting group description
    		 Participants received Imatinib 400 mg or 600 mg once daily (qd) (based on the participant\'s dose prior to randomization) for 48 months.

    Reporting group values
    		 Nilotinib Imatinib Total
    Number of subjects
    		 104 103 207
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 90 89 179
        From 65-84 years
    		 14 14 28
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 48.3 ± 13.26 49.9 ± 13.07 -
    Gender, Male/Female
    Units: Participants
        Female
    		 33 38 71
        Male
    		 71 65 136

    End points

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    End points reporting groups
    Reporting group title
    Nilotinib
    Reporting group description
    		 Participants received Nilotinib 400 mg orally twice daily (bid) for 48 months.

    Reporting group title
    Imatinib
    Reporting group description
    		 Participants received Imatinib 400 mg or 600 mg once daily (qd) (based on the participant\'s dose prior to randomization) for 48 months.

    Primary: Rate of confirmed best cumulative complete molecular response (CMR)

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    End point title
    		 Rate of confirmed best cumulative complete molecular response (CMR)
    End point description
    The rate of confirmed best cumulative CMR was defined as the percentage of participants who had confirmed CMR during the first 12 months of treatment after the randomization date. Participants who achieved confirmed best cumulative CMR during the first 12 months were considered responders. Participants who dropped out early or who did not provide sufficient data for any reason were considered to be non-responders. The definition of CMR is undetectable BCR-ABL (fusion gene formed between bcr gene from chromosome 22 and abl gene from chromosome 9) where BCR-ABL ratio in % international scale (IS) ≤ 0.00001 by real-time quantitative polymerase chain reaction (RQ-PCR) where there was no detectable BCR-ABL and 1) the test had a sensitivity of at least 4.5 logs below the standardized baseline; 2) RQ-PCR negativity was confirmed on the next RQ-PCR sample (usually 3 months later); and 3) the date of confirmed CMR was the date of the first of two negative results with sensitivity >4.5 logs.
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Nilotinib Imatinib
    Number of subjects analysed
    104
    103
    Units: Number of particiants
        Responders
    13
    6
        Non-responders
    91
    97
    Statistical analysis title
    		 Rate of confirmed best cumulative CMR
    Comparison groups
    Nilotinib v Imatinib
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.1083
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.096
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.766
         upper limit
    		 5.738
    Notes
    [1] - The null hypothesis for the primary endpoint was that there was no difference in the rate of confirmed best cumulative CMR between the two treatment arms during the first 12 months of treatment. The corresponding alternative hypothesis was that the rate of confirmed best cumulative CMR during the first 12 months of the treatment is different between the nilotinib and imatinib treatment arms.

    Secondary: Rate of confirmed best cumulative CMR

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    End point title
    		 Rate of confirmed best cumulative CMR
    End point description
    The rate of confirmed best cumulative CMR was defined as the percentage of participants who had confirmed CMR during the 24, 36 and 48 months post treatment after the randomization date. Participants who achieved confirmed best cumulative CMR during the first 12 months were considered responders. Participants who dropped out early or who did not provide sufficient data for any reason were considered to be non-responders. The definition of CMR is undetectable BCR-ABL (fusion gene formed between bcr gene from chromosome 22 and abl gene from chromosome 9) where BCR-ABL ratio in % international scale (IS) ≤ 0.00001 by RQ-PCR where there was no detectable BCR-ABL and 1) the test had a sensitivity of at least 4.5 logs below the standardized baseline; 2) RQ-PCR negativity was confirmed on the next RQ-PCR sample (usually 3 months later); and 3) the date of confirmed CMR was the date of the first of two negative results with sensitivity >4.5 logs.
    End point type
    Secondary
    End point timeframe
    24 months, 36 month, 48 months
    End point values
    		 Nilotinib Imatinib
    Number of subjects analysed
    104
    103
    Units: Number of participants
        24 months, Responders
    24
    11
        24 months, Non-responders
    80
    92
        36 months, Responders
    29
    21
        36 months, Non-responders
    75
    82
        48 months, Responders
    32
    21
        48 months, Non-responders
    72
    82
    No statistical analyses for this end point

    Secondary: Number of cross-over participants with CMR

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    End point title
    		 Number of cross-over participants with CMR [2]
    End point description
    The definition of CMR is undetectable BCR-ABL (fusion gene formed between bcr gene from chromosome 22 and abl gene from chromosome 9) where BCR-ABL ratio in % international scale (IS) ≤ 0.00001 by RQ-PCR where there was no detectable BCR-ABL and 1) the test had a sensitivity of at least 4.5 logs below the standardized baseline; 2) RQ-PCR negativity was confirmed on the next RQ-PCR sample (usually 3 months later); and 3) the date of confirmed CMR was the date of the first of two negative results with sensitivity >4.5 logs.
    End point type
    Secondary
    End point timeframe
    24 months, 36 months, 48 months
    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: Nilotinib arm (participants who crossed over from Imatinib) only is applicable to this outcome measure.
    End point values
    		 Nilotinib
    Number of subjects analysed
    46
    Units: Numner of participants
        24 months
    3
        36 months
    6
        48 months
    9
    No statistical analyses for this end point

    Secondary: Progression free survival (PFS)

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    End point title
    		 Progression free survival (PFS)
    End point description
    PFS was defined as the time from the date of randomization to the date of the earliest documented progression-defining event as follows: transformation to blast crisis or accelerated phase disease, or death from any cause.
    End point type
    Secondary
    End point timeframe
    48 months
    End point values
    		 Nilotinib Imatinib
    Number of subjects analysed
    104
    103
    Units: months
        median (confidence interval 95%)
    9999 (-9999 to 9999)
    9999 (-9999 to 9999)
    No statistical analyses for this end point

    Secondary: Event-free survival

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    End point title
    		 Event-free survival
    End point description
    Event-free survival was defined as the time from the date of randomization to the date of first occurrence of any of the following events on study treatment: loss of complete hematological response, confirmed loss of complete cytogenetic response (CCyR), confirmed loss of major molecular response (MMR), death from any cause during treatment, progression to the accelerated phase or blast crisis of chronic myelogenous leukemia (CML) per European Leukemia Network (ELN) criteria, whichever was earliest.
    End point type
    Secondary
    End point timeframe
    48 months
    End point values
    		 Nilotinib Imatinib
    Number of subjects analysed
    104
    103
    Units: Months
        median (confidence interval 95%)
    9999 (-9999 to 9999)
    9999 (-9999 to 9999)
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival was defined as the time from the date of randomization to the date of death due to any cause at any time during the study, including the follow-up period after discontinuation of treatment.
    End point type
    Secondary
    End point timeframe
    48 months
    End point values
    		 Nilotinib Imatinib
    Number of subjects analysed
    104
    103
    Units: Months
        median (confidence interval 95%)
    9999 (-9999 to 9999)
    9999 (-9999 to 9999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths 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
    18.0
    Reporting groups
    Reporting group title
    Nilotinib
    Reporting group description
    		 Nilotinib n=101

    Reporting group title
    Imatinib subset that crossed over to nilotinib
    Reporting group description
    		 Imatinib subset that crossed over to nilotinib n=46

    Reporting group title
    Imatinib
    Reporting group description
    		 Imatinib Up to crossover, n = 103 After cross over to nilotinib, n = 57

    Serious adverse events
    		 Nilotinib Imatinib subset that crossed over to nilotinib Imatinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 101 (20.79%)
    8 / 46 (17.39%)
    16 / 103 (15.53%)
         number of deaths (all causes)
    1
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ACUTE MYELOID LEUKAEMIA
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MALIGNANT MELANOMA
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    METASTASES TO PERITONEUM
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    NON-SMALL CELL LUNG CANCER METASTATIC
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PROSTATE CANCER
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 46 (0.00%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RENAL CELL CARCINOMA
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    ANKLE FRACTURE
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BACK INJURY
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 46 (2.17%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DRUG ADMINISTRATION ERROR
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 46 (2.17%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LIGAMENT RUPTURE
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MUSCLE INJURY
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL ARTERIAL OCCLUSIVE DISEASE
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL VASCULAR DISORDER
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 46 (2.17%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VASCULITIS
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE CORONARY SYNDROME
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 46 (2.17%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ATRIAL FLUTTER
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 46 (2.17%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CARDIOPULMONARY FAILURE
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CORONARY ARTERY DISEASE
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LEFT VENTRICULAR DYSFUNCTION
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERICARDITIS
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    CEREBRAL ARTERY OCCLUSION
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CEREBRAL ISCHAEMIA
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 46 (2.17%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    EMBOLIC STROKE
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 46 (2.17%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ANAL FISSURE
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 46 (2.17%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CROHN'S DISEASE
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INGUINAL HERNIA
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 46 (2.17%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    LUNG DISORDER
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 46 (0.00%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    BLADDER DILATATION
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEPHROLITHIASIS
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 46 (0.00%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    URINARY RETENTION
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    INTERVERTEBRAL DISC PROTRUSION
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 46 (2.17%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SPINAL COLUMN STENOSIS
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    CELLULITIS
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 46 (0.00%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INFECTED SKIN ULCER
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUNG INFECTION
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OSTEOMYELITIS
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 46 (2.17%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Nilotinib Imatinib subset that crossed over to nilotinib Imatinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    99 / 101 (98.02%)
    39 / 46 (84.78%)
    79 / 103 (76.70%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    10 / 101 (9.90%)
    1 / 46 (2.17%)
    6 / 103 (5.83%)
         occurrences all number
    10
    1
    6
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    9 / 101 (8.91%)
    5 / 46 (10.87%)
    4 / 103 (3.88%)
         occurrences all number
    11
    6
    4
    FATIGUE
         subjects affected / exposed
    16 / 101 (15.84%)
    6 / 46 (13.04%)
    8 / 103 (7.77%)
         occurrences all number
    19
    7
    8
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    7 / 101 (6.93%)
    2 / 46 (4.35%)
    3 / 103 (2.91%)
         occurrences all number
    12
    2
    3
    OEDEMA PERIPHERAL
         subjects affected / exposed
    6 / 101 (5.94%)
    1 / 46 (2.17%)
    7 / 103 (6.80%)
         occurrences all number
    9
    1
    9
    PAIN
         subjects affected / exposed
    7 / 101 (6.93%)
    1 / 46 (2.17%)
    3 / 103 (2.91%)
         occurrences all number
    7
    1
    3
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    11 / 101 (10.89%)
    4 / 46 (8.70%)
    9 / 103 (8.74%)
         occurrences all number
    13
    4
    10
    DYSPNOEA
         subjects affected / exposed
    3 / 101 (2.97%)
    3 / 46 (6.52%)
    1 / 103 (0.97%)
         occurrences all number
    5
    3
    1
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    6 / 101 (5.94%)
    0 / 46 (0.00%)
    6 / 103 (5.83%)
         occurrences all number
    6
    0
    6
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    6 / 101 (5.94%)
    2 / 46 (4.35%)
    4 / 103 (3.88%)
         occurrences all number
    6
    2
    4
    INSOMNIA
         subjects affected / exposed
    12 / 101 (11.88%)
    2 / 46 (4.35%)
    5 / 103 (4.85%)
         occurrences all number
    14
    2
    5
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    19 / 101 (18.81%)
    8 / 46 (17.39%)
    5 / 103 (4.85%)
         occurrences all number
    34
    11
    6
    AMYLASE INCREASED
         subjects affected / exposed
    9 / 101 (8.91%)
    2 / 46 (4.35%)
    7 / 103 (6.80%)
         occurrences all number
    17
    3
    8
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    14 / 101 (13.86%)
    6 / 46 (13.04%)
    10 / 103 (9.71%)
         occurrences all number
    17
    9
    13
    BILIRUBIN CONJUGATED INCREASED
         subjects affected / exposed
    4 / 101 (3.96%)
    4 / 46 (8.70%)
    0 / 103 (0.00%)
         occurrences all number
    8
    9
    0
    BLOOD BILIRUBIN INCREASED
         subjects affected / exposed
    10 / 101 (9.90%)
    2 / 46 (4.35%)
    1 / 103 (0.97%)
         occurrences all number
    19
    3
    1
    BLOOD CHOLESTEROL INCREASED
         subjects affected / exposed
    8 / 101 (7.92%)
    0 / 46 (0.00%)
    2 / 103 (1.94%)
         occurrences all number
    11
    0
    2
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    1 / 101 (0.99%)
    2 / 46 (4.35%)
    9 / 103 (8.74%)
         occurrences all number
    1
    2
    16
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    6 / 101 (5.94%)
    2 / 46 (4.35%)
    10 / 103 (9.71%)
         occurrences all number
    6
    3
    17
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    8 / 101 (7.92%)
    2 / 46 (4.35%)
    2 / 103 (1.94%)
         occurrences all number
    8
    2
    2
    GLOBULINS DECREASED
         subjects affected / exposed
    4 / 101 (3.96%)
    0 / 46 (0.00%)
    8 / 103 (7.77%)
         occurrences all number
    8
    0
    11
    HIGH DENSITY LIPOPROTEIN DECREASED
         subjects affected / exposed
    2 / 101 (1.98%)
    3 / 46 (6.52%)
    6 / 103 (5.83%)
         occurrences all number
    4
    4
    8
    LIPASE INCREASED
         subjects affected / exposed
    19 / 101 (18.81%)
    7 / 46 (15.22%)
    13 / 103 (12.62%)
         occurrences all number
    36
    8
    18
    LOW DENSITY LIPOPROTEIN INCREASED
         subjects affected / exposed
    2 / 101 (1.98%)
    4 / 46 (8.70%)
    3 / 103 (2.91%)
         occurrences all number
    3
    5
    4
    WEIGHT DECREASED
         subjects affected / exposed
    10 / 101 (9.90%)
    2 / 46 (4.35%)
    5 / 103 (4.85%)
         occurrences all number
    10
    2
    5
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    5 / 101 (4.95%)
    3 / 46 (6.52%)
    6 / 103 (5.83%)
         occurrences all number
    5
    4
    6
    HEADACHE
         subjects affected / exposed
    43 / 101 (42.57%)
    8 / 46 (17.39%)
    13 / 103 (12.62%)
         occurrences all number
    64
    11
    13
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    6 / 101 (5.94%)
    5 / 46 (10.87%)
    12 / 103 (11.65%)
         occurrences all number
    7
    6
    13
    Eye disorders
    CONJUNCTIVAL HAEMORRHAGE
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 46 (0.00%)
    6 / 103 (5.83%)
         occurrences all number
    1
    0
    10
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    12 / 101 (11.88%)
    5 / 46 (10.87%)
    8 / 103 (7.77%)
         occurrences all number
    17
    6
    10
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    13 / 101 (12.87%)
    5 / 46 (10.87%)
    7 / 103 (6.80%)
         occurrences all number
    22
    7
    9
    CONSTIPATION
         subjects affected / exposed
    15 / 101 (14.85%)
    3 / 46 (6.52%)
    0 / 103 (0.00%)
         occurrences all number
    19
    3
    0
    DIARRHOEA
         subjects affected / exposed
    14 / 101 (13.86%)
    4 / 46 (8.70%)
    19 / 103 (18.45%)
         occurrences all number
    16
    6
    26
    NAUSEA
         subjects affected / exposed
    22 / 101 (21.78%)
    4 / 46 (8.70%)
    16 / 103 (15.53%)
         occurrences all number
    25
    5
    18
    VOMITING
         subjects affected / exposed
    11 / 101 (10.89%)
    0 / 46 (0.00%)
    6 / 103 (5.83%)
         occurrences all number
    16
    0
    12
    Hepatobiliary disorders
    HYPERBILIRUBINAEMIA
         subjects affected / exposed
    10 / 101 (9.90%)
    6 / 46 (13.04%)
    0 / 103 (0.00%)
         occurrences all number
    20
    7
    0
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    11 / 101 (10.89%)
    4 / 46 (8.70%)
    0 / 103 (0.00%)
         occurrences all number
    12
    4
    0
    DRY SKIN
         subjects affected / exposed
    20 / 101 (19.80%)
    3 / 46 (6.52%)
    0 / 103 (0.00%)
         occurrences all number
    23
    3
    0
    PRURITUS
         subjects affected / exposed
    30 / 101 (29.70%)
    2 / 46 (4.35%)
    0 / 103 (0.00%)
         occurrences all number
    41
    6
    0
    RASH
         subjects affected / exposed
    30 / 101 (29.70%)
    9 / 46 (19.57%)
    4 / 103 (3.88%)
         occurrences all number
    54
    11
    4
    RASH FOLLICULAR
         subjects affected / exposed
    4 / 101 (3.96%)
    3 / 46 (6.52%)
    0 / 103 (0.00%)
         occurrences all number
    4
    3
    0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    16 / 101 (15.84%)
    6 / 46 (13.04%)
    10 / 103 (9.71%)
         occurrences all number
    21
    7
    11
    BACK PAIN
         subjects affected / exposed
    12 / 101 (11.88%)
    7 / 46 (15.22%)
    9 / 103 (8.74%)
         occurrences all number
    13
    7
    10
    MUSCLE SPASMS
         subjects affected / exposed
    15 / 101 (14.85%)
    1 / 46 (2.17%)
    18 / 103 (17.48%)
         occurrences all number
    16
    1
    22
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    10 / 101 (9.90%)
    2 / 46 (4.35%)
    8 / 103 (7.77%)
         occurrences all number
    14
    3
    8
    MYALGIA
         subjects affected / exposed
    14 / 101 (13.86%)
    6 / 46 (13.04%)
    2 / 103 (1.94%)
         occurrences all number
    22
    7
    3
    PAIN IN EXTREMITY
         subjects affected / exposed
    14 / 101 (13.86%)
    8 / 46 (17.39%)
    4 / 103 (3.88%)
         occurrences all number
    20
    8
    4
    Infections and infestations
    FOLLICULITIS
         subjects affected / exposed
    8 / 101 (7.92%)
    2 / 46 (4.35%)
    0 / 103 (0.00%)
         occurrences all number
    9
    2
    0
    INFLUENZA
         subjects affected / exposed
    9 / 101 (8.91%)
    2 / 46 (4.35%)
    9 / 103 (8.74%)
         occurrences all number
    11
    2
    9
    NASOPHARYNGITIS
         subjects affected / exposed
    9 / 101 (8.91%)
    2 / 46 (4.35%)
    5 / 103 (4.85%)
         occurrences all number
    15
    2
    6
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    20 / 101 (19.80%)
    7 / 46 (15.22%)
    14 / 103 (13.59%)
         occurrences all number
    30
    8
    18
    URINARY TRACT INFECTION
         subjects affected / exposed
    8 / 101 (7.92%)
    2 / 46 (4.35%)
    1 / 103 (0.97%)
         occurrences all number
    10
    2
    1
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    8 / 101 (7.92%)
    1 / 46 (2.17%)
    6 / 103 (5.83%)
         occurrences all number
    10
    3
    6
    HYPERCHOLESTEROLAEMIA
         subjects affected / exposed
    11 / 101 (10.89%)
    7 / 46 (15.22%)
    6 / 103 (5.83%)
         occurrences all number
    13
    8
    6
    HYPERGLYCAEMIA
         subjects affected / exposed
    4 / 101 (3.96%)
    6 / 46 (13.04%)
    6 / 103 (5.83%)
         occurrences all number
    7
    13
    9
    HYPERTRIGLYCERIDAEMIA
         subjects affected / exposed
    3 / 101 (2.97%)
    2 / 46 (4.35%)
    7 / 103 (6.80%)
         occurrences all number
    3
    2
    14
    HYPOPHOSPHATAEMIA
         subjects affected / exposed
    9 / 101 (8.91%)
    7 / 46 (15.22%)
    13 / 103 (12.62%)
         occurrences all number
    15
    12
    21

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jun 2009
    Amendment 1 was a global amendment to include an additional inclusion criterion: To be eligible for the study, patients must now had to have serum calcium levels within normal levels.
    20 May 2010
    Amendment 2 was a global amendment to correct and clarify two inclusion and one exclusion criterion. Inclusion criterion #4 was modified to remove the example “i.e. BCR-ABL level <1% IS”and to change the time frame between PCR tests to 8 weeks instead of 10 weeks. Inclusion criterion #10, which required phosphorus levels to be within normal limits, was removed. The criterion was also modified to require electrolytes ≥ lower limit of normal rather than within normal limits. Exclusion criterion #4, which states patients must not have had prior stem cell transplantation, was modified: Patients who had received an autologous transplant and were in chronic phase prior to transplant and never in accelerated phase or blast crisis were now eligible. Information regarding study drug and H1N1 vaccinations were also added.
    21 Mar 2012
    Amendment 3 was a global amendment to update the safety and to clarify survival follow-up. The protocol was amended in order to reflect what was captured in the case report forms prior to the Month 24 analysis.
    15 Jan 2014
    Amendment 4 was a global amendment to ensure alignment and consistency of pregnancy prevention language with the nilotinib program language, nilotinib label, and Novartis internal pregnancy guidelines. These changes have also been incorporated into the consent form. In addition, the risks associated with nilotinib in the consent form have been updated to reflect the current investigators brochure.
    05 Sep 2014
    Amendment 5 was a global amendment to remove the requirement for survival follow up for an additional 6 years after the study closure. In addition, the ICF was updated to include language that the biomarker samples that remain after analysis is completed (tumor, blood, plasma, and serum) may be kept for up to 15 years to be used for additi onal studies by Novartis.

    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, results of crossover studies and data using 999 as data points are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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