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    Clinical Trial Results:
    A Multicenter Phase 3 Randomised, Open-Label Study of Bosutinib Versus Imatinib in Adult Patients With Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia

    Summary
    EudraCT number
    2013-005101-31
    Trial protocol
    BE   GB   IT   SE   CZ   HU   SK   FI   NO   ES   DK   NL   PL   FR  
    Global end of trial date
    17 Apr 2020

    Results information
    Results version number
    v2(current)
    This version publication date
    03 May 2021
    First version publication date
    28 Jul 2018
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    B1871053
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02130557
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.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
    17 Apr 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the proportion of subjects demonstrating Major Molecular Response (MMR) at 12 months (48 weeks) in the Bosutinib arm with that of the Imatinib arm in newly diagnosed Philadelphia chromosome positive (Ph+) chronic phase (CP) chronic myelogenous leukemia (CML) subjects harboring b2a2 and/or b3a2 transcripts.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Jul 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 26
    Country: Number of subjects enrolled
    Mexico: 14
    Country: Number of subjects enrolled
    Singapore: 17
    Country: Number of subjects enrolled
    South Africa: 10
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    Thailand: 9
    Country: Number of subjects enrolled
    Ukraine: 81
    Country: Number of subjects enrolled
    United States: 88
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    Finland: 5
    Country: Number of subjects enrolled
    France: 18
    Country: Number of subjects enrolled
    Germany: 21
    Country: Number of subjects enrolled
    Hungary: 22
    Country: Number of subjects enrolled
    Italy: 36
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Norway: 6
    Country: Number of subjects enrolled
    Poland: 25
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    Spain: 35
    Country: Number of subjects enrolled
    Sweden: 15
    Country: Number of subjects enrolled
    Czechia: 11
    Country: Number of subjects enrolled
    United Kingdom: 42
    Worldwide total number of subjects
    536
    EEA total number of subjects
    215
    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)
    435
    From 65 to 84 years
    101
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    536 subjects were randomised in 1:1 ratio to Bosutinib and Imatinib groups in this study but 3 subjects were not treated in the Imatinib group.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Bosutinib
    Arm description
    Subjects with Philadelphia chromosome-positive CML received Bosutinib tablets at a dose of 400 milligram (mg), orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
    Arm type
    Experimental

    Investigational medicinal product name
    Bosutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Bosutinib at a dose of 400 mg, orally once daily.

    Arm title
    Imatinib
    Arm description
    Subjects with Philadelphia chromosome-positive CML received Imatinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
    Arm type
    Active comparator

    Investigational medicinal product name
    Imatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Imatinib at a dose of 400 mg, orally once daily.

    Number of subjects in period 1
    Bosutinib Imatinib
    Started
    268
    268
    Treated
    268
    265
    mITT population
    246
    241
    Completed
    232
    231
    Not completed
    36
    37
         Deceased
    14
    14
         Consent withdrawn by subject
    12
    12
         Investigator Request
    -
    2
         Unspecified
    2
    1
         Lost to follow-up
    6
    7
         Missing
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bosutinib
    Reporting group description
    Subjects with Philadelphia chromosome-positive CML received Bosutinib tablets at a dose of 400 milligram (mg), orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.

    Reporting group title
    Imatinib
    Reporting group description
    Subjects with Philadelphia chromosome-positive CML received Imatinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.

    Reporting group values
    Bosutinib Imatinib Total
    Number of subjects
    268 268 536
    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)
    215 220 435
        From 65-84 years
    53 48 101
        85 years and over
    0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    50.8 ± 15.40 50.9 ± 14.43 -
    Sex: Female, Male
    Units: subjects
        Female
    112 113 225
        Male
    156 155 311

    End points

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    End points reporting groups
    Reporting group title
    Bosutinib
    Reporting group description
    Subjects with Philadelphia chromosome-positive CML received Bosutinib tablets at a dose of 400 milligram (mg), orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.

    Reporting group title
    Imatinib
    Reporting group description
    Subjects with Philadelphia chromosome-positive CML received Imatinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.

    Primary: Percentage of Subjects With Major Molecular Response (MMR) at Month 12

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    End point title
    Percentage of Subjects With Major Molecular Response (MMR) at Month 12
    End point description
    MMR was defined as a ratio of breakpoint cluster region to abelson (BCR-ABL/ABL) less than or equal to (<=) 0.1 percent (%) on the international scale (IS) (greater than or equal to [>=] 3 log reduction from standardised baseline in ratio of BCR-ABL to ABL transcripts [>=3000 ABL required]) by quantitative reverse transcriptase polymerase chain reaction (RT-qPCR). The percentage of subjects with MMR at Month 12 are reported. Modified intent-to-treat (mITT) population included all randomised subjects with Ph+ CML harboring the b2a2 and/or b3a2 transcript and baseline BCR-ABL copies greater than (>) 0 with study drug assignment designated according to initial randomisation.
    End point type
    Primary
    End point timeframe
    Month 12
    End point values
    Bosutinib Imatinib
    Number of subjects analysed
    246
    241
    Units: percentage of subjects
        number (confidence interval 95%)
    47.2 (40.9 to 53.4)
    36.9 (30.8 to 43.0)
    Statistical analysis title
    Bosutinib versus Imatinib
    Statistical analysis description
    95% Confidence Interval (CI) for the odds ratio adjusted for sokal risk group and region are based on Mantel-Haenszel confidence limits.
    Comparison groups
    Bosutinib v Imatinib
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.01 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.547
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.072
         upper limit
    2.233
    Notes
    [1] - A total sample size of 500 Ph+ subjects is required for the study to provide >= 90% power to detect at least 15% difference (assuming 25% in the imatinib vs 40% in the bosutinib arm) in the MMR rates at 12 months (48 weeks) with a 1-sided alpha of 2.5%, and 2 interim futility analyses at 33% and 66% of subjects with adequate follow-up with early stopping for futility only (non-binding, O’Brien-Fleming analog beta spending function).
    [2] - 1-sided p-value based on CMH test for general association between treatment and response with stratification by sokal risk group (low, intermediate, high) and region (1-3) at time of randomisation. Statistical significance threshold: 1-sided 0.025.

    Secondary: Percentage of Subjects With Major Molecular Response (MMR) Up to Month 18

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    End point title
    Percentage of Subjects With Major Molecular Response (MMR) Up to Month 18
    End point description
    MMR was defined as a ratio of BCR-ABL/ABL <=0.1% on the international scale (>=3 log reduction from standardised baseline in ratio of BCR-ABL to ABL transcripts [>=3000 ABL required]) by quantitative RT-qPCR. The percentage of subjects with MMR for up to Month 18 are reported. mITT population included all randomised subjects with Ph+ CML harboring the b2a2 and/or b3a2 transcript and baseline BCR-ABL copies >0 with study drug assignment designated according to initial randomisation.
    End point type
    Secondary
    End point timeframe
    Up to Month 18
    End point values
    Bosutinib Imatinib
    Number of subjects analysed
    246
    241
    Units: percentage of subjects
        number (confidence interval 95%)
    61.0 (54.9 to 67.1)
    52.7 (46.4 to 59.0)
    Statistical analysis title
    Bosutinib versus Imatinib
    Statistical analysis description
    95% CI for the odds ratio adjusted for sokal risk group and region are based on Mantel-Haenszel confidence limits.
    Comparison groups
    Bosutinib v Imatinib
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.0303 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.418
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.986
         upper limit
    2.037
    Notes
    [3] - If the primary analysis was significant, each member of the short-term family (CCyR by Month 12, MMR by Month 18) was tested via Bonferroni’s procedure at the 1-sided level of 0.0125.
    [4] - 1-sided p-value based on CMH test for general association between treatment and response with stratification by sokal risk group (low, intermediate, high) and region (1-3) at time of randomisation. Statistical significance threshold: 1-sided 0.0125.

    Secondary: Kaplan-Meier Estimate of Probability of Retaining Major Molecular Response (MMR) at Month 48

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    End point title
    Kaplan-Meier Estimate of Probability of Retaining Major Molecular Response (MMR) at Month 48
    End point description
    The Kaplan-Meier curve was generated based on first date of MMR until date of confirmed loss of MMR or censoring, objectively documented, for responders only. Confirmed loss of MMR was BCR-ABL/ABL IS ratio >0.1% in association with >=5-fold increase in BCR-ABL/ABL IS ratio from lowest value achieved up to that time-point confirmed by second assessment at least 28 days later. Treatment discontinuation due to suboptimal response/treatment failure, progressive disease (PD) or death due to PD within 28 days of last dose were considered confirmed loss of MMR. PD defined as disease progression to accelerated phase (AP) or blast phase (BP) CML. mITT population included all randomised subjects with Ph+ CML harboring b2a2 and/or b3a2 transcript and baseline BCR-ABL copies >0 with study drug assignment designated according to initial randomisation and who achieved MMR (responders). Here, "Overall number of Subjects Analysed (N)" signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Month 48
    End point values
    Bosutinib Imatinib
    Number of subjects analysed
    182
    158
    Units: percentage of subjects
        number (confidence interval 95%)
    92.2 (86.8 to 95.4)
    92.0 (85.9 to 95.5)
    Statistical analysis title
    Bosutinib versus Imatinib
    Statistical analysis description
    Hazard ratio (95% CIs) are based on the treatment effect (Bosutinib compared with Imatinib) in a stratified (by Sokal risk group at randomisation and region) Cox proportional hazards model for the hazard of the respective event.
    Comparison groups
    Bosutinib v Imatinib
    Number of subjects included in analysis
    340
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    2.44
    Notes
    [5] - The medians have not been reached in either arm, as such, the premature estimated hazard ratio is provided.

    Secondary: Percentage of Subjects With Complete Cytogenetic Response (CCyR) Up to Month 12

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    End point title
    Percentage of Subjects With Complete Cytogenetic Response (CCyR) Up to Month 12
    End point description
    Complete Cytogenetic Response (CCyR) was based on the prevalence of Ph+ metaphases among cells in metaphase on a bone marrow (BM) aspirate. CCyR was achieved when there was 0% Ph+ metaphases among cells in a BM sample when at least 20 metaphases from a BM sample were analysed, or MMR if no BM was available. The percentage of subjects with CCyR for up to Month 12 are reported. mITT population included all randomised subjects with Ph+ CML harboring the b2a2 and/or b3a2 transcript and baseline BCR-ABL copies >0 with study drug assignment designated according to initial randomisation.
    End point type
    Secondary
    End point timeframe
    Up to Month 12
    End point values
    Bosutinib Imatinib
    Number of subjects analysed
    246
    241
    Units: percentage of subjects
        number (confidence interval 95%)
    77.2 (72.0 to 82.5)
    66.4 (60.4 to 72.4)
    Statistical analysis title
    Bosutinib versus Imatinib
    Statistical analysis description
    95% CI for the odds ratio adjusted for sokal risk group and region are based on Mantel-Haenszel confidence limits.
    Comparison groups
    Bosutinib v Imatinib
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    = 0.0037 [7]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.16
         upper limit
    2.61
    Notes
    [6] - If the primary analysis was significant, each member of the short-term family (CCyR by Month 12, MMR by Month 18) was tested via Bonferroni’s procedure at the 1-sided level of 0.0125.
    [7] - 1-sided p-value based on CMH test for general association between treatment and response with stratification by sokal risk group (low, intermediate, high) and region (1-3) at time of randomisation. Statistical significance threshold: 1-sided 0.0125.

    Secondary: Kaplan-Meier Estimate of Probability of Retaining Complete Cytogenetic Response (CCyR) at Month 48

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    End point title
    Kaplan-Meier Estimate of Probability of Retaining Complete Cytogenetic Response (CCyR) at Month 48
    End point description
    The Kaplan-Meier curve was generated based on the first date of CCyR until the date of the confirmed loss of CCyR or censoring, objectively documented, for responders only. Confirmed loss of CCyR was the presence of at least one Ph+ metaphase confirmed by a second assessment at least 28 days later. Treatment discontinuation due to suboptimal response/treatment failure, PD or death due to PD within 28 days of last dose were considered confirmed loss of CCyR. PD was defined as disease progression to AP or BP CML. mITT population included all randomised subjects with Ph+ CML harboring the b2a2 and/or b3a2 transcript and baseline BCR-ABL copies >0 with study drug assignment designated according to initial randomisation and who achieved CCyR (responders). Here, "N" signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Month 48
    End point values
    Bosutinib Imatinib
    Number of subjects analysed
    205
    185
    Units: percentage of subjects
        number (confidence interval 95%)
    97.4 (93.9 to 98.9)
    93.7 (88.9 to 96.5)
    Statistical analysis title
    Bosutinib versus Imatinib
    Statistical analysis description
    Hazard ratio (95% CIs) are based on the treatment effect (Bosutinib compared with Imatinib) in a stratified (by Sokal risk group at randomisation and region) Cox proportional hazards model for the hazard of the respective event.
    Comparison groups
    Bosutinib v Imatinib
    Number of subjects included in analysis
    390
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.14
         upper limit
    1.13
    Notes
    [8] - The medians have not been reached in either arm, as such, the premature estimated hazard ratio is provided.

    Secondary: Cumulative Incidence of Event Free Survival (EFS) Events

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    End point title
    Cumulative Incidence of Event Free Survival (EFS) Events
    End point description
    EFS: time from randomisation to death due to any cause, transformation to AP or BP at any time, confirmed loss of complete hematologic response (CHR), confirmed loss of CCyR or censoring. Loss of CHR defined as hematologic assessment of non-CHR (chronic phase, AP, or BP) confirmed by 2 assessments at least 4 weeks apart. Loss of CHR defined as appearance of any of the following: WBC count rises to >20.0*10^9/L, platelet count rises to >=600*10^9/L, appearance of palpable spleen or other extramedullary involvement proven by biopsy, appearance of 5% myelocytes in peripheral blood, appearance of blasts or promyelocytes in peripheral blood. Loss of CCyR defined as at least 1 Ph+ metaphase from analysis of <100 metaphases confirmed by follow up cytogenetic analysis after 1 month. Cumulative incidence of EFS defined as percentage of subjects with EFS event at Month 60 and adjusted for competing risk of treatment discontinuation without event. mITT population was analysed.
    End point type
    Secondary
    End point timeframe
    Up to Month 60
    End point values
    Bosutinib Imatinib
    Number of subjects analysed
    246
    241
    Units: percentage of subjects
        number (confidence interval 95%)
    6.9 (4.2 to 10.5)
    10.4 (6.9 to 14.6)
    Statistical analysis title
    Bosutinib versus Imatinib
    Statistical analysis description
    The hazard ratio (95% CIs) are based on the proportional subdistribution hazards model stratified by Sokal risk group and region.
    Comparison groups
    Bosutinib v Imatinib
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.0749 [10]
    Method
    Gray's test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.35
         upper limit
    1.17
    Notes
    [9] - If each member of the short-term family (CCyR by Month 12, MMR by Month 18) was significant, EFS and OS were tested sequentially via the Holm's testing procedure at the 1-sided family wise level of 0.025. If one member of the short-term family was significant, EFS and OS were tested sequentially at 1-sided 0.0125.
    [10] - 1-sided p-value based on Gray's test for comparing cumulative incidence function between treatment arms stratified by sokal risk group (low, intermediate, high) and region (1-3). Statistical significance threshold: 1-sided 0.0125.

    Secondary: Overall Survival (OS) Rate

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    End point title
    Overall Survival (OS) Rate
    End point description
    OS was defined as the time (in months) from randomisation to the occurrence of death due to any cause or censoring. Kaplan-meier analysis was used for determination of OS. Percentage of subjects who were alive were estimated in this endpoint. mITT population included all randomised subjects with Ph+ CML harboring the b2a2 and/or b3a2 transcript and baseline BCR-ABL copies >0 with study drug assignment designated according to initial randomisation.
    End point type
    Secondary
    End point timeframe
    Up to Month 60
    End point values
    Bosutinib Imatinib
    Number of subjects analysed
    246
    241
    Units: percentage of subjects
        number (confidence interval 95%)
    94.9 (91.1 to 97.0)
    94.0 (90.1 to 96.4)
    Statistical analysis title
    Bosutinib versus Imatinib
    Statistical analysis description
    The hazard ratio (95% CIs) are based on the treatment effect (Bosutinib compared with Imatinib) in a stratified (by Sokal risk group at randomisation and region) Cox proportional hazards model for the hazard of the respective event.
    Comparison groups
    Bosutinib v Imatinib
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.2827 [12]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.37
         upper limit
    1.73
    Notes
    [11] - If each member of the short-term family (CCyR by Month 12, MMR by Month 18) was significant, EFS and OS were tested sequentially via the Holm's testing procedure at the 1-sided family wise level of 0.025. If one member of the short-term family was significant, EFS and OS were tested sequentially at 1-sided 0.0125.
    [12] - 1-sided p-value based on log-rank test for comparing survival curves between treatment arms stratified by sokal risk group and region. OS was not tested as EFS was not significant.

    Other pre-specified: Summary of Trough Plasma Concentration by Complete Cytogenetic Response (CCyR) of Bosutinib

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    End point title
    Summary of Trough Plasma Concentration by Complete Cytogenetic Response (CCyR) of Bosutinib [13]
    End point description
    CCyR was based on the prevalence of Ph+ metaphases among cells in metaphase on a BM aspirate. CCyR was achieved when there was 0% Ph+ metaphases among cells in a BM sample when at least 20 metaphases from a BM sample were analysed, or MMR if no BM was available. Trough plasma concentration of subjects who had CCyR are presented in this endpoint. Pharmacokinetic (PK) population included all enrolled subjects who received at least 1 dose of bosutinib and had sufficient plasma results available. Here, "N" signifies number of subjects evaluable for this endpoint and "number analysed (n)" signifies subjects evaluable at specified time points only. Data for this endpoint was not planned to be collected and analysed for Imatinib arm as pre-specified in the protocol.
    End point type
    Other pre-specified
    End point timeframe
    Pre-dose on Days 28, 56 and 84
    Notes
    [13] - 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 was planned to be analysed for reporting arm “Bosutinib” only.
    End point values
    Bosutinib
    Number of subjects analysed
    191
    Units: nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Day 28 (n= 181)
    71.282 ± 46.0545
        Day 56 (n= 184)
    73.069 ± 45.1349
        Day 84 (n= 184)
    83.973 ± 64.3206
    No statistical analyses for this end point

    Other pre-specified: Summary of Trough Plasma Concentration by Major Molecular Response (MMR) of Bosutinib

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    End point title
    Summary of Trough Plasma Concentration by Major Molecular Response (MMR) of Bosutinib [14]
    End point description
    MMR was defined as a ratio of BCR-ABL/ABL <=0.1% on the international scale (>=3 log reduction from standardized baseline in ratio of BCR-ABL to ABL transcripts) by quantitative RT-qPCR. Trough plasma concentration of subjects who had MMR are presented in this endpoint. PK population included all enrolled subjects who received at least 1 dose of bosutinib and had sufficient plasma results available. Here, "N" signifies number of subjects evaluable for this endpoint and "n" signifies subjects evaluable at specified time points only. Data for this endpoint was not planned to be collected and analysed for Imatinib arm as pre-specified in the protocol.
    End point type
    Other pre-specified
    End point timeframe
    Pre-dose on Days 28, 56 and 84
    Notes
    [14] - 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 was planned to be analysed for reporting arm “Bosutinib” only.
    End point values
    Bosutinib
    Number of subjects analysed
    141
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 28 (n= 140)
    75.050 ± 51.9551
        Day 56 (n= 140)
    78.437 ± 43.6019
        Day 84 (n= 141)
    91.081 ± 72.1500
    No statistical analyses for this end point

    Other pre-specified: Summary of Trough Plasma Concentration by Presence of Grade 1 or Higher Adverse Events (AEs) of Bosutinib

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    End point title
    Summary of Trough Plasma Concentration by Presence of Grade 1 or Higher Adverse Events (AEs) of Bosutinib [15]
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. AE was assessed according to maximum severity grading based on NCI-CTCAE version 4.0. Grade 1=mild; Grade 2=moderate; within normal limits, Grade 3=severe or medically significant but not immediately life-threatening; Grade 4=life-threatening or disabling; urgent intervention indicated; Grade 5=death. Trough plasma concentration of subjects who had grade 1 or higher AE are presented in this endpoint. Data of plasma concentration is reported separately for each preferred term of AE. PK population included all enrolled subjects who received at least 1 dose of bosutinib and had sufficient plasma results available. Here, "N"=number of subjects evaluable for this endpoint and "n"=subjects evaluable at specified time points only. Data for this endpoint was not planned to be collected and analysed for Imatinib arm.
    End point type
    Other pre-specified
    End point timeframe
    Pre-dose on Days 28, 56 and 84
    Notes
    [15] - 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 was planned to be analysed for reporting arm “Bosutinib” only.
    End point values
    Bosutinib
    Number of subjects analysed
    177
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 28: Diarrhea (n= 177)
    69.402 ± 55.5005
        Day 28: Thrombocytopenia (n= 60)
    63.529 ± 40.9949
        Day 28: Rash (n= 84)
    74.779 ± 60.6257
        Day 28: Nausea (n= 86)
    66.011 ± 42.6437
        Day 28: Vomiting (n= 44)
    71.684 ± 60.7208
        Day 56: Diarrhea (n= 172)
    68.834 ± 42.6621
        Day 56: Thrombocytopenia (n= 61)
    65.327 ± 43.2859
        Day 56: Rash (n= 84)
    70.016 ± 38.7506
        Day 56: Nausea (n= 85)
    61.626 ± 44.4007
        Day 56: Vomiting (n= 40)
    65.980 ± 45.9064
        Day 84: Diarrhea (n= 165)
    81.269 ± 64.6462
        Day 84: Thrombocytopenia (n= 63)
    71.585 ± 33.6674
        Day 84: Rash (n= 85)
    89.080 ± 69.5237
        Day 84: Nausea (n= 80)
    77.702 ± 61.6179
        Day 84: Vomiting (n= 41)
    86.949 ± 55.3041
    No statistical analyses for this end point

    Other pre-specified: Summary of Trough Plasma Concentration by Presence of Grade 3 or Higher Adverse Events (AEs) of Bosutinib

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    End point title
    Summary of Trough Plasma Concentration by Presence of Grade 3 or Higher Adverse Events (AEs) of Bosutinib [16]
    End point description
    AE: any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. AE assessed according to maximum severity grading based on NCI-CTCAE version 4.0. Grade 1=mild; Grade 2=moderate; within normal limits, Grade 3=severe or medically significant but not immediately life-threatening; Grade 4=life-threatening or disabling; urgent intervention indicated; Grade 5=death. Trough plasma concentration of subjects who had grade 3 or higher AE are presented. Data of plasma concentration is reported separately for each preferred term of AE. PK population included all enrolled subjects who received at least 1 dose of bosutinib, had sufficient plasma results available. "N"=number of subjects evaluable for this endpoint and "n"=subjects evaluable at specified time points only. 99999=as only 1 subject was analysed, standard deviation could not be calculated. Data for this endpoint was not planned to be collected and analysed for Imatinib arm.
    End point type
    Other pre-specified
    End point timeframe
    Pre-dose on Days 28, 56 and 84
    Notes
    [16] - 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 was planned to be analysed for reporting arm “Bosutinib” only.
    End point values
    Bosutinib
    Number of subjects analysed
    24
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 28: Diarrhea (n= 19)
    87.769 ± 102.6181
        Day 28: Thrombocytopenia (n= 23)
    49.220 ± 36.3461
        Day 28: Rash (n= 4)
    71.150 ± 43.3246
        Day 28: Vomiting (n= 3)
    14.663 ± 21.5799
        Day 56: Diarrhea (n= 16)
    68.513 ± 45.2672
        Day 56: Thrombocytopenia (n= 24)
    56.853 ± 34.3892
        Day 56: Rash (n= 4)
    58.925 ± 18.8656
        Day 56: Vomiting (n= 1)
    38.200 ± 99999
        Day 84: Diarrhea (n= 17)
    76.782 ± 46.3006
        Day 84: Thrombocytopenia (n= 23)
    67.623 ± 35.3084
        Day 84: Rash (n= 3)
    83.967 ± 19.2542
        Day 84: Vomiting (n= 1)
    12.400 ± 99999
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Vital Signs Abnormalities

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    End point title
    Number of Subjects With Vital Signs Abnormalities
    End point description
    Criteria for vital signs abnormalities: systolic blood pressure <80 millimeter of mercury (mmHg), >210 mmHg; diastolic blood pressure <40 mmHg, >130 mmHg; heart rate <40 beats per minute (bpm), >150 bpm; temperature <32 degree celsius, >40 degree celsius; weight >=10% increase from baseline, >=10% decrease from baseline. The number of subjects with any vital sign abnormalities during On-treatment period are reported. On-Treatment was defined as values collected after the date of the first dose of test article until the last date of test article +28 days. Safety population included all subjects who received at least 1 dose of study medication with treatment assignments designated to actual study treatment received. Here, "N" signifies number of subjects evaluable for this endpoint.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to end of treatment (up to Month 60)
    End point values
    Bosutinib Imatinib
    Number of subjects analysed
    262
    263
    Units: subjects
    107
    109
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Laboratory Test Abnormalities Based on National Cancer Institute Common Terminology Criteria for AEs (NCI-CTCAE) Version 4.03

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    End point title
    Number of Subjects With Laboratory Test Abnormalities Based on National Cancer Institute Common Terminology Criteria for AEs (NCI-CTCAE) Version 4.03
    End point description
    Laboratory parameters included hematological (haemoglobin, lymphocytes [absolute], neutrophils [absolute], platelets and leukocytes) and biochemistry (albumin, alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, amylase, bilirubin, creatinine kinase, calcium, creatinine, glucose, potassium, lipase, magnesium, phosphate, sodium, urate) parameters. Abnormalities in laboratory tests were graded by NCI-CTCAE version 4.03 as Grade 1=mild; Grade 2=moderate; Grade 3=severe and Grade 4=life-threatening or disabling. The number of subjects with laboratory test abnormalities were reported. Safety population included all subjects who received at least 1 dose of study medication with treatment assignments designated to actual study treatment received.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to end of treatment (up to Month 60)
    End point values
    Bosutinib Imatinib
    Number of subjects analysed
    268
    265
    Units: subjects
        Grade 1
    6
    7
        Grade 2
    67
    59
        Grade 3
    133
    154
        Grade 4
    61
    45
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Clinically Significant Electrocardiogram (ECG) Abnormalities

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    End point title
    Number of Subjects With Clinically Significant Electrocardiogram (ECG) Abnormalities
    End point description
    Criteria for ECG abnormalities included heart rate: increase of >15 bpm from baseline value and >=120 bpm, decrease of >15 bpm from baseline value and <=45 bpm; PR interval: change of >=20 msec from baseline value and >=220 milliseconds (msec); QRS interval >=120 msec; QTcB interval >500 msec, increase of >60 msec from baseline; >450 msec (Men) or >470 msec (Women); QT interval using Fridericia’s correction (QTcF) >500 msec, increase of >60 msec from baseline, >450 msec (Men) or >470 msec (Women). The number of subjects with ECG abnormalities during On-treatment period are reported. On-Treatment was defined as values collected after the date of the first dose of test article until the last date of test article +28 days. Safety population included all subjects who received at least 1 dose of study medication with treatment assignments designated to actual study treatment received. Here, "N" signifies number of subjects evaluable for this endpoint.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to end of treatment (up to Month 60)
    End point values
    Bosutinib Imatinib
    Number of subjects analysed
    266
    262
    Units: subjects
    16
    13
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Adverse Events (AEs) Leading to Study Drug Discontinuation

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    End point title
    Number of Subjects With Adverse Events (AEs) Leading to Study Drug Discontinuation
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Safety population included all subjects who received at least 1 dose of study medication with treatment assignments designated to actual study treatment received.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to end of treatment (up to Month 60)
    End point values
    Bosutinib Imatinib
    Number of subjects analysed
    268
    265
    Units: subjects
    68
    38
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Treatment-Emergent Adverse Events by National Cancer Institute Common Terminology Criteria for AEs (NCI-CTCAE) (Version 4.0)

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    End point title
    Number of Subjects With Treatment-Emergent Adverse Events by National Cancer Institute Common Terminology Criteria for AEs (NCI-CTCAE) (Version 4.0)
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. AE was assessed according to severity grading based on NCI-CTCAE version 4.0. Grade 1=mild; Grade 2=moderate; Grade 3=severe or medically significant but not immediately life-threatening, hospitalisation or prolongation of hospitalisation indicated; Grade 4=life-threatening or disabling, urgent intervention indicated; Grade 5=death. Treatment-emergent events were events between first dose of study drug and up to 60 months that were absent before treatment that worsened relative to pretreatment state. If the same subject in a given treatment had more than 1 adverse event, only the maximum CTCAE was reported. Safety population included all subjects who received at least 1 dose of study medication with treatment assignments designated to actual study treatment received.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to end of treatment (up to Month 60)
    End point values
    Bosutinib Imatinib
    Number of subjects analysed
    268
    265
    Units: subjects
        Grade 1
    7
    24
        Grade 2
    61
    86
        Grade 3
    144
    120
        Grade 4
    50
    28
        Grade 5
    3
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of drug up to 28 days after last dose (up to Month 60)
    Adverse event reporting additional description
    Total deaths in study (randomisation up to month 60): for all randomised subjects (n=268 bosutinib; n=268 imatinib), not only for treated subjects, included deaths occurred after 28 days post last drug dose. SAEs, Non-SAEs: safety population (all subjects, regardless of Ph chromosome or transcript status, received at least 1 dose of study drug).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Bosutinib
    Reporting group description
    Subjects with Philadelphia chromosome-positive CML received bosutinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.

    Reporting group title
    Imatinib
    Reporting group description
    Subjects with Philadelphia chromosome-positive CML received imatinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.

    Serious adverse events
    Bosutinib Imatinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    98 / 268 (36.57%)
    68 / 265 (25.66%)
         number of deaths (all causes)
    14
    14
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    2 / 268 (0.75%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder papilloma
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoid tumour of the caecum
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer metastatic
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fallopian tube cancer stage III
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fibromatosis
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    2 / 268 (0.75%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 268 (0.37%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Unintended pregnancy
         subjects affected / exposed
    2 / 268 (0.75%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 268 (1.87%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Implant site haematoma
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Swelling face
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Pregnancy of partner
         subjects affected / exposed
    2 / 268 (0.75%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatic dysplasia
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 268 (0.75%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    4 / 268 (1.49%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 268 (0.37%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary toxicity
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 268 (0.75%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 268 (2.24%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 268 (0.75%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood sodium decreased
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 268 (0.37%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    2 / 268 (0.75%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 268 (0.75%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    4 / 268 (1.49%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 268 (0.75%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    2 / 268 (0.75%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pericarditis
         subjects affected / exposed
    2 / 268 (0.75%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuropericarditis
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Headache
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 268 (0.37%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 268 (0.37%)
    3 / 265 (1.13%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 268 (0.75%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    5 / 5
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 268 (0.00%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agranulocytosis
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal vein occlusion
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye haemorrhage
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ocular hypertension
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinopathy
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 268 (1.87%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 268 (0.37%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 268 (0.37%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising oesophagitis
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haematoma
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedematous pancreatitis
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    2 / 268 (0.75%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    2 / 268 (0.75%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    2 / 268 (0.75%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 268 (0.00%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 268 (0.00%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lichen planus
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus bladder
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    2 / 268 (0.75%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    4 / 268 (1.49%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    2 / 268 (0.75%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Endocrine disorders
    Thyroid disorder
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteochondrosis
         subjects affected / exposed
    1 / 268 (0.37%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 268 (0.75%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 268 (0.37%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    8 / 268 (2.99%)
    5 / 265 (1.89%)
         occurrences causally related to treatment / all
    2 / 8
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastroenteritis
         subjects affected / exposed
    6 / 268 (2.24%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 268 (1.12%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    3 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 268 (0.00%)
    3 / 265 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 268 (0.37%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 268 (0.00%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 268 (0.00%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida pneumonia
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective pericardial effusion
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 268 (0.37%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic infection
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    1 / 268 (0.37%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fournier's gangrene
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningococcal sepsis
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngitis fungal
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Bosutinib Imatinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    264 / 268 (98.51%)
    260 / 265 (98.11%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    26 / 268 (9.70%)
    29 / 265 (10.94%)
         occurrences all number
    47
    48
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    57 / 268 (21.27%)
    54 / 265 (20.38%)
         occurrences all number
    68
    89
    Pyrexia
         subjects affected / exposed
    44 / 268 (16.42%)
    29 / 265 (10.94%)
         occurrences all number
    70
    45
    Asthenia
         subjects affected / exposed
    34 / 268 (12.69%)
    24 / 265 (9.06%)
         occurrences all number
    49
    36
    Oedema peripheral
         subjects affected / exposed
    20 / 268 (7.46%)
    43 / 265 (16.23%)
         occurrences all number
    38
    73
    Influenza like illness
         subjects affected / exposed
    16 / 268 (5.97%)
    6 / 265 (2.26%)
         occurrences all number
    26
    7
    Face oedema
         subjects affected / exposed
    7 / 268 (2.61%)
    17 / 265 (6.42%)
         occurrences all number
    8
    29
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    29 / 268 (10.82%)
    14 / 265 (5.28%)
         occurrences all number
    39
    21
    Cough
         subjects affected / exposed
    30 / 268 (11.19%)
    26 / 265 (9.81%)
         occurrences all number
    40
    36
    Oropharyngeal pain
         subjects affected / exposed
    17 / 268 (6.34%)
    10 / 265 (3.77%)
         occurrences all number
    27
    14
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    18 / 268 (6.72%)
    19 / 265 (7.17%)
         occurrences all number
    24
    23
    Anxiety
         subjects affected / exposed
    15 / 268 (5.60%)
    15 / 265 (5.66%)
         occurrences all number
    19
    16
    Depression
         subjects affected / exposed
    9 / 268 (3.36%)
    14 / 265 (5.28%)
         occurrences all number
    11
    16
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    90 / 268 (33.58%)
    16 / 265 (6.04%)
         occurrences all number
    264
    28
    Aspartate aminotransferase increased
         subjects affected / exposed
    69 / 268 (25.75%)
    18 / 265 (6.79%)
         occurrences all number
    169
    25
    Lipase increased
         subjects affected / exposed
    56 / 268 (20.90%)
    30 / 265 (11.32%)
         occurrences all number
    156
    49
    Blood alkaline phosphatase increased
         subjects affected / exposed
    17 / 268 (6.34%)
    7 / 265 (2.64%)
         occurrences all number
    21
    9
    Blood creatinine increased
         subjects affected / exposed
    18 / 268 (6.72%)
    22 / 265 (8.30%)
         occurrences all number
    40
    56
    Amylase increased
         subjects affected / exposed
    25 / 268 (9.33%)
    10 / 265 (3.77%)
         occurrences all number
    72
    13
    Blood bilirubin increased
         subjects affected / exposed
    17 / 268 (6.34%)
    7 / 265 (2.64%)
         occurrences all number
    31
    9
    Blood creatine phosphokinase increased
         subjects affected / exposed
    14 / 268 (5.22%)
    33 / 265 (12.45%)
         occurrences all number
    35
    57
    Weight increased
         subjects affected / exposed
    8 / 268 (2.99%)
    20 / 265 (7.55%)
         occurrences all number
    10
    24
    Nervous system disorders
    Headache
         subjects affected / exposed
    58 / 268 (21.64%)
    41 / 265 (15.47%)
         occurrences all number
    119
    90
    Dizziness
         subjects affected / exposed
    25 / 268 (9.33%)
    23 / 265 (8.68%)
         occurrences all number
    34
    42
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    96 / 268 (35.82%)
    53 / 265 (20.00%)
         occurrences all number
    262
    130
    Anaemia
         subjects affected / exposed
    59 / 268 (22.01%)
    59 / 265 (22.26%)
         occurrences all number
    117
    161
    Neutropenia
         subjects affected / exposed
    33 / 268 (12.31%)
    61 / 265 (23.02%)
         occurrences all number
    85
    190
    Leukopenia
         subjects affected / exposed
    18 / 268 (6.72%)
    34 / 265 (12.83%)
         occurrences all number
    36
    107
    Lymphopenia
         subjects affected / exposed
    15 / 268 (5.60%)
    8 / 265 (3.02%)
         occurrences all number
    52
    29
    Eye disorders
    Periorbital oedema
         subjects affected / exposed
    4 / 268 (1.49%)
    44 / 265 (16.60%)
         occurrences all number
    6
    58
    Vision blurred
         subjects affected / exposed
    5 / 268 (1.87%)
    14 / 265 (5.28%)
         occurrences all number
    6
    20
    Conjunctival haemorrhage
         subjects affected / exposed
    2 / 268 (0.75%)
    18 / 265 (6.79%)
         occurrences all number
    3
    30
    Eyelid oedema
         subjects affected / exposed
    3 / 268 (1.12%)
    24 / 265 (9.06%)
         occurrences all number
    5
    42
    Dry eye
         subjects affected / exposed
    4 / 268 (1.49%)
    16 / 265 (6.04%)
         occurrences all number
    4
    16
    Lacrimation increased
         subjects affected / exposed
    1 / 268 (0.37%)
    18 / 265 (6.79%)
         occurrences all number
    1
    22
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    201 / 268 (75.00%)
    106 / 265 (40.00%)
         occurrences all number
    674
    319
    Nausea
         subjects affected / exposed
    100 / 268 (37.31%)
    112 / 265 (42.26%)
         occurrences all number
    194
    218
    Vomiting
         subjects affected / exposed
    55 / 268 (20.52%)
    54 / 265 (20.38%)
         occurrences all number
    123
    92
    Abdominal pain
         subjects affected / exposed
    61 / 268 (22.76%)
    25 / 265 (9.43%)
         occurrences all number
    88
    36
    Constipation
         subjects affected / exposed
    36 / 268 (13.43%)
    17 / 265 (6.42%)
         occurrences all number
    44
    19
    Abdominal pain upper
         subjects affected / exposed
    28 / 268 (10.45%)
    26 / 265 (9.81%)
         occurrences all number
    64
    63
    Dyspepsia
         subjects affected / exposed
    26 / 268 (9.70%)
    24 / 265 (9.06%)
         occurrences all number
    32
    33
    Abdominal distension
         subjects affected / exposed
    14 / 268 (5.22%)
    8 / 265 (3.02%)
         occurrences all number
    15
    9
    Toothache
         subjects affected / exposed
    14 / 268 (5.22%)
    7 / 265 (2.64%)
         occurrences all number
    16
    8
    Gastrooesophageal reflux disease
         subjects affected / exposed
    8 / 268 (2.99%)
    14 / 265 (5.28%)
         occurrences all number
    8
    14
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    61 / 268 (22.76%)
    39 / 265 (14.72%)
         occurrences all number
    93
    59
    Pruritus
         subjects affected / exposed
    30 / 268 (11.19%)
    10 / 265 (3.77%)
         occurrences all number
    42
    10
    Rash maculo-papular
         subjects affected / exposed
    13 / 268 (4.85%)
    16 / 265 (6.04%)
         occurrences all number
    21
    26
    Alopecia
         subjects affected / exposed
    15 / 268 (5.60%)
    14 / 265 (5.28%)
         occurrences all number
    17
    15
    Dry skin
         subjects affected / exposed
    20 / 268 (7.46%)
    14 / 265 (5.28%)
         occurrences all number
    23
    17
    Night sweats
         subjects affected / exposed
    5 / 268 (1.87%)
    14 / 265 (5.28%)
         occurrences all number
    6
    15
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    48 / 268 (17.91%)
    49 / 265 (18.49%)
         occurrences all number
    75
    76
    Back pain
         subjects affected / exposed
    32 / 268 (11.94%)
    25 / 265 (9.43%)
         occurrences all number
    45
    29
    Pain in extremity
         subjects affected / exposed
    26 / 268 (9.70%)
    39 / 265 (14.72%)
         occurrences all number
    33
    48
    Myalgia
         subjects affected / exposed
    13 / 268 (4.85%)
    48 / 265 (18.11%)
         occurrences all number
    21
    60
    Muscle spasms
         subjects affected / exposed
    10 / 268 (3.73%)
    81 / 265 (30.57%)
         occurrences all number
    20
    138
    Bone pain
         subjects affected / exposed
    8 / 268 (2.99%)
    19 / 265 (7.17%)
         occurrences all number
    19
    23
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    36 / 268 (13.43%)
    33 / 265 (12.45%)
         occurrences all number
    56
    59
    Nasopharyngitis
         subjects affected / exposed
    36 / 268 (13.43%)
    30 / 265 (11.32%)
         occurrences all number
    55
    50
    Urinary tract infection
         subjects affected / exposed
    26 / 268 (9.70%)
    18 / 265 (6.79%)
         occurrences all number
    34
    25
    Bronchitis
         subjects affected / exposed
    19 / 268 (7.09%)
    6 / 265 (2.26%)
         occurrences all number
    24
    7
    Influenza
         subjects affected / exposed
    24 / 268 (8.96%)
    14 / 265 (5.28%)
         occurrences all number
    31
    32
    Sinusitis
         subjects affected / exposed
    15 / 268 (5.60%)
    8 / 265 (3.02%)
         occurrences all number
    20
    8
    Gastroenteritis
         subjects affected / exposed
    12 / 268 (4.48%)
    17 / 265 (6.42%)
         occurrences all number
    14
    22
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    29 / 268 (10.82%)
    17 / 265 (6.42%)
         occurrences all number
    37
    17
    Hypophosphataemia
         subjects affected / exposed
    7 / 268 (2.61%)
    19 / 265 (7.17%)
         occurrences all number
    18
    39
    Hypokalaemia
         subjects affected / exposed
    6 / 268 (2.24%)
    23 / 265 (8.68%)
         occurrences all number
    11
    34

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Mar 2014
    Updated information for assessments of vital signs, inclusion/exclusion criteria, laboratory assessments, timing of efficacy endpoints, exploratory efficacy endpoints, study durations, timing of assessments, terms and definitions, study populations, adverse event assessments, and administrative information.
    14 Jan 2015
    Updated information for contact details, study duration, subject populations, inclusion/exclusion criteria definitions, bosutinib formulation details, assessment timings (e.g., schedule of events, pre-randomisation Sokal score assessment), timing of assessments, timing for collection of adverse events/reporting, study drug dosing requirements, compliance recording, statistical analysis (primary and secondary efficacy analysis), pharmacokinetic analysis, and administrative information.
    07 Dec 2016
    Updated information for change of sponsor details, sample size, study populations, methodology for statistical analyses, efficacy analysis, interim analyses, time to response description, extension phase visit window, sample drug diary cards, and administrative information.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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
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