Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   41189   clinical trials with a EudraCT protocol, of which   6743   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase II Study of Dasatinib Therapy in Children and Adolescents with Ph+ Leukemia with Resistance or Intolerance to Imatinib.

    Summary
    EudraCT number
    2008-002260-33
    Trial protocol
    IT   ES   FR   NL   GB   DE   Outside EU/EEA  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Dec 2017
    First version publication date
    30 Dec 2017
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    CA180-226
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00777036
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000567-PIP01-09
    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?
    Yes
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    01 Sep 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Sep 2016
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to determine whether dasatinib is safe and effective in children and adolescents with newly diagnosed chronic myeloid leukemia (CML), or in children with Ph+ acute lymphoblastic leukemia (ALL), accelerated or blast phases CML who relapse after imatinib or who are resistant or intolerant to imatinib. The side effects of this oral investigational drug in children and adolescents will be evaluated
    Protection of trial subjects
    The study was conducted in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Mar 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    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
    Argentina: 1
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Brazil: 15
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    India: 19
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Mexico: 14
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Singapore: 2
    Country: Number of subjects enrolled
    South Africa: 5
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United States: 23
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Russian Federation: 9
    Country: Number of subjects enrolled
    Korea, Republic of: 15
    Worldwide total number of subjects
    145
    EEA total number of subjects
    33
    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)
    3
    Children (2-11 years)
    63
    Adolescents (12-17 years)
    77
    Adults (18-64 years)
    2
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Subjects were enrolled at 80 sites (Argentina, Australia, Brazil, Canada, France, Germany, Great Britain, India, Italy, Korea, Mexico, Netherlands, Romania, Russia, Singapore, South Africa, Spain, and USA).

    Pre-assignment
    Screening details
    A total of 145 Subjects were enrolled and 130 Subjects were treated in the study. Reasons for non-treatment include 2 withdrew consent, 1 died, 11 failed to meet study criteria, and 1 other non-specified.

    Period 1
    Period 1 title
    On Treatment
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1
    Arm description
    Children and adolescents with CP-CML who were resistant or intolerant to imatinib received dasatinib tablets at 60 mg/m2 QD on a continuous oral regimen.
    Arm type
    Experimental

    Investigational medicinal product name
    Dasatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dasatinib tablets at 60 mg/m2 QD, with a maximum dose of 100 mg QD for subjects with high BSA

    Arm title
    Cohort 2
    Arm description
    Children and adolescents with Ph+ ALL, AP-CML or BP-CML who were resistant or intolerant to, or relapsed after imatinib therapy received dasatinib tablets at a dose schedule of 80 mg/m2 QD on a continuous oral regimen.
    Arm type
    Experimental

    Investigational medicinal product name
    Dasatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dasatinib tablets at dose schedule of 80 mg/m2 QD, with a maximum dose of 140 mg QD for subjects with high BSA

    Arm title
    Cohort 3
    Arm description
    Children and adolescents with CP-CML who were treatment-naive received dasatinib tablets at 60 mg/m2 QD or powder for oral suspension (PFOS) at 72 mg/m2 QD on a continuous oral regimen.
    Arm type
    Experimental

    Investigational medicinal product name
    Dasatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Dasatinib powder for oral suspension (PFOS) at 72 mg/m2 QD on a continuous oral regimen.

    Investigational medicinal product name
    Dasatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dasatinib tablets at 60 mg/m2 QD, with a maximum dose of 100 mg QD for subjects with high BSA

    Number of subjects in period 1 [1]
    Cohort 1 Cohort 2 Cohort 3
    Started
    29
    17
    84
    Completed
    14
    1
    61
    Not completed
    15
    16
    23
         Study Drug Toxicity
    -
    -
    1
         Non-compliance with Study Drug
    1
    -
    -
         Reason Not Specified
    4
    7
    12
         Adverse event, serious fatal
    -
    2
    -
         Progressive Disease
    5
    4
    6
         Consent withdrawn by subject
    3
    2
    3
         Maximum Clinical Benefit
    2
    -
    1
         Failure to Meet Study Criteria
    -
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 145 subjects were enrolled and 130 subjects were treated in the study and included in the baseline period. Reasons for non-treatment include 2 withdrew consent, 1 died, 11 failed to meet study criteria, and 1 other non-specified.
    Period 2
    Period 2 title
    Follow-Up
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1
    Arm description
    Children and adolescents with CP-CML who were resistant or intolerant to imatinib received dasatinib tablets at 60 mg/m2 QD on a continuous oral regimen.
    Arm type
    Experimental

    Investigational medicinal product name
    Dasatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dasatinib tablets at 60 mg/m2 QD, with a maximum dose of 100 mg QD for subjects with high BSA

    Arm title
    Cohort 2
    Arm description
    Children and adolescents with Ph+ ALL, AP-CML or BP-CML who were resistant or intolerant to, or relapsed after imatinib therapy received dasatinib tablets at a dose schedule of 80 mg/m2 QD on a continuous oral regimen.
    Arm type
    Experimental

    Investigational medicinal product name
    Dasatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dasatinib tablets at dose schedule of 80 mg/m2 QD, with a maximum dose of 140 mg QD for subjects with high BSA

    Arm title
    Cohort 3
    Arm description
    Children and adolescents with CP-CML who were treatment-naive received dasatinib tablets at 60 mg/m2 QD or powder for oral suspension (PFOS) at 72 mg/m2 QD on a continuous oral regimen.
    Arm type
    Experimental

    Investigational medicinal product name
    Dasatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dasatinib tablets at 60 mg/m2 QD, with a maximum dose of 100 mg QD for subjects with high BSA

    Investigational medicinal product name
    Dasatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dasatinib tablets at 60 mg/m2 QD, with a maximum dose of 100 mg QD for subjects with high BSA

    Number of subjects in period 2 [2]
    Cohort 1 Cohort 2 Cohort 3
    Started
    14
    13
    23
    Completed
    9
    5
    19
    Not completed
    5
    8
    4
         Reason Not Specified
    2
    -
    -
         Adverse event, serious fatal
    1
    8
    -
         Consent withdrawn by subject
    1
    -
    4
         Lost to follow-up
    1
    -
    -
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all participants who discontinued treatment entered the follow-up period

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    Children and adolescents with CP-CML who were resistant or intolerant to imatinib received dasatinib tablets at 60 mg/m2 QD on a continuous oral regimen.

    Reporting group title
    Cohort 2
    Reporting group description
    Children and adolescents with Ph+ ALL, AP-CML or BP-CML who were resistant or intolerant to, or relapsed after imatinib therapy received dasatinib tablets at a dose schedule of 80 mg/m2 QD on a continuous oral regimen.

    Reporting group title
    Cohort 3
    Reporting group description
    Children and adolescents with CP-CML who were treatment-naive received dasatinib tablets at 60 mg/m2 QD or powder for oral suspension (PFOS) at 72 mg/m2 QD on a continuous oral regimen.

    Reporting group values
    Cohort 1 Cohort 2 Cohort 3 Total
    Number of subjects
    29 17 84 130
    Age Categorical
    Units: Subjects
        < 2 years
    1 0 2 3
        >= 2 to < 7 years
    3 2 10 15
        >= 7 to < 12 years
    6 6 28 40
        >= 12 to < 18 years
    17 9 44 70
        >= 18 years
    2 0 0 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    12.60 ± 4.774 12.10 ± 3.680 11.95 ± 4.418 -
    Gender, Male/Female
    Units: Subjects
        Female
    16 9 39 64
        Male
    13 8 45 66
    Race/Ethnicity, Customized
    Units: Subjects
        White
    20 13 56 89
        Black or African American
    2 0 4 6
        Asian
    6 3 23 32
        American Indian or Alaska Native
    0 0 1 1
        Other
    1 1 0 2
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    2 0 5 7
        Not Hispanic or Latino
    4 0 20 24
        Unknown or Not Reported
    23 17 59 99
    Subject analysis sets

    Subject analysis set title
    Cohort 3a
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Children and adolescents with CP-CML who were treatment-naive received dasatinib tablets at 60 mg/m2 QD on a continuous oral regimen.

    Subject analysis set title
    Cohort 3b
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Children and adolescents with CP-CML who were treatment-naive received dasatinib powder for oral suspension (PFOS) at 72 mg/m2 QD on a continuous oral regimen.

    Subject analysis sets values
    Cohort 3a Cohort 3b
    Number of subjects
    51
    33
    Age Categorical
    Units: Subjects
        < 2 years
    1
    1
        >= 2 to < 7 years
    5
    5
        >= 7 to < 12 years
    16
    12
        >= 12 to < 18 years
    29
    15
        >= 18 years
    0
    0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    12.28 ± 4.084
    11.44 ± 4.912
    Gender, Male/Female
    Units: Subjects
        Female
    25
    14
        Male
    26
    19
    Race/Ethnicity, Customized
    Units: Subjects
        White
    31
    25
        Black or African American
    3
    1
        Asian
    16
    7
        American Indian or Alaska Native
    1
    0
        Other
    0
    0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    1
    4
        Not Hispanic or Latino
    13
    7
        Unknown or Not Reported
    37
    22

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    Children and adolescents with CP-CML who were resistant or intolerant to imatinib received dasatinib tablets at 60 mg/m2 QD on a continuous oral regimen.

    Reporting group title
    Cohort 2
    Reporting group description
    Children and adolescents with Ph+ ALL, AP-CML or BP-CML who were resistant or intolerant to, or relapsed after imatinib therapy received dasatinib tablets at a dose schedule of 80 mg/m2 QD on a continuous oral regimen.

    Reporting group title
    Cohort 3
    Reporting group description
    Children and adolescents with CP-CML who were treatment-naive received dasatinib tablets at 60 mg/m2 QD or powder for oral suspension (PFOS) at 72 mg/m2 QD on a continuous oral regimen.
    Reporting group title
    Cohort 1
    Reporting group description
    Children and adolescents with CP-CML who were resistant or intolerant to imatinib received dasatinib tablets at 60 mg/m2 QD on a continuous oral regimen.

    Reporting group title
    Cohort 2
    Reporting group description
    Children and adolescents with Ph+ ALL, AP-CML or BP-CML who were resistant or intolerant to, or relapsed after imatinib therapy received dasatinib tablets at a dose schedule of 80 mg/m2 QD on a continuous oral regimen.

    Reporting group title
    Cohort 3
    Reporting group description
    Children and adolescents with CP-CML who were treatment-naive received dasatinib tablets at 60 mg/m2 QD or powder for oral suspension (PFOS) at 72 mg/m2 QD on a continuous oral regimen.

    Subject analysis set title
    Cohort 3a
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Children and adolescents with CP-CML who were treatment-naive received dasatinib tablets at 60 mg/m2 QD on a continuous oral regimen.

    Subject analysis set title
    Cohort 3b
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Children and adolescents with CP-CML who were treatment-naive received dasatinib powder for oral suspension (PFOS) at 72 mg/m2 QD on a continuous oral regimen.

    Primary: Major Cytogenetic Response (MCyR) Rate

    Close Top of page
    End point title
    Major Cytogenetic Response (MCyR) Rate [1] [2]
    End point description
    Major Cytogenetic Response (MCyR) rate is defined as the proportion of all treated subjects who achieved a complete (0%) or partial (1%-35% Ph+ metaphases in at least 20 metaphases in bone marrow) cytogenetic response, expressed as percentage. The denominator of the MCyR response rate consists of all treated subjects in Cohort 1, and the numerator is all subjects in Cohort 1 achieving MCyR. 95% confidence interval was calculated by Clopper-Pearson exact method.
    End point type
    Primary
    End point timeframe
    From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This endpoint was only planned to analyze select arms
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was only planned to analyze select arms
    End point values
    Cohort 1
    Number of subjects analysed
    29
    Units: percentage of subjects
        number (confidence interval 95%)
    89.7 (72.6 to 97.8)
    No statistical analyses for this end point

    Primary: Complete Hematologic Response (CHR) Rate

    Close Top of page
    End point title
    Complete Hematologic Response (CHR) Rate [3] [4]
    End point description
    Complete Hematologic Response (CHR) rate is defined as the proportion of all treated subjects who achieve a confirmed CHR while on-study, expressed as percentage. CHR is defined as including no more than 5% blasts in bone marrow and normal white blood cell count without blasts in peripheral blood, expressed as percentage. The denominator of the CHR response rate consists of all treated subjects in Cohort 2, and the numerator is all subjects in Cohort 2 achieving CHR. 95% confidence interval was calculated by Clopper-Pearson exact method.
    End point type
    Primary
    End point timeframe
    From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only summary statistics were planned for this endpoint
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was only planned to analyze select arms
    End point values
    Cohort 2
    Number of subjects analysed
    17
    Units: percentage of subjects
        number (confidence interval 95%)
    29.4 (10.3 to 56.0)
    No statistical analyses for this end point

    Primary: Complete Cytogenetic Response (CCyR) Rate

    Close Top of page
    End point title
    Complete Cytogenetic Response (CCyR) Rate [5] [6]
    End point description
    Complete Cytogenetic Response (CCyR) rate is defined as the proportion of all treated subjects who achieve a CCyR while on-study, expressed as a percentage. CCyR rate is defined as 0% Ph+ metaphases in at least 20 metaphases in bone marrow. The denominator of the CCyR response rate consists of all treated subjects in Cohort 3, and the numerator is all subjects in Cohort 3 achieving CCyR. 95% confidence interval was calculated by Clopper-Pearson exact method.
    End point type
    Primary
    End point timeframe
    From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only summary statistics were planned for this endpoint
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was only planned to analyze select arms
    End point values
    Cohort 3
    Number of subjects analysed
    84
    Units: percentage of subjects
        number (confidence interval 95%)
    94.0 (86.7 to 98.0)
    No statistical analyses for this end point

    Secondary: Major Cytogenetic Response (MCyR) Rate in Cohort 2

    Close Top of page
    End point title
    Major Cytogenetic Response (MCyR) Rate in Cohort 2 [7]
    End point description
    Major Cytogenetic Response (MCyR) rate was defined as the proportion of all treated subjects who achieved a complete (0%) or partial (1%-35% Ph+ metaphases in at least 20 metaphases in bone marrow) cytogenetic response. The percentage of treated subjects in each arm with MCyR is reported.
    End point type
    Secondary
    End point timeframe
    From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was only planned to analyze select arms
    End point values
    Cohort 2
    Number of subjects analysed
    17
    Units: percent of subjects
        number (confidence interval 95%)
    58.8 (32.9 to 81.6)
    No statistical analyses for this end point

    Secondary: Complete Hematologic Response (CHR) Rate in Cohorts 1 and 3

    Close Top of page
    End point title
    Complete Hematologic Response (CHR) Rate in Cohorts 1 and 3 [8]
    End point description
    Complete Hematologic Response (CHR) rate defined as the proportion of all treated subjects who achieve a confirmed CHR while on-study. CHR is defined as including no more than 5% blasts in bone marrow and normal white blood cell count without blasts in peripheral blood. The percentage of treated subjects in each arm with CHR is reported.
    End point type
    Secondary
    End point timeframe
    From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was only planned to analyze select arms
    End point values
    Cohort 1 Cohort 3
    Number of subjects analysed
    29
    84
    Units: percentage of subjects
        number (confidence interval 95%)
    93.1 (77.2 to 99.2)
    96.4 (89.9 to 99.3)
    No statistical analyses for this end point

    Secondary: Rate of Best Cytogenetic Response

    Close Top of page
    End point title
    Rate of Best Cytogenetic Response
    End point description
    The number of subjects achieving their best on-study cytogenetic response was reported as a percentage of all treated subjects in that arm.
    End point type
    Secondary
    End point timeframe
    From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months)
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 3a Cohort 3b
    Number of subjects analysed
    29
    17
    84
    51
    33
    Units: percentage of subjects
    number (not applicable)
        Complete (0%)
    82.8
    29.4
    94.0
    96.1
    90.9
        Partial (>0% - 35%)
    6.9
    23.5
    2.4
    2.0
    3.0
        Minor (>35% - 65%)
    3.4
    0
    0
    0
    0
        Minimal (>65% - 95%)
    3.4
    0
    1.2
    2.0
    0
        No Response (>95% - 100%)
    0
    5.9
    0
    0
    0
        Unable to Determine
    3.4
    41.2
    2.4
    0
    6.1
    No statistical analyses for this end point

    Secondary: Time to Major Cytogenetic Response (MCyR)

    Close Top of page
    End point title
    Time to Major Cytogenetic Response (MCyR)
    End point description
    Time to MCyR is defined as the time from first dose of dasatinib until the first day MCyR criteria are met, computed only for subjects whose best response is MCyR.
    End point type
    Secondary
    End point timeframe
    From first dose until MCyR criteria are met (assessed up to September 2016, approximately 90 months)
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 3a Cohort 3b
    Number of subjects analysed
    26
    9
    81
    50
    31
    Units: months
        median (confidence interval 95%)
    3.1 (2.8 to 4.1)
    1.6 (0.5 to 5.7)
    3.0 (2.9 to 4.3)
    3.3 (2.9 to 5.6)
    3.0 (2.8 to 5.0)
    No statistical analyses for this end point

    Secondary: Duration of Major Cytogenetic Response (MCyR)

    Close Top of page
    End point title
    Duration of Major Cytogenetic Response (MCyR)
    End point description
    Duration of MCyR will be computed from the first day criteria are met for MCyR until the date PD is reported (or treatment is discontinued for PD) or death. Subjects who neither discontinue due to PD nor die will be censored on the date of their last hematologic or cytogenetic assessment, whichever comes last. Only subjects with MCyR were analyzed.
    End point type
    Secondary
    End point timeframe
    From first day criteria are met for MCyR until the date PD is reported or death (assessed up to September 2016, approximately 90 months)
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 3a Cohort 3b
    Number of subjects analysed
    26
    9
    81
    50
    31
    Units: months
        median (confidence interval 95%)
    99999 (54.9 to 99999)
    11.2 (0.3 to 99999)
    99999 (52.7 to 99999)
    99999 (52.7 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Complete Cytogenetic Response (CCyR)

    Close Top of page
    End point title
    Time to Complete Cytogenetic Response (CCyR)
    End point description
    Time to CCyR is defined as the time from first dose of dasatinib until the first day CCyR criteria are met, computed only for subjects whose best response is CCyR.
    End point type
    Secondary
    End point timeframe
    From first dose until CCyR criteria are met, assessed up to September 2016 (approximately 90 months)
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 3a Cohort 3b
    Number of subjects analysed
    24
    7
    79
    49
    30
    Units: months
        median (confidence interval 95%)
    3.9 (2.8 to 5.6)
    1.6 (0.5 to 5.7)
    5.6 (5.0 to 6.0)
    5.7 (3.7 to 6.2)
    5.6 (3.1 to 6.0)
    No statistical analyses for this end point

    Secondary: Duration of Complete Cytogenetic Response (CCyR)

    Close Top of page
    End point title
    Duration of Complete Cytogenetic Response (CCyR)
    End point description
    Duration of CCyR will be computed from the first day criteria are met for CCyR until the date PD is reported (or treatment is discontinued for PD) or death. Subjects who neither discontinue due to PD nor die will be censored on the date of their last hematologic or cytogenetic assessment, whichever comes last.
    End point type
    Secondary
    End point timeframe
    From first day criteria are met for CCyR until the date of progressive disease or death (assessed up to September 2016, approximately 90 months)
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 3a Cohort 3b
    Number of subjects analysed
    24
    5
    79
    49
    30
    Units: months
        median (confidence interval 95%)
    99999 (54.9 to 99999)
    99999 (1.0 to 99999)
    99999 (49.9 to 99999)
    99999 (49.9 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Rate at 2 years

    Close Top of page
    End point title
    Progression-Free Survival (PFS) Rate at 2 years
    End point description
    PFS is defined as time from the first dosing date until the time PD is first documented by the investigator or death. Subjects who die without a reported date of progression will be considered to have progressed on the date of death. Subjects who neither progress nor die will be censored on the date of their last cytogenetic or hematologic assessment. The percentages of progression-free subjects at 2 years are based on Kaplan-Meier estimation.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 3a Cohort 3b
    Number of subjects analysed
    29
    17
    84
    51
    33
    Units: percentage
        median (confidence interval 95%)
    81.7 (61.4 to 92.0)
    20.5 (3.7 to 46.4)
    95.1 (87.4 to 98.1)
    94.0 (82.6 to 98.0)
    96.8 (79.2 to 99.5)
    No statistical analyses for this end point

    Secondary: Time to Complete Hematologic Response (CHR)

    Close Top of page
    End point title
    Time to Complete Hematologic Response (CHR)
    End point description
    Time to CHR is defined as the time from first dose of dasatinib until the first day CHR criteria are met, provided they are confirmed 4 weeks later, computed only for subjects whose best response is CHR.
    End point type
    Secondary
    End point timeframe
    From first dose until CHR criteria are met, assessed up to September 2016 (approximately 90 months)
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 3a Cohort 3b
    Number of subjects analysed
    27
    5
    81
    51
    30
    Units: months
        median (confidence interval 95%)
    0.7 (0.5 to 1.8)
    2.5 (0.5 to 2.8)
    1.2 (0.9 to 1.4)
    1.2 (0.9 to 1.4)
    1.0 (0.7 to 1.8)
    No statistical analyses for this end point

    Secondary: Duration of Complete Hemotologic Response (CHR)

    Close Top of page
    End point title
    Duration of Complete Hemotologic Response (CHR)
    End point description
    Duration of CHR will be computed from the first day all criteria are met for CHR, provided they are confirmed 4 weeks later, until the date progressive disease (PD) is reported (or treatment is discontinued for PD) or death. Subjects who neither discontinue due to PD nor die will be censored on the date of their last hematologic assessment. Only subjects with CHR were analyzed.
    End point type
    Secondary
    End point timeframe
    From first day criteria are met for CHR until date of disease progression or death (assessed up to September 2016, approximately 90 months)
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 3a Cohort 3b
    Number of subjects analysed
    27
    5
    81
    51
    30
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (1.9 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Disease-Free Survival Rate at 2 years

    Close Top of page
    End point title
    Disease-Free Survival Rate at 2 years
    End point description
    Disease free survival is defined as time from CCyR for Subjects with newly diagnosed chronic phase CML and for Subjects with chronic phase CML who are resistant or intolerant to imatinib (cohort 3 and cohort 1), and as time from CHR for Subjects with advanced phase CML and PH + ALL (cohort 2) until the time progression is first documented by the investigator or death from any cause. The percentages of disease-free subjects at 2 years are based on Kaplan-Meier estimation.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 3a Cohort 3b
    Number of subjects analysed
    24
    5
    79
    49
    30
    Units: percentage
        median (confidence interval 95%)
    86.9 (64.6 to 95.6)
    60.0 (12.6 to 88.2)
    98.7 (91.2 to 99.8)
    97.9 (86.1 to 99.7)
    100 (100 to 100)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) Rate at 2 years

    Close Top of page
    End point title
    Overall Survival (OS) Rate at 2 years
    End point description
    OS is defined as time from the first dosing date until the time of death. All subjects will be followed yearly for survival for up to 5 years after treatment discontinuation. Subjects who have not died or who are lost to follow-up will be censored on the last date the subject is known to be alive. The percentages of surviving participants at 2 years are based on Kaplan-Meier estimation.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 3a Cohort 3b
    Number of subjects analysed
    29
    17
    84
    51
    33
    Units: percentage
        median (confidence interval 95%)
    96.4 (77.2 to 99.5)
    32.2 (10.6 to 56.4)
    100 (100 to 100)
    100 (100 to 100)
    100 (100 to 100)
    No statistical analyses for this end point

    Secondary: Major Molecular Response (MMR) Rate

    Close Top of page
    End point title
    Major Molecular Response (MMR) Rate
    End point description
    Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (qPCR). MMR for subjects with the p210 BCR-ABL transcript variant was defined as a ratio BCR-ABL/ABL <= 10-3 or 0.1% on the international scale. In this study, ABL was used as the control-gene. For a subject with the p190 BCR-ABL transcript variant (occurring in Cohort 2 only), on-study assessments were compared to the participant’s individual baseline BCR-ABL/ABL ratio and a reduction to < 0.1% or a 3-log reduction from baseline was considered an MMR.
    End point type
    Secondary
    End point timeframe
    From date of first treatment to date of MMR (assessed up to September 2016, approximately 90 months)
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 3a Cohort 3b
    Number of subjects analysed
    29
    17
    84
    51
    33
    Units: percentage of subjects
        number (confidence interval 95%)
    62.1 (42.3 to 79.3)
    29.4 (10.3 to 56.0)
    79.8 (69.6 to 87.7)
    88.2 (76.1 to 95.6)
    66.7 (48.2 to 82.0)
    No statistical analyses for this end point

    Secondary: Complete Molecular Response (CMR) Rate

    Close Top of page
    End point title
    Complete Molecular Response (CMR) Rate
    End point description
    Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (qPCR). CMR is defined as absence of BCR-ABL rearrangements by real-time qPCR analysis. The percentage of treated subjects with CMR is reported by arm.
    End point type
    Secondary
    End point timeframe
    From date of first treatment to date of CMR (assessed up to September 2016, approximately 90 months)
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 3a Cohort 3b
    Number of subjects analysed
    29
    17
    84
    51
    33
    Units: percentage
        number (confidence interval 95%)
    24.1 (10.3 to 43.5)
    17.6 (3.8 to 43.4)
    29.8 (20.3 to 40.7)
    43.1 (29.3 to 57.8)
    9.1 (1.9 to 24.3)
    No statistical analyses for this end point

    Secondary: Major Cytogenetic Response (MCyR) Rate up to 2 years

    Close Top of page
    End point title
    Major Cytogenetic Response (MCyR) Rate up to 2 years
    End point description
    Major Cytogenetic Response (MCyR) rate is defined as the proportion of all treated subjects who achieved a complete (0%) or partial (1%-35% Ph+ metaphases in at least 20 metaphases in bone marrow) cytogenetic response. The percentage of treated subjects with MCyR is reported by arm.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 3a Cohort 3b
    Number of subjects analysed
    29
    17
    84
    51
    33
    Units: percentage of subjects
    number (confidence interval 95%)
        12 months
    89.7 (72.6 to 97.8)
    58.8 (32.9 to 81.6)
    96.4 (89.9 to 99.3)
    98.0 (89.6 to 100.0)
    93.9 (79.8 to 99.3)
        24 months
    89.7 (72.6 to 97.8)
    58.8 (32.9 to 81.6)
    96.4 (89.9 to 99.3)
    98.0 (89.6 to 100.0)
    93.9 (79.8 to 99.3)
    No statistical analyses for this end point

    Secondary: Complete Cytogenetic Response (CCyR) Rate up to 2 years

    Close Top of page
    End point title
    Complete Cytogenetic Response (CCyR) Rate up to 2 years
    End point description
    Complete Cytogenetic Response (CCyR) rate is defined as the proportion of all treated subjects who achieve a CCyR while on-study. CCyR rate is defined as 0% Ph+ metaphases in at least 20 metaphases in bone marrow. The percentage of treated subjects with CCyR is reported by arm.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 3a Cohort 3b
    Number of subjects analysed
    29
    17
    84
    51
    33
    Units: percentage of subjects
    number (confidence interval 95%)
        12 months
    75.9 (56.5 to 89.7)
    41.2 (18.4 to 67.1)
    92.9 (85.1 to 97.3)
    96.1 (86.5 to 99.5)
    87.9 (71.8 to 96.6)
        24 months
    82.8 (64.2 to 94.2)
    41.2 (18.4 to 67.1)
    94.0 (86.7 to 98.0)
    96.1 (86.5 to 99.5)
    90.9 (75.7 to 98.1)
    No statistical analyses for this end point

    Secondary: Major Molecular Response (MMR) Rate up to 2 years

    Close Top of page
    End point title
    Major Molecular Response (MMR) Rate up to 2 years
    End point description
    Molecular response was assessed using BCR-ABL transcript levels measurement by real-time qPCR. MMR for Subjects with the p210 BCR-ABL transcript variant is defined according to the recommendations of Hughes et al. as a ratio BCR-ABL/ABL <= 10-3 or 0.1% on the international scale proposed by the authors. The standardized baseline, as established in the IRIS trial, is taken to represent 100% on the international scale and a 3-log reduction in ratio (BCR-ABL transcripts/ABL or BCR) from the standardized baseline (MMR) is fixed at 0.1%. In this study, ABL or other housekeeping gene, will be used as the control-gene. For a Subject with the p190 BCR-ABL transcript variant, on-study assessments will be compared to the Subject’s individual baseline BCR-ABL/ABL ratio and a reduction to < 0.1% or a 3-log reduction from baseline will be considered an MMR. The percentage of treated subjects with MMR is reported by arm.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 3a Cohort 3b
    Number of subjects analysed
    29
    17
    84
    51
    33
    Units: percentage of subjects
    number (confidence interval 95%)
        12 months
    41.4 (23.5 to 61.1)
    23.5 (6.8 to 49.9)
    52.4 (41.2 to 63.4)
    56.9 (42.2 to 70.7)
    45.5 (28.1 to 63.6)
        24 months
    55.2 (35.7 to 73.6)
    29.4 (10.3 to 56.0)
    70.2 (59.3 to 79.7)
    74.5 (60.4 to 85.7)
    63.6 (45.1 to 79.6)
    No statistical analyses for this end point

    Secondary: Complete Molecular Response (CMR) Rate up to 2 years

    Close Top of page
    End point title
    Complete Molecular Response (CMR) Rate up to 2 years
    End point description
    Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (qPCR). (CMR) is defined as absence of BCR-ABL rearrangements by real-time qPCR analysis. The percentage of treated subjects with CMR is reported by arm.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 3a Cohort 3b
    Number of subjects analysed
    29
    17
    84
    51
    33
    Units: percentage
    number (confidence interval 95%)
        12 months
    6.9 (0.8 to 22.8)
    11.8 (1.5 to 36.4)
    8.3 (3.4 to 16.4)
    9.8 (3.3 to 21.4)
    6.1 (0.7 to 20.2)
        24 months
    17.2 (5.8 to 35.8)
    11.8 (1.5 to 36.4)
    21.4 (13.2 to 31.7)
    29.4 (17.5 to 43.8)
    9.1 (1.9 to 24.3)
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug until the last dose of study drug plus 30 days
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Cohort 3a
    Reporting group description
    Children and adolescents with CP-CML who were treatment-naive received dasatinib tablets at 60 mg/m2 QD on a continuous oral regimen.

    Reporting group title
    Cohort 3b
    Reporting group description
    Children and adolescents with CP-CML who were treatment-naive received dasatinib powder for oral suspension (PFOS) at 72 mg/m2 QD on a continuous oral regimen.

    Reporting group title
    Cohort 1
    Reporting group description
    Children and adolescents with CP-CML who were resistant or intolerant to imatinib received dasatinib tablets at 60 mg/m2 QD on a continuous oral regimen.

    Reporting group title
    Cohort 2 BP-CML
    Reporting group description
    Children and adolescents with BP-CML who were resistant or intolerant to, or relapsed after imatinib therapy received dasatinib tablets at a dose schedule of 80 mg/m2 QD on a continuous oral regimen.

    Reporting group title
    Cohort 2 Ph+ ALL
    Reporting group description
    Children and adolescents with Ph+ ALL who were resistant or intolerant to, or relapsed after imatinib therapy received dasatinib tablets at a dose schedule of 80 mg/m2 QD on a continuous oral regimen.

    Serious adverse events
    Cohort 3a Cohort 3b Cohort 1 Cohort 2 BP-CML Cohort 2 Ph+ ALL
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 51 (37.25%)
    9 / 33 (27.27%)
    13 / 29 (44.83%)
    7 / 8 (87.50%)
    6 / 9 (66.67%)
         number of deaths (all causes)
    0
    0
    0
    1
    3
         number of deaths resulting from adverse events
    Vascular disorders
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Bone marrow transplant
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia recurrent
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Blast cell proliferation
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blast crisis in myelogenous leukaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukaemia recurrent
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 33 (6.06%)
    1 / 29 (3.45%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    2 / 8 (25.00%)
    2 / 9 (22.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 33 (9.09%)
    2 / 29 (6.90%)
    2 / 8 (25.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Personality change
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Genital haemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gun shot wound
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 33 (3.03%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 33 (3.03%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    6 / 7
    0 / 1
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    2 / 8 (25.00%)
    3 / 9 (33.33%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    3 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Leukopenia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    2 / 29 (6.90%)
    2 / 8 (25.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    4 / 4
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Arachnoiditis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial nerve disorder
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal ulcer
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 33 (9.09%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 33 (9.09%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial sepsis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myringitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    2 / 8 (25.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Upper aerodigestive tract infection
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cohort 3a Cohort 3b Cohort 1 Cohort 2 BP-CML Cohort 2 Ph+ ALL
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 51 (98.04%)
    33 / 33 (100.00%)
    27 / 29 (93.10%)
    7 / 8 (87.50%)
    9 / 9 (100.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 33 (9.09%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    5
    1
    0
    0
    Hot flush
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    5 / 51 (9.80%)
    4 / 33 (12.12%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    6
    5
    1
    0
    0
    Phlebitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Thrombophlebitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    3 / 51 (5.88%)
    3 / 33 (9.09%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    4
    1
    0
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Hypersensitivity
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    5
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Chest pain
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 33 (0.00%)
    3 / 29 (10.34%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    4
    0
    0
    Chills
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 33 (9.09%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    Fatigue
         subjects affected / exposed
    10 / 51 (19.61%)
    7 / 33 (21.21%)
    8 / 29 (27.59%)
    1 / 8 (12.50%)
    2 / 9 (22.22%)
         occurrences all number
    22
    18
    14
    1
    2
    Influenza like illness
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Malaise
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    0
    4
    Mass
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    3
    0
    0
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 33 (6.06%)
    1 / 29 (3.45%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    1
    5
    0
    Non-Cardiac chest pain
         subjects affected / exposed
    3 / 51 (5.88%)
    3 / 33 (9.09%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    3
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 33 (3.03%)
    3 / 29 (10.34%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    2
    1
    3
    1
    0
    Pain
         subjects affected / exposed
    6 / 51 (11.76%)
    5 / 33 (15.15%)
    3 / 29 (10.34%)
    1 / 8 (12.50%)
    1 / 9 (11.11%)
         occurrences all number
    9
    7
    3
    1
    2
    Peripheral swelling
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Pyrexia
         subjects affected / exposed
    23 / 51 (45.10%)
    10 / 33 (30.30%)
    14 / 29 (48.28%)
    1 / 8 (12.50%)
    5 / 9 (55.56%)
         occurrences all number
    77
    22
    46
    1
    12
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 33 (9.09%)
    2 / 29 (6.90%)
    1 / 8 (12.50%)
    1 / 9 (11.11%)
         occurrences all number
    2
    3
    3
    1
    2
    Insomnia
         subjects affected / exposed
    3 / 51 (5.88%)
    2 / 33 (6.06%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    2
    2
    0
    0
    Depression
         subjects affected / exposed
    4 / 51 (7.84%)
    1 / 33 (3.03%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    4
    1
    1
    0
    0
    Reproductive system and breast disorders
    Breast mass
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    Dysmenorrhoea
         subjects affected / exposed
    4 / 51 (7.84%)
    1 / 33 (3.03%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    14
    1
    3
    0
    0
    Menstruation irregular
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    0
    1
    Vaginal discharge
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    5
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 33 (6.06%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    Contusion
         subjects affected / exposed
    3 / 51 (5.88%)
    4 / 33 (12.12%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    6
    8
    3
    0
    0
    Foot fracture
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Sunburn
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 33 (3.03%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    Procedural pain
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    5
    0
    0
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 51 (5.88%)
    3 / 33 (9.09%)
    3 / 29 (10.34%)
    2 / 8 (25.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    4
    3
    3
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 51 (5.88%)
    4 / 33 (12.12%)
    4 / 29 (13.79%)
    3 / 8 (37.50%)
    1 / 9 (11.11%)
         occurrences all number
    5
    6
    5
    6
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    2 / 51 (3.92%)
    4 / 33 (12.12%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    4
    5
    0
    6
    0
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Blood urea increased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 51 (0.00%)
    5 / 33 (15.15%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    8
    1
    0
    0
    Gamma-Glutamyltransferase increased
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 51 (1.96%)
    5 / 33 (15.15%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    6
    0
    0
    0
    Platelet count decreased
         subjects affected / exposed
    2 / 51 (3.92%)
    11 / 33 (33.33%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    19
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 33 (3.03%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    1
    1
    0
    0
    Weight increased
         subjects affected / exposed
    3 / 51 (5.88%)
    3 / 33 (9.09%)
    2 / 29 (6.90%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    3
    5
    2
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    16 / 51 (31.37%)
    9 / 33 (27.27%)
    13 / 29 (44.83%)
    1 / 8 (12.50%)
    4 / 9 (44.44%)
         occurrences all number
    38
    20
    25
    6
    5
    Epistaxis
         subjects affected / exposed
    5 / 51 (9.80%)
    4 / 33 (12.12%)
    3 / 29 (10.34%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    5
    4
    4
    0
    1
    Dyspnoea
         subjects affected / exposed
    4 / 51 (7.84%)
    2 / 33 (6.06%)
    3 / 29 (10.34%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    6
    2
    7
    1
    0
    Nasal congestion
         subjects affected / exposed
    3 / 51 (5.88%)
    2 / 33 (6.06%)
    3 / 29 (10.34%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    4
    4
    5
    0
    0
    Pharyngeal erythema
         subjects affected / exposed
    3 / 51 (5.88%)
    5 / 33 (15.15%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    5
    8
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    10 / 51 (19.61%)
    11 / 33 (33.33%)
    6 / 29 (20.69%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    16
    18
    10
    1
    0
    Respiratory failure
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Productive cough
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    Respiratory tract congestion
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    Rhinalgia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Rhinitis allergic
         subjects affected / exposed
    3 / 51 (5.88%)
    3 / 33 (9.09%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    3
    2
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    11 / 51 (21.57%)
    4 / 33 (12.12%)
    3 / 29 (10.34%)
    1 / 8 (12.50%)
    1 / 9 (11.11%)
         occurrences all number
    15
    6
    4
    1
    1
    Wheezing
         subjects affected / exposed
    3 / 51 (5.88%)
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    3
    2
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 51 (19.61%)
    5 / 33 (15.15%)
    2 / 29 (6.90%)
    2 / 8 (25.00%)
    2 / 9 (22.22%)
         occurrences all number
    16
    16
    6
    5
    3
    Febrile neutropenia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    0
    0
    1
    Haemoglobinaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Leukopenia
         subjects affected / exposed
    3 / 51 (5.88%)
    2 / 33 (6.06%)
    2 / 29 (6.90%)
    2 / 8 (25.00%)
    0 / 9 (0.00%)
         occurrences all number
    6
    13
    2
    3
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    Neutropenia
         subjects affected / exposed
    17 / 51 (33.33%)
    8 / 33 (24.24%)
    6 / 29 (20.69%)
    4 / 8 (50.00%)
    3 / 9 (33.33%)
         occurrences all number
    35
    21
    14
    9
    8
    Lymphopenia
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    1
    2
    0
    3
    0
    Pancytopenia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    13 / 51 (25.49%)
    7 / 33 (21.21%)
    5 / 29 (17.24%)
    4 / 8 (50.00%)
    4 / 9 (44.44%)
         occurrences all number
    22
    17
    7
    12
    5
    Nervous system disorders
    Arachnoiditis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Brain oedema
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Dizziness
         subjects affected / exposed
    12 / 51 (23.53%)
    3 / 33 (9.09%)
    2 / 29 (6.90%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    19
    4
    3
    2
    0
    Dysgeusia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Facial paralysis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    24 / 51 (47.06%)
    15 / 33 (45.45%)
    17 / 29 (58.62%)
    3 / 8 (37.50%)
    5 / 9 (55.56%)
         occurrences all number
    82
    25
    52
    16
    9
    Neuropathy peripheral
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Somnolence
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    5 / 29 (17.24%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    5
    0
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 33 (6.06%)
    1 / 29 (3.45%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    3
    2
    1
    1
    0
    Eye oedema
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    4
    0
    0
    0
    Eye pain
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 33 (3.03%)
    3 / 29 (10.34%)
    0 / 8 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    4
    1
    3
    0
    2
    Periorbital oedema
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 33 (3.03%)
    1 / 29 (3.45%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    3
    1
    1
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    7 / 51 (13.73%)
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    8
    3
    0
    0
    0
    Hypoacusis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    18 / 51 (35.29%)
    7 / 33 (21.21%)
    10 / 29 (34.48%)
    1 / 8 (12.50%)
    2 / 9 (22.22%)
         occurrences all number
    42
    12
    37
    1
    4
    Anal fissure
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    12 / 51 (23.53%)
    4 / 33 (12.12%)
    8 / 29 (27.59%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    32
    9
    16
    0
    0
    Colitis
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 33 (3.03%)
    1 / 29 (3.45%)
    1 / 8 (12.50%)
    1 / 9 (11.11%)
         occurrences all number
    7
    2
    1
    1
    1
    Anal ulcer
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Constipation
         subjects affected / exposed
    9 / 51 (17.65%)
    5 / 33 (15.15%)
    4 / 29 (13.79%)
    2 / 8 (25.00%)
    0 / 9 (0.00%)
         occurrences all number
    11
    6
    4
    5
    0
    Diarrhoea
         subjects affected / exposed
    27 / 51 (52.94%)
    12 / 33 (36.36%)
    17 / 29 (58.62%)
    3 / 8 (37.50%)
    3 / 9 (33.33%)
         occurrences all number
    87
    21
    72
    3
    6
    Dyspepsia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Gastritis
         subjects affected / exposed
    6 / 51 (11.76%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    9
    1
    0
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Gingival bleeding
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 33 (6.06%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    Nausea
         subjects affected / exposed
    20 / 51 (39.22%)
    10 / 33 (30.30%)
    11 / 29 (37.93%)
    3 / 8 (37.50%)
    2 / 9 (22.22%)
         occurrences all number
    38
    24
    28
    3
    3
    Oral pain
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    2
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    2 / 51 (3.92%)
    4 / 33 (12.12%)
    0 / 29 (0.00%)
    2 / 8 (25.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    17
    0
    2
    1
    Tongue ulceration
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    Toothache
         subjects affected / exposed
    4 / 51 (7.84%)
    1 / 33 (3.03%)
    3 / 29 (10.34%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    4
    1
    5
    0
    1
    Vomiting
         subjects affected / exposed
    22 / 51 (43.14%)
    11 / 33 (33.33%)
    15 / 29 (51.72%)
    3 / 8 (37.50%)
    3 / 9 (33.33%)
         occurrences all number
    55
    30
    45
    14
    5
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Dysuria
         subjects affected / exposed
    4 / 51 (7.84%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    5
    1
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 51 (1.96%)
    7 / 33 (21.21%)
    3 / 29 (10.34%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    7
    5
    0
    1
    Dermatitis acneiform
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 33 (6.06%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    2
    2
    0
    0
    Alopecia
         subjects affected / exposed
    5 / 51 (9.80%)
    1 / 33 (3.03%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    6
    1
    2
    0
    0
    Dry skin
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 33 (0.00%)
    4 / 29 (13.79%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    0
    6
    0
    1
    Eczema
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 33 (3.03%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    Erythema
         subjects affected / exposed
    4 / 51 (7.84%)
    2 / 33 (6.06%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    4
    4
    2
    0
    0
    Petechiae
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 33 (3.03%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    4
    3
    1
    0
    1
    Papule
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    0
    1
    Rash
         subjects affected / exposed
    14 / 51 (27.45%)
    11 / 33 (33.33%)
    8 / 29 (27.59%)
    1 / 8 (12.50%)
    1 / 9 (11.11%)
         occurrences all number
    19
    25
    11
    1
    1
    Pruritus
         subjects affected / exposed
    7 / 51 (13.73%)
    4 / 33 (12.12%)
    5 / 29 (17.24%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    8
    4
    5
    0
    0
    Rash erythematous
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 33 (9.09%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    Rash papular
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    3
    1
    0
    0
    1
    Skin exfoliation
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    0
    1
    Skin hypopigmentation
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    2
    0
    1
    Skin induration
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Xeroderma
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Urticaria
         subjects affected / exposed
    3 / 51 (5.88%)
    3 / 33 (9.09%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    4
    6
    2
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    7 / 51 (13.73%)
    6 / 33 (18.18%)
    4 / 29 (13.79%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    14
    6
    6
    1
    0
    Arthralgia
         subjects affected / exposed
    11 / 51 (21.57%)
    6 / 33 (18.18%)
    6 / 29 (20.69%)
    1 / 8 (12.50%)
    1 / 9 (11.11%)
         occurrences all number
    22
    7
    15
    1
    1
    Bone pain
         subjects affected / exposed
    5 / 51 (9.80%)
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    1 / 8 (12.50%)
    3 / 9 (33.33%)
         occurrences all number
    5
    0
    1
    1
    3
    Coccydynia
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Groin pain
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    5 / 51 (9.80%)
    7 / 33 (21.21%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    9
    7
    4
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 51 (1.96%)
    4 / 33 (12.12%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    4
    1
    0
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Neck pain
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    2
    3
    0
    1
    0
    Myalgia
         subjects affected / exposed
    3 / 51 (5.88%)
    6 / 33 (18.18%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    9
    10
    0
    0
    Pain in jaw
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    3 / 29 (10.34%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    3
    0
    0
    Pain in extremity
         subjects affected / exposed
    11 / 51 (21.57%)
    14 / 33 (42.42%)
    15 / 29 (51.72%)
    2 / 8 (25.00%)
    0 / 9 (0.00%)
         occurrences all number
    24
    26
    23
    2
    0
    Tendonitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 51 (7.84%)
    1 / 33 (3.03%)
    2 / 29 (6.90%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    8
    1
    2
    2
    0
    Fluid retention
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 33 (9.09%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    7
    0
    0
    0
    Hypermagnesaemia
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    2
    2
    0
    3
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hyperphosphataemia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    4
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    4 / 33 (12.12%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    4
    0
    6
    0
    Hypocalcaemia
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 33 (9.09%)
    2 / 29 (6.90%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    2
    3
    2
    3
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    2 / 8 (25.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    1
    0
    5
    1
    Hypomagnesaemia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    2
    Bronchitis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    3 / 29 (10.34%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    3
    0
    0
    Cellulitis
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    1
    0
    0
    Conjunctivitis
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 33 (6.06%)
    3 / 29 (10.34%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    2
    3
    0
    0
    Ear infection
         subjects affected / exposed
    5 / 51 (9.80%)
    3 / 33 (9.09%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    10
    5
    2
    0
    1
    Febrile infection
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Folliculitis
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    7 / 51 (13.73%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    1 / 9 (11.11%)
         occurrences all number
    12
    0
    0
    1
    1
    Gastroenteritis viral
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    3
    0
    0
    Herpes virus infection
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Gingivitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    Hordeolum
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 33 (3.03%)
    2 / 29 (6.90%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    3
    0
    1
    Influenza
         subjects affected / exposed
    6 / 51 (11.76%)
    1 / 33 (3.03%)
    3 / 29 (10.34%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    14
    1
    3
    0
    0
    Localised infection
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 33 (6.06%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    2
    1
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    10 / 51 (19.61%)
    4 / 33 (12.12%)
    7 / 29 (24.14%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    16
    8
    9
    0
    0
    Oral herpes
         subjects affected / exposed
    4 / 51 (7.84%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    2 / 8 (25.00%)
    0 / 9 (0.00%)
         occurrences all number
    4
    1
    0
    3
    0
    Otitis media
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Pharyngitis
         subjects affected / exposed
    6 / 51 (11.76%)
    1 / 33 (3.03%)
    2 / 29 (6.90%)
    2 / 8 (25.00%)
    2 / 9 (22.22%)
         occurrences all number
    8
    1
    2
    3
    3
    Rhinitis
         subjects affected / exposed
    7 / 51 (13.73%)
    4 / 33 (12.12%)
    3 / 29 (10.34%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    10
    6
    3
    0
    1
    Sinusitis
         subjects affected / exposed
    3 / 51 (5.88%)
    2 / 33 (6.06%)
    4 / 29 (13.79%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    8
    2
    4
    0
    1
    Tonsillitis
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    3
    1
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    16 / 51 (31.37%)
    11 / 33 (33.33%)
    9 / 29 (31.03%)
    1 / 8 (12.50%)
    1 / 9 (11.11%)
         occurrences all number
    30
    25
    23
    1
    2
    Tooth infection
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    1
    0
    0
    Viral infection
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 33 (0.00%)
    3 / 29 (10.34%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    3
    0
    3
    0
    1

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Dec 2009
    The primary purpose of this amendment is to include a new cohort of pediatric subjects with newly diagnosed treatment-naive chronic phase chronic myelogenous leukemia (CP-CML) in this trial (Cohort #3) and to align the protocol with the Pediatric Investigational Plan (PIP). The changes include the following: - Expand the primary objective to include Cohort #3 - Clarify the study duration and drug dispensation. - Established a data monitoring committee (DMC). - In order to improve safety, subjects who have a dose escalation will also be required to have another ECG performed if one was not previously done at that dose. - In order to improve safety, Cohort #3 subjects are required to have ECGs and echocardiograms performed yearly. - Expand the dose selection rationale. - Expand and update safety and efficacy summaries. - Clarify inclusion criteria for all cohorts. - Clarify the resistance criteria for Ph+ ALL. - Clarify the dose escalation criteria for Cohort #2. - Clarify the exclusion criteria for subjects with extramedullary disease to include subjects with isolated CNS involvement. - Add the T315I mutation to the exclusion criteria. - Add hypersensitivity to the active substance or to any of the excipients to the exclusion criteria. - Add patients with hereditary problems of galactose intolerance or Lapp lactase deficiency or glucose-galactose malabsorption to the exclusion criteria. - Clarify statistical definitions, including the definitions for progression-free survival (PFS) and disease-free survival (DFS). - Clarification as to the mode of drug administration. - Synchronized visit and assessment schedules (Table 6.1-1). - Change the molecular analysis schedule to coincide with scheduled visits. - Add the long-term follow-up plan for patients on protocol therapy. - Indicate the modalities of body surface area calculation in children. - Change in the medical monitor of the trial. - Correction of typographical errors.
    04 Oct 2010
    The primary purpose of this amendment is to provide updated information regarding the use of dasatinib for first line treatment in adults with chronic phase CML as further justification to study the same patient population in children and adolescents (cohort #3). The changes include the following: - Expand Rationale in Section 1.3.1 - Revised estimated number of sites - Separated diagnosis criteria for cohort #3 for clarity - Clarified diagnosis criteria for cohort #2 - Revised resistance criteria to cap previous imatinib dose at 400 mg/day for subjects with high BSAs - Corrected multiple typographical errors - Clarified footnotes in flow chart
    12 Jun 2012
    The primary purpose of this amendment is to clarify the objective of estimating the complete cytogenetic response (CCyR) rate to dasatinib therapy in children and adolescents with newly diagnosed CP-CML who are treatment-naive. Additional changes to the protocol include: - Modify Definition of Complete and Major Molecular Response - Define disease free survival for each cohort - Addition of exploratory objective and endpoints for growth and development and bone mineral content - Primary and Secondary Endpoint Clarification - Clarification of Efficacy Analyses - Administrative Changes
    13 Dec 2012
    The purpose of this amendment is to expand cohort 3 to include a sub-cohort of 30 pediatric subjects < 18 years of age with treatment naive chronic phase CML who will receive dasatinib powder for oral suspension (PFOS). This increase in subject number will change our current plan to treat at least 50 newly diagnosed CP- CML pediatric subjects to 80 subjects in cohort 3. Subjects will be required to take the PFOS for a minimum of 12 months, during which data will be collected. We will assess the PK of dasatinib following oral administration of the PFOS in this sub-cohort. Hematologic, cytogenetic, and molecular responses by 12 months will be reported for the sub-cohort taking standard tablets, the sub-cohort using PFOS, and in Cohort 3 as a whole. Similarly, safety analysis will also be reported for both sub-cohorts (taking the standard tablets and PFOS) and in the cohort as a whole. We will also assess the taste properties of the PFOS formulation. This data collected and analyzed on this expanded cohort will be used support registration of the dasatinib PFOS in pediatric subjects. The dose of dasatinib when administered in PFOS formulation will be increased by 20% from the tablet dose, i.e, a dose of 72mg/m2 in this expanded cohort. The purpose of such dose adjustment is to match the exposure of the PFOS formulation to the reference tablet in order to maintain a desired efficacy. It was based on the findings from a bioequivalent study, which showed that AUC(INF) of the PFOS formulation was 19.2% lower compared to the reference tablet.
    18 Jul 2013
    The purpose of this amendment is to permanently close Cohort 2 to further enrollment and update the WOCBP guidelines.
    24 Oct 2013
    The purpose of this amendment is to correct the criteria for women of child bearing potential (WOCBP) and remove information on post menopausal women.
    13 Apr 2016
    This amendment: 1) adds testing for Hepatitis B virus (HBV) and 2) updates recommendations for methods of contraception and reemphasizes the need for contraception.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2021 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA