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    Clinical Trial Results:
    A Phase 3 randomized, double-blind study of induction (daunorubicin/cytarabine) and consolidation (high-dose cytarabine) chemotherapy + midostaurin (PKC412) or placebo in newly diagnosed patients <60 years of age with FLT3-mutated acute myeloid leukemia Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

    Summary
    EudraCT number
    		 2006-006852-37
    Trial protocol
    		 DE   ES   AT   CZ   NL   SK   HU   BE   IT   FR   GB  
    Global end of trial date
    26 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Apr 2023
    First version publication date
    09 Apr 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CPKC412A2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00651261
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.emain@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.emain@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Mar 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to determine if the addition of midostaurin to daunorubicin/cytarabine induction, high-dose cytarabine consolidation, and continuation therapy improved long-term overall survival (OS) in mutant fms-like tyrosine inase 3 (FLT3)-AML patients.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 May 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Austria: 12
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Czechia: 11
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 305
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Italy: 105
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Slovakia: 4
    Country: Number of subjects enrolled
    Spain: 22
    Country: Number of subjects enrolled
    United States: 223
    Worldwide total number of subjects
    717
    EEA total number of subjects
    479
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    717
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were enrolled across 13 countries at 177 study centers.

    Pre-assignment
    Screening details
    		 This study comprised of 3 phases: Induction, Consolidation and Continuation phase. The randomization was stratified by FLT3 mutation status.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Induction and Consolidation Chemotherapy Plus Midostaurin
    Arm description
    		 Patients received daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission received four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Midostaurin
    Investigational medicinal product code
    PKC412
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Induction Phase: 50 mg bid on Days 8-21 Consolidation Phase: 50 mg orally bid on Days 8-21 Continuation Phase: 50 mg bid orally on Days 1-28) for up to 12 cycles of 28 days.

    Investigational medicinal product name
    Daunorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Induction Phase: Daunorubicin 60 mg/m2/day by iv push or short infusion on Days 1−3 for up to 2 cycles

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Induction Phase: Cytarabine 200 mg/m2/day continuous iv infusion on Days 1-7 Consolidation Phase: high dose cytarabine (3000 mg/m2 iv every 12 hours on Days 1, 3, and 5) for up to 4 cycles

    Arm title
    		 Induction and Consolidation Chemotherapy Plus Placebo
    Arm description
    		 Patients received daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission received four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo was administered orally via a bid regimen

    Investigational medicinal product name
    Daunorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Induction Phase: Daunorubicin 60 mg/m2/day by iv push or short infusion on Days 1−3 for up to 2 cycles

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Induction Phase: Cytarabine 200 mg/m2/day continuous iv infusion on Days 1-7 Consolidation Phase: high dose cytarabine (3000 mg/m2 iv every 12 hours on Days 1, 3, and 5) for up to 4 cycles

    Number of subjects in period 1
    		Induction and Consolidation Chemotherapy Plus Midostaurin Induction and Consolidation Chemotherapy Plus Placebo
    Started
    360
    357
    Completed
    69
    52
    Not completed
    291
    305
         Pt off-treatment for other complicating disease
    3
    2
         Consent withdrawn by subject
    22
    40
         Disease progression
    58
    58
         Adverse Event
    32
    22
         Death
    18
    18
         Other
    44
    55
         Alternative therapy
    109
    107
         Untreated
    5
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Induction and Consolidation Chemotherapy Plus Midostaurin
    Reporting group description
    		 Patients received daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission received four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.

    Reporting group title
    Induction and Consolidation Chemotherapy Plus Placebo
    Reporting group description
    		 Patients received daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission received four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.

    Reporting group values
    		 Induction and Consolidation Chemotherapy Plus Midostaurin Induction and Consolidation Chemotherapy Plus Placebo Total
    Number of subjects
    		 360 357 717
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        median (full range (min-max))
    		 47.0 (19 to 59) 48.0 (18 to 60) -
    Gender Categorical
    Units: Subjects
        Female
    		 186 212 398
        Male
    		 174 145 319
    FLT3 mutational subtype
    Mutations in the gene encoding the trans-membrane tyrosine kinase FLT3. FLT3 internal tandem duplications (ITD) mutation which results in a duplication between 3 and greater than 100 amino acids most commonly located in the juxtamembrane region. Tyrosine kinase domain (TKD) point mutations are the remainder of those with FLT3 mutations. FLT3 testing was done centrally.
    Units: Subjects
        TKD (No ITD)
    		 81 81 162
        ITD Allelic ratio <0.7
    		 171 170 341
        ITD Allelic ratio >=0.7
    		 108 106 214
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 8 5 13
        Black or African American
    		 8 9 17
        White
    		 147 128 275
        More than one race
    		 2 1 3
        Unknown or Not Reported
    		 195 213 408

    End points

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    End points reporting groups
    Reporting group title
    Induction and Consolidation Chemotherapy Plus Midostaurin
    Reporting group description
    		 Patients received daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission received four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.

    Reporting group title
    Induction and Consolidation Chemotherapy Plus Placebo
    Reporting group description
    		 Patients received daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission received four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.

    Primary: Overall survival (OS) - Non-censored at the time of Stem Cell Transplantation (SCT)

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    End point title
    		 Overall survival (OS) - Non-censored at the time of Stem Cell Transplantation (SCT)
    End point description
    Overall survival (OS) was defined as the time interval from randomization to death from any cause. The median OS with 95% CI was estimated using the Kaplan-Meier method.
    End point type
    Primary
    End point timeframe
    Up to 10 years
    End point values
    		 Induction and Consolidation Chemotherapy Plus Midostaurin Induction and Consolidation Chemotherapy Plus Placebo
    Number of subjects analysed
    360
    357
    Units: months
        median (confidence interval 95%)
    67.71 (31.54 to 109.7)
    25.59 (18.53 to 42.87)
    Statistical analysis title
    		 Midostaurin vs. Placebo for OS (non-censorring)
    Comparison groups
    Induction and Consolidation Chemotherapy Plus Midostaurin v Induction and Consolidation Chemotherapy Plus Placebo
    Number of subjects included in analysis
    717
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1

    Secondary: Overall Survival - Censored at the time of SCT

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    End point title
    		 Overall Survival - Censored at the time of SCT
    End point description
    Overall survival (OS) was defined as the time interval from randomization to death from any cause. Any participants who received a stem cell transplant were censored at the time of transplant. The median OS with 95% CI was estimated using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Up to 10 years
    End point values
    		 Induction and Consolidation Chemotherapy Plus Midostaurin Induction and Consolidation Chemotherapy Plus Placebo
    Number of subjects analysed
    360
    357
    Units: months
        median (confidence interval 95%)
    999 (104.8 to 999)
    99 (27.43 to 999)
    Statistical analysis title
    		 Midostaurin vs. Placebo (Censored)
    Comparison groups
    Induction and Consolidation Chemotherapy Plus Midostaurin v Induction and Consolidation Chemotherapy Plus Placebo
    Number of subjects included in analysis
    717
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 1.07

    Secondary: Event free survival (EFS) - non-censored for SCT (Key Secondary endpoint)

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    End point title
    		 Event free survival (EFS) - non-censored for SCT (Key Secondary endpoint)
    End point description
    Event free survival (EFS) was defined as the time from randomization until the earliest qualifying event, including: failure to obtain a complete response (CR) on or before 60 days of initiation of protocol therapy; relapse; or death from any cause. Patients alive and event free at the time of analysis were censored on the date of last clinical assessment. The median EFS with 95% CI was estimated using the Kaplan-Meier method. Due to a higher than expected transplant rate, EFS was promoted to be a key secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 10 years
    End point values
    		 Induction and Consolidation Chemotherapy Plus Midostaurin Induction and Consolidation Chemotherapy Plus Placebo
    Number of subjects analysed
    360
    357
    Units: months
        median (confidence interval 95%)
    8.25 (5.45 to 11.07)
    2.99 (1.91 to 5.91)
    Statistical analysis title
    		 Midostaurin vs. Placebo - EFS
    Comparison groups
    Induction and Consolidation Chemotherapy Plus Midostaurin v Induction and Consolidation Chemotherapy Plus Placebo
    Number of subjects included in analysis
    717
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 0.94

    Secondary: Complete Response Rate (CRR)

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    End point title
    		 Complete Response Rate (CRR)
    End point description
    Percentage of participants who achieved a complete response (CR). A CR was defined as normalization of blood counts and a marrow showing less than 5% blasts occurring on or before day 60.
    End point type
    Secondary
    End point timeframe
    Induction therapy (up to 60 days)
    End point values
    		 Induction and Consolidation Chemotherapy Plus Midostaurin Induction and Consolidation Chemotherapy Plus Placebo
    Number of subjects analysed
    360
    357
    Units: Percentage of Subjects
        number (not applicable)
    58.9
    53.5
    Statistical analysis title
    		 Midostaurin vs. Placebo (CRR)
    Comparison groups
    Induction and Consolidation Chemotherapy Plus Midostaurin v Induction and Consolidation Chemotherapy Plus Placebo
    Number of subjects included in analysis
    717
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.073 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in proportions
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.13
    Notes
    [1] - One-sided p-value calculated using Cochran-Mantel-Haenszel test for two proportions adjusted for the FLT3 randomization stratum

    Secondary: Disease-free Survival (DFS) - non-censored at the time of SCT

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    End point title
    		 Disease-free Survival (DFS) - non-censored at the time of SCT
    End point description
    Disease free survival (DFS) is defined as the time from documentation of first clinical response (CR) at any time to the first of relapse or death from any cause in participants who achieved a CR.
    End point type
    Secondary
    End point timeframe
    Up to 10 years
    End point values
    		 Induction and Consolidation Chemotherapy Plus Midostaurin Induction and Consolidation Chemotherapy Plus Placebo
    Number of subjects analysed
    360
    357
    Units: months
        median (confidence interval 95%)
    26.74 (19.78 to 92.81)
    15.51 (11.33 to 23.46)
    Statistical analysis title
    		 Midostaurin vs. Placebo (DFS)
    Comparison groups
    Induction and Consolidation Chemotherapy Plus Midostaurin v Induction and Consolidation Chemotherapy Plus Placebo
    Number of subjects included in analysis
    717
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 0.95

    Secondary: Disease-free Survival (DFS) Rate one year after completing the planned continuation phase

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    End point title
    		 Disease-free Survival (DFS) Rate one year after completing the planned continuation phase
    End point description
    DFS was modified to reflect time from end of continuation to relapse/death from any cause. DFS was assessed for all patients having a CR within 60 days of treatment initiation, and who had completed continuation therapy (i.e. had taken study drug for a minimum of 335 days) and were still in CR. The outcome is presented as an estimated probability without an event at 1 year after completing continuation therapy for subjects.
    End point type
    Secondary
    End point timeframe
    one year after completion of continuation therapy
    End point values
    		 Induction and Consolidation Chemotherapy Plus Midostaurin Induction and Consolidation Chemotherapy Plus Placebo
    Number of subjects analysed
    59
    41
    Units: rate
        number (confidence interval 95%)
    0.74 (0.61 to 0.84)
    0.90 (0.76 to 0.96)
    Statistical analysis title
    		 Midostaurin vs Placebo (FFS rate)
    Comparison groups
    Induction and Consolidation Chemotherapy Plus Midostaurin v Induction and Consolidation Chemotherapy Plus Placebo
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 3.22

    Secondary: Stem cell transplantation (SCT) rates - Overall

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    End point title
    		 Stem cell transplantation (SCT) rates - Overall
    End point description
    Stem cell transplantation rates is defined as to compare the SCT rates whether they are similar in the two treatment groups
    End point type
    Secondary
    End point timeframe
    Up to 10 years
    End point values
    		 Induction and Consolidation Chemotherapy Plus Midostaurin Induction and Consolidation Chemotherapy Plus Placebo
    Number of subjects analysed
    360
    357
    Units: Percentage of Subjects
        number (not applicable)
    60.8
    55.5
    Statistical analysis title
    		 Midostaurin vs. Placebo (SCT)
    Comparison groups
    Induction and Consolidation Chemotherapy Plus Midostaurin v Induction and Consolidation Chemotherapy Plus Placebo
    Number of subjects included in analysis
    717
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in proportions
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.13

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Only Adverse Events (AEs) occurring after the date of the first study drug intake and up to 30 days after the last study drug intake are reported up to a maximum duration of 10 years. * In North America, 13 expected AEs had all grades collected. For al
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Induction and Consolidation Chemotherapy Plus Midostaurin
    Reporting group description
    		 Patients received daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission received four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.

    Reporting group title
    ALL Subjects
    Reporting group description
    		 This includes all subjects who participated in the trial.

    Reporting group title
    Induction and Consolidation Chemotherapy Plus Placebo
    Reporting group description
    		 Patients received daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission received four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.

    Serious adverse events
    		 Induction and Consolidation Chemotherapy Plus Midostaurin ALL Subjects Induction and Consolidation Chemotherapy Plus Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    172 / 345 (49.86%)
    346 / 680 (50.88%)
    174 / 335 (51.94%)
         number of deaths (all causes)
    15
    36
    21
         number of deaths resulting from adverse events
    9
    16
    7
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma of liver
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Testicular neoplasm
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 345 (0.58%)
    4 / 680 (0.59%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Phlebitis superficial
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    16 / 345 (4.64%)
    20 / 680 (2.94%)
    4 / 335 (1.19%)
         occurrences causally related to treatment / all
    6 / 17
    8 / 21
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 345 (0.29%)
    3 / 680 (0.44%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Oophorectomy
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site erythema
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    7 / 345 (2.03%)
    13 / 680 (1.91%)
    6 / 335 (1.79%)
         occurrences causally related to treatment / all
    6 / 8
    15 / 17
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 345 (0.29%)
    3 / 680 (0.44%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    2 / 345 (0.58%)
    6 / 680 (0.88%)
    4 / 335 (1.19%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 6
    2 / 4
         deaths causally related to treatment / all
    2 / 2
    4 / 5
    2 / 3
    Localised oedema
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injection site reaction
         subjects affected / exposed
    1 / 345 (0.29%)
    3 / 680 (0.44%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis in device
         subjects affected / exposed
    3 / 345 (0.87%)
    4 / 680 (0.59%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    Pyrexia
         subjects affected / exposed
    9 / 345 (2.61%)
    19 / 680 (2.79%)
    10 / 335 (2.99%)
         occurrences causally related to treatment / all
    3 / 14
    5 / 24
    2 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 345 (0.58%)
    3 / 680 (0.44%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Unevaluable event
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 345 (0.00%)
    4 / 680 (0.59%)
    4 / 335 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine haemorrhage
         subjects affected / exposed
    2 / 345 (0.58%)
    4 / 680 (0.59%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    3 / 345 (0.87%)
    4 / 680 (0.59%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal inflammation
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    2 / 345 (0.58%)
    2 / 680 (0.29%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    7 / 345 (2.03%)
    10 / 680 (1.47%)
    3 / 335 (0.90%)
         occurrences causally related to treatment / all
    3 / 7
    5 / 10
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    8 / 345 (2.32%)
    11 / 680 (1.62%)
    3 / 335 (0.90%)
         occurrences causally related to treatment / all
    2 / 8
    4 / 11
    2 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 345 (0.58%)
    2 / 680 (0.29%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal inflammation
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal pain
         subjects affected / exposed
    1 / 345 (0.29%)
    3 / 680 (0.44%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    15 / 345 (4.35%)
    27 / 680 (3.97%)
    12 / 335 (3.58%)
         occurrences causally related to treatment / all
    8 / 17
    14 / 30
    6 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    3 / 345 (0.87%)
    5 / 680 (0.74%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    7 / 345 (2.03%)
    7 / 680 (1.03%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    3 / 7
    3 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 345 (0.58%)
    3 / 680 (0.44%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary toxicity
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    3 / 345 (0.87%)
    3 / 680 (0.44%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract haemorrhage
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachypnoea
         subjects affected / exposed
    2 / 345 (0.58%)
    2 / 680 (0.29%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhinitis allergic
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Restlessness
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    2 / 345 (0.58%)
    3 / 680 (0.44%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood fibrinogen increased
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    2 / 345 (0.58%)
    4 / 680 (0.59%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 345 (0.58%)
    4 / 680 (0.59%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 345 (0.29%)
    3 / 680 (0.44%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    9 / 345 (2.61%)
    10 / 680 (1.47%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    9 / 10
    9 / 11
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    10 / 345 (2.90%)
    14 / 680 (2.06%)
    4 / 335 (1.19%)
         occurrences causally related to treatment / all
    9 / 11
    11 / 15
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    29 / 345 (8.41%)
    62 / 680 (9.12%)
    33 / 335 (9.85%)
         occurrences causally related to treatment / all
    20 / 30
    49 / 67
    29 / 37
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    24 / 345 (6.96%)
    52 / 680 (7.65%)
    28 / 335 (8.36%)
         occurrences causally related to treatment / all
    16 / 25
    40 / 58
    24 / 33
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    12 / 345 (3.48%)
    21 / 680 (3.09%)
    9 / 335 (2.69%)
         occurrences causally related to treatment / all
    7 / 12
    15 / 22
    8 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 345 (0.29%)
    5 / 680 (0.74%)
    4 / 335 (1.19%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 6
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    8 / 345 (2.32%)
    17 / 680 (2.50%)
    9 / 335 (2.69%)
         occurrences causally related to treatment / all
    8 / 8
    15 / 17
    7 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Troponin T increased
         subjects affected / exposed
    2 / 345 (0.58%)
    3 / 680 (0.44%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CD4 lymphocytes decreased
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Jaw fracture
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural bile leak
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiation mucositis
         subjects affected / exposed
    1 / 345 (0.29%)
    6 / 680 (0.88%)
    5 / 335 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 6
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post-traumatic pain
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Epidermolysis
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 345 (0.87%)
    3 / 680 (0.44%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 345 (0.58%)
    4 / 680 (0.59%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    6 / 345 (1.74%)
    8 / 680 (1.18%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    5 / 6
    7 / 8
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 345 (0.58%)
    3 / 680 (0.44%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    2 / 345 (0.58%)
    3 / 680 (0.44%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 345 (0.00%)
    2 / 680 (0.29%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    3 / 345 (0.87%)
    7 / 680 (1.03%)
    4 / 335 (1.19%)
         occurrences causally related to treatment / all
    2 / 3
    7 / 8
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    3 / 345 (0.87%)
    3 / 680 (0.44%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    4 / 345 (1.16%)
    7 / 680 (1.03%)
    3 / 335 (0.90%)
         occurrences causally related to treatment / all
    3 / 4
    5 / 7
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 345 (0.29%)
    3 / 680 (0.44%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    2 / 345 (0.58%)
    6 / 680 (0.88%)
    4 / 335 (1.19%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 6
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    Cerebrovascular accident
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 345 (0.00%)
    2 / 680 (0.29%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuroleptic malignant syndrome
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 345 (0.29%)
    4 / 680 (0.59%)
    3 / 335 (0.90%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    2 / 345 (0.58%)
    7 / 680 (1.03%)
    5 / 335 (1.49%)
         occurrences causally related to treatment / all
    1 / 2
    4 / 7
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    9 / 345 (2.61%)
    16 / 680 (2.35%)
    7 / 335 (2.09%)
         occurrences causally related to treatment / all
    7 / 9
    13 / 17
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    53 / 345 (15.36%)
    106 / 680 (15.59%)
    53 / 335 (15.82%)
         occurrences causally related to treatment / all
    33 / 70
    70 / 134
    37 / 64
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenic haematoma
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    External ear pain
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deafness
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    2 / 345 (0.58%)
    2 / 680 (0.29%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye pain
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periorbital oedema
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 345 (1.16%)
    10 / 680 (1.47%)
    6 / 335 (1.79%)
         occurrences causally related to treatment / all
    1 / 5
    5 / 11
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal ulcer
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anorectal discomfort
         subjects affected / exposed
    2 / 345 (0.58%)
    2 / 680 (0.29%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    11 / 345 (3.19%)
    21 / 680 (3.09%)
    10 / 335 (2.99%)
         occurrences causally related to treatment / all
    6 / 11
    10 / 21
    4 / 10
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Constipation
         subjects affected / exposed
    3 / 345 (0.87%)
    5 / 680 (0.74%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dental caries
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    7 / 345 (2.03%)
    17 / 680 (2.50%)
    10 / 335 (2.99%)
         occurrences causally related to treatment / all
    6 / 9
    12 / 19
    6 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eructation
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    2 / 345 (0.58%)
    2 / 680 (0.29%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    2 / 345 (0.58%)
    6 / 680 (0.88%)
    4 / 335 (1.19%)
         occurrences causally related to treatment / all
    1 / 2
    4 / 6
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 345 (0.00%)
    2 / 680 (0.29%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 345 (0.00%)
    2 / 680 (0.29%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Large intestinal haemorrhage
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    5 / 345 (1.45%)
    11 / 680 (1.62%)
    6 / 335 (1.79%)
         occurrences causally related to treatment / all
    6 / 8
    11 / 14
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral pain
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    0 / 345 (0.00%)
    2 / 680 (0.29%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 345 (0.29%)
    3 / 680 (0.44%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Salivary gland disorder
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 345 (1.16%)
    10 / 680 (1.47%)
    6 / 335 (1.79%)
         occurrences causally related to treatment / all
    7 / 8
    13 / 16
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 345 (0.58%)
    2 / 680 (0.29%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toothache
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    6 / 345 (1.74%)
    11 / 680 (1.62%)
    5 / 335 (1.49%)
         occurrences causally related to treatment / all
    3 / 6
    7 / 11
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 345 (0.00%)
    2 / 680 (0.29%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gallbladder disorder
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 345 (0.58%)
    7 / 680 (1.03%)
    5 / 335 (1.49%)
         occurrences causally related to treatment / all
    2 / 2
    5 / 7
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis exfoliative
         subjects affected / exposed
    11 / 345 (3.19%)
    15 / 680 (2.21%)
    4 / 335 (1.19%)
         occurrences causally related to treatment / all
    9 / 13
    12 / 17
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain of skin
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    2 / 345 (0.58%)
    2 / 680 (0.29%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperhidrosis
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Exfoliative rash
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dry skin
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Petechiae
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    3 / 345 (0.87%)
    3 / 680 (0.44%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 345 (0.58%)
    3 / 680 (0.44%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    8 / 345 (2.32%)
    10 / 680 (1.47%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    3 / 8
    3 / 10
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal haemorrhage
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urogenital haemorrhage
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral pain
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary bladder haemorrhage
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Diabetes insipidus
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 345 (0.29%)
    3 / 680 (0.44%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 345 (0.58%)
    4 / 680 (0.59%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 345 (0.00%)
    2 / 680 (0.29%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint effusion
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Trismus
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenoviral hepatitis
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acarodermatitis
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    2 / 345 (0.58%)
    2 / 680 (0.29%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal infection
         subjects affected / exposed
    2 / 345 (0.58%)
    5 / 680 (0.74%)
    3 / 335 (0.90%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 345 (0.00%)
    2 / 680 (0.29%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Candida infection
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 345 (0.29%)
    3 / 680 (0.44%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    2 / 345 (0.58%)
    5 / 680 (0.74%)
    3 / 335 (0.90%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    2 / 345 (0.58%)
    4 / 680 (0.59%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    25 / 345 (7.25%)
    38 / 680 (5.59%)
    13 / 335 (3.88%)
         occurrences causally related to treatment / all
    10 / 28
    15 / 42
    5 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 345 (0.29%)
    5 / 680 (0.74%)
    4 / 335 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 6
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    6 / 345 (1.74%)
    10 / 680 (1.47%)
    4 / 335 (1.19%)
         occurrences causally related to treatment / all
    2 / 6
    4 / 11
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium colitis
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterococcal infection
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis necroticans
         subjects affected / exposed
    2 / 345 (0.58%)
    2 / 680 (0.29%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis Escherichia coli
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    2 / 345 (0.58%)
    2 / 680 (0.29%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Furuncle
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    1 / 345 (0.29%)
    4 / 680 (0.59%)
    3 / 335 (0.90%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic infection fungal
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic infection
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    2 / 345 (0.58%)
    3 / 680 (0.44%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
    Infection
         subjects affected / exposed
    8 / 345 (2.32%)
    11 / 680 (1.62%)
    3 / 335 (0.90%)
         occurrences causally related to treatment / all
    3 / 8
    5 / 11
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incision site infection
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 345 (0.58%)
    4 / 680 (0.59%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lip infection
         subjects affected / exposed
    1 / 345 (0.29%)
    4 / 680 (0.59%)
    3 / 335 (0.90%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 5
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nail infection
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    12 / 345 (3.48%)
    18 / 680 (2.65%)
    6 / 335 (1.79%)
         occurrences causally related to treatment / all
    5 / 12
    8 / 18
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral fungal infection
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Opportunistic infection
         subjects affected / exposed
    2 / 345 (0.58%)
    5 / 680 (0.74%)
    3 / 335 (0.90%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 5
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Neutropenic sepsis
         subjects affected / exposed
    10 / 345 (2.90%)
    11 / 680 (1.62%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    4 / 10
    5 / 11
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 345 (0.29%)
    3 / 680 (0.44%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    27 / 345 (7.83%)
    55 / 680 (8.09%)
    28 / 335 (8.36%)
         occurrences causally related to treatment / all
    13 / 30
    26 / 60
    13 / 30
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    0 / 345 (0.00%)
    2 / 680 (0.29%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    19 / 345 (5.51%)
    37 / 680 (5.44%)
    18 / 335 (5.37%)
         occurrences causally related to treatment / all
    14 / 22
    27 / 41
    13 / 19
         deaths causally related to treatment / all
    2 / 3
    4 / 7
    2 / 4
    Rhinitis
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenic infection
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 345 (0.29%)
    3 / 680 (0.44%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    2 / 345 (0.58%)
    2 / 680 (0.29%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
    Pulmonary sepsis
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenic infection fungal
         subjects affected / exposed
    2 / 345 (0.58%)
    2 / 680 (0.29%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    7 / 345 (2.03%)
    16 / 680 (2.35%)
    9 / 335 (2.69%)
         occurrences causally related to treatment / all
    2 / 8
    7 / 19
    5 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 345 (0.58%)
    2 / 680 (0.29%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 345 (0.29%)
    3 / 680 (0.44%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    2 / 345 (0.58%)
    2 / 680 (0.29%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal infection
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    2 / 345 (0.58%)
    3 / 680 (0.44%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 345 (0.00%)
    4 / 680 (0.59%)
    4 / 335 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    5 / 345 (1.45%)
    8 / 680 (1.18%)
    3 / 335 (0.90%)
         occurrences causally related to treatment / all
    3 / 6
    3 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypermagnesaemia
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 680 (0.15%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 680 (0.15%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    8 / 345 (2.32%)
    13 / 680 (1.91%)
    5 / 335 (1.49%)
         occurrences causally related to treatment / all
    1 / 8
    2 / 13
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 680 (0.29%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    3 / 345 (0.87%)
    3 / 680 (0.44%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 345 (0.58%)
    4 / 680 (0.59%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    2 / 345 (0.58%)
    6 / 680 (0.88%)
    4 / 335 (1.19%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 6
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Induction and Consolidation Chemotherapy Plus Midostaurin ALL Subjects Induction and Consolidation Chemotherapy Plus Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    344 / 345 (99.71%)
    679 / 680 (99.85%)
    335 / 335 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    39 / 345 (11.30%)
    81 / 680 (11.91%)
    42 / 335 (12.54%)
         occurrences all number
    40
    86
    46
    Hypertension
         subjects affected / exposed
    24 / 345 (6.96%)
    43 / 680 (6.32%)
    19 / 335 (5.67%)
         occurrences all number
    26
    46
    20
    Haematoma
         subjects affected / exposed
    38 / 345 (11.01%)
    76 / 680 (11.18%)
    38 / 335 (11.34%)
         occurrences all number
    44
    86
    42
    Phlebitis superficial
         subjects affected / exposed
    17 / 345 (4.93%)
    38 / 680 (5.59%)
    21 / 335 (6.27%)
         occurrences all number
    18
    39
    21
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    245 / 345 (71.01%)
    481 / 680 (70.74%)
    236 / 335 (70.45%)
         occurrences all number
    337
    651
    314
    Chills
         subjects affected / exposed
    39 / 345 (11.30%)
    72 / 680 (10.59%)
    33 / 335 (9.85%)
         occurrences all number
    42
    78
    36
    Chest pain
         subjects affected / exposed
    15 / 345 (4.35%)
    33 / 680 (4.85%)
    18 / 335 (5.37%)
         occurrences all number
    18
    37
    19
    Injection site reaction
         subjects affected / exposed
    25 / 345 (7.25%)
    51 / 680 (7.50%)
    26 / 335 (7.76%)
         occurrences all number
    27
    59
    32
    Pyrexia
         subjects affected / exposed
    86 / 345 (24.93%)
    167 / 680 (24.56%)
    81 / 335 (24.18%)
         occurrences all number
    103
    197
    94
    Oedema peripheral
         subjects affected / exposed
    56 / 345 (16.23%)
    118 / 680 (17.35%)
    62 / 335 (18.51%)
         occurrences all number
    62
    136
    74
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    37 / 345 (10.72%)
    67 / 680 (9.85%)
    30 / 335 (8.96%)
         occurrences all number
    39
    73
    34
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    15 / 345 (4.35%)
    36 / 680 (5.29%)
    21 / 335 (6.27%)
         occurrences all number
    16
    39
    23
    Respiratory, thoracic and mediastinal disorders
    Laryngeal pain
         subjects affected / exposed
    33 / 345 (9.57%)
    61 / 680 (8.97%)
    28 / 335 (8.36%)
         occurrences all number
    37
    69
    32
    Hypoxia
         subjects affected / exposed
    11 / 345 (3.19%)
    30 / 680 (4.41%)
    19 / 335 (5.67%)
         occurrences all number
    11
    30
    19
    Epistaxis
         subjects affected / exposed
    71 / 345 (20.58%)
    129 / 680 (18.97%)
    58 / 335 (17.31%)
         occurrences all number
    79
    147
    68
    Dyspnoea
         subjects affected / exposed
    37 / 345 (10.72%)
    73 / 680 (10.74%)
    36 / 335 (10.75%)
         occurrences all number
    40
    78
    38
    Cough
         subjects affected / exposed
    53 / 345 (15.36%)
    107 / 680 (15.74%)
    54 / 335 (16.12%)
         occurrences all number
    66
    126
    60
    Pneumonitis
         subjects affected / exposed
    18 / 345 (5.22%)
    45 / 680 (6.62%)
    27 / 335 (8.06%)
         occurrences all number
    19
    46
    27
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    21 / 345 (6.09%)
    48 / 680 (7.06%)
    27 / 335 (8.06%)
         occurrences all number
    23
    57
    34
    Insomnia
         subjects affected / exposed
    36 / 345 (10.43%)
    60 / 680 (8.82%)
    24 / 335 (7.16%)
         occurrences all number
    44
    74
    30
    Depression
         subjects affected / exposed
    15 / 345 (4.35%)
    44 / 680 (6.47%)
    29 / 335 (8.66%)
         occurrences all number
    17
    49
    32
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    24 / 345 (6.96%)
    47 / 680 (6.91%)
    23 / 335 (6.87%)
         occurrences all number
    26
    52
    26
    Blood bilirubin increased
         subjects affected / exposed
    33 / 345 (9.57%)
    75 / 680 (11.03%)
    42 / 335 (12.54%)
         occurrences all number
    36
    85
    49
    Blood alkaline phosphatase increased
         subjects affected / exposed
    37 / 345 (10.72%)
    77 / 680 (11.32%)
    40 / 335 (11.94%)
         occurrences all number
    45
    90
    45
    C-reactive protein increased
         subjects affected / exposed
    22 / 345 (6.38%)
    52 / 680 (7.65%)
    30 / 335 (8.96%)
         occurrences all number
    26
    63
    37
    Alanine aminotransferase increased
         subjects affected / exposed
    102 / 345 (29.57%)
    199 / 680 (29.26%)
    97 / 335 (28.96%)
         occurrences all number
    147
    264
    117
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    34 / 345 (9.86%)
    61 / 680 (8.97%)
    27 / 335 (8.06%)
         occurrences all number
    35
    64
    29
    Aspartate aminotransferase increased
         subjects affected / exposed
    76 / 345 (22.03%)
    149 / 680 (21.91%)
    73 / 335 (21.79%)
         occurrences all number
    105
    194
    89
    Electrocardiogram QT prolonged
         subjects affected / exposed
    51 / 345 (14.78%)
    90 / 680 (13.24%)
    39 / 335 (11.64%)
         occurrences all number
    71
    118
    47
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    36 / 345 (10.43%)
    78 / 680 (11.47%)
    42 / 335 (12.54%)
         occurrences all number
    43
    89
    46
    Haemoglobin decreased
         subjects affected / exposed
    334 / 345 (96.81%)
    656 / 680 (96.47%)
    322 / 335 (96.12%)
         occurrences all number
    388
    749
    361
    Neutrophil count decreased
         subjects affected / exposed
    319 / 345 (92.46%)
    626 / 680 (92.06%)
    307 / 335 (91.64%)
         occurrences all number
    376
    719
    343
    Platelet count decreased
         subjects affected / exposed
    328 / 345 (95.07%)
    640 / 680 (94.12%)
    312 / 335 (93.13%)
         occurrences all number
    403
    774
    371
    Weight decreased
         subjects affected / exposed
    11 / 345 (3.19%)
    28 / 680 (4.12%)
    17 / 335 (5.07%)
         occurrences all number
    11
    28
    17
    Weight increased
         subjects affected / exposed
    18 / 345 (5.22%)
    26 / 680 (3.82%)
    8 / 335 (2.39%)
         occurrences all number
    18
    26
    8
    Injury, poisoning and procedural complications
    Radiation mucositis
         subjects affected / exposed
    132 / 345 (38.26%)
    261 / 680 (38.38%)
    129 / 335 (38.51%)
         occurrences all number
    156
    310
    154
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    25 / 345 (7.25%)
    53 / 680 (7.79%)
    28 / 335 (8.36%)
         occurrences all number
    26
    58
    32
    Nervous system disorders
    Headache
         subjects affected / exposed
    121 / 345 (35.07%)
    227 / 680 (33.38%)
    106 / 335 (31.64%)
         occurrences all number
    165
    297
    132
    Dysgeusia
         subjects affected / exposed
    9 / 345 (2.61%)
    26 / 680 (3.82%)
    17 / 335 (5.07%)
         occurrences all number
    9
    27
    18
    Dizziness
         subjects affected / exposed
    53 / 345 (15.36%)
    103 / 680 (15.15%)
    50 / 335 (14.93%)
         occurrences all number
    60
    115
    55
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    254 / 345 (73.62%)
    506 / 680 (74.41%)
    252 / 335 (75.22%)
         occurrences all number
    310
    613
    303
    Leukopenia
         subjects affected / exposed
    94 / 345 (27.25%)
    193 / 680 (28.38%)
    99 / 335 (29.55%)
         occurrences all number
    114
    225
    111
    Lymphopenia
         subjects affected / exposed
    73 / 345 (21.16%)
    149 / 680 (21.91%)
    76 / 335 (22.69%)
         occurrences all number
    97
    182
    85
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    14 / 345 (4.06%)
    31 / 680 (4.56%)
    17 / 335 (5.07%)
         occurrences all number
    16
    35
    19
    Vomiting
         subjects affected / exposed
    209 / 345 (60.58%)
    397 / 680 (58.38%)
    188 / 335 (56.12%)
         occurrences all number
    278
    512
    234
    Diarrhoea
         subjects affected / exposed
    260 / 345 (75.36%)
    508 / 680 (74.71%)
    248 / 335 (74.03%)
         occurrences all number
    349
    645
    296
    Dyspepsia
         subjects affected / exposed
    25 / 345 (7.25%)
    47 / 680 (6.91%)
    22 / 335 (6.57%)
         occurrences all number
    27
    51
    24
    Dysphagia
         subjects affected / exposed
    13 / 345 (3.77%)
    32 / 680 (4.71%)
    19 / 335 (5.67%)
         occurrences all number
    14
    34
    20
    Haemorrhoids
         subjects affected / exposed
    35 / 345 (10.14%)
    62 / 680 (9.12%)
    27 / 335 (8.06%)
         occurrences all number
    36
    64
    28
    Mouth haemorrhage
         subjects affected / exposed
    16 / 345 (4.64%)
    37 / 680 (5.44%)
    21 / 335 (6.27%)
         occurrences all number
    16
    43
    27
    Nausea
         subjects affected / exposed
    282 / 345 (81.74%)
    525 / 680 (77.21%)
    243 / 335 (72.54%)
         occurrences all number
    393
    715
    322
    Stomatitis
         subjects affected / exposed
    59 / 345 (17.10%)
    94 / 680 (13.82%)
    35 / 335 (10.45%)
         occurrences all number
    65
    104
    39
    Abdominal pain upper
         subjects affected / exposed
    38 / 345 (11.01%)
    74 / 680 (10.88%)
    36 / 335 (10.75%)
         occurrences all number
    43
    81
    38
    Abdominal pain
         subjects affected / exposed
    71 / 345 (20.58%)
    158 / 680 (23.24%)
    87 / 335 (25.97%)
         occurrences all number
    81
    178
    97
    Constipation
         subjects affected / exposed
    59 / 345 (17.10%)
    128 / 680 (18.82%)
    69 / 335 (20.60%)
         occurrences all number
    69
    144
    75
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    40 / 345 (11.59%)
    82 / 680 (12.06%)
    42 / 335 (12.54%)
         occurrences all number
    48
    95
    47
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    31 / 345 (8.99%)
    71 / 680 (10.44%)
    40 / 335 (11.94%)
         occurrences all number
    34
    78
    44
    Hyperhidrosis
         subjects affected / exposed
    36 / 345 (10.43%)
    57 / 680 (8.38%)
    21 / 335 (6.27%)
         occurrences all number
    43
    69
    26
    Dermatitis exfoliative
         subjects affected / exposed
    218 / 345 (63.19%)
    440 / 680 (64.71%)
    222 / 335 (66.27%)
         occurrences all number
    269
    544
    275
    Petechiae
         subjects affected / exposed
    88 / 345 (25.51%)
    156 / 680 (22.94%)
    68 / 335 (20.30%)
         occurrences all number
    102
    180
    78
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    21 / 345 (6.09%)
    32 / 680 (4.71%)
    11 / 335 (3.28%)
         occurrences all number
    23
    34
    11
    Arthralgia
         subjects affected / exposed
    39 / 345 (11.30%)
    57 / 680 (8.38%)
    18 / 335 (5.37%)
         occurrences all number
    44
    70
    26
    Back pain
         subjects affected / exposed
    58 / 345 (16.81%)
    100 / 680 (14.71%)
    42 / 335 (12.54%)
         occurrences all number
    67
    118
    51
    Bone pain
         subjects affected / exposed
    24 / 345 (6.96%)
    47 / 680 (6.91%)
    23 / 335 (6.87%)
         occurrences all number
    29
    56
    27
    Myalgia
         subjects affected / exposed
    19 / 345 (5.51%)
    38 / 680 (5.59%)
    19 / 335 (5.67%)
         occurrences all number
    24
    45
    21
    Pain in extremity
         subjects affected / exposed
    32 / 345 (9.28%)
    56 / 680 (8.24%)
    24 / 335 (7.16%)
         occurrences all number
    38
    66
    28
    Infections and infestations
    Neutropenic infection
         subjects affected / exposed
    11 / 345 (3.19%)
    28 / 680 (4.12%)
    17 / 335 (5.07%)
         occurrences all number
    11
    28
    17
    Nasopharyngitis
         subjects affected / exposed
    20 / 345 (5.80%)
    35 / 680 (5.15%)
    15 / 335 (4.48%)
         occurrences all number
    28
    45
    17
    Device related infection
         subjects affected / exposed
    53 / 345 (15.36%)
    93 / 680 (13.68%)
    40 / 335 (11.94%)
         occurrences all number
    61
    105
    44
    Conjunctivitis
         subjects affected / exposed
    22 / 345 (6.38%)
    39 / 680 (5.74%)
    17 / 335 (5.07%)
         occurrences all number
    22
    42
    20
    Oral herpes
         subjects affected / exposed
    14 / 345 (4.06%)
    31 / 680 (4.56%)
    17 / 335 (5.07%)
         occurrences all number
    15
    37
    22
    Pneumonia
         subjects affected / exposed
    28 / 345 (8.12%)
    60 / 680 (8.82%)
    32 / 335 (9.55%)
         occurrences all number
    29
    63
    34
    Urinary tract infection
         subjects affected / exposed
    16 / 345 (4.64%)
    42 / 680 (6.18%)
    26 / 335 (7.76%)
         occurrences all number
    16
    43
    27
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    45 / 345 (13.04%)
    103 / 680 (15.15%)
    58 / 335 (17.31%)
         occurrences all number
    50
    116
    66
    Hypocalcaemia
         subjects affected / exposed
    69 / 345 (20.00%)
    136 / 680 (20.00%)
    67 / 335 (20.00%)
         occurrences all number
    79
    155
    76
    Hypoalbuminaemia
         subjects affected / exposed
    66 / 345 (19.13%)
    129 / 680 (18.97%)
    63 / 335 (18.81%)
         occurrences all number
    81
    150
    69
    Hyperuricaemia
         subjects affected / exposed
    22 / 345 (6.38%)
    38 / 680 (5.59%)
    16 / 335 (4.78%)
         occurrences all number
    29
    50
    21
    Hyperglycaemia
         subjects affected / exposed
    75 / 345 (21.74%)
    139 / 680 (20.44%)
    64 / 335 (19.10%)
         occurrences all number
    109
    195
    86
    Hypokalaemia
         subjects affected / exposed
    92 / 345 (26.67%)
    191 / 680 (28.09%)
    99 / 335 (29.55%)
         occurrences all number
    110
    224
    114
    Hypomagnesaemia
         subjects affected / exposed
    36 / 345 (10.43%)
    76 / 680 (11.18%)
    40 / 335 (11.94%)
         occurrences all number
    37
    84
    47
    Hypophosphataemia
         subjects affected / exposed
    28 / 345 (8.12%)
    62 / 680 (9.12%)
    34 / 335 (10.15%)
         occurrences all number
    34
    74
    40
    Hyponatraemia
         subjects affected / exposed
    60 / 345 (17.39%)
    120 / 680 (17.65%)
    60 / 335 (17.91%)
         occurrences all number
    66
    131
    65

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Feb 2009
    Clarification of eligibility criterion for patients with neurologic symptoms; Changes in dose modification required in cases of QTc prolongation between 470 ms and 500 ms; Added dose modification requirement for cases of ≥grade-2 neurotoxicity due to high-dose cytarabine
    01 Apr 2009
    Change in dosing regimen for midostaurin/placebo continuation therapy from 14 days of each 28 day cycle to continuous daily dosing, continuing for 12 cycles, along with clarifying rationale; Adding dose modification requirement for cases of QTc prolongation; Clarifying dose modification requirements for nonhematologic toxicities of grade 3/4 severity; Change in prohibited ancillary therapy (i.e. use of aprepitant was not permitted)
    01 Dec 2009
    Changes in reporting of AEs for NNA sites as well as for their expedited reporting requirements; Addition of collection of concomitant medications; Revised information regarding drug accountability, storage and stability, and unblinding of midostaurin; Revision on statistical analyses to be performed for secondary endpoints; Revision on requirement for bone marrow aspiration during remission induction stage and response assessments.
    15 Dec 2010
    At the time of protocol version 1, the transplantation option was estimated to be available for about 15% of the population eligible for the study. This rate of withdrawal from study treatment for patients in first CR was factored into the estimate of sample size. At Amendment 4, based on blinded data from the study to date, 25% of all randomized patients were expected to have received an SCT. The sample size and power justification were therefore revised and justification for amending statistical considerations was added to reflect revised sample size; Addition of a new secondary objective to compare the OS in the two groups using an analysis in which patient who receive an SCT are censored at the time of transplantation.
    15 May 2011
    Revision of response assessment to include time requirement for bone marrow aspiration after recovery of ANC and platelet count to document complete response
    15 Sep 2011
    Changes in AE reporting for NA and NNA sites
    15 Nov 2011
    Update in administrative procedure for the unblinding of patients
    05 May 2013
    Editorial / Administrative changes
    15 Feb 2015
    Editorial / Administrative changes
    15 Jun 2015
    The protocol was amended to perform the final confirmatory analysis with a DCO of 01-Apr-2015 without waiting for the originally targeted 509 OS events to occur; The secondary endpoint EFS was promoted to a key secondary endpoint to be tested in a hierarchical manner if the OS endpoint is significant. In addition, the SCT rate was added as a secondary efficacy endpoint.
    27 Dec 2018
    Data submission for this study will now be performed using Medidata Rave; Adverse event reporting have been updated to reflect the use of CTCAE version 5.0 for serious adverse event reporting; Administrative changes

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

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

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