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    Clinical Trial Results:
    A phase III, randomized, double-blind study of chemotherapy with daunorubicin or idarubicin and cytarabine for Induction and intermediate dose cytarabine for consolidation plus midostaurin (PKC412) or chemotherapy plus placebo in newly diagnosed subjects with FLT-3 mutation negative acute myeloid leukemia (AML) Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate.

    Summary
    EudraCT number
    		 2017-003540-21
    Trial protocol
    		 DE   BE   IT   PT   FR   NO   ES   AT   HU   BG   PL  
    Global end of trial date
    12 Feb 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    14 Jul 2023
    First version publication date
    01 Mar 2022
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Aligning the outcome measure (All Collected Deaths) and the Adverse Events time frame to the other Novartis published results on ClinicalTrials.gov & NovCTR database.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CPKC412E2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02913261
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, +41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, +41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Feb 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Feb 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine if the addition of midostaurin to standard induction and consolidation therapy, followed by single agent post-consolidation therapy improves event free survival (EFS) in subjects with newly diagnosed FLT3-MN (signal ratio (SR) <0.05) AML.
    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
    20 Jul 2018
    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
    Argentina: 1
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Austria: 14
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Czechia: 10
    Country: Number of subjects enrolled
    France: 31
    Country: Number of subjects enrolled
    Germany: 165
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Italy: 79
    Country: Number of subjects enrolled
    Japan: 29
    Country: Number of subjects enrolled
    Norway: 7
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Portugal: 11
    Country: Number of subjects enrolled
    Spain: 63
    Country: Number of subjects enrolled
    Switzerland: 17
    Country: Number of subjects enrolled
    Taiwan: 11
    Country: Number of subjects enrolled
    Turkey: 8
    Country: Number of subjects enrolled
    United States: 8
    Worldwide total number of subjects
    501
    EEA total number of subjects
    396
    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)
    358
    From 65 to 84 years
    143
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Five hundred and three participants were randomized. However, the data analysis was considered for 501 participants only (250 participants in midostaurin arm and 251 participants in placebo arm).

    Pre-assignment
    Screening details
    		 Participants had to sign informed consent form before screening for enrollment. Participants started chemotherapy at day 1 and were randomized at day 8.

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Midostaurin + chemotherapy
    Arm description
    		 Participants received Midostaurin in Induction 50mg twice daily on Day 8 until 48 hrs before start of next cycle. During Induction 2 and consolidation 50mg twice daily on Day 4 until 48 hrs before start of next cycle. During post-consolidation 50mg twice daily for 28 consecutive days of each 28-day treatment cycle up to 12 cycles. For participants who could not tolerate the protocol-specified dosing schedule, dose interruptions and/or reductions were either recommended or mandated allowing participants to continue the study treatment. Chemotherapy consisted of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation.
    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
    50 mg twice daily

    Investigational medicinal product name
    Chemotherapy: daunorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    60 mg/m^2/d, day 1 -3 (induction 1), 50 mg/m^2/d, day 1 -3 (induction 2)

    Investigational medicinal product name
    Chemotherapy: cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m^2/d, days 1 -7 (induction 1), 1.5 g/m^2/day, q12h, day 1 -3 (induction 2 & Consolidation)

    Investigational medicinal product name
    Chemotherapy: idarubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    12 mg/m^2/d, day 1 -3 (induction 1), 10 mg/m^2/d, day 1 -3 (induction 2)

    Arm title
    		 Placebo + chemotherapy
    Arm description
    		 Participants received matching placebo to midostaurin with same dose, plus chemotherapy. Chemotherapy consisted of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg twice daily

    Investigational medicinal product name
    Chemotherapy: daunorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    60 mg/m^2/d, day 1 -3 (induction 1), 50 mg/m^2/d, day 1 -3 (induction 2)

    Investigational medicinal product name
    Chemotherapy: cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m^2/d, days 1 -7 (induction 1), 1.5 g/m^2/day, q12h, day 1 -3 (induction 2 & Consolidation)

    Investigational medicinal product name
    Chemotherapy: idarubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    12 mg/m^2/d, day 1 -3 (induction 1), 10 mg/m^2/d, day 1 -3 (induction 2)

    Number of subjects in period 1
    		Midostaurin + chemotherapy Placebo + chemotherapy
    Started
    250
    251
    Treated with Midostaurin/Placebo
    245
    249
    Completed
    2
    1
    Not completed
    248
    250
         Adverse event, serious fatal
    14
    9
         Physician decision
    60
    60
         Terminated by Sponsored
    46
    50
         Subject Decision
    15
    12
         Adverse event, non-fatal
    30
    34
         Failure to meet Continuation Criteria
    24
    28
         Withdrawal of informed consent
    20
    14
         Missing
    3
    13
         Lack of efficacy
    19
    11
         Guardian decision
    1
    1
         New Therapy for Study Indication
    16
    16
         Protocol deviation
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Midostaurin + chemotherapy
    Reporting group description
    		 Participants received Midostaurin in Induction 50mg twice daily on Day 8 until 48 hrs before start of next cycle. During Induction 2 and consolidation 50mg twice daily on Day 4 until 48 hrs before start of next cycle. During post-consolidation 50mg twice daily for 28 consecutive days of each 28-day treatment cycle up to 12 cycles. For participants who could not tolerate the protocol-specified dosing schedule, dose interruptions and/or reductions were either recommended or mandated allowing participants to continue the study treatment. Chemotherapy consisted of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation.

    Reporting group title
    Placebo + chemotherapy
    Reporting group description
    		 Participants received matching placebo to midostaurin with same dose, plus chemotherapy. Chemotherapy consisted of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation.

    Reporting group values
    		 Midostaurin + chemotherapy Placebo + chemotherapy Total
    Number of subjects
    		 250 251 501
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 182 176 358
        From 65-84 years
    		 68 75 143
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        median (full range (min-max))
    		 58.0 (19.0 to 78.0) 58.0 (18.0 to 79.0) -
    Sex: Female, Male
    Units: Participants
        Female
    		 122 106 228
        Male
    		 128 145 273
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 213 208 421
        Black or African American
    		 1 2 3
        Asian
    		 22 22 44
        Multiple
    		 1 1 2
        Missing
    		 13 18 31
    ECOG performance status
    Units: Subjects
        0 Status
    		 119 119 238
        1 Status
    		 107 115 222
        2 Status
    		 18 13 31
        3 Status
    		 2 0 2
        Missing Status
    		 4 4 8

    End points

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    End points reporting groups
    Reporting group title
    Midostaurin + chemotherapy
    Reporting group description
    		 Participants received Midostaurin in Induction 50mg twice daily on Day 8 until 48 hrs before start of next cycle. During Induction 2 and consolidation 50mg twice daily on Day 4 until 48 hrs before start of next cycle. During post-consolidation 50mg twice daily for 28 consecutive days of each 28-day treatment cycle up to 12 cycles. For participants who could not tolerate the protocol-specified dosing schedule, dose interruptions and/or reductions were either recommended or mandated allowing participants to continue the study treatment. Chemotherapy consisted of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation.

    Reporting group title
    Placebo + chemotherapy
    Reporting group description
    		 Participants received matching placebo to midostaurin with same dose, plus chemotherapy. Chemotherapy consisted of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation.

    Subject analysis set title
    CGP52421
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Active Midostaurin metabolite

    Subject analysis set title
    CGP62221
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Active Midostaurin metabolite

    Subject analysis set title
    CGP52421
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Active Midostaurin metabolite

    Subject analysis set title
    CGP62221
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Active Midostaurin metabolite

    Subject analysis set title
    GCP62221
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Active Midostaurin metabolite

    Subject analysis set title
    GCP52421
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Active Midostaurin metabolite

    Primary: Event Free Survival (EFS)

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    End point title
    		 Event Free Survival (EFS)
    End point description
    EFS was defined as the time from randomization to failure to obtain a complete remission (CR) or Complete remission with incomplete hematologic recovery (CRi) with adequate blood count recovery in induction, relapse after CR or CRi with adequate blood countrecovery or death due to any cause, whichever occurred first as assessed by the investigator.
    End point type
    Primary
    End point timeframe
    From date of Randomization up to approx. 30 months
    End point values
    		 Midostaurin + chemotherapy Placebo + chemotherapy
    Number of subjects analysed
    250
    251
    Units: Months
        median (confidence interval 95%)
    5.98 (2.33 to 8.97)
    5.88 (3.65 to 7.52)
    Statistical analysis title
    		 for EFS
    Comparison groups
    Midostaurin + chemotherapy v Placebo + chemotherapy
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.0239
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.31

    Secondary: Overall survival (OS) (Key Secondary)

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    End point title
    		 Overall survival (OS) (Key Secondary)
    End point description
    OS was defined as the time from randomization to date of death due to any cause. Patients entered the survival follow-up phase once they completed the safety follow up period (30 days after the last dose of midostaurin/placebo) in case of induction failure or if they had relapsed during post-treatment follow-up. Patients were then contacted by telephone every 3 months +/- 2 weeks or had a visit to follow up on their survival status, per Kaplan-Meier estimates.
    End point type
    Secondary
    End point timeframe
    Between randomization to date of death up to approx. 30 months
    End point values
    		 Midostaurin + chemotherapy Placebo + chemotherapy
    Number of subjects analysed
    250
    251
    Units: Months
        median (confidence interval 95%)
    99 (15.54 to 999)
    19.22 (13.8 to 999)
    Statistical analysis title
    		 For OS
    Comparison groups
    Midostaurin + chemotherapy v Placebo + chemotherapy
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8728
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.29

    Secondary: Percentage of participants with complete remission (CR) and complete remission with incomplete hematological recovery (CRi) but with adequate blood count recovery rate.

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    End point title
    		 Percentage of participants with complete remission (CR) and complete remission with incomplete hematological recovery (CRi) but with adequate blood count recovery rate.
    End point description
    Assessment was based on the International Working Group (IWG) criteria for AML as per investigator assessment. CR: Bone marrow: < 5% blasts no blasts with Auer rods; Peripheral blood: neutrophils ≥ 1.0 x 109/L platelets ≥ 100 x 109/L, no blasts; No evidence of extramedullary disease (such as central nervous system (CNS) or soft tissue involvement); Transfusion independent. CRi with adequate blood count recovery is defined as the following: Bone marrow < 5% blasts no blasts with Auer rods Peripheral blood Neutrophils >= 1.0 x 109/L and 50 x 109/L <=platelets < 100 x 109/L no blasts No evidence of extramedullary disease (such as CNS or soft tissue involvement).
    End point type
    Secondary
    End point timeframe
    At maximum 93 days from induction therapy start
    End point values
    		 Midostaurin + chemotherapy Placebo + chemotherapy
    Number of subjects analysed
    250
    251
    Units: Percentage of participants
        number (confidence interval 95%)
    59.2 (52.8 to 65.4)
    61.0 (54.6 to 67.0)
    No statistical analyses for this end point

    Secondary: Percentage of participants with Minimal Residual Disease (MRD) negative status

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    End point title
    		 Percentage of participants with Minimal Residual Disease (MRD) negative status
    End point description
    Participants with leukemic blasts below 0.1% were considered as MRD-negative based on leukemia-associated immunophenotype (LAIP). MRD was derived from bone marrow and blood data using cellular and molecular technologies and MRD status was measured using the flow cytometry assessments for LAIP irrespective of the investigator's overall clinical response assessment.
    End point type
    Secondary
    End point timeframe
    Between start and three months after end of treatment
    End point values
    		 Midostaurin + chemotherapy Placebo + chemotherapy
    Number of subjects analysed
    250
    251
    Units: Percentage of participants
        number (not applicable)
    40.8
    41.0
    No statistical analyses for this end point

    Secondary: Percentage of participants with Minimal Residual Disease (MRD) negative status during Post-consolidation Phase

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    End point title
    		 Percentage of participants with Minimal Residual Disease (MRD) negative status during Post-consolidation Phase
    End point description
    MRD- rate was defined as the rate of participants reaching MRD at any timepoint during Post-consolidation phase. Participants with leukemic blasts below 0.1% were considered as MRD-negative based on leukemia-associated immunophenotype (LAIP). MRD was derived from bone marrow and blood data using cellular and molecular technologies and MRD status was measured using the flow cytometry assessments for LAIP irrespective of the investigator's overall clinical response assessment.
    End point type
    Secondary
    End point timeframe
    Between start and three months after end of treatment
    End point values
    		 Midostaurin + chemotherapy Placebo + chemotherapy
    Number of subjects analysed
    45
    27
    Units: Percentage of participants
        number (not applicable)
    33.3
    33.3
    No statistical analyses for this end point

    Secondary: Time to Measurable Residual Disease (MRD) negativity by flow cytometry

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    End point title
    		 Time to Measurable Residual Disease (MRD) negativity by flow cytometry
    End point description
    Time to MRD- is defined as time from randomization to first occurrence of MRD-. Participants with leukemic blasts below 0.1% were considered as MRD-negative based on leukemia-associated immunophenotype (LAIP). MRD was derived from bone marrow and blood data using cellular and molecular technologies and MRD status was measured using the flow cytometry assessments for LAIP irrespective of the investigator's overall clinical response assessment.
    End point type
    Secondary
    End point timeframe
    From date of Randomization up to approx. 17 months
    End point values
    		 Midostaurin + chemotherapy Placebo + chemotherapy
    Number of subjects analysed
    250
    251
    Units: Days
        median (confidence interval 95%)
    2.27 (1.61 to 5.68)
    2.07 (1.68 to 6.80)
    No statistical analyses for this end point

    Secondary: Disease-free survival (DFS)

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    End point title
    		 Disease-free survival (DFS)
    End point description
    DFS as measured from the date of first CR or CRi with adequate blood count recovery to relapse or death due to any cause, whichever occurred first. Participants who did not relapse nor die were censored at the last adequate response assessment. Assessment was based on the IWG criteria for AML as per investigator assessment
    End point type
    Secondary
    End point timeframe
    From date of CR or CRi with adequate blood count recovery up to approx. 30 months
    End point values
    		 Midostaurin + chemotherapy Placebo + chemotherapy
    Number of subjects analysed
    148
    153
    Units: Months
        median (confidence interval 95%)
    10.5 (7.59 to 99)
    9.1 (6.87 to 12.02)
    Statistical analysis title
    		 For DFS
    Comparison groups
    Midostaurin + chemotherapy v Placebo + chemotherapy
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.63

    Secondary: Cumulative incidence of relapse (CIR)

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    End point title
    		 Cumulative incidence of relapse (CIR)
    End point description
    Cumulative Incidence of Relapse (CIR) was defined for participants with CR or CRi with adequate blood count recovery and was the time from achieving the CR or CRi with adequate blood count recovery until the onset of relapse from CR or CRi with adequate blood recovery. Participants without relapse were censored at the last adequate response assessment. Participants who died without relapse were counted as a competing cause of failure.
    End point type
    Secondary
    End point timeframe
    From date of CR or CRi with adequate blood count recovery up to approx. 30 months
    End point values
    		 Midostaurin + chemotherapy Placebo + chemotherapy
    Number of subjects analysed
    148
    153
    Units: Months
        median (confidence interval 95%)
    5.1 (2.83 to 7.56)
    6.6 (4.99 to 8.77)
    Statistical analysis title
    		 For CIR
    Comparison groups
    Midostaurin + chemotherapy v Placebo + chemotherapy
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.5866
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 2.87

    Secondary: Cumulative incidence of death (CID)

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    End point title
    		 Cumulative incidence of death (CID)
    End point description
    Cumulative Incidence of Death (CID) was defined for all participants achieving CR or CRi with adequate blood count recovery measured from the date of achievement of CR or CRi until the date of death due to any reason. Participants not known to have died were censored on the last contact date. Participants who experienced relapse were counted as a competing cause of failure.
    End point type
    Secondary
    End point timeframe
    From date of CR or CRi with adequate blood count recovery up to approx. 30 months
    End point values
    		 Midostaurin + chemotherapy Placebo + chemotherapy
    Number of subjects analysed
    148
    153
    Units: Months
        median (confidence interval 95%)
    99 (18.00 to 999)
    99 (14.42 to 999)
    Statistical analysis title
    		 For CID
    Comparison groups
    Midostaurin + chemotherapy v Placebo + chemotherapy
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7937
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 1.54

    Secondary: Time to CR or CRi with adequate blood count recovery

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    End point title
    		 Time to CR or CRi with adequate blood count recovery
    End point description
    Time to CR or CRi with adequate blood count recovery was defined as the time from randomization to CR or CRi with adequate blood count recovery whichever occurred first
    End point type
    Secondary
    End point timeframe
    At maximum 93 days from induction therapy start
    End point values
    		 Midostaurin + chemotherapy Placebo + chemotherapy
    Number of subjects analysed
    250
    251
    Units: Days
        median (confidence interval 95%)
    1.12 (1.02 to 1.41)
    1.15 (1.05 to 1.54)
    No statistical analyses for this end point

    Secondary: Time to partial and full neutrophil recovery

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    End point title
    		 Time to partial and full neutrophil recovery
    End point description
    The time to neutrophil recovery was assessed for the following criteria: number of days from start of treatment to the first day neutrophils ≥0.5 x 10^9/L, Number of days from start of treatment to the first day neutrophils ≥1.0 x 10^9/L
    End point type
    Secondary
    End point timeframe
    At maximum 93 days from induction therapy start
    End point values
    		 Midostaurin + chemotherapy Placebo + chemotherapy
    Number of subjects analysed
    250
    251
    Units: Months
    median (confidence interval 95%)
        Partial neutrophil recovery
    1.1 (0.82 to 1.15)
    0.9 (0.79 to 1.12)
        Full neutrophil recovery
    1.2 (1.05 to 1.48)
    1.1 (0.95 to 1.35)
    Statistical analysis title
    		 For neutrophil recovery - Pbo
    Comparison groups
    Midostaurin + chemotherapy v Placebo + chemotherapy
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.14
    Statistical analysis title
    		 For neutrophil recovery
    Comparison groups
    Midostaurin + chemotherapy v Placebo + chemotherapy
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.16

    Secondary: Time to partial and full platelet recovery

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    End point title
    		 Time to partial and full platelet recovery
    End point description
    Time to platelet recovery was assessed for the following criteria: number of days from start of treatment to the first day platelets ≥50 x 10^9/L (partial platelet recovery), number of days from start of treatment to the first day platelets ≥100 x 10^9/L (full platelet recovery).
    End point type
    Secondary
    End point timeframe
    At maximum 93 days from induction therapy start
    End point values
    		 Midostaurin + chemotherapy Placebo + chemotherapy
    Number of subjects analysed
    250
    251
    Units: Months
    median (confidence interval 95%)
        Partial platelet recovery
    99 (1.45 to 999)
    99 (3.5 to 999)
        Full platelet recovery
    0.953 (0.89 to 1.12)
    0.887 (0.85 to 0.92)
    Statistical analysis title
    		 For platelet recovery
    Comparison groups
    Midostaurin + chemotherapy v Placebo + chemotherapy
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.52
    Statistical analysis title
    		 For platelet recovery - Pbo
    Comparison groups
    Midostaurin + chemotherapy v Placebo + chemotherapy
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1

    Secondary: AUC0-t: Pharmacokinetic (PK) parameter for midostaurin and its metabolites: CGP52421 and CGP62221

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    End point title
    		 AUC0-t: Pharmacokinetic (PK) parameter for midostaurin and its metabolites: CGP52421 and CGP62221 [1]
    End point description
    The AUC from time zero to a measurable concentration sampling time (t) (mass x time x volume-1). Note: as the last sampling time was at 12 h, AUC0-12h was determined after the first dose, reported at Cycle 1, Day 8
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1hr, Post-dose 3hrs +/- 0.5hrs, 6hrs, 12 hrs
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned.
    End point values
    		 Midostaurin + chemotherapy CGP52421 CGP62221
    Number of subjects analysed
    20
    27
    27
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    14800 ( 37.5 )
    712 ( 78.4 )
    1830 ( 135 )
    No statistical analyses for this end point

    Secondary: Plasma concentrations for midostaurin and its metabolites: CGP52421 and CGP62221

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    End point title
    		 Plasma concentrations for midostaurin and its metabolites: CGP52421 and CGP62221 [2]
    End point description
    Serial pharmacokinetics (PK) samples were collected in all participants to assess the plasma concentrations of midostaurin, CGP52421 and CGP622. Plasma concentrations of midostaurin and its active metabolites CGP62221 and CGP52421 were measured using a validated liquid chromatography-tandem mass spectrometry (LC- MS/MS) assay and reported at Cycle 1, Day 8
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1hr, Post-dose 3hrs +/- 0.5hrs, 6hrs, 12 hrs
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned.
    End point values
    		 Midostaurin + chemotherapy CGP52421 CGP62221
    Number of subjects analysed
    0 [3]
    0 [4]
    0 [5]
    Units: ng/mL
    Notes
    [3] - Plasma concentrations for serial PK samples not calculated.They cannot be reported as a single value
    [4] - Plasma concentrations for serial PK samples not calculated.They cannot be reported as a single value
    [5] - Plasma concentrations for serial PK samples not calculated.They cannot be reported as a single value
    No statistical analyses for this end point

    Secondary: AUClast: Pharmacokinetic (PK) parameter for midostaurin and its metabolites: CGP52421 and CGP62221

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    End point title
    		 AUClast: Pharmacokinetic (PK) parameter for midostaurin and its metabolites: CGP52421 and CGP62221 [6]
    End point description
    The AUC from time zero to the last measurable concentration sampling time after the first dose reported at Cycle 1, Day 8
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1hr, Post-dose 3hrs +/- 0.5hrs, 6hrs, 12 hrs
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned.
    End point values
    		 Midostaurin + chemotherapy CGP52421 CGP62221
    Number of subjects analysed
    27
    27
    27
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    12200 ( 59.6 )
    493 ( 139 )
    1130 ( 249 )
    No statistical analyses for this end point

    Secondary: Cmax: Pharmacokinetic (PK) parameter for midostaurin and its metabolites: CGP52421 and CGP62221

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    End point title
    		 Cmax: Pharmacokinetic (PK) parameter for midostaurin and its metabolites: CGP52421 and CGP62221 [7]
    End point description
    The maximum (peak) observed plasma drug concentration after the first dose administration reported at Cycle 1, Day 8
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1hr, Post-dose 3hrs +/- 0.5hrs, 6hrs, 12 hrs
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned.
    End point values
    		 Midostaurin + chemotherapy CGP52421 GCP62221
    Number of subjects analysed
    27
    27
    27
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    1910 ( 37.8 )
    74.7 ( 72.3 )
    183 ( 128 )
    No statistical analyses for this end point

    Secondary: Tmax: Pharmacokinetic (PK) parameter for midostaurin and its metabolites: CGP52421 and CGP62221

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    End point title
    		 Tmax: Pharmacokinetic (PK) parameter for midostaurin and its metabolites: CGP52421 and CGP62221 [8]
    End point description
    The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration reported at Cycle 1, Day 8
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1hr, Post-dose 3hrs +/- 0.5hrs, 6hrs, 12 hrs
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned.
    End point values
    		 Midostaurin + chemotherapy CGP62221 GCP52421
    Number of subjects analysed
    27
    27
    27
    Units: hour (hr)
        geometric mean (geometric coefficient of variation)
    3.28 ( 101 )
    7.17 ( 57.8 )
    5.38 ( 89.9 )
    No statistical analyses for this end point

    Secondary: Total score for each time point for the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu)

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    End point title
    		 Total score for each time point for the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu)
    End point description
    The total FACT-Leu score consists of 44 items with total scores ranging from 0 to 176. Higher scores indicate better HRQoL. Negative changes from baseline indicate a worsening of HRQoL while positive changes indicate an improvement in HRQoL.
    End point type
    Secondary
    End point timeframe
    From date of Randomization up to approx. 18 months
    End point values
    		 Midostaurin + chemotherapy Placebo + chemotherapy
    Number of subjects analysed
    250
    251
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Baseline (n = 225, 223)
    122.8 ( 22.64 )
    123.1 ( 21.21 )
        Induction Phase (n = 137, 147)
    123.9 ( 21.50 )
    122.1 ( 19.51 )
        Induction I (n = 105, 90)
    124.8 ( 20.34 )
    123.5 ( 20.28 )
        Induction ll (n = 32, 57)
    121.0 ( 25.09 )
    119.8 ( 18.15 )
        Consolidation (prior) (n = 210, 196)
    135.9 ( 17.67 )
    136.9 ( 21.03 )
        Post- consolidation (n = 169, 114)
    143.7 ( 21.45 )
    140.1 ( 21.60 )
        Follow-up (n = 74, 111)
    136.4 ( 22.87 )
    139.2 ( 25.00 )
    No statistical analyses for this end point

    Secondary: Scores for each time point for the EQ5D-5L (a visual analogue scale (VAS))

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    End point title
    		 Scores for each time point for the EQ5D-5L (a visual analogue scale (VAS))
    End point description
    The EQ5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, slight problems, moderate problems, severe problems and extreme problems) that reflect increasing levels of difficulty. The patient is asked to indicate his/her current health state by selecting the most appropriate level in each of the 5 dimensions. The questionnaire also included a Visual Analogue Scale (VAS), where the patient is asked to rate current health status on a scale of 0 to 100, with 0 being the worst imaginable health state.
    End point type
    Secondary
    End point timeframe
    From date of Randomization up to approx. 18 months
    End point values
    		 Midostaurin + chemotherapy Placebo + chemotherapy
    Number of subjects analysed
    250
    251
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Baseline ( n= 225, 220)
    62.7 ( 22.98 )
    64.3 ( 22.15 )
        Induction Phase (n = 135, 146)
    67.9 ( 20.95 )
    64.4 ( 21.29 )
        Induction l (n = 104, 89)
    68.1 ( 21.02 )
    64.0 ( 21.92 )
        Induction ll (n = 31, 57)
    66.9 ( 21.03 )
    65.2 ( 20.44 )
        Consolidation (prior) (n = 207, 197)
    79.1 ( 15.42 )
    76.2 ( 16.37 )
        Post-consolidation (n = 167, 113)
    83.9 ( 15.00 )
    77.3 ( 14.92 )
        Follow-up ( n- 74, 112)
    74.3 ( 20.08 )
    73.4 ( 1972 )
    No statistical analyses for this end point

    Secondary: All Collected Deaths

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    End point title
    		 All Collected Deaths
    End point description
    On-treatment deaths were collected from start of treatment (FPFT) up to 30 days after study drug discontinuation, for a maximum duration of approx. 18 months. Randomized but not treated deaths were collected after randomization but before treatment with study drug. Post-treatment survival follow-up deaths were collected after the on-treatment period up to approx. 18 months. Participants who did not die during the on-treatment period and had not stopped study participation at the time of data cut-off (when study was terminated) were censored.
    End point type
    Secondary
    End point timeframe
    Start of study treatment up to 30 days post-treatment for approx. 1 year, prior to study treatment up to LPLV, approx. 18 months
    End point values
    		 Midostaurin + chemotherapy Placebo + chemotherapy
    Number of subjects analysed
    250
    251
    Units: Participants
        Total Deaths
    48
    54
        Randomized but not treated dealths
    2
    1
        Deaths on-treatment (n = 245, 249)
    25
    21
        Post-treatment survival follow-up deaths
    21
    32
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 573 days for midostaurin and up to a maximum duration of 416 days for Placebo
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    Midostaurin
    Reporting group description
    		 Midostaurin

    Serious adverse events
    		 Placebo Midostaurin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    114 / 249 (45.78%)
    95 / 245 (38.78%)
         number of deaths (all causes)
    53
    46
         number of deaths resulting from adverse events
    4
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Transitional cell carcinoma recurrent
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chloroma
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    0 / 249 (0.00%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    4 / 249 (1.61%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 4
    2 / 2
    Mucosal inflammation
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 249 (1.61%)
    4 / 245 (1.63%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Acute graft versus host disease
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft versus host disease in gastrointestinal tract
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung infiltration
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary toxicity
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    6 / 249 (2.41%)
    4 / 245 (1.63%)
         occurrences causally related to treatment / all
    3 / 6
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocyte count increased
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary function test decreased
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    3 / 249 (1.20%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Expired product administered
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 249 (1.20%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular dysfunction
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelopathy
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial spasm
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 249 (0.40%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aplastic anaemia
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    23 / 249 (9.24%)
    16 / 245 (6.53%)
         occurrences causally related to treatment / all
    12 / 32
    10 / 24
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 249 (0.80%)
    3 / 245 (1.22%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal fistula
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Jejunal stenosis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Mechanical ileus
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    3 / 249 (1.20%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Oral dysaesthesia
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue haematoma
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcerative duodenitis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 249 (0.80%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary fistula
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    3 / 249 (1.20%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity vasculitis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Thyrotoxic crisis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Chondrocalcinosis pyrophosphate
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytarabine syndrome
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acinetobacter infection
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess neck
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    0 / 249 (0.00%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida infection
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral fungal infection
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridial sepsis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 249 (0.80%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis clostridial
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatosplenic candidiasis
         subjects affected / exposed
    0 / 249 (0.00%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 249 (0.40%)
    3 / 245 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Pelvic abscess
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal abscess
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    1 / 249 (0.40%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    12 / 249 (4.82%)
    9 / 245 (3.67%)
         occurrences causally related to treatment / all
    3 / 12
    6 / 9
         deaths causally related to treatment / all
    2 / 3
    1 / 1
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    13 / 249 (5.22%)
    11 / 245 (4.49%)
         occurrences causally related to treatment / all
    6 / 16
    4 / 11
         deaths causally related to treatment / all
    1 / 1
    1 / 4
    Streptococcal infection
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    9 / 249 (3.61%)
    8 / 245 (3.27%)
         occurrences causally related to treatment / all
    1 / 9
    1 / 8
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    Streptococcal sepsis
         subjects affected / exposed
    0 / 249 (0.00%)
    3 / 245 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic mycosis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral myocarditis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Midostaurin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    245 / 249 (98.39%)
    242 / 245 (98.78%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    27 / 249 (10.84%)
    20 / 245 (8.16%)
         occurrences all number
    32
    25
    Hypotension
         subjects affected / exposed
    25 / 249 (10.04%)
    17 / 245 (6.94%)
         occurrences all number
    27
    20
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    15 / 249 (6.02%)
    17 / 245 (6.94%)
         occurrences all number
    20
    22
    Fatigue
         subjects affected / exposed
    26 / 249 (10.44%)
    36 / 245 (14.69%)
         occurrences all number
    32
    44
    Mucosal inflammation
         subjects affected / exposed
    50 / 249 (20.08%)
    47 / 245 (19.18%)
         occurrences all number
    60
    53
    Oedema
         subjects affected / exposed
    21 / 249 (8.43%)
    27 / 245 (11.02%)
         occurrences all number
    25
    46
    Oedema peripheral
         subjects affected / exposed
    38 / 249 (15.26%)
    44 / 245 (17.96%)
         occurrences all number
    44
    54
    Chills
         subjects affected / exposed
    11 / 249 (4.42%)
    16 / 245 (6.53%)
         occurrences all number
    13
    23
    Pain
         subjects affected / exposed
    8 / 249 (3.21%)
    15 / 245 (6.12%)
         occurrences all number
    9
    17
    Pyrexia
         subjects affected / exposed
    138 / 249 (55.42%)
    146 / 245 (59.59%)
         occurrences all number
    284
    308
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    43 / 249 (17.27%)
    44 / 245 (17.96%)
         occurrences all number
    57
    58
    Cough
         subjects affected / exposed
    37 / 249 (14.86%)
    33 / 245 (13.47%)
         occurrences all number
    46
    37
    Dyspnoea
         subjects affected / exposed
    27 / 249 (10.84%)
    28 / 245 (11.43%)
         occurrences all number
    35
    44
    Oropharyngeal pain
         subjects affected / exposed
    22 / 249 (8.84%)
    17 / 245 (6.94%)
         occurrences all number
    25
    23
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    25 / 249 (10.04%)
    16 / 245 (6.53%)
         occurrences all number
    29
    18
    Anxiety
         subjects affected / exposed
    15 / 249 (6.02%)
    9 / 245 (3.67%)
         occurrences all number
    18
    12
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    29 / 249 (11.65%)
    29 / 245 (11.84%)
         occurrences all number
    42
    45
    Aspartate aminotransferase increased
         subjects affected / exposed
    18 / 249 (7.23%)
    24 / 245 (9.80%)
         occurrences all number
    34
    33
    Blood alkaline phosphatase increased
         subjects affected / exposed
    13 / 249 (5.22%)
    9 / 245 (3.67%)
         occurrences all number
    16
    9
    Blood bilirubin increased
         subjects affected / exposed
    7 / 249 (2.81%)
    19 / 245 (7.76%)
         occurrences all number
    10
    23
    Platelet count decreased
         subjects affected / exposed
    50 / 249 (20.08%)
    34 / 245 (13.88%)
         occurrences all number
    119
    65
    Neutrophil count decreased
         subjects affected / exposed
    20 / 249 (8.03%)
    20 / 245 (8.16%)
         occurrences all number
    41
    45
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    26 / 249 (10.44%)
    17 / 245 (6.94%)
         occurrences all number
    36
    22
    Electrocardiogram QT prolonged
         subjects affected / exposed
    13 / 249 (5.22%)
    26 / 245 (10.61%)
         occurrences all number
    14
    32
    C-reactive protein increased
         subjects affected / exposed
    13 / 249 (5.22%)
    15 / 245 (6.12%)
         occurrences all number
    19
    19
    Weight increased
         subjects affected / exposed
    24 / 249 (9.64%)
    17 / 245 (6.94%)
         occurrences all number
    37
    41
    White blood cell count decreased
         subjects affected / exposed
    35 / 249 (14.06%)
    25 / 245 (10.20%)
         occurrences all number
    76
    45
    Injury, poisoning and procedural complications
    Transfusion reaction
         subjects affected / exposed
    11 / 249 (4.42%)
    13 / 245 (5.31%)
         occurrences all number
    15
    16
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    16 / 249 (6.43%)
    14 / 245 (5.71%)
         occurrences all number
    17
    15
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    23 / 249 (9.24%)
    14 / 245 (5.71%)
         occurrences all number
    36
    15
    Headache
         subjects affected / exposed
    64 / 249 (25.70%)
    70 / 245 (28.57%)
         occurrences all number
    102
    93
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    96 / 249 (38.55%)
    77 / 245 (31.43%)
         occurrences all number
    251
    166
    Febrile neutropenia
         subjects affected / exposed
    116 / 249 (46.59%)
    102 / 245 (41.63%)
         occurrences all number
    187
    185
    Leukopenia
         subjects affected / exposed
    31 / 249 (12.45%)
    20 / 245 (8.16%)
         occurrences all number
    56
    35
    Neutropenia
         subjects affected / exposed
    53 / 249 (21.29%)
    34 / 245 (13.88%)
         occurrences all number
    101
    63
    Pancytopenia
         subjects affected / exposed
    13 / 249 (5.22%)
    6 / 245 (2.45%)
         occurrences all number
    27
    17
    Thrombocytopenia
         subjects affected / exposed
    69 / 249 (27.71%)
    62 / 245 (25.31%)
         occurrences all number
    191
    167
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    46 / 249 (18.47%)
    41 / 245 (16.73%)
         occurrences all number
    54
    46
    Abdominal pain upper
         subjects affected / exposed
    34 / 249 (13.65%)
    24 / 245 (9.80%)
         occurrences all number
    40
    31
    Constipation
         subjects affected / exposed
    84 / 249 (33.73%)
    77 / 245 (31.43%)
         occurrences all number
    118
    112
    Diarrhoea
         subjects affected / exposed
    142 / 249 (57.03%)
    121 / 245 (49.39%)
         occurrences all number
    210
    185
    Dyspepsia
         subjects affected / exposed
    16 / 249 (6.43%)
    16 / 245 (6.53%)
         occurrences all number
    17
    17
    Haemorrhoids
         subjects affected / exposed
    18 / 249 (7.23%)
    27 / 245 (11.02%)
         occurrences all number
    21
    32
    Nausea
         subjects affected / exposed
    137 / 249 (55.02%)
    141 / 245 (57.55%)
         occurrences all number
    227
    273
    Neutropenic colitis
         subjects affected / exposed
    5 / 249 (2.01%)
    13 / 245 (5.31%)
         occurrences all number
    5
    14
    Vomiting
         subjects affected / exposed
    63 / 249 (25.30%)
    101 / 245 (41.22%)
         occurrences all number
    111
    188
    Stomatitis
         subjects affected / exposed
    36 / 249 (14.46%)
    39 / 245 (15.92%)
         occurrences all number
    41
    55
    Proctalgia
         subjects affected / exposed
    5 / 249 (2.01%)
    13 / 245 (5.31%)
         occurrences all number
    7
    16
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    32 / 249 (12.85%)
    28 / 245 (11.43%)
         occurrences all number
    37
    33
    Alopecia
         subjects affected / exposed
    14 / 249 (5.62%)
    11 / 245 (4.49%)
         occurrences all number
    14
    11
    Dry skin
         subjects affected / exposed
    8 / 249 (3.21%)
    14 / 245 (5.71%)
         occurrences all number
    12
    14
    Erythema
         subjects affected / exposed
    20 / 249 (8.03%)
    20 / 245 (8.16%)
         occurrences all number
    24
    26
    Petechiae
         subjects affected / exposed
    21 / 249 (8.43%)
    20 / 245 (8.16%)
         occurrences all number
    25
    32
    Rash
         subjects affected / exposed
    87 / 249 (34.94%)
    80 / 245 (32.65%)
         occurrences all number
    118
    116
    Rash maculo-papular
         subjects affected / exposed
    21 / 249 (8.43%)
    17 / 245 (6.94%)
         occurrences all number
    23
    24
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    14 / 249 (5.62%)
    22 / 245 (8.98%)
         occurrences all number
    18
    25
    Pain in extremity
         subjects affected / exposed
    15 / 249 (6.02%)
    23 / 245 (9.39%)
         occurrences all number
    19
    24
    Bone pain
         subjects affected / exposed
    13 / 249 (5.22%)
    7 / 245 (2.86%)
         occurrences all number
    14
    8
    Back pain
         subjects affected / exposed
    32 / 249 (12.85%)
    26 / 245 (10.61%)
         occurrences all number
    42
    29
    Infections and infestations
    Device related infection
         subjects affected / exposed
    16 / 249 (6.43%)
    9 / 245 (3.67%)
         occurrences all number
    18
    9
    Sepsis
         subjects affected / exposed
    13 / 249 (5.22%)
    13 / 245 (5.31%)
         occurrences all number
    14
    16
    Pneumonia
         subjects affected / exposed
    29 / 249 (11.65%)
    32 / 245 (13.06%)
         occurrences all number
    30
    34
    Folliculitis
         subjects affected / exposed
    4 / 249 (1.61%)
    16 / 245 (6.53%)
         occurrences all number
    4
    19
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    40 / 249 (16.06%)
    31 / 245 (12.65%)
         occurrences all number
    50
    39
    Hypoalbuminaemia
         subjects affected / exposed
    16 / 249 (6.43%)
    18 / 245 (7.35%)
         occurrences all number
    16
    19
    Hyperglycaemia
         subjects affected / exposed
    14 / 249 (5.62%)
    11 / 245 (4.49%)
         occurrences all number
    17
    12
    Hypocalcaemia
         subjects affected / exposed
    24 / 249 (9.64%)
    15 / 245 (6.12%)
         occurrences all number
    33
    19
    Hypokalaemia
         subjects affected / exposed
    102 / 249 (40.96%)
    95 / 245 (38.78%)
         occurrences all number
    171
    153
    Hypomagnesaemia
         subjects affected / exposed
    20 / 249 (8.03%)
    16 / 245 (6.53%)
         occurrences all number
    37
    27
    Hypophosphataemia
         subjects affected / exposed
    18 / 249 (7.23%)
    16 / 245 (6.53%)
         occurrences all number
    23
    22

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jun 2018
    No subject was enrolled into the study at the time of protocol amendment. Subjects who were screened in the CPKC412A2220 trial and confirmed to be FLT3 mutation negative (SR <0.05) could be offered the opportunity to participate in this study, CPKC412E2301, provided they met all the other inclusion criteria. This change was been made due to the implementation of Global Data Protection Regulation on 25-May-2018.

    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.
    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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