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    Clinical Trial Results:
    An open-label, multi-center, Phase IIIb study to assess the safety and efficacy of midostaurin (PKC412) in patients 18 years of age or older with newly diagnosed FLT3-mutated Acute Myeloid Leukemia who are eligible for “7+3” or “5+2” chemotherapy

    Summary
    EudraCT number
    		 2016-004440-12
    Trial protocol
    		 SE   FI   CZ   ES   HU   FR   BG   GR   SK   LT   IT   EE   HR   RO  
    Global end of trial date
    09 Jul 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jul 2022
    First version publication date
    24 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CPKC412A2408
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03379727
    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
    09 Jul 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To further assess the safety of midostaurin in induction, consolidation and maintenance therapy, including, the “7+3” regimen, daunorubicin (60-90 mg/m2/day), the substitution of daunorubicin by idarubicin (12mg/m2/day), cytarabine (100-200 mg/m2/day) and also allowing the “5+2” reduced dose regimen.
    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
    13 Feb 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 10
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    Czechia: 8
    Country: Number of subjects enrolled
    Estonia: 3
    Country: Number of subjects enrolled
    Finland: 11
    Country: Number of subjects enrolled
    France: 68
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Italy: 121
    Country: Number of subjects enrolled
    Lithuania: 10
    Country: Number of subjects enrolled
    Norway: 4
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    Serbia: 1
    Country: Number of subjects enrolled
    Slovakia: 11
    Country: Number of subjects enrolled
    Spain: 39
    Country: Number of subjects enrolled
    Sweden: 4
    Worldwide total number of subjects
    301
    EEA total number of subjects
    300
    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)
    203
    From 65 to 84 years
    97
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in 88 investigative sites in 15 countries.

    Pre-assignment
    Screening details
    		 Investigators had to obtain locally approved FMS-like tyrosine kinase 3 (FLT3) testing results prior to informed consent form signature to allow subjects to initiate Midostaurin treatment per protocol.

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

    Arms
    Arm title
    		 Midostaurin
    Arm description
    		 Patients went through 3 phases: Induction phase – Day (D)8 to D28 in combination with standard of care (7+3 or 5+2 chemotherapy) up to 2 cycles; Consolidation phase – D8 to D28 in combination with cytarabine up to 4 cycles; Maintenance phase – D1 to D28 up to 12 cycles
    Arm type
    		 Experimental

    Investigational medicinal product name
    cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    100-200mg/m2, Days 1 - 7 in Induction phase

    Investigational medicinal product name
    daunorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    60-90mg/m2, Days 1 - 3 in Induction phase

    Investigational medicinal product name
    idarubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    12 mg/m² IV qDay over 10-15 min, Days 1 - 3 in Induction phase

    Investigational medicinal product name
    midostaurin
    Investigational medicinal product code
    PKC412
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Midostaurin 50mg (two capsules 25 mg) orally twice daily on Day 8 up to Day 28, for 1-2 cycles, consolidation with cytarabine (Days 1, 3, 5) plus midostaurin (Days 8-28) for up to 4 cycles, and continuous dosing of midostaurin (Days 1-28) for up to 12 cycles (maintenance phase) or until relapse, unacceptable toxicity, death, physician’s decision, subject/guardian’s decision, protocol deviation, study termination by sponsor, lost to follow-up, technical problems, pregnancy, subject withdrew consent, or until the end of study, whichever event occurred first

    Number of subjects in period 1
    		Midostaurin
    Started
    301
    Completed
    52
    Not completed
    249
         Adverse event, serious fatal
    18
         Physician decision
    104
         Adverse event, non-fatal
    32
         Patient/guardian decision
    17
         Lost to follow-up
    1
         Lack of efficacy
    73
         Protocol deviation
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Midostaurin
    Reporting group description
    		 Patients went through 3 phases: Induction phase – Day (D)8 to D28 in combination with standard of care (7+3 or 5+2 chemotherapy) up to 2 cycles; Consolidation phase – D8 to D28 in combination with cytarabine up to 4 cycles; Maintenance phase – D1 to D28 up to 12 cycles

    Reporting group values
    		 Midostaurin Total
    Number of subjects
    		 301 301
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 203 203
        From 65-84 years
    		 97 97
        85 years and over
    		 1 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.8 ± 13.82 -
    Sex: Female, Male
    Units: participants
        Female
    		 160 160
        Male
    		 141 141
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 225 225
        Other
    		 18 18
        Unknown
    		 56 56
        Missing
    		 2 2

    End points

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    End points reporting groups
    Reporting group title
    Midostaurin
    Reporting group description
    		 Patients went through 3 phases: Induction phase – Day (D)8 to D28 in combination with standard of care (7+3 or 5+2 chemotherapy) up to 2 cycles; Consolidation phase – D8 to D28 in combination with cytarabine up to 4 cycles; Maintenance phase – D1 to D28 up to 12 cycles

    Primary: Percentage of patients with adverse events (AEs), Grade 3 & 4 AEs, serious adverse events (SAEs), AEs leading to discontinuation, and deaths up to 24 months (M24).

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    End point title
    		 Percentage of patients with adverse events (AEs), Grade 3 & 4 AEs, serious adverse events (SAEs), AEs leading to discontinuation, and deaths up to 24 months (M24). [1]
    End point description
    Safety of Midostaurin was represented by various types of AEs, SAEs & death up to M24. AE: the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent has been obtained. AE grades to characterize the severity of AEs were based on the Common Terminology Criteria for AEs ver. 4.03 with Grade (Gr) 1: mild; Gr 2: moderate; Gr 3: severe; Gr 4: life-threatening; Gr 5: death related to AE. AEs not related to hematological toxicities were generally of grade 1 or 2 severity. SAE: 1 of the following: is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, is medically significant, i.e. an event that jeopardizes the patient or may require medical or surgical intervention to prevent 1 of the outcomes listed above, requires inpatient hospitalization or prolongation of existing hospitalization with a few exceptions.
    End point type
    Primary
    End point timeframe
    Baseline up to approximatly 24 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis were used for summarize the main information for all end points
    End point values
    		 Midostaurin
    Number of subjects analysed
    301
    Units: Percentage of patients
    number (not applicable)
        Adverse events (AEs) - all grades
    98.0
        Grade >=3 AEs
    84.4
        Serious adverse events (SAEs) - all grades
    45.5
        AEs leading to discontinuation - all grades
    13.3
        Deaths
    6.3
    No statistical analyses for this end point

    Secondary: Percentage of patients with complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) as per local assessment

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    End point title
    		 Percentage of patients with complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) as per local assessment
    End point description
    CR/CRi rate is defined as the percentage of patients with complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) as per local assessment in Induction, Consolidation and Maintenance phases. CR/CRi rate was calculated based on the full analysis set (FAS). Complete remission (CR): Bone marrow blasts <5% with spicules; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC) >1.0 x109/L; platelet count >100 x 109/L; independence of red cell transfusions. CR with incomplete recovery (CRi): All CR criteria except for residual neutropenia (<1.0 x109/L) or thrombocytopenia (<100 x 109/L). 1 patient did not have FLT mutation, thus was not included in the efficacy assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 24 months
    End point values
    		 Midostaurin
    Number of subjects analysed
    300
    Units: Percentage of patients
    number (not applicable)
        Complete remission (CR)
    65.3
        Complete remission with incomplete recovery (CRi)
    15.3
    No statistical analyses for this end point

    Other pre-specified: Health Care Resource Utilization during Maintenance Phase: Number of hospitalizations reported

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    End point title
    		 Health Care Resource Utilization during Maintenance Phase: Number of hospitalizations reported
    End point description
    Collection of health care resource utilization (HCRU) data focused on hospitalization e.g. reason for the hospitalization. i.e. related to Acute myeloid leukemia (AML) symptoms, adverse events (and type of adverse events) or other reason, number of hospital days by facility/ward type (e.g. hospital unit, emergency room, intensive care unit), discharge reason, and the names of concomitant medications during hospital stay. These measures were used to quantify the number of hospital day's impact of therapy during the maintenance phase and derived components of the economic impact of midostaurin during maintenance. Number of hospitalizations reported is reporting the number of participants who were hospitalized during the study. Note: Exploratory endpoints are not mandatorily required per the Novartis Standard Operating Procedures. However, since this endpoint was inadvertently registered, we are now posting the results.
    End point type
    Other pre-specified
    End point timeframe
    During Maintenance Phase up to 12 months
    End point values
    		 Midostaurin
    Number of subjects analysed
    301
    Units: hospitalizations
    133
    No statistical analyses for this end point

    Other pre-specified: Health Care Resource Utilization during Maintenance Phase: Reason for hospitalization

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    End point title
    		 Health Care Resource Utilization during Maintenance Phase: Reason for hospitalization
    End point description
    Collection of health care resource utilization (HCRU) data focused on hospitalization e.g. reason for the hospitalization. i.e. related to AML symptoms, adverse events (and type of adverse events) or other reason, number of hospital days by facility/ward type (e.g. hospital unit, emergency room, intensive care unit), discharge reason, and the names of concomitant medications during hospital stay. These measures were used to quantify the number of hospital day's impact of therapy during the maintenance phase and derived components of the economic impact of midostaurin during maintenance. Reason for hospitalization is reporting percentage of hospitalizations due to adverse events or not during the study. Note: Exploratory endpoints are not mandatorily required per the Novartis Standard Operating Procedures. However, since this endpoint was inadvertently registered, we are now posting the results.
    End point type
    Other pre-specified
    End point timeframe
    During Maintenance Phase up to 12 months
    End point values
    		 Midostaurin
    Number of subjects analysed
    301
    Units: Percentage of hospitalizations
    number (not applicable)
        Hospitalization due to adverse event: Yes
    30.9
        Hospitalization due to adverse event: No
    19.9
    No statistical analyses for this end point

    Other pre-specified: Health Care Resource Utilization during Maintenance Phase: Length of stay

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    End point title
    		 Health Care Resource Utilization during Maintenance Phase: Length of stay
    End point description
    Collection of health care resource utilization (HCRU) data focused on hospitalization e.g. reason for the hospitalization. i.e. related to AML symptoms, adverse events (and type of adverse events) or other reason, number of hospital days by facility/ward type (e.g. hospital unit, emergency room, intensive care unit), discharge reason, and the names of concomitant medications during hospital stay. These measures were used to quantify the number of hospital day's impact of therapy during the maintenance phase and derived components of the economic impact of midostaurin during maintenance. Length of stay is the number of days participants stayed at various facilities. Note: Exploratory endpoints are not mandatorily required per the Novartis Standard Operating Procedures. However, since this endpoint was inadvertently registered, we are now posting the results.
    End point type
    Other pre-specified
    End point timeframe
    During Maintenance Phase up to 12 months
    End point values
    		 Midostaurin
    Number of subjects analysed
    301
    Units: days
        Intensive Care Unit
    34
        Emergency Room
    10
        General Ward
    88
        Rehabilitation Unit
    0
        Other Unit
    27
    No statistical analyses for this end point

    Other pre-specified: Health Care Resource Utilization during Maintenance Phase: Percentage of patients discharged

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    End point title
    		 Health Care Resource Utilization during Maintenance Phase: Percentage of patients discharged
    End point description
    Collection of health care resource utilization (HCRU) data focused on hospitalization e.g. reason for the hospitalization. i.e. related to AML symptoms, adverse events (and type of adverse events) or other reason, number of hospital days by facility/ward type (e.g. hospital unit, emergency room, intensive care unit), discharge reason, and the names of concomitant medications during hospital stay. These measures were used to quantify the number of hospital day's impact of therapy during the maintenance phase and derived components of the economic impact of midostaurin during maintenance. This provides the percentage of patients who were discharged to various wards. Note: Exploratory endpoints are not mandatorily required per the Novartis Standard Operating Procedures. However, since this endpoint was inadvertently registered, we are now posting the results.
    End point type
    Other pre-specified
    End point timeframe
    During Maintenance Phase up to 12 months
    End point values
    		 Midostaurin
    Number of subjects analysed
    301
    Units: Percentage of patients
    number (not applicable)
        Home
    36.9
        Long-term care facility
    2.0
        Hospice
    0.3
        Other
    6.3
        Missing
    1.7
    No statistical analyses for this end point

    Other pre-specified: Health Care Resource Utilization during Maintenance Phase: Duration of hospitalization

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    End point title
    		 Health Care Resource Utilization during Maintenance Phase: Duration of hospitalization
    End point description
    Collection of health care resource utilization (HCRU) data focused on hospitalization e.g. reason for the hospitalization. i.e. related to AML symptoms, adverse events (and type of adverse events) or other reason, number of hospital days by facility/ward type (e.g. hospital unit, emergency room, intensive care unit), discharge reason, and the names of concomitant medications during hospital stay. These measures were used to quantify the number of hospital day's impact of therapy during the maintenance phase and derived components of the economic impact of midostaurin during maintenance. Hospitalization duration is defined as the difference in days between admission and discharge dates. Note: Exploratory endpoints are not mandatorily required per the Novartis Standard Operating Procedures. However, since this endpoint was inadvertently registered, we are now posting the results.
    End point type
    Other pre-specified
    End point timeframe
    During Maintenance Phase up to 12 months
    End point values
    		 Midostaurin
    Number of subjects analysed
    301
    Units: days
        arithmetic mean (standard deviation)
    48.9 ± 41.68
    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 25 months (24 months plus 1 month (30 days) post treatment).
    Adverse event reporting additional description
    Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment. 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.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Induction
    Reporting group description
    		 Induction

    Reporting group title
    Maintenance
    Reporting group description
    		 Maintenance

    Reporting group title
    Overall
    Reporting group description
    		 Overall

    Reporting group title
    Consolidation
    Reporting group description
    		 Consolidation

    Serious adverse events
    		 Induction Maintenance Overall Consolidation
    Total subjects affected by serious adverse events
         subjects affected / exposed
    76 / 301 (25.25%)
    7 / 93 (7.53%)
    137 / 301 (45.51%)
    67 / 210 (31.90%)
         number of deaths (all causes)
    16
    0
    19
    3
         number of deaths resulting from adverse events
    3
    0
    4
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Leukaemic infiltration pulmonary
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 93 (1.08%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    3 / 301 (1.00%)
    2 / 210 (0.95%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    3 / 301 (1.00%)
    3 / 210 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    2 / 301 (0.66%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    3 / 301 (1.00%)
    0 / 93 (0.00%)
    3 / 301 (1.00%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    5 / 301 (1.66%)
    0 / 93 (0.00%)
    7 / 301 (2.33%)
    2 / 210 (0.95%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    4 / 7
    2 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    3 / 301 (1.00%)
    0 / 93 (0.00%)
    3 / 301 (1.00%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SARS-CoV-2 test negative
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anaphylactic transfusion reaction
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    2 / 301 (0.66%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    4 / 301 (1.33%)
    0 / 93 (0.00%)
    4 / 301 (1.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    2 / 301 (0.66%)
    2 / 210 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    1 / 2
    Cardiac dysfunction
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    2 / 301 (0.66%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    2 / 301 (0.66%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular dysfunction
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Central nervous system lesion
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral paralysis
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Blood and lymphatic system disorders
    Cytopenia
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    4 / 301 (1.33%)
    4 / 210 (1.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    7 / 9
    7 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    6 / 301 (1.99%)
    0 / 93 (0.00%)
    32 / 301 (10.63%)
    26 / 210 (12.38%)
         occurrences causally related to treatment / all
    6 / 8
    0 / 0
    25 / 45
    19 / 37
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 93 (1.08%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    5 / 301 (1.66%)
    0 / 93 (0.00%)
    5 / 301 (1.66%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    2 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    2 / 301 (0.66%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 93 (1.08%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    2 / 301 (0.66%)
    0 / 93 (0.00%)
    2 / 301 (0.66%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 93 (1.08%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis cholestatic
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 93 (1.08%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 93 (1.08%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal infection
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anorectal infection
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Candida infection
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium colitis
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Conjunctivitis
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related bacteraemia
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 93 (1.08%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    2 / 301 (0.66%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic candidiasis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    2 / 301 (0.66%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perineal cellulitis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    2 / 301 (0.66%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    9 / 301 (2.99%)
    1 / 93 (1.08%)
    13 / 301 (4.32%)
    3 / 210 (1.43%)
         occurrences causally related to treatment / all
    9 / 10
    1 / 1
    12 / 14
    2 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory moniliasis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 301 (1.33%)
    0 / 93 (0.00%)
    14 / 301 (4.65%)
    11 / 210 (5.24%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    10 / 16
    7 / 12
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Respiratory tract infection fungal
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    5 / 301 (1.66%)
    0 / 93 (0.00%)
    11 / 301 (3.65%)
    6 / 210 (2.86%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 0
    7 / 12
    4 / 7
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
    0 / 0
    Sinusitis fungal
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic mycosis
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypernatraemia
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acidosis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 93 (0.00%)
    1 / 301 (0.33%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Induction Maintenance Overall Consolidation
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    253 / 301 (84.05%)
    48 / 93 (51.61%)
    277 / 301 (92.03%)
    179 / 210 (85.24%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    15 / 301 (4.98%)
    6 / 93 (6.45%)
    32 / 301 (10.63%)
    17 / 210 (8.10%)
         occurrences all number
    16
    5
    44
    23
    Platelet count decreased
         subjects affected / exposed
    7 / 301 (2.33%)
    3 / 93 (3.23%)
    17 / 301 (5.65%)
    11 / 210 (5.24%)
         occurrences all number
    9
    3
    38
    26
    Electrocardiogram QT prolonged
         subjects affected / exposed
    19 / 301 (6.31%)
    1 / 93 (1.08%)
    24 / 301 (7.97%)
    5 / 210 (2.38%)
         occurrences all number
    23
    1
    33
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 301 (2.66%)
    3 / 93 (3.23%)
    18 / 301 (5.98%)
    10 / 210 (4.76%)
         occurrences all number
    9
    4
    27
    14
    Vascular disorders
    Hypertension
         subjects affected / exposed
    15 / 301 (4.98%)
    6 / 93 (6.45%)
    28 / 301 (9.30%)
    9 / 210 (4.29%)
         occurrences all number
    16
    7
    34
    11
    Hypotension
         subjects affected / exposed
    10 / 301 (3.32%)
    1 / 93 (1.08%)
    24 / 301 (7.97%)
    14 / 210 (6.67%)
         occurrences all number
    10
    1
    29
    18
    Nervous system disorders
    Headache
         subjects affected / exposed
    24 / 301 (7.97%)
    3 / 93 (3.23%)
    59 / 301 (19.60%)
    47 / 210 (22.38%)
         occurrences all number
    28
    3
    118
    87
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    34 / 301 (11.30%)
    4 / 93 (4.30%)
    52 / 301 (17.28%)
    36 / 210 (17.14%)
         occurrences all number
    45
    2
    107
    60
    Febrile neutropenia
         subjects affected / exposed
    67 / 301 (22.26%)
    0 / 93 (0.00%)
    88 / 301 (29.24%)
    44 / 210 (20.95%)
         occurrences all number
    73
    0
    141
    68
    Neutropenia
         subjects affected / exposed
    33 / 301 (10.96%)
    12 / 93 (12.90%)
    70 / 301 (23.26%)
    50 / 210 (23.81%)
         occurrences all number
    37
    15
    152
    100
    Thrombocytopenia
         subjects affected / exposed
    27 / 301 (8.97%)
    6 / 93 (6.45%)
    51 / 301 (16.94%)
    40 / 210 (19.05%)
         occurrences all number
    32
    6
    109
    71
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    18 / 301 (5.98%)
    2 / 93 (2.15%)
    30 / 301 (9.97%)
    16 / 210 (7.62%)
         occurrences all number
    19
    2
    40
    19
    Oedema peripheral
         subjects affected / exposed
    23 / 301 (7.64%)
    3 / 93 (3.23%)
    37 / 301 (12.29%)
    13 / 210 (6.19%)
         occurrences all number
    24
    3
    43
    16
    Pyrexia
         subjects affected / exposed
    93 / 301 (30.90%)
    3 / 93 (3.23%)
    139 / 301 (46.18%)
    72 / 210 (34.29%)
         occurrences all number
    135
    4
    266
    127
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    24 / 301 (7.97%)
    1 / 93 (1.08%)
    34 / 301 (11.30%)
    11 / 210 (5.24%)
         occurrences all number
    24
    1
    41
    16
    Abdominal pain upper
         subjects affected / exposed
    14 / 301 (4.65%)
    1 / 93 (1.08%)
    25 / 301 (8.31%)
    13 / 210 (6.19%)
         occurrences all number
    17
    1
    36
    18
    Constipation
         subjects affected / exposed
    32 / 301 (10.63%)
    2 / 93 (2.15%)
    65 / 301 (21.59%)
    41 / 210 (19.52%)
         occurrences all number
    35
    2
    105
    68
    Diarrhoea
         subjects affected / exposed
    97 / 301 (32.23%)
    8 / 93 (8.60%)
    121 / 301 (40.20%)
    40 / 210 (19.05%)
         occurrences all number
    116
    10
    176
    50
    Haemorrhoids
         subjects affected / exposed
    16 / 301 (5.32%)
    0 / 93 (0.00%)
    25 / 301 (8.31%)
    10 / 210 (4.76%)
         occurrences all number
    18
    0
    31
    13
    Nausea
         subjects affected / exposed
    76 / 301 (25.25%)
    18 / 93 (19.35%)
    121 / 301 (40.20%)
    67 / 210 (31.90%)
         occurrences all number
    94
    23
    249
    132
    Vomiting
         subjects affected / exposed
    57 / 301 (18.94%)
    3 / 93 (3.23%)
    69 / 301 (22.92%)
    33 / 210 (15.71%)
         occurrences all number
    74
    4
    140
    62
    Stomatitis
         subjects affected / exposed
    54 / 301 (17.94%)
    0 / 93 (0.00%)
    72 / 301 (23.92%)
    25 / 210 (11.90%)
         occurrences all number
    57
    0
    92
    35
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    20 / 301 (6.64%)
    1 / 93 (1.08%)
    27 / 301 (8.97%)
    9 / 210 (4.29%)
         occurrences all number
    25
    1
    39
    13
    Epistaxis
         subjects affected / exposed
    16 / 301 (5.32%)
    0 / 93 (0.00%)
    29 / 301 (9.63%)
    16 / 210 (7.62%)
         occurrences all number
    25
    0
    47
    22
    Oropharyngeal pain
         subjects affected / exposed
    6 / 301 (1.99%)
    0 / 93 (0.00%)
    18 / 301 (5.98%)
    12 / 210 (5.71%)
         occurrences all number
    6
    0
    20
    14
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    13 / 301 (4.32%)
    0 / 93 (0.00%)
    20 / 301 (6.64%)
    9 / 210 (4.29%)
         occurrences all number
    19
    0
    28
    9
    Petechiae
         subjects affected / exposed
    7 / 301 (2.33%)
    0 / 93 (0.00%)
    18 / 301 (5.98%)
    13 / 210 (6.19%)
         occurrences all number
    7
    0
    22
    15
    Rash
         subjects affected / exposed
    38 / 301 (12.62%)
    3 / 93 (3.23%)
    64 / 301 (21.26%)
    29 / 210 (13.81%)
         occurrences all number
    40
    3
    80
    37
    Pruritus
         subjects affected / exposed
    8 / 301 (2.66%)
    0 / 93 (0.00%)
    19 / 301 (6.31%)
    14 / 210 (6.67%)
         occurrences all number
    9
    0
    29
    20
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    14 / 301 (4.65%)
    1 / 93 (1.08%)
    18 / 301 (5.98%)
    5 / 210 (2.38%)
         occurrences all number
    14
    1
    21
    6
    Anxiety
         subjects affected / exposed
    8 / 301 (2.66%)
    1 / 93 (1.08%)
    16 / 301 (5.32%)
    11 / 210 (5.24%)
         occurrences all number
    8
    1
    23
    14
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 301 (1.33%)
    3 / 93 (3.23%)
    27 / 301 (8.97%)
    20 / 210 (9.52%)
         occurrences all number
    4
    3
    30
    23
    Arthralgia
         subjects affected / exposed
    2 / 301 (0.66%)
    3 / 93 (3.23%)
    16 / 301 (5.32%)
    11 / 210 (5.24%)
         occurrences all number
    2
    3
    18
    13
    Pain in extremity
         subjects affected / exposed
    9 / 301 (2.99%)
    0 / 93 (0.00%)
    17 / 301 (5.65%)
    8 / 210 (3.81%)
         occurrences all number
    11
    0
    20
    9
    Infections and infestations
    Device related infection
         subjects affected / exposed
    17 / 301 (5.65%)
    0 / 93 (0.00%)
    19 / 301 (6.31%)
    4 / 210 (1.90%)
         occurrences all number
    17
    0
    22
    5
    Pneumonia
         subjects affected / exposed
    16 / 301 (5.32%)
    1 / 93 (1.08%)
    27 / 301 (8.97%)
    11 / 210 (5.24%)
         occurrences all number
    16
    1
    28
    11
    Oral herpes
         subjects affected / exposed
    6 / 301 (1.99%)
    1 / 93 (1.08%)
    18 / 301 (5.98%)
    12 / 210 (5.71%)
         occurrences all number
    7
    1
    21
    13
    Sepsis
         subjects affected / exposed
    10 / 301 (3.32%)
    0 / 93 (0.00%)
    18 / 301 (5.98%)
    10 / 210 (4.76%)
         occurrences all number
    10
    0
    20
    10
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    45 / 301 (14.95%)
    1 / 93 (1.08%)
    58 / 301 (19.27%)
    19 / 210 (9.05%)
         occurrences all number
    53
    1
    80
    26

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Mar 2018
    To allow the use of historical bone marrow aspiration (BMA) result performed for AML diagnosis if available within 15 days before C1D1 of the first chemotherapy, in order to limit the repetition on this invasive assessment. An adaptation of the recovery periods in Induction phase and the first cycle of consolidation based on the RATIFY study results analysis To align between Section 5.3 exclusion criteria #8 and Section 6.4.1.2 Contraceptives with midostaurin, the duration of the post study contraception to 4 months, as per approved midostaurin labeling information.

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

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