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    Clinical Trial Results:
    A Phase 1b/2 Study of Entospletinib (GS-9973) Monotherapy and in Combination with Chemotherapy in Patients with Acute Myeloid Leukemia (AML)

    Summary
    EudraCT number
    		 2016-003353-16
    Trial protocol
    		 DE  
    Global end of trial date
    21 Feb 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    29 Nov 2019
    First version publication date
    17 Oct 2019
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Updated timeframe and description for endpoints.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-339-1559
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02343939
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.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
    21 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Feb 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study will evaluate the efficacy, safety, and tolerability of entospletinib (ENTO) when administered as monotherapy or in combination with chemotherapy in adults with acute myeloid leukemia (AML).
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2015
    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
    United States: 133
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Germany: 5
    Worldwide total number of subjects
    148
    EEA total number of subjects
    5
    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)
    56
    From 65 to 84 years
    83
    85 years and over
    9

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in the United States, Canada, and Germany. The first participant was screened on 01 July 2015.

    Pre-assignment
    Screening details
    		 233 participants were screened.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin
    Arm description
    		 Participants received ENTO 200 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (during induction chemotherapy).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet(s) administered orally every 12 hours

    Arm title
    		 Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin
    Arm description
    		 Phase1b/2: Participants received ENTO 400 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (induction chemotherapy). Phase 2 only: Participants who achieved a CR/CRi and did not require or could not proceed to allogeneic stem cell transplantation (SCT) were offered post-remission chemotherapy (cytarabine 3 g/m^2 intravenously every 12 hours on Days 1, 3, and 5 or 1 g/m^2 intravenously once daily on Days 1-5) in combination with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for at least 3 and up to 4 cycles. Participants who maintained a CR/CRi after 3 or 4 cycles were offered maintenance therapy with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for up to 12 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet(s) administered orally every 12 hours

    Arm title
    		 Group B Phase 1b ENTO 200 mg + Decitabine
    Arm description
    		 Participants received ENTO 200 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 200 mg as monotherapy after completing 2 maintenance cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet(s) administered orally every 12 hours

    Arm title
    		 Group B Phase 1b ENTO 400 mg + Decitabine
    Arm description
    		 Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet(s) administered orally every 12 hours

    Arm title
    		 Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In)
    Arm description
    		 As part of the safety run-in, participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of a 28-day cycle (Cycle 1). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet(s) administered orally every 12 hours

    Arm title
    		 Group B Phase 2 ENTO 400 mg + Decitabine (Randomized)
    Arm description
    		 Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet(s) administered orally every 12 hours

    Arm title
    		 Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized)
    Arm description
    		 Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet(s) administered orally every 12 hours

    Arm title
    		 Group C Phase 1b/2 ENTO 400 mg
    Arm description
    		 Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet(s) administered orally every 12 hours

    Arm title
    		 Group C Phase 1b ENTO 800 mg
    Arm description
    		 Participants received ENTO 800 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet(s) administered orally every 12 hours

    Number of subjects in period 1 [1]
    		Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b/2 ENTO 400 mg Group C Phase 1b ENTO 800 mg
    Started
    3
    50
    5
    6
    8
    17
    14
    35
    7
    Completed
    0
    2
    0
    0
    0
    0
    0
    0
    0
    Not completed
    3
    48
    5
    6
    8
    17
    14
    35
    7
         Consent withdrawn by subject
    3
    6
    1
    2
    2
    -
    -
    8
    6
         Adverse Event
    -
    -
    -
    -
    -
    1
    -
    -
    -
         Death
    -
    15
    4
    2
    5
    11
    8
    22
    1
         Treatment Failure
    -
    -
    -
    -
    -
    -
    2
    1
    -
         Study terminated by sponsor
    -
    27
    -
    1
    1
    5
    3
    4
    -
         Investigator's discretion
    -
    -
    -
    1
    -
    -
    1
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Three participants who were enrolled but not treated are not included in the subject disposition table.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin
    Reporting group description
    		 Participants received ENTO 200 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (during induction chemotherapy).

    Reporting group title
    Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin
    Reporting group description
    		 Phase1b/2: Participants received ENTO 400 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (induction chemotherapy). Phase 2 only: Participants who achieved a CR/CRi and did not require or could not proceed to allogeneic stem cell transplantation (SCT) were offered post-remission chemotherapy (cytarabine 3 g/m^2 intravenously every 12 hours on Days 1, 3, and 5 or 1 g/m^2 intravenously once daily on Days 1-5) in combination with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for at least 3 and up to 4 cycles. Participants who maintained a CR/CRi after 3 or 4 cycles were offered maintenance therapy with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for up to 12 cycles.

    Reporting group title
    Group B Phase 1b ENTO 200 mg + Decitabine
    Reporting group description
    		 Participants received ENTO 200 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 200 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 1b ENTO 400 mg + Decitabine
    Reporting group description
    		 Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In)
    Reporting group description
    		 As part of the safety run-in, participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of a 28-day cycle (Cycle 1). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 2 ENTO 400 mg + Decitabine (Randomized)
    Reporting group description
    		 Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized)
    Reporting group description
    		 Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group C Phase 1b/2 ENTO 400 mg
    Reporting group description
    		 Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Reporting group title
    Group C Phase 1b ENTO 800 mg
    Reporting group description
    		 Participants received ENTO 800 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Reporting group values
    		 Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b/2 ENTO 400 mg Group C Phase 1b ENTO 800 mg Total
    Number of subjects
    		 3 50 5 6 8 17 14 35 7 145
    Age categorical
    Units: Subjects
        < 65 Years
    		 3 32 0 1 1 1 0 17 0 55
        ≥ 65 years
    		 0 18 5 5 7 16 14 18 7 90
    Gender categorical
    Units: Subjects
        Female
    		 1 21 2 2 2 7 3 18 5 61
        Male
    		 2 29 3 4 6 10 11 17 2 84
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 2 0 0 0 0 0 2 0 4
        Not Hispanic or Latino
    		 3 48 5 6 7 15 13 33 7 137
        Not Permitted
    		 0 0 0 0 1 2 1 0 0 4
    Race
    Units: Subjects
        White/Caucasian
    		 3 44 3 6 6 14 11 31 7 125
        Black or African American
    		 0 5 2 0 1 0 1 2 0 11
        Asian
    		 0 0 0 0 0 0 0 1 0 1
        Other
    		 0 1 0 0 0 0 1 1 0 3
        Not Permitted
    		 0 0 0 0 1 3 1 0 0 5

    End points

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    End points reporting groups
    Reporting group title
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin
    Reporting group description
    		 Participants received ENTO 200 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (during induction chemotherapy).

    Reporting group title
    Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin
    Reporting group description
    		 Phase1b/2: Participants received ENTO 400 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (induction chemotherapy). Phase 2 only: Participants who achieved a CR/CRi and did not require or could not proceed to allogeneic stem cell transplantation (SCT) were offered post-remission chemotherapy (cytarabine 3 g/m^2 intravenously every 12 hours on Days 1, 3, and 5 or 1 g/m^2 intravenously once daily on Days 1-5) in combination with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for at least 3 and up to 4 cycles. Participants who maintained a CR/CRi after 3 or 4 cycles were offered maintenance therapy with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for up to 12 cycles.

    Reporting group title
    Group B Phase 1b ENTO 200 mg + Decitabine
    Reporting group description
    		 Participants received ENTO 200 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 200 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 1b ENTO 400 mg + Decitabine
    Reporting group description
    		 Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In)
    Reporting group description
    		 As part of the safety run-in, participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of a 28-day cycle (Cycle 1). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 2 ENTO 400 mg + Decitabine (Randomized)
    Reporting group description
    		 Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized)
    Reporting group description
    		 Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group C Phase 1b/2 ENTO 400 mg
    Reporting group description
    		 Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Reporting group title
    Group C Phase 1b ENTO 800 mg
    Reporting group description
    		 Participants received ENTO 800 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Subject analysis set title
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ENTO 200 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (during induction chemotherapy).

    Subject analysis set title
    Group A Phase 1b ENTO 400 mg + Cytarabine + Daunorubicin
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received ENTO 400 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (during induction chemotherapy).

    Subject analysis set title
    Group A Phase 2 ENTO 400 mg + Cytarabine + Daunorubicin
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (induction chemotherapy). Participants who achieved a CR/CRi and did not require or could not proceed to allogeneic stem cell transplantation (SCT) were offered post-remission chemotherapy (cytarabine 3 g/m^2 intravenously every 12 hours on Days 1, 3, and 5 or 1 g/m^2 intravenously once daily on Days 1-5) in combination with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for at least 3 and up to 4 cycles. Participants who maintained a CR/CRi after 3 or 4 cycles were offered maintenance therapy with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for up to 12 cycles.

    Subject analysis set title
    Group B Phase 1b ENTO 200 mg + Decitabine
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ENTO 200 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 200 mg as monotherapy after completing 2 maintenance cycles.

    Subject analysis set title
    Group B Phase 1b ENTO 400 mg + Decitabine
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Subject analysis set title
    Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    As part of the safety run-in, participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of a 28-day cycle (Cycle 1). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Subject analysis set title
    Group B Phase 2 ENTO 400 mg + Decitabine (Randomized)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Subject analysis set title
    Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Subject analysis set title
    Group C Phase 1b ENTO 400 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Subject analysis set title
    Group C Phase 1b ENTO 800 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ENTO 800 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Subject analysis set title
    Group C Phase 2 ENTO 400 mg (Cohort C1A - R/R AML)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with relapsed/refractory (R/R) acute myeloid leukemia (AML) received ENTO 400 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Subject analysis set title
    Group C Phase 2 ENTO 400 mg (Cohort C2 - MLL)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants R/R AML with mixed-lineage leukemia (MLL) received ENTO 400 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Subject analysis set title
    Group C Phase 2 ENTO 400 mg (Cohort C3 - Untreated AML)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with previously untreated AML who were unfit for chemotherapy or hypomethylating agents or refused chemotherapy or hypomethylating agent received ENTO 400 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Primary: Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs)

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    End point title
    		 Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) [1] [2]
    End point description
    DLTs refer to toxicities experienced during the first 28 days of study treatment that have been judged to be clinically significant and related to study treatment. DLT assessment was applicable only for Phase 1b and Phase 2 safety run-in participants. The DLT Analysis Set included all participants who received 21 days of ENTO (applicable to all groups) and all doses of cytarabine and daunorubicin in Group A Phase 1b, decitabine in Group B Phase 1b, or azacitidine in Group B Phase 2 safety run-in during the DLT assessment window; or experienced a DLT during the DLT assessment window.
    End point type
    Primary
    End point timeframe
    Group A: Cycle 0 Day 1 to Cycle 2 Day 28; Group B: Cycle 0 Day 1 to Cycle 1 Day 28; Group C: Cycle 1 Day 1 to Cycle 1 Day 28 (Cycle length: for Cycle 0 = 14 days, for all other cycles = 28 days)
    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: No statistical comparison was planned or performed.
    [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: The endpoint was planned to include data only for the specified arms.
    End point values
    		 Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group C Phase 1b/2 ENTO 400 mg Group C Phase 1b ENTO 800 mg
    Number of subjects analysed
    3
    6
    3
    6
    6
    6
    6
    Units: Percentage of Participants
        number (not applicable)
    0.0
    0.0
    0.0
    16.7
    0.0
    0.0
    16.7
    No statistical analyses for this end point

    Primary: Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction

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    End point title
    		 Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction [3]
    End point description
    Clinical response was assessed according to the International Working Group criteria (Cheson 2003). Morphologic CR included CR and cytogenetic CR (CRc). CR required all of the following: < 5% blasts in bone marrow aspirate; Neutrophils ≥ 1,000/microliter (mcL); Platelets ≥ 100,000/mcL; No extramedullary disease; No blasts with Auer rods detected; and Independent of transfusions. CRc, in addition to CR criteria, required reversion to a normal karyotype with an abnormal karyotype at the time of diagnosis. The Full Analysis Set included all participants who received at least 1 dose of study drug with treatment designated according to the planned treatment.
    End point type
    Primary
    End point timeframe
    At the end of induction (Group A: up to end of Cycle 2; Group B: up to end of Cycle 4) (cycle length = up to 28 days); Group C: From Day 1 until meeting the criteria for study treatment discontinuation (up to approximately 3 years)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical comparison was planned or performed.
    End point values
    		 Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b ENTO 400 mg + Cytarabine + Daunorubicin Group A Phase 2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b ENTO 400 mg Group C Phase 1b ENTO 800 mg Group C Phase 2 ENTO 400 mg (Cohort C1A - R/R AML) Group C Phase 2 ENTO 400 mg (Cohort C2 - MLL) Group C Phase 2 ENTO 400 mg (Cohort C3 - Untreated AML)
    Number of subjects analysed
    3
    9
    41
    5
    6
    8
    17
    14
    7
    7
    6
    13
    9
    Units: Percentage of Participants
        number (confidence interval 95%)
    66.7 (9.4 to 99.2)
    66.7 (29.9 to 92.5)
    46.3 (30.7 to 62.6)
    0.0 (0.0 to 52.2)
    16.7 (0.4 to 64.1)
    25.0 (3.2 to 65.1)
    0.0 (0.0 to 19.5)
    7.1 (0.2 to 33.9)
    0.0 (0.0 to 41.0)
    0.0 (0.0 to 41.0)
    0.0 (0.0 to 45.9)
    15.4 (1.9 to 45.4)
    11.1 (0.3 to 48.2)
    No statistical analyses for this end point

    Primary: Percentage of Participants With Composite Complete Remission at the End of Induction

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    End point title
    		 Percentage of Participants With Composite Complete Remission at the End of Induction [4]
    End point description
    Clinical response was assessed according to the International Working Group criteria (Cheson 2003). Composite complete remission included CR, CRc, and morphologic complete remission with incomplete blood count recovery (CRi). CR required all of the following: < 5% blasts in bone marrow aspirate; Neutrophils ≥ 1,000/mcL; Platelets ≥ 100,000/mcL; No extramedullary disease; No blasts with Auer rods detected; and Independent of transfusions. CRc, in addition to CR criteria, required reversion to a normal karyotype with an abnormal karyotype at the time of diagnosis. CRi required all of the CR criteria except the criterion of neutrophils and platelets. Participants in the Full Analysis Set were analyzed.
    End point type
    Primary
    End point timeframe
    At the end of induction (Group A: up to end of Cycle 2; Group B: up to end of Cycle 4) (cycle length = up to 28 days); Group C: From Day 1 until meeting the criteria for study treatment discontinuation (up to approximately 3 years)
    Notes
    [4] - 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: No statistical comparison was planned or performed.
    End point values
    		 Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b ENTO 400 mg + Cytarabine + Daunorubicin Group A Phase 2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b ENTO 400 mg Group C Phase 1b ENTO 800 mg Group C Phase 2 ENTO 400 mg (Cohort C1A - R/R AML) Group C Phase 2 ENTO 400 mg (Cohort C2 - MLL) Group C Phase 2 ENTO 400 mg (Cohort C3 - Untreated AML)
    Number of subjects analysed
    3
    9
    41
    5
    6
    8
    17
    14
    7
    7
    6
    13
    9
    Units: Percentage of Participants
        number (confidence interval 95%)
    100.0 (29.2 to 100)
    77.8 (40 to 97.2)
    65.9 (49.4 to 79.9)
    40.0 (5.3 to 85.3)
    50.0 (11.8 to 88.2)
    25.0 (3.2 to 65.1)
    23.5 (6.8 to 49.9)
    14.3 (1.8 to 42.8)
    14.3 (0.4 to 57.9)
    0.0 (0.0 to 41.0)
    0.0 (0.0 to 45.9)
    15.4 (1.9 to 45.4)
    11.1 (0.3 to 48.2)
    No statistical analyses for this end point

    Primary: Percentage of Participants With Overall Response at the End of Induction

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    End point title
    		 Percentage of Participants With Overall Response at the End of Induction [5]
    End point description
    Clinical response was assessed according to the International Working Group criteria (Cheson 2003). Overall response included CR, CRc, CRi, and partial remission (PR). CR required all of the following: < 5% blasts in bone marrow aspirate; Neutrophils ≥ 1,000/mcL; Platelets ≥ 100,000/mcL; No extramedullary disease; No blasts with Auer rods detected; and Independent of transfusions. CRc, in addition to CR criteria, required reversion to a normal karyotype with an abnormal karyotype at the time of diagnosis. CRi required all of the CR criteria except the criterion of neutrophils and platelets. PR required all of the following: ≥ 50% decrease in blasts in bone marrow aspirate to a range of 5% to 25%; Neutrophils ≥ 1,000/mcL; Platelets ≥ 100,000/mcL; Independent of transfusions; and A value of ≤ 5% blasts was also considered a PR if Auer rods were detected. Participants in the Full Analysis Set were analyzed.
    End point type
    Primary
    End point timeframe
    At the end of induction (Group A: up to end of Cycle 2; Group B: up to end of Cycle 4) (cycle length = up to 28 days); Group C: From Day 1 until meeting the criteria for study treatment discontinuation (up to approximately 3 years)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical comparison was planned or performed.
    End point values
    		 Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b ENTO 400 mg + Cytarabine + Daunorubicin Group A Phase 2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b ENTO 400 mg Group C Phase 1b ENTO 800 mg Group C Phase 2 ENTO 400 mg (Cohort C1A - R/R AML) Group C Phase 2 ENTO 400 mg (Cohort C2 - MLL) Group C Phase 2 ENTO 400 mg (Cohort C3 - Untreated AML)
    Number of subjects analysed
    3
    9
    41
    5
    6
    8
    17
    14
    7
    7
    6
    13
    9
    Units: Percentage of Participants
        number (confidence interval 95%)
    100.0 (29.2 to 100)
    77.8 (40 to 97.2)
    70.7 (54.5 to 83.9)
    40.0 (5.3 to 85.3)
    50.0 (11.8 to 88.2)
    25.0 (3.2 to 65.1)
    23.5 (6.8 to 49.9)
    14.3 (1.8 to 42.8)
    14.3 (0.4 to 57.9)
    0.0 (0 to 41)
    0.0 (0 to 45.9)
    15.4 (1.9 to 45.4)
    11.1 (0.3 to 48.2)
    No statistical analyses for this end point

    Secondary: Duration of Exposure of Entospletinib

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    End point title
    		 Duration of Exposure of Entospletinib
    End point description
    The Safety Analysis Set included all participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    First dose date up to approximately 3 years
    End point values
    		 Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b/2 ENTO 400 mg Group C Phase 1b ENTO 800 mg
    Number of subjects analysed
    3
    50
    5
    6
    8
    17
    14
    35
    7
    Units: weeks
        median (full range (min-max))
    8.6 (6.1 to 10.0)
    7.1 (0.9 to 72.9)
    13.7 (1.6 to 50.9)
    15.4 (1.9 to 58.9)
    10.1 (1.3 to 39.4)
    13.9 (1.9 to 40.0)
    10.1 (0.9 to 47.0)
    4.4 (1.4 to 15.6)
    7.6 (2.0 to 9.0)
    No statistical analyses for this end point

    Secondary: Event Free Survival (EFS)

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    End point title
    		 Event Free Survival (EFS)
    End point description
    EFS was defined as the time interval from the start of the study therapy until the date of treatment failure, acute myeloid leukemia (AML) relapse, or death from any cause, whichever occurred first. Participants who received other anti-cancer therapy (prior to the event if any) were censored. Median EFS was analyzed using Kaplan-Meier (KM) method. Participants in the Full Analysis Set were analyzed. 999 = not reached due to low number of participants with an event.
    End point type
    Secondary
    End point timeframe
    First dose date up to approximately 38 months
    End point values
    		 Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b ENTO 400 mg + Cytarabine + Daunorubicin Group A Phase 2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b ENTO 400 mg Group C Phase 1b ENTO 800 mg Group C Phase 2 ENTO 400 mg (Cohort C1A - R/R AML) Group C Phase 2 ENTO 400 mg (Cohort C2 - MLL) Group C Phase 2 ENTO 400 mg (Cohort C3 - Untreated AML)
    Number of subjects analysed
    3
    9
    41
    5
    6
    8
    17
    14
    7
    7
    6
    13
    9
    Units: months
        median (confidence interval 95%)
    999 (999 to 999)
    1.9 (0.9 to 1.9)
    9.0 (2.3 to 999)
    2.2 (0.5 to 4.7)
    2.9 (1.1 to 7.7)
    2.3 (0.5 to 9.0)
    3.2 (0.5 to 4.2)
    2.4 (2.1 to 3.9)
    1.8 (0.9 to 1.9)
    1.8 (0.5 to 1.9)
    1.0 (0.7 to 2.8)
    1.0 (0.8 to 2.7)
    1.7 (0.8 to 1.9)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time interval from the start of the study therapy to death from any cause. Median OS was analyzed using KM method. Participants in the Full Analysis Set were analyzed. 999 = not reached due to low number of participants with an event.
    End point type
    Secondary
    End point timeframe
    First dose date up to approximately 38 months
    End point values
    		 Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b ENTO 400 mg + Cytarabine + Daunorubicin Group A Phase 2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b ENTO 400 mg Group C Phase 1b ENTO 800 mg Group C Phase 2 ENTO 400 mg (Cohort C1A - R/R AML) Group C Phase 2 ENTO 400 mg (Cohort C2 - MLL) Group C Phase 2 ENTO 400 mg (Cohort C3 - Untreated AML)
    Number of subjects analysed
    3
    9
    41
    5
    6
    8
    17
    14
    7
    7
    6
    13
    9
    Units: months
        median (confidence interval 95%)
    37.1 (9.1 to 999)
    34.1 (1.2 to 999)
    999 (16.8 to 999)
    3.2 (0.8 to 12.7)
    5.3 (2.4 to 999)
    6.9 (1.4 to 999)
    7.3 (2.4 to 999)
    6.2 (3.2 to 10.2)
    5.9 (0.9 to 6.3)
    5.6 (0.5 to 8.4)
    8.2 (0.7 to 24.3)
    7.9 (3.3 to 11.9)
    2.2 (1.0 to 4.7)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Experiencing Treatment-Emergent Adverse Events

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    End point title
    		 Percentage of Participants Experiencing Treatment-Emergent Adverse Events
    End point description
    Participants in the Safety Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    First dose date up to the last dose date plus 30 days (maximum: 18 months)
    End point values
    		 Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b/2 ENTO 400 mg Group C Phase 1b ENTO 800 mg
    Number of subjects analysed
    3
    50
    5
    6
    8
    17
    14
    35
    7
    Units: Percentage of Participants
        number (not applicable)
    100.0
    100.0
    100.0
    100.0
    100.0
    100.0
    100.0
    100.0
    100.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced Laboratory Abnormalities

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    End point title
    		 Percentage of Participants Who Experienced Laboratory Abnormalities
    End point description
    Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each participant. Participants in the Safety Analysis Set who had non-missing postbaseline value prior to or on the last dosing date plus 30 days were analyzed.
    End point type
    Secondary
    End point timeframe
    First dose date up to the last dose date plus 30 days (maximum: 18 months)
    End point values
    		 Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b/2 ENTO 400 mg Group C Phase 1b ENTO 800 mg
    Number of subjects analysed
    3
    50
    5
    6
    8
    17
    14
    35
    7
    Units: Percentage of Participants
    number (not applicable)
        Any Laboratory Abnormality
    100
    100
    100
    100
    100
    94.1
    100
    100
    100
        Grade 3 or 4 Laboratory Abnormalities
    100
    98.0
    100
    100
    85.7
    94.1
    92.9
    82.9
    85.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    - All-Cause Mortality: First dose date up to approximately 38 months. - Adverse Events: First dose date up to the last dose date plus 30 days (maximum: 18 months)
    Adverse event reporting additional description
    The Safety Analysis Set included all participants who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin
    Reporting group description
    		 Participants received ENTO 200 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (during induction chemotherapy).

    Reporting group title
    Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin
    Reporting group description
    		 Phase1b/2: Participants received ENTO 400 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (induction chemotherapy). Phase 2 only: Participants who achieved a CR/CRi and did not require or could not proceed to allogeneic stem cell transplantation (SCT) were offered post-remission chemotherapy (cytarabine 3 g/m^2 intravenously every 12 hours on Days 1, 3, and 5 or 1 g/m^2 intravenously once daily on Days 1-5) in combination with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for at least 3 and up to 4 cycles. Participants who maintained a CR/CRi after 3 or 4 cycles were offered maintenance therapy with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for up to 12 cycles.

    Reporting group title
    Group B Phase 1b ENTO 200 mg + Decitabine
    Reporting group description
    		 Participants received ENTO 200 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 200 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 1b ENTO 400 mg + Decitabine
    Reporting group description
    		 Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In)
    Reporting group description
    		 As part of the safety run-in, participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of a 28-day cycle (Cycle 1). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 2 ENTO 400 mg + Decitabine (Randomized)
    Reporting group description
    		 Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized)
    Reporting group description
    		 Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group C Phase 1b/2 ENTO 400 mg
    Reporting group description
    		 Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Reporting group title
    Group C Phase 1b ENTO 800 mg
    Reporting group description
    		 Participants received ENTO 800 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Serious adverse events
    		 Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b/2 ENTO 400 mg Group C Phase 1b ENTO 800 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    23 / 50 (46.00%)
    5 / 5 (100.00%)
    5 / 6 (83.33%)
    7 / 8 (87.50%)
    11 / 17 (64.71%)
    7 / 14 (50.00%)
    19 / 35 (54.29%)
    4 / 7 (57.14%)
         number of deaths (all causes)
    2
    21
    5
    4
    5
    12
    11
    30
    6
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia recurrent
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    1 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter site haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung consolidation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin I increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuromyopathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    13 / 50 (26.00%)
    4 / 5 (80.00%)
    4 / 6 (66.67%)
    3 / 8 (37.50%)
    8 / 17 (47.06%)
    0 / 14 (0.00%)
    5 / 35 (14.29%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    11 / 16
    5 / 6
    5 / 7
    3 / 4
    8 / 14
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    2 / 14 (14.29%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 1
    0 / 0
    1 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    2 / 7 (28.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Device related infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis staphylococcal
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b/2 ENTO 400 mg Group C Phase 1b ENTO 800 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    50 / 50 (100.00%)
    5 / 5 (100.00%)
    6 / 6 (100.00%)
    7 / 8 (87.50%)
    17 / 17 (100.00%)
    14 / 14 (100.00%)
    33 / 35 (94.29%)
    7 / 7 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 3 (33.33%)
    7 / 50 (14.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    4 / 17 (23.53%)
    5 / 14 (35.71%)
    6 / 35 (17.14%)
    1 / 7 (14.29%)
         occurrences all number
    1
    8
    0
    0
    3
    6
    11
    8
    1
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    12 / 50 (24.00%)
    0 / 5 (0.00%)
    3 / 6 (50.00%)
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    1 / 7 (14.29%)
         occurrences all number
    0
    12
    0
    3
    0
    3
    0
    2
    1
    Haematoma
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    3
    0
    2
    0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    0
    0
    0
    Embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    0
    0
    0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    2
    0
    0
    0
    Hot flush
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    2 / 3 (66.67%)
    29 / 50 (58.00%)
    2 / 5 (40.00%)
    3 / 6 (50.00%)
    4 / 8 (50.00%)
    6 / 17 (35.29%)
    4 / 14 (28.57%)
    4 / 35 (11.43%)
    3 / 7 (42.86%)
         occurrences all number
    3
    35
    2
    3
    4
    9
    5
    4
    3
    Fatigue
         subjects affected / exposed
    1 / 3 (33.33%)
    14 / 50 (28.00%)
    3 / 5 (60.00%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
    9 / 17 (52.94%)
    6 / 14 (42.86%)
    10 / 35 (28.57%)
    3 / 7 (42.86%)
         occurrences all number
    1
    16
    3
    1
    2
    10
    6
    10
    3
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    9 / 50 (18.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    2 / 8 (25.00%)
    2 / 17 (11.76%)
    1 / 14 (7.14%)
    5 / 35 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    12
    0
    2
    2
    3
    1
    5
    0
    Chills
         subjects affected / exposed
    0 / 3 (0.00%)
    8 / 50 (16.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    5 / 14 (35.71%)
    4 / 35 (11.43%)
    0 / 7 (0.00%)
         occurrences all number
    0
    9
    0
    0
    0
    5
    5
    4
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    10 / 50 (20.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    4 / 35 (11.43%)
    0 / 7 (0.00%)
         occurrences all number
    0
    10
    1
    0
    0
    0
    1
    4
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    7 / 50 (14.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    7
    0
    1
    0
    2
    1
    1
    0
    Chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    2 / 14 (14.29%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    3
    4
    0
    Catheter site erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    0
    1
    0
    Face oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    0
    1
    0
    Malaise
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    2
    0
    0
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    2
    0
    0
    0
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    1
    0
    Catheter site pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    1
    0
    Catheter site rash
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Injection site erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    2 / 14 (14.29%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Catheter site dermatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Device related thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Feeling hot
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    General physical health deterioration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Injection site pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Performance status decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Reproductive system and breast disorders
    Scrotal oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    20 / 50 (40.00%)
    2 / 5 (40.00%)
    3 / 6 (50.00%)
    2 / 8 (25.00%)
    5 / 17 (29.41%)
    4 / 14 (28.57%)
    10 / 35 (28.57%)
    1 / 7 (14.29%)
         occurrences all number
    0
    23
    2
    3
    2
    6
    4
    10
    1
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    18 / 50 (36.00%)
    1 / 5 (20.00%)
    4 / 6 (66.67%)
    3 / 8 (37.50%)
    5 / 17 (29.41%)
    5 / 14 (35.71%)
    5 / 35 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    21
    1
    4
    4
    5
    6
    5
    0
    Epistaxis
         subjects affected / exposed
    0 / 3 (0.00%)
    10 / 50 (20.00%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    2 / 14 (14.29%)
    7 / 35 (20.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    16
    1
    3
    0
    3
    2
    7
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    10 / 50 (20.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    1 / 14 (7.14%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    12
    0
    0
    0
    4
    1
    3
    0
    Hypoxia
         subjects affected / exposed
    0 / 3 (0.00%)
    11 / 50 (22.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    11
    0
    0
    0
    2
    1
    1
    0
    Nasal congestion
         subjects affected / exposed
    0 / 3 (0.00%)
    7 / 50 (14.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    8
    1
    1
    0
    2
    0
    2
    0
    Pleural effusion
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 50 (8.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    2 / 14 (14.29%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    3
    2
    1
    0
    Productive cough
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    2 / 14 (14.29%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    1
    2
    2
    0
    Pulmonary oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    1
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    3 / 35 (8.57%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    0
    3
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    1
    1
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    0
    0
    2
    0
    Wheezing
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    0
    1
    0
    Atelectasis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    0
    Haemoptysis
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    0
    0
    0
    Sinus pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    1
    0
    0
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    1
    Pulmonary hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Rales
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Respiratory failure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    0
    Hiccups
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Lung infiltration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Paranasal sinus hyposecretion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Rhonchi
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Upper respiratory tract congestion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    16 / 50 (32.00%)
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
    4 / 14 (28.57%)
    7 / 35 (20.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    16
    2
    1
    1
    2
    4
    8
    0
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    7 / 50 (14.00%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    3 / 35 (8.57%)
    0 / 7 (0.00%)
         occurrences all number
    0
    8
    1
    2
    0
    1
    0
    3
    0
    Confusional state
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 50 (10.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    1 / 7 (14.29%)
         occurrences all number
    0
    6
    1
    0
    1
    2
    0
    2
    1
    Delirium
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    2
    0
    2
    0
    1
    0
    Depression
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 50 (10.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    5
    0
    0
    1
    0
    1
    1
    0
    Hallucination
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    1
    0
    0
    0
    Mental status changes
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    0
    0
    Restlessness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    1
    0
    0
    Apathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Suicidal ideation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    26 / 50 (52.00%)
    3 / 5 (60.00%)
    3 / 6 (50.00%)
    3 / 8 (37.50%)
    5 / 17 (29.41%)
    7 / 14 (50.00%)
    9 / 35 (25.71%)
    1 / 7 (14.29%)
         occurrences all number
    0
    38
    3
    3
    3
    7
    10
    10
    1
    White blood cell count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    18 / 50 (36.00%)
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
    7 / 17 (41.18%)
    5 / 14 (35.71%)
    4 / 35 (11.43%)
    1 / 7 (14.29%)
         occurrences all number
    0
    25
    2
    2
    3
    12
    11
    4
    1
    Neutrophil count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    16 / 50 (32.00%)
    2 / 5 (40.00%)
    2 / 6 (33.33%)
    2 / 8 (25.00%)
    4 / 17 (23.53%)
    2 / 14 (14.29%)
    6 / 35 (17.14%)
    2 / 7 (28.57%)
         occurrences all number
    0
    24
    2
    2
    3
    4
    5
    6
    2
    Blood bilirubin increased
         subjects affected / exposed
    0 / 3 (0.00%)
    12 / 50 (24.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    5 / 17 (29.41%)
    4 / 14 (28.57%)
    3 / 35 (8.57%)
    0 / 7 (0.00%)
         occurrences all number
    0
    12
    0
    0
    3
    7
    7
    3
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    6 / 50 (12.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
    7 / 14 (50.00%)
    2 / 35 (5.71%)
    2 / 7 (28.57%)
         occurrences all number
    0
    9
    1
    1
    1
    1
    13
    2
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    8 / 50 (16.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    4 / 35 (11.43%)
    2 / 7 (28.57%)
         occurrences all number
    0
    13
    0
    0
    4
    0
    7
    4
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    8 / 50 (16.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    1 / 17 (5.88%)
    2 / 14 (14.29%)
    3 / 35 (8.57%)
    1 / 7 (14.29%)
         occurrences all number
    0
    11
    0
    0
    4
    1
    6
    3
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
    4 / 17 (23.53%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    1
    1
    2
    4
    0
    1
    2
    Weight decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 50 (4.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    2 / 14 (14.29%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    1
    0
    0
    3
    3
    1
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 50 (10.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    5
    0
    1
    2
    0
    1
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    1 / 14 (7.14%)
    2 / 35 (5.71%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    2
    2
    1
    International normalised ratio increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 50 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    2 / 14 (14.29%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    3
    2
    1
    0
    Weight increased
         subjects affected / exposed
    2 / 3 (66.67%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    3
    0
    0
    0
    2
    0
    0
    0
    Troponin I increased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    1
    1
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    1
    1
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 50 (8.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    1
    0
    0
    0
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    3
    1
    1
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    2
    2
    0
    Amylase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    4 / 14 (28.57%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    7
    0
    0
    Lymphocyte count increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    1
    0
    0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    2 / 14 (14.29%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    0
    Body temperature increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Troponin increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    0
    Blood creatinine decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Blood phosphorus increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Chest X-ray abnormal
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Spleen palpable
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Ultrasound liver abnormal
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    4 / 35 (11.43%)
    1 / 7 (14.29%)
         occurrences all number
    0
    3
    1
    0
    0
    1
    1
    4
    1
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    6 / 50 (12.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    4 / 17 (23.53%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    7
    0
    0
    0
    5
    0
    0
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    1
    0
    0
    Transfusion reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    2
    0
    Eye contusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Pelvic fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Vascular access complication
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 3 (0.00%)
    7 / 50 (14.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    3 / 17 (17.65%)
    3 / 14 (21.43%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    7
    1
    0
    1
    3
    3
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    6 / 50 (12.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
    2 / 14 (14.29%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    7
    0
    2
    1
    3
    2
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 50 (10.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    5
    0
    1
    0
    0
    2
    1
    0
    Tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    2 / 14 (14.29%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    2
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    1
    0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    0
    1
    Angina pectoris
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    0
    Arrhythmia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Bradycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Diastolic dysfunction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 3 (33.33%)
    20 / 50 (40.00%)
    2 / 5 (40.00%)
    3 / 6 (50.00%)
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    2 / 14 (14.29%)
    6 / 35 (17.14%)
    2 / 7 (28.57%)
         occurrences all number
    1
    29
    2
    3
    0
    3
    2
    6
    2
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    14 / 50 (28.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    5 / 35 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    17
    0
    0
    0
    1
    1
    5
    0
    Dysgeusia
         subjects affected / exposed
    0 / 3 (0.00%)
    11 / 50 (22.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    3 / 8 (37.50%)
    2 / 17 (11.76%)
    3 / 14 (21.43%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    12
    0
    1
    3
    2
    4
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 50 (8.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    3 / 35 (8.57%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    1
    0
    4
    0
    Tremor
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    0
    2
    0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    0
    1
    0
    Syncope
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    1
    0
    0
    Amnesia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Encephalopathy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    1
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    Parosmia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    2 / 3 (66.67%)
    36 / 50 (72.00%)
    1 / 5 (20.00%)
    3 / 6 (50.00%)
    2 / 8 (25.00%)
    2 / 17 (11.76%)
    4 / 14 (28.57%)
    8 / 35 (22.86%)
    0 / 7 (0.00%)
         occurrences all number
    2
    53
    3
    3
    2
    3
    4
    12
    0
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    24 / 50 (48.00%)
    3 / 5 (60.00%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
    5 / 17 (29.41%)
    6 / 14 (42.86%)
    10 / 35 (28.57%)
    3 / 7 (42.86%)
         occurrences all number
    0
    28
    3
    4
    2
    8
    10
    11
    3
    Leukocytosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    1
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    2
    3
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    Neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Pancytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    2
    0
    2
    0
    Hypoacusis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Tinnitus
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    0
    0
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 3 (0.00%)
    10 / 50 (20.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    10
    0
    0
    0
    1
    0
    1
    0
    Dry eye
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 50 (8.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    1
    4
    0
    1
    0
    0
    0
    2
    0
    Eye pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    0
    0
    0
    Scleral hyperaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    1
    Eye haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Eye oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Lacrimation increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Optic nerve cupping
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Periorbital oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Ulcerative keratitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 3 (100.00%)
    34 / 50 (68.00%)
    4 / 5 (80.00%)
    4 / 6 (66.67%)
    4 / 8 (50.00%)
    5 / 17 (29.41%)
    7 / 14 (50.00%)
    15 / 35 (42.86%)
    2 / 7 (28.57%)
         occurrences all number
    4
    49
    4
    5
    4
    6
    9
    15
    3
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    34 / 50 (68.00%)
    1 / 5 (20.00%)
    3 / 6 (50.00%)
    3 / 8 (37.50%)
    9 / 17 (52.94%)
    4 / 14 (28.57%)
    14 / 35 (40.00%)
    4 / 7 (57.14%)
         occurrences all number
    2
    55
    1
    4
    4
    16
    9
    14
    4
    Constipation
         subjects affected / exposed
    1 / 3 (33.33%)
    20 / 50 (40.00%)
    3 / 5 (60.00%)
    4 / 6 (66.67%)
    6 / 8 (75.00%)
    10 / 17 (58.82%)
    9 / 14 (64.29%)
    3 / 35 (8.57%)
    0 / 7 (0.00%)
         occurrences all number
    1
    28
    3
    4
    7
    13
    14
    4
    0
    Vomiting
         subjects affected / exposed
    2 / 3 (66.67%)
    16 / 50 (32.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    6 / 17 (35.29%)
    5 / 14 (35.71%)
    8 / 35 (22.86%)
    1 / 7 (14.29%)
         occurrences all number
    2
    28
    0
    1
    1
    9
    7
    9
    2
    Abdominal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    13 / 50 (26.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    4 / 14 (28.57%)
    4 / 35 (11.43%)
    0 / 7 (0.00%)
         occurrences all number
    2
    15
    0
    2
    0
    1
    4
    4
    0
    Stomatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    8 / 50 (16.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    4 / 17 (23.53%)
    1 / 14 (7.14%)
    6 / 35 (17.14%)
    1 / 7 (14.29%)
         occurrences all number
    0
    8
    1
    1
    0
    5
    2
    6
    1
    Abdominal distension
         subjects affected / exposed
    0 / 3 (0.00%)
    7 / 50 (14.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    2 / 14 (14.29%)
    2 / 35 (5.71%)
    1 / 7 (14.29%)
         occurrences all number
    0
    7
    0
    2
    0
    0
    2
    2
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 50 (10.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    1 / 14 (7.14%)
    3 / 35 (8.57%)
    0 / 7 (0.00%)
         occurrences all number
    0
    5
    0
    1
    0
    3
    1
    3
    0
    Dyspepsia
         subjects affected / exposed
    0 / 3 (0.00%)
    8 / 50 (16.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    8
    0
    0
    2
    0
    0
    1
    0
    Oral pain
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 50 (10.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    5
    0
    1
    0
    4
    1
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 3 (33.33%)
    6 / 50 (12.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    7
    1
    0
    0
    0
    1
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    4 / 17 (23.53%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    4
    0
    2
    0
    Dry mouth
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    1
    1
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    1
    0
    2
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    1
    2
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    2 / 14 (14.29%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    2
    0
    0
    Angina bullosa haemorrhagica
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    0
    0
    1
    0
    Colitis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    1
    0
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    2
    0
    0
    0
    Proctalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    3 / 14 (21.43%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    4
    0
    0
    Anal incontinence
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    1
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    2
    0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    1
    0
    Lip pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    1
    Mouth haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    1
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    0
    Anal ulcer
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Tongue ulceration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    0
    Ascites
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Colitis ischaemic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Enterocolitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Faecaloma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Hiatus hernia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Ileus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Intestinal dilatation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Intra-abdominal haematoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Pancreatic disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Regurgitation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Salivary hypersecretion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 50 (8.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    1
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    1 / 3 (33.33%)
    21 / 50 (42.00%)
    1 / 5 (20.00%)
    3 / 6 (50.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    8 / 35 (22.86%)
    1 / 7 (14.29%)
         occurrences all number
    1
    27
    2
    3
    0
    0
    1
    8
    1
    Petechiae
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 50 (8.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    2 / 14 (14.29%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    1
    4
    0
    0
    0
    3
    2
    2
    0
    Pruritus
         subjects affected / exposed
    1 / 3 (33.33%)
    7 / 50 (14.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    1
    7
    0
    1
    0
    0
    0
    2
    0
    Alopecia
         subjects affected / exposed
    0 / 3 (0.00%)
    6 / 50 (12.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    6
    0
    0
    0
    1
    1
    1
    0
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    2
    1
    1
    0
    Skin ulcer
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 50 (10.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    5
    0
    0
    0
    1
    1
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    1
    0
    1
    0
    Erythema
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    1
    0
    0
    0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    1
    0
    Drug eruption
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Rash macular
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    Dermal cyst
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Ecchymosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Night sweats
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Pain of skin
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Rash papular
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Skin lesion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 3 (0.00%)
    8 / 50 (16.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
    3 / 14 (21.43%)
    3 / 35 (8.57%)
    0 / 7 (0.00%)
         occurrences all number
    0
    8
    0
    0
    1
    2
    3
    3
    0
    Haematuria
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 50 (10.00%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    5
    2
    0
    0
    1
    1
    0
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 50 (8.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    0
    0
    2
    0
    Urinary retention
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    1
    1
    1
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    1
    0
    0
    Dysuria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    1
    0
    0
    Micturition urgency
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    1
    Nephrolithiasis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Renal cyst
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 3 (33.33%)
    6 / 50 (12.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    6 / 35 (17.14%)
    1 / 7 (14.29%)
         occurrences all number
    1
    6
    0
    2
    0
    1
    0
    6
    1
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    7 / 50 (14.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    2 / 14 (14.29%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    8
    1
    0
    0
    3
    2
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    4 / 17 (23.53%)
    1 / 14 (7.14%)
    3 / 35 (8.57%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    0
    1
    1
    5
    1
    3
    1
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    6 / 50 (12.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    4 / 35 (11.43%)
    0 / 7 (0.00%)
         occurrences all number
    0
    6
    0
    0
    0
    1
    0
    4
    0
    Muscular weakness
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    2 / 14 (14.29%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    4
    2
    1
    0
    Bone pain
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 50 (8.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    1
    0
    1
    1
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    0
    1
    0
    Flank pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    Groin pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Myositis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Vertebral lesion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    0 / 3 (0.00%)
    11 / 50 (22.00%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    3 / 35 (8.57%)
    0 / 7 (0.00%)
         occurrences all number
    0
    12
    1
    2
    1
    1
    0
    3
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 50 (8.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    3 / 8 (37.50%)
    0 / 17 (0.00%)
    3 / 14 (21.43%)
    3 / 35 (8.57%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    1
    1
    3
    0
    3
    4
    0
    Device related infection
         subjects affected / exposed
    1 / 3 (33.33%)
    9 / 50 (18.00%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    11
    1
    2
    0
    0
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 50 (10.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    3 / 35 (8.57%)
    0 / 7 (0.00%)
         occurrences all number
    0
    5
    0
    0
    0
    0
    1
    5
    0
    Mucosal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    0
    0
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    1
    0
    1
    0
    Cellulitis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    1
    1
    0
    0
    0
    0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    1
    1
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    2
    1
    0
    0
    Sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    1
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    2
    0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    0
    0
    0
    Folliculitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    2
    0
    Bacteraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Candida infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Otitis externa
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Skin infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    0
    0
    Soft tissue infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    0
    0
    0
    Staphylococcal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Abdominal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Atypical pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Bacterial infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Bacterial sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Chronic sinusitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Corona virus infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Enterococcal bacteraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Leptotrichia infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Mycobacterium avium complex infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Perirectal abscess
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Postoperative wound infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Staphylococcal skin infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Tinea cruris
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Tooth abscess
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 3 (0.00%)
    22 / 50 (44.00%)
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    3 / 8 (37.50%)
    6 / 17 (35.29%)
    6 / 14 (42.86%)
    7 / 35 (20.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    25
    2
    1
    3
    7
    8
    7
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    10 / 50 (20.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    3 / 17 (17.65%)
    3 / 14 (21.43%)
    4 / 35 (11.43%)
    1 / 7 (14.29%)
         occurrences all number
    0
    15
    1
    0
    3
    5
    3
    5
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    7 / 50 (14.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
    4 / 14 (28.57%)
    3 / 35 (8.57%)
    1 / 7 (14.29%)
         occurrences all number
    0
    7
    1
    0
    1
    6
    6
    3
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 50 (8.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    4 / 17 (23.53%)
    5 / 14 (35.71%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    1
    1
    0
    9
    8
    2
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    2 / 14 (14.29%)
    4 / 35 (11.43%)
    1 / 7 (14.29%)
         occurrences all number
    0
    4
    0
    0
    0
    3
    2
    4
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
    2 / 14 (14.29%)
    1 / 35 (2.86%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    1
    1
    1
    1
    3
    1
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 50 (8.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    5 / 14 (35.71%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    1
    7
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    3 / 14 (21.43%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    4
    9
    2
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    3 / 14 (21.43%)
    1 / 35 (2.86%)
    1 / 7 (14.29%)
         occurrences all number
    0
    3
    0
    0
    2
    0
    6
    1
    1
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    2 / 17 (11.76%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    2
    2
    1
    0
    0
    Hypermagnesaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    4 / 14 (28.57%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    4
    1
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    3 / 17 (17.65%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    10
    0
    0
    1
    3
    1
    2
    0
    Hyperphosphataemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
    2 / 14 (14.29%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    1
    2
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    3
    0
    1
    Fluid overload
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    0
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    2 / 14 (14.29%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    5
    1
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Hypervolaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Hypophagia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Metabolic acidosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jan 2015
    - Increased the blood volume collected due to additional tube needed for biomarker testing - Added saliva sampling to serve as a source of DNA for whole exome sequencing to assess for germline mutations
    12 May 2015
    - Clarified the use and timing of bone marrow biopsy and aspirate samples - Removed optional buccal swab - Removed pharmacodynamics basophil activation test (BAT) assay collection for Groups A and B - Specified that blood and bone marrow biomarker samples were stored for optional future research - Clarified dosing delay and dose modification language
    24 Nov 2015
    - Updated DLT assessment windows - Included new information on concomitant medications with ENTO - Added contraindicated medications and additional creatine phosphokinase (CPK) monitoring - Added left ventricular ejection fraction inclusion criterion and included ECHO or MUGA at screening (all groups) and prior to re-induction (Group A only) - Extended the screening window for bone marrow biopsy and aspirate to 21 days - Added BAT assay sample time points for Group C at end of subsequent cycles and at End of Study and specified that BAT assay samples were only collected during the escalation phase - Updated Appendix 4 to align with standard protocol template - Aligned Appendix 5 with the International Working Group criteria - Updated and clarified the criteria for discontinuation of study treatment - Incorporated changes from Administrative Amendment dated 02 July 2015
    05 Aug 2016
    - Stated that the recommended Phase 2 dose (RP2D) was ENTO 400 mg and included the rationale for the dose selection - Removed the ENTO 800 mg dose level for Groups A and B - Increased the participant number to approximately 40 in Phase 2 for each of Groups A and B and approximately 75 for Group C - Added Group A postinduction cycles to evaluate ENTO in combination with cytarabine followed by ENTO monotherapy maintenance cycles in the dose expansion - Added a Group B safety run-in and DLT assessment of 6 participants to evaluate the safety of ENTO in combination with azacitidine prior to enrollment of the expansion cohort - Added a Group B arm in the dose expansion to evaluate ENTO in combination with azacitidine - Separated Group C relapsed/refractory and previously untreated participants into subcohorts for the dose expansion - Added a cohort C1B safety run-in and DLT assessment to evaluate ENTO in combination with mitoxantrone, etoposide, and cytarabine (MEC) - Updated the primary endpoints and objectives to include combinations with azacitidine and MEC - Updated and added schedule of assessment tables for all groups to include updated dose escalation assessments and dose expansion assessments - Added intensive PK sample collection to Group A on Cycle 1 Day 7 and to Cohort C1B on Cycle 1 Day 5 - Added disease assessment to the Group A and B Cycle 0 Day 14 bone marrow assessment - Updated Group A-specific inclusion and exclusion Criterion 1 to remove the age limit and to allow favorable risk AML participants - Updated Group C-specific inclusion criteria to include criteria that must have been met to be eligible for each subcohort - Updated the study discontinuation criteria to clarify the criterion that applied only to Group C and moved Group B language from criterion to the applicable sections - Updated Appendix 5 and Appendix 6 - Added Appendix 7 (defined MRD level) and new references
    14 Feb 2017
    - Updated the ENTO formulation composition, strength, and color per manufacturing changes - Added an exploratory optional biopsy to all groups’ study designs - Removed minimal residual disease (MRD) treatment criteria from the protocol - Clarified CR criteria - Clarified morphologic leukemia-free state criteria - Updated PK collection schedule for Groups A and C - Updated study procedures tables for all groups - Specified “Dose Escalation” and “Dose Expansion” as well as “Phase 1b” and “Phase 2” throughout the protocol, as needed - Updated relapse-free survival criteria - Add dose modification guidelines for toxicities on various study treatments - Updated prohibited medication requirements per current drug and safety data - Added new serum chemistry requirement for beta-2 microglobulin
    04 Aug 2017
    - Ascertained the benefit of a 5-day ENTO lead-in - Evaluated responses in specific risk groups of AML (< 60 years of age versus ≥ 60 years of age; de novo versus secondary AML) - Confirmed the overall response rate in Group A to enable planning of a global Phase 3 study - Cohort C1B was removed due to the lack of responses in the relapsed/refractory AML population. However, due to the most encouraging results in the MLL cohort, the development of ENTO in the relapsed/refractory setting concentrated on the MLL subsets. - Remove references to ENTO 100 mg - Incorporated German-specific requirements - Updated introduction to AML to align with ENTO Investigator’s Brochure Edition 8 - Added flow cytometry to determine blast percentage - Removed postinduction and replaced with postremission - Identified cohorts closed to enrollment - Emphasized participants were to be followed for survival
    15 Feb 2018
    - Removed Cohort A1 as interim analysis of Phase 1 and 2 Group A participants led to a CR rate no better than historical controls and this did not support enrollment to an AML study in “all comers AML” randomized to ENTO versus placebo plus cytarabine and daunorubicin (7+3). - Closed Group C3 screening due to the low enrollment rate of Group C3, lack of responses to ENTO monotherapy both during the lead-in period in Group A subjects and in all but one subject in C3, and the evolving treatment landscape for AML. Screening and enrollment activities were discontinued. - Removed all references to “placebo-to-match” and its formulation as only Cohort A1 involved treatment with a placebo. - Added note to indicate Group B Phase 1b enrollment completion. - Updated total subject number from 270 to 190 throughout the protocol to reflect removal of Cohort A1 (n = 80) - Renamed Drug Safety and Public Health (DSPH), a department at Gilead Sciences, to Pharmacovigilance and Epidemiology (PVE) effective December 1, 2017

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    21 Nov 2018
    Study was terminated by sponsor due to lack of response to ENTO monotherapy and the evolving treatment landscape for acute myeloid leukemia.
    -

    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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