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    Clinical Trial Results:
    An open-label, Phase I/II trial to determine the maximum tolerated dose and investigate safety, pharmacokinetics and efficacy of BI 836858 in combination with decitabine in patients with acute myeloid leukemia

    Summary
    EudraCT number
    		 2015-002892-30
    Trial protocol
    		 DE   ES   IT  
    Global end of trial date
    16 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Jan 2024
    First version publication date
    31 Jan 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1315.2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02632721
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Straße, Ingelheim am Rhein, Germany, 55216
    Public contact
    Boehringer Ingelheim Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.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
    24 Feb 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Jan 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jan 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Phase I Dose Escalation: To determine the maximum tolerated dose (MTD) and the recommended dose for Phase I Extension (RExP1D) and to investigate the safety, pharmacokinetics, and efficacy of BI 836858 in combination with decitabine. Phase I Extension: To collect additional data on safety, pharmacokinetics, and efficacy and to decide if the RExP1D would become the Recommended Phase II Dose (RP2D) of BI 836858 in combination with decitabine.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Aug 2016
    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
    Italy: 2
    Country: Number of subjects enrolled
    United States: 11
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    Germany: 32
    Worldwide total number of subjects
    63
    EEA total number of subjects
    52
    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)
    7
    From 65 to 84 years
    54
    85 years and over
    2

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This was an open-label, Phase I/II trial to determine the maximum tolerated dose and investigate safety, pharmacokinetics and efficacy of BI 836858 in combination with decitabine in patients with acute myeloid leukemia.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase I dose escalation: BI 836858 20 mg + decitabine
    Arm description
    		 20 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Decitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Investigational medicinal product name
    BI836858
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Arm title
    		 Phase I dose escalation: BI 836858 40 mg + decitabine
    Arm description
    		 40 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Decitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Investigational medicinal product name
    BI 836858
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Arm title
    		 Phase I dose escalation: BI 836858 80 mg + decitabine
    Arm description
    		 80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Decitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Investigational medicinal product name
    BI 836858
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Arm title
    		 Phase I Extension A: BI 836858 80 mg + decitabine
    Arm description
    		 80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Decitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Investigational medicinal product name
    BI 836858
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Arm title
    		 Phase I Extension B: BI 836858 80 mg + decitabine
    Arm description
    		 80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 5 consecutive days (standard treatment) from Day 1 to 5 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Decitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 5 consecutive days (standard treatment) from Day 1 to 5 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Investigational medicinal product name
    BI 836858
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 5 consecutive days (standard treatment) from Day 1 to 5 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Number of subjects in period 1 [1]
    		Phase I dose escalation: BI 836858 20 mg + decitabine Phase I dose escalation: BI 836858 40 mg + decitabine Phase I dose escalation: BI 836858 80 mg + decitabine Phase I Extension A: BI 836858 80 mg + decitabine Phase I Extension B: BI 836858 80 mg + decitabine
    Started
    4
    3
    9
    15
    18
    Completed
    0
    0
    0
    1
    2
    Not completed
    4
    3
    9
    14
    16
         Inadequate clinical condition
    -
    -
    -
    -
    1
         Dose limiting toxicity
    -
    -
    -
    1
    -
         Allergic reaction
    -
    -
    -
    1
    -
         Increase of white blood cell count
    -
    -
    -
    -
    1
         Refused to continue taking trial medication
    -
    1
    1
    1
    2
         Therapy refractory AML
    -
    -
    -
    -
    1
         Patient wish for other treatment
    -
    1
    -
    -
    -
         Relapsed Pneumonia
    -
    -
    -
    -
    1
         No meet eligibility
    -
    -
    -
    -
    1
         Adverse event, non-fatal
    -
    -
    2
    5
    3
         Receiving Decitabine locally
    -
    -
    1
    -
    -
         Allogeneic peripheral stem cell transplantation
    -
    -
    1
    -
    -
         Progressive disease
    3
    -
    4
    6
    5
         No benefit from study treatment
    1
    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: Worldwide 63 subjects were enrolled into the trial, whereof 49 subjects actually started in the trial.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase I dose escalation: BI 836858 20 mg + decitabine
    Reporting group description
    		 20 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Reporting group title
    Phase I dose escalation: BI 836858 40 mg + decitabine
    Reporting group description
    		 40 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Reporting group title
    Phase I dose escalation: BI 836858 80 mg + decitabine
    Reporting group description
    		 80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Reporting group title
    Phase I Extension A: BI 836858 80 mg + decitabine
    Reporting group description
    		 80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Reporting group title
    Phase I Extension B: BI 836858 80 mg + decitabine
    Reporting group description
    		 80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 5 consecutive days (standard treatment) from Day 1 to 5 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Reporting group values
    		 Phase I dose escalation: BI 836858 20 mg + decitabine Phase I dose escalation: BI 836858 40 mg + decitabine Phase I dose escalation: BI 836858 80 mg + decitabine Phase I Extension A: BI 836858 80 mg + decitabine Phase I Extension B: BI 836858 80 mg + decitabine Total
    Number of subjects
    		 4 3 9 15 18 49
    Age categorical
    Treated set: The treated set includes all patients who have received at least one dose of study medication (BI 836858 and/or decitabine).
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 1 2 3 0 0 6
        From 65-84 years
    		 3 1 6 14 18 42
        85 years and over
    		 0 0 0 1 0 1
    Age Continuous
    Treated set: The treated set includes all patients who have received at least one dose of study medication (BI 836858 and/or decitabine).
    Units: years
        arithmetic mean (standard deviation)
    		 72.0 ± 11.34 52.3 ± 27.61 66.3 ± 13.02 74.9 ± 6.62 76.6 ± 4.24 -
    Sex: Female, Male
    Treated set: The treated set includes all patients who have received at least one dose of study medication (BI 836858 and/or decitabine).
    Units: Participants
        Female
    		 1 2 4 7 6 20
        Male
    		 3 1 5 8 12 29
    Race (NIH/OMB)
    Treated set: The treated set includes all patients who have received at least one dose of study medication (BI 836858 and/or decitabine).
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0
        Asian
    		 0 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0
        Black or African American
    		 0 0 0 0 0 0
        White
    		 4 3 9 15 18 49
        More than one race
    		 0 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Phase I dose escalation: BI 836858 20 mg + decitabine
    Reporting group description
    		 20 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Reporting group title
    Phase I dose escalation: BI 836858 40 mg + decitabine
    Reporting group description
    		 40 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Reporting group title
    Phase I dose escalation: BI 836858 80 mg + decitabine
    Reporting group description
    		 80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Reporting group title
    Phase I Extension A: BI 836858 80 mg + decitabine
    Reporting group description
    		 80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Reporting group title
    Phase I Extension B: BI 836858 80 mg + decitabine
    Reporting group description
    		 80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 5 consecutive days (standard treatment) from Day 1 to 5 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Subject analysis set title
    Phase I: BI 836858 + decitabine
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comprises all dose cohorts during the Phase I dose escalation and extension parts. 20/40/80 milligram (mg) of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 (standard treatment: 5 consecutive days from Day 1 to 5) in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Primary: Phase I: Number of patients with dose limiting toxicity (DLT(s)) during first treatment cycle

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    End point title
    		 Phase I: Number of patients with dose limiting toxicity (DLT(s)) during first treatment cycle [1]
    End point description
    Number of patients with dose limiting toxicity (DLT(s)) for BI 836858 in combination with decitabine during first treatment cycle (Phase 1). DLT was defined as any non-disease-related non-haematological adverse event (AE) of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher. Expected non-haematological disease-related AEs were not to be regarded as a DLT. Bayesian logistic regression model (BLRM) with overdose control was used to determine the maximum tolerated dose (MTD), defined as highest dose with less than 25% risk of the true DLT rate being equal to or above 33%. Posterior probabilities of the DLT rate lying in the intervals [0.16, 0.33) (target dosing), and [0.33,1] (overdosing) are reported. Treated set: All subjects who were documented to have received at least one dose of trial medication.
    End point type
    Primary
    End point timeframe
    Up to 28 days (first treatment cycle).
    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: Endpoint has been analyzed descriptively.
    End point values
    		 Phase I dose escalation: BI 836858 20 mg + decitabine Phase I dose escalation: BI 836858 40 mg + decitabine Phase I dose escalation: BI 836858 80 mg + decitabine Phase I Extension A: BI 836858 80 mg + decitabine Phase I Extension B: BI 836858 80 mg + decitabine
    Number of subjects analysed
    4 [2]
    3 [3]
    9 [4]
    15
    18
    Units: Participants
    0
    0
    0
    1
    1
    Notes
    [2] - Probability of DLT rate in [0.16, 0.33) = 0.081; in [0.33,1] = 0.
    [3] - Probability of DLT rate in [0.16, 0.33) = 0.028; in [0.33,1] = 0.
    [4] - Probability of DLT rate in [0.16, 0.33) = 0.012; in [0.33,1] = 0.
    No statistical analyses for this end point

    Primary: Phase I: Maximum Tolerated Dose (MTD) of BI 836858 in combination with decitabine

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    End point title
    		 Phase I: Maximum Tolerated Dose (MTD) of BI 836858 in combination with decitabine [5]
    End point description
    The MTD of BI 836858 in combination with decitabine was estimated after the dose escalation part of the trial obtaining on the basis of DLTs observed during the first treatment cycle. However, for those patients who received more than one cycle of the combination treatment, all adverse events that constitute a DLT will be considered for re-estimation of the MTD based on the Bayesian logistic regression model (BLRM). MTD is defined as the highest dose of BI 836858 (in combination with decitabine) with less than 25% risk of the true DLT rate being above 33% during the MTD evaluation period. MTD evaluable set: All subjects who were entered, treated and completed first cycle of planned treatment or subjects received at least 2 doses of BI 836858 due to BI 836858-related toxicity but not replaced. 99999 = not applicable value. No formal MTD was determined due to no DLTs were reported during dose escalation and only 2 DLTs were observed in the extension phase.
    End point type
    Primary
    End point timeframe
    From first drug administration until end of treatment, up to 941 days.
    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: Endpoint has been analyzed descriptively.
    End point values
    		 Phase I: BI 836858 + decitabine
    Number of subjects analysed
    35
    Units: milligram
    99999
    No statistical analyses for this end point

    Secondary: Phase 1: Number of patients with objective response (CR + CRi)

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    End point title
    		 Phase 1: Number of patients with objective response (CR + CRi)
    End point description
    Number of patients with objective response (Complete remission (CR) + complete remission with incomplete remission (CRi)). CR was defined as bone marrow (BM) blasts < 5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count > 1.0 x 109/L [1,000/μL]; platelet count > 100 x 109/L [100,000/μL]; independence of red blood cells transfusions (no transfusion for 1 week prior to the assessment). No minimum duration of response is required. CRi was defined as all CR criteria except for residual neutropenia (< 1.0 x 109/L [1,000/μL]) or thrombocytopenia (< 100 x 109/L [100,000/μL]). Treated set: All subjects who were documented to have received at least one dose of trial medication.
    End point type
    Secondary
    End point timeframe
    From start of treatment until the earliest of progression, death or end of trial, up to 971 days.
    End point values
    		 Phase I dose escalation: BI 836858 20 mg + decitabine Phase I dose escalation: BI 836858 40 mg + decitabine Phase I dose escalation: BI 836858 80 mg + decitabine Phase I Extension A: BI 836858 80 mg + decitabine Phase I Extension B: BI 836858 80 mg + decitabine
    Number of subjects analysed
    4
    3
    9
    15
    18
    Units: Participants
        Objective response (CR + CRi)
    2
    0
    6
    7
    4
        Complete remission (CR)
    1
    0
    1
    3
    3
        Complete remission with incomplete recovery (CRi)
    1
    0
    5
    4
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first administration of trial medication until 30 days of residual effect period after the last administration of trial medication, up to 971 days.
    Adverse event reporting additional description
    Treated set: All subjects who were documented to have received at least one dose of trial medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Phase I dose escalation: BI 836858 20 mg + decitabine
    Reporting group description
    		 20 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Reporting group title
    Phase I dose escalation: BI 836858 40 mg + decitabine
    Reporting group description
    		 40 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Reporting group title
    Phase I Extension B: BI 836858 80 mg + decitabine
    Reporting group description
    		 80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 5 consecutive days (standard treatment) from Day 1 to 5 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Reporting group title
    Phase I Extension A: BI 836858 80 mg + decitabine
    Reporting group description
    		 80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Reporting group title
    Phase I dose escalation: BI 836858 80 mg + decitabine
    Reporting group description
    		 80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL).

    Serious adverse events
    		 Phase I dose escalation: BI 836858 20 mg + decitabine Phase I dose escalation: BI 836858 40 mg + decitabine Phase I Extension B: BI 836858 80 mg + decitabine Phase I Extension A: BI 836858 80 mg + decitabine Phase I dose escalation: BI 836858 80 mg + decitabine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    3 / 3 (100.00%)
    17 / 18 (94.44%)
    14 / 15 (93.33%)
    8 / 9 (88.89%)
         number of deaths (all causes)
    3
    2
    13
    11
    5
         number of deaths resulting from adverse events
    0
    1
    6
    5
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    3 / 4 (75.00%)
    1 / 3 (33.33%)
    5 / 18 (27.78%)
    5 / 15 (33.33%)
    2 / 9 (22.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 7
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 1
    0 / 1
    Acute myeloid leukaemia recurrent
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic neoplasm
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    3 / 15 (20.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood fibrinogen decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglossal nerve paresis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial nerve disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    White blood cell disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 3 (66.67%)
    5 / 18 (27.78%)
    5 / 15 (33.33%)
    5 / 9 (55.56%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 3
    4 / 10
    4 / 9
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    2 / 15 (13.33%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    2 / 9 (22.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac valve abscess
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 3 (66.67%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    3 / 18 (16.67%)
    2 / 15 (13.33%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 5
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    Pneumonia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    4 / 18 (22.22%)
    2 / 15 (13.33%)
    3 / 9 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 10
    0 / 3
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Septic shock
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase I dose escalation: BI 836858 20 mg + decitabine Phase I dose escalation: BI 836858 40 mg + decitabine Phase I Extension B: BI 836858 80 mg + decitabine Phase I Extension A: BI 836858 80 mg + decitabine Phase I dose escalation: BI 836858 80 mg + decitabine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    3 / 3 (100.00%)
    18 / 18 (100.00%)
    15 / 15 (100.00%)
    9 / 9 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anogenital warts
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Flushing
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Haematoma
         subjects affected / exposed
    3 / 4 (75.00%)
    0 / 3 (0.00%)
    3 / 18 (16.67%)
    2 / 15 (13.33%)
    1 / 9 (11.11%)
         occurrences all number
    5
    0
    5
    2
    1
    Hypertension
         subjects affected / exposed
    3 / 4 (75.00%)
    2 / 3 (66.67%)
    0 / 18 (0.00%)
    4 / 15 (26.67%)
    3 / 9 (33.33%)
         occurrences all number
    6
    3
    0
    4
    3
    Hypotension
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    2 / 18 (11.11%)
    2 / 15 (13.33%)
    2 / 9 (22.22%)
         occurrences all number
    1
    3
    2
    2
    2
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Phlebitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Superficial vein thrombosis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Thrombophlebitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    0
    0
    2
    Venous thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Face oedema
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Chills
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 3 (66.67%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    2 / 9 (22.22%)
         occurrences all number
    2
    2
    0
    1
    2
    Asthenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
    3 / 15 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    6
    3
    0
    Catheter site pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    0
    1
    Catheter site thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Chest discomfort
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Chest pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    1
    0
    1
    Fatigue
         subjects affected / exposed
    3 / 4 (75.00%)
    2 / 3 (66.67%)
    1 / 18 (5.56%)
    2 / 15 (13.33%)
    3 / 9 (33.33%)
         occurrences all number
    5
    6
    1
    3
    3
    Gait disturbance
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    1
    Treatment noncompliance
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Implant site pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Inflammation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Injection site reaction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Localised oedema
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    0
    0
    1
    Malaise
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Mucosal inflammation
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    4 / 18 (22.22%)
    3 / 15 (20.00%)
    3 / 9 (33.33%)
         occurrences all number
    1
    2
    7
    5
    3
    Oedema peripheral
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 3 (33.33%)
    6 / 18 (33.33%)
    7 / 15 (46.67%)
    4 / 9 (44.44%)
         occurrences all number
    4
    3
    10
    9
    5
    Pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    1
    1
    Peripheral swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Puncture site pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    3 / 4 (75.00%)
    1 / 3 (33.33%)
    4 / 18 (22.22%)
    4 / 15 (26.67%)
    2 / 9 (22.22%)
         occurrences all number
    4
    3
    8
    4
    5
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    General physical health deterioration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
    2 / 15 (13.33%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    Vessel puncture site pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Vessel puncture site swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Illness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    2 / 18 (11.11%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Vulvovaginal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Penile haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    0
    1
    2
    Pharyngeal erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    3 / 4 (75.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    2 / 9 (22.22%)
         occurrences all number
    3
    0
    1
    1
    2
    Nasal dryness
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    0
    0
    1
    Lung infiltration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Hypoxia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Hiccups
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 3 (0.00%)
    4 / 18 (22.22%)
    4 / 15 (26.67%)
    1 / 9 (11.11%)
         occurrences all number
    3
    0
    5
    4
    1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    0
    1
    Dyspnoea
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 3 (66.67%)
    2 / 18 (11.11%)
    0 / 15 (0.00%)
    3 / 9 (33.33%)
         occurrences all number
    7
    5
    2
    0
    5
    Cough
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
    0 / 15 (0.00%)
    6 / 9 (66.67%)
         occurrences all number
    1
    0
    6
    0
    8
    Atelectasis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Pleurisy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Tachypnoea
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Pulmonary pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    2
    Confusional state
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    2 / 15 (13.33%)
    2 / 9 (22.22%)
         occurrences all number
    1
    0
    0
    2
    2
    Depression
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    1
    1
    Disorientation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hallucination
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    3 / 18 (16.67%)
    1 / 15 (6.67%)
    2 / 9 (22.22%)
         occurrences all number
    1
    0
    3
    1
    2
    Nervousness
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Sleep disorder
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    0
    1
    Restlessness
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    0
    1
    1
    Persistent depressive disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Depressed mood
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Adjustment disorder with depressed mood
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    3 / 15 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    5
    5
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    2 / 15 (13.33%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    1
    6
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    4
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    3
    1
    1
    1
    0
    Blood fibrinogen decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Blood potassium decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    Blood sodium increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Blood urea increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Blood uric acid increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    2 / 9 (22.22%)
         occurrences all number
    0
    1
    1
    2
    3
    Cortisol decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    2
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
    3 / 15 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    7
    10
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Blood calcium decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    5
    0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    2 / 18 (11.11%)
    2 / 15 (13.33%)
    1 / 9 (11.11%)
         occurrences all number
    2
    8
    33
    14
    19
    Platelet count decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 3 (66.67%)
    5 / 18 (27.78%)
    3 / 15 (20.00%)
    4 / 9 (44.44%)
         occurrences all number
    7
    6
    21
    16
    62
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    1
    1
    Prothrombin time shortened
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Transaminases increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Weight increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 3 (66.67%)
    5 / 18 (27.78%)
    2 / 15 (13.33%)
    3 / 9 (33.33%)
         occurrences all number
    1
    3
    36
    18
    19
    White blood cell count increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Injury, poisoning and procedural complications
    Transplantation complication
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Transfusion reaction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    2
    Subcutaneous haematoma
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    Skin laceration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Skin injury
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Refractoriness to platelet transfusion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Procedural pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    0
    1
    1
    Infusion related reaction
         subjects affected / exposed
    3 / 4 (75.00%)
    3 / 3 (100.00%)
    11 / 18 (61.11%)
    8 / 15 (53.33%)
    4 / 9 (44.44%)
         occurrences all number
    17
    6
    19
    21
    33
    Fall
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 3 (0.00%)
    4 / 18 (22.22%)
    2 / 15 (13.33%)
    1 / 9 (11.11%)
         occurrences all number
    4
    0
    12
    4
    1
    Contusion
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    2
    Atrioventricular block
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Bradycardia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    0
    1
    Cardiovascular disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Mitral valve incompetence
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
    0 / 15 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    2
    0
    2
    0
    2
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Nervous system disorders
    Hypoaesthesia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Facial paralysis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Dizziness
         subjects affected / exposed
    3 / 4 (75.00%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    2 / 9 (22.22%)
         occurrences all number
    8
    4
    1
    1
    2
    Balance disorder
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 3 (0.00%)
    3 / 18 (16.67%)
    4 / 15 (26.67%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    3
    5
    0
    Presyncope
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Restless legs syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Syncope
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    3 / 18 (16.67%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    5
    0
    0
    Tremor
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hypogeusia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Hypoglossal nerve paresis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Acquired antithrombin III deficiency
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Anaemia
         subjects affected / exposed
    3 / 4 (75.00%)
    1 / 3 (33.33%)
    6 / 18 (33.33%)
    4 / 15 (26.67%)
    6 / 9 (66.67%)
         occurrences all number
    10
    3
    63
    23
    54
    Leukocytosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Thrombocytosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Neutropenia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    2 / 18 (11.11%)
    3 / 15 (20.00%)
    3 / 9 (33.33%)
         occurrences all number
    5
    2
    30
    8
    10
    Thrombocytopenia
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    2 / 15 (13.33%)
    2 / 9 (22.22%)
         occurrences all number
    3
    0
    32
    8
    13
    Leukopenia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Thrombotic microangiopathy
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    1
    1
    Vertigo
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    1
    1
    2
    Vestibular disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Dry eye
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    0
    1
    Eye haematoma
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Eye haemorrhage
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Eyelid bleeding
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Eyelid oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Macular oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Vitreous floaters
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Anal fissure
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Abdominal discomfort
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Abdominal distension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 3 (33.33%)
    2 / 18 (11.11%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    3
    1
    4
    2
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 3 (66.67%)
    2 / 18 (11.11%)
    2 / 15 (13.33%)
    0 / 9 (0.00%)
         occurrences all number
    1
    2
    5
    3
    0
    Anal incontinence
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    0
    1
    1
    Nausea
         subjects affected / exposed
    3 / 4 (75.00%)
    2 / 3 (66.67%)
    1 / 18 (5.56%)
    6 / 15 (40.00%)
    2 / 9 (22.22%)
         occurrences all number
    8
    6
    3
    7
    4
    Aphthous ulcer
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Constipation
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 3 (66.67%)
    6 / 18 (33.33%)
    7 / 15 (46.67%)
    4 / 9 (44.44%)
         occurrences all number
    2
    3
    9
    7
    7
    Diarrhoea
         subjects affected / exposed
    3 / 4 (75.00%)
    1 / 3 (33.33%)
    2 / 18 (11.11%)
    4 / 15 (26.67%)
    2 / 9 (22.22%)
         occurrences all number
    12
    1
    3
    7
    7
    Dyspepsia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Dysphagia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Glossodynia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Haematochezia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Haemorrhoids
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    1
    1
    0
    Mouth haemorrhage
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Anal inflammation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Odynophagia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    2 / 15 (13.33%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    Oral discomfort
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Proctalgia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    1
    1
    Proctitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Stomatitis
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    2 / 18 (11.11%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    1
    2
    0
    0
    Toothache
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    2 / 15 (13.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    0
    2
    1
    Vomiting
         subjects affected / exposed
    3 / 4 (75.00%)
    3 / 3 (100.00%)
    2 / 18 (11.11%)
    5 / 15 (33.33%)
    0 / 9 (0.00%)
         occurrences all number
    4
    5
    3
    7
    0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Hepatotoxicity
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    Decubitus ulcer
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Erythema
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    0
    1
    3
    Petechiae
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    2 / 15 (13.33%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Pruritus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    Purpura
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Rash
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    3 / 18 (16.67%)
    3 / 15 (20.00%)
    3 / 9 (33.33%)
         occurrences all number
    1
    1
    4
    4
    4
    Skin lesion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Urethral haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Renal haematoma
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Renal failure
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Oliguria
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Nocturia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Micturition urgency
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Incontinence
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Haematuria
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Dysuria
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    2 / 18 (11.11%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    3
    1
    0
    Back pain
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
    3 / 15 (20.00%)
    2 / 9 (22.22%)
         occurrences all number
    2
    1
    2
    5
    2
    Arthralgia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    4 / 15 (26.67%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    4
    1
    Flank pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Spinal pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    0
    2
    0
    4
    Osteoporosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Myopathy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Muscular weakness
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    1 / 9 (11.11%)
         occurrences all number
    2
    1
    0
    1
    1
    Muscle spasms
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    0
    0
    3
    Joint swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Bronchitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Cerebral fungal infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Device related infection
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    1
    0
    2
    Ecthyma
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Endocarditis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Enterococcal infection
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
    2 / 15 (13.33%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    1
    2
    1
    Herpes simplex viraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Intervertebral discitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    2
    1
    1
    1
    0
    Lip infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Skin candida
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    3 / 18 (16.67%)
    1 / 15 (6.67%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    3
    1
    1
    Otitis media
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Oral infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 3 (33.33%)
    2 / 18 (11.11%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    1
    2
    0
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    1
    0
    0
    0
    2
    Nail infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Mucosal infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Localised infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Vaginal infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Urinary tract infection enterococcal
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    COVID-19
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Cellulitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Decreased appetite
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 3 (66.67%)
    3 / 18 (16.67%)
    2 / 15 (13.33%)
    3 / 9 (33.33%)
         occurrences all number
    7
    6
    3
    2
    4
    Dehydration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Diabetic metabolic decompensation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Folate deficiency
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Gout
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    6
    0
    1
    0
    0
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Hypokalaemia
         subjects affected / exposed
    3 / 4 (75.00%)
    1 / 3 (33.33%)
    4 / 18 (22.22%)
    1 / 15 (6.67%)
    3 / 9 (33.33%)
         occurrences all number
    4
    1
    6
    1
    6
    Hypocalcaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    3 / 15 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    3
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Hypervolaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    Hyperphosphataemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Mar 2016
    The key changes to the original Clinical Trial Protocol (CTP) specified by Amendment 1 comprised clarifications and edits requested by the German Regulatory Authority.
    09 Jun 2016
    Changes specified by Amendment 2 comprised logistical or administrative aspects only.
    16 Dec 2016
    Changes specified by Amendment 3 comprised clarifications, corrections, further specification of dosing, and adjustments to the expected recruitment rate.
    06 Jul 2017
    Changes specified by Amendment 4 comprised clarifications, corrections, and addition of further Pharmacokinetic (PK), ADA (Anti-drug antibody), and biomarker sampling time points.
    22 Jun 2018
    Preliminary biomarker and Pharmacokinetic (PK) /Pharmacodynamic (PD) data from patients treated in 80 mg cohorts (Phase I Dose Escalation Cohort as well as Phase I Extension Cohort A) indicated that 80 mg might not be the optimal Recommended Phase II Dose (RP2D). It was therefore decided by the SMC and the Sponsor to include the option for further Dose Escalation cohorts to allow testing of higher doses of BI 836858 prior to starting the Phase II part of the trial (this further dose escalation was not performed due to trial termination). The benefit risk-assessment was also updated with new safety information and associated safety measures. Other changes specified by Amendment 5 comprised clarifications and corrections.
    21 Aug 2019
    After the Sponsor’s decision to discontinue development of BI 836858 and to stop further recruitment of patients into study 1315.2, trial participants still on treatment and with clinical benefit from BI 836858 and decitabine were offered to stay on treatment in this trial. With the aim to minimize the burden for trial participants, the mandatory protocol procedures were reduced for all patients in treatment cycles >7 (this included all 3 patients with ongoing treatment).

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Sponsor stopped development of the study drug before Phase II start. Phase II was not performed.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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