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    Clinical Trial Results:
    A Phase Ib Study of Eltrombopag and Azacitidine in Patients with High Risk Myelodysplastic Syndromes and Related Disorders

    Summary
    EudraCT number
    		 2013-000341-39
    Trial protocol
    		 GB  
    Global end of trial date
    07 Sep 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Sep 2021
    First version publication date
    23 Sep 2021
    Other versions
    Summary report(s)
    		 ELASTIC End of Trial Clinical Trial Summary Report

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RG_12-268
    Additional study identifiers
    ISRCTN number
    		 ISRCTN05858391
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Birmingham
    Sponsor organisation address
    Edgbaston, Birmingham, United Kingdom, B15 2TT
    Public contact
    Sonia Fox, University of Birmingham, +44 01214143289, elastic@trials.bham.ac.uk
    Scientific contact
    Sonia Fox, University of Birmingham, +44 01214143289, elastic@trials.bham.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Aug 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of eltrombopag (an oral thrombopoietin receptor agonist) in combination with azacitidine (the standard therapy) in patients with advanced myelodysplastic syndromes and related diseases by establishing the Maximum Tolerated Dose (MTD) and Optimum Biological Dose (OBD).
    Protection of trial subjects
    The Independent Safety Monitoring Committee (ISMC) met after every cohort to evaluate safety data and consider if the next cohort should be opened.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 31
    Worldwide total number of subjects
    31
    EEA total number of subjects
    0
    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)
    0
    From 65 to 84 years
    25
    85 years and over
    6

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This trial recruited patients with IPSS INT-2/high-risk Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukaemia (CMML-2) and Acute Myeloid Leukaemia (AML) with less than 30% blasts.

    Pre-assignment
    Screening details
    		 The following tests were performed during screening to ensure the patient was eligible and fit enough to participate in the trial: physical exam (including height, weight, blood pressure and spleen measurement), blood tests, ECG and a pregnancy test (if appropriate).

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 (25mg eltrombopag)
    Arm description
    		 Patients in this cohort received eltrombopag at their allocated dose (25mg) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles (each of 4 weeks duration). Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule).
    Arm type
    		 cohort

    Investigational medicinal product name
    eltrombopag
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received eltrombopag at their allocated dose (see below) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles, each of 4 weeks duration (with pre-defined delays up to a total of 6 weeks duration per cycle). Cohort 1: 25mg OD Cohort 2: 50mg OD Cohort 3: 100mg OD Cohort 4: 200mg OD Cohort 5: 300mg OD Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment.

    Investigational medicinal product name
    azacitidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for cutaneous solution
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients received a minimum of 3 cycles of azacitidine, starting at week 2 (day 8). Patients could receive up to 6 cycles of azacitidine whilst on trial. Treatment with azacitidine was continued as long as the patient continued to benefit or until disease progression as per its licences, at the discretion of the treating clinician. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule).

    Arm title
    		 Cohort 2 (50mg eltrombopag)
    Arm description
    		 Patients in this cohort received eltrombopag at their allocated dose (50mg) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles (each of 4 weeks duration). Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule)
    Arm type
    		 cohort

    Investigational medicinal product name
    eltrombopag
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received eltrombopag at their allocated dose (see below) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles, each of 4 weeks duration (with pre-defined delays up to a total of 6 weeks duration per cycle). Cohort 1: 25mg OD Cohort 2: 50mg OD Cohort 3: 100mg OD Cohort 4: 200mg OD Cohort 5: 300mg OD Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment.

    Investigational medicinal product name
    azacitidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for cutaneous solution
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients received a minimum of 3 cycles of azacitidine, starting at week 2 (day 8). Patients could receive up to 6 cycles of azacitidine whilst on trial. Treatment with azacitidine was continued as long as the patient continued to benefit or until disease progression as per its licences, at the discretion of the treating clinician. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule).

    Arm title
    		 Cohort 3 (100mg eltrombopag)
    Arm description
    		 Patients in this cohort received eltrombopag at their allocated dose (100mg) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles (each of 4 weeks duration). Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule)
    Arm type
    		 cohort

    Investigational medicinal product name
    azacitidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for cutaneous solution
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients received a minimum of 3 cycles of azacitidine, starting at week 2 (day 8). Patients could receive up to 6 cycles of azacitidine whilst on trial. Treatment with azacitidine was continued as long as the patient continued to benefit or until disease progression as per its licences, at the discretion of the treating clinician. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule).

    Investigational medicinal product name
    eltrombopag
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received eltrombopag at their allocated dose (see below) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles, each of 4 weeks duration (with pre-defined delays up to a total of 6 weeks duration per cycle). Cohort 1: 25mg OD Cohort 2: 50mg OD Cohort 3: 100mg OD Cohort 4: 200mg OD Cohort 5: 300mg OD Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment.

    Arm title
    		 Cohort 4 (200mg eltrombopag)
    Arm description
    		 Patients in this cohort received eltrombopag at their allocated dose (200mg) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles (each of 4 weeks duration). Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule)
    Arm type
    		 cohort

    Investigational medicinal product name
    eltrombopag
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received eltrombopag at their allocated dose (see below) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles, each of 4 weeks duration (with pre-defined delays up to a total of 6 weeks duration per cycle). Cohort 1: 25mg OD Cohort 2: 50mg OD Cohort 3: 100mg OD Cohort 4: 200mg OD Cohort 5: 300mg OD Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment.

    Investigational medicinal product name
    azacitidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for cutaneous solution
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients received a minimum of 3 cycles of azacitidine, starting at week 2 (day 8). Patients could receive up to 6 cycles of azacitidine whilst on trial. Treatment with azacitidine was continued as long as the patient continued to benefit or until disease progression as per its licences, at the discretion of the treating clinician. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule).

    Arm title
    		 Cohort 5 (300mg eltrombopag)
    Arm description
    		 Patients in this cohort received eltrombopag at their allocated dose (300mg) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles (each of 4 weeks duration). Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule)
    Arm type
    		 cohort

    Investigational medicinal product name
    eltrombopag
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received eltrombopag at their allocated dose (see below) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles, each of 4 weeks duration (with pre-defined delays up to a total of 6 weeks duration per cycle). Cohort 1: 25mg OD Cohort 2: 50mg OD Cohort 3: 100mg OD Cohort 4: 200mg OD Cohort 5: 300mg OD Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment.

    Investigational medicinal product name
    azacitidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for cutaneous solution
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients received a minimum of 3 cycles of azacitidine, starting at week 2 (day 8). Patients could receive up to 6 cycles of azacitidine whilst on trial. Treatment with azacitidine was continued as long as the patient continued to benefit or until disease progression as per its licences, at the discretion of the treating clinician. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule).

    Number of subjects in period 1
    		Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Started
    5
    3
    4
    4
    15
    Completed
    1
    2
    3
    2
    9
    Not completed
    4
    1
    1
    2
    6
         Adverse event, serious fatal
    -
    -
    -
    -
    1
         Treatment discontinuation
    -
    -
    1
    -
    -
         Disease progression
    -
    -
    -
    -
    1
         Toxicity
    2
    -
    -
    -
    -
         Died
    2
    1
    -
    2
    1
         Other toxicity
    -
    -
    -
    -
    3

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1 (25mg eltrombopag)
    Reporting group description
    		 Patients in this cohort received eltrombopag at their allocated dose (25mg) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles (each of 4 weeks duration). Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule).

    Reporting group title
    Cohort 2 (50mg eltrombopag)
    Reporting group description
    		 Patients in this cohort received eltrombopag at their allocated dose (50mg) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles (each of 4 weeks duration). Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule)

    Reporting group title
    Cohort 3 (100mg eltrombopag)
    Reporting group description
    		 Patients in this cohort received eltrombopag at their allocated dose (100mg) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles (each of 4 weeks duration). Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule)

    Reporting group title
    Cohort 4 (200mg eltrombopag)
    Reporting group description
    		 Patients in this cohort received eltrombopag at their allocated dose (200mg) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles (each of 4 weeks duration). Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule)

    Reporting group title
    Cohort 5 (300mg eltrombopag)
    Reporting group description
    		 Patients in this cohort received eltrombopag at their allocated dose (300mg) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles (each of 4 weeks duration). Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule)

    Reporting group values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag) Total
    Number of subjects
    		 5 3 4 4 15 31
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 74 (73 to 76) 80 (62 to 81) 72.5 (71 to 81) 69.5 (63 to 79) 75 (62 to 86) -
    Gender categorical
    Units: Subjects
        Female
    		 1 1 1 1 5 9
        Male
    		 4 2 3 3 10 22
    ECOG Performance Status
    Units: Subjects
        PS 0
    		 2 3 3 2 4 14
        PS 1
    		 2 0 1 2 6 11
        Not known
    		 0 0 0 0 4 4
        Missing
    		 1 0 0 0 1 2
    Spleen Assessment
    Units: Subjects
        Palpable
    		 1 0 1 0 0 2
        Not palpable
    		 4 3 3 2 10 22
        Not known
    		 0 0 0 0 3 3
        Not performed
    		 0 0 0 2 1 3
        Missing
    		 0 0 0 0 1 1
    Bone Marrow Cellularity
    Units: Subjects
        Hypocellular
    		 0 2 1 2 3 8
        Normal
    		 0 0 2 0 2 4
        Hypercellular
    		 3 1 1 2 9 16
        N/A
    		 2 0 0 0 0 2
        Missing
    		 0 0 0 0 1 1
    Bone marrow fibrosis grade
    Units: Subjects
        Grade 1
    		 2 1 1 1 6 11
        Grade 2
    		 0 0 1 0 1 2
        Grade 3
    		 0 0 0 0 1 1
        Grade 4
    		 0 0 0 1 0 1
        Missing
    		 3 2 2 2 7 16
    Karyotype
    Units: Subjects
        14/20 cells examined showed an abnormal hyperdiplo
    		 0 0 0 0 1 1
        43, XY-5add(6)(q13)-7-18-21+Mar(6)45,X,-Y(24)
    		 0 0 0 0 1 1
        44, XY, -5, -7, +8, -2, add (17)(pl?3), add(19)(q1
    		 0 0 0 0 1 1
        44 45, XX, -4, -5, -6, -9, add (11) (p?), +2mar, i
    		 1 0 0 0 0 1
        45, XY, -7 [3]/45, XY, del (12) (p12PB)[7]/46,XY [
    		 0 0 1 0 0 1
        45, XY, inv [3] (q21q 26-2), -7[10]
    		 0 0 0 0 1 1
        45,XY-7[4] / 46,XY[16] - total 20 examined
    		 0 0 0 0 1 1
        46 X,Y in 32 cells (Normal)
    		 0 0 0 1 0 1
        46 XY (Normal Karyotype)
    		 0 0 1 0 0 1
        46, XX, inv (2) (p13q35), r (11) (p13q13) [18]/47,
    		 0 0 0 0 1 1
        46, XX[20]
    		 0 0 0 0 1 1
        46, XY, add (5)(p15), del (5) (q1?3q33), -12+mar [
    		 1 0 0 0 0 1
        46XY
    		 0 0 0 1 0 1
        47, XY, +8[16]/47, XY, del(7)(q22q34),+8[4]
    		 0 0 0 0 1 1
        47, xx, +8, del(12) (p11.2) [7] / 46, xx [3]
    		 0 0 0 0 1 1
        47xx, +8[9]/46,xx
    		 0 0 0 0 1 1
        48, XY, +8 [3] / 46, XY [17]
    		 0 0 0 0 1 1
        5q31 and 7q31 deletions detected
    		 0 0 0 1 0 1
        Abnormal karotype with del (20q)
    		 1 0 0 0 0 1
        Abnormal karyotype including del(5q)
    		 0 0 0 0 1 1
        Abnormal karyotype with del (6q) and monosomy 7 45
    		 0 1 0 0 0 1
        Complex/monosomal karotype
    		 0 0 0 1 0 1
        Failed
    		 1 0 0 0 0 1
        Missing
    		 0 0 0 0 1 1
        Normal
    		 0 1 1 0 0 2
        Normal karyotope
    		 0 1 0 0 1 2
        Normal karytope 46, xY [20]
    		 0 0 1 0 1 2
        Not known
    		 1 0 0 0 0 1
    Number of transfusions per patient
    Units: Subjects
        0 transfusions
    		 3 1 2 2 8 16
        1 transfusion
    		 0 0 0 1 2 3
        2 transfusions
    		 1 1 1 0 1 4
        3 transfusions
    		 0 1 1 1 2 5
        4 transfusions
    		 0 0 0 0 1 1
        5 transfusions
    		 1 0 0 0 0 1
        8 transfusions
    		 0 0 0 0 1 1
    Disease Type
    Units: Subjects
        AML
    		 2 0 1 0 2 5
        INT 2 MDS
    		 1 3 2 1 5 12
        High risk MDS
    		 1 0 1 3 7 12
        CMML-2
    		 1 0 0 0 0 1
        Missing
    		 0 0 0 0 1 1
    WHO Disease classification
    Units: Subjects
        Refractory anaemia with excess blasts 1-RAEB (1)
    		 1 1 1 2 2 7
        Refractory anaemia with excess blasts 2-RAEB (2)
    		 0 2 1 2 6 11
        Refractory cytopenia with multilinegae dysplasia -
    		 0 0 1 0 3 4
        CMML (2)
    		 1 0 0 0 0 1
        Myelodysplastic/myeloproliferative disorder, uncla
    		 0 0 0 0 1 1
        AML with myelodysplasia
    		 3 0 1 0 2 6
        Missing
    		 0 0 0 0 1 1
    Prothrombin Time
    Units: Seconds
        median (full range (min-max))
    		 11.9 (11.3 to 13.8) 11.8 (10.4 to 13.0) 11.9 (1.0 to 12.3) 12.5 (10.3 to 13.0) 13.7 (11.0 to 35.6) -
    Activated partial thrombplastin time (APPT)
    Units: seconds
        median (full range (min-max))
    		 31.6 (22.8 to 35.9) 32.7 (27.2 to 48.4) 26.1 (0.9 to 32.6) 27.6 (25.0 to 34.0) 29.3 (24.5 to 38.1) -
    Fibrinogen
    Units: mg/dL
        median (full range (min-max))
    		 3.7 (3.5 to 4.1) 2.8 (2.8 to 2.8) 0 (0 to 0) 4.0 (2.8 to 6.9) 4.3 (1.4 to 5.0) -
    D-dimer
    Units: ng/mL
        median (full range (min-max))
    		 504.0 (142.0 to 9999.0) 627.0 (284.0 to 2570.0) 383.0 (383.0 to 383.0) 735.0 (735.0 to 735.0) 285.0 (77.7 to 3183.0) -
    Fibrin degradation products (FDP)
    Units: mg/L
        median (full range (min-max))
    		 2.2 (2.2 to 2.2) 0 (0 to 0) 0 (0 to 0) 0 (0 to 0) 0 (0 to 0) -
    Systolic blood pressure
    Units: mm Hg
        median (full range (min-max))
    		 123.5 (118.0 to 153.0) 143.0 (104.0 to 145.0) 129.0 (105.0 to 148.0) 143.0 (139.0 to 158.0) 122.5 (102.0 to 178.0) -
    Diastolic blood pressure
    Units: mm Hg
        median (full range (min-max))
    		 63.0 (56.0 to 76.0) 63.0 (61.0 to 70.0) 64.0 (57.0 to 72.0) 74.5 (64.0 to 96.0) 72.5 (52.0 to 92.0) -
    Pulse
    Units: bpm
        median (full range (min-max))
    		 76.5 (66.0 to 89.0) 70.0 (42.0 to 84.0) 66.5 (54.0 to 80.0) 80.5 (59.0 to 105.0) 73.0 (56.0 to 90.0) -
    Height
    Units: meters
        median (full range (min-max))
    		 1.7 (1.6 to 1.8) 1.6 (1.5 to 1.7) 1.7 (1.6 to 1.8) 1.7 (1.5 to 1.9) 1.7 (1.2 to 1.8) -
    Weight
    Units: kg
        median (full range (min-max))
    		 73.5 (58.2 to 106.2) 55.0 (52.6 to 82.3) 78.6 (70.4 to 90.1) 90.4 (75.0 to 94.0) 76.3 (36.5 to 131.1) -
    Body surface area (BSA)
    Units: m2
        median (full range (min-max))
    		 1.9 (1.6 to 2.3) 1.6 (1.5 to 1.9) 1.9 (1.3 to 2.1) 1.9 (1.4 to 2.1) 1.9 (1.5 to 2.2) -
    Spleen size
    Units: cm (largest diameter)
        median (full range (min-max))
    		 0.0 (0.0 to 0.0) 0.0 (0.0 to 0.0) 0.0 (0.0 to 0.1) 0 (0.0 to 0.0) 0.0 (0.0 to 0.0) -
    Neutrophils
    Units: Pecentage
        median (full range (min-max))
    		 2.8 (2.8 to 2.8) 12.0 (12.0 to 12.0) 47.6 (31.8 to 63.4) 40.9 (34.0 to 629.6) 13.0 (1.1 to 41.7) -
    Lymphocytes
    Units: Percentage
        median (full range (min-max))
    		 2.3 (2.3 to 2.3) 52.0 (52.0 to 52.0) 26.7 (17.1 to 36.4) 40.9 (17.0 to 277.8) 35.4 (1.1 to 277.8) -
    Metamyelocytes
    Units: Percentage
        median (full range (min-max))
    		 2.8 (2.8 to 2.8) 2.0 (2.0 to 2.0) 0 (0.0 to 0.0) 4.0 (4.0 to 4.0) 0.0 (0.0 to 0.0) -
    Myeoloctyes
    Units: Percentage
        median (full range (min-max))
    		 0.9 (0.9 to 0.9) 9.0 (9.0 to 9.0) 0 (0 to 0.0) 4.0 (4.0 to 4.0) 0.0 (0.0 to 4.0) -
    Promyelocytes
    Units: Percentage
        median (full range (min-max))
    		 0.6 (0.6 to 0.6) 0 (0 to 0) 0 (0 to 0) 2.0 (2.0 to 2.0) 0.0 (0.0 to 0.0) -
    Monocytes
    Units: Percentage
        median (full range (min-max))
    		 0.2 (0.2 to 0.2) 23.0 (23.0 to 23.0) 23.2 (14.6 to 31.8) 13.0 (4.5 to 37.0) 4.0 (0.1 to 20.8) -
    Eosinophils
    Units: Percentage
        median (full range (min-max))
    		 0.0 (0.0 to 0.0) 0 (0 to 0) 2.1 (1.8 to 2.4) 1.9 (1.0 to 4.5) 0.2 (0.0 to 1.3) -
    Basophils
    Units: Percentage
        median (full range (min-max))
    		 0.0 (0.0 to 0.0) 0 (0 to 0) 0.0 (0.0 to 0.0) 1.0 (0.0 to 7.4) 0.0 (0.0 to 0.0) -
    Blasts
    Units: Percentage
        median (full range (min-max))
    		 1.0 (1.0 to 1.0) 1.0 (0.0 to 2.0) 0.0 (0.0 to 0.0) 2.0 (2.0 to 2.0) 0.0 (0.0 to 42.0) -
    Nucleated red blood cells
    Units: Percentage
        median (full range (min-max))
    		 0 (0 to 0) 0 (0 to 0) 0 (0 to ) 20.0 (20.0 to 20.0) 0.0 (0.0 to 0.0) -
    Haemoglobin
    Units: g/L
        median (full range (min-max))
    		 97.0 (74.0 to 111.0) 103.0 (100.0 to 118.0) 109.5 (85.0 to 117.0) 94.0 (80.0 to 119.0) 100.5 (80.0 to 122.0) -
    Platelets
    Units: 109/L
        median (full range (min-max))
    		 14.0 (9.0 to 57.0) 19.0 (18.0 to 72.0) 40.0 (27.0 to 72.0) 32.5 (12.0 to 118.0) 37.0 (13.0 to 88.0) -
    Mean cell volume
    Units: fL
        median (full range (min-max))
    		 91.0 (87.0 to 101.0) 100.0 (97.0 to 112.0) 98.5 (87.0 to 116.0) 96.0 (74.0 to 108.0) 95.0 (80.0 to 111.0) -
    Mean cell haemoglobin
    Units: pg
        median (full range (min-max))
    		 29.6 (29.3 to 36.3) 33.2 (29.7 to 40.6) 33.3 (29.4 to 38.6) 31.6 (22.6 to 36.0) 31.6 (26.9 to 37.8) -
    White blood cell count
    Units: 109/L
        median (full range (min-max))
    		 2.8 (0.9 to 9.6) 3.2 (1.7 to 3.6) 2.8 (1.1 to 82.2) 3.8 (1.7 to 10.1) 2.9 (1.1 to 6.7) -
    Neutrophils (ANC)
    Units: 109/L
        median (full range (min-max))
    		 0.8 (0.0 to 2.7) 1.2 (0.8 to 1.5) 0.6 (0.3 to 2.6) 2.1 (0.7 to 5.6) 0.5 (0.2 to 2.8) -
    Lymphocytes
    Units: 109/L
        median (full range (min-max))
    		 1.5 (0.6 to 2.3) 1.5 (0.8 to 1.8) 0.7 (0.7 to 0.8) 1.3 (0.9 to 1.9) 1.4 (0.4 to 3.0) -
    Monocytes
    Units: 109/L
        median (full range (min-max))
    		 0.1 (0.0 to 0.2) 0.1 (0.0 to 0.6) 0.3 (0.0 to 0.7) 0.1 (0.1 to 0.3) 0.1 (0.1 to 1.0) -
    Eosinophils
    Units: 109/L
        median (full range (min-max))
    		 0.0 (0.0 to 0.0) 0.0 (0.0 to 0.0) 0.0 (0.0 to 0.1) 0.0 (0.0 to 0.3) 0.0 (0.0 to 0.8) -
    Basophils
    Units: 109/L
        median (full range (min-max))
    		 0.0 (0.0 to 0.0) 0.0 (0.0 to 0.0) 0.0 (0.0 to 0.0) 0.0 (0.0 to 0.8) 0.0 (0.0 to 0.1) -
    Blasts (peripheral blood)
    Units: Percentage
        median (full range (min-max))
    		 0.5 (0.0 to 1.0) 0.0 (0.0 to 0.0) 0 (0.0 to 0.0) 0.0 (0.0 to 0.0) 6.0 (0.0 to 42.0) -
    Morphology
    Morphology blasts
    Units: Percentage
        median (full range (min-max))
    		 21.0 (12.0 to 26.0) 10.5 (8.0 to 13.0) 8.0 (4.0 to 21.0) 6.5 (2.0 to 19.0) 14.0 (3.0 to 47.0) -
    Immunophenotyping
    Baseline blasts
    Units: Percentage
        median (full range (min-max))
    		 6.5 (5.0 to 23.0) 11.0 (6.0 to 11.0) 3.0 (3.0 to 3.0) 26.0 (26.0 to 26.0) 10.5 (0.00 to 18.0) -
    Trephine
    baseline blasts
    Units: Percentage
        median (full range (min-max))
    		 20.0 (20.0 to 20.0) 5.0 (5.0 to 5.0) 10.0 (5.0 to 15.0) 0 (0 to 0) 13.0 (5.0 to 20.0) -
    Time from diagnosis
    Units: days
        median (full range (min-max))
    		 17 (0.0 to 47.0) 56 (30 to 808) 36 (23 to 49) 31 (10 to 3137) 49 (9 to 1645) -

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1 (25mg eltrombopag)
    Reporting group description
    		 Patients in this cohort received eltrombopag at their allocated dose (25mg) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles (each of 4 weeks duration). Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule).

    Reporting group title
    Cohort 2 (50mg eltrombopag)
    Reporting group description
    		 Patients in this cohort received eltrombopag at their allocated dose (50mg) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles (each of 4 weeks duration). Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule)

    Reporting group title
    Cohort 3 (100mg eltrombopag)
    Reporting group description
    		 Patients in this cohort received eltrombopag at their allocated dose (100mg) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles (each of 4 weeks duration). Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule)

    Reporting group title
    Cohort 4 (200mg eltrombopag)
    Reporting group description
    		 Patients in this cohort received eltrombopag at their allocated dose (200mg) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles (each of 4 weeks duration). Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule)

    Reporting group title
    Cohort 5 (300mg eltrombopag)
    Reporting group description
    		 Patients in this cohort received eltrombopag at their allocated dose (300mg) from day 1 (i.e. a week before cycle 1 of azacitidine) and continuously through the first two azacitidine cycles (each of 4 weeks duration). Patients were then given a third cycle of azacitidine alone to allow a period of ‘wash-out’ prior to bone marrow assessment. The dose of azacitidine was 75mg/m2 daily sub-cutaneous for 7 days (5 days on, 2 days off, 2 days on schedule)

    Primary: Number of Patients Experiencing a Dose Limiting Toxicity

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    End point title
    		 Number of Patients Experiencing a Dose Limiting Toxicity [1]
    End point description
    A DLT was defined by the following safety and tolerability parameters assessed using the NCI CTC Criteria v4: Progression of disease was not considered a DLT. However, a number of studies in this patient population have described disease progression in patients receiving TpoR agonists. In some cases there were transient blast percentage rises whilst in others there was true disease progression. The precise role of TpoR agonists in this is unclear. An AE deemed to be unrelated to Eltrombopag was not considered a DLT.
    End point type
    Primary
    End point timeframe
    Dose limiting toxicity (DLT) was defined by safety and tolerability parameters within 5 weeks (1 cycle of treatment).
    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: The protocol states all analyses will be descriptive. The primary outcome is the number of patients experiencing a dose limiting toxicity according to the protocol definition. This does not require formal statistical analysis.
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    3
    3
    3
    3
    3
    Units: patients
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Optimal Biological Dose

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    End point title
    		 Optimal Biological Dose
    End point description
    The Optimal Biological dose (OBD) of eltrombopag in combination with azacitidine was defined as the dose of eltrombopag, provided this is the MTD or less, which maintains a platelet count within the range 100-250 x 10-9/L immediately prior to azacitidine treatment. The number of patients that met the OBD definition for at least one time point is reported.
    End point type
    Secondary
    End point timeframe
    from the date at which patients began treatment until the date they stopped trial treatment.
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    5
    3
    4
    4
    15
    Units: Number of patients
    0
    1
    3
    1
    5
    No statistical analyses for this end point

    Secondary: Platelet Response (SPC criteria) at Cycle 1

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    End point title
    		 Platelet Response (SPC criteria) at Cycle 1
    End point description
    After cycles 1 and 2 of Azacitidine, response will be defined by the recovery of platelet count to nadir platelet count + (0.5 x [baseline count – nadir count]). Non- response will be defined as the failure to achieve this. Number of patients with a platelet response after cycle 1 is reported.
    End point type
    Secondary
    End point timeframe
    Platelet response was determined after completion of Cycle 1
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    5
    3
    4
    4
    15
    Units: patients
    2
    3
    3
    3
    11
    No statistical analyses for this end point

    Secondary: Platelet Response (SPC criteria) at Cycle 2

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    End point title
    		 Platelet Response (SPC criteria) at Cycle 2
    End point description
    After cycles 1 and 2 of Azacitidine, response will be defined by the recovery of platelet count to nadir platelet count + (0.5 x [baseline count – nadir count]). Non- response will be defined as the failure to achieve this. Number of patients with a platelet response after cycle 2 is reported.
    End point type
    Secondary
    End point timeframe
    Platelet response was determined after completion of Cycle 2.
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    5
    3
    4
    4
    15
    Units: Number of patients
    0
    3
    3
    2
    7
    No statistical analyses for this end point

    Secondary: Number of units of Platelet Transfusions

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    End point title
    		 Number of units of Platelet Transfusions
    End point description
    The number of units of platelet transfusions during treatment
    End point type
    Secondary
    End point timeframe
    Measured throughout the treatment period for each patient.
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    5
    3
    4
    4
    15
    Units: Number
        number (not applicable)
    38
    2
    41
    5
    84
    No statistical analyses for this end point

    Secondary: Number of red cell transfusions

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    End point title
    		 Number of red cell transfusions
    End point description
    Number of red cell transfusions given to patients within each cohort throughout their treatment.
    End point type
    Secondary
    End point timeframe
    Throughout the treatment period.
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    5
    3
    4
    4
    15
    Units: number
        arithmetic mean (full range (min-max))
    4.8 (0 to 8)
    2.3 (0 to 4)
    9.8 (0 to 16)
    0.8 (0 to 3)
    6.2 (0 to 22)
    No statistical analyses for this end point

    Secondary: WHO Bleeding assessments during treatment

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    End point title
    		 WHO Bleeding assessments during treatment
    End point description
    Bleeding events measured using the WHO Bleeding Scale during treatment
    End point type
    Secondary
    End point timeframe
    During the trial
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    1
    2
    2
    2
    5
    Units: Number
    number (not applicable)
        Event Grade 0
    2
    10
    9
    4
    8
        Event Grade 1
    2
    1
    3
    2
    1
        Event Grade 2
    0
    1
    1
    0
    2
        Event Grade 3
    0
    0
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Bone marrow blast percentage - Morphology - Cycle 1

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    End point title
    		 Bone marrow blast percentage - Morphology - Cycle 1
    End point description
    Morphology percentage blasts
    End point type
    Secondary
    End point timeframe
    Cycle 1
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    3
    2
    4
    3
    10
    Units: Number
        median (full range (min-max))
    26 (5 to 43)
    21 (15 to 27)
    14 (6 to 88)
    13 (9 to 20)
    9.5 (0 to 47.0)
    No statistical analyses for this end point

    Secondary: Bone marrow blast percentage - Immunophenotyping - Cycle 1

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    End point title
    		 Bone marrow blast percentage - Immunophenotyping - Cycle 1
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    3
    3
    2
    2
    8
    Units: numbers
        median (full range (min-max))
    13 (10 to 15)
    18 (12 to 19)
    37 (9 to 65)
    16 (11 to 21)
    9 (1 to 29)
    No statistical analyses for this end point

    Secondary: Bone marrow blast percentage - Trephine - Cycle 1

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    End point title
    		 Bone marrow blast percentage - Trephine - Cycle 1
    End point description
    Trephine Percentage
    End point type
    Secondary
    End point timeframe
    Cycle 1
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    0 [2]
    2
    3
    0 [3]
    4
    Units: Numbers
        median (full range (min-max))
    ( to )
    14 (10 to 18)
    24 (8 to 40)
    ( to )
    12.5 (10 to 50)
    Notes
    [2] - Trephine not assessed for any patients in this cohort
    [3] - No trephine blasts assessed in cohort 4 at cycle 1
    No statistical analyses for this end point

    Secondary: Haematological improvement

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    End point title
    		 Haematological improvement
    End point description
    Haematological response criteria Based on the CLINICAL APPLICATION AND PROPOSAL FOR MODIFICATION OF THE INTERNATIONAL WORKING GROUP (IWG) RESPONSE CRITERIA IN MYELODYSPLASIA
    End point type
    Secondary
    End point timeframe
    Across all cycles
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    5
    3
    4
    4
    15
    Units: number of patients
        Erythroid response
    0
    0
    0
    0
    1
        Platelet Response
    0
    1
    2
    1
    5
        Neutrophil response
    0
    1
    0
    0
    1
        Relapse/progression after HI
    0
    0
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Achievement of Platelet Response according to IWG Criteria - Cycle 1, week 1

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    End point title
    		 Achievement of Platelet Response according to IWG Criteria - Cycle 1, week 1
    End point description
    The IWG 2006 criteria. These define platelet response as an absolute increase of ≥ 30 × 109/L for patients starting with > 20 × 109/L platelets or increase from baseline < 20 × 109/L to > 20 × 109/L and by at least 100%. Criteria will be considered modified until week 8 as improvements will not be able to be classed as having lasted at least 8 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Week 1
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    1
    3
    4
    3
    14
    Units: Patients
        No
    1
    3
    4
    2
    12
        Yes
    0
    0
    0
    1
    2
    No statistical analyses for this end point

    Secondary: Achievement of Platelet Response according to IWG Criteria - Cycle 1, week 2

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    End point title
    		 Achievement of Platelet Response according to IWG Criteria - Cycle 1, week 2
    End point description
    The IWG 2006 criteria. These define platelet response as an absolute increase of ≥ 30 × 109/L for patients starting with > 20 × 109/L platelets or increase from baseline < 20 × 109/L to > 20 × 109/L and by at least 100%. Criteria will be considered modified until week 8 as improvements will not be able to be classed as having lasted at least 8 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 1, week 2
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    4
    3
    4
    3
    14
    Units: Patients
        No
    4
    2
    4
    2
    13
        Yes
    0
    1
    0
    1
    1
    No statistical analyses for this end point

    Secondary: Achievement of Platelet Response according to IWG Criteria - Cycle 1, week 3

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    End point title
    		 Achievement of Platelet Response according to IWG Criteria - Cycle 1, week 3
    End point description
    The IWG 2006 criteria. These define platelet response as an absolute increase of ≥ 30 × 109/L for patients starting with > 20 × 109/L platelets or increase from baseline < 20 × 109/L to > 20 × 109/L and by at least 100%. Criteria will be considered modified until week 8 as improvements will not be able to be classed as having lasted at least 8 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 1, week 3
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    4
    3
    4
    3
    14
    Units: Patients
        No
    4
    1
    4
    1
    13
        Yes
    0
    2
    0
    2
    1
    No statistical analyses for this end point

    Secondary: Achievement of Platelet Response according to IWG Criteria - Cycle 1, week 4

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    End point title
    		 Achievement of Platelet Response according to IWG Criteria - Cycle 1, week 4
    End point description
    The IWG 2006 criteria. These define platelet response as an absolute increase of ≥ 30 × 109/L for patients starting with > 20 × 109/L platelets or increase from baseline < 20 × 109/L to > 20 × 109/L and by at least 100%. Criteria will be considered modified until week 8 as improvements will not be able to be classed as having lasted at least 8 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 1, week 4
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    4
    3
    4
    3
    14
    Units: Patients
        No
    3
    2
    4
    2
    12
        Yes
    1
    1
    0
    1
    2
    No statistical analyses for this end point

    Secondary: Achievement of Platelet Response according to IWG Criteria - Cycle 1, week 5

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    End point title
    		 Achievement of Platelet Response according to IWG Criteria - Cycle 1, week 5
    End point description
    The IWG 2006 criteria. These define platelet response as an absolute increase of ≥ 30 × 109/L for patients starting with > 20 × 109/L platelets or increase from baseline < 20 × 109/L to > 20 × 109/L and by at least 100%. Criteria will be considered modified until week 8 as improvements will not be able to be classed as having lasted at least 8 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Week 5
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    3
    3
    4
    3
    14
    Units: Patients
        No
    2
    2
    2
    1
    8
        Yes
    1
    1
    2
    2
    6
    No statistical analyses for this end point

    Secondary: Achievement of Platelet Response according to IWG Criteria - Cycle 2, week 1

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    End point title
    		 Achievement of Platelet Response according to IWG Criteria - Cycle 2, week 1
    End point description
    The IWG 2006 criteria. These define platelet response as an absolute increase of ≥ 30 × 109/L for patients starting with > 20 × 109/L platelets or increase from baseline < 20 × 109/L to > 20 × 109/L and by at least 100%. Criteria will be considered modified until week 8 as improvements will not be able to be classed as having lasted at least 8 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 2, Week 1
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    2
    3
    4
    3
    12
    Units: Patients
        No
    2
    1
    2
    2
    6
        Yes
    0
    2
    2
    1
    6
    No statistical analyses for this end point

    Secondary: Achievement of Platelet Response according to IWG Criteria - Cycle 2, week 2

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    End point title
    		 Achievement of Platelet Response according to IWG Criteria - Cycle 2, week 2
    End point description
    The IWG 2006 criteria. These define platelet response as an absolute increase of ≥ 30 × 109/L for patients starting with > 20 × 109/L platelets or increase from baseline < 20 × 109/L to > 20 × 109/L and by at least 100%. Criteria will be considered modified until week 8 as improvements will not be able to be classed as having lasted at least 8 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 2, week 2
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    2
    3
    4
    2
    12
    Units: Patients
        No
    2
    0
    2
    1
    8
        Yes
    0
    3
    2
    1
    4
    No statistical analyses for this end point

    Secondary: Achievement of Platelet Response according to IWG Criteria - Cycle 2, week 3

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    End point title
    		 Achievement of Platelet Response according to IWG Criteria - Cycle 2, week 3
    End point description
    The IWG 2006 criteria. These define platelet response as an absolute increase of ≥ 30 × 109/L for patients starting with > 20 × 109/L platelets or increase from baseline < 20 × 109/L to > 20 × 109/L and by at least 100%. Criteria will be considered modified until week 8 as improvements will not be able to be classed as having lasted at least 8 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 2, week 3
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    1
    3
    4
    2
    11
    Units: Patients
        No
    1
    1
    2
    1
    7
        Yes
    0
    2
    2
    1
    4
    No statistical analyses for this end point

    Secondary: Achievement of Platelet Response according to IWG Criteria - Cycle 2, week 4

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    End point title
    		 Achievement of Platelet Response according to IWG Criteria - Cycle 2, week 4
    End point description
    The IWG 2006 criteria. These define platelet response as an absolute increase of ≥ 30 × 109/L for patients starting with > 20 × 109/L platelets or increase from baseline < 20 × 109/L to > 20 × 109/L and by at least 100%. Criteria will be considered modified until week 8 as improvements will not be able to be classed as having lasted at least 8 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 2, week 4
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    1
    3
    4
    2
    11
    Units: Patients
        No
    1
    0
    1
    1
    7
        Yes
    0
    3
    3
    1
    4
    No statistical analyses for this end point

    Secondary: Achievement of Platelet Response according to IWG Criteria - Cycle 3, week 1

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    End point title
    		 Achievement of Platelet Response according to IWG Criteria - Cycle 3, week 1
    End point description
    The IWG 2006 criteria. These define platelet response as an absolute increase of ≥ 30 × 109/L for patients starting with > 20 × 109/L platelets or increase from baseline < 20 × 109/L to > 20 × 109/L and by at least 100%. Criteria will be considered modified until week 8 as improvements will not be able to be classed as having lasted at least 8 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 3, week 1
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    1
    3
    4
    2
    11
    Units: Patients
        No
    1
    0
    1
    1
    5
        Yes
    0
    3
    3
    1
    6
    No statistical analyses for this end point

    Secondary: Achievement of Platelet Response according to IWG Criteria - Cycle 3, week 2

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    End point title
    		 Achievement of Platelet Response according to IWG Criteria - Cycle 3, week 2
    End point description
    The IWG 2006 criteria. These define platelet response as an absolute increase of ≥ 30 × 109/L for patients starting with > 20 × 109/L platelets or increase from baseline < 20 × 109/L to > 20 × 109/L and by at least 100%. Criteria will be considered modified until week 8 as improvements will not be able to be classed as having lasted at least 8 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 3, week 2
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    1
    3
    4
    2
    11
    Units: Patients
        No
    1
    0
    1
    1
    6
        Yes
    0
    3
    3
    1
    5
    No statistical analyses for this end point

    Secondary: Achievement of Platelet Response according to IWG Criteria - Cycle 3, week 3

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    End point title
    		 Achievement of Platelet Response according to IWG Criteria - Cycle 3, week 3
    End point description
    The IWG 2006 criteria. These define platelet response as an absolute increase of ≥ 30 × 109/L for patients starting with > 20 × 109/L platelets or increase from baseline < 20 × 109/L to > 20 × 109/L and by at least 100%. Criteria will be considered modified until week 8 as improvements will not be able to be classed as having lasted at least 8 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 3, week 3
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    1
    3
    4
    2
    11
    Units: Patients
        No
    1
    1
    1
    1
    7
        Yes
    0
    2
    3
    1
    4
    No statistical analyses for this end point

    Secondary: Achievement of Platelet Response according to IWG Criteria - Cycle 3, week 4

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    End point title
    		 Achievement of Platelet Response according to IWG Criteria - Cycle 3, week 4
    End point description
    The IWG 2006 criteria. These define platelet response as an absolute increase of ≥ 30 × 109/L for patients starting with > 20 × 109/L platelets or increase from baseline < 20 × 109/L to > 20 × 109/L and by at least 100%. Criteria will be considered modified until week 8 as improvements will not be able to be classed as having lasted at least 8 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 3, week 4
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    1
    3
    4
    2
    11
    Units: Patients
        No
    1
    1
    2
    1
    6
        Yes
    0
    2
    2
    1
    5
    No statistical analyses for this end point

    Secondary: Achievement of Platelet Response according to IWG Criteria - Cycle 4

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    End point title
    		 Achievement of Platelet Response according to IWG Criteria - Cycle 4
    End point description
    The IWG 2006 criteria. These define platelet response as an absolute increase of ≥ 30 × 109/L for patients starting with > 20 × 109/L platelets or increase from baseline < 20 × 109/L to > 20 × 109/L and by at least 100%. Criteria will be considered modified until week 8 as improvements will not be able to be classed as having lasted at least 8 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 4
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    1
    3
    3
    2
    11
    Units: Patients
        No
    1
    0
    1
    1
    3
        Yes
    0
    3
    2
    1
    8
    No statistical analyses for this end point

    Secondary: Achievement of Platelet Response according to IWG Criteria - Cycle 5

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    End point title
    		 Achievement of Platelet Response according to IWG Criteria - Cycle 5
    End point description
    The IWG 2006 criteria. These define platelet response as an absolute increase of ≥ 30 × 109/L for patients starting with > 20 × 109/L platelets or increase from baseline < 20 × 109/L to > 20 × 109/L and by at least 100%. Criteria will be considered modified until week 8 as improvements will not be able to be classed as having lasted at least 8 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 5
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    1
    3
    3
    2
    11
    Units: Patients
        No
    1
    1
    1
    1
    3
        Yes
    0
    2
    2
    1
    8
    No statistical analyses for this end point

    Secondary: Achievement of Platelet Response according to IWG Criteria - Cycle 6

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    End point title
    		 Achievement of Platelet Response according to IWG Criteria - Cycle 6
    End point description
    The IWG 2006 criteria. These define platelet response as an absolute increase of ≥ 30 × 109/L for patients starting with > 20 × 109/L platelets or increase from baseline < 20 × 109/L to > 20 × 109/L and by at least 100%. Criteria will be considered modified until week 8 as improvements will not be able to be classed as having lasted at least 8 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 6
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    1
    3
    3
    2
    9
    Units: Patients
        No
    1
    0
    2
    1
    4
        Yes
    0
    3
    1
    1
    5
    No statistical analyses for this end point

    Secondary: Activity of MDS treatment per IWG response criteria

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    End point title
    		 Activity of MDS treatment per IWG response criteria
    End point description
    Disease response at cycle 3 according to IWG response criteria
    End point type
    Secondary
    End point timeframe
    Cycle 3
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    5
    3
    4
    4
    15
    Units: Patients
        Complete Remission
    0
    0
    1
    0
    2
        Marrow CR
    0
    0
    2
    0
    2
        Partial Remission
    0
    1
    0
    0
    2
        Stable Disease
    0
    2
    1
    2
    4
        Disease Progression
    1
    0
    0
    0
    1
        Missing, no response assumed
    4
    0
    0
    2
    4
    No statistical analyses for this end point

    Secondary: Activity of MDS treatment per IWG response criteria

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    End point title
    		 Activity of MDS treatment per IWG response criteria
    End point description
    Disease Assessment according to IWG response criteria at Cycle 6
    End point type
    Secondary
    End point timeframe
    Cycle 6
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    5
    3
    4
    4
    15
    Units: Patients
        Complete Remission
    0
    1
    0
    0
    2
        Marrow CR
    0
    1
    0
    0
    3
        Partial remission
    0
    0
    1
    0
    1
        Stable disease
    0
    0
    1
    2
    2
        Disease progression
    1
    0
    1
    0
    0
        Missing, no response assumed
    4
    1
    1
    2
    7
    No statistical analyses for this end point

    Secondary: Bone marrow blast percentage - Morphology - Cycle 3

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    End point title
    		 Bone marrow blast percentage - Morphology - Cycle 3
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 3
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    1
    2
    3
    2
    8
    Units: percent
        median (full range (min-max))
    11 (11 to 11)
    3.5 (3 to 4)
    10 (1 to 11)
    15 (14 to 16)
    5 (0 to 49)
    No statistical analyses for this end point

    Secondary: Bone marrow blast percentage - Trephine - Cycle 3

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    End point title
    		 Bone marrow blast percentage - Trephine - Cycle 3
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 3
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    0 [4]
    2
    2
    0 [5]
    4
    Units: percent
        median (full range (min-max))
    ( to )
    5 (5 to 5)
    9 (8 to 10)
    ( to )
    5 (0 to 30)
    Notes
    [4] - Trephine not measured at cycle 3 for any patients in cohort 1
    [5] - No trephine assessments for this cohort at cycle 3
    No statistical analyses for this end point

    Secondary: Bone marrow blast percentage - Immunophenotyping - Cycle 3

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    End point title
    		 Bone marrow blast percentage - Immunophenotyping - Cycle 3
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 3
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    1
    3
    3
    1
    6
    Units: percent
        median (full range (min-max))
    12 (12 to 12)
    9 (4 to 15)
    11 (1 to 14)
    11 (11 to 11)
    0.5 (0 to 25)
    No statistical analyses for this end point

    Secondary: Bone marrow blast percentage - Morphology - Cycle 6

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    End point title
    		 Bone marrow blast percentage - Morphology - Cycle 6
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 6
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    0 [6]
    2
    2
    2
    5
    Units: percent
        median (full range (min-max))
    ( to )
    0 (0 to 0)
    38.5 (0 to 77)
    10 (1 to 19)
    3 (0 to 5)
    Notes
    [6] - No morphology assessments measured in this cohort at cycle 6
    No statistical analyses for this end point

    Secondary: Bone marrow blast percentage - Trephine - Cycle 6

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    End point title
    		 Bone marrow blast percentage - Trephine - Cycle 6
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 6
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    0 [7]
    2
    3
    1
    4
    Units: percent
        median (full range (min-max))
    ( to )
    2.5 (0 to 5)
    10 (5 to 70)
    10 (10 to 10)
    2.5 (0 to 5)
    Notes
    [7] - No trephines assessed for this cohort at cycle 6
    No statistical analyses for this end point

    Secondary: Bone marrow blast percentage - Immunophenotyping - Cycle 6

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    End point title
    		 Bone marrow blast percentage - Immunophenotyping - Cycle 6
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 6
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    1
    2
    2
    1
    5
    Units: percent
        median (full range (min-max))
    13 (13 to 13)
    2.5 (2 to 3)
    33.5 (4 to 63)
    9 (9 to 9)
    1 (0 to 3)
    No statistical analyses for this end point

    Secondary: Number of azacitidine cycles delayed per patient

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    End point title
    		 Number of azacitidine cycles delayed per patient
    End point description
    End point type
    Secondary
    End point timeframe
    During the treatment period
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    4
    3
    4
    3
    14
    Units: Number
    number (not applicable)
        0 cycles delayed
    4
    1
    3
    3
    8
        1 cycle delayed
    0
    2
    0
    0
    3
        2 cycles delayed
    0
    0
    1
    0
    3
    No statistical analyses for this end point

    Secondary: Length of azacitidine delays

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    End point title
    		 Length of azacitidine delays
    End point description
    End point type
    Secondary
    End point timeframe
    During Treatment
    End point values
    		 Cohort 1 (25mg eltrombopag) Cohort 2 (50mg eltrombopag) Cohort 3 (100mg eltrombopag) Cohort 4 (200mg eltrombopag) Cohort 5 (300mg eltrombopag)
    Number of subjects analysed
    4
    3
    4
    3
    14
    Units: Cycles delayed
    number (not applicable)
        No cycle delay
    12
    15
    21
    15
    56
        1 day delay
    0
    0
    0
    0
    3
        7 days delay
    0
    2
    0
    0
    1
        9 days delay
    0
    0
    0
    0
    1
        13 days delayed
    0
    0
    0
    0
    1
        21 days delayed
    0
    0
    0
    0
    1
        22 days delayed
    0
    0
    0
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were reported from the date of commencement of protocol defined treatment until 30 days after the administration of the last trial treatment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    All patients
    Reporting group description
    		 Whilst the de fined `safety population' is de fined as patients who received at least one dose of both treatments, the data presented here includes all patients registered to the trial for completeness.

    Serious adverse events
    		 All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 30 (83.33%)
         number of deaths (all causes)
    15
         number of deaths resulting from adverse events
    9
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - other
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences causally related to treatment / all
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Immune system disorders - other
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Cardiac disorders
    Left ventricular systolic dysfunction
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Heart failure
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Movements involuntary
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Intracranial haemorrhage
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    7 / 30 (23.33%)
         occurrences causally related to treatment / all
    8 / 8
         deaths causally related to treatment / all
    3 / 3
    Anaemia
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Middle ear inflammation
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastric haemorrhage
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders - other
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal and urinary disorders - other
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hematuria
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Infections and infestations - other
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 30 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    14 / 30 (46.67%)
         occurrences all number
    16
    Injection site reaction
         subjects affected / exposed
    11 / 30 (36.67%)
         occurrences all number
    12
    Pyrexia
         subjects affected / exposed
    9 / 30 (30.00%)
         occurrences all number
    10
    Edema limbs
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    5
    General disorders and administration site conditions - other
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    5
    Flu like symptoms
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    3
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Pain
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    7 / 30 (23.33%)
         occurrences all number
    11
    Epistaxis
         subjects affected / exposed
    9 / 30 (30.00%)
         occurrences all number
    12
    Respiratory, thoracic and mediastinal disorders - other
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    4
    Cough
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Pleural effusion
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Psychiatric disorders
    Confusion
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    4
    Insomnia
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    4
    Blood bilirubin increased
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    6
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    5
    Bruising
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Cardiac disorders
    Chest pain - cardiac
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Cardiac disorders - Other
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 30 (20.00%)
         occurrences all number
    6
    Headache
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    6
    Lethargy
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 30 (26.67%)
         occurrences all number
    23
    Febrile neutropenia
         subjects affected / exposed
    7 / 30 (23.33%)
         occurrences all number
    8
    Platelet count decreased
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    13
    Neutrophil count decreased
         subjects affected / exposed
    7 / 30 (23.33%)
         occurrences all number
    38
    Blood and lymphatic system disorders - Other
         subjects affected / exposed
    6 / 30 (20.00%)
         occurrences all number
    7
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    15 / 30 (50.00%)
         occurrences all number
    26
    Constipation
         subjects affected / exposed
    16 / 30 (53.33%)
         occurrences all number
    19
    Nausea
         subjects affected / exposed
    15 / 30 (50.00%)
         occurrences all number
    18
    Vomiting
         subjects affected / exposed
    9 / 30 (30.00%)
         occurrences all number
    10
    Abdominal pain
         subjects affected / exposed
    6 / 30 (20.00%)
         occurrences all number
    7
    Gastrointestinal disorders - other
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    5
    Oral hemorrhage
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders - other
         subjects affected / exposed
    6 / 30 (20.00%)
         occurrences all number
    8
    Pruritus
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    6
    Rash maculo-papular
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    7
    Dry skin
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Purpura
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Skin hyperpigmentation
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    3
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Hematuria
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    4
    Musculoskeletal and connective tissue disorders - other
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    4
    Arthralgia
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Infections and infestations
    Lung infection
         subjects affected / exposed
    8 / 30 (26.67%)
         occurrences all number
    9
    Sepsis
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    4
    Skin infection
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Upper respiratory infection
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Infections and infestations - other
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    7
    Lip infection
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Wound infection
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Hypokalemia
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    4
    Hypophosphatemia
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    5
    Anorexia nervosa
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jun 2015
    Update to eligibility criteria Update to definition of Dose Limiting Toxicity to specify the event must be at least possibly related to eltrombopag. Update to schedule of events - clarifications Update to trial personnel Update to registration phone number Clarification of allowed dose modifications Update to Adverse Event reporting - abnormal laboratory findings do not need to be reported unless they meet specific criteria. Update to CRF list Update to response assessment reporting to include Hematological Improvement according to IWG critera Update to archiving period Addition of Appendices 7 (Prohibited concomitant medication and 8 (IWG Response Criteria) Minor corrections and clarifications
    25 Apr 2016
    Update to trial personnel Update to registration phone number Update to Trial Treatment details (Eltrombopag only) - change from clinical trial stock to commercial supply. Update to definition of Dose Limiting Toxicity to exclude disease progression Update to Adverse Event reporting to include reporting of overdoses Clarification of Sample Collection Update to Data Collection to add Transfusion Form Minor corrections and clarifications

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

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