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    Clinical Trial Results:
    A longitudinal 2-year bone marrow study of eltrombopag olamine (SB-497115-GR) in previously treated adults, with chronic immune (idiopathic) thrombocytopenic purpura (ITP).

    Summary
    EudraCT number
    2009-010421-39
    Trial protocol
    DE   CZ   FR   HU   IT  
    Global end of trial date
    06 May 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Apr 2016
    First version publication date
    09 Apr 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TRA112940
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    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
    23 Dec 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the levels of bone marrow fibers (reticulin and/or collagen) at baseline and any change from baseline after 1 and 2 years of treatment with eltrombopag in adult subjects with chronic ITP
    Protection of trial subjects
    Additional testing in case of Abnormal Bone Marrow Biopsy Findings Subjects with post-baseline increase in bone marrow fibers to grade MF-2 or -3 on European Consensus scale or grade 3 or 4 on the Bauermeister scale will have the following assessments performed: 1. Peripheral blood smear to evaluate the presence of teardrop erythrocytes, nucleated red blood cells or any other relevant abnormality. 2. Testing for JAK2 (V617F) mutation. 3. Ultrasound evaluation of the size of the liver and spleen. 4. Blood sample for TGF-β measurement. Ultrasound of Liver and Spleen During the study, ultrasound of liver and spleen will be performed when a post-baseline increase of clinically significant bone marrow abnormality such as reticulin grade of either MF-2 or MF-3 on European Consensus scale or Grade 3 or 4 on Bauermeister scale is recorded or at any other time at the investigator discretion. Peripheral Blood Smear A peripheral blood smear should be performed at the Screening Visit, pre-dose Day 1, once every 4 weeks (or every 8 weeks if the dose of eltrombopag and concomitant ITP, if any, is stable for 3 months) during the treatment period, at the end of treatment visit or at the early withdrawal, and at 4-week follow-up visit. ECG A 12-lead ECG will be obtained for each subject during screening. During the study, an ECG can also be performed at the discretion of investigator, when clinically indicated. Renal Monitoring Renal function will be assessed in all subjects pre-dose on Day 1. Throughout the study, serum creatinine will be measured once every two weeks and will serve as the main tool to check for global renal function.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 May 2010
    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
    Czech Republic: 11
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Korea, Republic of: 20
    Country: Number of subjects enrolled
    Pakistan: 28
    Country: Number of subjects enrolled
    Russian Federation: 27
    Country: Number of subjects enrolled
    United States: 3
    Country: Number of subjects enrolled
    Hong Kong: 12
    Country: Number of subjects enrolled
    India: 25
    Worldwide total number of subjects
    167
    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)
    151
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 167 participants (par.) were enrolled and received at least one dose of study medication. The 5 enrolled participants from center 082877 were excluded from the analysis due to the following: serious good clinical practice (GCP) findings related to informed consent, source documents and investigator study oversight.

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

    Arms
    Arm title
    Eltrombopag
    Arm description
    Participants received an Open-label treatment of eltrombopag administered as a tablet for up to 2 years (104 weeks), followed by a follow-up period of up to 6 months (only 4 weeks for most participants). The starting dose of eltrombopag was 50 milligrams (mg), once daily (QD). East Asian participants started at a dose of 25 mg QD. The maximum dose allowed was 75 mg daily. Dose modifications were allowed based upon each participant’s individual platelet count response.
    Arm type
    Experimental

    Investigational medicinal product name
    Eltrombopag
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet in 12.5 mg, 25 mg, 50 mg, and 75 mg. Starting dose of 50mg once daily (25 mg once daily for subjects of East Asian ancestry). Dosing regimen then individualized based on platelet counts.

    Number of subjects in period 1 [1]
    Eltrombopag
    Started
    162
    Completed
    118
    Not completed
    44
         Physician decision
    1
         Lack of efficacy
    11
         Adverse event, serious fatal
    3
         Adverse event, non-fatal
    19
         Consent withdrawn by subject
    7
         Lost to follow-up
    3
    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: A total of 167 participants were enrolled and received at least one dose of study medication. The 5 enrolled participants from center 082877 were excluded from the analysis due to the following: serious good clinical practice (GCP) findings related to informed consent, source documents and investigator study oversight.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Eltrombopag
    Reporting group description
    Participants received an Open-label treatment of eltrombopag administered as a tablet for up to 2 years (104 weeks), followed by a follow-up period of up to 6 months (only 4 weeks for most participants). The starting dose of eltrombopag was 50 milligrams (mg), once daily (QD). East Asian participants started at a dose of 25 mg QD. The maximum dose allowed was 75 mg daily. Dose modifications were allowed based upon each participant’s individual platelet count response.

    Reporting group values
    Eltrombopag Total
    Number of subjects
    162 162
    Age categorical
    Units: Subjects
    Age continuous
    All Treated Subjects (ATS) Population: all participants who received at least one dose of study medication excluding the 5 participants from Center 082877.
    Units: years
        arithmetic mean (standard deviation)
    43.1 ± 16.31 -
    Gender categorical
    All Treated Subjects (ATS) Population: all participants who received at least one dose of study medication excluding the 5 participants from Center 082877.
    Units: Subjects
        Female
    104 104
        Male
    58 58
    Race
    All Treated Subjects (ATS) Population: all participants who received at least one dose of study medication excluding the 5 participants from Center 082877.
    Units: Subjects
        Asian - Central/South Asian Heritage
    47 47
        Asian - East Asian Heritage
    32 32
        Asian - South East Asian Heritage
    1 1
        White - White/Caucasian/European Heritage
    81 81
        Missing
    1 1

    End points

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    End points reporting groups
    Reporting group title
    Eltrombopag
    Reporting group description
    Participants received an Open-label treatment of eltrombopag administered as a tablet for up to 2 years (104 weeks), followed by a follow-up period of up to 6 months (only 4 weeks for most participants). The starting dose of eltrombopag was 50 milligrams (mg), once daily (QD). East Asian participants started at a dose of 25 mg QD. The maximum dose allowed was 75 mg daily. Dose modifications were allowed based upon each participant’s individual platelet count response.

    Primary: Number of participants with bone marrow (BM) fibers of MF Grade 0, 1, 2 and 3 on the European Consensus (EC) scale at Baseline

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    End point title
    Number of participants with bone marrow (BM) fibers of MF Grade 0, 1, 2 and 3 on the European Consensus (EC) scale at Baseline [1]
    End point description
    The evaluation of fibrosis was performed using BM biopsies in which the amount of fibrosis was assessed by the EC Grading Scale. This method distinguishes four degrees of fibrosis (myelofibrosis [MF]-0 to MF-3). MF Grade (G) 0 is scattered linear reticulin with no intersections (cross-overs) corresponding to normal BM; MF Grade 1 is loose network of reticulin with many intersections, especially in perivascular areas; MF Grade 2 is diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis; MF Grade 3 is diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis. Baseline is defined as the most recent centrally-reviewed BM biopsy prior to first dose of eltrombopag in the study. All Treated Subjects (ATS) Population: all par. who received >=1 dose of study medication excluding the 5 par. from center 082877.
    End point type
    Primary
    End point timeframe
    Baseline
    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: Data for this endpoint has been analysed descriptively using counts and percentages as planned in the study protocol and analysis plan.
    End point values
    Eltrombopag
    Number of subjects analysed
    159 [2]
    Units: Participants
        MF-0
    150
        MF-1
    9
        MF-2
    0
        MF-3
    0
    Notes
    [2] - ATS Population.Par. with bone marrow biopsy data available in the relevant time period were included
    No statistical analyses for this end point

    Primary: Number of participants with a positive or negative collagen level at Baseline

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    End point title
    Number of participants with a positive or negative collagen level at Baseline [3]
    End point description
    The number of participants with a positive or negative collagen level was analyzed. Baseline is defined as the most recent centrally-reviewed BM biopsy prior to first dose of eltrombopag in the study.
    End point type
    Primary
    End point timeframe
    Baseline
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Data for this endpoint has been analysed descriptively using counts and percentages as planned in the study protocol and analysis plan.
    End point values
    Eltrombopag
    Number of subjects analysed
    159 [4]
    Units: Participants
        Negative
    159
        Positive
    0
    Notes
    [4] - ATS Population.Par. with bone marrow biopsy data available in the relevant time period were included
    No statistical analyses for this end point

    Primary: Number of participants with indicated grade change from Baseline in the EC grading scale at 1 year

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    End point title
    Number of participants with indicated grade change from Baseline in the EC grading scale at 1 year [5]
    End point description
    The change from baseline to on-treatment assessments of European Consensus (EC) scale was analyzed. On-treatment is defined as during the treatment period (including dose interruptions) and up to 14 days after the end of the treatment period. MF-0 is scattered linear reticulin with no intersections (cross-overs) corresponding to normal BM; MF-1 is loose network of reticulin with many intersections, especially in perivascular areas; MF-2 is diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis; MF-3 is diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis. Baseline is defined as the most recent centrally-reviewed BM biopsy prior to first dose of eltrombopag in the study.
    End point type
    Primary
    End point timeframe
    Baseline and 1 year
    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: Data for this endpoint has been analysed descriptively using counts and percentages as planned in the study protocol and analysis plan.
    End point values
    Eltrombopag
    Number of subjects analysed
    127 [6]
    Units: Participants
        MF-0 to MF-0
    82
        MF-0 to MF-1
    33
        MF-0 to MF-2
    2
        MF-0 to MF-3
    2
        MF-1 to MF-0
    3
        MF-1 to MF-1
    2
        MF-1 to MF-2
    1
        MF-1 to MF-3
    0
        MF-2 to MF-0
    0
        MF-2 to MF-1
    0
        MF-2 to MF-2
    0
        MF-2 to MF-3
    0
        MF-3 to MF-0
    0
        MF-3 to MF-1
    0
        MF-3 to MF-2
    0
        MF-3 to MF-3
    0
        Missing to MF-0
    2
        Missing to MF-1
    0
        Missing to MF-2
    0
        Missing to MF-3
    0
    Notes
    [6] - ATS Population.Par. with bone marrow biopsy data available in the relevant time period were included
    No statistical analyses for this end point

    Primary: Number of participants with indicated change from Baseline in the EC grading scale at 2 years

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    End point title
    Number of participants with indicated change from Baseline in the EC grading scale at 2 years [7]
    End point description
    The change from baseline to on-treatment assessments of European Consensus (EC) scale was analyzed. On-treatment is defined as during the treatment period (including dose interruptions) and up to 14 days after the end of the treatment period. MF-0 is scattered linear reticulin with no intersections (cross-overs) corresponding to normal BM; MF-1 is loose network of reticulin with many intersections, especially in perivascular areas; MF-2 is diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis; MF-3 is diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis. Baseline is defined as the most recent centrally-reviewed BM biopsy prior to first dose of eltrombopag in the study.
    End point type
    Primary
    End point timeframe
    Baseline and 2 years
    Notes
    [7] - 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: Data for this endpoint has been analysed descriptively using counts and percentages as planned in the study protocol and analysis plan.
    End point values
    Eltrombopag
    Number of subjects analysed
    93 [8]
    Units: Participants
        MF-0 to MF-0
    79
        MF-0 to MF-1
    9
        MF-0 to MF-2
    0
        MF-0 to MF-3
    0
        MF-1 to MF-0
    2
        MF-1 to MF-1
    1
        MF-1 to MF-2
    0
        MF-1 to MF-3
    0
        MF-2 to MF-0
    0
        MF-2 to MF-1
    0
        MF-2 to MF-2
    0
        MF-2 to MF-3
    0
        MF-3 to MF-0
    0
        MF-3 to MF-1
    0
        MF-3 to MF-2
    0
        MF-3 to MF-3
    0
        Missing to MF-0
    2
        Missing to MF-1
    0
        Missing to MF-2
    0
        Missing to MF-3
    0
    Notes
    [8] - ATS Population.Par. with bone marrow biopsy data available in the relevant time period were included
    No statistical analyses for this end point

    Primary: Number of participants with a positive or negative collagen level at 1 year

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    End point title
    Number of participants with a positive or negative collagen level at 1 year [9]
    End point description
    The change from Baseline to on-treatment assessments of collagen level was analyzed. On-treatment is defined as during the treatment period (including dose interruptions) and up to 14 days after the end of the treatment period.
    End point type
    Primary
    End point timeframe
    1 year
    Notes
    [9] - 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: Data for this endpoint has been analysed descriptively using counts and percentages as planned in the study protocol and analysis plan.
    End point values
    Eltrombopag
    Number of subjects analysed
    127 [10]
    Units: Participants
        Negative to Negative
    120
        Negative to Positive
    5
        Positive to Negative
    0
        Positive to Positive
    0
        Missing to Negative
    2
        Missing to Positive
    0
    Notes
    [10] - ATS Population.Par. with bone marrow biopsy data available in the relevant time period were included
    No statistical analyses for this end point

    Primary: Number of participants with a positive or negative collagen level at 2 year

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    End point title
    Number of participants with a positive or negative collagen level at 2 year [11]
    End point description
    The change from Baseline to on-treatment assessments of collagen level was analyzed. On-treatment is defined as during the treatment period (including dose interruptions) and up to 14 days after the end of the treatment period.
    End point type
    Primary
    End point timeframe
    2 years
    Notes
    [11] - 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: Data for this endpoint has been analysed descriptively using counts and percentages as planned in the study protocol and analysis plan.
    End point values
    Eltrombopag
    Number of subjects analysed
    93 [12]
    Units: Participants
        Negative to Negative
    90
        Negative to Positive
    1
        Positive to Negative
    0
        Positive to Positive
    0
        Missing to Negative
    2
        Missing to Positive
    0
    Notes
    [12] - ATS Population.Par. with bone marrow biopsy data available in the relevant time period were included
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated maximum toxicity grade for the indicated clinical chemistry parameters at any time post-Baseline during the study

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    End point title
    Number of participants with the indicated maximum toxicity grade for the indicated clinical chemistry parameters at any time post-Baseline during the study
    End point description
    Clinical chemistry parameters were summarized according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0: G0, none; G1, mild; G2, moderate; G3, severe; G4, life-threatening or disabling. Clinical chemistry parameters included: albumin, alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino transferase (AST), total bilirubin, calcium (hypercalcemia), calcium (hypocalcemia), potassium (hyperkalemia), potassium (hypokalemia), sodium (hypernatremia), sodium (hyponatremia), inorganic phosphorus, creatine kinase (CK) and creatinine. Baseline values were obtained at Day 1.Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). The maximum post-Baseline toxicity grade includes any scheduled or unscheduled post-Baseline assessment during.
    End point type
    Secondary
    End point timeframe
    From Week 1 up to Week 104 and up to 6 months follow-up (4 weeks for most participants) (up to approximately 2.5 years)
    End point values
    Eltrombopag
    Number of subjects analysed
    162 [13]
    Units: Participants
        Albumin, G0, n=162
    151
        Albumin, G1, n=162
    5
        Albumin, G2, n=162
    6
        Albumin, G3, n=162
    0
        Albumin, G4, n=162
    0
        ALP, G0, n=162
    125
        ALP, G1, n=162
    35
        ALP, G2, n=162
    2
        ALP, G3, n=162
    0
        ALP, G4, n=162
    0
        ALT, G0, n=162
    109
        ALT, G1, n=162
    37
        ALT, G2, n=162
    8
        ALT, G3, n=162
    7
        ALT, G4, n=162
    1
        AST, G0, n=162
    99
        AST, G1, n=162
    48
        AST, G2, n=162
    8
        AST, G3, n=162
    5
        AST, G4, n=162
    2
        Total bilirubin, G0, n=162
    103
        Total bilirubin, G1, n=162
    40
        Total bilirubin, G2, n=162
    17
        Total bilirubin, G3, n=162
    2
        Total bilirubin, G4, n=162
    0
        Calcium (hypercalcemia), G0, n=162
    159
        Calcium (hypercalcemia), G1, n=162
    2
        Calcium (hypercalcemia), G2, n=162
    1
        Calcium (hypercalcemia), G3, n=162
    0
        Calcium (hypercalcemia), G4, n=162
    0
        Calcium (hypocalcemia), G0, n=162
    92
        Calcium (hypocalcemia), G1, n=162
    57
        Calcium (hypocalcemia), G2, n=162
    12
        Calcium (hypocalcemia), G3, n=162
    0
        Calcium (hypocalcemia), G4, n=162
    1
        Potassium (hyperkalemia), G0, n=162
    138
        Potassium (hyperkalemia), G1, n=162
    14
        Potassium (hyperkalemia), G2, n=162
    5
        Potassium (hyperkalemia), G3, n=162
    5
        Potassium (hyperkalemia), G4, n=162
    0
        Potassium (hypokalemia), G0, n=162
    123
        Potassium (hypokalemia), G1, n=162
    35
        Potassium (hypokalemia), G2, n=162
    0
        Potassium (hypokalemia), G3, n=162
    4
        Potassium (hypokalemia), G4, n=162
    0
        Sodium (hypernatremia), G0, n=162
    138
        Sodium (hypernatremia), G1, n=162
    20
        Sodium (hypernatremia), G2, n=162
    2
        Sodium (hypernatremia), G3, n=162
    2
        Sodium (hypernatremia), G4, n=162
    0
        Sodium (hyponatremia), G0, n=162
    137
        Sodium (hyponatremia), G1, n=162
    21
        Sodium (hyponatremia), G2, n=162
    0
        Sodium (hyponatremia), G3, n=162
    3
        Sodium (hyponatremia), G4, n=162
    1
        Inorganic phosphorus, G0, n=162
    100
        Inorganic phosphorus, G1, n=162
    0
        Inorganic phosphorus, G2, n=162
    52
        Inorganic phosphorus, G3, n=162
    10
        Inorganic phosphorus, G4, n=162
    0
        CK, G0, n=16
    15
        CK, G1, n=16
    1
        CK, G2, n=16
    0
        CK, G3, n=16
    0
        CK, G4, n=16
    0
        Creatinine, G0, n=162
    149
        Creatinine, G1, n=162
    8
        Creatinine, G2, n=162
    3
        Creatinine, G3, n=162
    0
        Creatinine, G4, n=162
    2
    Notes
    [13] - ATS Population
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated maximum toxicity grade for the indicated hematology parameters at any time post-Baseline during the study

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    End point title
    Number of participants with the indicated maximum toxicity grade for the indicated hematology parameters at any time post-Baseline during the study
    End point description
    Hematology parameters were summarized according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0: G0, none; G1, mild; G2, moderate; G3, severe; G4, life-threatening or disabling. Hematology parameters included: hemoglobin (increased), hemoglobin (anemia), lymphocyte count (increased), lymphocyte count (decreased), total absolute neutrophil count (ANC), platelet count and white blood cell (WBC) count. Baseline values were obtained at Day 1. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). The maximum post-Baseline toxicity grade includes any scheduled or unscheduled post-Baseline assessment during.
    End point type
    Secondary
    End point timeframe
    From Week 1 up to Week 104 and up to 6 months follow-up (4 weeks for most participants) (up to approximately 2.5 years)
    End point values
    Eltrombopag
    Number of subjects analysed
    162 [14]
    Units: Participants
        Hemoglobin (increased), G0, n=162
    143
        Hemoglobin (increased), G1, n=162
    17
        Hemoglobin (increased), G2, n=162
    1
        Hemoglobin (increased), G3, n=162
    1
        Hemoglobin (increased), G4, n=162
    0
        Hemoglobin (anemia), G0, n=162
    55
        Hemoglobin (anemia), G1, n=162
    63
        Hemoglobin (anemia), G2, n=162
    31
        Hemoglobin (anemia), G3, n=162
    13
        Hemoglobin (anemia), G4, n=162
    0
        Lymphocyte count (increased), G0, n=161
    122
        Lymphocyte count (increased), G1, n=161
    0
        Lymphocyte count (increased), G2, n=161
    39
        Lymphocyte count (increased), G3, n=161
    0
        Lymphocyte count (increased), G4, n=161
    0
        Lymphocyte count (decreased), G0, n=161
    86
        Lymphocyte count (decreased), G1, n=161
    36
        Lymphocyte count (decreased), G2, n=161
    26
        Lymphocyte count (decreased), G3, n=161
    13
        Lymphocyte count (decreased), G4, n=161
    0
        Total ANC, G0, n=161
    140
        Total ANC, G1, n=161
    12
        Total ANC, G2, n=161
    3
        Total ANC, G3, n=161
    3
        Total ANC, G4, n=161
    3
        Platelet count, G0, n=162
    2
        Platelet count, G1, n=162
    8
        Platelet count, G2, n=162
    3
        Platelet count, G3, n=162
    26
        Platelet count, G4, n=162
    123
        WBC, G0, n=162
    135
        WBC, G1, n=162
    21
        WBC, G2, n=162
    3
        WBC, G3, n=162
    3
        WBC, G4, n=162
    0
    Notes
    [14] - ATS Population
    No statistical analyses for this end point

    Secondary: Number of participants with any adverse event (AE) or serious adverse event (SAE) started on-therapy + 1 day, >1 to 30 days post therapy and >30 days post therapy

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    End point title
    Number of participants with any adverse event (AE) or serious adverse event (SAE) started on-therapy + 1 day, >1 to 30 days post therapy and >30 days post therapy
    End point description
    On-therapy + 1 day is defined as AEs started between the first dose of eltrombopag and up to the day after the last dose of eltrombopag; >1 to 30 days post therapy is defined as AEs that started more than 1 day and up to 30 days after the last dose of eltrombopag; >30 days post therapy is defined as AEs started that started more than 30 days after the last dose of eltrombopag. An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose: results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability or incapacity, or is a congenital anomaly or birth defect. Medical or scientific judgment should be exercised in other situations.
    End point type
    Secondary
    End point timeframe
    From Week 1 up to Week 104 and up to 6 months follow-up (4 weeks for most participants) (up to approximately 2.5 years)
    End point values
    Eltrombopag
    Number of subjects analysed
    162 [15]
    Units: Participants
        Any AE, on-therapy + 1 day
    141
        Any SAE, on-therapy + 1 day
    41
        Any AE, >1 to 30 days post therapy
    12
        Any SAE, >1 to 30 days post therapy
    5
        Any AE, >30 days post therapy
    9
        Any SAE, >30 days post therapy
    1
    Notes
    [15] - ATS Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment SAEs and non-serious AEs are defined as events occuring from the start of the treatment (Day 1) up to Week 104 and including the follow-up period of up to 6 months (only 4 weeks for most participants) (up to approximately 2.5 years).
    Adverse event reporting additional description
    SAEs and non-serious AEs were collected in participants of the ATS Population, comprised of all participants who had received at least one dose of study medication.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Eltrombopag
    Reporting group description
    -

    Serious adverse events
    Eltrombopag
    Total subjects affected by serious adverse events
         subjects affected / exposed
    42 / 162 (25.93%)
         number of deaths (all causes)
    4
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Salivary gland cancer
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    T-cell lymphoma
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 162 (1.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Local swelling
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychosomatic disease
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    3 / 162 (1.85%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Joint dislocation
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    2 / 162 (1.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 162 (1.23%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 162 (1.23%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 162 (1.23%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 162 (1.23%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 162 (1.23%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    2 / 162 (1.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Cerebral venous thrombosis
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lethargy
         subjects affected / exposed
    2 / 162 (1.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Transverse sinus thrombosis
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 162 (1.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 162 (1.85%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Gingival bleeding
         subjects affected / exposed
    2 / 162 (1.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 162 (1.23%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 162 (1.23%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cholecystitis infective
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Fungal infection
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gallbladder empyema
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash pustular
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sialoadenitis
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tooth abscess
         subjects affected / exposed
    2 / 162 (1.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Eltrombopag
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    114 / 162 (70.37%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    13 / 162 (8.02%)
         occurrences all number
    19
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 162 (5.56%)
         occurrences all number
    13
    Fatigue
         subjects affected / exposed
    15 / 162 (9.26%)
         occurrences all number
    16
    Influenza like illness
         subjects affected / exposed
    15 / 162 (9.26%)
         occurrences all number
    23
    Pain
         subjects affected / exposed
    9 / 162 (5.56%)
         occurrences all number
    23
    Pyrexia
         subjects affected / exposed
    18 / 162 (11.11%)
         occurrences all number
    25
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    10 / 162 (6.17%)
         occurrences all number
    15
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    11 / 162 (6.79%)
         occurrences all number
    15
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 162 (8.02%)
         occurrences all number
    20
    Aspartate aminotransferase increased
         subjects affected / exposed
    12 / 162 (7.41%)
         occurrences all number
    17
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 162 (6.79%)
         occurrences all number
    14
    Iron deficiency anaemia
         subjects affected / exposed
    9 / 162 (5.56%)
         occurrences all number
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    24 / 162 (14.81%)
         occurrences all number
    38
    Epistaxis
         subjects affected / exposed
    15 / 162 (9.26%)
         occurrences all number
    21
    Oropharyngeal pain
         subjects affected / exposed
    16 / 162 (9.88%)
         occurrences all number
    35
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    10 / 162 (6.17%)
         occurrences all number
    12
    Headache
         subjects affected / exposed
    30 / 162 (18.52%)
         occurrences all number
    129
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    12 / 162 (7.41%)
         occurrences all number
    32
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    9 / 162 (5.56%)
         occurrences all number
    15
    Abdominal pain upper
         subjects affected / exposed
    14 / 162 (8.64%)
         occurrences all number
    24
    Diarrhoea
         subjects affected / exposed
    21 / 162 (12.96%)
         occurrences all number
    34
    Dyspepsia
         subjects affected / exposed
    16 / 162 (9.88%)
         occurrences all number
    25
    Gingival bleeding
         subjects affected / exposed
    16 / 162 (9.88%)
         occurrences all number
    26
    Nausea
         subjects affected / exposed
    21 / 162 (12.96%)
         occurrences all number
    37
    Vomiting
         subjects affected / exposed
    15 / 162 (9.26%)
         occurrences all number
    29
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    17 / 162 (10.49%)
         occurrences all number
    36
    Pruritus
         subjects affected / exposed
    12 / 162 (7.41%)
         occurrences all number
    14
    Purpura
         subjects affected / exposed
    10 / 162 (6.17%)
         occurrences all number
    12
    Rash
         subjects affected / exposed
    9 / 162 (5.56%)
         occurrences all number
    11
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    22 / 162 (13.58%)
         occurrences all number
    33
    Back pain
         subjects affected / exposed
    17 / 162 (10.49%)
         occurrences all number
    33
    Pain in extremity
         subjects affected / exposed
    14 / 162 (8.64%)
         occurrences all number
    30
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 162 (5.56%)
         occurrences all number
    13
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    17 / 162 (10.49%)
         occurrences all number
    27
    Upper respiratory tract infection
         subjects affected / exposed
    20 / 162 (12.35%)
         occurrences all number
    49
    Viral infection
         subjects affected / exposed
    13 / 162 (8.02%)
         occurrences all number
    23

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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