A Longitudinal 2-year Bone Marrow Study of Eltrombopag in Previously Treated Adults, With Chronic Immune (Idiopathic) Thrombocytopenic Purpura (ITP)

Study Overview
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Brief Summary
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A open-label, multi-center 2-year safety study to ascertain the baseline levels of bone marrow fibers in previously treated adults with chronic immune (idiopathic) thrombocytopenic purpura (ITP) and to evaluate the long-term effect of eltrombopag on bone marrow fibers. The study will also describe the long-term safety and tolerability of oral eltrombopag treatment in subjects with chronic ITP.

Detailed Description
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This is a phase IV, open-label safety study, designed to determine baseline levels of bone marrow fibers in previously treated adults with chronic immune (idiopathic) thrombocytopenic purpura (ITP)and to evaluate the long-term effect of eltrombopag on bone marrow reticulin and/or collagen fibers. The duration of the screening period is up to 8 weeks. Eltrombopag will be administered for at least 2-years followed by a 4-week follow-up period. Bone marrow biopsies will be performed at screening, after 1-year and 2-years of eltrombopag treatment, and at early withdrawal of treatment. The screening bone marrow biopsy should be performed within 8 weeks of planned start of study medication and the bone marrow biopsy block must be available for central laboratory processing.

Official Title
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A Longitudinal 2-year Bone Marrow Study of Eltrombopag Olamine (SB-497115-GR) in Previously Treated Adults, With Chronic Immune (Idiopathic) Thrombocytopenic Purpura (ITP)

Conditions
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Purpura, Thrombocytopaenic, Idiopathic

Intervention / Treatment
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* Drug: Eltrombopag olamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have signed and dated a written informed consent and be able to understand and comply with protocol requirements and instructions. Adults (≥18 years) diagnosed with chronic ITP according to the American Society for Hematology/British Committee for Standards in Hematology (ASH/BCSH) guidelines [George, 1996; BCSH, 2003; Provan, 2009]. In addition, a peripheral blood smear should support the diagnosis of ITP with no evidence of other disease causative of thrombocytopenia (e.g., pseudo thrombocytopenia, myelofibrosis). The physical examination should not suggest any disease, which may cause thrombocytopenia other than ITP. Subjects must be physically eligible for serial bone marrow biopsies and must have a bone marrow biopsy performed during screening, and be willing to remain on the study for at least 2 years with annual bone marrow biopsies. Subjects, who previously received eltrombopag or romiplostim, must have completed treatment with these therapies at least 6 months prior to the screening bone marrow biopsy. Subjects must have the following clinical chemistry values: ALT and AST < 2xULN; Bilirubin <1.5xULN (except for Gilbert's Syndrome); Subjects are practicing an acceptable method of contraception as specified in the protocol. In France, subjects will be eligible for inclusion in this study, only if either affiliated to or a beneficiary of a social security category. Exclusion Criteria: Subjects with any clinically relevant abnormality, other than ITP, or any other medical condition or circumstance, which in the opinion of the investigator makes the subject unsuitable for participation in the study or suggests another primary diagnosis (e.g., thrombocytopenia is secondary to another disease). Subjects with any concurrent malignant disease and/or a recent history of cancer treatment with systemic chemotherapy and/or radiotherapy. Exception: Subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. Subjects with any prior history of arterial or venous thrombosis (stroke, transient ischemic attack, myocardial infarction, deep vein thrombosis or pulmonary embolism), AND ≥ two of the following risk factors: hormone replacement therapy, systemic contraception (containing estrogen), smoking, diabetes, hypercholesterolemia, hypertension, cancer, hereditary thrombophilic disorders (e.g., Factor V Leiden, ATIII deficiency, etc), or any family history of arterial or venous thrombosis. Subjects with screening bone marrow fibers of either MF Grade 3 using European Consensus scale or Grade 4 using Bauermeister scale. Subjects with a QTc >450 msec or > 480 msec for subjects with Bundle Branch Block. Female subjects who are nursing or pregnant (positive serum or urine β-human chorionic gonadotrophin (β-hCG) pregnancy test) at screening. Subjects treated with an investigational drug (other than a thrombopopoetin-receptor (TPO-R) agonist) within 30 days or five half-lives (whichever is longer) preceding the first dose of eltrombopag in the study. (For romiplostim or eltrombopag, see inclusion criterion #4). Subjects treated with any TPO-R agonist other than romiplostim or eltrombopag. Subjects with recent history of alcohol/drug abuse as determined by the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open Label<br>Oral eltrombopag once daily, starting dose 50 mg (or 25 mg for subjects of East Asian ancestry). | Drug: Eltrombopag olamine<br>* Thrombopoietin receptor agonist<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Bone Marrow (BM) Fibers of MF Grade 0, 1, 2 and 3 on the European Consensus (EC) Scale at Baseline | 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. | Baseline | 
| Number of Participants With a Positive or Negative Collagen Level at Baseline | 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. | Baseline | 
| Number of Participants With Indicated Grade Change From Baseline in the EC Grading Scale at 1 Year | 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. | Baseline and 1 year | 
| Number of Participants With Indicated Change From Baseline in the EC Grading Scale at 2 Years | 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. | Baseline and 2 years | 
| Number of Participants With a Positive or Negative Collagen Level at 1 Year | 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. | 1 year | 
| Number of Participants With a Positive or Negative Collagen Level at 2 Year | 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. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With the Indicated Maximum Toxicity Grade for the Indicated Clinical Chemistry Parameters at Any Time Post-Baseline During the Study | 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 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. | 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) | 
| Number of Participants With the Indicated Maximum Toxicity Grade for the Indicated Hematology Parameters at Any Time Post-Baseline During the Study | 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. | 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) | 
| 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 | 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. | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immune (idiopathic) thrombocytopenic purpura (ITP), bone marrow fibers, eltrombopag olamine, thrombopoietin receptor agonist