Study to Assess the Safety and Efficacy of Eltrombopag in Chinese Refractory or Relapsed Severe Aplastic Anemia (SAA) Subjects.

Study Overview
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Brief Summary
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This is a non-randomized, open-label, phase II study to assess the efficacy and safety of eltrombopag in Chinese subjects with refractory or relapsed severe aplastic anemia (SAA). Treatment with eltrombopag will be started at 25 mg/day and increased by 25 mg/day every 2 weeks according to the platelet count up to 150 mg/day. The hematological response rate will be assessed at 3, 6 months and 1 year after starting the study treatment (Week 13, 26 and 52).

Detailed Description
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This is a bridging study to support China registration. An estimation strategy rather than a formal hypothesis testing was pursued. Twenty subjects were enrolled into the study. Treatment with eltrombopag started at 25 mg/day and increased by 25 mg/day every 2 weeks according to the platelet count, up to 150 mg/day. Hematological response rate was assessed at 3, 6 months and 1 year (Week 13, 26 and 52) after starting the study treatment. Subjects in whom the treatment was found to be effective at 6 months continued to receive the treatment. Eltrombopag was discontinued if the treatment was ineffective at 6 months. Subjects were to discontinue eltrombopag before 6 months if any of the treatment discontinuation criteria were met. Analysis set for the primary endpoint is Full Analysis Set (FAS) and subjects who discontinue from the study before Week 26 were treated as non-responders in the response analysis. Eltrombopag treatment was provided to subjects who were considered to require continued treatment at Week 26. After Week 26, if all of the hematologic response criteria (i.e., platelet count > 50×109/L, hemoglobin level > 100 g/L without transfusion, and neutrophil count > 1.0×109/L) remained fulfilled for more than 8 weeks, the dose of eltrombopag was decreased by half. If the response continued for further 8 weeks even at the decreased dose, the treatment was discontinued. If a decrease in any of the hematologic values (i.e., platelet count < 30×109/L, hemoglobin < 90 g/L, or neutrophil count < 0.5×109/L) was found after dose reduction, the dose was increased to the previous level. Furthermore, after treatment interruption, the treatment was restarted if any of the hematologic values decreased to the above-mentioned levels. The response assessment and safety evaluation were performed at Week 52. The Extension part of this study started 1 year (Week 52) after the initiation of study treatment. This part was included in the study with an ethical consideration for subjects who required continued treatment. The continued treatment was provided up to the launch of eltrombopag after approval. Follow-up visit was performed 30 days after the discontinuation of eltrombopag treatment. To better understand the PK characteristics of eltrombopag in Chinese SAA patient population, intensive PK blood samples was collected only in the initial 12 Chinese subjects receiving 25 mg/day dose after reaching steady-state to provide evaluable full PK profiles. Steady-state trough concentrations were collected at other dose levels and in other subjects.

Official Title
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A Non-randomized, Open-label, Multi-center, Phase II Study to Assess the Safety and Efficacy of Eltrombopag in Chinese Subjects With Refractory or Relapsed Severe Aplastic Anemia

Conditions
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Aplastic Anemia

Intervention / Treatment
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* Drug: Eltrombopag 25 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chinese patients aged greater than or equal to 18 years old. Patient with a previous diagnosis of severe aplastic anemia and had insufficient response following at least one treatment course in the period time of > 6 months of immunosuppression with a regimen containing anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG), and/or cyclophosphamide, or alemtuzumab. Platelet count ≤ 30 × 10^9/L at screening. Patient must not currently have the option of stem cell transplantation. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Patient with QTcF (Fridericia's QT correction formula) at screening <450 msec, or <480 msec with bundle branch block, as determined via the mean of a triplicate ECG and assessed at site. Exclusion Criteria: Treatment with ATG/ALG, cyclophosphamide or alemtuzumab in the past 6 months. Congenital aplastic anemia AST or ALT ≥3 times the upper limit of normal. Creatinine, total bilirubin, and alkaline phosphatase (ALP) ≥ 1.5× local ULN (total bilirubin ≥ 2.5 × local ULN with Gilbert's Syndrome). Paroxysmal nocturnal hemoglobinuria (PNH) granulocyte clone size determined by flow cytometry ≥ 50%. Presence of chromosomal aberration (-7/7q- detected by fluorescence in situ hybridization (FISH), or other aberrations detected by G-band staining). Evidence of a clonal hematologic bone marrow disorder on cytogenetics. Past medical history of thromboembolism within 6 months or current use of anticoagulants. Have any concomitant malignancies and must be fully recovered from treatment for any other malignancy and have been disease-free for 5 years. Patient with clinically significant. Patient with known hepatocellular disease Presences of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening. Cardiac disorder (NYHA) functional classification Grade II/III/IV Past medical history of immediate or delayed hypersensitivity to compounds chemically similar to eltrombopag or their excipients. Treatment with another investigational product within 30 days. Prior treatment with eltrombopag, romiplostim, or any other TPO (thrombopoietin) receptor agonist. Positive result for HIV (Human Immunodeficiency Virus) antibody test. Pregnant or nursing (lactating) woman. Woman of child-bearing potential. Other protocol-defined inclusion/exclusion criteria may apply.

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: Eltrombopag<br>Subjects will start eltrombopag treatment at 25 mg/day since Day 1. | Drug: Eltrombopag 25 mg<br>* film-coated tablets containing 25 mg of eltrombopag free acid in each tablet<br>* Other names: ETB115;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematologic response rate | Hematologic response rate is defined as the percentage of all subjects who meet any of the IWG criteria (International Working Group). | 6 months (Week 26) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematologic response rate | Hematologic response rate is defined as the percentage of all subjects who meet any of the IWG criteria (International Working Group). | Week 13 and Week 52 | 
| Changes in platelet count | Changes in platelet count in the absence of platelet transfusion. | Baseline to Week 26 or up to 3.5 years | 
| Changes in hemoglobin count | Changes in hemoglobin in the absence of RBC (Red Blood Cell) transfusion. | Baseline to Week 26 or up to 3.5 years | 
| Changes in neutrophil count | Changes in neutrophil count in the absence of G-CSF (Granulocyte Colony Stimulating Factor). | Baseline to Week 26 or up to 3.5 years | 
| Time to hematologic response | Time to hematologic response (any response according to the response criteria for the primary endpoint). | Baseline to Week 26 or up to 3.5 years | 
| Duration of hematologic response | Duration of hematologic response (any response according to the response criteria for the primary endpoint). | Baseline to Week 26 or up to 3.5 years | 
| Frequency of transfusion | Frequency of transfusion (platelet and RBC (Red Blood Cell)) | Baseline to Week 26 or up to 3.5 years | 
| Volume of transfusion | Volume of transfusion (platelet and RBC (Red Blood Cell)) | Baseline to Week 26 or up to 3.5 years | 
| Plasma concentration of eltrombopag including the trough concentrations | Plasma concentration of eltrombopag including the trough. | Baseline to Week 26 | 
| Rate of clonal evolution | Rate of clonal evolution including clonal evolution to PNH (Paroxysmal Nocturnal Hemoglobinuria), evolution to AML (Acute Myeloid Leukemia) or MDS (Myelodysplastic Syndromes). | Baseline to Week 26 or up to 3.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Severe Aplastic Anemia, Eltrombopag, ETB115, Chinese subject, Chinese refractory or relapsed SAA subjects, refractory severe aplastic anemia, relapsed severe aplastic anemia