Eltrombopag in Combination With Rabbit Anti-thymocyte Globulin/Cyclosporine A in Naive Aplastic Anemia (AA) Subjects

Study Overview
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Brief Summary
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This was an open label, non-randomized, phase II study of eltrombopag in combination with rabbit ATG/CsA in subjects with moderate or more severe AA who did not received prior ATG/ALG-based immunosuppressive therapy. The objective was to assess additive effects of eltorombopag on overall response rate (ORR) at 6 months (Week 26) of treatment with ATG/CsA. Subjects were assessed at least weekly for safety during the period from the start of ATG/CsA to 4 weeks after the start of administration of eltrombopag. After that, subjects had visits every 2 weeks until Week 26. Subjects in whom the treatment was assessed as effective at Week 26 could continued treatment with eltrombopag after 6 months when clinically indicated at the discretion of the investigator. There were five follow-up visits: at discontinuation of the treatment of eltrombopag, and Weeks 1, 2, 3, 4 and 26 after treatment discontinuation. As this study was the first Japanese phase II study in which this product was administered in combination with ATG/CsA to subjects with naive moderate or more severe AA, the subject number of this study was determined to be 10 based on the feasibility survey.

Official Title
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A Non-randomized, Phase II Study of Eltrombopag in Combination With Rabbit Anti-thymocyte Globulin/Cyclosporine A (ATG/CsA) in Subjects With Moderate or More Severe Aplastic Anemia Who Have Not Received Prior ATG/Anti-lymphocyte Globulin (ALG)-Based Immunosuppressive Therapy

Conditions
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Aplastic Anemia

Intervention / Treatment
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* Drug: Eltrombopag
* Drug: Rabbit ATG
* Drug: CsA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Japanese subjects aged >=18 and <71 years at the time of informed consent. Note: subjects aged >=71 and <75 may be eligible when clinically indicated at the discretion of the investigator by mutual agreement with Novartis medical advisor. Diagnosed with moderate or more severe AA according to the diagnostic criteria of AA. The severity classification is: Stage I - Mild - Other than the stages below; Stage II - Moderate - At least two of the following conditions are met: Reticulocyte <60,000/microliter, Neutrophil <1,000/microliter, Platelet <50,000/microliter; Stage III - Moderately severe - At least two of the following conditions are met and regular red blood cell transfusion (a need for transfusion of >=2 units per month) is required: Reticulocyte <60,000/microliter, Neutrophil <1,000/microliter, Platelet <50,000/microliter; Stage IV - Severe - At least two of the following conditions are met: Reticulocyte <20,000/microliter, Neutrophil <500/microliter, Platelet <20,000/microliter; Stage V - Very severe - At least one of the following conditions is met in addition to neutrophil <200/microliter: Reticulocyte <20,000/microliter, Platelet <20,000/microliter. Subjects who are considered an indication for the treatment with rabbit ATG and CsA. Adequate baseline organ function defined by the following criteria: Alanine aminotransferase (ALT), aspartate aminotransferase (AST)<=3 × local upper limit of normal (ULN) Creatinine, total bilirubin, and alkaline phosphatase (ALP) <1.5 × local ULN (total bilirubin <2.5 × local ULN with Gilbert's Syndrome) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS): 0 or 1 Subjects with QTcF<450 millisecond (msec) or QTcF<480 msec with branch block: QTc is QT interval corrected by Fridericia formula (QTcF), machine ,or manual overread. QTcF is based on single or averaged QTc value of triplicate ECG. Subjects are able to understand and comply with protocol requirements and instructions. Subjects have signed and dated informed consent. Subjects who meet one of the following conditions: Male subjects who have a female partner of childbearing potential must either have a prior vasectomy or agree to use an acceptable method of contraception from time of enrollment in the study until 16 weeks after the last dose of eltrombopag (based upon the lifecycle of sperm). Female subjects of non-childbearing potential (who are physiologically unable to become pregnant) defined as: Premenopausal women with documented bilateral oophorectomy, bilateral tubal ligation, or hysterectomy; or postmenopausal women after at least 12 months of natural amenorrhea [if uncertain, postmenopausal state should be confirmed by hematology result of follicle stimulating hormone (FSH) >40 milli-international units (mIU)/milliliter (mL) or estradiol <40 picogram (pg)/mL (<140 picomoles (pmol)/L)]. Female subjects of childbearing potential: Defined as those not meeting the definition of non-childbearing potential. Female subjects of childbearing potential must have a negative serum human chorionic gonadotropin (hCG) or urine pregnancy test within 7 days prior to the first dose of ATG/CsA. It is recommended that the pregnancy test should be performed as close as possible to the first dose of ATG/CsA. Female subjects with a positive pregnancy test must be excluded from the study. Subjects with a negative pregnancy test must use acceptable contraception including abstinence after the pregnancy test. Subjects must agree to use the acceptable contraception including abstinence from 14 days prior to the first dose of ATG/CsA until 28 days after the last dose of eltrombopag. Exclusion Criteria: Diagnosis of congenital AA (e.g. Fanconi anemia or Dyskeratosis congenital). Subjects who have a sibling donor with matched human leukocyte antigen (HLA) or who underwent hematopoietic stem cell transplantation (HSCT) previously. However, such subjects may be enrolled if HSCT is not indicated, or the subject does not want to undergo HSCT. Subjects with abnormal chromosome (monosomy 7 detected by fluorescence in situ hybridization (FISH), or other aberrations detected by G-band staining). Note: Subjects with abnormal chromosome which is not adopted into the clone definition of An International System for Human Cytogenetic Nomenclature (ISCN) may be enrolled after consulting with medical monitor. Previous ATG/ALG-based immunosuppressive therapy or steroid pulse therapy for AA. Treatment with CsA within 6 months before administration of ATG. Subjects with a paroxysmal nocturnal hemoglobinuria (PNH) clone size in granulocytes of >50% by flow cytometric analysis. Pre-existing cardiac disease (congestive heart failure New York Heart Association (NYHA) Grade II/III/IV), or arrhythmias known to involve the risk of thromboembolic events (e.g. atrial fibrillation) Past history of thromboembolic event (including anti-phospholipid antibody syndrome) and current use of anticoagulants. Subjects with past or current malignancy. Note : Subjects who have a history of completely resected malignant tumor and have been disease-free for 5 years are eligible. Subjects who test positive for hepatitis B surface (HBs) antigen, hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) antibody at screening. Infection not adequately responding to appropriate therapy. Subject with liver cirrhosis Subjects with any clinically significant severe cardiac, renal, or hepatic medical condition. Pregnant women (a positive serum or urine pregnancy test within 7 days prior to the first dose of ATG/CsA or lactating women) Note: Female subjects who are lactating are eligible to participate if they discontinue nursing prior to the first dose of ATG/CsA and refrain from nursing until 5 days after the completion of treatment with eltrombopag. Known hypersensitivity, intolerance or allergy to rabbit ATG, cyclosporine A, eltrombopag or any of their excipients. Current alcohol or drug abuse. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) proceeding the first dose of ATG/CsA. Subjects who is not candidates for ATG. Subjects who is not candidates for CsA. History of treatment with eltrombopag, romiplostim or other thrombopoietin-receptor (TPO-R) agonists.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eltrombopag+rabbit ATG/CsA arm<br>Subjects received rabbit ATG diluted by 500 mL of saline or 5% glucose injection at a dose of 2.5 to 3.75 mg per kilogram (kg) per day for 5 days as a slow intravenous infusion over 6 hours. CsA was administered at a dose of 3 mg per kg twice a day from day 0. The dose level was adjusted based on the monitoring of blood level or renal function. Eltrombopag was initiated on day 14 and it could be delayed up to 2 weeks if the subject had infection, serum sickness, or other adverse events. Eltrombopag wasadministered orally once a day at fasting at an initial dose of 75 mg, and the dose adjusted every 2 weeks according to the platelet count. Eltrombopag and CsA were continued until Week 26.After Week 26, eligible subjects received eltrombopag; and CsA was tapered or maintained as per the investigator's discretion. | Drug: Eltrombopag<br>* Eltrombopag was provided as white round film-coated tablets containing 12.5 mg or 25 mg of eltrombopag free acid (SB-497115-GR, eltrombopag).<br>Drug: Rabbit ATG<br>* Rabbit ATG, as an intravenous drip infusion, diluted by 500 mL of saline or 5% glucose injection was administered at a dose of 2.5 to 3.75 mg per kg per day as a slow intravenous infusion over 6 hours.<br>Drug: CsA<br>* CsA as capsules, oral solution, or fine granule, was administered at a dose of 3 mg per kg twice a day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR at 6 Months: Overall Response Rate (ORR) Defined as the Number of Participants Who Met the Criteria of Either Complete Response (CR) or Partial Response (PR) at Week 26 | ORR will be calculated after 6 months of eltrombopag administration by measuring platelet, reticulocyte, neutrophil and transfusion independence. ORR includes Complete Response (CR) and Partial Response (PR) Rate. | Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR at 3 Months | ORR will be calculated after 3 months of eltrombopag administration by measuring platelet, reticulocyte, neutrophil and transfusion independence. | Week 14 | 
| Complete Response (CR), and Partial Response (PR) Rate at 3 Months | CR and PR will be calculated after 3 months of eltrombopag administration by measuring platelet, reticulocyte, neutrophil and transfusion independence. | Week 14 | 
| CR Rate Based on the Criteria Used in NIH 12-H-0150 Study at 6 Months | CR criteria used in NIH 12-H-150 study is as follows: Hemoglobin >10 gram (g)/ deciliter (dL), and Absolute neutrophil count (ANC) >1,000/microliter, and Platelets >100,000/microliter. | Week 26 | 
| Changes in Hematology Parameters (Haemoglobin) in the Absence of Platelet Transfusion | The change in hematology values ( haemoglobin) were evaluated. | Week 26 and week 104 | 
| Changes in Hematology Parameters in the Absence of Platelet Transfusion | The change in hematology values from baseline for platelets, neutrophils and reticulocytes were evaluated. | Week 26 and week 104 | 
| Frequency of Platelet and Red Blood Cells (RBC) Transfusions | RBC transfusion dependency defined as at least one RBC transfusion within 8 weeks prior to D1. Platelet or RBC transfusions will be based on physician's subjective judgement. Platelet transfusion will be done if the platelet count is less than 10×10^9/liter (L) with significant bleeding tendency or the platelet count is less than 20×10^9/L with pyrexia. RBC transfusion will be done to keep the hemoglobin concentration at over 7 g/dL or in the presence of clinical symptoms such as dyspnea. | Baseline, Week 26 | 
| Volume of Platelet and RBC Transfusions | Platelet or RBC transfusions will be based on physician's subjective judgement. Platelet transfusion will be done if the platelet count is less than 10×10^9/L with significant bleeding tendency or the platelet count is less than 20×10^9/L with pyrexia. RBC transfusion will be done to keep the hemoglobin concentration at over 7 g/dL or in the presence of clinical symptoms such as dyspnea. | Baseline, Week 26 | 
| The Proportion of Subjects Whose Transfusion Unit (or Volume) Are Decreased or Who Became Transfusion (Platelet, RBC) Independent | The proportions of the subjects for whom the amount of blood transfusion (platelets and RBC) decreased or the proportions of the subjects for whom blood transfusion (platelets and RBC) became unnecessary. Platelet transfusion will be done if the platelet count is less than 10×10^9/L with significant bleeding tendency or the platelet count is less than 20×10^9/L with pyrexia. RBC transfusion will be done to keep the hemoglobin concentration at over 7 g/dL or in the presence of clinical symptoms such as dyspnea. | Week 26 | 
| Duration of Hospitalization | Duration of hospitalization is the time period from the administration of ATG up to discharge. | Week 26 | 
| Time to Onset of CR and PR | The time to onset of CR and PR will be determined by measuring platelet, reticulocyte, neutrophil and transfusion independence. | Week 26 | 
| Duration of CR or PR | Duration for CR or PR will be determined by measuring platelet, reticulocyte, neutrophil and transfusion independence. | Week 104 | 
| Degree of Exposure to Eltrombopag : Average Daily Dose |  | Week 104 | 
| Degree of Exposure to Eltrombopag : Cumulative Dose | The cumulative dose of drug administered to the subject will be calculated. | Week 104 | 
| Degree of Exposure to Eltrombopag : Days on Study |  | Week 104 | 
| Number of Participants With Adverse Events | Adverse events will be collected from the start of study treatment until the approval. | though study completion , approximately 2 years | 
| Vital Signs (Blood Pressure) as a Measure of Safety and Tolerability | Vital sign measurements : blood pressure | baseline and Week 26 | 
| 12-lead Electrocardiogram (ECG) as Measure of Safety and Tolerability | Triplicate 12-lead ECGs will be obtained at designated time points during the study using an ECG machine that calculates the heart rate and measures PR, QRS, QT, and QT interval corrected by Fridericia formula (QTcF) intervals. | Baseline, Week 26 | 
| The Trough Concentrations of Eltrombopag Following Repeat Doses of at 75 mg, 50 mg and 25 mg | Blood samples will be collected after repeat (14 days) doses of eltrombopag 75, 50, 25 mg to determine the plasma eltrombopag concentration prior to the next dose. | day 15 | 
| The Concentration After 4 Hours of Dose of Eltrombopag 75 mg | Blood sample will be collected at 4 hours after repeat (14 days) dose of eltrombopag 75 mg | day 15 | 
| Composite of Laboratory Parameters Assessment as a Safety Measure (Haemoglobin and Albumin). | The laboratory test values (haemoglobin and albumin) were calculated at each time point of evaluation. | Baseline, Week 26 | 
| Composite of Laboratory Parameters Assessment as a Safety Measure (Lymphocytes and Neutrophils). | The laboratory test values (lymphocytes and neutrophils) were calculated at each time point of evaluation. | Baseline, Week 26 | 
| Composite of Laboratory Parameters Assessment as a Safety Measure (Alcaline Phosphatase and Aspartate Amino Transferase) . | The laboratory test values (Alcaline Phosphatase and Aspartate Amino Transferase) were calculated at each time point of evaluation. | Baseline, Week 26 | 
| Composite of Laboratory Parameters Assessment as a Safety Measure. | The laboratory test values (hematological /biochemical examinations) were calculated at each time point of evaluation. | Baseline, Week 26 | 
| Vital Signs (Temperature) as a Measure of Safety and Tolerability | Vital sign measurements : temperature | baseline and Week 26 | 
| Vital Signs (Pulse Rate) as a Measure of Safety and Tolerability | Vital sign measurements : pulse rate. | baseline and Week 26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Eltrombopag, rabbit anti-thymocyte globulin, additive effect, cyclosporine A, bone marrow, hematopoietic stem cells, pancytopenia, leukopenia, platelets, throbocytopenia, mature blood cells, bone marrow biopsy