Eltrombopag for the Treatment of Thrombocytopenia Due to Low- and Intermediate Risk Myelodysplastic Syndromes

Study Overview
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Brief Summary
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Myelodysplastic syndromes (MDS) prevail in older age and are characterized by ineffective erythropoiesis and peripheral cytopenias. Supportive therapy is the main therapeutic option for most patients. Quality of Life (QoL) is mainly deteriorated by anemia and by the limitations associated with thrombocytopenia, neutropenia and transfusion dependence. The only available treatment for severe thrombocytopenia, in the presence of bleeding, is platelet transfusion. Eltrombopag is an orally bioavailable agonist of the thrombopoietin receptor. In adult patients with chronic immune thrombocytopenia (ITP), Eltrombopag rapidly increases platelet counts and significantly reduces bleeding episodes during treatment. Eltrombopag is well tolerated. In 2007, Eltrombopag has received the Orphan Drug Designation for the treatment of ITP (EMEA/OD/031/07), and in 2008 the Food and Drug Association approved Eltrombopag for the treatment of ITP refractory or resistant. It has been shown that in patients affected by MDS and by acute myeloid leukemia, Eltrombopag neither increases the proliferation, nor the clonogenic growth capacity of bone marrow blasts. Furthermore, Eltrombopag induces an increase in the megakaryocytic differentiation and in the formation of normal megakaryocytic colonies. These results provide the rationale for pursuing further research on Eltrombopag for the treatment of thrombocytopenia in case of MDS. The study is open to adult patients with myelodysplastic syndrome (MDS) with thrombocytopenia and low- or intermediate-1 IPSS risk (Index Prognostic Score System). Severe thrombocytopenia associated with MDS may lead to death from hemorrhage, even in low prognostic risk patients. The benefit of platelet transfusion is short-termed. Patients become refractory in the long term. The availability of a treatment that induces the increase of platelet count is extremely important, either in terms of quality of life, and in overall survival.

Official Title
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Eltrombopag for the Treatment of Thrombocytopenia Due to Low- and Intermediate Risk Myelodysplastic Syndromes (EQoL-MDS)

Conditions
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Myelodysplastic Syndromes, Thrombocytopenia

Intervention / Treatment
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* Drug: Eltrombopag/Revolade
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult subjects (18 years of age or older) with low or intermediate-1 IPSS risk MDS and stable disease. Subjects must have a platelet count taken within the 4 weeks prior to randomization that is <30 Gi/L. Subjects must be ineligible or relapsed or refractory to receive other treatment options (such as azacitidine or lenalidomide) and must be ineligible to receive intensive chemotherapy or autologous/allogeneic stem cell transplantation. Subjects must have platelet count and platelet transfusion data available over a period of 8 weeks prior to randomization. During the 2 months prior to randomization, subjects must have a baseline Bone Marrow examination which includes cytomorphology and cytogenetics. Histopathology should be performed. Erythropoiesis-stimulating agents (ESAs) in anemic subjects or granulocyte colonystimulating factor (G-CSF) in subjects with severe neutropenia and recurrent infections are allowed during the study as per accepted standards. Subjects who enter the study on ESAs or G-CSF should continue at the same dose schedule until the optimal dose of study medication has been established. ECOG (Eastern Cooperative Oncology Group) Performance Status 0-3 Subject is able to understand and comply with protocol requirements and instructions. Subject has signed and dated informed consent. Adequate baseline organ function defined by the criteria below: total bilirubin (except for Gilbert's Syndrome) ≤ 1.5 x Upper Limit Normal Alanine aminotransferase and Aspartate aminotransferase ≤ 3 x Upper Limit Normal creatinine ≤ 2 x Upper Limit Normal albumin must not be below the lower limit of normal by more than 20%. Subject is practicing an acceptable method of contraception. Female subjects (or female partners of male subjects) must either be of non-childbearing potential (hysterectomy, bilateral oophorectomy, bilateral tubal ligation or post-menopausal >1 year), or of childbearing potential and use of an highly effective method of contraception from 2 weeks prior to administration of study medication, throughout the study, and 28 days after completion or premature discontinuation from the study. Exclusion Criteria: MDS with intermediate-2 or high IPSS risk. History of treatment for cancer other than MDS with systemic chemotherapy and/or radiotherapy within the last 2 years. History of treatment with romiplostim or other Thrombopoietin receptor agonists. Pre-existing cardiovascular disease (including congestive heart failure, New York Heart Association Grade III/IV), or arrhythmia known to increase the risk of thromboembolic events (e.g. persistent atrial fibrillation), or subjects with a QTc >450 msec (QTc >480 msec for subjects with Bundle Branch Block). BM fibrosis that leads to an inability to aspirate marrow for assessment. Peripheral monocytosis > 1000/uL prior to Day 1 of study medication. Leukocytosis >=25,000/uL prior to Day 1 of study medication. Female subjects who are nursing or pregnant (positive serum or urine Beta-human chorionic gonadotropin [B-hCG] pregnancy test) at screening or pre-dose on Day 1. Current alcohol or drug abuse. Treatment with an Investigational Product within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication. Active and uncontrolled infections. Subjects infected with Hepatitis B, C or Human Immunodeficiency Virus (HIV).

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 (Eltrombopag)<br>Arm 1 is the active treatment arm | Drug: Eltrombopag/Revolade<br>* Eltrombopag 50 mg once daily has been selected as the starting dose for this study. Thereafter, dependent on platelet response the dose of study medication can be increased by 50 mg every 2 weeks, up to a maximum dose of 300 mg once daily (150 mg in subjects of East Asian ethnicity).<br>|
| Placebo Comparator: Arm 2 (Placebo)<br>Arm 2 is the control arm | Other: Placebo<br>* The administration is the same of eltrombopag<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | Proportion of patients achieving a complete response (CR) or response (R) during the treatment period | Six months | 
| Safety and Tolerability (number of adverse events) | Safety and tolerability in terms of frequency of adverse events (AE) and serious adverse events (SAE) | Six month | 
| Duration of platelet response |  | five years | 
| long-term safety and tolerability (number adverse events in the long term) | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 and number of adverse events reporting in accordance with CTCAE v4.0 | five years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life (QoL) score | to evaluate the changes of the quality of life in the two arms | six months | 
| number of monthly platelet transfusions |  | six months | 
| duration of transfusion independence |  | six months | 
| time to response | time to response (time from starting treatment to time of achievement of CR or PR) | six months | 
| incidence and severity of bleeding | incidence and severity of bleeding using the WHO (World Health Organization)Bleeding Scale | six months | 
| overall survival | overall survival (OS) at 2 and at 5 years | 2 and 5 years | 
| leukemia-free survival (LFS) | leukemia-free survival (LFS) at 2 and at 5 years (events for LFS are defined as death and progression to AML); | 2 and 5 years |