E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult patients with low or intermediate-1 IPSS risk MDS and thrombocytopenia |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10035534 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate 1. Response rate: The proportion of patients achieving a complete response (CR) or response (R) during the six month treatment period, for subjects receiving eltrombopag relative to placebo (see Platelet Response Section 5.4.4) 2. Safety and tolerability in terms of frequency of adverse events (AE)s and serious adverse events (SAE), for subjects receiving eltrombopag relative to placebo. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of treatment on: 1. Quality of life (QoL) scores for subjects receiving eltrombopag relative to placebo 2. The number of monthly platelet transfusions in subjects receiving eltrombopag compared to the placebo group 3. The duration of transfusion independence as measured in weeks and months for subjects receiving eltrombopag relative to placebo. 4. Time to response (time from starting treatment to time of achievement of CR or PR) between treatment groups as measured by the MDS response criteria 5. The incidence and severity of bleeding using the WHO Bleeding Scale (see Section 8: WHO Bleeding Scale).for subjects receiving eltrombopag relative to placebo 6. Overall survival (OS) at 2 years. Event for OS in both arms is death and patients are censored at the date of last contact if alive. 7. Leukemia-free survival (LFS) at 2 years [22]. Events for LFS in both arms are death and progression to AML. 8. To evaluate eltrombopag population pharmacokinet |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Adult subjects (18 years of age or older) with low or intermediate-1 IPSS risk MDS and stable disease. 2. Subjects must have a platelet count taken within the 4 weeks prior to randomization that is <30 Gi/L. 3. Subjects must be ineligible or relapsed or refractory to receive other treatment options (such as azacitidine) and must be ineligible to receive intensive chemotherapy or autologous/allogeneic stem cell transplantation. 4. Subjects must have platelet count and platelet transfusion data available over a period of 8 weeks prior to randomization. 5. During the 2 months prior to randomization, subjects must have a baseline BM examination which includes cytomorphology and cytogenetics. Histopathology should be performed. 6. 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 [23]. 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. 7. ECOG Performance Status 0-3 (Appendix 4). 8. Subject is able to understand and comply with protocol requirements and instructions. 9. Subject has signed and dated informed consent. 10. Adequate baseline organ function defined by the criteria below: total bilirubin (except for Gilbert’s Syndrome) ≤ 1.5xULN ALT and AST ≤ 3xULN creatinine ≤ 2xULN albumin must not be below the lower limit of normal by more than 20%. 11. 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. |
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E.4 | Principal exclusion criteria |
1. MDS with intermediate-2 or high IPSS risk 2. History of treatment for cancer other than MDS or sAML/MDS with systemic chemotherapy and/or radiotherapy within the last 2 years. 3. History of treatment with romiplostim or other TPO-R agonists. 4. Pre-existing cardiovascular disease (including congestive heart failure, New York Heart Association [NYHA] 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). 5. BM fibrosis that leads to an inability to aspirate marrow for assessment. 6. Spleen size >14 cm (length as per ultrasound examination). 7. Leukocytosis >=25,000/uL prior to Day 1 of study medication. 8. 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. 9. Current alcohol or drug abuse. 10. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication. 11. Active and uncontrolled infections. 12. Subjects infected with Hepatitis B, C or Human Immunodeficiency Virus (HIV). |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Proportion of patients obtaining CR or R during the six month treatment period, for subjects receiving eltrombopag relative to placebo 2. Safety and tolerability parameters including non-hematological laboratory Grade 3/Grade 4 toxicities, change in bone marrow blast counts from baseline and adverse events reporting for subjects receiving eltrombopag relative to placebo |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | Yes |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 20 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |