| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Thrombocytopenic Subjects with Myelodysplastic Syndromes or Acute Myeloid Leukemia |
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| E.1.1.1 | Medical condition in easily understood language |
Low platelet counts due to advanced myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
|
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028534 |
| E.1.2 | Term | Myelodysplastic syndrome NOS |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10060356 |
| E.1.2 | Term | Acute myeloid leukaemia without mention of remission |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1 open-label, 8 week first part of the study are:
• To evaluate the safety and tolerability of eltrombopag.
• To determine optimal dose escalation scheme for use in Part 2 of the study by assessing the dose of eltrombopag required to achieve platelet count response.
• To characterize plasma eltrombopag pharmacokinetics (steady-state plasma eltrombopag Cmax, tmax, AUC(0-τ), CL/F, and half-life).
Part 2: • The primary objective of this study is to determine reduction in the number of clinically relevant thrombocytopenic events
(CRTE) in subjects with MDS or AML who have Grade 4 thrombocytopenia (<25 Gi/L) and are treated with eltrombopag compared to those treated with placebo.
Part 3: The objectives of the study are to evaluate the long-term durability of clinical benefit and the long-term safety and tolerability of eltrombopag in subjects with MDS and AML |
|
| E.2.2 | Secondary objectives of the trial |
Part 2 of Study:
Secondary objectives compare the following in subjects treated with eltrombopag and placebo:
• To evaluate hematologic improvement
• To evaluate the effect of eltrombopag on platelet counts
• To evaluate the effect of eltrombopag on the need for platelet transfusions.
• To evaluate the effect of eltrombopag on the duration of platelet transfusion independence.
• To evaluate the effect of eltrombopag on bleeding symptoms.
• To evaluate MDS and AML disease outcomes
• To evaluate the safety and tolerability of eltrombopag.
• To evaluate effect of eltrombopag on medical resource utilization.
• To evaluate effect of eltrombopag on healthrelated quality of life. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Adult subjects (18 years of age or older) with MDS or AML (bone marrow blasts ≤50%) with thrombocytopenia due to bone marrow insufficiency from the disease or prior treatment. Subjects with transient thrombocytopenia due to active treatment with disease modifying agents or chemotherapy (except for hydroxyurea) are excluded.
2. Subjects must have Grade 4 thrombocytopenia (platelet counts <25 Gi/L) due to bone marrow insufficiency (or platelet count ≥25 Gi/L due to platelet transfusion).
In addition, subjects must have had at least one of the following during the 4 week screening period: platelet transfusion, or symptomatic bleeding or platelet count <10 Gi/L. Subjects whose thrombocytopenia below 10 Gi/L is due to causes other than bone marrow insufficiency (e.g., fever, infection, autoimmune disease) are not eligible.
3. Subjects must have platelet count, bleeding and platelet transfusion data available over a period of at least 4 weeks prior to randomization.
4. Prior systemic treatment for malignancy, with the exception of hydroxyurea (see Section 6.1.2), must have been discontinued prior to entry into the study:
• at least 4 weeks before Day 1 for the following: chemotherapy, demethylating agents (azacitidine or decitabine), lenalidomide, thalidomide, clofarabine and IL-11(oprelvekin);
• at least 8 weeks before Day 1 for antithymocyte/antilymphocyte globulin.
5. Subjects with a prior stem cell transplant (SCT) must have relapsed after the SCT.
6. Subjects must have stable disease (as defined by treatment guidelines and investigator discretion) and, in the opinion of the investigator, must be expected to complete a 12 week treatment period.
7. ECOG Status 0-2.
8. Subject must be able to understand and comply with protocol requirements and instructions.
9. Subject has signed and dated an informed consent form.
10. Adequate baseline organ function defined by the criteria below:
• total bilirubin ≤ 1.5xULN except for Gilbert’s syndrome or cases clearly not indicative of inadequate liver function (i.e. elevation of indirect (hemolytic) bilirubin in the absence of ALT abnormality)
• ALT ≤ 3xULN
• creatinine ≤ 2.5xULN
11. Women must be either of non-child bearing potential (see Section 7.3.12.2.1, for definition) or women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study (See Section 7.3.12.2, for acceptable methods of birth control). Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment.
12. In France, a subject will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category |
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| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Subjects with MDS and an IPSS of low or intermediate-1 risk.
2. Subjects with a diagnosis of acute promyelocytic or megakaryocytic leukemia or AML secondary to a myeloproliferative neoplasm.
3. History of treatment with romiplostim or other TPO-R agonists.
4. Subjects with a QTc >480 msec (QTc >510 msec for subjects with Bundle Branch Block) at baseline.
5. Subjects with a palpable spleen must have a splenic ultrasound to confirm spleen length is ≤16 cm. Subjects with palpable spleen >16 cm are not eligible.
6. Leukocytosis ≥25,000/uL on Day 1 of treatment with study medication.
7. Subjects with known thrombophilic risk factors. Exception: Subjects for whom the potential benefits of participating in the study outweigh the potential risks of thromboembolic events, as determined by the investigator.
8. Female subjects who are nursing or pregnant (positive serum or urine β-human chorionic gonadotropin [β-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 (e.g. sepsis).
12. Subjects infected with Hepatitis B, C or Human Immunodeficiency Virus (HIV).
13. Subjects with liver cirrhosis (as determined by the investigator).
14. Subjects receiving or planned to receive any prohibited medication (see Section 6.2).
15. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to eltrombopag or excipient (microcrystalline cellulose, mannitol, polyvinylpyrrolidine, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol 400 and polysorbate 80) that contraindicates the subjects’ participation.
16. In France, subjects who have participated in any study using an investigational drug during the previous 30 days. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 2 of Study:
The primary endpoint is clinically relevant thrombocytopenic events (CRTE) during weeks 5-12 of treatment. CRTE are defined as:
• platelet counts <10 Gi/L, or
• platelet transfusions, or
• ≥Grade 3 hemorrhagic adverse events. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Screening, Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 11,
End of Therapy – Week 12,
Early Withdrawal Visit, Follow up Visit – Week 1, 2, 3 & 4 |
|
| E.5.2 | Secondary end point(s) |
Part 2 of Study:
Secondary endpoints compare the following in subjects treated with eltrombopag and placebo:
• Hematologic improvement (platelets, neutrophils and hemoglobin)
• Assessment of platelet counts throughout the study
• Number of platelet transfusions
• Duration of platelet transfusion-independence.
• The occurrence and severity of bleeding, measured using the WHO Bleeding Scale.
• Disease response and disease progression
• Physical exam findings, clinical monitoring, vital signs, clinical laboratory tests, and adverse event reporting (including
hemorrhagic and transfusion-related adverse events).
• Medical resource utilization, including specifically due to thrombocytopenia and hemorrhage.
• FACT-TH-18 and the EQ-5D |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Screening, Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 11, End of Therapy – Week 12, Early Withdrawal Visit, Follow Up Visits – Week 1, 2, 3 & 4 |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| 3 Part sequential Study design. |
|
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 54 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Belgium |
| Brazil |
| Canada |
| Czech Republic |
| France |
| Germany |
| Greece |
| Hong Kong |
| Hungary |
| India |
| Israel |
| Italy |
| Korea, Republic of |
| Netherlands |
| Peru |
| Poland |
| Russian Federation |
| Spain |
| Taiwan |
| Thailand |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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