| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult subject (18 years of age older) with low or intermediate-1 IPSS risk MDS with isolated del(5q) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Myelodisplastic syndrome, a neoplasm of the bone marrow, characterized by altered blood cell growth and subsequent anemia |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10028536 |
| E.1.2 | Term | Myelodysplastic syndromes |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10067096 |
| E.1.2 | Term | 5q minus myelodysplastic syndrome |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 the effect of eltrombopag treatment relative to placebo on the incidence of the “composite endpoint” (PLT<25 Gi/L or bleeding event with WHO bleeding score >1 or study discontinuation), in the first 24 weeks, after experiencing PLT<100 Gi/L |
|
| E.2.2 | Secondary objectives of the trial |
1. The composite endpoint during the entire study period
2. Safety and tolerability in terms of frequency of adverse events (AE)s and serious adverse events (SAE).
3. Cytogenetic responses, according to IWG 2006 criteria.
4. Duration of cytogenetic response.
5. Hb changes within the first 24 weeks.
6. Erythroid response, transfusion-independence (TI) and duration of TI.
7. Changes in QOL scores.
8. Progression Free Survival (PFS) and Overall Survival (OS).
9. Maintenance of a 10 mg lenalidomide dosing. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adult subjects (18 years of age or older) with MDS and low or intermediate-1 IPSS risk and del5q as a single abnormality, at the time of their screening and enrollment into the study
2. Subjects must not have received any prior treatment course with any
immunomodulating agent nor TPO-R agonists
3. Subjects must be dependent on regular packed RBC transfusions, as defined by international working group 2006 criteria, and must have a PLT count taken within the 4 weeks prior to screening that is >25 Gi/L.[12]
4. Absolute Neutrophil Counts (ANC) ≥ 0.5 GiL
5. Resistant or refractory to erythropoetic stimulating agents (ESAs) and/or serum erythropoetin levels > 500 miU/L
6. Subjects must not have received erythropoetic stimulating agents (ESAs) 2 months prior to screening
7. Subjects must be ineligible or relapsed or refractory to receive treatment options of azacitidine and decitabine.
8. Subjects must not have received hypomethylating agents 2 months prior to screening
9. Subjects must have PLT count and RBC and PLT transfusion data available over a period of 8 weeks prior to screening.
10. During the 2 months prior to randomization, subjects must have a baseline BM examination including all of the following: cytomorphology, cytogenetics and histology
11. Bone Marrow histology for patients with hypocellular BM aspirat
12. ECOG Performance Status must be 0-3.
13. The following clinical chemistries MUST NOT exceed the upper limit of normal (ULN) reference range: creatinine, ALT, AST, total bilirubin (except for Gilbert's Syndrome), gamma-gt and alkaline phosphatase. In addition, albumin must not be below the lower limit of normal (LLN) by more than 10%.
14. If subject meets the criteria for childbearing potential:
a. Negative pregnancy test in female subjects within the 3 days prior to Day 1
of 1st cycle and effective contraception for at least 4 weeks.
b. Subject is practicing an acceptable method of contraception (documented in
chart). 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.
15. Criteria for women of non-childbearing potential:
A female patient or a female partner of a male patient is considered to have
childbearing potential unless she meets at least one of the following criteria:
a. Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year (amenorrhoea
following cancer therapy or during lactation does not rule out childbearing
potential).
b. Premature ovarian failure confirmed by a gynaecologist
c. Previous bilateral salpingo-oophorectomy, or hysterectomy
d. XY genotype, Turner syndrome, uterine agenesis.
16. Subject is able to understand and comply with protocol requirements and
instructions.
17. Subject has signed and dated informed consent. |
|
| E.4 | Principal exclusion criteria |
1. MDS with intermediate-2 or high IPSS risk
2. Additional cytogenetic abnormalities
3. Transfusion independence (TI) by IWG 2006 criteria [12]
4. ANC < 0.5 Gi/L and/or PLT counts < 25 Gi/L
5. History of treatment for cancer with systemic chemotherapy and/or radiotherapy within the last 2 years.
6. History of treatment with immunomodulatory drugs or other TPO-R agonists.
7. Thrombophilia, pre-existing history of thrombosis, 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. atrial fibrillation), or subjects with a QTc >450 msec (QTc >480 msec for subjects with Bundle Branch Block)
8. Subjects with deep thrombosis
9. BM fibrosis that leads to an inability to aspirate marrow for assessment.
10. Leukocytosis >=25,000/uL prior to Day 1 of study medication.
11. Monocytosis > 1000/ uL prior to Day 1 of study medication.
12. Female subjects who are nursing or pregnant (positive serum or urine Beta-human chorionic gonadotropin [B-hCG] pregnancy test).
13. Women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme illustrated in sections 6.4 are met (see sections 6.4).
14. Known hypersensitivity to lenalidomide.
15. Known hypersensitivity to Revolade or excipients
16. Current alcohol or drug abuse.
17. Treatment with an Investigational Product within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication.
18. Active and uncontrolled infections.
19. Subjects infected with Hepatitis B, C or Human Immunodeficiency Virus (HIV). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects amongst those experiencing PLT < 100 Gi/L within the first 24 weeks experiencing the “composite endpoint” (PLT<25 Gi/L or bleeding event with WHO bleeding score >1 or study discontinuation), in the first 24 weeks after experiencing PLT<100 Gi/L. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Overall proportion of subjects experiencing the composite endpoint during the entire study period
2. Safety and tolerability in terms of frequency of adverse events (AE)s and serious adverse events (SAE).
3. Proportion of cytogenetic responses, according to IWG 2006 criteria.
4. Duration of cytogenetic response.
5. Hb changes within the first 24 weeks.
6. Erythroid response, transfusion-independence (TI) and duration of TI.
7. Changes in QOL scores.
8. 3-year PFS and OS from baseline.
9. Proportion of patients maintaining a 10 mg lenalidomide dosing during the first 24 weeks and in the follow-up period. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | No |
| E.8.1.4 | Double blind | Yes |
| 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.8.2.4 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 59 |
| 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 | No |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| 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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