E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Transfusion-dependant, low-or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality |
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E.1.1.1 | Medical condition in easily understood language |
myelosydplastic syndrome is a disorder of the bone marrow, leading to a reduced number of red blood cells. “Deletion 5q[31]” means that the bone-marrow cells present a certain genetic characteristic |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 compare the efficacy of 2 doses of lenalidomide to that of placebo in subjects with red blood cell (RBC) transfusion-dependent low- or intermdiate-1-risk (International Prognosis Scoring System [IPSS]) MDS associated with a deletion (del) 5q[31] cytogenetic abnormality. |
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E.2.2 | Secondary objectives of the trial |
To compare the safety of 2 doses of lenalidomide to that of placebo in subjects with RBC transfusion-dependent low- or intermdiate-1-risk MDS associated with a deletion (del) 5q[31] cytogenetic abnormality. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Pre-randomization Phase:
1. Must understand and voluntarily sign an informed consent form.
2. Must be ≥18 years of age at the time of signing the informed consent form
3. Must be able to adhere to the study visit schedule and other protocol requirements.
4. Concurrent corticosteroids used for medical conditions other than MDS is allowed provided subject is on a stable or decreasing dose for ≥1week prior to study entry
5. Prior thalidomide allowed
6. Documented diagnosis of MDS that meets IPSS criteria for low- to intermediate-1-risk disease and has an associated del 5q[31] cytogenetic abnormality (the deleted chromosomal region must include 5q[31]
7. RBC transfusion-dependent anemia defined as not having any consecutive 56 days without a RBC transfusion within at least the immediate 112 days (4 months). Note: A 112 day documented transfusion history is required for subjects to enter the double-blind phase of the study.
Double-blind randomization Phase:
As point 1-3, 6 and 7 above, plus:
1. Baseline RBC transfusion requirement has been calculated
2. Female subjects of childbearing potential must:
- Understand that the study medication could have a potential teratogenic risk
- Agree to use, and be able to comply with, effective contraception without
interruption, 28 days before starting study drug, throughout study drug therapy
(including dose interruptions) and for 28 days after the end of study drug therapy,
even if she has amenorrhoea. This applies unless the subject commits to absolute and continued abstinence confirmed on a monthly basis. The following are effective
methods of contraception: implant, Levonorgestrel-releasing intrauterine system, Medroxyprogesterone acetate depot, Tubal sterilisation, Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by two negative semen analyses, Ovulation inhibitory progesterone-only pills (i.e., desogestrel).
- Agree to have a medically supervised pregnancy test with a minimum sensitivity of
25 IU/ml not more than 3 days from the start of study medication once the subject has been on effective contraception for at least 28 days. This requirement also applies to females of childbearing potential who practice complete and continued abstinence.
- Agree to have a medically supervised pregnancy test every 28 days including 28 days after the end of study treatment, except in the case of confirmed tubal sterilization. These tests should be performed not more than 3 days before the start of next treatment. This requirement also applies to females of childbearing potential who practice complete and continued abstinence.
8. Male subjects must:
- Agree to use condoms throughout study drug therapy, during any dose interruption and for 7 days after cessation of study therapy if their partner is of childbearing potential and has no contraception.
- Agree not to donate semen during study drug therapy and for 7 days after end of
study drug therapy.
9. All subjects must:
- Agree to abstain from donating blood while taking study drug therapy and for 7 days following discontinuation of study drug therapy.
- Agree not to share study medication with another person and to return all unused
study drug to the investigator |
|
E.4 | Principal exclusion criteria |
Pre-randomization phase:
1. Pregnant or lactating females.
2. Prior therapy with lenalidomide
3. Proliferative (WBC≥12,000/mL) chronic myelomonocytic leukemia (CMML)
4. Prior ≥grade-2 NCI CTCAE allergic reaction to thalidomide
5. Prior desquamating (blistering) rash while taking thalidomide
6. Prior history of malignancy other than MDS (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for ≥3years
7. Use of cytotoxic chemotherapeutic agents or experimental agents (agents that are not commercially available) for the treatment of MDS within 28 days of Day 1 of the Pre-Randomization Phase.
8. Less than 6 months since prior allogeneic bone marrow transplantation of Day 1 of the Pre-Randomization Phase.
9. Less than 3 months since prior autologous bone marrow or stem cell transplantation of Day 1 of the Pre-Randomization Phase.
10. Less than 28 days since prior myelosuppressive anticancer biologic therapy of Day 1 of the Pre-Randomization Phase.
11. Use of erythropoiesis stimulating growth factors (e.g. recombinant human erythropoietin (rHuEPO) within 28 days or long-acting erythropoiesis stimulating growth factor (e.g. darbepoetin) with 56 days of Day 1 of the Pre-Randomization Phase
12. Use of androgens other than to treat hypogonadism is prohibited.
13. Known HIV-1 positivity
14. Any serious medical condition or psychiatric illness that will prevent the subject from signing the informed consent form or will place the subject at unacceptable risk if he or she participates in the study
Double-blind randomization Phase:
As points 1-6, 12, 13 and 14 above, plus:
1. Any of the following laboratory abnormalities:
- Absolute neutrophil count (ANC) < 500 cells/ μL (0.5 x 10^9/L)
- Platelet count < 25,000/μL (25 x 10^9/L)
- Serum creatinine > 2.0 mg/dL (177 mmol/L)
- Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase
(SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase
(SGPT) > 3.0 x upper limit of normal (ULN) unless it is clinically due to iron
overload from blood transfusions.
- Serum total bilirubin > 1.5 mg/dL
2. Clinically significant anemia owing to iron, B12, or folate deficiencies, or autoimmune or hereditary hemolysis or gastrointestinal bleeding (the subject must have a marrow aspirate that is evaluable for storage iron)
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|
E.5 End points |
E.5.1 | Primary end point(s) |
RBC transfusion independence for ≥ 26 weeks (182 days) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
1.Erythroid response (major and minor according to International MDS Working Group Criteria).
2.Duration of RBC transfusion independence defined to be the number of days between the last transfusion prior to the start of the transfusion-free period and the first transfusion after the transfusion-free period.
3.Change of blood hemoglobin (Hb) concentration from baseline in subjects who
achieve a major erythroid response
4.Erythroid response (major and minor according to International MDS Working Group Criteria) at one year.
5.Change in platelet counts from baseline
6.Change in absolute neutrophil counts from baseline
7.Cytogenetic response (according to the International MDS Working Group Criteria)
8.Bone marrow response (according to the International MDS Working Group Criteria)
9.Safety (type, frequency, and severity [National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE) version 3.0] of adverse events
(AEs), and relationship of AEs to lenalidomide)
10.Quality of Life (QoL) assessments: [the four components (Physical, Social/Family,
Emotional and Functional Well-Being) and total of the 27-item FACT-G, together
with the 13-item fatigue subscale, the total of the Additional Concerns, and the total
of all items on the FACT-An (the FACT-G items plus the items under Additional
Concerns} and EQ-5D [at initial visit only])
11.Overall Survival (OS)
12.Time to Acute Myeloid Leukemia (AML) Transformation |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to 52 weeks
2. Up to 52 weeks
3. Baseline, up to 52 weeks
4. up to 52 weeks
5. up to 52 weeks
6. up to week 52
7. up to 52 weeks
8. up to 52 weeks
9. up to week 52
10. Baseline, Week 12
11. up to 3 years after the last subject has completed/discontinued from the open-label phase
12. up to 3 years after the last subject has completed/discontinued from the open-label phase |
|
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 | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
additional open-label extension phase |
|
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 | 3 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
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 |
Belgium |
France |
Germany |
Israel |
Italy |
Spain |
Sweden |
United Kingdom |
|
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
|
See protocol. The follow-up period will last up to 3 years after the last subject has completed/discontinued from the Open-Label Phase. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
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 | 8 |
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 |