| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| TRANSFUSION-DEPENDENT ANEMIA DUE TO IPSS LOW OR INTERMEDIATE-1 RISK MYELODYSPLASTIC SYNDROMES WITHOUT DELETION 5Q [31] AND UNRESPONSIVE OR REFRACTORY TO ERYTHROPOIESIS-STIMULATING AGENT |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068361 |
| E.1.2 | Term | MDS |
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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 compare the efficacy of lenalidomide versus placebo in subjects with red blood cell (RBC) transfusion-dependent low or Int-1 risk MDS associated with any karyotype except deletion 5q[31] and unresponsive or refractory to erythropoiesis-stimulating agents in the overall population and in the pre-specified subgroup of subjects with an erythroid differentiation signature predictive of lenalidomide response |
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| E.2.2 | Secondary objectives of the trial |
•To evaluate the safety of lenalidomide versus placebo in subjects with RBC transfusion-dependent low or Int-1 risk MDS associated with any karyotype except deletion 5q[31] and unresponsive or refractory to erythropoiesis-stimulating agents.
•To evaluate the impact of lenalidomide therapy on health-related quality of life (HRQOL) and healthcare resource utilization.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Must understand and voluntarily sign an informed consent form.
2.Age ≥ 18 years at the time of signing the informed consent form.
3.Must be able to adhere to the study visit schedule and other protocol requirements including willingness to undergo bone marrow aspirate and biopsy as indicated in the study protocol.
4.Must be able to complete patient-reported outcome assessments either independently or with minimal assistance from trained clinic personnel or caregiver.
5.Must have a documented diagnosis of MDS according to WHO 2008 classification (Brunning, 2008) associated with the following features:
- IPSS low or intermediate-1 risk
- Any karyotype except del 5q [31] (at least 20 analyzable metaphases are required for standard G-banding cytogenetic analysis at screening).
6.Must have transfusion-dependent anemia that meets the following criteria:
- Average transfusion requirement of ≥2 units‡/28 days of pRBCs confirmed for a minimum of 112 days immediately preceding randomization.
- No consecutive 56 days that was RBC transfusion-free during the 112 days immediately preceding randomization.
7.Must be unresponsive or refractory to erythropoiesis-stimulating agents, based on one of the following two criteria:
- Transfusion-dependence in subjects previously treated with an ESA (requires a minimum ESA trial of > 40,000 U/week r-HuEPO x 8 weeks or equivalent dose of darbepoetin), or
- Serum erythropoietin level of > 500 mU/mL (measured when Hgb < 9.5 g/dL) in subjects not previously treated with an ESA.
8.Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.
9.Concurrent corticosteroids used for medical conditions other than MDS is allowed provided subject is on a stable or decreasing dose for ≥ 1 week prior to randomization.
10.Females of childbearing potential (FCBP) must undergo pregnancy testing based on the frequency outlined in Appendices 21.2 and 21.3 and 21.4 and pregnancy results must be negative.
11.Unless practicing complete abstinence from heterosexual intercourse, sexually active FCPB must agree to use adequate contraceptive methods as specified in Appendices 21.2 and 21.3 and 21.4.
12.Males (including those who have had a vasectomy) must use barrier contraception (condoms) when engaging in sexual activity with FCBP as specified Appendices 21.2 and 21.3 and 21.4.
13.Males must agree not to donate semen or sperm during the duration specified in Appendices 21.2 and 21.3 and 21.4.
14. All subjects must:
- Understand that the investigational product could have a potential teratogenic risk.
- Agree to abstain from donating blood while taking investigational product and following discontinuation of investigational product (see Appendices 21.2 and 21.3 and 21.4)
- Agree not to share investigational product with another person.
- Be counseled about pregnancy precautions and risks of fetal exposure (see Appendices 21.2 and 21.3 and 21.4).
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| E.4 | Principal exclusion criteria |
1.Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
2.Pregnant or lactating females.
3.Prior history of malignancies, other than MDS, unless the subject has been free of the disease for ≥ 3 years. However, subjects with the following history/concurrent conditions may enroll at any time:
- Basal cell carcinoma of the skin
- Carcinoma in situ of the cervix
- Incidental histologic finding of prostate cancer (Tumor Node Metastasis (TNM) stage of T1a or T1b)
4. Known Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV) infection.
5.Prior therapy with lenalidomide.
6.Any of the following laboratory abnormalities:
- Absolute neutrophil count (ANC) < 500/μL (0.5 x 109/L)
- Platelet count < 50,000/μL (50 x 109/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)
- o serum bilirubin levels > 1.5 x ULN;
serum bilirubin levels > 1.5 x ULN are acceptable if these can be attributed to ineffective erythropoiesis (as indicated by bone marrow findings). Subjects with ineffective erythropoiesis may have a decreased haptoglobin level, elevated indirect bilirubin level and/or lactate dehydrogenase level. Autoimmune hemolytic anemia (as indicated by positive Coombs’ testing) is an exclusion criterion.
7. Hypersensitivity to thalidomide including
- Prior ≥ grade-2 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 3.0 allergic reaction to thalidomide
- Prior desquamating (blistering) rash while taking thalidomide
8.Renal insufficiency (CrCl < 60 mL/min by Cockroft-Gault method)
9.Uncontrolled hyperthyroidism or hypothyroidism.
10.≥ Grade-2 neuropathy.
11.Use of cytotoxic chemotherapeutic or investigational agents to treat MDS within 28 days prior to randomization or ongoing adverse events from previous treatment with investigational drugs, regardless of the time period.
12.Use of an erythropoiesis stimulating agent within the 56 days prior to randomization.
13.Prior allogeneic or autologous stem cell transplantation.
14.Concurrent use of androgens other than to treat hypogonadism.
15.Clinically significant anemia due to iron, B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding.
- If marrow stain for iron is not available, the transferrin saturation (iron/total iron binding capacity Fe/TIBC) must be >20% or serum ferritin must be >100 ng/dL.
16.Prior history of deep venous thrombosis (DVT) or pulmonary embolus (PE) within 3 years of randomization.
17.Significant active cardiac disease within the previous 6 months including:
- New York Heart Association class II-IV congestive heart failure
- Unstable angina or angina requiring surgical or medical intervention
- Myocardial infarction
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| E.5 End points |
| E.5.1 | Primary end point(s) |
•Proportion of subjects in the
- overall population and in the
- pre-specified subgroup of subjects with an erythroid differentiation gene expression signature predictive of lenalidomide response (Ebert, 2008).
achieving red blood cell (RBC) transfusion independence (using International Working Group (IWG) 2006 criteria)
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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 | 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 | Yes |
| 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 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| 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 | Information not present in EudraCT |
| 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 |
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| 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
|
| The expected duration of the study is 6 years, consisting of a 2 year enrollment period, blinded lenalidomide or placebo treatment for up to one year after the last subject is randomized, and an additional 3 years to complete the follow-up period. The study will end after follow-up has been completed for all patients. |
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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 | 6 |
| 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 | 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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