| 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 |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068361 |
| E.1.2 | Term | MDS |
| 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 compare the efficacy of lenalidomide versus placebo in subjects with red blood cell (RBC) transfusiondependent low or Int-1 risk MDS associated with any karyotype except deletion 5q[31] and unresponsive or refractory to erythropoiesis-stimulating agents in the ITT population and in the pre-specified subgroup of subjects with an erythroid differentiation signature predictive of lenalidomide response |
|
| 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 erythropoiesisstimulating agents.
•To evaluate the impact of lenalidomide therapy on health-related quality of life (HRQOL) and healthcare resource utilization. |
|
| 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.
classification (Brunning, 2008) associated with the following features:
- IPSS low or intermediate-1 risk (subjects who were once a higher risk
IPSS are excluded)
- 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.
- Hemoglobin levels at the time of or within 7 days prior to transfusions
must have been ≤ 9.0 g/dL¶ for the transfusions to qualify as required
for the purpose of providing evidence of transfusion-dependent anemia
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 other erythropoietin agent), or
- Serum erythropoietin level of > 500 mU/mL 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 21.4 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 21.4.
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 21.4.
13.Males must agree not to donate semen or sperm during the duration
specified in Appendices 21.2 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 21.4)
- Agree not to share investigational product with another person.
- Be counseled about pregnancy precautions and risks of fetal exposure
(see Appendices 21.2 and 21.4).
Footnote:
¶ Hemoglobin levels ≤ 9.5 g/dL are acceptable if standard practice for
clinical management of the subject. |
|
| 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 ≥ 5 years. However, subjects with the following
history/concurrent conditions are allowed:
- 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 immunomodulating or immunosuppressive agents,
or epigenetic or DNA modulating agents. Subjects who received
investigational agents are also excluded.
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.
Subjects with ineffective erythropoiesis may have a decreased
haptoglobin level, elevated indirect bilirubin level and/or lactate
dehydrogenase level (refer to Appendix 21.10). Autoimmune hemolytic
anemia is an exclusion criterion.
7. Renal insufficiency (CrCl < 40 mL/min by Cockroft-Gault method)
8. Uncontrolled hyperthyroidism or hypothyroidism.
9. ≥ Grade-2 neuropathy.
10. Use of an erythropoiesis stimulating agent within the 56 days prior
to randomization.
11. Prior allogeneic or autologous stem cell transplantation.
12. Concurrent use of androgens other than to treat hypogonadism.
13. 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
14. Prior history of deep venous thrombosis (DVT) or pulmonary
embolus (PE) within 3
years of randomization.
15. 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Proportion of subjects in the
- ITT 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 for at least 8 weeks (using International Working Group (IWG) 2006 criteria) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Up to 6 years for each subject (likely to be 6 months to 2 years) |
|
| E.5.2 | Secondary end point(s) |
Evaluate the safety of lenalidomide versus placebo. [ Time Frame: at least 6 years from study start through follow-up ]
Evaluate the impact of lenalidomide therapy on health-related quality of life (HRQOL) and use of healthcare resources. [ Time Frame: at least 6 years from study start through follow-up ]
|
|
| 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 | 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.8.2.4 | 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 | 68 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Czech Republic |
| France |
| Germany |
| Israel |
| Italy |
| Poland |
| Portugal |
| Spain |
| Turkey |
| 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
|
The expected duration of the study is 6 years, consisting of a 3 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 all patients have completed the follow-up period (at least 5 years after randomization) or all
patients have died, whichever is shorter. |
|
| 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 |
Print
