|E.1 Medical condition or disease under investigation
|E.1.1||Medical condition(s) being investigated ||
|subjects with International Prognostic Scoring Systems (IPSS) Low or Intermediate 1 risk myelodysplastic syndromes (MDS) who require any transfusion, compared with placebo, through Week 48.
|E.1.2 Medical condition or disease under investigation
|E.1.2||Classification code ||10028536
|E.1.2||Term ||Myelodysplastic syndromes
|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 ||
|The primary objective is to demonstrate that epoetin alfa treatment reduces the proportion of anemic subjects with IPSS Low or Intermediate 1 risk MDS who require any transfusion, compared with placebo, through Week 48.
|E.2.2||Secondary objectives of the trial ||
|The secondary objectives include both efficacy and safety endpoints and are as follows:
To compare the time to first transfusion after Day 28, the time to transfusion dependence, as defined by the 2006 IWG criteria after Day 28, the erythroid response rate using 2006 IWG criteria at Week 24 and Week 48, the cumulative number of RBC units transfused per subject through Weeks 24 and 48, a lack of erythropoietin accumulation after treatment with epoetin alfa once every week for 48 weeks
To assess the long-term safety of epoetin alfa treatment measured by a composite endpoint of time to MDS progression (see Attachment 7), AML, or death, the individual components of safety endpoints, including time to MDS progression (see Attachment 7), time to AML, and overall survival, progression free survival, the proportion of subjects with a TVE, the proportion of subjects whose disease progresses to AML by Week 52 and at the time of clinical cutoff
|E.2.3||Trial contains a sub-study || No
|E.3||Principal inclusion criteria ||
|Subjects must satisfy the following criteria to be enrolled in the study:
1. Male or female at least 18 years of age.
2. Diagnosis of MDS according to WHO or FAB pathologic
classification via bone marrow studies performed within 12 weeks
3. Documentation of an IPSS score indicating Low- or Intermediate-1
risk disease, based on bone marrow studies, including cytogenetics
and peripheral blood counts, performed within 12 weeks before
4. Screening hemoglobin concentration of 10.0 g/dL or less. The
screening hemoglobin concentration is defined as the average of at
least 2 measurements taken at least 1 week apart during the 2-week
period before randomization and not influenced by RBC transfusion
(i.e., no RBC transfusions within 1 week before hemoglobin
5. A baseline hemoglobin measurement collected within 24 hours prior
to the first dose of study drug must measure 10.5 g/dL or less.
6. Has not been transfusion dependent at any time during the previous
6 months before randomization. A subject is considered to be
transfusion dependent if he or she has received 4 or more RBC units
for MDS-related anemia during a consecutive 8-week period
(2006 IWG criteria).
7. Baseline serum erythropoietin concentration of less than
8. Adequate iron stores, defined as serum ferritin greater than
100 ng/mL or transferrin saturation greater than 20% or both,
measured within the 14-day screening period or adequate iron stores
as demonstrated by recent (within 12 weeks) bone marrow
examination with iron stain.
9. Documentation of adequate vitamin B12 and folate levels (above the
lower limit of the reference range for the laboratory performing the
assay), as measured within 12 weeks before randomization.
10. Adequate hematologic function, defined as an absolute neutrophil
count of at least 1,000/mm3 and a platelet count of at least
50,000/mm3, not influenced by platelet transfusions within the
previous 3 days.
11. Life expectancy of at least 12 months (12 months or longer).
12. ECOG performance status of 0, 1 or 2 (Attachment 4).
13. Female subjects with reproductive potential must be surgically
sterile, abstinent, or practicing an effective method of birth control
(e.g., prescription oral contraceptives, contraceptive injections,
intrauterine device, double-barrier method [spermicidal jelly or foam
with condoms or diaphragm], contraceptive patch, male partner
sterilization) before entry and throughout the study and have a
negative serum or urine beta human chorionic gonadotropin (β-hCG)
pregnancy test at screening.
14. Willingness to adhere to the prohibitions and restrictions specified in
15. Subjects (or their legally acceptable representatives) must sign an
informed consent document indicating that they understand the
purpose of and procedures required for the study and are willing to
participate in the study.
16. Subjects who agree to participate in DNA pharmacogenomic research
(or their legally acceptable representatives) must sign an informed
consent indicating willingness to participate in the pharmacogenomic
component of the study, where local regulations permit. Refusal to
consent for this component does not exclude a subject from
participation in the clinical study.
|E.4||Principal exclusion criteria||
|1. Anemia attributed to factors other than MDS (including iron
deficiency, vitamin B12 or folate deficiencies, hemolysis, chronic
renal failure, or gastrointestinal bleeding).
2. Secondary MDS (MDS arising after chemotherapy, immunotherapy
or radiation therapy/exposure).
3. Proliferative (WBC of at least 12,000/mm3) chronic myelomonocytic
leukemia (CMML) or atypical chronic myelogenous leukemia
4. Active malignancy within the past year except basal cell or squamous
cell skin cancer or carcinoma in situ of the cervix or breast.
5. Known history of HIV Type 1 seropositivity.
6. History (within 12 months) of deep venous thrombosis (includes
proximal and distal), pulmonary embolism, or other venous
thrombosis. Prior superficial thrombophlebitis is not an exclusion
7. History (within 6 months) of cerebrovascular accident (includes
ischemic, embolic, and hemorrhagic cerebrovascular accident),
transient ischemic attack, acute coronary syndrome (including
myocardial ischemia, unstable angina, Q wave myocardial infarction,
non-Q wave myocardial infarction), or other arterial thrombosis.
8. Currently receiving therapeutic anticoagulants (prophylactic
anticoagulants are acceptable).
9. Uncontrolled hypertension (defined as a systolic pressure of
160 mmHg or higher or a diastolic pressure of 110 mmHg or higher
10. New onset seizures (within 3 months before randomization) or poorly
11. Clinically significant, uncontrolled disease or dysfunction of the
pulmonary, cardiovascular, endocrine, neurologic, gastrointestinal, or
genitourinary systems not attributable to MDS.
12. Pregnancy or breast feeding.
13. Known hypersensitivity to mammalian-cell derived products or to
14. Prior or concurrent treatment with epoetin alfa or any other approved
or experimental ESA (e.g., epoetin beta, darbepoetin), within the
previous 12 months before randomization.
15. Use of experimental agents or devices for any reason within the
previous 8 weeks before randomization.
16. Prior use of any approved or experimental agent for the treatment of
MDS (e.g., cytotoxic chemotherapeutic agents, thalidomide,
lenalidomide, tipifarnib, lonafarnib, azacitidine, decitabine, and
17. Prior (within the previous 2 weeks) or concurrent treatment with
G-CSF or granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment of neutropenia.
18. Major infection requiring hospitalization and antibiotics within
2 weeks before randomization.
19. Major surgery within 4 weeks before randomization or planned major
surgery before Week 52.
20. Planned stem cell harvest of bone marrow or high-dose
chemotherapy with stem cell transplantation before Week 52.
21. Previous bone marrow or stem cell transplantation.
22. Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center and family members of the employees or the investigator.
|E.5 End points
|E.5.1||Primary end point(s)||
|Selection of a transfusion based variable as the primary endpoint reflects the currently accepted clinically meaningful outcome for registration studies of erythropoietic agents. The proportion of subjects who remain transfusion free from Day 29 through Week 48 was selected as the primary efficacy endpoint to account for the lag time between the start of erythropoietin treatment and its effect on hematopoiesis.
|E.6 and E.7 Scope of the trial
|E.6||Scope of the trial
|E.6.9||Dose response|| Yes
|E.7||Trial type and phase
|E.7.1||Human pharmacology (Phase I)|| No
|E.7.1.1||First administration to humans|| Information not present in EudraCT
|E.7.1.2||Bioequivalence study|| Information not present in EudraCT
|E.7.1.3||Other|| Information not present in EudraCT
|E.22.214.171.124||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.8.1.3||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.8.2|| Comparator of controlled trial
|E.8.2.1||Other medicinal product(s)|| No
|E.8.2.2||Placebo || Yes
The trial involves single site in the Member State concerned
|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|| Yes
|E.8.5.1||Number of sites anticipated in the EEA||6
|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||
|E.8.7||Trial has a data monitoring committee|| Yes
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||
|E.8.9.1||In the Member State concerned months||64
|E.8.9.1||In the Member State concerned days||
|E.8.9.2||In all countries concerned by the trial months||64