Darbepoetin Alfa in Patients With Anemic Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)

Inclusion Criteria:

• Low or intermediate-1 risk MDS patients per International Prognostic Scoring System (IPSS) at the time of randomisation, as determined by complete blood count (CBC)during screening and bone marrow examination and marrow cytogenetic analysis performedwithin 16 weeks prior to randomisation. Subject cannot have been rendered low orintermediate-1 risk by prior disease modifying therapy. Bone marrow slides must beavailable for centralized review at any time throughout the study

• World Health Organization (WHO) classification of refractory anemia (RA), refractoryanemia with ring sideroblasts (RARS), refractory cytopenias with multilineagedysplasia (RCMD), MDS-unclassified (MDSU), MDS with isolated del(5q) (5q- syndrome) orrefractory anaemia with excess blasts-1 (RAEB-1)

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 assessedduring screening

• Haemoglobin level ≤ 10.0 g/dL as assessed by the local laboratory; sample obtainedwithin 7 days prior to randomisation (retest during screening is acceptable)

• Adequate transferrin saturation (Tsat) (≥ 15%) and serum ferritin (≥ 10 ng/mL) asassessed by the central laboratory during screening (supplementation and retest duringscreening is acceptable)

• Adequate serum folate (≥ 4.5 nmol/L [≥ 2.0 ng/mL]) or RBC folate (≥ 317 nmol/L [≥ 140ng/mL]) as assessed by the local laboratory during screening (supplementation andretest during screening is acceptable)

• Adequate vitamin B12 (≥ 148 pmol/L [≥ 200 pg/mL]) as assessed by the local laboratoryduring screening (supplementation and retest during screening is acceptable)

• 18 years of age or older

• Subject or subject's legally acceptable representative has provided informed consent -

Exclusion Criteria:

• Previously diagnosed with intermediate-2 or high risk MDS per IPSS

• Therapy-related or secondary MDS

• History of acute leukemia

• Evidence of bone marrow collagen fibrosis

• Inherited anaemia (eg, haemoglobinopathy, thalassemia, red cell membrane defect, redcell enzyme deficiency), active hemorrhage, red cell aplasia, haemolytic anaemia

• History of malignancies other than curatively treated non-melanoma skin or in situcarcinoma

• History of thrombosis within 6 months prior to randomisation

• Previous bone marrow or stem cell transplantation

• Uncontrolled angina, uncontrolled heart failure, or uncontrolled cardiac arrhythmia asdetermined by the investigator at screening. Subjects with known myocardial infarctionwithin 6 months prior to randomisation

• Uncontrolled hypertension defined as systolic blood pressure ≥ 160 mmHg and/ordiastolic blood pressure ≥ 100 mmHg at screening

• Clinically significant systemic infection or uncontrolled chronic inflammatory disease (ie, rheumatoid arthritis, inflammatory bowel disease) as determined by theinvestigator at screening

• History of seizure disorder (subject with previous history of seizure disorder will beeligible for the study if he/she had no evidence of seizure activity within 5 years ofrandomisation and is currently free of antiseizure medication)

• Previous or ongoing use of erythropoiesis-stimulating agent (ESA) therapy, eg,recombinant human erythropoietin (rHuEpo), darbepoetin alfa

• High transfusion demand: receiving a total of ≥ 4 units of RBC transfusion duringeither of 2 consecutive 8-week periods (ie, days -113 to -57 or days -56 to 0) priorto randomisation

• Received any RBC transfusion within 14 days prior to randomisation

• Received cytotoxic chemotherapy for any oncologic indication or planning to receivecytotoxic chemotherapy during the double-blind treatment period of the study

• Received biologic response modifiers (eg, thalidomide, lenalidomide, arsenic trioxide,azacitidine, decitabine) to treat MDS or planning to receive biologic responsemodifiers during the double-blind treatment period of the study

• Received myeloablative or craniospinal radiation or planning to receive myeloablativeor craniospinal radiation during the double-blind treatment period of the study

• Received granulocyte colony stimulating factor (G-CSF) therapy within 30 days prior torandomization or planning to receive G-CSF therapy during the double-blind treatmentperiod of the study (temporary use of G-CSF for neutropenia with fever and/orinfection is acceptable)

• Abnormal renal function (serum creatinine level > 2 times the upper limit of therespective normal range [ULN]) as assessed by the central laboratory at screening

• Abnormal liver function (total bilirubin > 2 times, alanine aminotransferase [ALT] oraspartate aminotransferase [AST] > 3 times ULN) as assessed by the central laboratoryat screening. (Subjects with abnormal bilirubin at screening due to documentedGilbert's Disease are eligible if all other criteria are met.)

• Serum endogenous erythropoetin (EPO) level > 500 mU/mL as assessed by the centrallaboratory at screening

• Known seropositivity for human immunodeficiency virus (HIV) or diagnosis of acquiredImmunodeficiency syndrome (AIDS), positive for hepatitis B surface antigen, orseropositive for hepatitis C virus

• Subjects with active ethanol abuse, as judged by the investigator

• Currently enrolled in another investigational device or drug study, or less than 30days since ending another investigational device or drug study(s), or receiving otherinvestigational agent(s)

• Female subject is not willing to use highly effective contraception during treatmentand for at least 1 month after the end of treatment

• Female subject is pregnant or planning to become pregnant within 1 month after the endof treatment

• Subject has known sensitivity to any of the products to be administered during dosing

• Subject has previously been randomised into this study

• Subject will not be available for protocol-required study visits, to the best of thesubject and investigator's knowledge

• Subject has any kind of disorder that, in the opinion of the investigator, maycompromise the ability of the subject to give written informed consent and/or tocomply with all required study procedures

• Confirmed history of neutralising antibody activity to rHuEpo or darbepoetin alfa