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

Study Overview
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Brief Summary
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The primary objective was to assess the superiority of darbepoetin alfa versus placebo on the incidence of red blood cell transfusions during the 24-week double-blind treatment period in anemic patients with low or intermediate-1 risk MDS.

Detailed Description
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This study consists of a 3-week screening period, a 24-week double-blind treatment period, and a 48-week active treatment period and the long-term follow-up period. An end of treatment period (EOTP) visit occurs at week 25, or 3 weeks after last dose of investigational product (IP) for participants who withdraw from the study. After entering the active treatment period, an end of active treatment period (EOATP) visit occurs at week 72 / 73, or 3 weeks after the last dose of darbepoetin alfa. Long-term follow-up (LTFU) will occur every 26 weeks (± 4 weeks) from the EOATP visit (or EOTP visit if the participant does not enter the active treatment period) and will continue for a minimum of 3 years from the first dose of IP. Follow-up may occur through clinic visit or telephone contacts. Information on the participant's survival and progression to AML status will be collected during LTFU.

Official Title
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A Multicenter, Randomised, Double-blind, Placebo-controlled Study of Darbepoetin Alfa for the Treatment of Anaemic Subjects With Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)

Conditions
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MDS

Intervention / Treatment
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* Drug: Darbepoetin alfa
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 performed within 16 weeks prior to randomisation. Subject cannot have been rendered low or intermediate-1 risk by prior disease modifying therapy. Bone marrow slides must be available for centralized review at any time throughout the study World Health Organization (WHO) classification of refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), refractory cytopenias with multilineage dysplasia (RCMD), MDS-unclassified (MDSU), MDS with isolated del(5q) (5q- syndrome) or refractory anaemia with excess blasts-1 (RAEB-1) Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 assessed during screening Haemoglobin level ≤ 10.0 g/dL as assessed by the local laboratory; sample obtained within 7 days prior to randomisation (retest during screening is acceptable) Adequate transferrin saturation (Tsat) (≥ 15%) and serum ferritin (≥ 10 ng/mL) as assessed by the central laboratory during screening (supplementation and retest during screening is acceptable) Adequate serum folate (≥ 4.5 nmol/L [≥ 2.0 ng/mL]) or RBC folate (≥ 317 nmol/L [≥ 140 ng/mL]) as assessed by the local laboratory during screening (supplementation and retest during screening is acceptable) Adequate vitamin B12 (≥ 148 pmol/L [≥ 200 pg/mL]) as assessed by the local laboratory during 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, red cell enzyme deficiency), active hemorrhage, red cell aplasia, haemolytic anaemia History of malignancies other than curatively treated non-melanoma skin or in situ carcinoma 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 as determined by the investigator at screening. Subjects with known myocardial infarction within 6 months prior to randomisation Uncontrolled hypertension defined as systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg at screening Clinically significant systemic infection or uncontrolled chronic inflammatory disease (ie, rheumatoid arthritis, inflammatory bowel disease) as determined by the investigator at screening History of seizure disorder (subject with previous history of seizure disorder will be eligible for the study if he/she had no evidence of seizure activity within 5 years of randomisation 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 during either of 2 consecutive 8-week periods (ie, days -113 to -57 or days -56 to 0) prior to randomisation Received any RBC transfusion within 14 days prior to randomisation Received cytotoxic chemotherapy for any oncologic indication or planning to receive cytotoxic 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 response modifiers during the double-blind treatment period of the study Received myeloablative or craniospinal radiation or planning to receive myeloablative or craniospinal radiation during the double-blind treatment period of the study Received granulocyte colony stimulating factor (G-CSF) therapy within 30 days prior to randomization or planning to receive G-CSF therapy during the double-blind treatment period of the study (temporary use of G-CSF for neutropenia with fever and/or infection is acceptable) Abnormal renal function (serum creatinine level > 2 times the upper limit of the respective normal range [ULN]) as assessed by the central laboratory at screening Abnormal liver function (total bilirubin > 2 times, alanine aminotransferase [ALT] or aspartate aminotransferase [AST] > 3 times ULN) as assessed by the central laboratory at screening. (Subjects with abnormal bilirubin at screening due to documented Gilbert's Disease are eligible if all other criteria are met.) Serum endogenous erythropoetin (EPO) level > 500 mU/mL as assessed by the central laboratory at screening Known seropositivity for human immunodeficiency virus (HIV) or diagnosis of acquired Immunodeficiency syndrome (AIDS), positive for hepatitis B surface antigen, or seropositive 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 30 days since ending another investigational device or drug study(s), or receiving other investigational agent(s) Female subject is not willing to use highly effective contraception during treatment and for at least 1 month after the end of treatment Female subject is pregnant or planning to become pregnant within 1 month after the end of 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 the subject and investigator's knowledge Subject has any kind of disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or to comply with all required study procedures Confirmed history of neutralising antibody activity to rHuEpo or darbepoetin alfa

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Darbepoetin alfa<br>Participants received darbepoetin alfa 500 µg every three weeks (Q3W) for 24 weeks in the double-blind treatment period, and continued to receive darbepoetin alfa 500 µg Q3W during the active treatment period for an additional 48 weeks. | Drug: Darbepoetin alfa<br>* Administered by subcutaneous injection every 3 weeks<br>* Other names: Aranesp;|
| Placebo Comparator: Placebo<br>Participants received placebo subcutaneous injection every 3 weeks (Q3W) for 24 weeks during the double-blind treatment period. From week 25 participants received darbepoetin alfa 500 µg Q3W during the active treatment period for 48 weeks. | Drug: Placebo<br>* Administered by subcutaneous injection every 3 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With at Least One Red Blood Cell (RBC) Transfusion During the Double-blind Treatment Period |  | Week 5 to Week 25 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved an Erythroid Response Based on International Working Group (IWG) 2006 Criteria in the Double-blind Treatment Period | International Working Group 2006 erythroid response was defined as achieving an initial ≥ 1.5 g/dL increase in hemoglobin from baseline and sustaining an average rise of ≥ 1.5 g/dL in a rolling 56-consecutive day period in the absence of RBC transfusion. Participants with no hemoglobin collected to the minimum time required to observe an IWG erythroid response (Week 13) were considered non-responders. | Up to 24 weeks | 
| Number of Participants With Adverse Events | The severity of each adverse event was graded using the the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grading scale, where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening and grade 5 = death. Prespecified adverse events of interest for darbepoetin alfa, based on clinical data in anemic patients with cancer, included the following categories: hypersensitivity, cardiac failure, hypertension, malignancies, embolic and thrombolic events, venous thromboembolic events (VTEs), central nervous system vascular disorders, and ischemic heart disease. | From first dose of study drug until the end of the double-blind treatment period; 24 weeks. | 
| Number of Participants With Disease Progression to Acute Myeloid Leukemia (AML) | Transformation to AML was assessed according to WHO guidelines in the absence of IP and any haematopoietic growth factors (2 weeks off dosing). Bone marrow and/or cytogenetic report confirmation of AML was required (marrow or peripheral blast cells ≥ 20%, presence of pathognomic AML cytogenetic change, or evidence of marrow blast criteria for erythroleukemia). A pathology report confirming other leukemias such as chloroma (granulocytic sarcoma, myeloid sarcoma) or leukemia cutis also constituted transformation to AML. | 24 weeks | 
| Number of Participants With Malignancies Other Than AML, Basal Cell Carcinoma, or Squamous Cell Carcinoma of the Skin |  | Up to 24 weeks | 
| Number of Participants Who Developed Neutralizing Antibodies to Darbepoetin Alfa | Two validated assays were used to detect the presence of anti-darbepoetin alfa antibodies. Samples were first tested in an immunoassay to detect antibodies capable of binding to darbepoetin alfa. Samples confirmed to be positive for binding antibodies were subsequently tested in a cell-based assay to determine neutralizing activity against darbepoetin alfa. If a sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the sample was defined as positive for neutralizing antibodies. The number of participants who developed antibodies to darbepoetin alfa is defined as participants who were neutralizing antibody positive post-baseline with a negative or no result at baseline. | Baseline and end of double-blind treatment period (24 weeks) | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) | The FACIT-Fatigue scale was a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means not at all, and 4 means very much. The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue. A positive change from baseline score indicates an improvement. End of treatment period (EOTP) analysis includes last available values. | Baseline, and weeks 13 and 25 | 
| Change From Baseline in EuroQol-5D (EQ-5D) Visual Analog Scale (VAS) | The EQ-5D visual analog scale (VAS) is a global evaluation of overall health state with scores ranging from 0 (worse health state a participant can imagine) to 100 (best health state a participant can imagine). End of treatment period (EOTP) analysis includes last available values. | Baseline, and weeks 13 and 25 | 
| Percentage of Participants With a Clinically Meaningful Improvement in Fatigue | The FACIT-Fatigue scale was a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means not at all, and 4 means very much. The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue. Clinically meaningful improvement in fatigue is defined as an increase of ≥ 3 points in the FACIT-Fatigue subscale score, from baseline to EOTP. | Baseline to week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomized, Darbepoetin alfa, Myelodysplastic Syndromes, Placebo-controlled, low risk MDS, intermediate-1 risk MDS, International Prognostic Scoring System