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Darbepoetin Alfa in Anemic Low or Intermediate-1 Risk MDS Subjects

Information source: Amgen
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: MDS

Intervention: Darbepoetin alfa (Drug); Placebo (Drug)

Phase: Phase 3

Status: Active, not recruiting

Sponsored by: Amgen

Official(s) and/or principal investigator(s):
MD, Study Director, Affiliation: Amgen

Summary

This is a Phase 3, multicenter, randomised, double-blind, placebo-controlled trial of darbepoetin alfa 500 μg administered once every 3 weeks (Q3W) to approximately 141 low or intermediate-1 risk anaemic MDS subjects who have not previously received erythropoiesis-stimulating agents (ESAs) or biologic response modifiers to treat MDS. 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 subjects 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 Q3W (2 weeks after the last dose of darbepoetin alfa administered every 2 weeks [Q2W]) for subjects who withdraw from the study. Long-term follow-up (LTFU) will occur every 26 weeks (± 4 weeks) from the EOATP visit (or EOTP visit if the subject 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 subject's survival and progression to AML status will be collected during LTFU. Approximately 141 subjects who meet all eligibility requirements will be randomised in a 2: 1 ratio to 1 of 2 groups: 1. darbepoetin alfa 500 μg Q3W (n=94) 2. placebo Q3W (n=47) Randomisation will be stratified by the International Prognostic Scoring System (IPSS) category (low versus intermediate-1) established at screening.

Clinical Details

Official title: 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)

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Supportive Care

Primary outcome: To assess the superiority of darbepoetin alfa versus placebo on the incidence of RBC transfusions during the double-blind treatment period.

Secondary outcome:

Adverse events, including treatment-emergent adverse events of interest (eg, pure red cell aplasia [PRCA]; thrombovascular events (TVE) [arterial thrombovascular events (ATE) and venous thrombovascular events (VTE)])

Mortality through EOTP, EOATP, and LTFU

Disease progression to acute myeloid leukemia (AML) through EOTP, EOATP, and LTFU

Proportion of subjects acheiving International Working Group (IWG) erythroid response during the double-blind treatment period.

Attaining a clinically meaningful change from baseline to EOTP in FACIT-F: improvement (at least a 3-point increase), deterioration (at least a 3-point decrease), unchanged (less than a 3-point in either direction)

Change in patient-reported fatigue and overall health status from baseline to week 13, EOTP, week 31, week 42/43, week 54/55, and week 72/73/ EOATP as measured by the Functional Assessment of Chronic Illness Therapy (FACIT-F) & EuroQOL-5D

Malignancies other than AML, basal cell carcinoma, or squamous cell carcinoma of the skin through EOTP

Neutralising antibody formation to darbepoetin alfa

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Low or intermediate-1 risk MDS patients per 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 centralised review at any time throughout the study

- World Health Organization (WHO) classification of refractory anaemia (RA), refractory

anaemia 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 International

Prognostic Scoring System (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 ESA therapy, eg, 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 G-CSF therapy within 30 days prior to randomisation 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

Locations and Contacts

Research Site, Innsbruck 6020, Austria

Research Site, Linz 4020, Austria

Research Site, Salzburg 5020, Austria

Research Site, Wien 1140, Austria

Research Site, Brugge 8000, Belgium

Research Site, Bruxelles 1200, Belgium

Research Site, Charleroi 6000, Belgium

Research Site, Gent 9000, Belgium

Research Site, Haine St. Paul - La Louviere 7100, Belgium

Research Site, Hasselt 3500, Belgium

Research Site, Leuven 3000, Belgium

Research Site, Liege 4000, Belgium

Research Site, Ottignies 1340, Belgium

Research Site, Roeselare 8800, Belgium

Research Site, Sint-Niklaas 9100, Belgium

Research Site, Brno 625 00, Czech Republic

Research Site, Hradec Kralove 500 05, Czech Republic

Research Site, Olomouc 775 20, Czech Republic

Research Site, Ostrava-Poruba 708 52, Czech Republic

Research Site, Praha 10 100 34, Czech Republic

Research Site, Praha 2 128 08, Czech Republic

Research Site, Praha 2 128 20, Czech Republic

Research Site, Praha 5 150 06, Czech Republic

Research Site, Zlin 760 01, Czech Republic

Research Site, Avignon Cedex 9 84902, France

Research Site, Bobigny cedex 93009, France

Research Site, Caen 14033, France

Research Site, Lyon Cédex 3 69437, France

Research Site, Lyon 69009, France

Research Site, Nantes Cedex 1 44035, France

Research Site, Nice Cedex 3 06202, France

Research Site, Paris Cedex 10 75475, France

Research Site, Paris 75015, France

Research Site, Pontoise Cedex 95301, France

Research Site, Toulouse Cedex 9 31059, France

Research Site, Vandoeuvre les Nancy 54511, France

Research Site, Dresden 01307, Germany

Research Site, Göttingen 37075, Germany

Research Site, Hannover 30625, Germany

Research Site, Köln 50677, Germany

Research Site, Leipzig 04103, Germany

Research Site, Mannheim 68167, Germany

Research Site, Regensburg 93053, Germany

Research Site, Rotenburg (Wümme) 27356, Germany

Research Site, Ulm 89081, Germany

Research Site, Athens 11527, Greece

Research Site, Athens 12462, Greece

Research Site, Ioannina 45110, Greece

Research Site, Patra 26500, Greece

Research Site, Thessaloniki 57010, Greece

Research Site, Alessandria 15100, Italy

Research Site, Bologna 40138, Italy

Research Site, Genova 16132, Italy

Research Site, Milano 20122, Italy

Research Site, Palermo 90146, Italy

Research Site, Pavia 27100, Italy

Research Site, Pesaro 61100, Italy

Research Site, Pisa 56127, Italy

Research Site, Reggio Calabria 89124, Italy

Research Site, Rionero in Vulture PZ 85028, Italy

Research Site, Roma 00161, Italy

Research Site, San Giovanni Rotondo FG 71013, Italy

Research Site, Udine 33100, Italy

Research Site, Basel 4031, Switzerland

Research Site, Luzern 6000, Switzerland

Research Site, Muensterlingen 8596, Switzerland

Research Site, Zurich 8091, Switzerland

Research Site, Zaragoza, Aragón 50009, Spain

Research Site, Salamanca, Castilla León 37007, Spain

Research Site, Barcelona, Cataluña 08003, Spain

Research Site, Valencia, Comunidad Valenciana 46010, Spain

Research Site, Valencia, Comunidad Valenciana 46026, Spain

Additional Information

AmgenTrials clinical trials website

Starting date: December 2011
Last updated: August 10, 2015

Page last updated: August 20, 2015

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