Clinical trial NCT01362140: Darbepoetin Alfa in Patients With Anemic Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: MDS
Keywords: Randomized
Darbepoetin alfa
Myelodysplastic Syndromes
Placebo-controlled
low risk MDS
intermediate-1 risk MDS
International Prognostic Scoring System
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2011-05-30
Enrollment: 147
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants With at Least One Red Blood Cell (RBC) Transfusion During the Double-blind Treatment Period
timeFrame: Week 5 to Week 25
Secondary outcomes:
measure: Percentage of Participants Who Achieved an Erythroid Response Based on International Working Group (IWG) 2006 Criteria in the Double-blind Treatment Period
timeFrame: Up to 24 weeks
measure: Number of Participants With Adverse Events
timeFrame: From first dose of study drug until the end of the double-blind treatment period; 24 weeks.
measure: Number of Participants With Disease Progression to Acute Myeloid Leukemia (AML)
timeFrame: 24 weeks
measure: Number of Participants With Malignancies Other Than AML, Basal Cell Carcinoma, or Squamous Cell Carcinoma of the Skin
timeFrame: Up to 24 weeks
measure: Number of Participants Who Developed Neutralizing Antibodies to Darbepoetin Alfa
timeFrame: Baseline and end of double-blind treatment period (24 weeks)
measure: Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F)
timeFrame: Baseline, and weeks 13 and 25
measure: Change From Baseline in EuroQol-5D (EQ-5D) Visual Analog Scale (VAS)
timeFrame: Baseline, and weeks 13 and 25
measure: Percentage of Participants With a Clinically Meaningful Improvement in Fatigue
timeFrame: Baseline to week 24
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Research Site
city: Linz
country: Austria
facility: Research Site
city: Salzburg
country: Austria
facility: Research Site
city: Wien
country: Austria
facility: Research Site
city: Brugge
country: Belgium
facility: Research Site
city: Bruxelles
country: Belgium
facility: Research Site
city: Charleroi
country: Belgium
facility: Research Site
city: Gent
country: Belgium
facility: Research Site
city: Haine Saint Paul - La Louviere
country: Belgium
facility: Research Site
city: Hasselt
country: Belgium
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Liege
country: Belgium
facility: Research Site
city: Ottignies
country: Belgium
facility: Research Site
city: Roeselare
country: Belgium
facility: Research Site
city: Sint-Niklaas
country: Belgium
facility: Research Site
city: Brno
country: Czechia
facility: Research Site
city: Hradec Kralove
country: Czechia
facility: Research Site
city: Olomouc
country: Czechia
facility: Research Site
city: Ostrava-Poruba
country: Czechia
facility: Research Site
city: Praha 10
country: Czechia
facility: Research Site
city: Praha 2
country: Czechia
facility: Research Site
city: Praha 2
country: Czechia
facility: Research Site
city: Praha 5
country: Czechia
facility: Research Site
city: Zlin
country: Czechia
facility: Research Site
city: Avignon Cedex 9
country: France
facility: Research Site
city: Bobigny cedex
country: France
facility: Research Site
city: Caen
country: France
facility: Research Site
city: Lyon Cédex 3
country: France
facility: Research Site
city: Lyon
country: France
facility: Research Site
city: Nantes Cedex 1
country: France
facility: Research Site
city: Nice Cedex 3
country: France
facility: Research Site
city: Paris Cedex 10
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Pontoise Cedex
country: France
facility: Research Site
city: Toulouse Cedex 9
country: France
facility: Research Site
city: Vandoeuvre les Nancy
country: France
facility: Research Site
city: Dresden
country: Germany
facility: Research Site
city: Göttingen
country: Germany
facility: Research Site
city: Hannover
country: Germany
facility: Research Site
city: Köln
country: Germany
facility: Research Site
city: Leipzig
country: Germany
facility: Research Site
city: Mannheim
country: Germany
facility: Research Site
city: Regensburg
country: Germany
facility: Research Site
city: Rotenburg (Wümme)
country: Germany
facility: Research Site
city: Ulm
country: Germany
facility: Research Site
city: Athens
country: Greece
facility: Research Site
city: Athens
country: Greece
facility: Research Site
city: Ioannina
country: Greece
facility: Research Site
city: Patra
country: Greece
facility: Research Site
city: Thessaloniki
country: Greece
facility: Research Site
city: Alessandria
country: Italy
facility: Research Site
city: Bologna
country: Italy
facility: Research Site
city: Genova
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Palermo
country: Italy
facility: Research Site
city: Pavia
country: Italy
facility: Research Site
city: Pesaro
country: Italy
facility: Research Site
city: Pisa
country: Italy
facility: Research Site
city: Reggio Calabria
country: Italy
facility: Research Site
city: Rionero In Vulture PZ
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: San Giovanni Rotondo FG
country: Italy
facility: Research Site
city: Udine
country: Italy
facility: Research Site
city: Zaragoza
country: Spain
facility: Research Site
state: Aragón
city: Salamanca
country: Spain
facility: Research Site
state: Castilla León
city: Barcelona
country: Spain
facility: Research Site
state: Cataluña
city: Valencia
country: Spain
facility: Research Site
state: Comunidad Valenciana
city: Valencia
country: Spain
facility: Research Site
state: Comunidad Valenciana
city: Basel
country: Switzerland
facility: Research Site
city: Luzern
country: Switzerland
facility: Research Site
city: Muensterlingen
country: Switzerland
facility: Research Site
city: Zurich
country: Switzerland
facility: Research Site
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Platzbecker U, Symeonidis A, Oliva EN, Goede JS, Delforge M, Mayer J, Slama B, Badre S, Gasal E, Mehta B, Franklin J. A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes. Leukemia. 2017 Sep;31(9):1944-1950. doi: 10.1038/leu.2017.192. Epub 2017 Jun 19.