A Three-part Study of Eltrombopag in Thrombocytopenic Subjects With Myelodysplastic Syndromes or Acute Myeloid Leukemia (ASPIRE)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis
ClinicalTrials.gov Identifier:
NCT01440374
First received: September 15, 2011
Last updated: May 6, 2016
Last verified: May 2016
  Purpose

This is a worldwide, three-part (Part 1: open-label, Part 2: randomized, double-blind, Part 3: extension), multi-center study to evaluate the effect of eltrombopag in subjects with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who have thrombocytopenia due to bone marrow insufficiency from their underlying disease or prior chemotherapy. This objective will be assessed by a composite primary endpoint that consists of the following: the proportion of ≥Grade 3 hemorrhagic adverse events, or platelet counts <10 Gi/L, or platelet transfusions. Patients with MDS or AML and Grade 4 thrombocytopenia due to bone marrow insufficiency from their underlying disease or prior chemotherapy will be enrolled in the study. No low or intermediate-1 risk MDS subjects will be enrolled in the study.

Subjects must have had at least one of the following during the 4 weeks prior to enrolment: platelet count <10 Gi/L, platelet transfusion, or symptomatic hemorrhagic event. Supportive standard of care (SOC), including hydroxyurea, will be allowed as indicated by local practice throughout the study. The study will have 3 sequential parts. Subjects who are enrolled in Part 1 (open-label) cannot be enrolled in Part 2 of the study (randomized, double-blind); however, subjects who complete the treatment period for Part 1 or Part 2 (8 and 12 weeks, respectively) will continue in Part 3 (extension) if the investigator determines that the subject is receiving clinical benefit on treatment.


Condition Intervention Phase
Thrombocytopaenia
Drug: eltrombopag
Drug: placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
Official Title: A Three-part Study of Eltrombopag in Thrombocytopenic Subjects With Myelodysplastic Syndromes or Acute Myeloid Leukemia (Part 1: Open-label, Part 2: Randomized, Double-blind, Part 3: Extension)

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Number of Participants With Platelet Response up to Week 8 During Part 1 [ Time Frame: From Baseline up to Week 8 during Part 1 ] [ Designated as safety issue: No ]
    A participant was considered as a responder if he/she met the following response criteria: a Baseline platelet count <20 Giga cells per liter (Gi/L) and a post-Baseline increased to >20 Gi/L and at least 2 times the Baseline value; or a Baseline platelet count >=20 Gi/L and a post-Baseline absolute platelet count increased to >=50 Gi/L and at least 2 times the Baseline value. The response criteria was evaluated at each visit. Increase in platelet count observed up to 3 days after a platelet transfusion was not considered as a platelet response. The Part 1 Population was comprised of all participants enrolled into Part 1.

  • Percentage of Participants With Clinically Relevant Thrombocytopenic Events (CRTE) From Week 5 up to Week 12 During Part 2 [ Time Frame: From Week 5 up to Week 12 during Part 2 ] [ Designated as safety issue: No ]
    A participant was considered to have a CRTE at a given assessment if he/she had platelet counts <10 Gi/L, or platelet transfusions, or >=Grade 3 hemorrhagic adverse events. CRTEs during Weeks 5 to 12 were compared between treatments using a generalized linear mixed model. Average of weekly proportion of subjects with CRTE during Week 5 to 12 was estimated for each treatment. Intent to Treat (ITT) Population was comprised of all randomized participants during Part 2.


Enrollment: 162
Study Start Date: September 2011
Study Completion Date: December 2015
Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part 1, Open Label
100 mg daily (50 mg for subjects of East Asian heritage), intrasubject dose escalations to a maximum dose 300 mg (150 mg for subjects of East Asian heritage) are allowed.
Drug: eltrombopag
100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage)
Other Name: Promacta
Experimental: Part 2, eltrombopag arm
100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage)
Drug: eltrombopag
100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage)
Other Name: Promacta
Experimental: Part 2, placebo arm
100 mg matching placebo daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg matching placebo (150 mg for subjects of East Asian heritage)
Drug: placebo
100 mg matching placebo daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg matching placebo (150 mg for subjects of East Asian heritage)
Experimental: part 3 extension
100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage)
Drug: eltrombopag
100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage)
Other Name: Promacta

  Eligibility

Ages Eligible for Study:   18 Years to 110 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult subjects (18 years of age or older) with MDS or AML (bone marrow blasts ≤50%) with thrombocytopenia due to bone marrow insufficiency from the disease or prior treatment. Subjects with transient thrombocytopenia due to active treatment with disease modifying agents or chemotherapy (except for hydroxyurea) are excluded
  • Subjects must have Grade 4 thrombocytopenia (platelet counts <25 Gi/L) due to bone marrow insufficiency (or Grade 4 thrombocytopenia, but platelet count greater than or equal to 25 Gi/L due to platelet transfusion). In addition, subjects must have had at least one of the following during the 4 week screening period: platelet transfusion, or symptomatic bleeding or platelet count <10 Gi/L. Subjects whose thrombocytopenia below 10 Gi/L is due to causes other than bone marrow insufficiency (e.g., fever, infection, autoimmune disease) are not eligible.
  • Subjects must have platelet count, bleeding and platelet transfusion data available over a period of at least 4 weeks prior to randomization.
  • Prior systemic treatment for malignancy, with the exception of hydroxyurea, must have been discontinued prior to entry into the study: at least 4 weeks before Day 1 for the following: chemotherapy, demethylating agents (azacitidine or decitabine), lenalidomide, thalidomide, clofarabine and IL-11(oprelvekin); at least 8 weeks before Day 1 for antithymocyte/antilymphocyte globulin.
  • Subjects with a prior stem cell transplant (SCT) must have relapsed after the SCT.
  • Subjects must be stable and, in the opinion of the investigator, be expected to complete a 12 week treatment period.
  • ECOG Status 0-2.
  • Subject must be able to understand and comply with protocol requirements and instructions.
  • Subject has signed and dated an informed consent form.
  • Adequate baseline organ function defined by the criteria below: total bilirubin ≤ 1.5xULN except for Gilbert's syndrome or cases clearly not indicative of inadequate liver function (i.e. elevation of indirect (hemolytic) bilirubin in the absence of ALT abnormality), ALT ≤ 3xULN, creatinine ≤ 2.5xULN
  • Women must be either of non-child bearing potential or women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to the first dose of study treatment.
  • In France, a subject will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.

Exclusion Criteria:

  • Subjects with MDS and an IPSS of low or intermediate-1 risk at screening.
  • Subjects with a diagnosis of acute promyelocytic or megakaryocytic leukemia or AML secondary to a myeloproliferative neoplasm.
  • History of treatment with romiplostim or other TPO-R agonists.
  • Subjects with a QTc >480 msec (QTc >510 msec for subjects with Bundle Branch Block).
  • Leukocytosis ≥25,000/uL on Day 1 of treatment with study medication.
  • Subjects with known thrombophilic risk factors. Exception: Subjects for whom the potential benefits of participating in the study outweigh the potential risks of thromboembolic events, as determined by the investigator.
  • Female subjects who are nursing or pregnant (positive serum or urine β-human chorionic gonadotropin [β-hCG] pregnancy test) at screening or pre-dose on Day 1.
  • Current alcohol or drug abuse.
  • Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication.
  • Active and uncontrolled infections (e.g. sepsis, hepatitis B, hepatitis C).
  • Subjects infected with Human Immunodeficiency Virus (HIV).
  • Subjects with liver cirrhosis (as determined by the investigator).
  • Subjects receiving or planned to receive any prohibited medication.
  • Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to eltrombopag or excipient (microcrystalline cellulose, mannitol, polyvinylpyrrolidone, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol 400 and polysorbate 80) that contraindicates the subjects' participation.
  • In France, subjects who have participated in any study using an investigational drug during the previous 30 days.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01440374

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Locations
United States, Arizona
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Phoenix, Arizona, United States, 85016
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Hot Springs, Arkansas, United States, 71913
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Jonesboro, Arkansas, United States, 72401
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Los Angeles, California, United States, 90095
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Stanford, California, United States, 94305
United States, Florida
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Jacksonville, Florida, United States, 32256
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Orlando, Florida, United States, 32806
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West Palm Beach, Florida, United States, 33401
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Augusta, Georgia, United States, 30912
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Baltimore, Maryland, United States, 21201
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Boston, Massachusetts, United States, 02115
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Kansas City, Missouri, United States, 64128
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Hackensack, New Jersey, United States, 07601
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Voorhees, New Jersey, United States, 08043
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Bornx, New York, United States, 10467
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Philadelphia, Pennsylvania, United States, 19140
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Seattle, Washington, United States, 98108
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Milwaukee, Wisconsin, United States, 53226
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Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina, C1431FWO
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La Plata, Buenos Aires, Argentina, B1900AXI
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Ciudad Autonoma de Buenos Aires, Argentina, C1025ABH
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Ciudad Autónoma de Buenos Aires, Argentina, 1405
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Antwerpen, Belgium, 2060
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Brasschaat, Belgium, 2930
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Brugge, Belgium, 8000
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Bruxelles, Belgium, 1000
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Gent, Belgium, 9000
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Leuven, Belgium, 3000
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Yvoir, Belgium, 5530
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Goiânia - GO, Goiás, Brazil, 74605-020
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Curitiba, Paraná, Brazil, 81520-060
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Porto Alegre, Rio Grande Do Sul, Brazil, 90035-903
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Rio de Janeiro, Brazil, 20211-030
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São Paulo, Brazil, 01236030
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Halifax, Nova Scotia, Canada, B3H 2Y9
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Toronto, Ontario, Canada, M5G 2M9
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Montreal, Quebec, Canada, H3T 1E2
Czech Republic
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Brno, Czech Republic, 625 00
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Praha 10, Czech Republic, 100 34
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Praha, Czech Republic, 128 20
Germany
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Mannheim, Baden-Wuerttemberg, Germany, 68167
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Stuttgart, Baden-Wuerttemberg, Germany, 70199
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Goettingen, Niedersachsen, Germany, 37075
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Athens, Greece, 11527
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Beer-Sheva, Israel, 84101
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Haifa, Israel, 31048
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Jerusalem, Israel, 91120
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Petach-Tikva, Israel, 49100
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Ramat Gan, Israel, 52621
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Rehovot, Israel, 76100
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Amsterdam, Netherlands, 1081 HV
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Chorzow, Poland, 41-500
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Warszawa, Poland, 02-097
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San Juan, Puerto Rico, 00927
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Nizhniy Novgorod, Russian Federation, 603126
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Petrozavodsk, Russian Federation, 185019
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St'Petersburg, Russian Federation, 191024
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St'Petersburg, Russian Federation, 197341
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St. Petersburg, Russian Federation, 197 089
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Barcelona, Spain, 08036
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Sponsors and Collaborators
Novartis
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis
ClinicalTrials.gov Identifier: NCT01440374     History of Changes
Other Study ID Numbers: 114968 
Study First Received: September 15, 2011
Results First Received: March 10, 2016
Last Updated: May 6, 2016
Health Authority: Spain: Agencia Espanola de Medicamentos y Productos Sanitarios
Netherlands: Centrale Commissie Mensgesbonden Onderzoek (Central Committee on Research Involving Human Subjects) Den Haag (The Hague), The Netherlands
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Korea: Food and Drug Administration
Mexico: Secretaría de Salud
Taiwan: Food and Drug Administration, Department of Health, Executive Yuan
Greece: National Organization of Medicines
Hungary: National Institute of Pharmacy
Thailand: Food and Drug Administration
United States: Food and Drug Administration
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Thailand: Ministry of Public Health
Italy: Ministry of Health
Hong Kong: Department of Health
Israel: State of Israel Ministry of Health, Health Technology and Infrastructure Administration, Medical Devices Department
Poland: URZ.D REJESTRACJI PRODUKTÓW LECZNICZYCH, WYROBÓW MEDYCZNYCH I PRODUKTÓW BIOBÓJCZYCH,CEBK
Germany: Bundesinstitut für Arzneimittel und Medizinprodukte
Belgium: Federaal Agentschap voor Geneesmiddelen en Gezondheidsproducten
Russian Federation: Ministry of Health and social development of Russian Federation, Federal
Brazil: Agência Nacional de Vigilância Sanitária (ANVISA)
Peru: General Directorate of Pharmaceuticals, Devices, and Drugs
India: Drugs Controller General of India (DCGI)
Czech Republic: State Institute for Drug Control

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Thrombocytopenia
Leukemia
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Blood Platelet Disorders

ClinicalTrials.gov processed this record on August 25, 2016