Romiplostim Treatment of Thrombocytopenia in Subjects With Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
Amgen
ClinicalTrials.gov Identifier:
NCT00614523
First received: January 31, 2008
Last updated: August 9, 2013
Last verified: August 2013
  Purpose

The Data Monitoring Committee (DMC) for study 20060198 recommended that all subjects discontinue treatment of study drug and continue to be followed for long term follow-up. Amgen adopted the DMC recommendation.


Condition Intervention Phase
MDS
Myelodysplastic Syndromes
Thrombocytopenia
Drug: Placebo
Biological: Romiplostim
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Supportive Care
Official Title: A Randomized, Double Blind, Placebo Controlled Study Evaluating the Efficacy and Safety of Romiplostim Treatment of Thrombocytopenia in Subjects With Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)

Resource links provided by NLM:


Further study details as provided by Amgen:

Primary Outcome Measures:
  • Number of Clinically Significant Bleeding Events [ Time Frame: Test Treatment Period (Weeks 1-26) ] [ Designated as safety issue: No ]
    A clinically significant bleeding event is defined as any bleeding event of grade ≥ 2 per the modified World Health Organization (WHO) bleeding scale: • Grade 0 = no bleeding • Grade 1 = petechia or mucosal or retinal bleeding not requiring intervention • Grade 2 = melena, hematemesis, hematuria, hemoptysis • Grade 3 = bleeding required red cell transfusion • Grade 4 = retinal bleeding with visual impairment • Grade 5 = non-fatal cerebral bleeding • Grade 6 = fatal cerebral bleeding • Grade 7 = fatal non-cerebral bleeding. Bleeding events that continue for more than 7 days were counted as separate events every eighth day. Multiple events that arose from one organ system on one day were collapsed into one single event. Bleeding events with a start date between the first dose date and the last dose date of the test treatment period+7 days are included.


Secondary Outcome Measures:
  • Annualized Rate of Platelet Transfusion Events [ Time Frame: Test Treatment Period (Weeks 1-26) ] [ Designated as safety issue: No ]
    A discrete platelet transfusion is any number of platelet transfusion administered within a 3-day period. Transfusions administered more than 3 days apart are counted as separate events. Transfusion given in the absence of any bleeding, when platelet count is >10x10^9/L, is not counted as a platelet transfusion event. Events with start date between the first dose date and the last dose date of the test treatment period +7 days are included. Exposure adjusted event rate per 100 patient-years = (events / patient-years * 100). Patient Year = total patient years of exposure to investigational product during 26 weeks test treatment period.

  • Annualized Rate of Overall Bleeding Events [ Time Frame: Test Treatment Period (Weeks 1-26) ] [ Designated as safety issue: No ]
    The time from first dose of study drug to the last dose of 26-week test treatment period. A bleeding event is defined as any bleeding event reported during the test treatment period. Bleeding events that continue for more than 7 days are counted as separate events every eighth day. Multiple events that arose from one organ system on one day are collapsed into one single event. Exposure adjusted event rate per 100 patient-years = events / patient-year * 100).

  • Annualized Rate of Total Platelet Transfusion Units [ Time Frame: Test Treatment Period (Weeks 1-26) ] [ Designated as safety issue: No ]
    The time from first dose of study drug to the last dose of 26-week test treatment period. A unit of platelets is defined as a single pack of pooled platelet-rich plasma comprised of 6 to 8 individual platelet concentrate packs (200 to 400 mL), a single pack of pooled buffy-coat concentrate, or 1 apheresis (single donor) concentrate. Exposure adjusted event rate per 100 patient-years = events / patient-years * 100.

  • Number of Participants With Platelet Hematologic Improvement (HI-P) [ Time Frame: Test Treatment Period (Weeks 1-26) ] [ Designated as safety issue: No ]
    Platelet Hematologic Improvemen defined by the international working group (IWG) as: an absolute increase in platelet count of ≥ 30 x 10^9/L for a patient starting with a platelet count of ≥ 20 x 10^9/L or an increase in platelet count from < 20 x 10^9/L to ≥ 20 x 10^9/L and by at least 100% in a patient that started with a platelet count < 20 x 10^9/L. To account for any possible contribution from platelet transfusions, platelet counts within 3 days following administration of platelet transfusion is not counted towards the platelet hematologic improvement endpoint. If no platelet measurements are available on the weekly scheduled dose day, then that week is not counted towards the platelet hematologic improvement endpoint.

  • Exposure-adjusted Total Duration of Platelet Hematologic Improvement (HI-P) in the Absence of Platelet Transfusions [ Time Frame: Test Treatment Period (Weeks 1-26) ] [ Designated as safety issue: No ]
    Duration for participants who did not report HI-P during the period is 0. A platelet hematologic improvement (HI-P) is defined by an MDS International Working criteria as patients with a baseline platelet count of ≥ 20 x 10^9/L achieving an absolute increase of ≥ 30 x 10^9/L or increasing the platelet count to above 20 x 10^9/L and by at least 100% in patients with a baseline of < 20 x 10^9/L for at least 8 consecutive weeks. To account for any possible contribution from platelet transfusions, platelet counts within 3 days following administration of platelet transfusion is not counted towards the platelet hematologic improvement endpoint. If no platelet measurements are available on the weekly scheduled dose day, then that week is not counted towards the platelet hematologic improvement endpoint. The durations of HI-P are cumulative if more than one incidence occurred. Exposure adjusted event rate per 100 patient-weeks = total number of weeks / patient-weeks * 100.

  • Number of Participants Who Died [ Time Frame: From randomization to 58 weeks, the end of study visit or the closest available follow-up information up to 58 weeks from the long term follow-up for those who discontinued the study early, with a data cut-off date of 20 July 2012. ] [ Designated as safety issue: No ]
  • Time to Death [ Time Frame: From randomization to 58 weeks, the end of study visit or the closest available follow-up information up to 58 weeks from the long term follow-up for those who discontinued the study early, with a data cut-off date of 20 July 2012. ] [ Designated as safety issue: No ]
    Overall survival was calculated using Kaplan-Meier methods. For patients who discontinued early, additional information from the long term follow-up are added (closest available follow-up information up to 58 weeks).

  • Kaplan-Meier Estimate of Survival at Month 12 [ Time Frame: Month 12, with a data cut-off date of 20 July 2012. ] [ Designated as safety issue: No ]
    Overall survival was calculated using Kaplan-Meier methods.

  • Annualized Rate of Patient-reported Bleeding Events [ Time Frame: Test Treatment Period (Weeks 1-26) ] [ Designated as safety issue: No ]
    The number of bleeding events was obtained from the thrombocytopenia symptoms (Th-symptoms) survey. Patients reported spontaneous bleeding to have occurred 0, 1 or 2, 3 or 4, 5 or 6, or 7 or more times in the past week. The lower threshold of bleeding counts is used for conservative purposes (i.e., the "3" is used for the response option of "3 or 4 times"). Exposure adjusted event rate per 100 patient-years = number of events / patient-year * 100.


Enrollment: 250
Study Start Date: July 2008
Estimated Study Completion Date: March 2016
Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Romiplostim
Weekly subcutaneous dosing based on platelet count for 26 weeks during the Test Treatment Period and for 24 weeks during the Extended Treatment Period, separated by a 4-week interim washout period. Starting dose is at 750 μg, up to a maximum dose of 1000 μg, or reduced to a minimum of 250 μg.
Biological: Romiplostim
Romiplostim is supplied in a 5 mL single use glass vial as a sterile, white, preservative-free, lyophilized powder.
Placebo Comparator: Placebo
Weekly subcutaneous dosing with blinded matching placebo dose level for 26 weeks during the Test Treatment Period and for 24 weeks during the Extended Treatment Period, separated by a 4-week interim washout period.
Drug: Placebo
Placebo is supplied in a 5 mL single use glass vial as a sterile, white, preservative-free, lyophilized powder.

Detailed Description:

This is a Phase 2, multicenter, randomized, double blind, placebo controlled study designed to assess the efficacy and safety of romiplostim (formerly, AMG 531) treatment in thrombocytopenic MDS patients. The study is composed of a 26-week placebo controlled test treatment period (romiplostim versus Placebo), a 4 week interim wash-out period, a 24-week placebo controlled extended treatment period, and a 4-week follow-up period followed by an End of Study (EOS) visit. During the interim wash-out period, a bone marrow biopsy will be performed in the absence of growth factor to assess changes in the marrow. In the extended treatment period, safety assessments will continue and participants will be allowed to receive any standard of care treatments for MDS. Patients will be followed for survival for an additional 60 months following the End of Study (EOS) visit.

  Eligibility

Ages Eligible for Study:   18 Years to 90 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria: • Diagnosis of MDS using the World Health Organization (WHO) classification for myeloid neoplasms as assessed during the screening period. • Per MDS International Prognostic Scoring System (IPSS), low or intermediate-1 risk MDS as assessed during the screening period. • Mean of the 2 platelet counts taken within 4 weeks prior to randomization must be: - ≤ 20 x 10^9/L, (with no individual count >30 x 10^9/L during the screening period), with or without history of bleeding associated with diagnosis of MDS, OR - ≤ 50 x 10^9/L, (with no individual count >60 x 10^9/L during the screening period) with a history of bleeding associated with the diagnosis of MDS. • Patients must be ≥18 and ≤ 90 years of age at time of informed consent. Patients between 85 and 90 years of age must have been diagnosed with MDS ≤ 5 years from study start. • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. • Adequate liver function, as evidenced by alanine aminotransferase (ALT) ≤ 3 times laboratory normal range, aspartate aminotransferase (AST) ≤ 3 times laboratory normal range and total bilirubin ≤ 2.0 times laboratory normal range. (Adequate liver function for patients with confirmed diagnosis of Gilbert's Disease evidenced by ALT ≤ 3 times laboratory normal range, and AST ≤ 3 times laboratory normal range.) • Serum creatinine concentration ≤ 2 mg/dl (≤176.8 μmol/L). • Bone marrow biopsy and aspirate with cytogenetics within 3 months of starting first dose of investigational product. • Written Informed Consent. Exclusion Criteria: • Have ever received any disease-modifying treatment for MDS. • Previously diagnosed with intermediate-2 or high risk MDS using the IPSS. • Prior history of leukemia, aplastic anemia, or other non-MDS related bone marrow stem cell disorder. • Prior history of hematopoietic stem cell transplantation. • Persistent peripheral blood monocytosis (≥ 3 months with an absolute monocyte count >1,000/μL) or known diagnosis of Chronic Myelomonocytic Leukemia per French-American-British Classification System for MDS (FAB) criteria. • Prior malignancy (other than in situ cervical cancer, non-melanoma skin cancer, or in situ carcinoma) unless treated with curative intent and without evidence of disease for ≥ 3 years before randomization. • Active or uncontrolled infections. • Unstable angina, congestive heart failure (New York Heart Association [NYHA] > class II), uncontrolled hypertension (diastolic >100 mmHg), uncontrolled cardiac arrhythmia, or recent (within 1 year) myocardial infarction. • History of arterial thrombosis (eg, stroke or transient ischemic attack) within the past year. • History of venous thrombosis that currently requires anti-coagulation therapy. • Received Interleukin (IL)-11 within 4 weeks of first dose of investigational product. • Have previously received any thrombopoietic growth factor. • Receipt of granulocyte-colony stimulating factor, (G-CSF), pegylated-G-CSF, or granulocyte macrophage-colony stimulating factor (GM-CSF) within 4 weeks of first dose of investigational product. • Planned receipt of peg-G-CSF or GM-CSF after first dose of investigational product. • Pregnant or breast feeding. • Patients of reproductive potential who are not using adequate contraceptive precautions, in the judgment of the investigator. Amgen recommends double barrier contraception is used for all applicable patients enrolled on this study. A double barrier method is defined as two methods of contraception, for example 2 actual barrier methods, or one actual barrier method and one hormonal method. • Patient has known sensitivity to any recombinant E coli-derived product (eg, Infergen®, Neupogen®, Somatropin, and Actimmune). • Previously enrolled into the 20060198 study or another romiplostim study. • Inability to comply with study procedures. • Patient currently is enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00614523

Sponsors and Collaborators
Amgen
Investigators
Study Director: MD Amgen
  More Information

Additional Information:
No publications provided

Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT00614523     History of Changes
Other Study ID Numbers: 20060198
Study First Received: January 31, 2008
Results First Received: January 20, 2012
Last Updated: August 9, 2013
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration
Australia: Human Research Ethics Committee
Australia: Therapeutic Goods Administration
Austria: AGES - PharmaMed Austria Institut Wissenschaft & Information
Austria: Bundesamt fur Sicherheit im Gesundheitswesen
Austria: Bundesamt für Sicherheit im Gesundheitswesen
Austria: Central Ethics Committee
Austria: Competant Authority
Austria: Secretariat of Health
Belgium: Federal Agency for Medicines and Health Products, FAMHP
Belgium: Directorate-General for Medicinal Products
Belgium: Federal Public Service (FPS) Health, Food Chain Safety and Environment
Belgium: FPS of Public Health, Food Chain Security and Environment
Belgium: Pharmaceutical Inspectorate
Belgium: Service Public Federal Sante Publiquest, Securite de la Chaine alimentaire et Environnement
Belgium: Service Public Fédéral Santé Publique, Sécurité de la Chaîne alimentaire et Environnement
Canada: Health Canada
Canada: Health Products and Food Branch
Canada: Institutional Review Board
Czech Republic: State Institute for Drug Control
Czech Republic: Statni ustav pro kontrolu leciv
Denmark: Central Ethics Committee
Austria: Federal Ministry for Health and Women
Denmark: Danish Medicines Agency
Denmark: Laegemiddelstyrelsen
Denmark: Ministry of Health
EU: CHMP
European Union: European Medicines Agency
France and Sweden: European Medicines Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
France: CCPPRB Central Ethics Committee
France: Ministry of Health
Germany: Federal Institute for Drugs and Medical Devices
Germany: Paul_Ehrlich-Institut Bundesamt fur Sera und Impfstoffe
Hungary: National Institute of Pharmacy
Ireland: Irish Medicines Board
Italy: Local Ethics Committees
Italy: Ministry of Health
Netherlands: CCMO (Centrale Commissie Mensgebonden Onderzoek): Central Committee Human Bound Research
Netherlands: Medicines Evaluation Board
Netherlands: Medisch Centrum Rijnmond_Zuid, lcatie Zuider
Norway: Norwegian Medicines Agency
Poland: Drug Institut
Russia: Ministry of Health
Slovakia: Ministry of Health
Slovakia: State Institiute for Drug Control
Slovakia: Štátny ústav pre kontrolu lieciv
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Spain: Spanish Agency of Medicines
Spain: Spanish Drug Agency
Sweden: Central Ethics Committee
Sweden: Lakemedelsverket
Sweden: Medical Products Agency
Switzerland: Agency for Therapeutic Products
Switzerland: Local Ethics Committee
Switzerland: Swissmedic (Swiss Agency for Therapeutic Products)
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Russia: Federal Service for Surveillance in the field of Healthcare and Social Development (a body of the Ministry of Health)
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United States: Food and Drug Administration
United States: Western Institutional Review Board

Keywords provided by Amgen:
MDS
Low Risk MDS
Intermediate-1 Risk MDS
Thrombocytopenia

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Thrombocytopenia
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Blood Platelet Disorders

ClinicalTrials.gov processed this record on August 28, 2014