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PRevention Of BLeeding in hEmatological Malignancies With Antifibrinolytic (Epsilon Aminocaproic Acid) (PROBLEMA)

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ClinicalTrials.gov Identifier: NCT02074436
Recruitment Status : Recruiting
First Posted : February 28, 2014
Last Update Posted : May 10, 2019
Sponsor:
Information provided by (Responsible Party):
Ana G. Antun, MD, Emory University

Tracking Information
First Submitted Date  ICMJE February 26, 2014
First Posted Date  ICMJE February 28, 2014
Last Update Posted Date May 10, 2019
Study Start Date  ICMJE May 2014
Estimated Primary Completion Date May 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 1, 2014)
Proportion of patients who develop major bleeding episodes (WHO grades 3-4) [ Time Frame: 6 months ]
The primary objective of this study is to compare the proportion of patients who develop major bleeding episodes (WHO grades 3-4) in the group randomized to receive prophylactic EACA versus standard of care prophylactic platelet transfusions.
Original Primary Outcome Measures  ICMJE
 (submitted: February 26, 2014)
Primary Objective [ Time Frame: 6 months ]
The primary objective of this study is to compare the proportion of patients who develop major bleeding episodes (WHO grades 3-4) in the group randomized to receive prophylactic EACA versus standard of care prophylactic platelet transfusions.
Change History Complete list of historical versions of study NCT02074436 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE PRevention Of BLeeding in hEmatological Malignancies With Antifibrinolytic (Epsilon Aminocaproic Acid)
Official Title  ICMJE Randomized Trial of Epsilon Aminocaproic Acid Versus Platelet Transfusions for the Prevention of Bleeding in Thrombocytopenic Patients With Hematological Malignancies
Brief Summary

STUDY BACKGROUND AND PURPOSE:

Patients with hematological malignancies (blood-related cancers) often develop thrombocytopenia (low platelet count), which can be made worse by cancer treatment.

Preventive (prophylactic) platelet transfusion remains the standard of care for thrombocytopenic patients. However, bleeding remains a significant problem in these patients, affecting approximately 20% of patients with acute myeloid leukemia and 34-58% of hematopoietic stem cell transplant recipients. Platelet transfusion refractoriness, the repeated failure to obtain satisfactory response to platelet transfusions, is a common problem. Alternatives to platelet transfusions are desperately needed for these patients.

Epsilon aminocaproic acid (EACA) blocks a process called fibrinolysis that is an essential step in the bleeding process. EACA is approved by the FDA for the treatment of severe bleeding-related diseases and complications. A small study has shown EACA to be well tolerated and associated with low risk of bleeding in patients with hematological malignancies.

This study will compare EACA versus standard prophylactic platelet transfusion for the prevention of bleeding in thrombocytopenic patients with hematological malignancies.

STUDY DESCRIPTION:

This is Phase II study to compare EACA versus standard prophylactic platelet transfusion to prevent bleeding in thrombocytopenic patients with hematological malignancies. Patients who are eligible to take part must give their written agreement before they can be enrolled.

The study will enroll 100 patients who will be assigned randomly to take EACA twice daily or to undergo standard prophylactic platelet transfusion. Patients will be followed for any bleeding events, need for platelet transfusion, and any side effects experienced. Patients will complete questionnaires to assess their quality of life while on the study.

Detailed Description

Study Treatments: Epsilon aminocaproic acid (EACA) vs. standard prophylactic platelet transfusions.

Study Title: Randomized Trial of Epsilon Aminocaproic Acid versus Platelet Transfusions for the Prevention of Bleeding in Thrombocytopenic Patients with Hematological Malignancies. (PROBLEMA trial: PRevention Of BLeeding in hEmatological Malignancies with Antifibrinolytic agents (epsilon aminocaproic acid).

Phase: Randomized Phase 2

Eligible Population: Adult patients with acute or chronic thrombocytopenia in the setting of hematological malignancies.

Summary and Study Rationale: Compare EACA to standard prophylactic platelet transfusion for the prevention of bleeding in thrombocytopenic patients with hematological malignancies.

Study Design: prospective, randomized, controlled trial.

Study Endpoints: The primary endpoint is to compare the proportion of patients who develop major (grades 3-4) bleeding in each arm.

Diagnosis and Main Inclusion Criteria: Age > 18 with hematological malignancies. Acute or chronic thrombocytopenia with platelet counts < 20 x 10⁹/L.

Number of Patients: 100 patients, 50 patients in each arm

Duration of Patient Participation: 6 months

Approximate Duration of Study: 3 years

Dosage and Administration:1,000 mg twice a day orally

Prohibited Medications/Treatment: Hydroxyurea and procoagulant agents including DDAVP, recombinant Factor VII or prothrombin complex concentrate are prohibited in patients receiving EACA.

Safety Evaluations: Clinical assessment once weekly during the first 30 days and then monthly for 6 months, complete blood count and bleeding score twice weekly the first 30 days, and then according to standard of care or at discretion of treating physician.

Statistical Analysis

  • Population Analysis

    • Intention to treat (ITT) population: The ITT population includes all patients who are randomized to the study. Patients will be stratified and analyzed according to the treatment to which they were assigned.
    • Safety Population: The safety population includes all patients who have received at least 1 dose of EACA. Patients included in the safety population will be analyzed according to the treatment they received.
    • Per-protocol Population: The per-protocol population includes all patients who are randomized, receive at least one dose of study drug, and have no major protocol violations that could be expected to impact response data.
  • Study Endpoints

    • Primary Endpoint: is to compare at the end of the study, the proportion of patients with major bleeding during the study period among patients randomized to receive either EACA or standard of care prophylactic platelet transfusions.
    • Secondary Endpoints include:

      • Proportion of patients with any bleeding during the study period in each arm
      • The total number of units of platelets transfused in each arm at the end of the study
      • Quality of life as measured in each arm before the study and at the end of the study
      • Safety in each arm
  • Sample Size: This randomized, open-label phase II study is designed to compare the proportion of patient with major bleeding ever noted during the study. Patients will be assigned to receive prophylactic EACA (experimental arm) or prophylactic platelet (standard of care) in a 1:1 fashion. Previous studies suggest that the proportions of patients with major bleeding will be expected to be 8% and 30% in experimental arm and standard of care arm, respectively. With one sided Fisher's exact test, the sample size of 45 patients in each arm will achieve a power of 80% at the significance level of 5% to test whether prophylactic EACA can prevent major bleeding better than the standard of care. After adjusting for a 10% drop out rate, the actual required sample size will be 50 patients per arm. Therefore, the total sample size of the study will be 100 patients.
  • Efficacy Analysis

    • Primary Endpoint Analysis will be performed using a one-sided Fisher's exact test to compare the proportions of patients with major bleeding during the whole study between the two arms. The significance level is set at 0.05. This primary analysis will be based on the ITT population.
    • Secondary Endpoint Analysis: one-sided t-test will be used to compare the total number of any bleeding episode noted during the study between the two arms. Two-sided t-test will be employed to compare the total number of units of platelets transfused at the end of the study between the two arms. Appropriate statistical tests (Chi-square test, t-test, Wilcoxon's rank sum test, etc.) will be conducted to compare the each score of the quality of life between the two arms before the study and at the end of the study, respectively. The change of each score of the quality of life from before the study to the end of the study will also be compared between the two arms. The safety in each arm will be also compared with Fisher's exact test. The analyses of secondary endpoints will be performed on the ITT population and the significance level will be kept at 0.05 for all tests.
  • Safety Analysis: All patients receiving at least 1 dose of study drug will be considered evaluable for safety. Patients will be analyzed for safety according to the treatment which they received. Listings of laboratory test results will also be generated, and descriptive statistics summarizing the changes in laboratory tests over time will be presented. Exposure to study drug over time will also be summarized. The adverse events incidence rates, as well as the frequency of occurrence of overall toxicity, categorized by toxicity grades (severity) will be described for each treatment arm and be compared between two arms using two-sided Chi-square test or t-test.
  • Quality of Life Analysis: Quality of life and health outcomes measures are being collected using EuroQoL instruments before the study and at the end of the study. Means and medians of raw scores of these questionnaires will be summarized for each treatment group for each domain and be compared between the two arms with t-test or Wilcoxon ranks sum test.
  • Interim Analysis: Three interim analyses are planned after 11 patients in each arm have been randomized and their results have been obtained. Each interim analysis will focus on the primary endpoint, the proportion of patients with major bleeding ever noted during the study. To maintain an overall Type I error rate of 0.05 (1-sided), an O'Brien Fleming approach will be used which requires a 1-sided p-value < 0.001 at the first interim analysis (at 25% of total sample size). If this boundary is not crossed, then the study will continue and the second interim analysis will be conducted at 50% of the total sample side which requires a 1-sided significance level of 0.004. If this boundary is not crossed at the second interim analysis then, the study will continue and a third interim analysis will be conducted at 75% of the total sample side which requires a 1-sided significance level of 0.019. If this boundary is not crossed, the final primary analysis will be performed after completing 100% of the sample size using a 0.043 one-sided significance level.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Hematological Malignancies
  • Thrombocytopenia
Intervention  ICMJE
  • Drug: EACA
    EACA 1000 mg twice a day. Patients will receive platelet transfusion in case of grade ≥ 2 bleeding.
    Other Names:
    • Amicar
    • Aminocaproic acid
  • Other: Platelet transfusion
    Prophylactic platelet transfusion. Additional platelet transfusions will be administered in case of grade ≥ 2 bleeding.
Study Arms  ICMJE
  • Experimental: Prophylactic EACA
    Prophylactic EACA 1000 mg PO twice daily if platelets < 20 x 10⁹/L
    Intervention: Drug: EACA
  • Active Comparator: Platelet transfusion
    Platelet transfusion if platelet count is < 20 x 10⁹/L in the outpatient or < 10 x 10⁹/L in the inpatient setting
    Intervention: Other: Platelet transfusion
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 26, 2014)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 2021
Estimated Primary Completion Date May 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age > 18 with a hematological malignancy
  • Informed consent
  • Thrombocytopenia with untransfused platelet counts < 20 x 10⁹/L in the out-patient or in the in-patient setting and one of the following criteria:

    • Acute thrombocytopenia in patients with hematological malignancies who are in remission and are receiving myelosuppressive consolidation chemotherapy that is expected to induce marrow aplasia for at least 2 weeks; or
    • Acute or chronic thrombocytopenia in patients with acute leukemia (myeloblastic or lymphoblastic) receiving induction or re-induction chemotherapy that is expected to induce marrow aplasia for at least 2 weeks; or
    • Expected chronic thrombocytopenia in patients with newly diagnosed marrow failure syndromes, myelodysplastic syndromes, aplastic anemia, chronic myelomonocytic leukemia or myelofibrosis; or
    • Expected chronic thrombocytopenia in patients with relapsed or refractory hematological malignancies; or
    • Hematopoietic stem cell transplant recipients with chronic thrombocytopenia due to chronic graft-versus-host disease (GVHD) or other causes

Exclusion Criteria:

  • Acute promyelocytic leukemia
  • Patient receiving anticoagulation
  • Patient receiving antiplatelet agents
  • Patient treated with antifibrinolytic agents (including EACA) within 14 days prior to screening
  • Subjects receiving procoagulant agent including DDAVP, recombinant factor VII or prothrombin complex concentrate within 24 hours of enrollment
  • Subject with known congenital bleeding disorders or platelet dysfunction
  • Disseminated intravascular coagulation
  • Fibrinogen level < 150 mg/dl
  • Patients with known lupus anticoagulant or positive antiphospholipid antibody
  • History of arterial or venous thromboembolic disease 6 months prior to screening
  • Patient requiring platelet transfusion threshold of > 20 x 10⁹/L
  • Active grade ≥ 2 bleeding at the time of randomization, including hematuria
  • History of grade 4 bleeding
  • Hematopoietic stem cell transplant recipient within 100 days post-transplant
  • Pregnancy
  • Known allergy to EACA
  • History of veno-occlusive disease of the liver
  • Myocardial infarction 6 months prior to screening
  • Unstable angina
  • Grade 2 renal dysfunction: creatinine > 2-3 times the upper limit of normal
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 19 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ana G. Antun, MD, MSc 404-593-6732 ana.antun@emoryhealthcare.org
Contact: Shannon Gleason 404-778-4334 shannon.gleason@emory.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02074436
Other Study ID Numbers  ICMJE IRB00066504
Winship2429-13 ( Other Identifier: Winship Cancer Institute/Emory University )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Ana G. Antun, MD, Emory University
Study Sponsor  ICMJE Emory University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Ana G. Antun, MD, MSc Emory University
PRS Account Emory University
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP