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Defibrotide TMA Prophylaxis Pilot Trial

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ClinicalTrials.gov Identifier: NCT03384693
Recruitment Status : Recruiting
First Posted : December 27, 2017
Last Update Posted : October 11, 2018
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco

Brief Summary:
Thrombotic microangiopathy (TMA) is a common complication in the stem cell transplant population. Certain populations within the hematopoietic stem cell transplant (HSCT) population are at a higher risk than others. Defibrotide is an endothelial stabilizing agent which may prevent the endothelial damage that triggers TMA in HSCT patients. The feasibility, safety, and efficacy of defibrotide prophylaxis in a pediatric transplant population is unknown. Twenty five patients age 0 to 30 years receiving autologous or allogeneic hematopoeitic stem cell transplant who meet TMA high risk criteria will be enrolled. Patients will receive Defibrotide for 28-35 days starting before conditioning, and will be closely monitored for any adverse events up through 6 months post-transplant. The feasibility of administering defibrotide will be evaluated as well as incidence of TMA.

Condition or disease Intervention/treatment Phase
Thrombotic Microangiopathies Drug: Defibrotide Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Defibrotide 6.25mg/kg administered intravenously for 28-35 days
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A Pilot Trial of Using Pre-Transplant Risk Stratification and Prophylactic Defibrotide to Prevent Serious Thrombotic Microangiopathy in High-Risk Hematopoietic Stem Cell Transplant Patients
Actual Study Start Date : May 1, 2018
Estimated Primary Completion Date : July 31, 2020
Estimated Study Completion Date : July 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Prophylactic Defibrotide
6.25mg/kg administered intravenously every 6 hours for 28 to 35 days, starting on the day before conditioning is initiated.
Drug: Defibrotide
Defibrotide is an anticoagulant and fibrinolytic agent that has been shown to be an effective treatment in other endothelial disorders such as hepatic veno-occlusive disease.
Other Name: Defitelio




Primary Outcome Measures :
  1. Incidence of missed doses of defibrotide [feasibility] [ Time Frame: From first treatment with study drug to 6 months post-transplant ]
    Feasibility will be determined with regard to administration concurrently with chemotherapy and supportive medications before, during, and after stem cell infusion.

  2. Incidence of reportable Serious Adverse Events [safety] [ Time Frame: From first treatment with study drug to 6 months post-transplant ]
    Safety will be assessed by evaluating drug-related Serious Adverse Events that occur after prophylactic administration of defibrotide. Analyses will be performed for all patients having received at least one dose of study drug.

  3. Incidence of clinically significant bleeding requiring discontinuation of therapy [safety] [ Time Frame: From first treatment with study drug to 6 months post-transplant ]

    Bleeding will be assessed using Common Toxicity for Adverse Events version 4.03.

    For grade 2 bleeding, study drug will be held until it resolves to grade 1 or lower. Study drug will be permanently discontinued at grade 3 bleeding or higher. Analyses will be performed for all patients having received at least one dose of study drug.


  4. Incidence of hypersensitivity reaction requiring discontinuation of therapy [safety] [ Time Frame: From first treatment with study drug to 6 months post-transplant ]

    Hypersensitivity reaction will be assessed using Common Toxicity for Adverse Events version 4.03.

    For grade 2 hypersensitivity reaction, study drug will be held until it resolves to grade 1 or lower. Study drug will be permanently discontinued at grade 3 hypersensitivity reaction or higher. Analyses will be performed for all patients having received at least one dose of study drug.



Secondary Outcome Measures :
  1. Incidence of TMA in patients enrolled on the study compared to historical controls. [ Time Frame: 6 months post-transplant ]
    Evidence of microangiopathy, with either clinical markers/organ dysfunction or presence of biomarkers, or one of the following: 1) presence of schistocytes in peripheral blood; 2) Histologic evidence of microangiopathy on a tissue specimen; 3) Undetectable haptoglobin with increased reticulocyte counts. If there is no evidence of microangiopathy but at least one clinical marker or at least 3 biomarkers, the participant will meet the criteria for TMA incidence.

  2. Incidence of severe TMA [ Time Frame: 6 months post-transplant ]
    Severe TMA is defined as any TMA meeting the criteria in Objective 2 with the following complications: renal dysfunction requiring dialysis, pleural or pericardial effusion requiring any medical or surgical intervention, central nervous system dysfunction including seizure or posterior reversible encephalopathy syndrome, or death.


Other Outcome Measures:
  1. Incidence of elevation of single or combination of biomarkers predictive of development of TMA [ Time Frame: 6 months post-transplant ]
    Values will be analyzed to determine whether any one biomarker or a combination of biomarkers may be predictive of TMA development or severity.

  2. Incidence of TMA [ Time Frame: Day 30, day 100 and day 180 post-transplant ]
    TMA will defined as per the criteria listed under Outcome 2.

  3. Non relapse mortality [ Time Frame: Day 100 and day 180 post-transplant ]
    Deaths which cannot be attributed to disease relapse or progression



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Ages Eligible for Study:   up to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. Age 0-30 years of age
  2. Life expectancy > 6 months
  3. Eastern Cooperative Oncology Group or Karnofsky Performance Status >40
  4. Meets minimum organ function requirements per institutional standard of care guiding clearance for autologous or allogeneic stem cell transplantation.
  5. Patients must meet TMA High-Risk criteria 5A or 5B below:

5A. Patients undergoing tandem autologous transplant with thiotepa in one or more of the conditioning regimens

OR:

5B. . Patients with at least 3 of the following characteristics:

  1. >10 years of age
  2. Non-Caucasian race/ Hispanic ethnicity
  3. Undergoing haploidentical transplant
  4. Minor ABO blood group mismatch

Exclusion Criteria:

  1. Age >30 years
  2. Life expectancy < 6 months
  3. Known bleeding diathesis or bleeding risk deemed by the treating physician to be a contraindication to administration of anticoagulants.
  4. Known hypersensitivity reaction to defibrotide
  5. Any patient not meeting TMA High-Risk criteria
  6. Pregnant women are excluded from this study because they will be receiving teratogenic therapy as part of the stem cell transplant.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03384693


Contacts
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Contact: Christopher Dvorak, MD 415-476-2188 Christopher.Dvorak@ucsf.edu
Contact: Christine Higham, MD 415-476-2188 Christine.Higham@ucsf.edu

Locations
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United States, California
Benioff Children's Hospital at UCSF Medical Center Recruiting
San Francisco, California, United States, 94143
Contact: Chris Dvorak, MD    415-476-2188    dvorakc@peds.ucsf.edu   
Principal Investigator: Chis Dvorak, MD         
Sponsors and Collaborators
University of California, San Francisco
Investigators
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Principal Investigator: Christopher Dvorak, MD University of California, San Francisco

Publications:

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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03384693     History of Changes
Other Study ID Numbers: 17-23356
First Posted: December 27, 2017    Key Record Dates
Last Update Posted: October 11, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie the results reported in scientific journals after de-identification.
Supporting Materials: Study Protocol
Time Frame: Beginning 3 months and ending 5 years following article publication
Access Criteria: Researchers can submit a request for access to the study Steering Committee. If the proposal is determined to be methodologically sound, data requestors will need to sign a data access agreement prior to gaining access.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by University of California, San Francisco:
hematopoeitic stem cell transplant
prophylactic defibrotide

Additional relevant MeSH terms:
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Vascular Diseases
Thrombotic Microangiopathies
Cardiovascular Diseases
Thrombocytopenia
Blood Platelet Disorders
Hematologic Diseases
Defibrotide
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors