Defibrotide TMA Prophylaxis Pilot Trial

September 14, 2021 updated by: University of California, San Francisco

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

This is an open-label, single arm pilot study of defibrotide given as prophylaxis to patients receiving a conditioned stem cell transplant for the purpose of preventing post-transplant microangiopathy. The University of California San Francisco Blood and Marrow Transplant program reviewed all cases of non-relapse related death from 2012 through 2015 and identified a complication of endothelial injury known as transplant associated thrombotic microangiopathy (TMA) as the most common cause of transplant related mortality in its patient population. TMA is a multi-system disease in which widespread endothelial injury leads to microangiopathic hemolytic anemia, intravascular platelet activation and formation of thrombi within the microcirculation. Diagnosis of TMA can be difficult as systemic signs and symptoms of TMA are often similar to other common transplant complications, such as medication induced hypertension and cytopenias. The reported prevalence of TMA is varied likely due to diagnostic uncertainty and transplant center expertise, but large retrospective studies have reported it as 10-39%, with the majority of cases occurring in the first 100 days after transplant. Of the patients who develop TMA, approximately half of them will develop severe disease. Outcomes are poor with a reported 30-50% mortality rate and as high as 80% in patients with severe disease. Furthermore, survivors of TMA may have significant morbidity (e.g. renal failure and need for long-term dialysis, heart failure, and significantly prolonged hospital admission). There is no gold standard of treatment for TMA. Supportive care includes renal support, discontinuation of calcineurin inhibitors, and treatment of infections. Treatment options include plasma exchange, complement cascade blockade, and defibrotide. Early treatment is crucial to decrease morbidity and mortality.

Despite the early recognition and treatment of TMA, poor outcomes occur when patients are treated with complement blockade alone. This suggests that complement activation may trigger a complex cascade of parallel inflammatory mediators that lead to end organ damage independent of the complement pathway. The goal is to prevent TMA whenever possible via augmentation of endothelial repair. 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. It is a polydeoxyribonucleotide salt that blocks plasminogen activator inhibitor-1 (PAI-1) and attenuates the effect of tumor necrosis factor. It also increases prostaglandin E2 and prostacyclin levels which alters the platelet activity adhesion and aggregation and relaxes the smooth muscle of blood vessel walls. All of this likely protects the endothelium from damage. It has been shown that patients with TMA who were treated with defibrotide had a 77% response rate.

The use of defibrotide in the context of veno occlusive disease (VOD) treatment and prevention has been studied extensively, including a landmark report showing that defibrotide given to children during stem cell transplant conditioning is safe and effective in the prevention of veno-occlusive disease. Also, defibrotide showed a 67-77% response rate when used as treatment in patients who developed TMA. However, there has not been a prospective study to show that such prophylaxis is effective in the prevention of TMA in pediatric patients undergoing hematopoetic stem cell transplant (HCT).

Patients will receive Defibrotide 6.25mg/kg via two hour intravenous infusions given every 6 hours. Defibrotide will start the day before conditioning is initiated, and will last for 28 to 35 days. During defibrotide administration, participants will have assessments of administration feasibility, hypersensitivity reaction, and bleeding. All hematopoietic stem cell transplant standard of care evaluations will be conducted, including routine clinical evaluations and laboratory assessments.

Patients will be followed for 6 months post-HSCT, or until death, whichever occurs first. All patients will be evaluated for toxicity from the time of their first treatment with the study drug. The study will use the CTCAE v4.03 for reporting of non-hematologic adverse events and modified criteria for hematologic adverse events. Patients removed from study for unacceptable treatment related adverse event(s) will be followed until resolution or stabilization of all treatment-related adverse events to Grade 2 or lower.

Biomarkers indicative of endothelial damage and TMA activity will be drawn to assess subclinical TMA activity as well as risk for subsequent development of TMA while on defibrotide. These include plasma free hemoglobin, suppression of tumorigenicity, angiopoietin 2, and plasminogen activator inhibitor - 1. Study labs will be assessed at 4 time points prior to Day +21, and at diagnosis of TMA.

Study Type

Interventional

Enrollment (Actual)

25

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • San Francisco, California, United States, 94143
        • Benioff Children's Hospital at UCSF Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 30 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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 Names:
  • Defitelio

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percent of Total Doses of Defibrotide That Were Missed [Feasibility]
Time Frame: From first treatment with study drug to day +21 post Transplant
Feasibility will be determined with regard to administration concurrently with chemotherapy and supportive medications before, during, and after stem cell infusion.
From first treatment with study drug to day +21 post Transplant
Participants With Reportable Serious Adverse Events [Safety] Per CTACAE v5 Grade 3 or Higher
Time Frame: From first treatment with study drug to 6 months post-transplant
Safety was assessed by evaluating drug-related Serious Adverse Events per CTACAE v5 that occur after prophylactic administration of defibrotide. Analyses will be performed for all patients having received at least one dose of study drug.
From first treatment with study drug to 6 months post-transplant
Participants With Clinically Significant Bleeding Requiring Discontinuation of Therapy [Safety]
Time Frame: From first treatment with study drug to 6 months post-transplant
Bleeding was assessed using Common Toxicity Criteria for Adverse Events version 4.03. (CTCAE). Study drug was permanently discontinued at grade 3 bleeding or higher. Analyses will be performed for all patients having received at least one dose of study drug.
From first treatment with study drug to 6 months post-transplant
Participants With 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 Criteria 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.
From first treatment with study drug to 6 months post-transplant

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Patients With TMA Enrolled on the Study
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.

Based on prior analysis at our center, we anticipated an incidence of TA-TMA of 28.2% (95 CI, 17.8-38.6%) in the high-risk patients undergoing allogeneic transplants and 40% (95% CI, 13.9-69.5%) in the neuroblastoma patients undergoing planned tandem HSCT
6 months post-transplant
Number of Patients With 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.
6 months post-transplant

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
6 months post-transplant
Incidence of TMA
Time Frame: Day 30, day 100 and day 180 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.
Day 30, day 100 and day 180 post-transplant
Non Relapse Mortality
Time Frame: Day 100 and day 180 post-transplant
Deaths which cannot be attributed to disease relapse or progression
Day 100 and day 180 post-transplant

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, San Francisco

Investigators

  • Principal Investigator: Christine Higham, MD, University of California, San Francisco

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2018

Primary Completion (Actual)

July 31, 2020

Study Completion (Actual)

July 31, 2020

Study Registration Dates

First Submitted

December 11, 2017

First Submitted That Met QC Criteria

December 19, 2017

First Posted (Actual)

December 27, 2017

Study Record Updates

Last Update Posted (Actual)

September 16, 2021

Last Update Submitted That Met QC Criteria

September 14, 2021

Last Verified

September 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 17-23356

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

Individual participant data that underlie the results reported in scientific journals after de-identification.

IPD Sharing Time Frame

Beginning 3 months and ending 5 years following article publication

IPD Sharing 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.

IPD Sharing Supporting Information Type

  • Study Protocol

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Thrombotic Microangiopathies

Clinical Trials on Defibrotide

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in China

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe