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Defibrotide for the Treatment of Severe Hepatic Veno-Occlusive Disease in Hematopoetic Stem Cell Transplant Patients

This study has been completed.
Sponsor:
Collaborator:
FDA Office of Orphan Products Development
Information provided by (Responsible Party):
Jazz Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT00358501
First received: July 28, 2006
Last updated: December 2, 2016
Last verified: December 2016
  Purpose
The purpose of this study is to (1) demonstrate the efficacy and safety (toxicity) of 25 mg/kg/day of Defibrotide in patients with severe veno-occlusive disease (sVOD) and (2) evaluate serum and endothelial markers of veno-occlusive disease (VOD) through the analysis of blood samples.

Condition Intervention Phase
Severe Hepatic Veno-Occlusive Disease
Drug: Defibrotide
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Defibrotide for the Treatment of Severe Hepatic Veno-Occlusive Disease in Hematopoetic Stem Cell Transplant Patients: A Historically-Controlled, Multi-Center Phase 3 Study to Determine Safety & Efficacy

Resource links provided by NLM:


Further study details as provided by Jazz Pharmaceuticals:

Primary Outcome Measures:
  • Survival at Day+100 Following Hematopoietic Stem Cell Transplant [ Time Frame: Day+100 post hematopoietic stem cell transplant ]
    The 95.1% CI instead of 95% CI is used for the final analysis to provide a small adjustment for the fact that an interim analysis was performed.

  • Complete Response by Day+100 Post Hematopoietic Stem Cell Transplant [ Time Frame: Day+100 post hematopoietic stem cell transplant ]
    The 95.1% CI instead of 95% CI is used for the final analysis to provide a small adjustment for the fact that an interim analysis was performed.


Secondary Outcome Measures:
  • Survival at Day+180 Post Hematopoietic Stem Cell Transplantation [ Time Frame: 180 days post hematopoietic stem cell transplant ]
    The 95.1% CI instead of 95% CI is used for the final analysis to provide a small adjustment for the fact that an interim analysis was performed.

  • Percentage of Participants With Treatment-Emergent Adverse Events [ Time Frame: Through 30 days from the last dose of Defibrotide ]

Other Outcome Measures:
  • Historical Control Group Adverse Event Information [ Time Frame: Through 30 days from the last dose of Defibrotide ]
    Historical Control group was not assessed for severity


Enrollment: 134
Study Start Date: July 2006
Study Completion Date: March 2015
Primary Completion Date: September 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Defibrotide
Defibrotide treatment
Drug: Defibrotide
Defibrotide 6.25 mg/kg i.v. administered four times a day via 2 hour continuous infusion. Minimum duration 21 days.
No Intervention: Historical Control
Historical control group

Detailed Description:

This is a historically-controlled, multicenter, open label Phase 3 study to determine the safety and efficacy of 25 mg/kg/day of Defibrotide (DF) for the treatment of severe VOD in hematopoietic stem cell transplantation (HSCT) patients.

In this study, the term "severe VOD" is defined as those patients who meet the Baltimore diagnostic criteria for VOD (total bilirubin >/= 2.0 mg/dL plus two of the following: ascites, >/=5% weight gain and hepatomegaly), who also have multi-organ failure (i.e., pulmonary and/or renal dysfunction). This represents a group of patients in whom mortality at Day+100 has been estimated to be >80%.

Comparisons: The primary parameter is Complete Response at 100 days following stem cell transplant, utilizing historical controls as a comparator. The historical control database will be generated through a retrospective medical chart review performed at participating centers; the survival outcome of patients who would otherwise have met eligibility criteria for this trial will be compared to the survival observed in patients prospectively treated with Defibrotide. Secondary parameters include survival rate at 100 days and 6 months post stem cell transplantation (SCT), and special studies of endothelial and serum markers for VOD. This study will assess safety of the dose and schedule in this setting.

  Eligibility

Ages Eligible for Study:   Child, Adult, Senior
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Clinical diagnosis of VOD, defined by jaundice (bilirubin >/= 2 mg/dL) and at least 2 of the following clinical findings, by Day+21 post stem cell transplant: ascites; weight gain >/= 5% above baseline weight; hepatomegaly.
  • Severe VOD, defined as VOD with multi-organ failure, i.e., presence of one or both of the following, by Day+28 post stem cell transplant: renal or pulmonary dysfunction.
  • Provide voluntary written informed consent.

Exclusion Criteria:

  • Pre-existing (prior to SCT) cirrhosis
  • An alternative diagnosis for weight gain, ascites and jaundice
  • Graft-versus-host disease (GVHD) grade B or higher involving liver or gut or grade C or higher involving skin
  • Prior solid organ transplant
  • Dependent on dialysis prior to and/or at the time of SCT
  • Dependent on oxygen supplementation prior to SCT
  • Significant acute bleeding or hemodynamic instability
  • Requirement for the use of any medications that increase risk of hemorrhage will be excluded from the treatment group
  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: NCT00358501

  Show 25 Study Locations
Sponsors and Collaborators
Jazz Pharmaceuticals
FDA Office of Orphan Products Development
Investigators
Principal Investigator: Paul Richardson, M.D. Dana-Farber Cancer Institute
  More Information

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Jazz Pharmaceuticals
ClinicalTrials.gov Identifier: NCT00358501     History of Changes
Obsolete Identifiers: NCT00410917
Other Study ID Numbers: 2005-01
Study First Received: July 28, 2006
Results First Received: March 26, 2016
Last Updated: December 2, 2016

Keywords provided by Jazz Pharmaceuticals:
Defibrotide
Severe veno occlusive disease
Multi organ failure
Stem cell transplant
Liver
Regimen related toxicity
Day 100 survival

Additional relevant MeSH terms:
Hepatic Veno-Occlusive Disease
Liver Diseases
Digestive System Diseases
Vascular Diseases
Cardiovascular Diseases
Defibrotide
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors

ClinicalTrials.gov processed this record on May 22, 2017