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

Primary Purpose

Severe Hepatic Veno-Occlusive Disease

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Defibrotide
Sponsored by
Jazz Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Severe Hepatic Veno-Occlusive Disease focused on measuring Defibrotide, Severe veno occlusive disease, Multi organ failure, Stem cell transplant, Liver, Regimen related toxicity, Day 100 survival

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Defibrotide

Historical Control

Arm Description

Defibrotide treatment

Historical control group

Outcomes

Primary Outcome Measures

Survival at Day+100 Following 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
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
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

Full Information

First Posted
July 28, 2006
Last Updated
December 2, 2016
Sponsor
Jazz Pharmaceuticals
Collaborators
FDA Office of Orphan Products Development
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1. Study Identification

Unique Protocol Identification Number
NCT00358501
Brief Title
Defibrotide for the Treatment of Severe Hepatic Veno-Occlusive Disease in Hematopoetic Stem Cell Transplant Patients
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
Study Type
Interventional

2. Study Status

Record Verification Date
December 2016
Overall Recruitment Status
Completed
Study Start Date
July 2006 (undefined)
Primary Completion Date
September 2008 (Actual)
Study Completion Date
March 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Jazz Pharmaceuticals
Collaborators
FDA Office of Orphan Products Development

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Severe Hepatic Veno-Occlusive Disease
Keywords
Defibrotide, Severe veno occlusive disease, Multi organ failure, Stem cell transplant, Liver, Regimen related toxicity, Day 100 survival

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
134 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Defibrotide
Arm Type
Experimental
Arm Description
Defibrotide treatment
Arm Title
Historical Control
Arm Type
No Intervention
Arm Description
Historical control group
Intervention Type
Drug
Intervention Name(s)
Defibrotide
Intervention Description
Defibrotide 6.25 mg/kg i.v. administered four times a day via 2 hour continuous infusion. Minimum duration 21 days.
Primary Outcome Measure Information:
Title
Survival at Day+100 Following Hematopoietic Stem Cell Transplant
Description
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.
Time Frame
Day+100 post hematopoietic stem cell transplant
Title
Complete Response by Day+100 Post Hematopoietic Stem Cell Transplant
Description
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.
Time Frame
Day+100 post hematopoietic stem cell transplant
Secondary Outcome Measure Information:
Title
Survival at Day+180 Post Hematopoietic Stem Cell Transplantation
Description
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.
Time Frame
180 days post hematopoietic stem cell transplant
Title
Percentage of Participants With Treatment-Emergent Adverse Events
Time Frame
Through 30 days from the last dose of Defibrotide
Other Pre-specified Outcome Measures:
Title
Historical Control Group Adverse Event Information
Description
Historical Control group was not assessed for severity
Time Frame
Through 30 days from the last dose of Defibrotide

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paul Richardson, M.D.
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Principal Investigator
Facility Information:
City
Duarte
State/Province
California
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United States
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Palo Alto
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California
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Denver
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Colorado
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Atlanta
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Chicago
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Illinois
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Maywood
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Indianapolis
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Indiana
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Baltimore
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Boston
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Ann Arbor
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Minneapolis
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Rochester
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St. Louis
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Missouri
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Omaha
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Nebraska
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Hackensack
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New Jersey
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New York
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New York
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Durham
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North Carolina
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United States
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Columbus
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Ohio
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Portland
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Oregon
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Philadelphia
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Houston
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Texas
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Seattle
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Washington
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Vancouver
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British Columbia
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Canada
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Toronto
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Ontario
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Canada
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Montreal
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Quebec
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
12393437
Citation
Richardson PG, Murakami C, Jin Z, Warren D, Momtaz P, Hoppensteadt D, Elias AD, Antin JH, Soiffer R, Spitzer T, Avigan D, Bearman SI, Martin PL, Kurtzberg J, Vredenburgh J, Chen AR, Arai S, Vogelsang G, McDonald GB, Guinan EC. Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. Blood. 2002 Dec 15;100(13):4337-43. doi: 10.1182/blood-2002-04-1216. Epub 2002 Aug 1.
Results Reference
background
Citation
Richardson, Soiffer, Antin, Voss, Jin, Kurtzberget al. Defibrotide (DF) for the Treatment of Severe Veno-Occlusive Disease (VOD) and Multi-System Organ Failure (MOF) Post SCT: Final Results of a Phase II, Multicenter, Randomized Study and Preliminary Analyses of Surrogate Markers and Ultrasound Findings. [abstract]. Blood. 2004;104 (11).
Results Reference
background
PubMed Identifier
26825712
Citation
Richardson PG, Riches ML, Kernan NA, Brochstein JA, Mineishi S, Termuhlen AM, Arai S, Grupp SA, Guinan EC, Martin PL, Steinbach G, Krishnan A, Nemecek ER, Giralt S, Rodriguez T, Duerst R, Doyle J, Antin JH, Smith A, Lehmann L, Champlin R, Gillio A, Bajwa R, D'Agostino RB Sr, Massaro J, Warren D, Miloslavsky M, Hume RL, Iacobelli M, Nejadnik B, Hannah AL, Soiffer RJ. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016 Mar 31;127(13):1656-65. doi: 10.1182/blood-2015-10-676924. Epub 2016 Jan 29.
Results Reference
derived

Learn more about this trial

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

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