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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.

ClinicalTrials.gov Identifier: NCT00358501

Recruitment Status : Completed

First Posted : August 1, 2006

Results First Posted : January 30, 2017

Last Update Posted : January 30, 2017

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborator:

FDA Office of Orphan Products Development

Information provided by (Responsible Party):

Jazz Pharmaceuticals

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.

Condition or disease	Intervention/treatment	Phase
Severe Hepatic Veno-Occlusive Disease	Drug: Defibrotide	Phase 3

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.

Study Design

Layout table for study information

Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	134 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (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
Study Start Date :	July 2006
Actual Primary Completion Date :	September 2008
Actual Study Completion Date :	March 2015

Resource links provided by the National Library of Medicine

Drug Information available for: Defibrotide sodium

Genetic and Rare Diseases Information Center resources: Hepatic Veno-occlusive Disease

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
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

Outcome Measures

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

Eligibility Criteria

Information from the National Library of Medicine

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, Learn About Clinical Studies.

Layout table for eligibility information

Ages Eligible for Study:	Child, Adult, Older Adult
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

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): NCT00358501

Locations

Layout table for location information

United States, California

Duarte, California, United States

Palo Alto, California, United States
United States, Colorado

Denver, Colorado, United States
United States, Georgia

Atlanta, Georgia, United States
United States, Illinois

Chicago, Illinois, United States

Maywood, Illinois, United States
United States, Indiana

Indianapolis, Indiana, United States
United States, Maryland

Baltimore, Maryland, United States
United States, Massachusetts

Boston, Massachusetts, United States
United States, Michigan

Ann Arbor, Michigan, United States
United States, Minnesota

Minneapolis, Minnesota, United States

Rochester, Minnesota, United States
United States, Missouri

St. Louis, Missouri, United States
United States, Nebraska

Omaha, Nebraska, United States
United States, New Jersey

Hackensack, New Jersey, United States
United States, New York

New York, New York, United States
United States, North Carolina

Durham, North Carolina, United States
United States, Ohio

Columbus, Ohio, United States
United States, Oregon

Portland, Oregon, United States
United States, Pennsylvania

Philadelphia, Pennsylvania, United States
United States, Texas

Houston, Texas, United States
United States, Washington

Seattle, Washington, United States
Canada, British Columbia

Vancouver, British Columbia, Canada
Canada, Ontario

Toronto, Ontario, Canada
Canada, Quebec

Montreal, Quebec, Canada

Sponsors and Collaborators

Jazz Pharmaceuticals

FDA Office of Orphan Products Development

Investigators

Layout table for investigator information

Principal Investigator:	Paul Richardson, M.D.	Dana-Farber Cancer Institute

More Information

Publications:

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.

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).

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Layout table for additonal information

Responsible Party:	Jazz Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT00358501
Obsolete Identifiers:	NCT00410917
Other Study ID Numbers:	2005-01
First Posted:	August 1, 2006 Key Record Dates
Results First Posted:	January 30, 2017
Last Update Posted:	January 30, 2017
Last Verified:	December 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:

Layout table for 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

To Top