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

NCT ID: NCT00358501

Last Updated: 2017-01-30

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

134 participants

Study Classification

INTERVENTIONAL

Study Start Date

2006-07-31

Study Completion Date

2015-03-31

Brief Summary

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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

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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.

Conditions

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Severe Hepatic Veno-Occlusive Disease

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Defibrotide

Defibrotide treatment

Group Type EXPERIMENTAL

Defibrotide

Intervention Type DRUG

Defibrotide 6.25 mg/kg i.v. administered four times a day via 2 hour continuous infusion. Minimum duration 21 days.

Historical Control

Historical control group

Group Type NO_INTERVENTION

No interventions assigned to this group

Interventions

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Defibrotide

Defibrotide 6.25 mg/kg i.v. administered four times a day via 2 hour continuous infusion. Minimum duration 21 days.

Intervention Type DRUG

Eligibility Criteria

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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
Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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FDA Office of Orphan Products Development

FED

Sponsor Role collaborator

Jazz Pharmaceuticals

INDUSTRY

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Paul Richardson, M.D.

Role: PRINCIPAL_INVESTIGATOR

Dana-Farber Cancer Institute

Locations

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Duarte, California, United States

Site Status

Palo Alto, California, United States

Site Status

Denver, Colorado, United States

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Atlanta, Georgia, United States

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Chicago, Illinois, United States

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Maywood, Illinois, United States

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Indianapolis, Indiana, United States

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Baltimore, Maryland, United States

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Boston, Massachusetts, United States

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Ann Arbor, Michigan, United States

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Minneapolis, Minnesota, United States

Site Status

Rochester, Minnesota, United States

Site Status

St Louis, Missouri, United States

Site Status

Omaha, Nebraska, United States

Site Status

Hackensack, New Jersey, United States

Site Status

New York, New York, United States

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Durham, North Carolina, United States

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Columbus, Ohio, United States

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Portland, Oregon, United States

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Philadelphia, Pennsylvania, United States

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Houston, Texas, United States

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Seattle, Washington, United States

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Vancouver, British Columbia, Canada

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Toronto, Ontario, Canada

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Montreal, Quebec, Canada

Site Status

Countries

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United States Canada

References

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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.

Reference Type BACKGROUND
PMID: 12393437 (View on PubMed)

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).

Reference Type BACKGROUND

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.

Reference Type DERIVED
PMID: 26825712 (View on PubMed)

Related Links

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http://www.gentium.com/Defibrotide.aspx

Click here for more information about Defibrotide.

Other Identifiers

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2005-01

Identifier Type: -

Identifier Source: org_study_id

NCT00410917

Identifier Type: -

Identifier Source: nct_alias

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