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

Severe Hepatic Veno Occlusive Disease Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00358501
• Other study ID #: 2005-01
• Status: Completed
• Phase: Phase 3
• First received: July 28, 2006
• Last updated: February 2, 2016
• Start date: July 2006
• Est. completion date: March 2015

Study information

• Verified date: June 2011
• Source: Jazz Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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 VOD through the analysis of blood samples.

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 SCT 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 MOF (i.e., pulmonary and/or renal dysfunction). This represents a group of patients in whom mortality at D+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 eligiblity 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 SCT, and special studies of endothelial and serum markers for VOD. This study will assess safety of the dose and schedule in this setting.

Other known NCT identifiers

• NCT00410917

Recruitment information / eligibility

• Status: Completed
• Enrollment: 102
• Est. completion date: March 2015
• Est. primary completion date: September 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

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

• 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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Budd-Chiari Syndrome
• Hepatic Veno-Occlusive Disease
• Severe Hepatic Veno Occlusive Disease

Intervention

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

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Jazz Pharmaceuticals	FDA Office of Orphan Products Development

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (2)

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. Epub 2002 Aug 1. — View 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).

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Complete Response at D+100 post stem cell transplant		Day + 100 post stem cell transplant	No
Secondary	Survival at D+100 following stem cell transplant		Day + 100 post stem cell transplant	No
Secondary	Long-term (6 month) survival rate		180 days post stem cell transplant	No
Secondary	Safety of the selected dose and schedule		through 30 days from the last dose of Defibrotide	Yes