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

Phase 3

Completed

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.

Recruitment & 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
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

Arm && Interventions

Group	Intervention	Description
Defibrotide	Defibrotide	Defibrotide treatment

Primary Outcome Measures

Name	Time	Method
Survival at Day+100 Following Hematopoietic Stem Cell Transplant	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	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

Name	Time	Method
Survival at Day+180 Post Hematopoietic Stem Cell Transplantation	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	Through 30 days from the last dose of Defibrotide