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

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.

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