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

Study Overview
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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.

Official Title
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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

Conditions
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Severe Hepatic Veno-Occlusive Disease

Intervention / Treatment
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* Drug: Defibrotide


Participation Criteria
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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
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Defibrotide<br>Defibrotide treatment | Drug: Defibrotide<br>* Defibrotide 6.25 mg/kg i.v. administered four times a day via 2 hour continuous infusion. Minimum duration 21 days.<br>|
| No Intervention: Historical Control<br>Historical control group | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival at Day+100 Following 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. | Day+100 post hematopoietic stem cell transplant | 
| Complete Response by 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. | Day+100 post hematopoietic stem cell transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival at Day+180 Post Hematopoietic Stem Cell Transplantation | 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. | 180 days post hematopoietic stem cell transplant | 
| Percentage of Participants With Treatment-Emergent Adverse Events |  | Through 30 days from the last dose of Defibrotide | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Defibrotide, Severe veno occlusive disease, Multi organ failure, Stem cell transplant, Liver, Regimen related toxicity, Day 100 survival