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

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

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.

Study Overview

• Status: Completed
• Conditions: Severe Hepatic Veno-Occlusive Disease
• Intervention / Treatment: Drug: Defibrotide

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.

• Study Type: Interventional
• Enrollment (Actual): 134
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada
  • Ontario
    • Toronto, Ontario, Canada
  • Quebec
    • Montreal, Quebec, Canada
• United States
  • California
    • Duarte, California, United States
    • Palo Alto, California, United States
  • Colorado
    • Denver, Colorado, United States
  • Georgia
    • Atlanta, Georgia, United States
  • Illinois
    • Chicago, Illinois, United States
    • Maywood, Illinois, United States
  • Indiana
    • Indianapolis, Indiana, United States
  • Maryland
    • Baltimore, Maryland, United States
  • Massachusetts
    • Boston, Massachusetts, United States
  • Michigan
    • Ann Arbor, Michigan, United States
  • Minnesota
    • Minneapolis, Minnesota, United States
    • Rochester, Minnesota, United States
  • Missouri
    • St. Louis, Missouri, United States
  • Nebraska
    • Omaha, Nebraska, United States
  • New Jersey
    • Hackensack, New Jersey, United States
  • New York
    • New York, New York, United States
  • North Carolina
    • Durham, North Carolina, United States
  • Ohio
    • Columbus, Ohio, United States
  • Oregon
    • Portland, Oregon, United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
  • Texas
    • Houston, Texas, United States
  • Washington
    • Seattle, Washington, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Historical Control Group Adverse Event Information	Historical Control group was not assessed for severity	Through 30 days from the last dose of Defibrotide

Collaborators and Investigators

• Sponsor: Jazz Pharmaceuticals
• Collaborators: FDA Office of Orphan Products Development
• Investigators: Principal Investigator: Paul Richardson, M.D., Dana-Farber Cancer Institute

Publications and helpful links

General Publications

• 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.
• 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).
• 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.

Study record dates

Study Major Dates

• Study Start: July 1, 2006
• Primary Completion (Actual): September 1, 2008
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: July 28, 2006
• First Submitted That Met QC Criteria: July 28, 2006
• First Posted (Estimate): August 1, 2006

Study Record Updates

• Last Update Posted (Estimate): January 30, 2017
• Last Update Submitted That Met QC Criteria: December 2, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: Stem cell transplant; Liver; Defibrotide; Multi organ failure; Severe veno occlusive disease; Regimen related toxicity; Day 100 survival
• Additional Relevant MeSH Terms: Digestive System Diseases; Cardiovascular Diseases; Vascular Diseases; Liver Diseases; Hepatic Veno-Occlusive Disease; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Defibrotide
• Other Study ID Numbers: 2005-01