Clinical trial NCT00358501: Defibrotide for the Treatment of Severe Hepatic Veno-Occlusive Disease in Hematopoetic Stem Cell Transplant Patients
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Severe Hepatic Veno-Occlusive Disease
Keywords: Defibrotide
Severe veno occlusive disease
Multi organ failure
Stem cell transplant
Liver
Regimen related toxicity
Day 100 survival
Lead sponsor: Jazz Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: FDA Office of Orphan Products Development
First posted: 2006-08-01
Enrollment: 134
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Survival at Day+100 Following Hematopoietic Stem Cell Transplant
timeFrame: Day+100 post hematopoietic stem cell transplant
measure: Complete Response by Day+100 Post Hematopoietic Stem Cell Transplant
timeFrame: Day+100 post hematopoietic stem cell transplant
Secondary outcomes:
measure: Survival at Day+180 Post Hematopoietic Stem Cell Transplantation
timeFrame: 180 days post hematopoietic stem cell transplant
measure: Percentage of Participants With Treatment-Emergent Adverse Events
timeFrame: Through 30 days from the last dose of Defibrotide
Other outcomes:
measure: Historical Control Group Adverse Event Information
timeFrame: Through 30 days from the last dose of Defibrotide
Locations:
city: Duarte
country: United States
state: California
city: Palo Alto
country: United States
state: California
city: Denver
country: United States
state: Colorado
city: Atlanta
country: United States
state: Georgia
city: Chicago
country: United States
state: Illinois
city: Maywood
country: United States
state: Illinois
city: Indianapolis
country: United States
state: Indiana
city: Baltimore
country: United States
state: Maryland
city: Boston
country: United States
state: Massachusetts
city: Ann Arbor
country: United States
state: Michigan
city: Minneapolis
country: United States
state: Minnesota
city: Rochester
country: United States
state: Minnesota
city: St. Louis
country: United States
state: Missouri
city: Omaha
country: United States
state: Nebraska
city: Hackensack
country: United States
state: New Jersey
city: New York
country: United States
state: New York
city: Durham
country: United States
state: North Carolina
city: Columbus
country: United States
state: Ohio
city: Portland
country: United States
state: Oregon
city: Philadelphia
country: United States
state: Pennsylvania
city: Houston
country: United States
state: Texas
city: Seattle
country: United States
state: Washington
city: Vancouver
country: Canada
state: British Columbia
city: Toronto
country: Canada
state: Ontario
city: Montreal
country: Canada
state: Quebec
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Paul Richardson, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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).
citation: 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.