5-day Defibrotide Treatment for Hepatic SOS/VOD

Phase II Open Label Study to Assess Efficacy of 5-day Defibrotide Treatment for Hepatic SOS/VOD

Sinusoidal Obstruction Syndrome (SOS), also referred to as hepatic veno-occlusive disease (VOD), is rare but serious complication of allogeneic stem cell transplantation (allo-SCT). Defibrotide is the only FDA approved therapy to treat SOS and has significantly improved outcomes. When applied early, SOS symptoms often quickly improve and an abbreviated course can be applied. This study is looking at an abbreviated 5 day course of defibrotide in those patients with a complete response to therapy with the primary outcome being day 100 overall survival as compared to history data.

Study Overview

• Status: Recruiting
• Conditions: Bone Marrow Transplant Complications; Sinusoidal Obstruction Syndrome; Veno-occlusive Disease
• Intervention / Treatment: Drug: Defibrotide

Detailed Description

Sinusoidal obstructive syndrome (SOS) has a reported mean incidence of 13.7% and even among those undergoing reduced intensity conditioning regimens is approximately 9%. SOS is a clinical syndrome characterized by painful hepatomegaly, jaundice, ascites, fluid retention, and weight gain. The onset is usually before day 35 after stem cell infusion. SOS ranges in severity from a mild reversible disease to a severe syndrome associated with multiorgan failure (MOF) and death. Prior to the introduction of defibrotide, severe SOS was nearly universally fatal with a mortality rate approaching 100% by day 100 after allo-SCT.

The diagnosis of SOS/VOD is clinical and should be considered in any patient who has undergone hematopoietic stem cell transplantation and develops liver dysfunction. Patients with mild or moderate disease have reasonably good outcomes with supportive therapy alone while in contrast prognosis is much worse in severe SOS which occurs in about 25-30% cases.

Defibrotide is the only established Food and Drug Administration (FDA) approved therapy to treat SOS. It is now approved for use in adults and children with SOS with renal or pulmonary dysfunction following HCT. The standard treatment is 25 mg/kg/day in 4 divided doses of 6.25 mg/kg for 21 days. However, responses are frequently brisk and complete in many patients thus it has been postulated that in responding patients this treatment course could be abbreviated given the risk for adverse events such as hypotension/shock and hemorrhage.

This is an open label pilot study evaluating an abbreviated 5 (as compared to 21) day course of defibrotide in patients with confirmed SOS. The primary outcome is day 100 survival as compared to historical data.

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Patrick A Hagen, MD, MPH; Phone Number: 708-327-3157; Email: patrick.hagen@lumc.edu
• Study Contact Backup: Name: Mary Lee; Phone Number: 708-327-2241; Email: mlee@luc.edu

Study Locations

• United States
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Recruiting
      • Loyola University Medical Center
      • Contact: Mary Lee, RN; Phone Number: 708-327-2241; Email: mlee@luc.edu
      • Principal Investigator: Patrick Hagen, MD
      • Contact: Patrick A Hagen, MD; Phone Number: 708-327-3157; Email: patrick.hagen@lumc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients who underwent allogeneic stem cell transplantation
2. Age >/= 18 years
3. Diagnosed hepatic SOS/VOD either by Baltimore Criteria or Modified Seattle Criteria including up to 60 days post-transplantation.

Exclusion Criteria:

1. Significant uncontrolled bleeding
2. Prior or concurrent systemic t-PA
3. Concomitant use of therapeutic heparin or other anticoagulants (except use of heparin for central access patency)
4. Hemodynamic instability (>1 pressor gent to maintain blood pressure)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Defibrotide; 5 day course of defibrotide at standard dosing 25 mg/kg/day in 4 divided doses of 6.25 mg/kg. If not in CR by day 5, will be given for >/= 21 days or per discretion of enrolling physician.	Drug: Defibrotide; 25 mg/kg/day at 4 divided doses of 6.25 mg/kg, 2-h infusion given for 5 days, if not in CR treatment continued for >/= 21 days or per discretion of enrolling physician.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Day 100 overall survival	Assess day 100 survival of 5-day defibrotide treatment for hepatic SOS/VOD in allogeneic stem cell transplant patients compared to standard 21-day treatment in the reported literature.	100 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete response day 100	Assess complete response (CR) rates for hepatic SOS/VOD by day +100 defined as resolution of parameters used to document SOS/VOD.	100 days
Complete response day 5	Assess complete response (CR) rates for hepatic SOS/VOD by day +5 as defined by resolution of parameters used to document SOS/VOD.	5 days
Complete response day 30	Assess complete response (CR) rates for hepatic SOS/VOD by day +30 as defined by resolution of parameters used to document SOS/VOD.	30 days

Collaborators and Investigators

• Sponsor: Loyola University
• Investigators: Principal Investigator: Patrick A Hagen, MD, Loyola University

Study record dates

Study Major Dates

• Study Start (Actual): March 11, 2021
• Primary Completion (Anticipated): May 1, 2022
• Study Completion (Anticipated): August 1, 2022

Study Registration Dates

• First Submitted: March 16, 2020
• First Submitted That Met QC Criteria: March 16, 2020
• First Posted (Actual): March 18, 2020

Study Record Updates

• Last Update Posted (Actual): April 23, 2021
• Last Update Submitted That Met QC Criteria: April 22, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Bone Marrow Transplant; allogeneic stem cell transplant; defibrotide; Sinusoidal; Veno-occlusive
• 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: 212665

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes