Safety and Efficacy of Perioperative Remodulin® in Orthotopic Liver Transplant Recipients

A Single Center, Randomized, Double-Blind, Parallel Placebo-Controlled Study of the Safety and Efficacy of Perioperative Remodulin® in Orthotopic Liver Transplant Recipients

Patients undergoing orthotopic liver transplant will experience some degree of clinical and/or biochemical hepatic dysfunction. This early injury is known as primary graft dysfunction and varies from minor abnormalities to primary nonfunction. Prostaglandin-class drugs, including prostacyclin and its analogs, could represent an important advance toward the goal of reducing transplant related morbidity, mortality and associated costs by providing these benefits.

Study Overview

• Status: Withdrawn
• Conditions: Liver Transplant
• Intervention / Treatment: Drug: Placebo; Drug: treprostinil sodium

Detailed Description

In vitro and in vivo research has consistently demonstrated an array of potential beneficial effects of prostanoids under both immune and non-immune circumstances relevant to liver allografts. (1-3) Recent reviews summarize the pharmacologic rationale and nonclinical and clinical experience supporting for the use of prostanoids, including prostacyclin and its analogs, in reducing early morbidity and mortality associated with liver transplantation. Prostaglandin-class drugs, including prostacyclin and its analogs, could represent an important advance toward the goal of reducing transplant related morbidity, mortality and associated costs by providing these benefits. Additionally, the reduction in serum creatinine and reduced need for post-operative dialysis observed in some studies has implications in protecting the kidneys from the nephrotoxic affects of the immunosuppressant agents, especially during the early post-operative period.

As a chemically stable analog of prostacyclin (PGI2), peri-operative intravenous administration of Remodulin is hypothesized to ameliorate or prevent reperfusion damage and thereby decrease hospitalization time and improve the clinical outcome of liver transplantation, compared to placebo control. Remodulin, as a prostanoid, is expected to facilitate restoration of the blood supply to the revascularized graft, and to provide the well-characterized protective effects of this class of compounds in liver transplant patients.

• Study Type: Interventional
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center, Starzl Transplantation Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Accepted as a liver transplant candidate at the University of Pittsburgh Medical Center
• Be receiving a cadaver donor liver transplant
• Treated in accordance with the standard of care protocol(s) in effect for liver transplant recipients at the University of Pittsburgh Medical Center.

Exclusion Criteria:

• Receiving a living done liver transplant
• Receiving a donor liver with a cold ischemia time less that 6 hours
• Receiving a donor liver with macrosteatosis greater than 30%
• Receiving any investigation drug with the except of alemtuzamab (Camphath)
• Failed liver transplant in previous 180 days
• Prior organ transplant or cell infusion
• Undergoing multi-organ transplant
• Pregnant or nursing female

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Matching placebo	Drug: Placebo
Experimental: Remodulin; Remodulin initiated as a continuous IV infusion at a dose of 2.5 ng/kg/min after subjects have been assessed as hemodynamically stable in the ICU. Dose may be escalated in 1.25- to 2.5-ng/kg/min increments, up to 7.5 ng/kg/min, with a target dose of 5 ng/kg/min, based on tolerability. The dose will be maintained at the maximum tolerated dose, not to exceed 7.5 ng/kg/min for 5 days after the transplantation surgery.	Drug: treprostinil sodium; A single dose strength of treprostinil sodium (1.0 mg/mL) and matching placebo will be provided in 20-mL multi-dose vials. The study drug will be started after induction of anesthesia and increased incrementally to a target dose of 10 ng/kg/min during surgery and 48 hours post-operative; Other Names: Remodulin; UT 15

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of the initial hospitalization (days) following transplantation		up to 180 days
Area under the curve (AUC) of serum aspartate transaminase (AST) levels.	The difference in serum AST as measured by AUC during the first seven days post-transplant will be compared between placebo and Remodulin treatment groups. AST is a serum transaminase marker of hepatic injury, and the AUC of AST levels represents the total magnitude of injury the liver experiences against time.	7 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Serum AST and alanine transaminase (ALT ) levels after transplant (Peak and Area Under the Curve [AUC])	7 days
Primary allograft nonfunction defined as patient death or retransplant within 30 days due to liver failure	30 days
Graft survival	30 days, 90 days and 180 days
Subject survival at	Day 30, 90, and 180
Post-transplant renal function	30 days
Duration of time spent in the intensive care unit (ICU; days) during the initial hospitalization.	up to 180 days
Intra-operative blood product usage	1 day
Death from any cause	180 days
Total costs for initial transplant hospitalization	up to 180 days

Collaborators and Investigators

• Sponsor: United Therapeutics
• Collaborators: University of Pittsburgh Medical Center
• Investigators: Principal Investigator: Amadeo Marcos, MD, University of Pittsburgh Medical Center; Principal Investigator: Raman Venkataramanan, Ph.D, F.C.P., University of Pittsburgh Medcial Center

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Estimated): June 1, 2010
• Study Completion (Estimated): June 1, 2010

Study Registration Dates

• First Submitted: October 19, 2012
• First Submitted That Met QC Criteria: June 20, 2013
• First Posted (Estimated): June 21, 2013

Study Record Updates

• Last Update Posted (Estimated): December 19, 2023
• Last Update Submitted That Met QC Criteria: December 12, 2023
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Keywords: Prostacyclin; Reperfusion Injury; Liver Transplant; Remodulin; Treprostinil sodium; Primary Nonfunction
• Additional Relevant MeSH Terms: Antihypertensive Agents; Treprostinil
• Other Study ID Numbers: RIV-LT-301