Safety and Efficacy of Treprostinil in Ischemia and Reperfusion Injury in Adult Orthotopic Liver Transplantation

Sponsor

Abhinav Humar, MD (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01481974

Collaborator

(none)

Enrollment

Locations

Arm

119

Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The overall purpose of this study is to evaluate the safety, pharmacokinetics and preliminary efficacy of a five-days post-operative course of Treprostinil in liver transplant patients.

The hypothesis of this study is that Treprostinil can be safely administered post-operatively in liver transplant patients. Once safety is documented future studies will address its ability to ameliorate or prevent reperfusion mediated dysfunction of the liver graft and thereby reduce morbidity, leading to shorter hospital stays as compared to historical controls.

Condition or Disease	Intervention/Treatment	Phase
Ischemia Reperfusion Injury	Drug: Treprostinil	Phase 1/Phase 2

Detailed Description

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 minimizing the effect of ischemia and re perfusion injury of the liver graft. 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. Routine use of prostaglandins (PGE1 and PGI2), however, was limited by its instability and short half life.

Treprostinil, as a prostanoid (prostacyclin analog), is expected to facilitate restoration of the blood supply to the revascularized graft and provide the well-characterized protective effects of this class of compounds in liver transplant patients. Treprostinil has the advantage of a longer elimination half-life than other prostanoids previously tested in these patients. Treprostinil is expected to significantly protect the graft from ischemia and re perfusion injury.

This is a pilot study to evaluate the safety, pharmacokinetics and preliminary efficacy of Treprostinil in orthotopic liver transplant patients as a first step to evaluate its use in prevention of ischemia and reperfusion injury of the grafted liver.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Evaluation of the Safety and Preliminary Efficacy of Perioperative Treprostinil in Preventing Ischemia and Reperfusion Injury in Adult Orthotopic Liver Transplant Recipients

Study Start Date :

Dec 1, 2012

Anticipated Primary Completion Date :

Nov 1, 2022

Anticipated Study Completion Date :

Nov 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treprostinil This is a single center, open-label, dose-escalation Phase I/II study of Treprostinil.	Drug: Treprostinil The Treatment Phase will begin at the initiation of Treprostinil after induction of anesthesia for the transplant surgery and continues throughout the surgery and for approximately a total of 120 hours. Treatment phase activities include: • Initiation of Treprostinil after the patient is hemodynamically stable following transplant surgery. (Treprostinil dosing will follow a standard 3 + 3 phase 1 design. Other Names: Brand name: REMODULIN

Arm

Intervention/Treatment

Experimental: Treprostinil

This is a single center, open-label, dose-escalation Phase I/II study of Treprostinil.

Drug: Treprostinil

The Treatment Phase will begin at the initiation of Treprostinil after induction of anesthesia for the transplant surgery and continues throughout the surgery and for approximately a total of 120 hours. Treatment phase activities include: • Initiation of Treprostinil after the patient is hemodynamically stable following transplant surgery. (Treprostinil dosing will follow a standard 3 + 3 phase 1 design.

Other Names:

Brand name: REMODULIN

Outcome Measures

Primary Outcome Measures

Serum ALT concentration after treprostinil treatment in liver transplant patients [Day 7]
The liver injury marker such as alanine aminotransferase (ALT) will be measured in order to evaluate the protective effect of treprostinil in liver transplant recipients.

Secondary Outcome Measures

Pharmacokinetics of treprostinil in liver transplant patients [0, 2, 4, 6, 12, 18, 24, 30, 36, 42, 48, 72, 96 and 120 hrs during therapy and approximately 0.5, 1, 2, 4, 6, 8, 12 and 24 hr post study drug termination]
Clearance and half life

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Have signed appropriate informed consent.
Be between 18 years and 65 years of age.
Have been accepted as a liver transplant candidate at the University of Pittsburgh Medical center (UPMC).
Be receiving a cadaver donor liver transplant.
Be treated in accordance with the standard of care protocol(s) currently in effect for liver transplant recipients at the UPMC, including immunosuppression and other elements of pre- and post-operative care.

Exclusion Criteria:

Subjects must not:

Be receiving a living donor liver transplant.
Be receiving a donor liver with a cold ischemia time less than 5 hours or greater than 12 hours.
Be receiving any investigational drug (a drug other than Treprostinil administered under an IND) or participating in any other investigational study, with the exception of alemtuzumab (Campath).
Be receiving any prostanoid to treat portopulmonary hypertension.
Have had a failed liver transplant within the previous 180 days.
Be undergoing multi-organ transplantation (transplantation of organs other than liver at the same time as the liver transplantation procedure).
Have fulminant hepatic failure
Model for end stage liver diseases (MELD) score of > 40
Hepatitis C positive donor liver
On renal replacement therapy at the time of study
Be receiving any non-standard immunosuppression protocol or other non-standard treatment that could affect interpretation of the study results.
Those currently receiving treatment for portopulmonary hypertension.
Those with significant cardiovascular disease including treatment with inotropes.
Have any known hypersensitivity to prostaglandins, prostacyclin or treprostinil.
If female, be pregnant or nursing (as confirmed by urine pregnancy test at Baseline).
HIV positive
Individuals who are allergic to iodine
Individuals who are receiving methylene blue
A donor liver with macrosteatosis greater than 40% if biopsy results are available