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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01481974
Recruitment Status : Active, not recruiting
First Posted : November 30, 2011
Last Update Posted : January 9, 2020
Sponsor:
Information provided by (Responsible Party):
Abhinav Humar, MD, University of Pittsburgh

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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : December 2012
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


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 Name: Brand name: REMODULIN




Primary Outcome Measures :
  1. Serum ALT concentration after treprostinil treatment in liver transplant patients [ Time Frame: 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 :
  1. Pharmacokinetics of treprostinil in liver transplant patients [ Time Frame: 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Have signed appropriate informed consent.
  2. Be between 18 years and 65 years of age.
  3. Have been accepted as a liver transplant candidate at the University of Pittsburgh Medical center (UPMC).
  4. Be receiving a cadaver donor liver transplant.
  5. 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:

  1. Be receiving a living donor liver transplant.
  2. Be receiving a donor liver with a cold ischemia time less than 5 hours or greater than 12 hours.
  3. 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).
  4. Be receiving any prostanoid to treat portopulmonary hypertension.
  5. Have had a failed liver transplant within the previous 180 days.
  6. Be undergoing multi-organ transplantation (transplantation of organs other than liver at the same time as the liver transplantation procedure).
  7. Have fulminant hepatic failure
  8. Model for end stage liver diseases (MELD) score of > 40
  9. Hepatitis C positive donor liver
  10. On renal replacement therapy at the time of study
  11. Be receiving any non-standard immunosuppression protocol or other non-standard treatment that could affect interpretation of the study results.
  12. Those currently receiving treatment for portopulmonary hypertension.
  13. Those with significant cardiovascular disease including treatment with inotropes.
  14. Have any known hypersensitivity to prostaglandins, prostacyclin or treprostinil.
  15. If female, be pregnant or nursing (as confirmed by urine pregnancy test at Baseline).
  16. HIV positive
  17. Individuals who are allergic to iodine
  18. Individuals who are receiving methylene blue
  19. A donor liver with macrosteatosis greater than 40% if biopsy results are available

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01481974


Locations
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United States, Pennsylvania
Abhinav Humar
Pittsburgh, Pennsylvania, United States, 15261
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15261
Sponsors and Collaborators
Abhinav Humar, MD
Investigators
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Principal Investigator: Abhinav Humar, M.D. University of Pittsburgh Medical Center
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Responsible Party: Abhinav Humar, MD, MD, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT01481974    
Other Study ID Numbers: STUDY19100094
First Posted: November 30, 2011    Key Record Dates
Last Update Posted: January 9, 2020
Last Verified: January 2020
Keywords provided by Abhinav Humar, MD, University of Pittsburgh:
liver transplantation
treprostinil
Additional relevant MeSH terms:
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Reperfusion Injury
Ischemia
Wounds and Injuries
Pathologic Processes
Vascular Diseases
Cardiovascular Diseases
Postoperative Complications
Treprostinil
Antihypertensive Agents