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YSPSL for Prevention of Ischemic Reperfusion Injury in Patients Undergoing Cadaveric Orthotopic Liver Transplantation (YSPSL)

Primary Purpose

Ischemia Reperfusion Injury

Status

Unknown status

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

recombinant P-selectin glycoprotein ligand Ig fusion protein

Viaspan® and saline

About this trial

This is an interventional prevention trial for Ischemia Reperfusion Injury focused on measuring liver transplantation, cadaveric liver transplantation, ischemic reperfusion injury, primary non-function, delayed non-Function, poor early graft function, YSPSL, recombinant PSGL-Ig

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patient will be a recipient of a primary (first) ABO compatible cadaveric liver allograft
Patient's age is less than 18 years
Patient is not a recipient of a multivisceral transplant or simultaneous kidney transplant
Patient has not undergone prior organ or cellular transplant of any type
Patient has a Model for End Stage Liver Disease (MELD) score of ≤38
Cold ischemia time (CIT) anticipated to be less than 14 hours
Donor liver procured by UCLA liver team
Veno-veno bypass is not planned to be used for the patient (e.g. no prior surgery or other factor that indicates a risk for excessive blood loss and therefore a need for veno-veno bypass +/- autologous recovery during surgery)
For patients who are women of childbearing potential, patient has a negative pregnancy test (either urine or serum) within 48 hours prior to transplant
Patient (male and female) is willing to use an acceptable form of birth control for at least 3 months post-treatment
Patient is willing and able to sign informed consent.

Exclusion Criteria:

Patient has a prior organ transplant of any type
Patient has known allergic or intolerance reactions to human immune globulins, antibodies, or components of the formulation or known contraindication to administration of YSPSL
Patient has an uncontrolled active infection (on antibiotics with controlled infection is not an exclusion)
Patient has active Hepatitis B virus (HBV)/transplant for HBV related cirrhosis
Patient has previously participated in this study or another study with YSPSL
Patient has received investigational therapy within 90 days prior to the transplant procedure
Patient has current drug or alcohol abuse or, in the opinion of the investigator, is at risk for poor compliance with the visits in this protocol (no drug testing required)
Patient is a pregnant or nursing female, a female of childbearing potential planning to become pregnant within the duration of this study, or is not practicing birth control
Patient is planned to receive a living donor liver transplant
Patient lives >200 miles away or otherwise is not able to participate in study follow-up visits
Donor body mass index >40
Donor liver biopsy >40% macrosteatotic fat
Donor age >70.

Sites / Locations

UCLA School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Arm Description

Active Group: (18 subjects) YSPSL administered as an ex vivo flush (20 mg YSPSL in Viaspan® 200 mL total volume) into the portal vein prior to transplant at the back table; YSPSL 1 mg/kg administered IV to the transplant recipient PRIOR to arterial reperfusion of the liver. One extra IV dose of 1 mg/kg will be given at the end of the procedure only to patients that have experienced an intraoperative blood loss of greater than 10 units.

Placebo Control: (18 subjects) Ex vivo flush of placebo control (200 mL Viaspan®) into the portal vein prior to transplant and 0.1 mL/kg placebo control (saline) IV to the transplant recipient PRIOR to arterial reperfusion of the liver. One additional infusion of 0.1 mL/kg placebo control (saline) will be given at the end of the procedure to patients that have experienced an intraoperative blood loss of greater than 10 units.

Outcomes

Primary Outcome Measures

Safety will be evaluated by clinical and laboratory assessments, an abbreviated pharmacokinetic (PK) profile of the administered dose of YSPSL, and graft function and patient and graft survival through 6 months post-transplant.

Secondary Outcome Measures

To evaluate the potential efficacy of prophylaxis with YSPSL on ischemia reperfusion injury (IRI) as assessed by proposed efficacy evaluations of IRI in liver transplants, in patients who meet eligibility criteria for the trial.

Full Information

NCT ID

NCT00876902

First Posted

April 3, 2009

Last Updated

April 6, 2009

Sponsor

Y's Therapeutics, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT00876902

Brief Title

YSPSL for Prevention of Ischemic Reperfusion Injury in Patients Undergoing Cadaveric Orthotopic Liver Transplantation

Acronym

YSPSL

Official Title

A Controlled, Prospective, Blinded, Randomized, Single-Center, Study of YSPSL for Prevention of Ischemic Reperfusion Injury in Patients Undergoing Cadaveric Orthotopic Liver Transplantation

Study Type

Interventional

2. Study Status

Record Verification Date

April 2009

Overall Recruitment Status

Unknown status

Study Start Date

May 2008 (undefined)

Primary Completion Date

March 2009 (Actual)

Study Completion Date

October 2009 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor

Y's Therapeutics, Inc.

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The study is designed to assess the feasibility of evaluating YSPSL for the amelioration of ischemia reperfusion injury following liver transplantation by administering YSPSL into the liver graft directly ex vivo via the portal vein and to the recipient intravenously prior to reperfusion. This study is an extension of the recent pilot study YSPSL-0002 with an almost identical study protocol. The rationale of this and the previous study is based on the recent observation that P-selectin expression has been associated in liver grafts with prolonged cold storage times and rejection. By examining biomarkers of IRI including P-selectin by immunohistochemistry and/or quantitative PCR, liver histology and hepatic blood flow using established techniques, the goal of this study is to evaluate the feasibility of using these modalities for future studies of safety and efficacy.

Detailed Description

YSPSL-0003 is an extension into 36 patients of the previous 12 patient pilot study YSPSL-0002 under an almost identical study protocol with extended inclusion criteria. Like YSPSL-0002, YSPSL-0003 is a single-center (UCLA), randomized, placebo-controlled, double-blind study. Patients are randomly assigned to either active study drug (Active group) or placebo (Control group) prior to transplantation. The active study drug dose includes both a 1 mg/kg IV infusion for the recipient and a 20 mg [approximately 0.27 mg/kg] as an ex vivo flush. The doses are administered via 2 separate infusions of study agent: one 20 mg dose into the portal vein of the liver prior to implantation as an ex vivo flush with Viaspan®; and the second infusion of 1 mg/kg intravenously into the recipient, when technically feasible, prior to the hepatic artery anastomosis. Placebo of a volume equivalent to active study drug is prepared for administration to the control group to help maintain the blind. Those patients that experience an intraoperative blood loss of >10 units, receive an additional 1 mg/kg IV infusion of study agent (or placebo equivalent) at the end of the transplant surgery. The Investigator/Sponsor is blinded to the treatment assignment for each patient. Randomization assignment is maintained by UCLA's clinical pharmacist.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Ischemia Reperfusion Injury

Keywords

liver transplantation, cadaveric liver transplantation, ischemic reperfusion injury, primary non-function, delayed non-Function, poor early graft function, YSPSL, recombinant PSGL-Ig

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

36 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Experimental

Arm Description

Arm Title

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

recombinant P-selectin glycoprotein ligand Ig fusion protein

Other Intervention Name(s)

rPSGL-Ig, Torapsel

Intervention Description

The active study drug dose includes both a 1 mg/kg IV infusion for the recipient and a 20 mg [approximately 0.27 mg/kg] as an ex vivo flush. The doses will be administered via 2 separate infusions of study agent: one 20 mg dose into the portal vein of the liver prior to implantation as an ex vivo flush with Viaspan®; and the second infusion of 1 mg/kg intravenously into the recipient, when technically feasible, prior to the hepatic artery anastomosis. Those patients that experience an intraoperative blood loss of >10 units, will receive an additional 1 mg/kg IV infusion of study agent at the end of the transplant surgery.

Intervention Type

Drug

Intervention Name(s)

Viaspan® and saline

Other Intervention Name(s)

Placebo

Intervention Description

Placebo of a volume equivalent to active study drug will be prepared for administration to the control group to help maintain the blind. Those patients that experience an intraoperative blood loss of >10 units, will receive an additional 1 mg/kg IV infusion of placebo equivalent at the end of the transplant surgery.

Primary Outcome Measure Information:

Title

Time Frame

6 months post trasplant

Secondary Outcome Measure Information:

Title

Time Frame

6 months post transplant

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patient will be a recipient of a primary (first) ABO compatible cadaveric liver allograft Patient's age is less than 18 years Patient is not a recipient of a multivisceral transplant or simultaneous kidney transplant Patient has not undergone prior organ or cellular transplant of any type Patient has a Model for End Stage Liver Disease (MELD) score of ≤38 Cold ischemia time (CIT) anticipated to be less than 14 hours Donor liver procured by UCLA liver team Veno-veno bypass is not planned to be used for the patient (e.g. no prior surgery or other factor that indicates a risk for excessive blood loss and therefore a need for veno-veno bypass +/- autologous recovery during surgery) For patients who are women of childbearing potential, patient has a negative pregnancy test (either urine or serum) within 48 hours prior to transplant Patient (male and female) is willing to use an acceptable form of birth control for at least 3 months post-treatment Patient is willing and able to sign informed consent. Exclusion Criteria: Patient has a prior organ transplant of any type Patient has known allergic or intolerance reactions to human immune globulins, antibodies, or components of the formulation or known contraindication to administration of YSPSL Patient has an uncontrolled active infection (on antibiotics with controlled infection is not an exclusion) Patient has active Hepatitis B virus (HBV)/transplant for HBV related cirrhosis Patient has previously participated in this study or another study with YSPSL Patient has received investigational therapy within 90 days prior to the transplant procedure Patient has current drug or alcohol abuse or, in the opinion of the investigator, is at risk for poor compliance with the visits in this protocol (no drug testing required) Patient is a pregnant or nursing female, a female of childbearing potential planning to become pregnant within the duration of this study, or is not practicing birth control Patient is planned to receive a living donor liver transplant Patient lives >200 miles away or otherwise is not able to participate in study follow-up visits Donor body mass index >40 Donor liver biopsy >40% macrosteatotic fat Donor age >70.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Stefan Hemmerich, PhD

Organizational Affiliation

Y's Therapeutics, Inc.

Official's Role

Study Director

Facility Information:

Facility Name

UCLA School of Medicine

City

Los Angeles

State/Province

California

ZIP/Postal Code

90095

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

12201360

Citation

Amersi F, Farmer DG, Shaw GD, Kato H, Coito AJ, Kaldas F, Zhao D, Lassman CR, Melinek J, Ma J, Volk HD, Kupiec-Weglinski JW, Busuttil RW. P-selectin glycoprotein ligand-1 (rPSGL-Ig)-mediated blockade of CD62 selectin molecules protects rat steatotic liver grafts from ischemia/reperfusion injury. Am J Transplant. 2002 Aug;2(7):600-8. doi: 10.1034/j.1600-6143.2002.20704.x.

Results Reference

background

PubMed Identifier

21401865

Citation

Busuttil RW, Lipshutz GS, Kupiec-Weglinski JW, Ponthieux S, Gjertson DW, Cheadle C, Watkins T, Ehrlich E, Katz E, Squiers EC, Rabb H, Hemmerich S. rPSGL-Ig for improvement of early liver allograft function: a double-blind, placebo-controlled, single-center phase II study. Am J Transplant. 2011 Apr;11(4):786-97. doi: 10.1111/j.1600-6143.2011.03441.x. Epub 2011 Mar 14.

Results Reference

derived

Links:

URL

http://www.ncbi.nlm.nih.gov/pubmed/12201360?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

Description

YSPSL (rPSGL-Ig) treatment affords benefit in animal model of liver transplantation

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YSPSL for Prevention of Ischemic Reperfusion Injury in Patients Undergoing Cadaveric Orthotopic Liver Transplantation

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