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

Ischemia Reperfusion Injury Clinical Trial

— 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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00876902
• Other study ID #: YSPSL-0003-PF.3
• Secondary ID: IND 101,040
• Status: Active, not recruiting
• Phase: Phase 2
• First received: April 3, 2009
• Last updated: April 6, 2009
• Start date: May 2008
• Est. completion date: October 2009

Study information

• Verified date: April 2009
• Source: Y's Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 36
• Est. completion date: October 2009
• Est. primary completion date: March 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Ischemia Reperfusion Injury
• Reperfusion Injury

Intervention

Drug:
• recombinant P-selectin glycoprotein ligand Ig fusion protein
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.
• Viaspan® and saline
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.

Locations

Country	Name	City	State
United States	UCLA School of Medicine	Los Angeles	California

Sponsors (1)

Lead Sponsor	Collaborator
Y's Therapeutics, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.		6 months post trasplant	Yes
Secondary	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.		6 months post transplant	No

External Links

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