Pilot Trial of Eculizumab Therapy to Reduce Preservation Injury in Human Macrosteatotic Liver Transplantation

A Matched Intervention Pilot Trial of Eculizumab Therapy to Reduce Preservation Injury in Human Macrosteatotic Liver Transplantation

The number of liver transplants that can be performed is limited by the availability of organs. Livers that are steatotic (i.e., infiltrated by triglycerides and other fatty substances) are usually not used for transplants, due to increased risk of adverse events and deaths post-transplant. The investigators propose administering eculizumab to patients receiving macrosteatotic liver transplants and hypothesize that doing so will mitigate post-surgical adverse outcomes.

Study Overview

• Status: Withdrawn
• Conditions: End Stage Liver Disease
• Intervention / Treatment: Drug: Eculizumab; Other: No intervention

Detailed Description

Mortality from liver disease accounts for approximately 34,000-36,000 annualized deaths and represents 11.5 deaths per 100,000 persons in the United States(1). Liver transplant is the only established treatment for end-stage liver disease (ESLD) and advancements over the past decade have resulted in excellent long-term survival rates(2). Liver transplant is limited solely by organ availability, as the numbers of available organs for transplant has remained stagnant. Compounding this problem is the rising global public health problem of fatty liver disease, with projected increases in incidence of non-alcoholic liver disease (NASH), both in the West and in Asia(3). One potential source of liver grafts is donors with moderate to severe macrosteatosis, as grafts from these donors are routinely discarded due to greater associated patient morbidity and mortality(4-6). When these grafts are used for transplantation, the clinical metrics of preservation injury are directly correlated with the degree of steatosis(7). Steatotic liver grafts represent the single largest source of potential donor livers that currently remains unutilized and methods aimed at their successful use would directly lead to reduced mortality in patients with ESLD. Evidence from pre-clinical models indicates that complement-mediated mechanisms play a critical role in the pathogenesis of preservation injury, particularly in the presence of macrosteatosis(8, 9). Expansion of the donor pool using established, FDA-approved therapeutics that inhibit terminal complement offer an expedited and practical solution to this problem.

The investigators therefore hypothesize that complement activation downstream of C5 crucially mediates post-transplant liver allograft injury associated with preservation, ischemia and reperfusion (heretofore referred to as preservation injury) and that macrosteatosis enhances the graft's susceptibility to this complement-dependent injury. As a corollary, the investigators hypothesize that the anti-C5 mAb eculizumab will limit post-transplant preservation injury despite macrosteatosis, thereby decreasing early post-transplant liver dysfunction, and ultimately resulting in greater utilization of macrosteatotic livers for transplantation, with consequent reduction in mortality for patients with end-stage liver disease.

This study will test safety and efficacy of complement inhibition with eculizumab in the ESLD population receiving macrosteatotic liver transplants. The study will also determine if known associations of hepatic lipid metabolism and innate immune responses are mitigated under conditions of complement inhibition.

If an adverse reaction occurs during the administration of (IP), the infusion may be slowed or stopped at the discretion of the Investigator. If the infusion is slowed, the total infusion time should not exceed two hours. The adverse reaction will be considered an AE/SAE and needs to be reported.

• Study Type: Interventional
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age>18, weight>40kg
• Recipients of first liver transplant
• Biopsy proven macrosteatosis of > or = 20%
• Cold ischemia time < 8 hours
• Recipients of brain-dead deceased donors

Exclusion Criteria:

• Dual organ transplants
• ABO incompatible
• Meningococcal vaccination refusal
• Dual barrier contraception refusal
• Recipients with acute liver failure
• Recipients with Hepatitis B or C viral loads
• Physiological MELD Score>35
• Donor liver biopsy showing combined Microsteatosis+Macrosteatosis>70%

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Current end stage liver disease patients; Eculizumab	Drug: Eculizumab; Eculizumab will be given at a dose of 1200mg diluted in 0.9% sodium chloride (NaCl) to 5mg/mL for a total volume of 240 mL administered by IV infusion over 25-45 minutes in the anhepatic-phase during the transplant procedure, and a second dose of 900mg diluted in 0.9% NaCl to 5mg/mL for a total volume of 180 mL administered by IV infusion over 25-45 minutes will be given 24 hours following the first dose.
Other: Historical controls; The Ochsner database will be used to obtain 5 historical matches for each study participant. Matching criteria for each patient will include: 1) gender; 2) (MELD) Score ± 5; 3) age ± 5 years; 4) body mass index (BMI) ± 5 kg/m2; 5) donor macrosteatosis ± 5%; and 6) CIT± 3 hours.	Other: No intervention; Historical control arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Degree of Hepatocellular Injury	Hepatocellular injury will be assessed by aminotranferase (AST) that will be measured for 7 days following transplant.	Days 1-7 following liver transplant.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Alanine transaminase (ALT) recovery time	ALT will be measured for 7 days following transplant	Days 1-7 following liver transplant.
Seven-day peak post-transplant (GCT)	GCT will be measured for 7 days following transplant	Days 1-7 following liver transplant.
Gamma-glutamyl transpeptidase (GCT) recovery time	GCT will be measured for 7 days following transplant	Days 1-7 following liver transplant.
International Normalized Ratio (INR) recovery time	INR will be measured for 7 days following transplant	Days 1-7 following liver transplant.
Seven-day peak post-transplant creatinine	creatinine will be measured for 7 days following transplant	Days 1-7 following liver transplant.

Other Outcome Measures

Outcome Measure	Time Frame
One-year incidence of biopsy-proven acute transplant rejection	One year from date of transplant
Post-transplant blood loss	One year from date of transplant
One-year all-cause mortality	One year from date of transplant
One-year graft survival	One year from date of transplant
One-year all-cause infections	One year from date of transplant
One-year all-cause re-operation	One year from date of transplant
One-year all-cause hospital re-admission	One year from date of transplant
One-year biliary complications	One year from date of transplant
One-year vascular complications	One year from date of transplant

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Alexion Pharmaceuticals; Ochsner Health System
• Investigators: Principal Investigator: Sanjay Kulkarni, M.D., Yale University

Study record dates

Study Major Dates

• Study Start (Anticipated): October 1, 2021
• Primary Completion (Anticipated): April 30, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: March 9, 2018
• First Submitted That Met QC Criteria: March 9, 2018
• First Posted (Actual): March 16, 2018

Study Record Updates

• Last Update Posted (Actual): April 8, 2021
• Last Update Submitted That Met QC Criteria: April 5, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Failure; Hepatic Insufficiency; Liver Diseases; End Stage Liver Disease; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Eculizumab
• Other Study ID Numbers: 2000021373

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes