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

NCT ID: NCT03468140

Last Updated: 2021-04-08

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: EARLY_PHASE1
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-10-01
• Study Completion Date: 2023-12-31

Brief Summary

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.

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.

Conditions

End Stage Liver Disease

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Current end stage liver disease patients

Eculizumab

Group Type: EXPERIMENTAL

Eculizumab

Intervention Type: DRUG

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.

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.

Group Type: OTHER

No intervention

Intervention Type: OTHER

Historical control arm

Interventions

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.

Intervention Type: DRUG

No intervention

Historical control arm

Intervention Type: OTHER

Eligibility Criteria

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%

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ochsner Health System

OTHER

Sponsor Role: collaborator

Alexion Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: collaborator

Yale University

OTHER

Sponsor Role: lead

Responsible Party

Sanjay Kulkarni

Associate Professor of Surgery (Transplant) and of Medicine (Nephrology)

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Sanjay Kulkarni, M.D.

Role: PRINCIPAL_INVESTIGATOR

Yale University

Locations

Ochsner Clinic Foundation

New Orleans, Louisiana, United States

Countries

United States

Other Identifiers

2000021373

Identifier Type: -

Identifier Source: org_study_id