Clinical trial NCT03468140: Pilot Trial of Eculizumab Therapy to Reduce Preservation Injury in Human Macrosteatotic Liver Transplantation
Official title: A Matched Intervention Pilot Trial of Eculizumab Therapy to Reduce Preservation Injury in Human Macrosteatotic Liver Transplantation
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: EARLY_PHASE1
Conditions: End Stage Liver Disease
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: Ochsner Health System
name: Alexion Pharmaceuticals, Inc.
First posted: 2018-03-16
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Five end-stage liver disease (ESLD) patients will be matched to 5 historical controls.
Primary purpose: TREATMENT

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.

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%

Primary outcomes:
measure: Degree of Hepatocellular Injury
timeFrame: Days 1-7 following liver transplant.
Secondary outcomes:
measure: Alanine transaminase (ALT) recovery time
timeFrame: Days 1-7 following liver transplant.
measure: Seven-day peak post-transplant (GCT)
timeFrame: Days 1-7 following liver transplant.
measure: Gamma-glutamyl transpeptidase (GCT) recovery time
timeFrame: Days 1-7 following liver transplant.
measure: International Normalized Ratio (INR) recovery time
timeFrame: Days 1-7 following liver transplant.
measure: Seven-day peak post-transplant creatinine
timeFrame: Days 1-7 following liver transplant.
Other outcomes:
measure: One-year incidence of biopsy-proven acute transplant rejection
timeFrame: One year from date of transplant
measure: Post-transplant blood loss
timeFrame: One year from date of transplant
measure: One-year all-cause mortality
timeFrame: One year from date of transplant
measure: One-year graft survival
timeFrame: One year from date of transplant
measure: One-year all-cause infections
timeFrame: One year from date of transplant
measure: One-year all-cause re-operation
timeFrame: One year from date of transplant
measure: One-year all-cause hospital re-admission
timeFrame: One year from date of transplant
measure: One-year biliary complications
timeFrame: One year from date of transplant
measure: One-year vascular complications
timeFrame: One year from date of transplant
Locations:
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
Study officials:
affiliation: Yale University
name: Sanjay Kulkarni, M.D.
role: PRINCIPAL_INVESTIGATOR
References: