Pilot Trial of Eculizumab Therapy to Reduce Preservation Injury in Human Macrosteatotic Liver Transplantation
| Status: | Recruiting |
|---|---|
| Conditions: | Gastrointestinal |
| Therapuetic Areas: | Gastroenterology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 2/24/2019 |
| Start Date: | March 1, 2019 |
| End Date: | December 31, 2020 |
| Contact: | Sanjay Kulkarni, M.D. |
| Email: | sanjay.kulkarni@yale.edu |
| Phone: | (203) 785 - 2565 |
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.
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.
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.
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.
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%
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