Hypothermic Machine Preservation-Phase 2

Study Overview
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Brief Summary
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This is a study comparing a technique of continuous circulation to the liver as a means of preventing liver damage during transportation to the transplant hospital. This new technique of Machine Perfusion (MP) will be compared to the standard technique where the liver is maintained in a bag of solution on ice without circulation. The investigators will evaluate and compare the outcomes of the transplants with the new technique to the standard technique. There will be 24 MP patient's in the study. The investigators have previously used this technique with success in 20 human liver transplant patients. The investigators think there will be a benefit in terms of less damage to and better function of the donor liver which will result in faster recovery for the patients. This protective effect may allow us to successfully transplant more patients and prevent people from dying while waiting for a liver transplant.

Detailed Description
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It is our hypothesis that liver machine perfusion will increase the safe utilization of the existing supply of extended criteria donor (ECD) livers by (1) increasing the quality and duration of preservation thereby reducing the clinical effects reperfusion injury (2) improving early outcomes in patients receiving ECD liver allografts (3) developing reliable markers for pretransplant assessment of the potential graft (4) giving surgeons more confidence when transplanting ECD livers and (5) allowing an avenue for ex vivo manipulation of the liver to protect or restore a transiently injured liver. The proposed study is a matched cohort design. Potential subjects will be recruited from the Center for Liver Disease and Transplantation (CLDT) active Liver Transplant Waiting List. The Principal Investigator as well as the CoInvestigators, are all actively involved in the pre transplant evaluation process. Patients who are on the Waiting List and have provided written consent to receive an ECD graft will be recruited for this trial. Subjects will be matched with 24 historical control patients who received similar cold stored ECD grafts. Subjects will be matched on known covariates including donor age, donation after cardiac death, steatosis, both warm and cold ischemia times, recipient age, Model End-Stage Liver Disease (MELD) score and disease etiology. Subjects will be noncritically ill, not in an intensive care unit, and have a MELD < 35 in order to minimize the variability in outcome in the sickest patients. All subjects must provide written informed consent and meet the inclusion and exclusion criteria. Subjects will be followed for one year post transplantation, in conjunction with their routine liver transplant followup appointments. Retention of subjects for this trial will not be a challenge, in that the followup visit time points (postoperative days 1 through the discharge date, 7, 14, 30, 90, 180 and 365) are all consistent with our standard of care.

Official Title
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Hypothermic Machine Preservation of Extended Criteria Liver Allografts for Transplantation

Conditions
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Liver Damage

Intervention / Treatment
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* Device: The Medtronic Portable Bypass System (PBS®)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed IRB consent by patient or patient's legally appointed representative. Be at least 18 years of age; male or female. Listed with UNOS for liver transplantation. Organ declined by at least one transplant center Extended criteria donor as defined by: Presence of hepatitis C antibody Donation after Cardiac Death (DCD) Severe Hypernatremia: donor serum sodium >165 meq/L for at least 12 hours prior to procurement Donor age ≥65 years Presence of significant steatosis >25% macrovesicular by biopsy Evidence of significant donor ischemic injury Current donor serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1000 IU/L Ischemic injury evidenced by prolonged hypotension, high pressor requirement and/or rising serum liver function tests or one test more than five times the upper limit of normal (AST, ALT, or Total Bilirubin) Exclusion Criteria: Patients in whom the donor liver will be subjected to less than 4 hours of cold ischemia (surgeon desires immediate implantation) Patient hospitalized in intensive care unit (ICU) at time of transplantation and/or physiologic MELD score >35 Dual organ recipient ABO incompatibility Retransplantation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: Hypothermic Machine Perfusion Group<br>The Medtronic Portable Bypass System (PBS®) with Model 550 Bioconsole and the BioCal® blood temperature control module will be used for machine perfusion of liver grafts. These products are commercially available and used in clinical practice for cardiopulmonary bypass and extracorporeal membrane oxygenation. The Medtronic system utilizes an atraumatic centrifugal pump that can deliver the flow rates approximating portal venous flow in human livers, and it has modules for online membrane oxygenation, and electronic flow measurement. | Device: The Medtronic Portable Bypass System (PBS®)<br>* Will be used for machine perfusion of liver grafts.<br>* Other names: Medtronic Portable Bypass System (PBS®);|
| No Intervention: Matched control group<br>The proposed study is a matched cohort design. Subjects will be matched with 24 historical control patients who received similar cold stored ECD grafts. Subjects will be matched on known covariates including donor age, donation after cardiac death, steatosis, both warm and cold ischemia times, recipient age, MELD score and disease etiology. Additional analyses will be performed on historical control blood and/or tissue samples previously collected and stored in the study's sample repository. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Survival at One Year Post-Transplantation |  | Post-Operative Day 1 to Day 365 | 
| Graft Survival at One Year Post-Transplantation | Analysis was based on the amount of liver allografts in each cohort that were deemed to be clinically functional at 1 year post-transplantation (i.e. no re-transplantation required). | Post-Operative Day 1 to Day 365 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Primary Graft Nonfunction | Incidence of Primary Graft Nonfunction (PNF), defined as follows: Relisted for orthotopic liver transplantation (OLT) within 7 days of OLT, not for vascular thromboses Alanine aminotransferase (ALT) >2000 and one or both of: acidosis with pH <7.3 or lactate >2X (two times) normal International normalized ratio (INR) >2.5 | Post-Operative Day 1 to Day 7 | 
| Incidence of Early Allograft Dysfunction (EAD) | Incidence of Early Allograft Dysfunction (EAD), defined as follows: Bilirubin >10 on post-operative day (POD)#7 International normalized ratio (INR) >1.6 on POD#7 Transaminase level (aspartate aminotransferase (AST) or alanine aminotransferase (ALT)) >2000 within the first 7 days | Within the first 7 days post-transplantation | 
| Incidence of Post-Operative Complications | Incidence of Retransplants or Hepatic Artery Thrombosis (HAT) within 1 month post-transplantation | 1 Month Post-Transplantation | 
| Incidence of Bile Leaks | Incidence of bile leaks. | Post-Operative Day 1 to Day 365 | 
| Incidence of Re-Operation For Bleeding | Incidence of patients who required re-operation for a bleeding event | Post-Operative Day 1 to Day 365 | 
| Incidence of Hernia Events Within 1 Year Post-Transplantation |  | Post-Operative Day 1 to Day 365 | 
| Hospital Length of Stay (Index Transplant Hospitalization) | Length of transplant hospital stay post-transplantation (Index Transplant Hospitalization) | First admission after transplant | 
| Time With Stent (Days) | Measure of biliary complications as evidenced by mean time with stent (in days). | Post-Operative Day 1 to Day 365 | 
| Incidence of Biliary Strictures | Incidence of biliary strictures. | Post-Operative Day 1 to Day 365 | 
| Incidence of Endoscopic Retrograde Cholangiopancreatographies (ERCPs) | Incidence of endoscopic retrograde cholangiopancreatographies (ERCPs) | Post-Operative Day 1 to Day 365 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ECD liver transplant allografts, Hypothermic machine perfusion, Cold storage preservation, liver transplant, portable bypass system, machine perfusion preservation, extended criteria liver