Hypothermic Oxygenated Perfusion (HOPE) of Human Liver Grafts

Study Overview
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Brief Summary
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The purpose of this study is, in a randomized trial, to test a newly developed machine perfusion technique of human liver allografts before transplantation. Ischemia-reperfusion injury is universal in organ transplantation and leads to varying degrees of graft dysfunction. Despite this fact, the preservation method in organ transplantation has been left unchanged for many years and remains simple static cold storage. Given the scarce donor supply, an increasing number of so called marginal or extended criteria donor organs have been used for liver transplantation, grafts which were previously rarely considered. In addition, allocation policy has changed in many countries, and livers are currently often distributed by the severity of the recipient's disease. As a result, transplant candidates present sicker, with higher MELD (Model for end stage liver disease) scores, at the time of transplant,and the risk of graft dysfunction or even failure due to reperfusion injury is high after the use of marginal livers in sick recipients. Machine liver perfusion techniques have been significantly improved during the past decade to decrease reperfusion injury, and a number of promising results show beneficial effects in various animal transplant models by either normothermic or hypothermic oxygenated continuous liver perfusion. These techniques generally require machine liver perfusion immediately after organ procurement. However, continuous perfusion has several drawbacks, including major logistic efforts and risk of organ damage during perfusion and transport. Our group, therefore, focused on the practicability of machine liver perfusion. We developed an endischemic hypothermic oxygenated perfusion (HOPE) concept through the portal vein only. This technique can be easily applied in the operation room shortly before transplantation of the recipient, thus after organ transport and back table preparation. Recently, the beneficial effect of a similar approach has been confirmed in human liver grafts by a phase I non randomized trial. These results prove feasibility and safety of an endischemic hypothermic machine perfusion approach and warrant further randomized studies.

Detailed Description
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The study consists on two groups, a perfusion group and a control group. Patients on the waiting list for liver transplantation with proven written consent will be recruited and randomized during organ procurement. Randomization will be performed by computer (secutrial). Perfusion will be started in the operation room after regular organ procurement, transport and back table preparation. The perfusion procedure will not delay the implantation due to the fact that recipient hepatectomy usually takes 2 hours. During this procedure, hypothermic oxygenated perfusion (HOPE group) for one hour will be performed vs continued cold storage (Control group). We will use commercially available and approved IGL solution (Institut George Lopez) as perfusate for machine perfusion. Subjects will be followed for one year after transplantation. 10 European centers are participating in this study, Randomization is stratified by center.

Official Title
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A Randomized Multicenter Study on the Effects of Hypothermic Oxygenated Perfusion (HOPE) on Human Liver Grafts Before Transplantation

Conditions
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Hepatocellular Injury

Intervention / Treatment
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* Device: Hypothermic oxygenated perfusion (HOPE)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult (≥18 years) patients with acute liver failure or liver cirrhosis (CHILD A, B or C) and/ or malignant liver tumors requiring liver transplantation Whole liver graft Signed informed consent Exclusion Criteria: Split graft Living donor liver transplantation Grafts donated after cardiac arrest (DCD grafts) Domino transplantation Combined liver transplant Cold storage > 15h acute and unexpected medical contraindication

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: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hypothermic oxygenated perfusion (HOPE)<br>Application of HOPE for 1 hour | Device: Hypothermic oxygenated perfusion (HOPE)<br>* Application of HOPE for 1 hour, perfusion rate 150-300 ml/min, pressure controlled, perfusion pressure < 3 mm Hg, perfusion route portal vein, recirculating system, perfusion volume 2 L, perfusate Institute George Lopez solution (IGL-1), perfusate temperature 4-6 °C, perfusate oxygenation 150-200 mm Hg<br>|
| No Intervention: Control group: no intervention<br>Conventional cold storage (IGL-1) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| major complications after liver transplantation | post transplant complication Clavien >= III within 1 year after transplant | During the first year postoperatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Laboratory parameters post transplant | Serum concentrations of bilirubin, AST, ALT, INR; Factor V | during first week, & 3,6,9,12 months | 
| Cholangiopathy | Biliary complications | during 12 months after transplant | 
| hospital stay, ICU stay | length of hospital and ICU stay after liver transplantation | during 12 months after transplant | 
| Patient and graft survival | one year patient and graft survival | during 12 months after transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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liver transplantation, machine liver perfusion, extended criteria liver grafts, donation after cardiac death, hypothermic machine liver perfusion, liver reperfusion injury