Hypothermic Oxygenated Perfusion for Extended Criteria Donors in Liver Transplantation (HOPExt)

Study Overview
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Brief Summary
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Given the scarce donor supply, an increasing number of so-called marginal or extended criteria donor (ECD) organs have been used for liver transplantation. These ECD liver grafts are, however, known to be associated with a higher rate of early allograft dysfunction (EAD) and primary non-function because of a greater vulnerability to ischemia-reperfusion injury. The end-ischemic Hypothermic Oxygenated Machine Perfusion (HOPE) technique may improve outcomes of liver transplantation with ECD grafts by decreasing reperfusion injury. The study aim is to assess the efficacy of HOPE used before transplantation of ECD liver grafts from brain-dead donors in reducing postoperative EAD within the first 7 postoperative days (POD) compared to simple cold static storage. The study is comparative open-label, multicenter, national, prospective, randomized, in two parallel groups, using the gold standard procedure as control.

Detailed Description
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This multicentric randomized controlled trial concerns adult patients undergoing whole liver transplantation in any of the 8 participating centers in France, who will receive an ECD liver graft from a brain-dead donor. After providing written informed consent prior to the performance of any study specific procedure, the recruited patients will be randomized either in the experimental group (HOPE group) or in the control group. In the HOPE group, ECD liver grafts will undergo a hypothermic oxygenated perfusion (HOPE) via the portal vein for a period of 1 to 4 hours (minimum 1 hour) after the back-table phase (graft preparation), in parallel with the recipient hepatectomy, using the CE-certified Liver Assist® perfusion pump/device (Organ Assist®, the Netherlands) with Machine Perfusion Solution (Belzer-MPS, CE-certified). The control group will consist of a classic static cold (4°C) storage with Institute George Lopez (IGL-1)® solution from graft harvesting until liver transplantation, which is the gold standard procedure in liver transplantation. The primary endpoint will be early allograft dysfunction (EAD) according to Olthoff's criteria, which will be compared with the Model of Early Allograft Function score (MEAF score) and the Liver Graft Assessment Following Transplantation risk factor (L-GrAFT). According to the primary endpoint, a sample size of 133 patients per randomized group (266 in total) is needed. The duration of the inclusion period is expected to be 36 months with a 1-year follow-up for each patient. The potential impacts of the study are expected on 3 levels: (1) for the patient, decreased postoperative morbidity and mortality of liver transplantation with ECD donors; (2) for the French liver transplantation community, familiarization with liver machine perfusion, and (3) economically, decreased costs of liver transplantation (health economic analysis included in the study).

Official Title
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End-ischemic Hypothermic Oxygenated Perfusion for Extended Criteria Donors in Liver Transplantation - A Multicenter, Randomized Controlled Trial

Conditions
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Liver Transplantation

Intervention / Treatment
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* Device: End-ischemic Hypothermic Oxygenated Machine Perfusion (HOPE)
* Device: classic static cold storage


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent prior to the performance of any study specific procedure Affiliated to the French social security system Recipient age ≥ 18 years Patients undergoing primary liver transplantation. Candidate for a first elective liver transplantation, whatever the indication, with a liver graft harvested from a brain-dead ECD defined by the presence of at least one of the following criteria: Donor age > 65 years Intensive care unit stay > 7 days BMI > 30 Proven macro-steatosis biopsy ≥ 30% Natremia > 155 mmol/L at any time AST > 150 IU/mL at any time ALT > 170 IU/mL at any time. Exclusion Criteria: Fulminant hepatic failure Retransplantation Split liver transplantation Living donor liver transplantation Grafts donated after cardiac arrest (DCD grafts) Domino transplantation Combined liver transplant Unexpected medical contraindication to liver transplantation Patient participating in other interventional research, excluding routine care research (old regulation) and category 2 research not interfering with primary endpoint analysis Patient under legal protection Patient deprived of liberty by a judicial or administrative decision Patient refusing to participate in the study Pregnant or lactating women Inability to understand information concerning the protocol

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HOPE group<br>hypothermic oxygenated perfusion | Device: End-ischemic Hypothermic Oxygenated Machine Perfusion (HOPE)<br>* In the experimental group, ECD liver grafts will first undergo a classical static cold (4°C) storage with Institute George Lopez (IGL-1)® solution from graft harvesting until transport to the transplantation center. They will then undergo a hypothermic oxygenated perfusion (HOPE) via the portal vein for a period of 1 to 4 hours (minimum 1 hour) after the back-table phase (graft preparation), in parallel with the recipient hepatectomy, using the CE-certified Liver Assist® perfusion pump/device (Organ Assist®, the Netherlands) with Machine Perfusion Solution (Belzer-MPS, CE-certified).<br>|
| Active Comparator: Control group<br>classic static cold storage | Device: classic static cold storage<br>* The control group will consist of a classic static cold (4°C) storage with Institute George Lopez (IGL-1)® solution from graft harvesting until liver transplantation, which is the gold standard procedure in liver transplantation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early allograft dysfunction (EAD) according to Olthoff criteria. | EAD is defined by the presence of at least one of the following criteria: Bilirubin level > 10 mg/dL (i.e. 171 µmol/L) on POD 7 International Normalized Ratio (INR) > 1.6 on POD 7 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels > 2000 IU/L within the first 7 PODs Additionally EAD will be also assessed by the MEAF score and the L-GrAFT risk factor. | During the first postoperative week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Model of Early Allograft Function score (MEAF score). | The MEAF score includes bilirubin, ALT max and INR max at postperative day 3. Range 0 (better outcome) to 10 (worse outcome) | During the first 3 postoperative days. | 
| Liver Graft Assessment Following Transplantation risk factor (L-GrAFT) | L-GrAFT includes aspartate aminotransferase (AST), INR, total bilirubin and platelets every day until postoperative day 10. Range -6 (better outcome) to +6 (worse outcome) | During the first 10 postoperative days. | 
| Untargeted liver graft metabolic profiling | Untargeted liver graft metabolic profiling (by High-Resolution Nuclear Magnetic Resonance - 1H HR-Nuclear Magnetic Resonance (NMR) Spectrometer) on liver graft biopsies on the back-table before and after liver machine perfusion. | Day of liver transplantation (Day 0) | 
| Occurrence of post-reperfusion syndrome | Defined as a 50% decrease in median arterial pressure during the 5 minutes following the graft revascularization | Day of liver transplantation (Day 0) | 
| 90-day morbidity and mortality | Severe postoperative complications (Dindo-Clavien ≥3) / death | During the first 90 days after surgery. | 
| Length of intermediate care unit stay (days) | Duration of intermediate care unit stay | From randomization until intermediate care unit discharge, estimated up to 7 days | 
| Length of hospital stay (days) | Duration of hospital stay | From randomization until hospital discharge, estimated up to 21 days | 
| Liver contrast-enhanced MRI including a Magnetic Resonance CholangioPancreatography (MRCP) | Assessment of intra- and extrahepatic biliary complications (except for patients who underwent a re-transplanted during the study). | Within 1 year after liver transplantation | 
| 3-month and one-year patient and graft survivals | Actuarial graft and patient's survival rates | within one year after liver transplantation | 
| Hospital costs (Euros) of liver transplantation | Hospital costs of liver transplantation | At one year after liver transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver Transplantation, Liver machine perfusion, extended criteria donor