Clinical trial NCT03929523: Hypothermic Oxygenated Perfusion for Extended Criteria Donors in Liver Transplantation (HOPExt)
Official title: End-ischemic Hypothermic Oxygenated Perfusion for Extended Criteria Donors in Liver Transplantation - A Multicenter, Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Liver Transplantation
Keywords: Liver Transplantation
Liver machine perfusion
extended criteria donor
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2019-04-29
Enrollment: 266
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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

Primary outcomes:
measure: Early allograft dysfunction (EAD) according to Olthoff criteria.
timeFrame: During the first postoperative week
Secondary outcomes:
measure: Model of Early Allograft Function score (MEAF score).
timeFrame: During the first 3 postoperative days.
measure: Liver Graft Assessment Following Transplantation risk factor (L-GrAFT)
timeFrame: During the first 10 postoperative days.
measure: Untargeted liver graft metabolic profiling
timeFrame: Day of liver transplantation (Day 0)
measure: Occurrence of post-reperfusion syndrome
timeFrame: Day of liver transplantation (Day 0)
measure: 90-day morbidity and mortality
timeFrame: During the first 90 days after surgery.
measure: Length of intermediate care unit stay (days)
timeFrame: From randomization until intermediate care unit discharge, estimated up to 7 days
measure: Length of hospital stay (days)
timeFrame: From randomization until hospital discharge, estimated up to 21 days
measure: Liver contrast-enhanced MRI including a Magnetic Resonance CholangioPancreatography (MRCP)
timeFrame: Within 1 year after liver transplantation
measure: 3-month and one-year patient and graft survivals
timeFrame: within one year after liver transplantation
measure: Hospital costs (Euros) of liver transplantation
timeFrame: At one year after liver transplantation
Other outcomes:
Locations:
city: Clichy
country: France
facility: Department of HPB surgery and liver transplantation Beaujon University Hospital
city: Grenoble
country: France
facility: CHU Grenoble Alpes - Department of HPB surgery and liver transplantation
city: Lille
country: France
facility: Department of HPB surgery and liver transplantation Claude Huriez University Hospital
city: Lyon
country: France
facility: Hospices Civils de Lyon
city: Paris
country: France
facility: APHP - Pitié Salpétrière
city: Rennes
country: France
facility: Department of HPB surgery and liver transplantation Pontchaillou University Hospital
city: Strasbourg
country: France
facility: Hôpital Hautepierre - Department of HPB surgery and liver transplantation
city: Villejuif
country: France
facility: Department of HPB surgery and liver transplantation Paul Brousse University Hospital
Study officials:
affiliation: APHP Beaujon
name: Mickael LESURTEL
role: PRINCIPAL_INVESTIGATOR
References:
citation: Olthoff KM, Kulik L, Samstein B, Kaminski M, Abecassis M, Emond J, Shaked A, Christie JD. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl. 2010 Aug;16(8):943-9. doi: 10.1002/lt.22091.
citation: Pareja E, Cortes M, Hervas D, Mir J, Valdivieso A, Castell JV, Lahoz A. A score model for the continuous grading of early allograft dysfunction severity. Liver Transpl. 2015 Jan;21(1):38-46. doi: 10.1002/lt.23990. Epub 2014 Nov 24.
citation: Agopian VG, Harlander-Locke MP, Markovic D, Dumronggittigule W, Xia V, Kaldas FM, Zarrinpar A, Yersiz H, Farmer DG, Hiatt JR, Busuttil RW. Evaluation of Early Allograft Function Using the Liver Graft Assessment Following Transplantation Risk Score Model. JAMA Surg. 2018 May 1;153(5):436-444. doi: 10.1001/jamasurg.2017.5040.