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

Liver Transplantation Clinical Trial

— HOPExt  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03929523
• Other study ID #: 69HCL19_0034
• Secondary ID: 2019-A00546-51
• Status: Completed
• Phase: N/A
• Start date: September 10, 2019
• Est. completion date: March 13, 2023

Study information

• Verified date: March 2023
• Source: Hospices Civils de Lyon
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 266
• Est. completion date: March 13, 2023
• Est. primary completion date: March 13, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Hypothermia
• Liver Transplantation

Intervention

Device:
• End-ischemic Hypothermic Oxygenated Machine Perfusion (HOPE)
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).
• classic static cold storage
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

Locations

Country	Name	City	State
France	Department of HPB surgery and liver transplantation Beaujon University Hospital	Clichy
France	CHU Grenoble Alpes - Department of HPB surgery and liver transplantation	Grenoble
France	Department of HPB surgery and liver transplantation Claude Huriez University Hospital	Lille
France	Hospices Civils de Lyon	Lyon
France	APHP - Pitié Salpétrière	Paris
France	Department of HPB surgery and liver transplantation Pontchaillou University Hospital	Rennes
France	Hôpital Hautepierre - Department of HPB surgery and liver transplantation	Strasbourg
France	Department of HPB surgery and liver transplantation Paul Brousse University Hospital	Villejuif

Sponsors (1)

Lead Sponsor	Collaborator
Hospices Civils de Lyon

Country where clinical trial is conducted

France, 

References & Publications (3)

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. Erratum In: JAMA Surg. 2018 May 1;153(5):498. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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.
Secondary	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)
Secondary	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)
Secondary	90-day morbidity and mortality	Severe postoperative complications (Dindo-Clavien =3) / death	During the first 90 days after surgery.
Secondary	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
Secondary	Length of hospital stay (days)	Duration of hospital stay	From randomization until hospital discharge, estimated up to 21 days
Secondary	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
Secondary	3-month and one-year patient and graft survivals	Actuarial graft and patient's survival rates	within one year after liver transplantation
Secondary	Hospital costs (Euros) of liver transplantation	Hospital costs of liver transplantation	At one year after liver transplantation