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

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ClinicalTrials.gov Identifier: NCT03929523
Recruitment Status : Not yet recruiting
First Posted : April 29, 2019
Last Update Posted : July 19, 2019
Sponsor:
Information provided by (Responsible Party):
Hospices Civils de Lyon

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.


Condition or disease Intervention/treatment Phase
Liver Transplantation Device: End-ischemic Hypothermic Oxygenated Machine Perfusion (HOPE) Device: classic static cold storage Not Applicable

Detailed Description:

This multicentric randomized controlled trial concerns adult patients undergoing whole liver transplantation in any of the 6 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 24 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).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 266 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: End-ischemic Hypothermic Oxygenated Perfusion for Extended Criteria Donors in Liver Transplantation - A Multicenter, Randomized Controlled Trial
Estimated Study Start Date : September 2019
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : September 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: HOPE group
hypothermic oxygenated perfusion
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).

Active Comparator: Control group
classic static cold storage
Device: 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




Primary Outcome Measures :
  1. Early allograft dysfunction (EAD) according to Olthoff criteria. [ Time Frame: During the first postoperative week ]

    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/mL within the first 7 PODs Additionally EAD will be also assessed by the MEAF score and the L-GrAFT risk factor.


Secondary Outcome Measures :
  1. Model of Early Allograft Function score (MEAF score). [ Time Frame: During the first 3 postoperative days. ]
    The MEAF score includes bilirubin, ALT max and INR max at postperative day 3. Range 0 (better outcome) to 10 (worse outcome)

  2. Liver Graft Assessment Following Transplantation risk factor (L-GrAFT) [ Time Frame: During the first 10 postoperative days. ]
    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)

  3. Untargeted liver graft metabolic profiling [ Time Frame: Day of liver transplantation (Day 0) ]
    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.

  4. Occurrence of post-reperfusion syndrome [ Time Frame: Day of liver transplantation (Day 0) ]
    Defined as a 50% decrease in median arterial pressure during the 5 minutes following the graft revascularization

  5. 90-day morbidity and mortality [ Time Frame: During the first 90 days after surgery. ]
    Severe postoperative complications (Dindo-Clavien ≥3) / death

  6. Length of intermediate care unit stay (days) [ Time Frame: From randomization until intermediate care unit discharge, estimated up to 7 days ]
    Duration of intermediate care unit stay

  7. Length of hospital stay (days) [ Time Frame: From randomization until hospital discharge, estimated up to 21 days ]
    Duration of hospital stay

  8. Liver contrast-enhanced MRI including a Magnetic Resonance CholangioPancreatography (MRCP) [ Time Frame: Within 1 year after liver transplantation ]
    Assessment of intra- and extrahepatic biliary complications

  9. 3-month and one-year patient and graft survivals [ Time Frame: within one year after liver transplantation ]
    Actuarial graft and patient's survival rates

  10. Hospital costs (Euros) of liver transplantation [ Time Frame: At one year after liver transplantation ]
    Hospital costs of liver transplantation



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • Concurrent participation in any other interventional clinical trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03929523


Contacts
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Contact: Mickael LESURTEL +33 4 72 07 11 00 mickael.lesurtel@chu-lyon.fr
Contact: Mahé RAFFIN +33 4 26 73 27 38 mahe.raffin@chu-lyon.fr

Locations
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France
Department of HPB surgery and liver transplantation Beaujon University Hospital Not yet recruiting
Clichy, France, 92210
Contact: Olivier SOUBRANE    +33 1 40 87 50 00    olivier.soubrane@aphp.fr   
Department of HPB surgery and liver transplantation Claude Huriez University Hospital Not yet recruiting
Lille, France, 59037
Contact: Emmanuel BOLESLAWSKI    +33 3 20 44 42 60    emmanuel.boleslawski@chru-lille.fr   
Hospices Civils de Lyon Not yet recruiting
Lyon, France, 69004
Contact: Mickaël LESURTEL    +33 4 72 07 11 00    mickael.lesurtel@chu-lyon.fr   
Contact: Mahé RAFFIN    +33 4 26 73 27 38    mahe.raffin@chu-lyon.fr   
Department of HPB surgery and liver transplantation Pontchaillou University Hospital Not yet recruiting
Rennes, France, 35033
Contact: Michel RAYAR       michel.rayar@chu-rennes.fr   
Department of HPB surgery and liver transplantation Hôpital Hautepierre Not yet recruiting
Strasbourg, France, 67200
Contact: Philippe BACHELLIER       philippe.bachellier@chru-strasbourg.fr   
Department of HPB surgery and liver transplantation Paul Brousse University Hospital Not yet recruiting
Villejuif, France, 94804
Contact: René ADAM    +33 1 45 59 30 49    rene.adam@aphp.fr   
Sponsors and Collaborators
Hospices Civils de Lyon
Investigators
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Principal Investigator: Mickael LESURTEL Hospices Civils de Lyon

Publications:
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Responsible Party: Hospices Civils de Lyon
ClinicalTrials.gov Identifier: NCT03929523     History of Changes
Other Study ID Numbers: 69HCL19_0034
2019-A00546-51 ( Other Identifier: ANSM )
First Posted: April 29, 2019    Key Record Dates
Last Update Posted: July 19, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Hospices Civils de Lyon:
Liver Transplantation
Liver machine perfusion
extended criteria donor

Additional relevant MeSH terms:
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Hypothermia
Body Temperature Changes
Signs and Symptoms
Liver Extracts
Hematinics