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Hypothermic Oxygenated (HOPE) Versus Normothermic Machine Perfusion (NMP) in Human Liver Transplantation (HOPE-NMP)

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ClinicalTrials.gov Identifier: NCT04644744
Recruitment Status : Active, not recruiting
First Posted : November 25, 2020
Last Update Posted : December 20, 2021
Sponsor:
Information provided by (Responsible Party):
Georg Lurje, MD, Charite University, Berlin, Germany

Brief Summary:
The common practice of conventional cold storage (CCS) organ preservation has changed little since the initial introduction of the original University of Wisconsin (UW) organ preservation solution in the late 1980s. CCS relies on hypothermia to decelerate metabolism and reduce oxygen demand in order to prolong the time of ischemia without rapid functional graft impairment, therefore merely delaying graft damage. While CCS only prolongs storage time and limits the damage sustained during the period of cold ischemia, ex-vivo machine perfusion (MP) appears to be capable of reversing some of these effects. Currently, two main paradigms prevail in the clinical approach to liver allograft MP: hypothermic oxygenated MP (HOPE) may be seen as a dynamic alternative of the traditional organ preservation based on hypothermia-induced deceleration of metabolism, which aims to combine the positive effects of hypothermia observed in classical cold storage (e.g. technical simplicity, relative safety, decreased metabolism) with the positive effects of dynamic preservation (e.g. controlled sheer stress mediated gene activation, removal of metabolites, transport of oxygen and ATP recharging). Normothermic perfusion (NMP) aims at re-equilibration of cellular metabolism by preserving the organ at physiological temperatures whilst ensuring sufficient oxygen and nutrient supply. In both approaches, the perpetual circulation and moderate shear-stress sustain endothelial functionality. While past and current clinical trials were designed to compare different MP approaches with CCS as the clinical standard, a direct comparison between different end-ischemic MP techniques (HOPE versus NMP) is still lacking. The purpose of this study is to test the effects of end-ischemic NMP versus end-ischemic HOPE technique in a multicentre prospective randomized controlled clinical trial (RCT) on ECD liver grafts in DBD liver-transplantation (HOPE-NMP). Two-hundred-thirteen (n = 213) human whole organ liver grafts will be submitted to either 4-24 hours of NMP (n = 85) or 2-3 hours of HOPE (n = 85) directly before implantation and going to be compared to a control-group of patients (n = 43) transplanted with static cold storage preserved ECD-allografts. Primary (surgical complications as assessed by the comprehensive complication index [CCI]) and secondary (among others laboratory values, graft- and patient survival, hospital costs, hospital stay) endpoints are going to be analysed.)

Condition or disease Intervention/treatment Phase
Hepatocellular Injury Liver Transplant Disorder Device: Hypothermic oxygenated perfusion (HOPE) Device: Normothermic machine perfusion (NMP) Not Applicable

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 213 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized controlled trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: End-ischemic Hypothermic Oxygenated (HOPE) vs. Normothermic Machine Perfusion (NMP) Compared to Conventional Cold Storage in Donation After Brain Death Liver Transplantation; a Prospective Multicentre Randomized Controlled Trial (HOPE-NMP)
Actual Study Start Date : January 14, 2021
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Hypothermic oxygenated perfusion (HOPE)
Application of end-ischemic Hypothermic machine perfusion (HOPE) for a minimum of 2 hours (until hepatectomy)
Device: Hypothermic oxygenated perfusion (HOPE)
HOPE for 1 hour via the portal vein in a recirculating and pressure controlled system (2-3 mm Hg), 0.1 ml/g liver/min, perfusion volume 3-4 L, Belzer (UW) machine perfusion solution, perfusate temperature 10 °C, perfusate oxygenation pO2 of 60-80 kPa
Other Name: Hypothermic machine perfusion (HMP)

Experimental: Normothermic machine perfusion (NMP)
Application of end-ischemic normothermic machine perfusion (NMP) for a minimum of 4 hours (up to 24 hours)
Device: Normothermic machine perfusion (NMP)
End-ischemic NMP will be continued throughout the recipient hepatectomy and until the transplanting team is ready to implant the liver. The minimum protocol-stipulated NMP duration is 4 hours, the time needed for ATP repletion in animal studies. Total NMP preservation time will be according to the official recommendations of the manufacturer (4-24 hours) and at the discretion of the local transplant centre. The liver allograft will be disconnected from the OrganOx metra® device immediately prior to transplantation and flushed with three litres of HTK via the hepatic artery and the portal vein.

Active Comparator: Conventional cold storage (CCS)
Conventional cold storage
Device: Hypothermic oxygenated perfusion (HOPE)
HOPE for 1 hour via the portal vein in a recirculating and pressure controlled system (2-3 mm Hg), 0.1 ml/g liver/min, perfusion volume 3-4 L, Belzer (UW) machine perfusion solution, perfusate temperature 10 °C, perfusate oxygenation pO2 of 60-80 kPa
Other Name: Hypothermic machine perfusion (HMP)

Device: Normothermic machine perfusion (NMP)
End-ischemic NMP will be continued throughout the recipient hepatectomy and until the transplanting team is ready to implant the liver. The minimum protocol-stipulated NMP duration is 4 hours, the time needed for ATP repletion in animal studies. Total NMP preservation time will be according to the official recommendations of the manufacturer (4-24 hours) and at the discretion of the local transplant centre. The liver allograft will be disconnected from the OrganOx metra® device immediately prior to transplantation and flushed with three litres of HTK via the hepatic artery and the portal vein.




Primary Outcome Measures :
  1. Postoperative complications [ Time Frame: After the first 90-days postoperatively ]
    Comprehensive Complication Index (CCI) (assessed after the first 90-days postoperatively)


Secondary Outcome Measures :
  1. Peak alanine aminotransferase (ALT) [ Time Frame: During the first week postoperatively ]
    Peak serum alanine aminotransferase-ALT

  2. Peak aspartate aminotransferase (AST) [ Time Frame: During the first week postoperatively ]
    Peak serum aspartate aminotransferase-AST

  3. Early allograft dysfunction (EAD) [ Time Frame: During the first week postoperatively ]
    Olthoff criteria (bilirubin 10mg/dL on day 7, international normalized ratio 1.6 on day 7, and alanine or aspartate aminotransferases >2000 IU/L)

  4. Primary non-function (PNF) [ Time Frame: During the first week postoperatively ]
    Graft with poor function requiring re-transplantation or leading to death within 7 days after the primary procedure without any identifiable cause of graft failure

  5. Biliary complications [ Time Frame: at 6 months postoperatively ]
    as assessed by MRI / MRCP

  6. Organ utilization rate [ Time Frame: During the first week postoperatively ]
    Rate of donor-allograft offers that result in liver transplantation

  7. Total organ preservation time [ Time Frame: Before preservation (HOPE or NPM or CCS), after liver implantation (0-3 hours) ]
    Organ logistics

  8. Duration and costs of initial intensive care unit (ICU) stay [ Time Frame: Subjects will be followed for 6 months postoperatively ]
    Length of initial Intensive care unit (ICU) stay is determined in days of admission following liver transplantation.

  9. Duration of hospital stay [ Time Frame: Subjects will be followed for 6 months postoperatively ]
    Length of hospital stay is determined in days of hospital admission after discharge and up to six months after liver transplantation

  10. Costs of hospital stay [ Time Frame: Subjects will be followed for 6 months postoperatively ]
    Costs of hospital stay is determined in days of hospital admission after discharge and up to six months after liver transplantation

  11. Postoperative complications [ Time Frame: Subjects will be followed for one year postoperatively ]
    According to the Comprehensive complication index (CCI)

  12. Postoperative major complications [ Time Frame: Subjects will be followed for one year postoperatively ]
    According to the Clavien-Dindo complication score

  13. One-year recipient- and graft survival [ Time Frame: Subjects will be followed for one year postoperatively ]
    One year patient and graft survival



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Signed informed consent
  • Patients 18 years or older
  • Patients suffering from end stage-liver disease and/or malignant liver tumours
  • Listed for OLT
  • Receiving ECD-allografts

Exclusion Criteria:

  • Recipients of split or living donor liver transplants
  • Previous liver transplantation
  • Combined transplantations (liver-kidney, liver-lung, etc.)
  • Participation in other liver related trials
  • The subject received an investigational drug within 30 days prior to inclusion
  • The subject is unwilling or unable to follow the procedures outlined in the protocol
  • The subject is mentally or legally incapacitated
  • Patient is not able to understand the procedures due to language barriers
  • Family members of the investigators or employees of the participating departments

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): NCT04644744


Locations
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Germany
University Hospital RWTH Aachen, Department of Surgery and Transplantation
Aachen, Germany, 52074
Charité Universitätsmedizin - Berlin, Campus Charité Mitte | Campus Virchow-Klinikum
Berlin, Germany, 13353
Medizinische Hochschule Hannover (MHH), Department of Surgery and Transplantation
Hannover, Germany, 30625
University Hospital Heidelberg, Department of Surgery and Transplantation
Heidelberg, Germany, 69120
Sponsors and Collaborators
Charite University, Berlin, Germany
Investigators
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Principal Investigator: Georg Lurje, M.D. Charite University, Berlin, Germany
Additional Information:
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Responsible Party: Georg Lurje, MD, Consultant HPB- and Transplant Surgeon, Charite University, Berlin, Germany
ClinicalTrials.gov Identifier: NCT04644744    
Other Study ID Numbers: EA2/270/20
First Posted: November 25, 2020    Key Record Dates
Last Update Posted: December 20, 2021
Last Verified: December 2021
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 Georg Lurje, MD, Charite University, Berlin, Germany:
ex-vivo machine Perfusion
Hypothermic oxygenated machine perfusion
Normothermic machine perfusion
Orthotopic liver transplantation
Extended criteria donation
Donation after brain death
HOPE
NMP
Additional relevant MeSH terms:
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Hypothermia
Body Temperature Changes