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HOPE for Human Extended Criteria and Donation After Brain Death Donor (ECD-DBD) Liver Allografts (HOPE-ECD-DBD)

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ClinicalTrials.gov Identifier: NCT03124641
Recruitment Status : Unknown
Verified October 2017 by Georg Lurje, M.D., University Hospital, Aachen.
Recruitment status was:  Recruiting
First Posted : April 24, 2017
Last Update Posted : October 12, 2017
Sponsor:
Information provided by (Responsible Party):
Georg Lurje, M.D., University Hospital, Aachen

Brief Summary:

The purpose of this study is to test the effects of hypothermic oxygenated machine perfusion (HOPE) in a phase-II prospective multicenter randomized clinical trial (RCT) on extended criteria donor allografts (ECD) in donation after brain death (DBD) orthotropic liver-transplantation (OLT) (HOPE-ECD-DBD). Human whole organ liver grafts will be submitted to 1-2 hours of HOPE via the portal vein directly before implantation and going to be compared to a control-group of patients transplanted after conventional cold storage (CCS). Primary (early graft injury) and secondary (e.g. postoperative complications, hospital stay, survival) objectives are going to be analysed in a 12 month follow up. Ischemia-reperfusion (I/R) injury and inflammation will be assessed using liver tissue, serum and bile samples as well as machine perfusion perfusate.

To improve the availability of donor allografts and reduce waiting list mortality, graft acceptance criteria were extended increasingly over the decades. The use of extended criteria donor (ECD) allografts is associated with higher incidences of primary graft non-function (PNF) and/or delayed graft function (DGF). As such, several strategies have been developed aiming at "reconditioning" poor quality ECD grafts. HOPE has been tested intensively in pre-clinical animal experiments. Although, its known that HOPE can exert its reconditioning effect via cellular and mitochondrial pathways in the endothelial and parenchymal cells, there is still scarce evidence available on the exact subcellular mechanism of HOPE induced organ protection in the clinical scenario of liver transplantation. In donation after cardiac death (DCD) OLT, the positive effects of HOPE have been shown to reduce the incidence of biliary complications, mitochondrial damage and improve the overall cellular energy-status.

In the HOPE setting, organ perfusion is performed in the transplant center shortly before the actual implantation with oxygenated perfusate using an extra corporal organ perfusion system. The first clinical study with this promising technique was recently reported in a Swiss cohort of patients who received DCD allografts. In organ donation after brain death (DBD), the only legally accepted approach for organ donation in most countries, HOPE and its effect on early graft injury and postoperative complications remains to be elucidated.


Condition or disease Intervention/treatment Phase
Hepatocellular Injury Liver Transplant Device: Hypothermic oxygenated perfusion (HOPE) Procedure: Conventional cold storage (CCS) Not Applicable

Detailed Description:

The present RCT comprises two groups, a perfusion (group 1; HOPE) and a control conventional cold storage (group 2; CCS) group. Patients with proven written informed consent on waiting list for orthotopic liver transplantation will be recruited. Randomization is performed with an online randomizing tool for clinical trials (www.randomizer.at) at the time of allograft arrival at the transplant center and acceptance of the organ for transplantation. Stratified randomization model will be used to ensure balance of prognostic variables between the treatment groups.

In case of randomisation to group 1, HOPE will be applied to the allograft in the operation room, directly after the back table preparation. The application of HOPE to the liver allograft will not delay the implantation due to the fact that it is performed parallel to the recipient hepatectomy.

Commercially available and machine-perfusion approved Belzer MPS® UW solution (Belzer Organ Preservation Solutions, Bridge for Life) will be used as perfusate for machine perfusion.

Patients will be followed for one year after OLT.

Interim analysis: After n=12 per randomized group is reached, data will be analyzed by an independent Data Monitoring Committee. The RCT will be stopped if one of the following criteria is reached:

Significantly higher serum ALT levels (p<0.001 using Student's t-test) in the HOPE group compared to the CCS group (Efficacy).

The proportion of Grade ≥ III complications is significantly higher (p<0.05, Fischer's exact test) in the HOPE group when compared to the CCS group (Safety).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 46 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized controlled trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Hypothermic Oxygenated Machine Perfusion (HOPE) for Liver Transplantation of Human Liver Allografts From Extended Criteria Donors (ECD) in Donation After Brain Death (DBD); a Prospective Multicenter Randomized Controlled Trial (HOPE ECD-DBD)
Actual Study Start Date : September 24, 2017
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : June 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Hypothermic oxygenated perfusion (HOPE)
Application of Hypothermic machine perfusion (HOPE) for 1-2 hours
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)

Active Comparator: Conventional cold storage (CCS)
Conventional cold storage
Procedure: Conventional cold storage (CCS)
Conventional static cold storage (CCS) on temperature 4-6 °C from organ procurement
Other Name: CCS




Primary Outcome Measures :
  1. Early graft injury [ Time Frame: During the first week postoperatively (absolute and relative delta) ]
    Peak serum alanine aminotransferase-ALT


Secondary Outcome Measures :
  1. Postoperative complications [ Time Frame: Subjects will be followed for one year postoperatively ]
    Clavien-Dindo complication score

  2. Cumulative postoperative complications [ Time Frame: Subjects will be followed for one year postoperatively ]
    Comprehensive complication index (CCI)

  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. Duration of intensive care stay [ Time Frame: Subjects will be followed for one year postoperatively ]
    Duration of ICU stay

  5. Duration of hospital stay [ Time Frame: Subjects will be followed for one year postoperatively ]
    Duration of hospitalisation

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

  7. Ischemia-reperfusion injury and inflammatory responses [ Time Frame: Before preservation (HOPE or CCS), after liver implantation (0-3 hrs) ]
    Liver samples taken upon arrival of the organ (before HOPE or corresponding cold-storage), and at the end of the implantation procedure before closure of the abdomen

  8. (in selected centers) Biliary epithelial cell injury [ Time Frame: Postoperative days 1, 2, and 3 ]
    Bile samples collected from T-Drain



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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:

-Patients with signed informed consent, suffering from end stage-liver disease and/or malignant liver tumors listed for liver transplantation and receiving ECD organs.

ECD Criteria are defined as:

  • Donors 65 years of age and older
  • Intensive therapy of the donor was required before donation for at least 7 days, --Obesity of the donor with a Body Mass Index > 30
  • Fatty liver (with histology) > 40 %
  • Serum-Sodium > 165 mmol/l
  • Serum AST or ALT > 3 x normal, Serum-Bilirubin > 2 mg/dl)

Exclusion Criteria:

  • Recipients of split of 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 department

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): NCT03124641


Contacts
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Contact: Georg Lurje, M.D. +492418035048 glurje@ukaachen.de
Contact: Zoltan Czigany, M.D. +492418037823 zczigany@ukaachen.de

Locations
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Belgium
Ghent University Hospital and Medical School Not yet recruiting
Ghent, Belgium
Contact: Xavier Rogiers, Professor       Xavier.Rogiers@uzgent.be   
Czechia
Department of Transplantation Surgery, Institute for Clinical and Experimental Medicine Recruiting
Praha, Czechia
Contact: Jiří Froněk, Professor       jifr@medicon.cz   
Germany
Department of Surgery and Transplantation, University Hospital RWTH Aachen Recruiting
Aachen, Germany, 52074
Contact: Georg Lurje, M.D.    +492418035048    glurje@ukaachen.de   
Romania
Fundeni Clinical Institute Center of General Surgery & Liver Transplantation Not yet recruiting
Bucharest, Romania
Contact: Irinel Popescu, Professor       irinel.popescu220@gmail.com   
Contact: Florin Botea, MD       boteaflorin@yahoo.com   
Sponsors and Collaborators
University Hospital, Aachen
Investigators
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Principal Investigator: Georg Lurje, M.D. RWTH Aachen University

Additional Information:
Publications:
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Responsible Party: Georg Lurje, M.D., Attending Transplant Surgeon, University Hospital, Aachen
ClinicalTrials.gov Identifier: NCT03124641     History of Changes
Other Study ID Numbers: EK 049/17
First Posted: April 24, 2017    Key Record Dates
Last Update Posted: October 12, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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, M.D., University Hospital, Aachen:
Hypothermic oxygenated machine perfusion
Orthotopic liver transplantation
Extended criteria donation
Donation after brain death
HOPE
Additional relevant MeSH terms:
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Brain Death
Death
Pathologic Processes
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Coma
Unconsciousness
Consciousness Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Liver Extracts
Hematinics