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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Hypothermic Oxygenated Machine Perfusion (HOPE) for Orthotopic Liver Transplantation of Human Liver Allografts From Extended Criteria Donors (ECD) in Donation After Brain Death

Brief Summary:

The purpose of this study is to test the effects of hypothermic oxygenated machine perfusion (HOPE) in a phase-II prospective 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 hour 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 function) 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 and serum samples.

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 t

Detailed Summary:

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 the admission 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).


Sponsor: University Hospital, Aachen

Current Primary Outcome: Early graft function [ Time Frame: During the first week postoperatively ]

Peak serum alanine aminotransferase-ALT


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Postoperative complications [ Time Frame: Subjects will be followed for one year postoperatively ]
    Clavien-Dindo complication score
  • Cumulative postoperative complications [ Time Frame: Subjects will be followed for one year postoperatively ]
    Comprehensive complication index (CCI)
  • Duration of intensive care stay [ Time Frame: Subjects will be followed for one year postoperatively ]
    Duration of ICU stay
  • Duration of hospital stay [ Time Frame: Subjects will be followed for one year postoperatively ]
    Duration of hospitalisation
  • One-year recipient- and graft survival [ Time Frame: Subjects will be followed for one year postoperatively ]
    One year patient and graft survival
  • 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


Original Secondary Outcome:

  • Postoperative complications [ Time Frame: Subjects will be followed for one year postoperatively ]
    Clavien-Dindo complication score
  • Cummulative postoperative complications [ Time Frame: Subjects will be followed for one year postoperatively ]
    Comprehensive complication index (CCI)
  • Duration of intensive care stay [ Time Frame: Subjects will be followed for one year postoperatively ]
    Duration of ICU stay
  • Duration of hospital stay [ Time Frame: Subjects will be followed for one year postoperatively ]
    Duration of hospitalisation
  • One-year recipient- and graft survival [ Time Frame: Subjects will be followed for one year postoperatively ]
    One year patient and graft survival
  • Inflammatory response and reperfusion injury [ Time Frame: Before preservation (HOPE or CCS), during reperfusion after liver implantation (0-3 hr) ]
    Liver samples taken after procurement, before HOPE, after HOPE or after cold storage, respectively, and at the end of implantation before closure of the abdomen to evaluate the amount of ischemia reperfusion (I/R) injury.


Information By: University Hospital, Aachen

Dates:
Date Received: March 20, 2017
Date Started: April 9, 2017
Date Completion: June 2019
Last Updated: April 24, 2017
Last Verified: April 2017