HOPE for Human Extended Criteria and Donation After Brain Death Donor (ECD-DBD) Liver Allografts
Condition: Hepatocellular Injury; Liver Transplant
MeSH terms: Brain Death
Study type: Interventional

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.
    

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).
    

Intervention name(s): Hypothermic oxygenated perfusion (HOPE); Conventional cold storage (CCS)
Intervention type(s): Device; Procedure
Intervention description(s): 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; Conventional static cold storage (CCS) on temperature 4-6 °C from organ procurement
Other intervention name(s): Hypothermic machine perfusion (HMP); CCS
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomized controlled trial
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hypothermic oxygenated machine perfusion; Orthotopic liver transplantation; Extended criteria donation; Donation after brain death; HOPE