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 : Active, not recruiting
First Posted : April 24, 2017
Last Update Posted : October 8, 2020
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|
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).
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||46 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||Randomized controlled trial|
|Masking:||None (Open Label)|
|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|
|Actual Primary Completion Date :||October 7, 2020|
|Estimated Study Completion Date :||October 7, 2021|
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
- Early graft injury [ Time Frame: During the first week postoperatively (absolute and relative delta) ]Peak serum alanine aminotransferase-ALT
- 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)
- 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)
- 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
- (in selected centers) Biliary epithelial cell injury [ Time Frame: Postoperative days 1, 2, and 3 ]Bile samples collected from T-Drain
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
|Ghent University Hospital and Medical School|
|Department of Transplantation Surgery, Institute for Clinical and Experimental Medicine|
|Department of Surgery and Transplantation, University Hospital RWTH Aachen|
|Aachen, Germany, 52074|
|Fundeni Clinical Institute Center of General Surgery & Liver Transplantation|
|Principal Investigator:||Georg Lurje, M.D.||RWTH Aachen University|