Hypothermic Oxygenated Perfusion (HOPE) of Human Liver Grafts
The purpose of this study is, in a phase II randomized trial, to test a newly developed machine perfusion technique of human liver allografts before transplantation.
Ischemia-reperfusion injury is universal in organ transplantation and leads to varying degrees of graft dysfunction. Despite this fact, the preservation method in organ transplantation has been left unchanged for many years and remains simple static cold storage. Given the scarce donor supply, an increasing number of so called marginal or extended criteria donor organs have been used for liver transplantation, grafts which were previously rarely considered. In addition, allocation policy has changed in many countries, and livers are currently often distributed by the severity of the recipient's disease. As a result, transplant candidates present sicker, with higher MELD (Model for end stage liver disease) scores, at the time of transplant,and the risk of graft dysfunction or even failure due to reperfusion injury is high after the use of marginal livers in sick recipients.
Machine liver perfusion techniques have been significantly improved during the past decade to decrease reperfusion injury, and a number of promising results show beneficial effects in various animal transplant models by either normothermic or hypothermic oxygenated continuous liver perfusion. These techniques generally require machine liver perfusion immediately after organ procurement. However, continuous perfusion has several drawbacks, including major logistic efforts and risk of organ damage during perfusion and transport.
Our group, therefore, focused on the practicability of machine liver perfusion. We developed an endischemic hypothermic oxygenated perfusion (HOPE) concept through the portal vein only. This technique can be easily applied in the operation room shortly before transplantation of the recipient, thus after organ transport and back table preparation.
Recently, the beneficial effect of a similar approach has been confirmed in human liver grafts by a phase I non randomized trial. These results prove feasibility and safety of an endischemic hypothermic machine perfusion approach and warrant further randomized studies.
|Hepatocellular Injury||Device: Hypothermic oxygenated perfusion (HOPE)||Phase 2|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||A Double Blinded Randomized Study on the Effects of Hypothermic Oxygenated Perfusion (HOPE) on Human Liver Grafts Before Transplantation|
- Postoperative peak ALT levels in blood serum (area under the curve) [ Time Frame: During the first week postoperatively ]Serum ALT (Alanin Aminotransferase)
- Postoperative outcome (Dindo/Clavien classification) [ Time Frame: Subjects will be followed for one year postoperatively ]
- Hospital- and ICU stay [ Time Frame: postoperative course ]Duration of hopitalization and ICU stay
- Inflammatory response and reperfusion injury [ Time Frame: before and after preservation, during reperfusion (0-3 hr) after liver implantation ]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.
- Patient and graft survival [ Time Frame: one year ]one year patient and graft survival
- outcome (Clavien/Dindo classification)in terms of extended criteria donor grafts [ Time Frame: 1 year postoperatively ]Subgroup analysis
|Study Start Date:||April 2015|
|Estimated Study Completion Date:||April 2019|
|Estimated Primary Completion Date:||April 2018 (Final data collection date for primary outcome measure)|
Active Comparator: Hypothermic oxygenated perfusion (HOPE)
Application of HOPE for 1 hour
Device: Hypothermic oxygenated perfusion (HOPE)
Application of HOPE for 1 hour, perfusion rate 150-300 ml/min, pressure controlled, perfusion pressure < 3 mm Hg, perfusion route portal vein, recirculating system, perfusion volume 2 L, perfusate Institute George Lopez solution (IGL-1), perfusate temperature 4-6 °C, perfusate oxygenation 150-200 mm Hg
No Intervention: Control group: no intervention
Conventional cold storage (IGL-1)
The study consists on two groups, a perfusion group and a control group. Patients on the waiting list for liver transplantation with proven written consent will be recruited and randomized during organ procurement. Randomization will be performed by computer (www.randomizer.at). Perfusion will be started in the operation room after regular organ procurement, transport and back table preparation. The perfusion procedure will not delay the implantation due to the fact that recipient hepatectomy usually takes 2 hours. During this procedure, hypothermic oxygenated perfusion (HOPE group) for one hour will be performed vs continued cold storage (Control group).
We will use commercially available and approved IGL solution (Institut George Lopez) as perfusate for machine perfusion.
Subjects will be followed for one year after transplantation.
Interim analysis will take be performed for safety and ethical purposes. As soon as we reach 20 patients per randomized group, data will be analyzed by an independent Data Monitoring Committee. The trial will be immediately stopped if one of the following is satisfied:
- Efficacy: If the mean ALT levels are statistically significantly higher (p<0.001, Student's T-test) in the HOPE group when compared to the Control group.
- Safety: If the proportion of complications (Grade ≥ III) is statistically significantly higher (p<0.05, Fischer's Exact 2-sided Test) in the HOPE group when compared to the Control group.
A subgroup analysis will be performed in terms of adjusting to extended criteria donor grafts.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01317342
|Contact: Philipp Dutkowski, Professor, MD||0041 44 255 firstname.lastname@example.org|
|University Hospital of Zurich||Not yet recruiting|
|Zurich, Switzerland, 8091|
|Contact: Philipp Dutkowski, PD, MD 0041 44 255 4236 email@example.com|
|Contact: Michelle De Oliveira, MD 0041 44 255 3300 firstname.lastname@example.org|
|Principal Investigator: Philipp Dutkowski, Professor, MD|
|Sub-Investigator: Michelle De Oliveira, MD|
|University of Zurich||Recruiting|
|Zurich, Switzerland, 8091|
|Contact: Philipp Dutkowski, Professor 0041 44 255 4236 email@example.com|
|Principal Investigator:||Philipp Dutkowski, PD, MD||Department of Surgery and Transplantation, University Hospital Zurich|