Hypothermic Oxygenated Machine Perfusion (HOPE) for Liver Transplantation of Human Liver Allografts From Extended Criteria Donors (ECD) in Donation After Brain Death (DBD); a Multicenter Randomized Controlled Trial (HOPE ECD-DBD)
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 46
- 试验地点
- 7
- 主要终点
- Early graft injury
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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
结局指标
主要结局
Early graft injury
时间窗: During the first week postoperatively (absolute and relative delta)
Peak serum alanine aminotransferase-ALT
次要结局
- Duration of intensive care stay(Subjects will be followed for one year postoperatively)
- Cumulative postoperative complications(Subjects will be followed for one year postoperatively)
- Postoperative complications(Subjects will be followed for one year postoperatively)
- Duration of hospital stay(Subjects will be followed for one year postoperatively)
- Early allograft dysfunction (EAD)(During the first week postoperatively)
- One-year recipient- and graft survival(Subjects will be followed for one year postoperatively)
- (in selected centers) Biliary epithelial cell injury(Postoperative days 1, 2, and 3)
- Ischemia-reperfusion injury and inflammatory responses(Before preservation (HOPE or CCS), after liver implantation (0-3 hrs))
研究者
Georg Lurje, M.D.
Attending Transplant Surgeon
University Hospital, Aachen