Transplantation of Discarded Livers Following Normothermic Machine Perfusion: A Multicenter RESTORE Trial

修改后的项目总结/摘要 肝移植是终末期肝病（包括某些肝癌）患者的最终治疗方法。然而，很大一部分患者，特别是那些有终末期肝病模型（MELD）评分的患者，24和衰弱性肝脏疾病，如肝细胞癌，肝内胆管癌和结肠直肠肝转移，由于供体肝脏短缺而不接受这种挽救生命的手术。延迟肝移植不仅影响死亡风险和生活质量，而且增加医疗费用。目前的供体利用做法将加剧现有的器官短缺。许多肝脏被拒绝移植，因为外科医生根据他/她对器官的主观评估怀疑其可行性。此外，由于类似的问题，许多额外的肝脏甚至从未恢复。在移植前进行可靠和客观的测试来评估边缘肝的存活能力将有助于外科医生对边缘供体肝的可用性做出明智的决定。来自我们小组和其他人的累积证据支持常温机器灌注（NMP），在正常体温下泵送含氧血液与营养物质和药物，以维持器官的正常代谢活动，是一种安全可行的边缘肝脏修复方法。此外，NMP为移植团队提供了一个独特的机会，通过评估肝脏移植物的血流动力学状态和代谢功能来测试肝脏的活力。在我们的单中心I期试验（NCT 04483102）的基础上，我们建议进行一项II期单臂多中心试验（mRESTORE），该试验将在客观活力测试后移植NMP治疗的先前下降的孤儿肝。该研究将在研究资助期（最长4年）内评价患者和移植物存活率以及二次移植结局，包括胆道并发症，进行机制研究，并评价移植NMP处理的肝脏（否则将被丢弃）的成本效益。九家肝移植中心及其服务于不同种族/民族患者的OPO将参与本研究。在规划阶段，我们将最终确定研究设计和方案，获得监管部门的批准，并建立运营基础设施（例如，病例报告表、方案监测计划），以便及时实施mRESTORE。在过渡到全面研究后，我们将向患者移植NMP治疗的先前下降的边缘肝，并研究其移植结果。此外，我们还将研究受先前下降的边缘供体肝脏的NMP影响的肝细胞损伤机制，确定NMP的肝功能障碍表型与相关的移植结果，并评估使用NMP治疗的肝移植的成本效益。我们的研究结果将为增加可移植肝脏数量的实用策略提供信息，这将改变当前供体利用实践的范式，并最终改善肝脏移植的可及性并挽救生命。

MODIFIED PROJECT SUMMARY/ABSTRACT Liver transplantation is the definitive treatment for patients with end-stage liver disease, including some liver cancers. However, a significant proportion of patients, particularly those with the Model for End-stage Liver Disease (MELD) score ??24 and debilitating liver diseases, such as hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and colorectal liver metastases, do not receive this life-saving surgery due to a shortage in donor livers. Delayed liver transplantation not only affects the mortality risk and quality of life but also increases health care costs. The current donor utilization practice will exacerbate the existing organ shortage. Many livers are declined for transplantation because a surgeon doubts its viability based on his/her subjective assessment of the organ. Also, many additional livers are never even recovered because of similar concerns. A reliable and objective testing to assess the viability of marginal livers before transplant will help surgeons make informed decisions on the usability of marginal donor livers. Accumulating evidence from our group and others supports that normothermic machine perfusion (NMP) that pumps oxygenated blood with nutrients and medications at normal body temperature to maintain normal metabolic activity of the organ is a safe and feasible means of reconditioning marginal livers. In addition, NMP provides a unique opportunity for the transplant team to test viability of livers by assessing hemodynamic state and metabolic function of the liver graft. Building upon our single center phase 1 trial (NCT04483102), we propose to conduct a phase 2 single-arm multicenter trial (mRESTORE) that will transplant NMP-treated previously declined orphan livers after objective viability testing. The study will evaluate patient and graft survival and secondary transplant outcomes, including biliary complications, for the duration of the study funding period (up to 4 years), conduct mechanistic studies, and evaluate the cost-effectiveness of transplantation of NMP-treated livers that would otherwise have been discarded. Nine liver transplant centers and their OPOs that serve race/ethnically diverse patients will participate in this study. During the planning phase, we will finalize the study design and protocol, obtain regulatory approvals and build the operational infrastructure (e.g., case report forms, protocol monitoring plan) to enable timely implementation of the mRESTORE. After the transition to the full study, we will transplant NMP-treated previously declined marginal livers to patients and study their transplant outcomes. In addition, we will investigate hepatocellular injury mechanisms that are affected by NMP of previously declined marginal donor livers, identify liver dysfunction phenotypes of NMP with associated transplant outcomes, and evaluate the cost-effectiveness of the utilization of NMP-treated liver transplantation. Our study findings will inform a practical strategy to increase the number of transplantable livers, which will shift the paradigm of current donor utilization practices and ultimately improve access to liver transplants and save lives.