Extra-corporeal liver cross-circulation in the treatment of acute-on-chronic liver failure: a safety and feasibility study

Research question Is 72-hour extra-corporeal liver cross-circulation (ELC), using donor human livers declined for transplantation, safe and feasible in the treatment of acute-on-chronic liver failure (ACLF)? Background ACLF is associated with substantial short-term mortality. Current treatment comprises intensive medical care, with transplantation only feasible for a minority of patients. The event that triggers acute liver decompensation in ACLF is often reversible, if the patient can be supported long enough to allow liver recovery, but there is no effective temporary liver support system. Artificial and bio-artificial systems have been unable to replace the complex roles of a liver, reflected in their failure to improve survival. In ELC, a patient s blood is treated by perfusion through a donor liver maintained outside the body. This more comprehensive hepatic replacement differentiates ELC from other liver support systems. A novel ELC system (metra-ELC) has been developed by modifying the OrganOx metra normothermic perfusion device. In a porcine liver failure model, metra-ELC significantly improved biochemical and clinical parameters, without thrombocytopenia, haemolysis or thrombo-embolic complications. In a human decedent model, metra-ELC using genetically-modified porcine livers was feasible over 72 hours. The auxiliary livers used in this study will be those from deceased human donors, declined for transplantation. Many are declined due to risk of long-term complications but exhibit short-term function sufficient to provide effective temporary support. Aims Evaluate the safety and feasibility of metra-ELC over 72 hours using human donor livers in the treatment of ACLF. Generate preliminary effect and endpoint data, through comparison with matched historical controls, to inform the design of an efficacy trial. Methods This is a phase 1 study of 20 adult patients with ACLF grade II-IIIa not listed for transplant, who will undergo ELC for a maximum of 24 (patients 1-5) or 72 hours (patients 6-20). They will be compared to 40 historical controls treated at the study centres within 5 years, matched to age, CLIF-SOFA and transplant listing status. The primary outcome is 28-day patient survival. Secondary outcomes include incidence of serious/device-related adverse events, feasibility measures (e.g. liver recruitment rate), biochemical/clinical effect (e.g. CLIF-SOFA), length of hospital/ICU stay and 90-day (transplant-free) survival. Exploratory outcomes will evaluate auxiliary liver function, immunological and haematological impact. Timelines The planned study length is 36 months: 9 months set-up/regulatory approval; 18 months recruitment; 3 months follow-up; 6 months analysis/reporting. Anticipated impact If successful, this study will demonstrate that 72-hour ELC is safe and feasible. It will inform the design of a subsequent multi-centre randomised controlled trial: effect size estimation; sample size calculation; endpoint selection ELC duration declined liver logistics; selection criteria metra-ELC refinement health economic pathway analysis. ELC has potential to become a cost-effective intervention to bridge ACLF patients to recovery or to transplantation – in a clinically improved state when a transplantable liver is available. Dissemination Results will be presented at national and international hepatology/transplant conferences and published in a high-impact clinical journal. A plain English summary will be co-developed with patient representatives for dissemination to patient groups.