An Open Label, Non-randomised, Prospective, Single Arm, 2-part Trial, Using Normothermic Machine Liver Perfusion NMLP to Test Viability and Transplantation of Marginal Livers

Deaths from liver disease have soared by 40 per cent in a decade and continue to rise. Liver transplantation is a highly successful treatment of end stage liver disease, fulminant hepatic failure and early stage primary liver cancer. The demand for donor livers for transplantation greatly exceeds supply and approximately 20% of patients die whilst awaiting transplantation. Normothermic machine liver perfusion (NMLP) is a novel technique developed for the purposes of organ preservation, which we have also found allows monitoring of liver graft function ex-vivo by measuring bile production, whilst permitting objective assessment of liver biochemistry and blood flow. The OrganOx metra, the NMLP device we are using, is CE marked but is not currently licensed for this particular use and the livers will not be transported using this device (which the CE mark currently covers). The device will be used at a particular site (in this case University Hospitals Birmingham) and after a period of static cold storage during which the liver will be transported to the hospital for testing on the device. The study population will be extended criteria donor livers, rejected for transplantation by all UK centres, which are then found to be functioning during perfusion and transplanted into "medium to low-risk" liver transplant recipients. VITTAL is an open label, non-randomised, prospective, single arm, 2-part trial the objectives of which are to:

• Further validate liver viability assessment criteria
• Perform the phase 2 study transplanting successfully resuscitated "rejected" livers
• Establish the feasibility of NMLP as a means to increase the number of transplantable livers.
• Identify novel biomarkers that are indicative of liver quality and function In terms of intervention, the procurement and transplantation of the organs will follow the current standard of care. The only deviation from the current standard will be the normothermic perfusion of organs following static cold storage in order to test their ability to function. This study is based on results from a 5-case pilot series which transplanted low-risk recipients with organs that had been rejected for transplantation but had been shown to function on the normothermic machine perfusion device. This work is currently in the process of being published. The main risk would be the transplantation of a non-functioning graft (resulting in a case of primary non-function that could result in re-transplantation or patient death.) Based on our pre-clinical research and clinical pilot series we believe the criteria we have identified that indicate organ function are stringent and significantly reduce this risk.