Evaluate the Feasibility and Safety of Long-term Preservation of Human Livers before Transplantation.

Transplantation of initially unsuitable livers following extended organ perfusion is an open-label, non-randomised, prospective, single-arm trial, using normothermic extended organ perfusion (NEOP) to test viability and then transplant marginal livers. It will be conducted at the Australian National Liver Transplant Unit (ANLTU) at Royal prince Alfred Hospital. We propose a parallel phase I/II clinical trial to evaluate simultaneously the safety and efficacy of NEOP. The design uses two linked components assessing: (Aim 1) the safety and feasibility of NEOP as a technique to safely increase the number of transplantable livers and (Aim 2) (once initial safety has been demonstrated) achievement of successful transplantation of the NEOP treated marginal livers. (Aim 1) uses a two-stage adaptive design, requiring up to 54 ‘marginal’ livers to be perfused. (Aim 2) uses a three-stage adaptive design and requires 27 NEOP treated marginal livers to be transplanted. Success is measured by a 90-day graft survival. The duration of machine perfusion will be dictated by graft viability/function and logistics. Viability criteria are assessed at 4 hours and then every 4 hours up to 96 hours. Graft is perfused until satisfy viability criteria up to 96 hours. Once criteria have been met, the recipient operation will be scheduled to occur as soon as practicable in ‘daylight hours’. Explantation, implantation and reperfusion of the liver will be carried out in using standardised techniques by the on-call transplant surgeon. The liver will remain on the machine until after the explantation has taken place at which point it will be flushed by 2 L of cold HTK immediately prior to implantation. A red-cell based perfusate is prepared using 4 units of donated packed red cells, 2 units of donated fresh frozen plasma, 200ml of 20% albumin and 1L of normal saline. The system is anticoagulated throughout using enoxaparin (100mg twice daily) and the perfusate is “cleaned” prior to connecting the liver by continuous circulation of perfusate through the dialysis filter and correction of electrolyte abnormalities. Supportive perfusion at physiological conditions is continued, and the grafts are continuously assessed. The organ will be perfused using extended organ perfusion system (EOPS). This system is automated and allow minimal intervention of perfusionist. EOPS autoregulate dyalisis, ventilation, nutrition, acid-base, and glucose. A trained perfusionist will supervises the EOPS> Controlled rewarming was performed with a 1° increase in temperature per hour for 4 degree celsius (from the initial 32° to 36 degree Celsius) to maintain perfusion in a temperature range conducive to red blood cell survival and minimise the effects of ischaemia reperfusion injury. Organ will be perfused The same partecipants can be enrolled into each stage , initial safety and transplant efficacy stage. As we have used adaptive designs, there are planned formal interim assessments for both (A) feasibility of NEOP and (B) successful transplantation of rescued livers. Recruitment will continue during interim assessment.. The collection and reporting of adverse events (AEs) will be in accordance with the therapeutic goods administration frame- work for clinical studies. The reporting period for AEs will commence at visit 1 and end at the 24-month follow-up. All AEs, device deficiencies and adverse device event (ADEs) will be reported using the applicable electronic case report form (eCRF). AEs will be reported in accordance with Clavien-Dindo classification of surgical complications. Two-stage design Using a Simon’s two-stage design : Interim assessment stage 1A of accrual: 24 marginal grafts will be perfused and assessed in the first stage. Grafts will be transplanted depending on the criteria achieved. The procedure will be considered infeasible if there are fewer than eight recovered livers meet criteria and are transplanted. If more than eight livers are transplanted, we will proceed to Stage 2. Final stage 2A of accrual: Up to additional 30 marginal grafts will be perfused. We would consider the procedure feasible if there are at least 27 transplanted livers out of 54 perfused livers. Interim assessment stage 1B: Following transplantation in three patients, the trial will stop early (concluding p=0.73) if there are fewer than two patients achieving 90-day survival. If two or more patients reach the primary end point of 90-day survival, an additional eight transplantations will be performed. Interim assessment stage 2B: Following transplantation in 11 patients (combined first and second stages) the trial will stop early (concluding p=0.73) if there are 7 or fewer successes. If 8 or more patients reach the primary end point, an additional 11 transplantations will be performed. Final stage 3B: Following transplantation in 22 patients in all three stages, the trial will be successful if at least 18 patients reach the primary end-point of 90-day survival.