CLOTBUST-L: An open-label, multicentre, randomised controlled trial to evaluate the efficacy of ex situ fibrinolysis during normothermic perfusion in liver transplantation from donation after circulatory death donors

Research question: Is fibrinolysis using tissue plasminogen activator (TPA) with fresh frozen plasma (plasma) infused during normothermic machine perfusion (NMP) of Donation after Circulatory Death (DCD) donor livers superior to the current standard of care in reducing the incidence of ischaemic cholangiopathy following transplantation?

Background: Liver transplantation is life-saving treatment for patients with end-stage liver disease but the disparity between the waiting list and the availability of donor organs means that one in nine patients die while waiting for a transplant. Meanwhile, many donor livers go unused each year due to concerns about their safety and post-transplant function.

This problem is particularly pronounced with DCD donor livers which comprised 46% of UK deceased donors in 2022-23; only 38% of DCD donor livers were transplanted, compared to 78% of livers from donation after brain death (DBD) donors. This is because DCD livers have poorer outcomes than DBD livers, in large part because of their susceptibility to ischaemic cholangiopathy.

Our pilot studies suggest a microvascular pathogenesis of the biliary strictures in ischaemic cholangiopathy, mediated by fibrin plugging of peribiliary vessels. Proof-of-concept studies showed delivery of TPA and plasma (as a source of plasminogen) during ex situ NMP could clear fibrin from peribiliary vessels with a significant reduction in the incidence of symptomatic cholangiopathy after DCD liver transplantation.

Aims and objectives: The aim of this study is to assess the efficacy of delivering TPA plus plasma during NMP in reducing ischaemic cholangiopathy after DCD liver transplantation. The effect of this intervention on donor liver utilisation rates and on clinical outcomes will also be assessed.

Methods: Livers from DCD donors that are accepted for transplantation by participating centres will be randomised to either TPA+plasma during NMP or to standard of care. The latter will consist of simple cold storage or NMP alone, according to current practice at the accepting centre. The primary endpoint will be the incidence of symptomatic cholangiopathy at six months post-transplant.

Secondary endpoints will include liver utilisation rates, early allograft dysfunction, graft and patient survival, complication rates and safety of the intervention.

Timelines for delivery: The proposed study duration is 54 months: 6 months for set-up, 36 months for recruitment, 6 months for follow up and 6 months for reporting and dissemination.

Anticipated impact and dissemination: This study will provide the evidence needed to determine whether TPA+plasma during NMP is effective at reducing the incidence of ischaemic cholangiopathy after DCD liver transplantation to the rates seen with DBD livers. Should this be proven to be the case, this study has the potential to transform liver transplantation by improving patient experience and clinical outcomes and by increasing confidence in the use of DCD donor livers.

Outcomes from the study will be disseminated via patient newsletters, patient groups and through social media in addition to scientific communication at conferences and in medical literature. These will also be provided to key NHS bodies and decision makers, including NICE, NHS Blood and Transplant and NHS England.