Evaluation of DIALIVE, a novel Liver Dialysis Device for the treatment of patients with Acute on Chronic Liver Failure Grade 3

Research Question Whether treatment of patients with DIALIVE in addition to standard-of-care will result in significantly greater resolution of acute on chronic liver failure (ACLF) compared with patients receiving standard-of-care alone. Background ACLF occurs in cirrhosis patients hospitalised with a liver-related complication.

It is characterised by multiorgan failure and 28-day mortality of 25-80%. ACLF affects 15-20,000 people/year in UK. Specific treatment for this syndrome is a significant unmet need.

The only treatment that improves survival is liver transplantation, which is limited by organ availability and patient eligibility.

To meet this critical medical challenge, the ALIVER-2.0 consortium has developed an innovative liver dialysis device - DIALIVE - which specifically targets the underlying mechanisms of ACLF.

DIALIVE is based on our discovery that: (i) albumin, a circulating protein involved in detoxification, has irreversibly reduced function in ACLF and (ii) a build-up of endotoxins in the blood increases risk of infection in liver failure.

In a first-in-man, randomised-controlled trial of DIALIVE vs. standard-of-care (SOC) alone, we demonstrated that DIALIVE is safe for patients, it significantly reduced time to resolution of ACLF and led to significant improvements in the main underlying pathophysiological mechanisms of ACLF.

We now need to confirm in adequately powered studies whether DIALIVE resolves ACLF in a significantly greater proportion of patients when applied to the sickest patient cohort, those with ACLF-grade 3, in whom 28-day mortality exceeds 80%. It is in this group of patients, with an extremely poor prognosis, that our study will focus.

Aims and Objectives Aim: To perform a clinical trial to assess the benefit of DIALIVE for patients at highest risk of ACLF-related death (ACLF-3) and facilitate a clear route towards its adoption and commercialisation.

Primary trial objective: To determine whether treatment with DIALIVE (in addition to SOC) will resolve ACLF in a significantly greater proportion of patients with ACLF-3, compared with SOC alone. Secondary trial objective: To further assess device safety, performance, efficacy and economic viability.

Methods We will conduct a randomised (1:1), controlled, multi-centre clinical trial to compare outcomes for patients treated with DIALIVE and SOC, and those receiving SOC alone (n=64 total).

Co-primary outcomes are (i) To demonstrate that DIALIVE treatment resolves ACLF in a larger proportion of patients compared with SOC alone at Day-10 (ii) To demonstrate that resolution of ACLF within 10 days is prognostic for 28-day transplant-free survival. For success, both end points must be met.

We will also determine the safety profile and performance of DIALIVE, quantify pathophysiologically relevant biomarkers and conduct a health-economic analysis. Timelines for delivery Project deliverables: 3-years; additional 2-years for DIALIVE to be available in the NHS.

Anticipated Impact and Dissemination We will submit the clinical evaluation report from this study to the UK MHRA for a UKCA mark and European notified bodies for a CE-mark. The public engagement plan will involve lay summaries, a public-facing symposium and media dissemination.

Results of our study will also be disseminated to academic and professional audiences through publications in leading scientific journals and presentations at international conferences.