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Development of DIALIVE, a novel Liver Dialysis Device for the treatment of patients with Acute on Chronic Liver Failure (ACLF)

Periodic Reporting for period 2 - ALIVER (Development of DIALIVE, a novel Liver Dialysis Device for the treatment of patients with Acute on Chronic Liver Failure (ACLF))

Reporting period: 2018-07-01 to 2019-12-31

Liver disease incidence is increasing with about 170K patients dying from liver failure each year in Europe. In liver failure, the accumulation of protein bound toxins and increased susceptibility to infection cause multi-organ failure and death. Liver transplantation is the only treatment known to prolong life but is limited by the availability of organs. A efficacious ‘liver dialysis device” is an unmet clinical need. The ALIVER Consortium has developed and optimised a novel ‘liver dialysis device” DIALIVE. The patented DIALIVE device is based upon our discovery that (i) albumin, a circulating protein involved in detoxification, is damaged irreversibly and (ii) endotoxemia contributes to increased risk of infection in liver failure. DIALIVE removes and replaces albumin and removes endotoxin. In animal models of liver failure was shown to be safe, reducing endotoxemia and albumin and immune function and prolonging survival. The ALIVER Consortium, which comprises experts in liver failure, SMEs and charities, has used the ALIVER funding to complete the first randomised controlled human clinical trial in patients with acute on chronic liver failure (ACLF). The final formal report is due in summer 2020, but an informal assessment of data so far indicates that DIALIVE has met the primary endpoints and many secondary endpoints for this trial. This means that DIALIVE has moved from TLR5 to TLR7/8 during the course of the ALIVER program. In addition, the potential health benefits of DIALIVE have been characterised, laying the groundwork for a robust manufacturing, distribution and reimbursement strategy. At the time of grant submission, it was considered that during the grant period a CE-mark would be obtainable. Since then, the rules on CE Marking have changed, leading to delays in the CE Marking process for all medical device companies, and it is now likely that a CE Mark will be secured after the end of the grant period. It is worth noting that during the grant period the only other innovative “liver dialysis system” in development (the US system called ELAD) was unsuccessful in clinical trials. This means that Dialive has established a substantial technical lead in liver dialysis. Additionally, the ALIVER Consortium have identified that DIALIVE targets ‘cytokine storm’ and are hoping to repurpose the device for the treatment of the sickest patients with COVID-19 infection at high risk of mortality.
WP 1 aims to deliver on the regulatory and ethical aspects of the program and to deliver the documentation required for the conduct of this clinical trial. An ISO-13485 compliant Quality Management System was established to assure the product meets the essential requirements defined by the Medical Device Directive (93/42/EECO).

The focus of WP2 is the production, assembly, transport, training aspects of DIALIVE. It involves packaging and labelling the components that make up DIALIVE into one clinical investigator box. Each component is CE-marked and is commercially available; the oXiris filter, (which removes endotoxin), the septeX filter (which removes albumin) and the connection tubing. WP2 requires the development of a full set of the Standard Operating Procedures (SOPs) and the planning and execution of all training on all clinical sites in conformance with international regulations.
The Hepalbin filter from Albutec (and ALIVER consortium member), has been added to DIALIVE. The manufacturers of commercially available albumin undergoes virus inactivation and the addition of stabilizing molecules to increase the shelf life. These stabilizers may limit the albumin’s binding capacity for that toxins that contribute to morbidity and mortality in severe liver disease. By incorporating the Hepalbin filter into the DIALIVE protocol we address these concerns.

EF-Clif has responsibility for implementing WP3 working with FAKKEL. EF-CLIF has focused on structural support of the trial, whereas FAKKEL implemented, managed and coordinated the execution of the trials, including work performed by CRO-subcontractors.
The goals of WP3 are:
1. To ensure an appropriate clinical trial support through the creation of a management system.
2. Conduct the trials in compliance with the currently approved protocol/amendments, following ISO 14155 GCP guidance and with the applicable regulatory requirements, and develop a plan for the regulatory procedures.
3. Ensure that the trials are adequately monitored for each-site before, during and after the trials.

Both site activation and patient recruitment were slower than anticipated, which prompted opening of more clinical sites.

WP 4 focuses on the conduct of the trial in adherence with the approved study protocol to determine the safety and tolerability of DIALIVE in patients with ACLF (DIALIVE safety) according to the Standard Operating Procedures used by Yaqrit and FAKKEL. It ensures that patients are managed in accordance with Good Clinical Practice (ISO 14155) and that clinical data is collected and handled correctly to achieve the primary and secondary endpoints. Although the trial was planned to be conducted in 8 widely distributed European referral hospitals for liver diseases, for different reasons only 5 hospitals were activated initially. New centres fulfilling the established requirements were identified, and invited to join the study. Ultimately 11 sites were opened.
WP 6 focuses on biobanking and analyses of clinical samples from DIALIVE – SAFETY (WP4); and DIALIVE – EFFICACY (WP5) study.
WP 8 focuses on the dissemination, exploitation and communication activities. During the first period of the programme a project website was established and the first dissemination and exploitation plan developed. A patient awareness video has been approved. The IP portfolio management policy has been established along with the publication and authorship, and the DIALIVE has granted patents (or notification of grant) in major territories.
With the ALIVER clinical trial, the DIALIVE system is now the world leader in innovative liver dialysis systems. Its main potential competitor, a US system called ELAD, was withdrawn from development because it failed to demonstrate a survival benefit in liver disease patients. DIALIVE is now well placed to reduce morbidity and even mortality in patients with alcoholic cirrhosis. The opportunity for a substantial socio-economic benefit for this patient group and society as a whole is closer than it has ever been. In addition, and as stated above, the effect DIALIVE has on the cytokine storm allows the device to be repurposed for the treatment of patients with severe COVID-19 infection.