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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - ALIVER (Development of DIALIVE, a novel Liver Dialysis Device for the treatment of patients with Acute on Chronic Liver Failure (ACLF))

Teaser

Summary

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 availability of organs. A clinically efficacious â€˜liver dialysis deviceâ€™ is an uet clinical need. The ALIVER Consortium has developed and optimised a novel â€˜liver dialysis deviceâ€™ DIALIVE. The DIALIVE device is protected by world-wide patents and is based upon our discovery that (i) albumin, a circulating protein involved in detoxification is reduced irreversibly in function and (ii) endotoxemia contributes to increased risk of infection in liver failure. DIALIVE incorporates albumin removal and albumin replacement and, endotoxin removal and is a TRL5. In animal models of liver failure, DIALIVE was shown to be easy to use and safe. DIALIVE reduced endotoxaemia and, improved albumin and immune function and, prolonged survival. The ALIVER Consortium, which comprised of experts in liver failure, SMEâ€™s and charities proposes to perform clinical trials of DIALIVE in patients with acute on chronic liver failure (ACLF). During the grant period a CE-mark will be obtained and the device will progress to a TRL7/8. Consultation with Regulatory bodies confirms that if the trials are successful, a CE-mark is highly likely, Grifols, (a large plasma proteins company) is a potential licensee of the technology if the studies proposed by ALIVER Consortium are positive.

The objectives of DIALIVE are to:
1. To develop and manufacture YAQ-002 to the quality required by the Medical Devices Directive.
2. Achieve regulatory and ethical approval and perform two studies to define its safety and efficacy in ACLF patients, in 18 European hospitals.
3. Define healthcare benefits and a reimbursement strategy.
4. Disseminate and exploit the results to benefit patients, the EU healthcare system, create new jobs and grow the healthcare industry in Europe.

Work performed

The focus of WP 1 is 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 has been established that assures the product meets the essential requirements as defined by the Medical Device Directive (93/42/EECO). The development of a technical file and the approved clinical trials protocol will assist with the new CE mark application as described in WP4.

The focus of Work package 2 is concerned with the production, assembly transport, training and technical aspects of DIALIVE. It involves packaging and labelling the three components, that make up the DIALIVE circuit into one clinical investigator box. Each component is CE marked and is commercially available; the oXiris filter, (a membrane that adsorbs endotoxin from the blood), the septeX filter (removes abnormal albumin) and the connection tubing. WP2 is concerned with the development of the Standard Operating Procedures (SOPâ€™s) and the planning and execution of all training on all clinical sites.
The Hepalbin filter from Albutec, has been incorporated into the DIALIVE protocol to filter the albumin prior to administration, at the end of the treatment session. Commercially available albumin undergoes various steps of virus inactivation and storage with manufacturers adding stabilizing molecules to their pharmaceutical preparations to increase the shelf life of their product. These stabilizers could potentially reduce the binding capacity for toxins which may lead to endotoxaemia and neutrophil dysfunction, further contributing to morbidity and mortality associated with severe liver disease. By incorporating the hepalbin filter into the DIALIVE protocol and removing any impurities before being infused, allegedly we are potentially optimizing the binding capacity of the replacement albumin.

EF-Cliff are overall responsible for implementing Work Package 3, but have worked in close collaboration with FAKKEL. EF-CLIF have focused on the creation of the required structural support of the trial; whereas FAKKEL are responsible for implementing, managing and coordinating the development of the Clinical Trials, including those activities conducted directly by themselves and performed by other CRO-subcontractors.
The goals of WP 3 are:
1. To ensure an appropriate clinical trial support and management system is developed and available to support execution of the clinical trials.
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 has been much slower than originally anticipated, which has prompted the move to open more clinical sites in the hope of escalating the number of potential patients and aid recruitment. New study centres have been approached and will hopefully be participating in the trial from Q3, 2018.

Work package 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 all patients are managed in accordance with Good Clinical Practice (ISO 14155), and that all clinical data is collected and handled correctly to achieve the primary and secondary endpoints. Although the trial was initially planned to be conducted in 8 widely distributed European referral hospitals for liver diseases, for different reasons only 5 hospitals have been activated to date. Due to slow recruitment rates, new centres fulfilling the established requirements have now been identified to join the study, and will hopefully be open to recruitme

Final results

The programme has established a robust QC system in line with ISO 13485. In animal models with acute liver failure DIALIVE established a favourable efficacy profile. If we continue in this manner then DIALIVE may impact morbidity and even mortality in patients with alcoholic cirrhosis. The socio-economic impact will be significant if efficacy is proven in the next stage of the trial.