Community Research and Development Information Service - CORDIS

H2020

ARISE Report Summary

Project ID: 643597
Funded under: H2020-EU.3.1.

Periodic Reporting for period 1 - ARISE (Aortic Valve Replacement using Individualised Regenerative Allografts: Bridging the Therapeutic Gap)

Reporting period: 2015-01-01 to 2016-06-30

Summary of the context and overall objectives of the project

Young patients with severe aortic valve disease today are facing a real dilemma. Once the indication for aortic valve replacement has been confirmed by their physician, they have to choose either a mechanical valve replacement option, which directly affects their quality of life as strict life-long blood anticoagulation is needed. These “blood thinners” have an inherent risk for severe bleeding episodes, which needs to be considered in both professional and leisure activities. Biological heart valve prostheses as another option unfortunately do degenerate much quicker in young patients.

The lack of a reasonable aortic valve prosthesis for young patients has driven research in tissue engineering concepts. The basis for current tissue-engineering concepts is either artificial polymeric or biological scaffolds, which may derive from human tissue donation or animals. Total artificial tissue-engineered heart valve concepts would solve many unmet clinical demands such as permanent availability of different sizes and lengths.

However, long-term animal models have not delivered satisfactory results so far due to the lack of mechanical stability of the total artificial matrices, leading to early failure of valvular function. Tissue-engineered biological scaffolds of porcine origin have failed dramatically in a number of paediatric patients, resulting in cautious scepticism regarding animal-derived matrices.
In contrast, decellularised matrices based on non-cryopreserved human valves, which form the basis for ARISE, have provided initial auspicious clinical results which warrant further prospective clinical research:

Tudorache I, Horke A, Cebotari S, Sarikouch S, Boethig D, Breymann T, Beerbaum P, Bertram H, Westhoff-Bleck M, Theodoridis K, Bobylev D, Cheptanaru E, Ciubotaru A, Haverich A. Decellularized aortic homografts for aortic valve and aorta ascendens replacement. Eur J Cardiothorac Surg. 2016 Jul;50(1):89-97. OPEN ACCESS

The project’s objective is therefore to determine the feasibility, safety and efficacy of decellularised regenerative heart valves for aortic valve replacement. The ARISE consortium comprises six leading European centres for cardiac surgery (Hannover Medical School, London - Royal Brompton and Harefield National Health Service Trust, Barcelona – August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and the Hospital Clinic of Barcelona, Leiden University Medical Centre, Padua University and the Azienda Ospedaliera di Padova Clinical Center, University Hospitals Leuven ) and the innovative small enterprise corlife oHG, that will process the donated valves. Project management for the study and support regarding ethical issues is organized by the Leibniz University Hannover. The ARISE clinical trial will include 120 patients.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Within the first reporting period a robust governance structure for the ARISE project was established including the implementation of an external Ethics and Governance Council (EGC) to provide independent supervision and advice for the whole project. The Leibniz University Hannover is liaising closely with the EGC to ensure external supervision and advice throughout the whole project and to generate new knowledge on ethics, legal and social issues in regenerative medicine. An Ethics and Governance Framework (EGF) has been established, giving advice and guidelines on how to deal with important ethical aspects of the project.

Corlife oHG submitted the application for the approval of the decellularized human aortic valve, Arise AV, to the Paul Ehrlich Institute (PEI) in Germany, the medical regulatory body and the German federal institute for vaccines and biomedicines, and received the approval on the 14th of July 2015. After the approval the ARISE study protocol has been handed in at the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP), a network coordinated by the European Medicines Agency (EMA), that aims to strengthen the monitoring of the benefit-risk balance of medicinal products in Europe. The study was accepted and received the ENCePP seal on the 29th of July 2015.

The ARISE (Aortic Valve Replacement using Individualised Regenerative Allografts) clinical study started on the 24th of September 2015 when the first patient was operated by a team of surgeons at Hannover Medical School.

So far 13 patients could successfully be treated with a decellularized aortic heart valve. 11 patients have been operated at Hannover Medical School (Germany) and 2 at the Hospital Clinic of Barcelona (Spain). To collect medical data for statistical analysis, the ARISE consortium has also implemented advanced database infrastructure to provide long-term data acquisition on the overall performance of the transplanted heart valves, the ARISE Registry.

All project partners have actively disseminated the idea and the results of the ARISE project within the general society and the scientific community. They distributed project leaflets to relevant organizations, took part in several important conferences, organized different information events and have published already 6 peer-reviewed articles. A promotional video has been created together with the ESPOIR project. The video shows an interview with a young woman having received a decellularized aortic heart valve about 2 years ago and simple information on the decellularization process and can be viewed via the projects website (www.arise-clinicaltrial.eu).

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

As aortic valve replacement is the most frequently performed valve operation, a reduced reoperation rate would have relevant impact on direct and indirect health costs. If the mean time to reoperation, which is currently 8-10 years for biological prostheses, could be expanded by the use of decellularised heart valves at least to 15(-20) years, the reoperation rate would be halved. As nearly every tenth heart valve operation is a ‘redo’ operation, this would lead to enormous direct cost reduction given the high numbers (65,000 per year) of heart valve operations in the EU. A lowered reoperation rate would also reduce the risk for heart failure as the myocardium is not exposed to pressure and/or volume overload by degeneration of biological valve prostheses and thereby limit health costs for the treatment of congestive heart failure. In conclusion, as the number of humans with congenital heart defects is growing and the population in the EU is ageing in general, thereby leading to higher health costs, a reduction of costs for heart valve replacement could compensate for this to some extent.

To date, regenerative medicine, which by nature involves human tissue or cells, is limited within Europe by a number of individual national legislations which complicates the development of an industry sector in European regenerative medicine. The ARISE project may serve as a flagship project for this industry sector, as these trans-national barriers are addressed during the study initiation phase. This will facilitate faster approvals for European clinical trials in this field in the future, thereby directly supporting the often small start-up companies which are today faced with time-consuming and cost-intensive applications to multiple national authorities. Reimbursement for regenerative therapies based on human tissue or cells is crucial for the survival of these enterprises and European-wide consensus is needed to allow for a reasonable and fair industrial profit. The fast approval of the ARISE valve and study by PEI an ENCePP already shows, the first impact ARISE and its predecessor study ESPOIR have had on relevant authorities.

Ethical issues, especially important in the evolving field of regenerative medicine, will be directly addressed within ARISE via the work of the Leibniz University Hannover and the Ethics and Governance Council. Clear and transparent information on these aspects will be made available via the project website to minimize patient concerns and to raise awareness among the general public throughout Europe regarding the importance of tissue donation, in line with the aims of the EU Tissue Directive (2004/23/EC).

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