Development of Haemodynamic Solutions in Renal Dialysis Venous Access Failure Mid-Term Review 3rd June 2015 Confidential

Welcome Introductions Programme Review

A joint industry-academia research programme to overcome the scientific and technical barriers to the understanding, development and adoption of technologies to combat the significant clinical problem of the failure of renal dialysis venous access.

Project Review A joint industry-academia research programme to overcome the scientific and technical barriers to the understanding, development and adoption of technologies to combat the significant clinical problem of the failure of renal dialysis venous access. The partnership is between the Universities of: Dundee, Limerick, Queen Elizabeth Hospital Birmingham and commercial partners: Vascular Flow Technologies Ltd Guerbet

Objectives of Mid-Term Co-Ordinators Report Scientific – Graeme Houston The scientific, technological or socio-economic reasons for carrying out the research the research objectives of the network; scientific highlights of the work so far Partner Benefits Transfer of Knowledge & Networking – Jerry Wyatt & Shona Matthew secondment implementation vs Gantt chart planning recruitment – new knowledge acquisition network wide events and events open to external participants benefits for each institution Management – Jerry Wyatt & Shona Matthew Financial aspects any proposed re-orientations of the networks’ activities dissemination IPR Impact – Graeme Houston Benefits Dissemination Lasting collaborations Complementary skills acquisition Career development

The Problem Haemodialysis The number of patients reaching end stage renal failure and requiring renal replacement therapy continues to increase at a rate of around 5% per year across Europe Haemodialysis (HD) therefore remains a common treatment modality with over a quarter of a million patients on haemodialysis in Europe (ERA-EDTA Registry 2009) This number which is double the number of patients on dialysis 15 years ago and is projected to continue to increase at 4-6% per year

The Problem Renal dialysis venous access (ReDVA) methods are: arteriovenous fistula (AVF) formation, arteriovenous graft (AVG) implantation or central venous catheter (CVC) insertion

The Problem Renal dialysis venous access (ReDVA) problems: AVF maturation variable The AVF failure rate from multiple studies and at multiple sites at one year is around 50%, AVG failure rates between 60-80% at one year. Close surveillance of the AVF or AVG to avoid occlusion results in around 50% needing a procedure in the first year CVC catheters associated with: High mortality High infection rates Hospital attendances

ReDVA Failure ReDVA long-term effectiveness limited by the formation of vessel narrowing (stenosis) due to venous intimal hyperplasia (VIH) Causes VIH: Turbulence Anatomical Geometry Tissue Compliance mismatch Tissue mediators VIH

ReDVA Failure ReDVA long-term effectiveness limited by the formation of vessel narrowing (stenosis) due to venous intimal hyperplasia (VIH) Causes VIH: Turbulence Anatomical Geometry Tissue Compliance mismatch Tissue mediators VIH Haemodynamics in ReDVA important but poorly understood.

Key Research Objectives The development of new methods of assessment of ReDVA using imaging techniques - CT/MRI/Ultrasound Flow rig simulations of ReDVA models Computational fluid dynamics (CFD) of patient’s 3D geometries and observes flow patterns to predict wall stress patterns implicated with vascular occlusion. Development and assessment of new vascular devices for ReDVA.

The Project Work Packages Lead Partner 1 Research Supervision and Management UNIVDUN 2 Data Mining and Prospective Data Sharing QEHB 3 New Methods of Assessment Using Imaging Techniques GU 4 Flow Rig Simulations of ReDVA Models UNIVDUN 5 Computational Fluid Dynamics Analysis UL 6 Serum Biomarkers of ReDVA Failure UNIVDUN 7 Mapping of Strategies of New Vascular Devices VFT

The Partners’ Expertise University of Dundee (UNIVDUN): Cardiovascular interventions imaging, vascular biology and cardiovascular hemodynamic in a wide range of vascular conditions. UNIVDUN will co-ordinate the programme and contribute clinical imaging, flow rig analysis, ultrasound analysis. University of Limerick (UNIVLIM): Cardiovascular fluid dynamics. UNIVLIM will co-ordinate the Computational Fluid Dynamics modelling and cellular/vascular models. Queen Elizabeth Hospital Birmingham (QEHB): The largest UK renal replacement therapy unit with expertise in renal access imaging, salvage and the underlying mechanisms of venous intimal hyperplasia. Vascular Flow Technologies Ltd (VFT): Global vascular graft products and cardiovascular fluid dynamics research. VFT will contribute commercial experience in the field of cardiovascular devices. Guerbet (GU): Established expertise in contrast media, both for MRI and for CT. GU will bring competences about the safety and efficacy of its products to optimize the protocol of the study and help in the interpretation of the data.

Scientific Highlights The development of new methods of assessment of ReDVA using imaging techniques. Development protocols for Ultrasound and MRI imaging protocols MRI assessment of peripheral veins , central veins prior to, immediately after ReDVA surgery or implantation and at follow-up

Scientific Highlights Flow rig simulations of ReDVA models. Computational fluid dynamics (CFD) .

Scientific Highlights Development and assessment of new vascular devices. Mapping of combination strategies of surgical technique, vascular devices and medical therapy to optimize vascular access long term patency for clinical trial evaluations. Clinical literature reviews Cochrane Reviews Approval ERBP and ERA collaboration for new guideline development Spiral central venous catheters Spiral stents

UNIVDUN MT Review Meeting 3rd June 2015

GU MT Review Meeting 3rd June 2015

UL MT Review Meeting 3rd June 2015

QEHB MT Review Meeting 3rd June 2015

VFT MT Review Meeting 3rd June 2015

Financial MT Review Meeting 3rd June 2015 ReDVA Budget Fellow Months   Fellow Months Budget € Initial Secondment Initial recruitment Current secondment Current recruitment Original Current QEHB 32 24 11 12 510407 220591 VFT 6 18 270628 207300 GU 16 149605 155198 UL 50 30 537846 771231 UD 36 48 39 60 1166741 1249517 Total 122 114 120 2635227 2603837 Difference 31391 MT Review Meeting 3rd June 2015

Benefits to each Institution Limerick Clinical Imaging Expertise Ultrasound, MRI Application of CFD in Commercial Development MRI Contrast Agent Protocol design Pulse sequences 3D data Different Fistula Models Regulatory Processes Guerbet Clinical imaging expertise - vascular access: Ultrasound, MRI Optimising imaging contrast products Current Trends -Vascular Access Surgery. Impact of Failure Flow Phantom Research Interventional Devices Data Mining QEHB Clinical Imaging and Surveillance of Vascular Access US & MRI MRI Contrast Media Research & Use Data Mining Development – Regulatory Processes Medical Interventional Device Research MT Review Meeting 3rd June 15

Benefits to each Institution VFT Clinical Imaging Expertise MRI & US Current Trends in Vascular Access Surgery Impact of VA Failure Flow Phantom Research CFD Research Vascular Haemodynamics – Improving Patient Outcome Medical Interventional Device Research Dundee Medical Device Research & Development CFD in the application of medical device development Commercial Approach Vascular Access Surgery MRI Contrast Agent Data Mining MT Review Meeting 3rd June 15

MT Review Meeting 3rd June 15 Milestones Milestone Name/Comment Month M1.1 Project website – Completed M3 M2.1 Clinical data mining & analysis - Completed M12 M5.1 Imaging data collection – Continuing M18 – M36 M3.1 Validation of US/MRI techniques M24 M1.2 Fellow career development plans – Completed for all current ER’s and ESR’s M30 MT Review Meeting 3rd June 15

MT Review Meeting 3rd June 15 Deliverables Del No Centre Description of work Completed by Deadline D6.1 UD Serum Analysis UNIVDUN M12: Completed D2.1 QEHB Data collection & archiving imaging VFT/UNIVDUN/UNIVLIM M18:Completed D3.1 GU Standardisation of US/MRI techniques across ReDVA centres. GU/VFT/UNIVDUN/QEHB/UNIVLIM M18: Completed D4.1 UD/UL Identification of different fistula models. UNIVLIM/VFT D5.1 UL Acquisition of patient 3D MRI data UNIVDUN/VFT M18: Continuing towards M36 D3.2 Validation of imaging techniques across ReDVA centres (MRI,US) GU/UNIVDUN/VFT/QEHB M24: On target D5.2 Construction of CFD meshes VFT/UNIVLIM/UNIVDUN MT Review Meeting 3rd June 15

Knowledge Transfer/Training Opportunities Available to UL-VFT & UD-VFT Secondees, UD Recruit Interventional Radiology Course Session with Vascular Surgeon Designing an MRI Protocol MR Imaging Techniques – Pulse Sequences Supercomputing Overview Flow Rig Simulations Ultrasound Techniques including Elastography Developing a Pre-Clinical Model CAD Stent Design All secondees are actively encourage to attend course/conferences/meetings MT Review Meeting 3rd June 15

Knowledge Transfer/Training Opportunities Open to QEHB-GU & UD-GU Secondees Cochrane training modules on systematic reviews and meta-analysis of diagnostic test accuracy studies (University of Amsterdam and University of Birmingham). Cochrane author training module for diagnostic test accuracy systematic reviews (university of Birmingham) Seminar and meeting with European Renal Association regarding guidelines group and data extraction from scientific literature. Guerbet introductory program.  Medical and regulatory affairs training Theory of MRI and contrast agents. MT Review Meeting 3rd June 15

Presentations Presentations 27 Presentations British Society of Interventional Radiology Vascular Access Society of Great Britain and Ireland Annual Conference of the Bioengineering Section of the Royal Academy of Medicine in Ireland World Congress of Nephrology American Society of Nephrology Vascular Access Society Conference Sessions VAS Round table session – Outreach-ReDVA Project VASA Plenary Session

Publications Less than two years into the project we have a number of publications submitted to journals Publications Accepted: 2 Journal of Vascular Access & EJVES Accepted pending minor revisions: 1 Journal of Vascular Access Under peer review: 11 Various Journals

Workshops & Teleconferences Paris April 2014 Novel and established methods of imaging vascular access (RR and SG) Impact of VA failure on the patient and the NHS (SB) The Scottish Renal registry (SB) Factors affecting clinical decision making in VA (PS) Paris July 2014 Handling large data and systematic reviews and EROS(Dr Evi Nagler, ERBP) Birmingham October 2015 Under discussion - Focus on flow rig simulations and CFD? Teleconferences Regular teleconferences are held between ReDVA partners. Nationwide data collaboration

Dissemination Public & Academic Focus on transfer of knowledge and training for fellows Many successes linked to our work – publications & presentations The ReDVA website provides free availability of our results – abstracts, publications. Collaborations emerging from ReDVA that may seed future funding applications Commitment to outreach: Peers, Public and Patients……

Commitment to Outreach Continuing commitment to outreach: Each centre to participate in two events Month Activity 12 Dundee Science Festival 18 Round Table Session (VAS) 20 Arts & Science Festival Birmingham 24 University of Dundee Open Day (CRC) The ReDVA Website www.redva.eu ReDVA Newsletters MT Review Meeting 3rd June 15

Impact

Impact Key Impacts: ReDVA 2015-2017 New Secondee/ Recruitment Guideline Development Clinical Trial Product Development – Pre-clinical assessment Imaging Protocol Adoption Dissemination

Impact Dissemination Scientific Publications: Abstracts: US, EU, UK Accepted manuscripts: J Vasc Access Surg, J Biomech Eng Submitted Manuscripts: J Vasc Access Accepted Cochrane Review Public/Professional Engagement: Renal Patient Forum UK Renal Registry/ Kidney Research UK/NIHR Guideline Development: ERA and European Best Practice

External Collaborations Academic: Partners: Dundee, Limerick, Birmingham External: UK - Edinburgh, Belfast, Glasgow, Cardiff, London EU – Amsterdam, Leipzig, Linz US – Washington, Cinncinati Clinical: European Renal association/ ERBP Guideline Development US Kidney Foundation/ Kidney Research UK Commercial: Partners: VFT, Guerbet UK – Toshiba, Siemens EU – H2020 submissions

Lasting Collaborations Partner Benefits –Knowledge Exchange/Projects: Collaborative Research – Academic/Commercial Literature Review Staff Development Commercial Focus Product Development Market Research Wider Benefits: Scientific Meeting Presentation Training Opportunities Outreach – Public engagement

Skills Acquisition Partners Knowledge Transfer Academic/Industrial partnerships Clinical Data Handling Basic Science Techniques Commercial Focus Product Development Product Safety Assessment

Skills Acquisition Secondees and Recruits Clinical Research: Clinical Trials Registry Data Clinical data Mining Health Informatics Guideline Development Literature Review

Skills Acquisition Secondees and Recruits Basic Research: Flow Rig Computational Fluid Dynamics Computer aided Design Prototype testing Regulatory Processes Imaging Research: Image Analysis Imaging Contrast Media Patient Risks

Career Development Secondees PhD Completion Clinical Researchers Post Doctorate Training Academic/Commercial Opportunities: Project management Accountability Differences Academic/Commercial goals Training Courses

Questions Thank you for your attention. Any questions?