COPE information session

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1 COPE information session ESOT Congress - 15 September 2015 This project has received funding from the European Union s Seventh Framework Programme for research, technological development and demonstration under grant agreement no Nuffield Department of Surgical Sciences University of Oxford Agenda 1. Welcome and Introduction 2. COPE clinical trials - Normothermic liver perfusion vs static cold storage - Oxygenated hypothermic kidney reconditioning vs static cold storage - Non-oxygenated hypothermic vs oxygenated hypothermic kidney perfusion 3. Trial set-up and trial logistics 4. COPE biobank: sample collection and scientific remit 5. COPE experimental work programmes 6. Conclusions & questions This project has received funding from the European Union s Seventh Framework Programme for research, technological development and demonstration under grant agreement no Nuffield Department of Surgical Sciences University of Oxford 1

Introduction Introduction COPE Consortium for Organ Preservation in Europe Organ Ox metra device Kidney

Transplantation 6 countries (FR, DE, ES, UK, NL, BE) 3 multi-centre international clinical trials 2

Union s 7 th Framework Programme for Research Duration of 4.

University Clinic Essen University Medical Centre Groningen University of Leuven Universite Pierre et Marie

2 Introduction Introduction COPE Consortium for Organ Preservation in Europe Organ Ox metra device Kidney Assist Organ Assist 14 Partners: 8 Educational Institutions 5 SME s European Society of Organ Transplantation 6 countries (FR, DE, ES, UK, NL, BE) 3 multi-centre international clinical trials 2 multi-centre experimental programmes 1 consolidated biobank Dissemination programme Funded by the European Union s 7 th Framework Programme for Research Duration of 4.5 years from January 2013 until June 2017 University of Oxford FCRB Barcelona University Clinic Bonn University Clinic Essen University Medical Centre Groningen University of Leuven Universite Pierre et Marie Curie Paris, Paris VI INSERM, Universite de Poitiers ESOT: European Society for Organ Transplantation AQIX Ltd. Hemarina S.A. Med-Assist B.V. Organ Assist Products B.V. OrganOx Ltd. 2

3 Introduction Introduction 3

4 Agenda 1. Welcome and Introduction 2. COPE clinical trials - Normothermic liver perfusion vs static cold storage - Oxygenated hypothermic kidney reconditioning vs static cold storage - Non-oxygenated hypothermic vs oxygenated hypothermic kidney perfusion 3. Trial set-up and trial logistics 4. COPE biobank: sample collection and scientific remit 5. COPE experimental work programmes 6. Conclusions & questions This project has received funding from the European Union s Seventh Framework Programme for research, technological development and demonstration under grant agreement no Nuffield Department of Surgical Sciences University of Oxford Background Shortage of livers for transplantation: 2011/ Tx; 1186 registered Recent increase in organ donors Mainly DCD or ECD risk of EAD, PNF, IC 2012/13 132/507 Tx using DCD liver Need a means of increasing pool of donors considered suitable for liver transplantation 4

5 COPE Clinical Trials Normothermic Liver Perfusion Blood-based perfusate Fully-cannulated circuit Physiological pressures, flows Physiological temperature Blood gas regulation Nutrition & key additives infused 5

6 COPE Clinical Trials OrganOx metra Phase-1 clinical trial (KCH, Birmingham) 20 patients transplanted with normothermically-perfused livers Good postoperative recoveries, all patients discharged 6

COPE Clinical Trials The Trial Work Package 2 of COPE Sponsorship: University of Oxford Phase-3 randomised, controlled, openlabel 260 patients 1:1 randomization to SCS and NMP 7 European liver

7 COPE Clinical Trials The Trial Work Package 2 of COPE Sponsorship: University of Oxford Phase-3 randomised, controlled, openlabel 260 patients 1:1 randomization to SCS and NMP 7 European liver transplant centers UK: - QEH, Birmingham - Addenbrooke s, Cam - KCH, London - Royal Free, London Belgium: Leuven Germany: Essen Spain: Barcelona Recruitment and Eligibility Need 24hrs to consider Sent info by post Initial OP discussion Liver eligibility Donor >16yrs Not living/split/far Recipient eligibility >18yrs Able to consent Not acute liver failure/multiple organs 7

COPE Clinical Trials Outcomes Primary end-point Peak transaminase by postoperative day 7 Secondary end-points Early allograft damage (EAD) Bilirubin >170; INR>1.

8 COPE Clinical Trials Outcomes Primary end-point Peak transaminase by postoperative day 7 Secondary end-points Early allograft damage (EAD) Bilirubin >170; INR>1.6; AST peak >2000 by day 7 Reperfusion syndrome (30% drop in BP) ICU & hospital stay Need for renal replacement therapy Graft, patient survival (6 months) Graft function (6 months) MRCP at 6 months Health economic analysis (incl QOL) Organ utilisation/discard Trial Activity at Each Site Randomised Transplanted 8

9 COPE Clinical Trials Challenges the Device Primed 9

10 Liver Backtable & Cannulation PV Twist 10

11 COPE Clinical Trials Liver Backtable HA 11

12 COPE Clinical Trials Liver Backtable The OrganOx metra - start of perfusion Start After 10 secs After 60 secs 12

13 COPE Clinical Trials Monitoring Transport and Storage Back of ambulance Mains power Transplant operation Following explant, liver is flushed and transplanted 13

14 COPE Clinical Trials Jun-14 Jul-14 Aug-14 Sep-14 Oct-14 Nov-14 Dec-14 Jan-15 Feb-15 Mar-15 Apr-15 May-15 Jun-15 Jul-15 Aug-15 Sep-15 Oct-15 Nov-15 Dec-15 Jan-16 Feb-16 Mar-16 Apr-16 May-16 Jun-16 Challenges Theatre Logistics 53 transplanted NMP livers >50% 12+hr pres time >20% 16+hr pres time Surgeons planning theatre logistics around NMP Challenges Non-transplants Required Total randomised Total transplanted Number needed Linear (Total transplanted) 14

15 COPE Clinical Trials Interesting case 1 steatosis Interesting case 2 elderly DCD 15

16 COPE Clinical Trials Interesting cases 3 Simultaneous NMP Interesting cases 3 Simultaneous NMP 70yr DBD severe steatosis 28yr IVDU DCD hypoxic liver injury 16

17 Agenda 1. Welcome and Introduction 2. COPE clinical trials - Normothermic liver perfusion vs static cold storage - Oxygenated hypothermic kidney reconditioning vs static cold storage - Non-oxygenated hypothermic vs oxygenated hypothermic kidney perfusion 3. Trial set-up and trial logistics 4. COPE biobank: sample collection and scientific remit 5. COPE experimental work programmes 6. Conclusions & questions This project has received funding from the European Union s Seventh Framework Programme for research, technological development and demonstration under grant agreement no Nuffield Department of Surgical Sciences University of Oxford Overview Randomised controlled trial Clinical Lead by Prof. Andreas Paul, University Hospital Essen (D) Sponsored by the University of Oxford (UK) Participating sites: Essen (D) Leuven (BE) Groningen & Maastricht (NL) Oxford (UK) Kidney Assist machines used for hypothermic perfusion provided by COPE partner Organ Assist Products B.V. Target of 262 transplanted kidneys across all sites 17

COPE Clinical Trials COPE-POMP: Background and Rationale Organ shortage -> acceptance of older & marginal donor grafts DGF: Decreased long term graft survival Earlier

18 COPE Clinical Trials COPE-POMP: Background and Rationale Organ shortage -> acceptance of older & marginal donor grafts DGF: Decreased long term graft survival Earlier graft loss Increases risk of acute rejection and allograft dysfuncion Ischemia injury during organ preservation -> modifiable risk factor COPE-POMP: Background and Rationale 18

19 COPE Clinical Trials COPE-POMP: Background and Rationale Treckmann et al., Transplant Int, 2011 COPE-POMP: Background and Rationale Hypothermic reconditioning (4h) of porcine kidney grafts by short-term preimplantation machine perfusion Gallinat et al., Transplantation,

20 COPE Clinical Trials COPE-POMP: Objectives SCS vs. SCS + short-term HMRP+O 2 in ECD (DBD) kidneys Objectives: I EP - 1-year graft survival II EP - egfr, incidence and duration of DGF, SGF, PNF incidence of acute rejection episodes, quality of life measures, III EP - health economic implications / resource use Multi-centre, participant-blinded, randomized, controlled, parallel group, prospective superiority study 12 months follow-up COPE-POMP: Inclusion / Exclusion Criteria Inclusion criteria donor kidney: Exclusion criteria donor kidney: Inclusion criteria trial participant: Exclusion criteria trial participant: DBDs, UNOS ECD*-criteria Kidneys used for multi-organ Tx Kidneys procured from DCD donors Double kidney Tx within the same recipient Donor 85yrs 18yrs listed for renal Tx (ET or NHSBT waiting list) provided written informed consent Participation in another perfusion trial Scheduled to undergo multi-organ Tx Planned dual-kidney Tx *Expanded Criteria Donor (ECD): - Donor age 60 years - Donor age between 50 and 59 years + 2 of 3 criteria: 1) Hypertension 2) S-Creatinine > 1.5 mg/dl 3) Cause of death: Cerebrovascular accident 20

at 25mmHg Flow limit 500ml/ml 4 C Renal resistance & flow measures

21 COPE Clinical Trials Kidney Assist Composition and Setting Belzer s machine perfusion solution & O 2 Pulsatile flow (60bpm) Pressure set at 25mmHg Flow limit 500ml/ml 4 C Renal resistance & flow measures Machine Perfusion Organ Assist COPE-POMP: Protocol Outline / Logistics 21

COPE Clinical Trials COPE-POMP: Patient Follow up Days 1-7 and 14 Month 3 and 6 Month 12

survival survival - EuroQol (month 3) Primary outcome analysis - Graft survival Secondary

(resource use log) - EuroQol Study Close & Outcome Reporting COPE-POMP: Sample Collection &

22 COPE Clinical Trials COPE-POMP: Patient Follow up Days 1-7 and 14 Month 3 and 6 Month 12 Secondary outcome analysis - Biochemical function - Dialysis requirement - Graft & Patient survival Secondary outcome analysis - Biochemical function - Dialysis requirement - Graft & Patient survival - EuroQol (month 3) Primary outcome analysis - Graft survival Secondary outcome analysis - Biochemical function - Patient survival - Health economic analysis (resource use log) - EuroQol Study Close & Outcome Reporting COPE-POMP: Sample Collection & Processing 22

COPE Clinical Trials COPE-POMP: Data Sources & Data

(perfusate, blood, biopsy) Perfusate, Machine Data

14, months 3 / 6 / 12 EuroQol: Day of / before Tx, months 3

after Tx COPE-POMP: January September 2015 Kidneys

23 COPE Clinical Trials COPE-POMP: Data Sources & Data Collection Biological specimen: Perfusion Data: Time of Tx (perfusate, blood, biopsy) Perfusate, Machine Data Electronic Data collection (ecrf): Time of Tx, days 1-7, day 14, months 3 / 6 / 12 EuroQol: Day of / before Tx, months 3 & 12 Resource use log: Time of discharge after Tx 12 months after Tx COPE-POMP: January September 2015 Kidneys randomised and transplanted SCS + HRMP, 19 SCS, 22 Centers: Oxford Leuven Essen Groningen 23

24 Agenda 1. Welcome and Introduction 2. COPE clinical trials - Normothermic liver perfusion vs static cold storage - Oxygenated hypothermic kidney reconditioning vs static cold storage - Non-oxygenated hypothermic vs oxygenated hypothermic kidney perfusion 3. Trial set-up and trial logistics 4. COPE biobank: sample collection and scientific remit 5. COPE experimental work programmes 6. Conclusions & questions This project has received funding from the European Union s Seventh Framework Programme for research, technological development and demonstration under grant agreement no Nuffield Department of Surgical Sciences University of Oxford Overview Randomised controlled trial Clinical Lead by Prof. Jacques Pirenne, University of Leuven (BE) Sponsored by the University of Oxford (UK) Participating sites: Leuven (+ Belgian Transplant Centres) Groningen (+ Dutch Transplant Centres) Oxford (+ UK Transplant Centres) Total of 83 kidney pairs Kidney Assist machines used for hypothermic perfusion provided by COPE partner Organ Assist Products B.V. 24

25 COPE Clinical Trials Rationale Does O2 during hypothermic machine perfusion improve 1y graft function? Experimental studies: benefit of + O2 no clinical studies comparing HMP + O2 vs HMP-O2 Endpoints primary: 24 h creatinine 1 year (mgfr) secondary: DGF, Functional DGF PNF GS and PS@ 1 year 3 mo, 6 mo and 1y AR-Bx Length hospital stay Donors Inclusion criteria: 50y 2 different recipients 2 kidneys transplantable Recipients Inclusion criteria: 18 end-stage renal failure active waiting list Exclusion criteria: combined Tx planned dual Tx Paired randomization & intention to treat analysis Randomisation at the donor centre Continuous machine perfusion 25

26 Donors randomised Kidney pairs transplanted Only 1 kidney transplanted 26

27 Trial setup and logistics Agenda 1. Welcome and Introduction 2. COPE clinical trials - Normothermic liver perfusion vs static cold storage - Oxygenated hypothermic kidney reconditioning vs static cold storage - Non-oxygenated hypothermic vs oxygenated hypothermic kidney perfusion 3. Trial set-up and trial logistics 4. COPE biobank: sample collection and scientific remit 5. COPE experimental work programmes 6. Conclusions & questions This project has received funding from the European Union s Seventh Framework Programme for research, technological development and demonstration under grant agreement no Nuffield Department of Surgical Sciences University of Oxford Trial Preparation What we did What we needed Who did it How it works 27

28 Trial setup and logistics Trial setup and logistics - Project Plan Regulatory Aspects - Sponsorship & Insurance - MHRA approval 26 February REC approvals 11 April 2014 to 17 th November R&D applications 23 May 2014 to 23 June Contracts March to December

29 Trial setup and logistics Trial setup and logistics Machines and equipment Machines & Equipment 29

30 Trial setup and logistics Trial setup and logistics Transport Sample Storage 30

Trial setup and logistics Trial setup and logistics Staff Chief Investigator Principal

Economist Researchers Students Transplant Technicians Senior Biorepository Manager Senior

coordinators Logistics Eligible Organ Identified Research Team Mobilised Equipment

31 Trial setup and logistics Trial setup and logistics Staff Chief Investigator Principal Investigators Local Investigators Business Partners Project Manager Statisticians Health Economist Researchers Students Transplant Technicians Senior Biorepository Manager Senior Informatics Manager QUOD Team NHSBT Eurotransplant UKCRN Research nurses Transplant coordinators Logistics Eligible Organ Identified Research Team Mobilised Equipment Collected Travel to transplant site Data & Samples Collected Equipment returned Go home get some zeds 31

32 COPE Biobank Agenda 1. Welcome and Introduction 2. COPE clinical trials - Normothermic liver perfusion vs static cold storage - Oxygenated hypothermic kidney reconditioning vs static cold storage - Non-oxygenated hypothermic vs oxygenated hypothermic kidney perfusion 3. Trial set-up and trial logistics 4. COPE biobank: sample collection and scientific remit 5. COPE experimental work programmes 6. Conclusions & questions This project has received funding from the European Union s Seventh Framework Programme for research, technological development and demonstration under grant agreement no Nuffield Department of Surgical Sciences University of Oxford Goals of the COPE Biobank: To establish a centralised clinical biobank with samples from three trials across five countries Perform multivariate risk modelling using data on demographic variables, function and clinical outcome. To assess organ viability with established biomarkers and identify and validate promising new clinical biomarkers during liver NMP and kidney HMP. To enhance insight in mechanisms of ischaemia/reperfusion injury pertinent to the preservation strategies used in the clinical trials. To monitor the safety and immunological aspects of the proposed technologies. 32

COPE Biobank COPE Biobank Sample Types collected in the trials Liver Trial Liver biopsies: - before preservation - after preservation - after reperfusion Bile duct biopsies - After preservation -

33 COPE Biobank COPE Biobank Sample Types collected in the trials Liver Trial Liver biopsies: - before preservation - after preservation - after reperfusion Bile duct biopsies - After preservation - After reperfusion Plasma & serum - Donor plasma and serum - Recipient plasma and serum after anaesthesia - Recipient plasma and serum after reperfusion Urine - Recipient urine after anaesthesia - Recipient urine after reperfusion Bile Perfusate Kidney Trials Kidney biopsies: - after reperfusion Plasma & serum - Donor plasma and serum - Recipient plasma and serum after anaesthesia - Recipient plasma and serum after reperfusion Perfusate How are samples collected? Blood tubes (EDTA & SST) Urine tubes Tubes for tissue (RNAlater/Dry ice & formalin) Tubes for bile and perfusate Tubes for transferring samples after centrifugation Plastic pipettes for transfer 33

transplantation outcomes Parallel research interests Understand underlined mechanisms of kidney and

34 COPE Biobank COPE Biobank Research Initiatives Core research aim: Validate in the molecular level the clinical trial outcomes Identify biomarkers of donor organ quality predictive of transplantation outcomes Parallel research interests Understand underlined mechanisms of kidney and liver ischemia and repair Design improved preservation methods and interventions to repair and resuscitate organs 34

COPE Biobank - Omics Profiling Proteomics

assays Proteomics Metabolomics MicroRNA Agenda 1.

COPE clinical trials - Normothermic liver

hypothermic kidney reconditioning vs static cold

oxygenated hypothermic kidney perfusion 3.

COPE biobank: sample collection and scientific

Conclusions & questions This project has

Seventh Framework Programme for research,

35 COPE Biobank - Omics Profiling Proteomics Transcriptomics MicroRNA Proteomics Immuno assays Proteomics Metabolomics MicroRNA Agenda 1. Welcome and Introduction 2. COPE clinical trials - Normothermic liver perfusion vs static cold storage - Oxygenated hypothermic kidney reconditioning vs static cold storage - Non-oxygenated hypothermic vs oxygenated hypothermic kidney perfusion 3. Trial set-up and trial logistics 4. COPE biobank: sample collection and scientific remit 5. COPE experimental work programmes 6. Conclusions & questions This project has received funding from the European Union s Seventh Framework Programme for research, technological development and demonstration under grant agreement no Nuffield Department of Surgical Sciences University of Oxford 35

36 Agenda 1. Welcome and Introduction 2. COPE clinical trials - Normothermic liver perfusion vs static cold storage - Oxygenated hypothermic kidney reconditioning vs static cold storage - Non-oxygenated hypothermic vs oxygenated hypothermic kidney perfusion 3. Trial set-up and trial logistics 4. COPE biobank: sample collection and scientific remit 5. COPE experimental work programmes 6. Conclusions & questions This project has received funding from the European Union s Seventh Framework Programme for research, technological development and demonstration under grant agreement no Nuffield Department of Surgical Sciences University of Oxford Thank you for your interest! This project has received funding from the European Union s Seventh Framework Programme for research, technological development and demonstration under grant agreement no Nuffield Department of Surgical Sciences University of Oxford 36

Transplantation Society. Transplantation Building Bridges to Excellence. World Wide Transplantation. Outline 9/28/2016

Transplantation Society. Transplantation Building Bridges to Excellence. World Wide Transplantation. Outline 9/28/2016 Transplantation Society Transplantation Building Bridges to Excellence How can we use our collective wisdom/education to optimize transplantation outcomes? development of the science and clinical practice