Community Research and Development Information Service - CORDIS

Periodic Report Summary 2 - COPE (Consortium on Organ Preservation in Europe)

Project Context and Objectives:
The discrepancy between organ supply and demand remains the biggest challenge facing the transplant community today. In order to increase the amount of available donor organs, transplant specialists are increasingly turning to sub-optimal donor organs. Organs from such donors usually have normal or near normal function before death, but retrieval, storage and transplantation cause progressive injury to the organ. Injury is predominantly caused by inadequate or absent delivery of oxygen and nutrients, either in the warm or cold preservation environment.

To face these challenges, new techniques to improve organ preservation are being developed including:
• Normothermic liver machine perfusion (NMP)
• Hypothermic kidney machine perfusion (HMP)
• Novel additives for preservation solutions

These strategies are all directed to the vital period that starts at the time of circulatory arrest and extends to the point of transplantation. Specifically, they will tackle the following challenges:
• Exposure of donor organs to ischaemic injury whilst the organs remain in the donor.
• Progressive deterioration of the organ during conventional organ preservation.
• Repair of the organ during preservation using perfusate and pharmacological interventions.
• Identification of reliable predictors of organ viability using biological and other pre-transplant parameters.

The COPE consortium is the official organ preservation task force of ESOT and consists of a number of European transplantation centres, front running transplantation research groups and a number of SMEs involved in developing perfusion fluids and technology. Together, they will be able to generate the statistical power and protocols necessary to test, validate and promote these new organ preservation techniques and increase the number of available solid donor organs.

The four strategic objectives of the programme are:
1. To test in clinical trials a number of novel clinical approaches to repairing and preserving high-risk donor organs
2. To investigate in experimental models a number of novel scientific approaches to organ repair and regeneration.
3. To develop new objective methods to measure and predict the viability and outcome of donated organs.
4. To develop an integrated network of academic clinicians and scientists in Europe that, in collaboration with SMEs and ESOT, will develop and implement new medical therapies and devices in organ transplantation.

The Consortium has successfully rolled out its three clinical trials across five European countries with over 25 participating Transplant Centres. In the process of trial recruitment, data and sample collection is undertaken and will form the basis for analysing these novel preservation techniques.

Project Results:
Administration, management and governance:
• Signing of Consortium Agreement (CA) and distribution of EU pre-financing payments
• Hiring of project staff including COPE Project Manager, Trials Co-ordinator, Biobank Coordinator, Statistician and PhD student to support the trials
• Kick off meeting delivered in Jan 2013.
• Governance structure established to support the COPE Consortium
• Management tools and project plans put in place to support project monitoring
• 1st COPE project amendment successfully managed
• 1st COPE report covering January 2013 - June 2014 successfully submitted and accepted
• COPE Annual Meetings held in February 2014 and March 2015 with the next meeting scheduled for April 2016.
• COPE Management Board holding monthly conference calls to discuss ongoing progress of the project

Trial and experimental design:
• WP8 has coordinated the detailed design of the three clinical trials:
o WP2: Normothermic liver machine perfusion against cold static storage.
o WP3: End preservation kidney reconditioning against continuous cold static storage for Extended Criteria Donor (ECD) kidneys.
o WP4: Oxygenated hypothermic machine perfusion of the kidney against conventional hypothermic machine perfusion for older Donors after Cardiac Death (DCD).
• WP1 had to be terminated and was removed from the DoW. More details on the reasons and justifications can be found in the amendment documents.
• Recruitment of additional partners to increase recruitment rates
• Following establishment of the regulatory and logistical framework, the three COPE clinical trials started recruiting patients. More details on the different dates of first patient inclusion can be found in the milestone section.
• WP5 and 6 have developed experimental plans and carried out their first set of experiments to investigate the role of cell-free perfusion media for the purposes of liver and kidney transplantation and to support the metabolic reconditioning of organs ex-vivo.
• In addition the experimental work packages have begun to evaluate the bio-physical optimisation of pre-implantation resuscitation of organs and the effects of different temperatures on regional perfusion of abdominal organs in the donor.

Logistics for clinical trials:
• WP2, 3 and 4 successfully rolled out logistical procedures for the clinical trials across all partner sites
• A team of ‘Transplant Technician’ (TT) hired in the UK and on the continent providing 24 hour rota cover for sample and data collection
• Three online databases established to facilitate data collection
• Trial devices constructed and other consumables continuously ordered
• Ambulance services in the UK and on the continent equipped to be able to carry the OrganOx metra device for WP2

Regulatory approvals:
• Ethical approval achieved in all partner sites for all trials. More details on the individual approvals per WP and per Beneficiary can be found in the milestone table.
• Sponsorship contracts between the University of Oxford and the COPE trial partners finalised
• Equipment contracts finalised with OrganOx Ltd. and Organ Assist Products B.V. for the respective trial devices
• In the UK, site agreements and R&D approvals finalised with the NHS Trusts involved in all trials
• In The Netherlands and Belgium, local approvals have been achieved for the cooperating Transplant Centres for WP3 and WP4

Establishment of a bio-repository:
• Centralised bio-specimen collection protocols for all three clinical trials established
• Sample collection kits created and distributed and consumables ordered and delivered.
• Sample collection has begun in all clinical trials and all participating sites
• Established a process for requesting samples/data for sub-study
• Processes for sample transport from the continental partners to the biorepository in Oxford established and rolled out

Potential Impact:
The COPE project aims to deliver solutions to one of the greatest challenges in transplantation at present; the shortage of good quality organs for transplantation. Every year the demand for organs for transplantation is increasing, yet despite the increasing awareness of organ donors we are seeing poorer quality organs offered for transplantation. This is partly because more and more organs are coming from older donors with additional co-morbidities such as diabetes and hypertension. These organs are very susceptible to preservation injury.

The COPE consortium aims to protect and preserve these organs by using next generation machine perfusion technologies through a combination of clinical trials and experimental innovations:

WP2: This clinical trial investigates using machine perfusion technologies to preserve livers from deceased donors at normal body temperature in comparison to storing the liver on ice. By using physiological conditions we hypothesise that we can prevent injury to the allograft and potentially also rejuvenate the liver during this machine preservation period.
Results of the recently completed Phase I trial performed by P J Friend et al. has demonstrated not only safety of the Organ-Ox device, but also logistical feasibility and the ability of the device to prevent hepatocyte injury. The Phase III RCT being performed by the COPE Consortium will be the largest trial of its type in liver preservation ever performed, and has the real potential to be a ‘game changer’ allowing not only allowing to preserve livers, but also allowing for the assessment of livers during the ex-vivo phase. Recruitment for this trial has now started in the UK and to date 8 liver transplants have been randomised into the trial.
As will all of the clinical trials, this trial will not only evaluate clinical endpoints but also evaluate the health economic benefit of normothermic machine perfusion of the liver.

WP3: This clinical trial investigates the role of perfusing kidneys from extended criteria donors (ECD) for 2 hours prior to implantation. The European Machine perfusion trial performed by Moers et al. demonstrated the ability of hypothermic machine perfusion to improve 1 and 3 year graft survival of kidneys from ECDs (Moers, Gallinat et al. 2013).
Although logistically feasible to transport kidney machines, the benefit against cold storage may be seen with a short period of hypothermic oxygenated resuscitation prior to implantation. This clinical trial evaluates this question. A cost-benefit analysis will also be important to establish the effectiveness of this technology.

WP4: Kidneys from older DCD donors are known to have very poor outcomes. Recent experimental evidence has suggested that oxygenated machine perfusion has an added benefit over conventional non-oxygenated machine perfusion of kidneys. We are investigating this question in a phase III multi-centre European RCT. In addition to establishing the effects of oxygenation on longer term kidney function, we explore the effects on graft and patient survival and on the cost implications of adding oxygen to hypothermically perfused kidneys.

WP5 and WP6: These experimental work packages aim to deliver technical innovations to enhance machine perfusion technologies. To date the work packages are using alternative perfusion media aiming for a cell-free oxygen carrying system which is effective, cheap and can replace traditional oxygen carrying media such as blood (used in WP2). The experimental group aims to optimise kidney and liver preservation techniques and evaluates the role of intervening in the donor using normothermic regional machine perfusion of abdominal organs, resuscitating organs even prior to their explantation.

WP7: Using a centralised bio-repository WP7 aims to identify biomarkers which can be used to predict the outcomes of transplantation and also aims to profile organs. With such a profiling system we aim to develop an algorithm which will facilitate transplant professionals in making decisions about which organs to transplant. In addition we aim to create new insights into the mechanisms of injury of organ preservation and protective mechanisms. WP7 will support sub-studies into other areas of molecular, cellular and immune-biology.

WP8, 9 and 10: These work packages support the management, dissemination and design and execution of clinical trials and experimental studies. They work by integrating the work performed across the COPE Consortium.

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