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Consortium on Organ Preservation in Europe

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

Executive Summary:
Organ transplantation has become the preferred treatment for end-stage organ failure, but its great success has created a new challenge: the gap between demand and supply. This discrepancy has necessitated the acceptance of more organs from older and higher-risk donors, to at least maintain the required annual number of transplants. Organs from such donors usually have near normal function before death, but are more susceptible to the progressive cascade of injuries incurred in donor management, the retrieval operation, and storage during transport. This damage to the organ negatively affects function and survival.

The Consortium for Organ Preservation in Europe (COPE) was formed to investigate innovative strategies in organ preservation to address this critical period of injury between retrieval and implantation. The consortium engaged 15 partners across six countries with a clear goal: “make the untransplantable, transplantable,” thereby increasing available organ supply, shortening waitlists, extending lives, and cutting healthcare costs.

COPE developed three large international multicentre clinical trials to investigate the following techniques to improve preservation and increase organ utilisation:

• Ex-vivo Normothermic Machine Perfusion (NMP) of livers (Liver NMP);
• Ex-vivo Hypothermic Machine Perfusion (HMP) with oxygen of kidneys (COMPARE);
• Combining Static Cold Storage (SCS) with End-HMP with oxygen in kidneys (POMP).

COPE also conducted experimental work programmes to optimize conditions for organ preservation and repair during kidney and liver perfusion. Finally, COPE developed a biorepository of samples from the clinical trials to enable research into biomarkers to predict organ quality and enhance understanding of the mechanisms of organ injury and repair.

The project faced considerable international regulatory delays in launching the clinical trials as well as slower-than-projected recruitment, so some of COPE’s work is still ongoing. However, the consortium has already delivered significant findings that contribute to a better scientific insight in key aspects of organ preservation and how clinical practice is affected by new techniques of organ storage. The trial results available so far show that the improved preservation strategies justify acceptance and transplantation of more donor livers and kidneys, without compromising, and in fact improving organ function and survival of higher risk donor organs. In addition, COPE has designed and trialed the complex logistics process needed to implement these techniques into regular clinical practice, providing a model for national Health Authorities to adopt if desired. Meanwhile, the experimental work of COPE has yielded several innovations to kidney and liver perfusion protocols that will reduce injury and enable better prediction of graft function.

The COPE biorepository and biomarker research are underway, investigating mechanistic and clinical aspects during hypothermic and normothermic perfusion preservation. The results of these analyses will allow a better insight in the subtle balance between injury and repair and indicate where additional and timely intervention may be needed to further improve the quality of donor organs. These planned investigations building on the work of COPE in the coming year will potentially impact on health policy throughout the EU as we continue to share our findings.
Project Context and Objectives:
The discrepancy between organ supply and demand remains one of the biggest challenges facing the transplant community today. Recent figures from NHSBT, for instance, show over 6,000 patients on the organ transplant waiting list, while only 5,092 transplants were performed in the last year. For its part, Eurotransplant reported 4,386 kidney transplants in 2017, with an active waiting list at year-end of 11,105.

To increase the amount of available donor organs, transplant specialists are increasingly turning to sub-optimal organs from older and higher risk deceased donors, e.g. donation after circulatory death (DCD) donors and extended criteria donors (ECD). Organs from such donors usually have normal or near normal function before death, but are more susceptible to the progressive injuries incurred during donor management, the retrieval operation and storage, and subsequent transplantation. Damage is predominantly caused by haemodynamic and hormonal instability in the donor, and inadequate or absent metabolism without oxygen and nutrients during organ preservation in the cold when bridging from the donor to the recipient centre.

To address these challenges, the COPE consortium set out to explore multiple innovative techniques to improve organ preservation. The project’s investigative priorities were all directed at the vital period that starts at the time of circulatory arrest and extends to the point of implantation at the time of transplantation. COPE tested multiple interventions in organ preservation and transportation aimed at reducing injury and enhancing repair, while also engaging in advanced research to better understand the mechanisms and biomarkers of organ injury. In this way, the project sought to both make marginal organs more fit for transplant, and to improve ways of predicting which organs would ultimately be transplantable and life-sustaining. This combined approach would yield gains in patient health (by increasing transplant supply and shortening waitlist times) and health care cost efficiency (by improving operational logistics and reducing expensive instances of graft failure).

WP2: Ex-vivo normothermic liver machine perfusion, protection and reconditioning
This work package delivered an international randomized controlled clinical multicenter trial comparing continuous normothermic machine perfusion (NMP) of the liver starting at the donor site immediately after retrieval versus conventional static cold storage (SCS) in all types of donors.

WP3: Ex-vivo hypothermic kidney machine perfusion, protection and reconditioning of ECD grafts
This work package delivered an international randomized controlled clinical multicenter trial to evaluate pre-implantation reconditioning of donor kidneys using oxygenated hypothermic machine perfusion (END-HMP) following a period of conventional static cold storage (SCS) in extended criteria donors (ECD).

WP4: Ex-vivo hypothermic kidney machine perfusion, protection and reconditioning of DCD grafts
This work package delivered an international randomized controlled clinical trial involving all donor and transplant hospitals in two countries to evaluate the efficacy of the addition of oxygen delivery during hypothermic machine perfusion (HMP) in kidneys, from retrieval to implantation in donation after circulatory death (DCD) donors.

WP5: Translational experimental studies in liver repair, regeneration, and preservation
This work package used experimental study models to explore several potential improvements to ex-vivo liver perfusion. The experiments tested cell-free perfusates, slow rewarming procedures, and cold flushes, all with the aim of establishing optimal regeneration conditions for damaged livers via short-term pre-implantation liver perfusion.

WP6: Translational experimental studies in kidney repair, regeneration, and preservation
This work package used experimental study models to explore possibilities for improvement of kidney conditioning by better preservation methods. The experiments tested alternatives for blood perfusion, slow rewarming procedures, and NMP parameters, all with the aim of establishing optimal regeneration conditions for damaged kidneys via short-term pre-implantation kidney perfusion.

WP7: Organ evaluation and biomarkers to predict graft viability and outcomes
This work package established a biorepository of samples from donors, organs and recipients obtained during the three clinical trials. The biorepository was then used for further studies to identify mechanisms and validate novel clinical biomarkers to predict organ viability and better understand organ injury pathways. Some of these studies were planned as core deliverables within the grant, while others were ancillary proposals developed and submitted by consortium researchers as the project unfolded.

One original work package, WP1, was initially envisioned to perform a randomized controlled trial in a few centres in two countries comparing in-situ normothermic regional perfusion (NRP using ECMO) versus conventional static cold storage (SCS) or hypothermic machine perfusion (HMP) in Maastricht Category II donors. Unfortunately, WP1 had to be abandoned as in one country new regulations released by the health Authorities did not allow randomization of techniques anymore, while in the other country the projected numbers turned out to be much smaller than expected, thus making sufficient recruitment impossible.

To administer, support, and optimize methodology for this multifaceted work, three further work packages were implemented with the following objectives:

WP8: Study design, statistical analysis, and cost effectiveness
This work package oversaw patient safety, trial methodology, and trial analysis, including health economic reports.

WP9: COPE Communication and Exploitation
This work package oversaw the dissemination of COPE publicity and findings to diverse audiences through all possible channels, particularly leveraging ESOT’s network.

WP10: COPE Management
This work package oversaw all of the administrative matters of COPE, including management of budgets and finance, internal communication between partners, liaising with and reporting to the EC, and arrangement of the consortium’s annual meetings and monthly management board calls.

In summary, the developed project organization and infractructure enabled COPE to address 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 has served as the official organ preservation task force of ESOT. COPE included more than 25 European transplant centres in seven countries, front running transplantation research groups and a number of SMEs involved in developing perfusion fluids, technology, and logistics in organ donation. Together, these partners generated the transplant volume, statistical power and protocols necessary to test, validate, and promote these new organ preservation techniques and increase the number of available solid donor organs.
Project Results:
Results obtained during the six years of the COPE project will be discussed per work package. We note at the outset that the project faced several significant delays. Initial delays were regulatory, related to contracts and R & D arrangements across the various partners sites. Consequently, each trial launched later than expected. WP3 and WP4 each faced recruitment that was much slower than projected, due to changes in health policy in partner countries that reduced the number of potential recruits for one of the kidney trials. These trial delays then cascaded into the biorepository research, as not all samples were available in the expected time frame to carry out the planned proteomics analyses.

In addition to requesting a no-cost extension, the COPE partnership made extraordinary efforts to make up for lost time in the clinical trials. This was particularly the case in WP3, where the addition of multiple recruitment centres in 2017 was the crucial factor that enabled successful completion of recruitment by the end of the grant. We are pleased to say at this point that, although not all objectives were achieved by month 66, all are scheduled for completion and arrangements are in place to finish the work after the formal end of the grant. Deliverables detailing completion of objectives, or the anticipated pathway to completion, have been submitted to the Commission.

In the experimental studies, the first round of research on the initial objectives yielded unexpected and not satisfactory results. This necessitated changes in the research protocols, including a shift from a small to a large animal model (rat to pigs). The changes did allow these work packages to achieve results in their first two deliverables, but in each study the third deliverable was sacrificed due to lack of time and resources.

As noted in the previous section, the project initially envisioned an additional clinical trial in Work Package 1, which was terminated formally by amendment as the work package leaders in the two respective countries determined they could not recruit enough patients to complete the trial.

WP2: Liver NMP Reduces Discards and Improves Preservation Time.
During normothermic machine perfusion (NMP) a liver is perfused with oxygenated blood, medications and nutrients at 37oC. This more physiological method of preservation may improve outcomes after liver transplantation when compared with conventional static cold storage (SCS) in an ice box. Furthermore, the OrganOx metra facilitates functional testing and assessment of livers in the device, allowing surgeons more rigorous parameters to assess viability for transplant. Prior to COPE, liver NMP had not been subject to the rigour of a randomised trial to demonstrate successful implementation under current organ retrieval and transplantation practice.

This RCT across four countries involved seven European transplant centres. Livers from adult donors declared dead using brainstem death criteria (DBD) or after controlled circulatory death (type III DCD) were randomly assigned (1:1) to continuous NMP or SCS. The primary end point was the difference in peak-AST, requiring 220 transplants (90% power). Secondary endpoints included: organ utilisation, preservation time, early allograft dysfunction (EAD), one year graft and patient survival and ischaemic cholangiopathy on MRCP.
270 livers (133 SCS, 137 NMP) were enrolled, consisting of 192 DBD and 78 DCD organs. 48 livers were discarded (32 SCS [15 DBD, 17 DCD] vs 16 NMP [10 DBD, 6 DCD]; p<0.01).
Table 1 below shows recruitment per centre:

The results of the randomised trial WP2 undertaken by the COPE consortium have shown that implementation of this technology is both technologically and logistically viable. Specific trial outcomes were published as the cover article in the May 4 issue of Nature and included the following highlights:
- A 50% lower level of graft injury, as measured by hepatocellular enzyme release of amino aspartate transferase (AST).
- An increased utilization of organs by reducing the discard rate by 50% compared to cold stored livers.
- An increase in the organ preservation time by 54%.
- No significant difference in bile duct complications despite the use of higher risk organs.
- No impact on graft or patient survival.
Thus, NMP livers show better early graft function than SCS in terms of peak-AST and EAD, both of which are surrogates for long-term graft outcomes. This is despite better organ utilisation of higher risk donor livers and longer preservation times in the NMP group.

Publication of the health economic analysis is pending, and thus details are still confidential and will not be included in this report. However, in general, it has become evident that the reduction in organ discard rate will provide the chief health economic advantage. The increase in preservation time could also have a major impact on transplant logistics, reducing surgical costs by allowing better scheduling and fewer “out of hours” procedures. The results of this unique trial will improve the patient experience, as fewer discards and better organ assessment will lead to fewer cancelled transplants and longer preservation times will allow patients more notice to prepare for their procedures. Follow-up studies to further explore these outcomes are underway.

Furthermore, involvement in a trial of this scope provided OrganOx with significant user feedback which led to progressive design improvements in the device over the course of the trial.

WP3: POMP Trial Outcome Pending
POMP set out to compare the impact in kidney transplantation after SCS alone versus SCS plus HMP using extended criteria donor (ECD) kidneys. The trial thus could have a tremendous logistical impact, as perfusing kidneys in the transplant centre prior to implantation is obviously much simpler and cheaper than continuous perfusion throughout transport from donor to recipient. If SCS plus HMP proves more beneficial than SCS alone, we would expect to see greater adoption of kidney HMP, particularly in countries where machine perfusion has not yet been established as a standardised method for organ preservation.

The primary trial endpoint is death censored graft survival at 1 year. Working in 5 countries (United Kingdom, Germany, Belgium, Netherlands, and Hungary), POMP successfully transplanted the required 262 kidneys between January 2015 and May 2018.

WP3 observed a slow inclusion of 3-5 kidney transplants per month within the first twelve months after the first patient had been recruited. This was below the estimated recruitment rate of approximately 11 kidneys per month. The slow inclusion rate was predominantly due to the overall decline of donor kidneys. In order to achieve Milestone 17, additional European transplant centres joined WP3 in 2016 and early 2017, which include Cardiff (UK), Royal Free (UK), and UCL Brussels (Belgium), Berlin (Germany) and Budapest (Hungary). The result was a steep increase in recruitment numbers, and an average of about 11 randomisations per month. We are particularly appreciative for the contribution of the colleagues in Budapest, who transplanted 46 kidneys in just 15 months.

Table 2: WP3 recruitment timeline

Milestone 17 (last patient recruited) was achieved on May 18th, 2018, which means that one-year follow-up with the final patient is due in May 2019. The final milestones and deliverables on this work package will thus be completed around September 2019. In the meantime, the WP3 team is following up with patients and progressively cleaning and completing data. Furthermore, biorepository samples for research proposals related to WP3 will soon be handed out, so we expect results from those studies throughout 2018-2019.

WP4: Oxygenation Benefits Kidneys from Older DCD Category III Donors
The primary objective of COMPARE was to compare the effect of oxygenated versus non-oxygenated continuous hypothermic machine perfusion (HMP) on graft function of kidneys retrieved from controlled DCD Category III (awaiting circulatory death) donors aged 50 years or older. The primary endpoint is the estimated Glomerular filtration rate at 1 year after transplantation (time window of 30 days) as defined by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation.

Secondary objectives are to compare graft and patient survival, the incidence of delayed graft function, biochemical kidney function, measured and estimated GFR as a surrogate of kidney function, the incidence of primary non-function and acute rejection between HMP+O2 and HMP-O2 kidneys and to assess the feasibility and safety of HMP+O2 as a method of organ preservation. Additionally, this work package envisioned a health economic analysis to explore the implications of HMP+O2 and HMP-O2 in kidney preservation.

Working in three countries (Belgium, the Netherlands, and the United Kingdom), the COMPARE trial randomised 197 kidney pairs from DCD donors over 50 years of age. One kidney of a pair was preserved by hypothermic machine perfusion without active oxygenation (control arm) and the other kidney was preserved by hypothermic machine perfusion with active oxygenation (treatment arm).

The strength of the consortium model was perhaps best displayed in WP4, which encountered numerous unforeseen delays. The consortium managed to adapt and implement several strategies to overcome these setbacks.

The logistics behind the WP4 trial – where randomisation needed to take place very early in the kidney donation process and where the trial treatments involved the mounting of a kidney on a machine perfusion device at the donor hospital – proved challenging. Therefore, Med Assist was added as an SME partner of the COPE consortium in June 2014 to organise the logistical part of the protocol in Belgium and the Netherlands where all transplant centres participated. Med Assist proved to be essential to the feasibility of the trial with its extreme logistical extreme complexity.

The translation of EU good clinical practice guidelines into the several EU countries involved in the COPE consortium has also brought its challenges. Due to potential problems with clinical trial insurance over the different countries and participating sites of all the COPE trials, the sponsorship for all trials was taken over by Oxford University. The regulatory approvals needed to turn over the sponsorship took longer than we had anticipated. It took nearly a year for the regulatory issues to be resolved despite the effort of all National Investigators and their associates to speed up the process as much as possible.

Inclusion rates were slower than foreseen. Analyses of these data showed that donors were not being missed but that more potential kidney pairs were lost before randomisation (donor procedures not proceeding, one of both kidneys not transplantable) and there were consent issues in the recipient centres. Local Investigators were reminded and encouraged to ask patients for consent. Trial recruitment needed to be prolonged and the end of follow-up was projected to fall outside of the grant timeline. An extension of the grant was requested and approved by the EU commission and we managed to complete follow-up and data collection / clean-up within the lifetime of the grant.

During the RCT’s several issues have been observed related to the device and its use. Organ Assist has built an intensive training program for use of the Kidney Assist-transport and made multiple improvements on the machine. The consortium was extremely cooperative, helpful and understanding in this process.

Thus, COMPARE successfully completed recruitment and reached the final patient follow-up milestone in April 2018, wth 274 kidneys available for final analyses (212 as part of a kidney pair, 62 as a single kidney).

Table 3: COMPARE recruitment by country

Data clean-up and completion efforts were especially challenging in this trial, given early difficulties in designing the database and the subsequent need to collect initial data on paper forms. The team spent most of May and June reviewing data and sending queries to the recruitment centres. To complete and quality-check all data, the team has also had to liaise with the national transplant registries. These matters have delayed the beginning of analysis of this trial; while now the trial outcome is ready, the health economic analysis is planned but not yet complete.

As regards clinical outcome, preliminary analysis has shown a statistically significant increase in graft survival rate for the kidneys that were actively oxygenated during hypothermic machine perfusion while additional refined analysis will find out whether the difference in kidney function with a better filtration rate after oxygenation becomes significant. Further details about these outcomes are confidential pending publication. The full statistical analyses is awaited and will, amongst others, look at a sensitivity analysis of the primary endpoint in which kidneys that were lost before the primary endpoint was reached (either because of graft failure or because of patient death) will be taken into account. We are continuing with the full analyses as specified in the statistical analysis plan.

Technologically speaking, Organ Assist has benefitted significantly from their involvement with COPE. They were involved in two work packages (WP3 and WP4) in which the CE certified Kidney Assist-transport perfusion device was evaluated in two multicentre Randomised Controlled Clinical Trials.

The Kidney Assist is unique by fully oxygenating the kidney during hypothermic perfusion. Although the Kidney Assist had been tested in the clinical setting, the COPE RCTs were the first during which the device was used in day-by-day actual clinical practice, and by a number of different users with different degrees of experience. The continuous feedback of these users triggered a number of improvements, such as:
• The development of a patch holder for dual arteries
• Measures were taken to prevent the rare chance of accidental emptying of the reservoir. The location of the pressure sensor was changed, and an alarm to detect empty reservoir and duration of the situation was implemented.
• To make the device more robust against ingress of water, the push-dial button has been replaced by push buttons.
• To prevent possible kinking of the oxygen tube, thickness is increased.
• User-Friendliness has been improved by adding extra storage space for samples, changing the lid closing hooks, improving the filling line spike and reduce the number of 'clicks' necessary to set-up the machine.

WP5: Key Advances in Optimising Regeneration Conditions for Pre-implantation Liver Perfusion
The liver NMP trial demonstrated the safety and efficacy of this technology for clinical practice, but obviously many questions remain about the optimal methods and modalities for perfusion. WP5 conducted translational experimental studies to investigate some of these questions, seeking to optimise conditions for liver repair and regeneration during perfusion. This included experiments in modified perfusates as well as tests in whether slow rewarming of a perfused organ would limit organ injury and improve transplant outcomes.

Aqix RSI proved to be a viable solution for machine perfusion of liver grafts, enabling a gradual rewarming from 8°C up to normothermia. Thus, short-term reconditioning perfusion after preceding conventional cold storage could be shown to significantly reduce reperfusion injury compared to cold storage alone. The possibility of increasing the temperature during the rewarming perfusion up to normothermia also enhances the accuracy of evaluating the grafts viability and to predict ulterior outcome of the livers after transplantation.

While functional improvement of the graft upon reperfusion was not significantly different from the results after rewarming perfusion up to only 20°C, rewarming up to normothermia (37°C) appeared to be more suitable for the functional evaluation of the liver prior to transplantation. These results have been published in Clinical Transplant (“Controlled oxygenated rewarming up to normothermia for pretransplant reconditioning of liver grafts”). We are also in the process of translating these findings into clinical practice.

Finally, the experimental package tested an intervention to improve performance of rewarmed grafts: During the period of disconnection from the machine and re-establishment of blood perfusion after transplant, should rewarmed grafts be left alone, or subjected to a second cooling via cold flush? The details of these outcomes are confidential pending publication.

WP6: Key Advances in Optimising Regeneration Conditions for Pre-implantation Kidney Perfusion
Similar to WP5’s objectives in liver perfusion, the main goal of WP6 was to explore possibilities for improvement of kidney conditioning by better preservation methods. While the clinical trials tested two hypotheses regarding hypothermic machine perfusion for kidneys (kidney HMP), the experimental work packages researched the next steps to improve kidney perfusion methods. This included normothermic perfusion (NMP), slow rewarming, and alternatives for blood perfusion.

The first scientific question was to see if the combined use of two commercially available products by our partners could serve as an alternative for blood perfusion. This was tested initially in isolated perfused rat kidneys, with unsatisfactory results.
Consultation with consortium partners yielded the suggestion that the results obtained could point to species or size related issues. The work package moved to experiment with a porcine model, to gain a closer resemblance to human physiology in terms of metabolism and size. In order to reduce the amount of laboratory animals, the work package successfully developed a slaughterhouse model with the use of the hypothermic machine from our partner Organ Assist.

The details of most WP6 work are confidential pending publication. Speaking broadly, however, WP6 used this model to show that improved preservation by machine perfusion is essential for obtaining kidneys with good functionality. Other key findings were the addition of specific amino acids and vasoactive control. Both the Groningen and Poitiers group further used this model in the COPE environment.

The Groningen group studied the effect of different oxygen concentrations during preservation. The results obtained indicated that in this model compared to Cold Storage, Machine Perfusion clearly results in better preserved kidneys. The addition of oxygen resulted in improvement of energy status, but did not result in significantly improved early function.

The other issue explored was whether perfusates require a colloid as water-retaining substance during cold (Poitiers) and warm (Groningen) perfusion.

The Poitiers group has extensive experience in porcine transplantation and research on colloids during preservation. They therefore investigated different concentration of colloids in combination with Aqix-RSI during cold (and RT) flush, perfusion and re-oxygenation. To reduce the use of laboratory animals some investigations were first performed in kidneys retrieved from other experiments. The model that was developed by the Poitiers group was similar to the Groningen model with a slightly different base solution (and warm ischaemia time. The results of this work remain confidential pending publication.

Consortium partner Aqix recommending testing Aqix-RSI in a warm environment, so the WP6 team performed additional experiments in Groningen and Poitiers. Using the slaughterhouse model, Groningen tested the addition of BSA or Dextran. The preliminary results indicate that during normothermic perfusion with Aqix plus a colloid, a reasonable function is seen, though lower than blood. Possibly the oxygen requirement of the kidney can not be met without an oxygen carrier. Further studies with Aqix-RSI + colloid supplemented with red blood cells will be investigated to rule out this issue.

In Poitiers, Aqix + PEG (or BSA) were tested in preservation, before evaluation with blood perfusion. The results indicated that compared during preservation at 37 degrees a colloid is needed. As in Groningen the addition of amino acids resulted in better function. However, the preservation capacity, as compared to the reference (KPS), is not substantially improved.

The final experiment of WP6 was to test the best Aqix-RSI solution compared to the reference in a real transplantation model. At the time of drafting this report not all results are available. The primary outcome defined as graft function, however, showed similar functionality after preservation.

Summary of key results from WP6:
Kidney cold perfusion:
• Machine perfusion is essential to preserve pre-injured kidneys.
• The addition of oxygen show minor effect in the isolated perfusion model.
• Slow rewarming of kidneys after cold perfusion leads to better function.
• The use of colloids (BSA, PEG or Dextrans) is needed during perfusion with Aqix-RSI.

Kidney warm perfusion:
• Aqix-RSI during normothermic perfusion requires a colloid.
• Addition of amino acids increases renal function.
• Aqix-RSI with colloids could be further improved with red blood cells.
• Preservation capacity of Aqix-RSI with PEG is similar to reference in the ex vivo model.
• Preservation capacity of Aqix-RSI with PEG in vivo is comparable to the ex vivo model.
• The initial performance of Aqix-RSI with PEG+AA is similar to the reference (HMP-KPS + oxygen).

Technological results:
• Real-time in-line oxygen measurement was introduced
• A slaughter house porcine kidney perfusion model was successfully developed
• Perfusion modalities were improved
• Results of the ex vivo perfusion and in vivo transplantation are comparable.

WP7: Core Deliverables Pending, with Key Sub-studies Illuminating Details of Liver NMP
The major role of the WP7 work-package was to establish a biorepository to identify biomarkers of organ quality, predicting the outcome after transplantation of standard and higher risk donor organs. The WP7 team designed and developed a single biorepository to house the samples from all clinical trials (WP2, WP3 and WP4). Centralised protocols were created to obtain blood, urine, perfusate and tissue samples and for their safe storage. At the end of patients’ follow-up post-transplant for each clinical trial, the samples collected will be analysed by proteomics and transcriptomics technologies to develop profiles predictive of transplant outcomes.

The sample analyses envisioned as deliverables 7.1 and 7.2 have not yet been achieved due to the delays mentioned above in the clinical trials. Plans and funding are in place to carry out this work throughout autumn 2018 and winter and spring 2019, in keeping with the timelines for the conclusion of each trial. Much of the past year in this work package has been spent on preparation, including tests to ensure that all of the envisioned analysis can be completed in cases where sample collection was lower than planned.

Additionally, the biobank supported sub-studies looking into mechanisms of injury to organs, and investigating the effects of machine perfusion. In total the bio-repository has received 43 proposals for research (including proposals related to deliverables 7.1 and 7.2). Some of these had overlapping interests and investigative questions, and thus collaborative research groups have been formed to explore ischaemic reperfusion injury (IRI) in the liver, as well as bile duct injury. The IRI study has involved pathology scoring for all of the tissue samples collected in the liver study, due for completion in September. This will generate a shared data set that the IRI researchers can use to explore their particular questions.

Some of the sub-studies involving the liver have already proceeded due to their specific sample or data requirements. These have included investigation of diverse factors such as coagulant production during liver NMP, impact of liver NMP on outcomes for steatotic livers, and bile production during perfusion. A full confidential list of these sub-studies is attached to this report.

WP8: Key Research Outcomes
WP8 was essentially a support package to ensure the safe and effective running of the three clinical trials included in the COPE project. As such, the S&T foreground is limited.

However, WP8 did perform literature reviews of the underlying technologies used in the clinical trials in order to determine the current state of the art and inform the design of the trials, one of which was published as a peer-reviewed article. These essentially demonstrated a paucity of existing clinical trial evidence for the interventions being tested, justifying and informing the trials undertaken.

The other main foreground is the health economic analysis performed for WP2. Whilst it does not demonstrate an economic benefit of normothermic machine preservation of the liver, it did lead to some interesting analysis as to how to measure the economics of such devices, highlighting the fact that traditional health economic frameworks may not be appropriate. It also led to some interesting work as to the economic impact of a discarded liver, which will be of use in future studies using organ utilisation as an endpoint.

WP9-10: Lessons Learned in Managing a Complex Multi-Country Health Research Consortium
At the time of design, the COPE clinical trials were the largest ever undertaken in the EU. As such, the experience gained and lessons learned in managing a project of this scope should be of vital interest in planning future similar projects.
Happily, most partners and participants found the consortium itself to be a fruitful and effective collaboration. The backbone of the consortium’s internal communication strategy was a series of annual meetings held in Oxford, involving participants across all partners and work packages. This kind of face-to-face interaction was irreplaceable in building effective relationships, particularly as key project staff came and went over the course of six years. Annual meetings were supplemented via monthly Management Board teleconferences and a regular email newsletter, with targeted teleconferences and meetings to address particular work package issues as required. In addition, given the long periods of time between EU-mandated interim reports, COPE implemented a system of internal reports every six months, following the EU Interim Report templates. This provided accountability for work packages, and also ensured that the Project Office was routinely alerted to any potential issues in the completion of the work and could take steps accordingly. All in all, work package leaders have testified that this communication structure enabled the consortium to act as a productive “condensation point” for the exchange, refinement and dissemination of new ideas and research concepts.

Work package leaders have also noted that the consortium policies were clear and transparent, helping to smooth out the difficulties in working relationships that often occur in such large projects. This was particularly important given that some of the SMEs involved were actually direct competitors; the project would have been much poorer (if not impossible) without either competitor, but it only worked by laying out very clear lines of responsibility and demarcation between such parties. Future projects should heed both halves of this lesson.

The collaboration between academy and industry has proven invaluable for both sides. Universities, for instance, provided useful models for the rapid training and deployment of transplant technicians, and the SMEs involved benefitted tremendously from the resources available to universities to navigate the considerable regulatory hurdles involved in bringing a medical device into clinical practice. OrganOx and Organ Assist in particular benefited from the scale of the trials, which generated a critical volume of user feedback that enabled key improvements in device design and user training. On the other hand, a trial of this magnitude allowed the universities to work with many diverse (and often disparate) parts of the healthcare services involved, building valuable bridges which will continue to yield benefits in future partnerships.

Another advantage of a consortium this wide and broad was the availability of resources to meet key challenges. The regulatory delays that the project faced in launching the clinical trials were significant and would not likely have been surmountable without the resources offered by a research university of Oxford calibre. On the other hand, the recruitment delays were only solvable by the inclusion of more centres (particularly in Budapest for WP3), and doors for this inclusion were opened by the personal and professional connections held by consortium partners. In fact, once WP2 was actually underway, it completed recruitment four months faster than anticipated—a rare achievement for a clinical trial! Such networks have also been very useful for building project awareness and disseminating early results; consequently, we are hopeful for rapid uptake of life-saving transplant innovations across Europe and beyond, once all project results are complete.

Furthermore, the diversity of the consortium extended across many different medical and non-medical professionals, scientists and logistical technologists. This diverse approach leads to constructive implications, as well as improvement of administrative and methodological tasks along the way.

The consortium structure has also played a major role in ensuring quality and efficiency of research in the bio-repository. The WP7 team standardised SOPs and arranged for sample transport across all sites, limiting pre-analytical variability and ensuring that differences found in –omics profiles are due to true biological differences between samples. Crucially, co-operation between consortium partners led to the creation of collaborative research working groups, investigating ischaemia-reperfusion and bile duct injury in liver samples from the WP2 trial. Data obtained from these groups and –omics profiles will also be made available across the consortium. This approach has reduced duplication of effort and excess consumption of precious biological samples, and all researchers will stand to benefit from the share pool of data created that in the end will allow to be used as a future -omics library for reference.

Another notable area of efficiency was the decision to consolidate trial oversight and methodology (design, analysis, and safety monitoring) for all trials into a single work package (WP8). This approach allowed for the development of deeper working relationships between the medical and non-medical staff, as well as consistency in analytical personnel across time and work packages. Consequently, our analyses were more efficient, as we had less work to do in onboarding new or additional statistical personnel for the trial analyses.

Potential Impact:

By evaluating, refining and implementing novel techniques in organ preservation, COPE has brought developments from the bench to the bedside. By answering some of the most important hurdles facing organ preservation we have achieved a greater scientific understanding of the mode of action of potential treatments. We have also, of course, identified new challenges and hypotheses and completed 3 clinical trials in organ preservation evaluating novel techniques and strategies that the field of transplantation was keen to test in order to advance clinical practive and improve outcomes for patients.

The liver trial was a landmark study in the field, and the results have received the following awards: The Transplantation Society (Young Investigators Award); European Society of Organ Transplantation (Best Abstract Award); International Liver Transplant Society (Rising Star Award); American Transplant Congress (Young Investigators Award); and also received the prestigious Medawar Medal from the British Transplantation Society. Follow-up studies are already underway or being planned to extend our understanding of continuous liver NMP versus NMP plus cold storage, as well as the health economic impacts of liver NMP. More generally, the demonstration of safety and efficacy of liver NMP has opened up avenues to explore the technology’s wider potential, with interest from groups who wish to use liver NMP to administer therapeutic interventions (defatting, stem cell treatments, high-dose chemotherapy), investigate mechanisms of cancer spread, and develop organ reconditioning centres.

Furthermore, the experimental liver studies showed the promise of reducing liver injury through controlled oxygenated rewarming, and clinical studies are being planned to carry this idea forward.

The two kidney trials that we have completed will reveal the role of hypothermic machine perfusion as such, including its timing and the use of oxygenation and how this strategy may affect clinical practice in higher risk donor organs. Both trials will lead the way for transplant centres and Competent Health Authorities how to implement national strategies in kidney preservation adopting feasible and affordable models to improve utilization and outcomes in kidney transplantation.

More broadly, without a European collaboration, the clinical trials and experimental studies would not have been feasible in such a short time period. By creating a strong scientific collaboration we assembled experts from across Europe to accelerate scientific discoveries in organ preservation. This allowed a unique opportunity to create technology and skills transfer networks across collaborating institutions. This Consortium remains committed to a lasting scientific collaboration to answer the most important challenges facing organ preservation.

Using machine perfusion devices and novel perfusion media we protected and preserved older and higher risk kidney and liver allografts, making transplantable a certain percentage of organs deemed untransplantable. We have seen this most clearly in the liver NMP trial, where the 50% reduction in organ discard rate would significantly impact transplant wait times. The liver experimental studies further developed refinements in the protocol which will reduce liver injury and should thus lead to better post-transplant results. Though details remain confidential pending publication, the results of the COMPARE trial also indicate that oxygenation during kidney HMP will positively impact transplant outcomes for patients.

So far, the known trial outcomes and experimental results have yielded discoveries that can improve outcomes for transplant recipients. As these findings are implemented, we expect to see reduction in the incidence of acute and chronic rejection, post-operative complications, the need for post-operative dialysis, and possibly even the need for high dose immunosuppressants, improving patient and graft survival. The POMP trial results and WP7 analyses are still outstanding, but we are hopeful that both will contribute further findings with similar impact on patients.

In addition to improving the physical health of patients the improved accessibility to good quality allografts will lead to an improvement in the quality of life for patients with regards to their psychological health, social functioning, sexual functioning, ability to perform daily activities and sense of general well being. Less than one third of patients are who have end stage liver or kidney disease are able to achieve employment. Following transplantation however, over a half of patients are able to return to work within six months.

By demonstrating the utility, safety and cost-effectiveness of novel preservation techniques, this initiative will benefit health economies. Continued refinement of technologies, will increase their efficiency and suitability for clinical application allowing the establishment of best practice protocols, clinical recommendations and guidelines.

The COPE initiative will have a positive impact on health economies by improving accessibility to good quality life- saving organ transplants, reducing the need for re-transplantation and additional medical therapies, such as dialysis. This will be cost-beneficial for healthcare systems in addition to the cost benefit of transplantation over other modalities of organ failure treatment. For example: after the 2nd year of kidney transplantation €40,000 is saved annually when compared to maintaining patients on dialysis. As a consequence, in Europe an increase in kidney transplantation of only 10% annually will result in a saving of more than €70 million per year (source: Eurotransplant). This figure does not even include the benefit of improving graft longevity, which is a reasonable expectation, if preservation injury is reduced.

By establishing the utility of preservation strategies and allowing collaborations between academia and industry, this initiative has advanced the technologies of SMEs in the health sector. OrganOx has already seen intense interest in the results of the liver NMP trial and is moving forward with FDA approval in the United States. At the same time COPE has generated much interest in Asia especially in China where we have been invited to present our studies and technology several times during the lifetime of the grant. Organ Assist and OrganOx have both benefited from the visibility of the trials, as well as from the large scale of user feedback generated by the trial, resulting in multiple improvements to their respective perfusion devices to improve reliability, training, and user experience. These gains have generated growth for both companies, and both expect more in the foreseeable future, with Organ Assist due to benefit considerably from the positive COMPARE results and even more so if the POMP results are favourable. Aqix and Hemarina also both stand to gain from the advances we have made in demonstrating their potential roles in machine perfusion. Finally, the creation of an entirely new entity, Med Assist, to handle the logistics of introducing perfusion into standard practice has created new jobs and generated new knowledge that is of use to health authorities (see below).


The prevalence of end-stage chronic kidney disease in the United Kingdom is estimated being between 4.1-8% in the over 18-age group. In the UK alone, this means that 1.7-3.5 million people are affected by chronic kidney disease, with currently over 39,000 patients receiving renal replacement therapy. In the Eurotransplant zone over 10,000 patients are awaiting life saving renal transplantation (source: Eurotransplant). Patients with chronic kidney disease suffer from a number of complications including cardiovascular disease, anaemia, mineral and bone disorders, malnutrition, infections and cancers to name a few. Renal transplantation delays and reverses the deleterious effects of kidney dysfunction. A study published in the Journal of the American Society of Nephrology, suggests that kidney transplantation can increase the life expectancy of patients by over three times when compared to renal replacement therapy.

1,700 patients are on the waiting list for a liver transplant in the Eurotransplant zone (source: Eurotransplant). Liver transplantation is a life saving therapy for those with end-stage liver failure secondary to disease processes such as alcoholic liver disease, hepatitis or autoimmune conditions such as primary biliary cirrhosis. Liver transplantation is emerging as the treatment of choice for patients, with hepatocellular carcinoma who meet the Milan criteria (<5cm for a single lesion or multiple lesions (no more than three) with the largest measuring <3cm). It is predicted over the course of the next decade the number of patients with end-stage liver disease secondary to fatty liver disease and metabolic syndromes will increase substantially, placing additional demands on the precious supply of liver allografts.

Our initiative will increase the number of good quality organs available for transplantation, addressing the disparity between supply and demand in the realms of kidney and liver transplantation. Through increasing accessibility to transplantation we aim to decrease the disease burden of end-stage kidney and liver disease and their associated complications.


OrganOx normothermic ex-vivo liver machine perfusion device, OrganOx (Oxford, UK): As mentioned, there has been keen international interest already in the liver NMP results. The EU health authorities have been kept advised of trial progress and remain extremely interested in the results, and OrganOx is pursuing FDA approval for the metra. The United States is the largest transplant market in the world, and this approval would unlock access for the metra to many other countries, thus yielding considerable economic benefits for OrganOx.
Kidney Assist, Organ Assist (Groningen, The Netherlands): Kidney Assist has achieved CE certification. Prior to the current trials, hypothermic kidney machine perfusion was recognised as improving outcomes for marginal kidney allografts thanks to a study by COPE researchers. The addition of oxygen to the perfusion media, as suggested by pre-clinical evaluation, could refine this technology to provide even greater benefits in relation to short and long term outcomes. Demonstrating the utility of pre-implantation HMP on resuscitating kidney allografts, using Kidney Assist, could increase the uptake of this technology as a more cost-effective means of rescuing injured allografts.

The main competitor for Kidney Assist, is the Lifeport® system (Organ Recovery Systems, USA). The benefits of the Kidney Assist machine over the Lifeport® include its dedicated perfusion pressure and flow monitoring and active oxygenator, allowing modulation of the graft’s physiological environment. For experimental studies this allowed the evaluation of additional parameters.

AQIX®RS-I, (AQIX, London, UK): This novel agent has shown promise in experimental studies. During a four-year period, we aim to refine the application of AQIX, including establishing the optimal colloid and dosage. This will lead to the evaluation of AQIX®RS-I in proof of concept clinical studies and ensure the necessary safety and regulatory approvals are achieved.

Hemarina M101 (Hemarina, Morlaix, France): This compound will be refined in pre-clinical experiments, optimal dosages, colloids and effects during ex-vivo liver and kidney preservation will be evaluated. We aim to develop this technology to enable application in proof of concept studies, again, achieving the necessary regulatory and safety approvals.

Med Assist: Hypothermic machine perfusion was not a wide spread preservation method at the start of this trial. Donor surgeons were not familiar with the device, nor how to safely place kidneys on the device. As all donor hospitals in Belgium and the Netherlands, and a few in the South of the UK were involved, it would have been too time and resource consuming to ensure proper training of all of these donor surgeons. Furthermore, it would not have been possible to appoint trial personnel in over 100 donor hospitals to ensure that trial specific protocols were adhered to and the necessary data was collected.

Therefore, Med Assist was added as an SME partner of the COPE consortium. Med Assist organised the logistical part of the protocol in Belgium and the Netherlands. Med Assist was officially added as partner in June 2014. The incorporation of Med Assist as a new SME to the project as well as the recruitment of the proper personnel was essential to ascertain the feasibility of the trial as it is logistically extremely complex.

During the trial, Med Assist evaluated the device training sessions, asked for feedback from the transplant technicians and hospitals and they became aware that the Transplant Technicians, responsible for the logistics, needed a more broader training then was foreseen. They expanded the training sessions, developed an E-learning tool and added an exam that every new Transplant Technician needed to pass.
Further they learned what the ideal profile of a transplant technician should be: communicative, assertive but polite, stress-resistant and taking interest in the technical part of a medical device. In this way they were able to improve selection of new transplant technicians.

In January 2016, the Netherlands copied the COPE logistical system when they implemented hypothermic machine perfusion preservation of all kidneys as a standard of care. Consequently, the logistical model is now established as a reference point for other health authorities who may wish to adopt kidney HMP as the standard of care in the future.


COPE was committed to a rapid and effective dissemination of project results and knowledge. Through internal dissemination we aim to share information with COPE collaborators, through external dissemination we aim to engage with the European and International scientific, clinical and patient community. The mechanisms of dissemination are described in the following two sections. INTERNAL DISSEMINATION OF RESULTS AND KNOWLEDGE
Effective internal dissemination was absolutely crucial for a project with this many partners and locations. We needed to reinforce collaboration and ensure cohesive and complementary approaches by Consortium members. The internal dissemination, overseen by the Management Board, was achieved through annual Consortium meetings, monthly management board calls, a regular e-newsletter, the COPE website, and consistent work package meetings with remove partners joining via teleconference as needed.

Furthermore, in order to facilitate the interim EU scientific reports, work package leaders were required to submit internal reports every six months, following the EU reporting template. This enabled the Project Office to effectively track progress and address delays or other potential obstacles to project completion. EXTERNAL DISSEMINATION OF RESULTS AND KNOWLEDGE
The full listing of dissemination activities is available in annex A.2. The external dissemination activities of COPE were aimed at:
• Scientific community
• General public; including the patients’ association
• Health care authorities and caregivers
• Professional boards
• Students
• Pharmacological industry

By disseminating knowledge outside of the Consortium we sought to increase the interest and support for science in general, research into organ preservation and the work of COPE in particular.

Consortium partners are experts in organ preservation, boasting expertise in scientific, clinical and translational aspects. At the cutting edge of science and healthcare, the Consortium partners have proven track records of publishing work in high impact journals. Through publishing in scientific peer-reviewed journals, COPE disseminated (and will continue to disseminate) findings to the transplant community. The project highlight so far has been the May 2018 cover article in Nature, sharing the results of the liver NMP trial; the article’s Altmetric score places it in the top 1% of scholarly papers published.

In addition, presentations have been made at national and international conferences. These have included national meetings of Transplant Societies, the ESOT congress, the American Transplant Congress, the World Transplant Congress, and the International Liver Transplant Society Congress in Lisbon. WP2 results have been further shared at conferences in Hong Kong and Brazil. COPE had a significant presence at the ESOT 2017 Congress, with a spotlight presentation during a session on EU-funded projects.

As Principal Investigator, Prof. Ploeg has presented on COPE progress several times to the EU Competent Health Authorities. These policymakers have shown keen interest in the advances COPE is making, and we are very excited to have this avenue for the translation of our results into life-saving policy and practice.

The COPE work has been presented at a number of national Transplanatation Society meetings in Europe. Also, a closer collaboration with Chinese transplant centres and Organ Procurement Authorities has been agreed to translate the COPE preservation strategies and possibly help implement for their use in China as one of the largest transplant communities in the world.

Translational dissemination, transfer of knowledge from scientists to clinicians, has been and will continue to be performed through peer- reviewed journal publications, presentations at national and international meetings and through transplant bodies e.g. the American Society for Transplantation. New knowledge will be incorporated in the education of postdoctoral fellows, PhD students and undergraduates. Once all of the project results are in, we expect to work closely with ESOT to integrate findings into their educational curricula.

Dissemination of results and knowledge to the general public has been achieved via press releases through the University press offices to regional and national press. Of particular interest was the appearance of Prof. Ploeg on BBC Radio for Inside Health in 2016, explaining new advances in organ transplant. Furthermore, the Nature article publication achieved widespread popular press, with coverage on the BBC, the Times, the Washington Post, the Japan Times, and other outlets around the world.

Exploitation plans are detailed in appendix B.2 but it is important to note that the work of COPE is not entirely complete. The outcomes of POMP are still outstanding, as are the results of the biomarker and graft validation analyses. Thus at this juncture it is impossible to fully detail the anticipated exploitation of results from the project.

That said, the consortium aimed to validate clinically a number of newly developed organ preservation methods that were not widely used when the project was conceived. We have already made achievements along these lines, particularly in the area of liver perfusion. Follow-up studies are planned or underway to further explore the implications of these results, and the relevant health authorities are in various stages of considering the adoption of liver NMP in standard treatment.

Furthermore, the SMEs in the project will continue to exploit the results and build on their individual expertise. OrganOx has used the COPE trial data to support their FDA approval application. Organ Assist has made multiple improvements to their device over the course of the project in response to user feedback. Aqix and Hemarina will both benefit from the findings of the experimental studies on new ways to improve and deploy their perfusate compounds.

Finally, it is worth noting that when the Netherlands adopted kidney perfusion as its standard of care midway through the life of our project, COPE’s logistical experience proved an invaluable resource to aid in the implementation of this policy. Organ Assist in particular found that the iterative improvements in device design and user training driven by the COPE experience put them in prime position to scale up their operation to meet the needs of the Dutch health system.

List of Websites:
See for latest project news, publications, and research proposals.
For further information contact:
Prof. Rutger J. Ploeg
Nuffield Department of Surgical Sciences
University of Oxford
Oxford Transplant Centre
Churchill Hospital, Old Road, Headington
Oxford OX3 7LE
+44 1865 223872