Pilot, open, prospective, randomized, multicentre trial on quality assessment of declined liver grafts by normothermic ex vivo machine perfusion for decreasing time to transplantation: study protocol for the ExTra-Trial

Pilot, open, prospective, randomized, multicentre trial on quality assessment of declined liver grafts by normothermic ex vivo machine perfusion for decreasing time to transplantation: study protocol for the ExTra-Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Method Article Pilot, open, prospective, randomized, multicentre trial on quality assessment of declined liver grafts by normothermic ex vivo machine perfusion for decreasing time to transplantation: study protocol for the ExTra-Trial Simon Moosburner, Igor M. Sauer, Mateja Mandac, Dominik P. Modest, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6834797/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Liver transplantation remains the only curative option for end-stage liver disease, yet high waitlist mortality and organ scarcity continue to challenge the field. The randomized multicentric ExTra trial aims to improve donor utilization by evaluating whether normothermic machine perfusion (NMP) allows for safe transplantation of liver grafts that would otherwise be discarded. Methods The ExTra trial is a prospective, randomized, multicentre study conducted across German transplant centres. Participants listed for liver transplantation with a ReMELD-Na-Score ≤ 21 who are not eligible for Standard or Non-Standard Exceptions will be randomized for a one-year intervention period into two groups: the experimental arm, in which they have - in addition to regular organ allocation - the extra option to receive a graft that was initially deemed non-transplantable based on clinical criteria, but meets specified quality criteria after at least four hours of NMP, and the control arm, which consists of conventional allocation procedures alone. The primary endpoint is time-to-transplant, defined as the period between randomization and transplantation. Secondary outcomes include competing events (death, disease progression, or recovery without transplantation), graft and patient survival, quality of life, and cost-effectiveness. Additional analyses will assess early graft function, ICU and hospital stay, biliary complications, and 1-year post-transplant outcomes. A centralized biobank will collect perfusate, tissue, and blood samples for biomarker research. Safety will be monitored through quarterly reviews by the Data and Safety Monitoring Board (DSMB). Discussion The ExTra trial seeks to establish NMP as a tool for improving organ utilization and reducing waitlist mortality by quality assessment of severely marginal liver grafts. Nearly all German transplant centres have expressed their interest in participating, though limited access to NMP devices and lack of reimbursement remain key barriers to broader implementation of this technology in Germany. By generating high-quality clinical and translational data, the trial has the potential to reshape the liver graft allocation process, provide key insights in liver physiology, and contribute to the development of biomarkers for organ assessment by NMP. The findings will be essential for future integration of NMP into clinical routine. Trial registration : ClinicalTrials.gov NCT06874296. Registered March 2025 Hepatobiliary & Transplant Surgery Liver Transplantation RCT Extended Criteria Donors Waitlist Time Figures Figure 1 Figure 2 Introduction Background and rationale {6a} Liver transplantation (LT) is the preferred treatment for patients with advanced liver cirrhosis, hepatocellular carcinoma within Milan criteria, and severe metabolic or autoimmune liver disease (1). However, the number of patients on the liver transplant waiting list exceeds the number of available organs. In Germany, the success of LT has been undermined by a dramatic decline in organ donations over the past decade (2, 3). In 2022, only 748 out of 1,296 patients (58%) on the waiting list received a liver graft. The outcome for patients on the waiting list remains unsatisfactory: A study from Essen showed that the 12-month survival rate without transplantation was 46%, compared to 78% after a liver transplant (4). Comprehensive data from the Eurotransplant registry show that between 2006 and 2015, 32% of patients were removed from the waiting list because they became too ill to receive a graft or died while waiting (5). This problem particularly affects patients with a lab MELD ≤25 who are not eligible for Standard or Non-Standard Exception criteria. These patients wait significantly longer for a graft (2022: 112 vs. 54 days, p<0.001) and have a significantly lower 12-month transplantation rate (44% vs. 70%, p<0.001, unpublished data) compared to the general population of listed patients. The imbalance between supply and demand is further exacerbated by the fact that about 24% of all liver grafts offered for transplantation in Germany are declined due to the donor's age or overall morbidity (6). This issue exists worldwide, with discard rates in the USA being similarly high (13%) (7). The liver allocation process in Germany is strictly regulated and managed by Eurotransplant, in cooperation with the German organ procurement organization `Deutsche Stiftung Organtransplantation´ (DSO, German Organ Transplantation Foundation). Each organ is allocated according to a specific algorithm. The decision to accept or reject a liver graft for a recipient is based on appropriately matching the donor's clinical data with that of a potential recipient, as well as logistical considerations. To address the current organ shortage, liver grafts from donors with extended criteria (ECD) are increasingly used for transplantation. However, up to 24% of all liver grafts offered for transplantation are declined, mainly due to the donor's age, macrosteatosis, or long cold ischemia time, as these factors are associated with an increased risk of graft dysfunction, graft failure, and death, particularly in recipients with a high MELD score. The decision-making process is primarily based on the subjective expertise of the accepting transplant surgeon, supported by scores that consider both donor and recipient factors. Objective tools for assessing graft function are not routinely used in clinical practice for conventional static cold storage or hypothermic oxygenated liver machine perfusion. Pilot studies have shown that NMP enables the assessment of organs clinically deemed unsuitable for transplantation using viability criteria such as lactate clearance or bile production(8, 9). Transplantation of initially declined liver grafts following quality assessment by NMP has been investigated in seven non-randomized, single-centre clinical studies in the UK, the Netherlands, Australia, and the USA (10-16). The commercially available OrganOx Metra (OrganOx Limited, Oxford, UK), the Liver Assist device (XVIVO B.V., Groningen, Netherlands), and a non-commercial device developed in Cleveland were used in these studies. The OrganOx Metra and the institutionally developed device were used for pure end-ischemic perfusion (10, 11, 13, 14, 16), while the protocol established in Groningen for the Liver Assist device consisted of one hour of hypothermic oxygenated machine perfusion (HOPE), followed by controlled oxygenated rewarming (COR) and 2.5 hours of NMP for quality assessment(12, 15). The ExTra trial will randomize patients on the waiting list to demonstrate that declined liver grafts, which meet predefined quality criteria after at least four hours of NMP, can be used to reduce the waiting time for liver transplantation in patients with a low MELD score who are not eligible for Standard or Non-Standard Exceptions. This is of clinical relevance given the increasing number of livers declined for transplantation in Germany, despite new technologies enabling quality assessment of these potentially transplantable organs. The utilization rate of grafts, safety, cost-effectiveness, and the effect on the waiting list practice will be evaluated as secondary endpoints. The results of this study could therefore change clinical practice in Germany and help address the medical-social dilemma of organ shortages in liver transplantation by integrating graft quality assessment through NMP into clinical practice. This could enable the acceptance of livers that are currently declined, which would certainly increase organ utilization in Germany. To further leverage the impact of this clinical study, a translational companion study will be conducted to identify novel biomarkers for assessing and predicting graft quality in NMP. Objectives {7} The objective of the ExTra trial is to demonstrate that the waiting time for liver transplantation in patients with a ReMELD-Na-Score ≤21 (equivalent to MELD ≤25), who are not eligible for Standard or Non-Standard Exception criteria, can be significantly reduced by utilizing liver grafts that were initially deemed non-transplantable based on clinical criteria but meet predefined quality criteria after at least four hours of end-ischemic NMP, compared to patients who are not offered this option. The result will be verified by a randomized control group without the ExTra treatment option. Randomization against the standard treatment is necessary to evaluate the current waiting time in this population, as the number of actual grafts performed depends heavily on the availability of grafts as well as the performance and acceptance criteria of the individual transplant centres. Access to the regular allocation process is available to all candidates in the entire study population, regardless of randomization, at any time. Trial design {8} This is a prospective, multicentre, randomized, open-label, two-arm clinical study. Since all interventions and all medical devices used in the study are CE-certified and are used in accordance with the intended purpose defined by the respective manufacturer, without any additional burdensome or invasive measures, the study qualifies as a clinical study under §47 (3) of the German Medical Devices Act (MPDG). The study is conducted in accordance with the Professional Code of Conduct for Physicians ( Berufsordnung der Ärzte ). The study population will be randomized 1:1 to the experimental or control arm (Figure 1). Liver transplantation in the context of regular organ allocation can be performed in both arms according to the centre’s decision, i.e. using static cold storage, hypothermic or normothermic machine perfusion for organ preservation. Quality assessment of grafts judged clinically unacceptable by NMP is reserved for the experimental arm. The experimental intervention, i.e. the ExTra option, will be offered for a period of 12 months from randomization, due to the expected medical deterioration of patients on the waiting list. It is important to note that in the experimental arm, treatment consists of either: receiving a liver transplant with a graft that has been declined by all German transplant centres but meets established objective quality criteria during NMP, or receiving a liver transplant via the regular liver allocation process when a graft becomes available, whichever occurs first. Declined liver grafts considered for quality assessment must not have macrovesicular steatosis >60%, fibrosis grade >F3, or cirrhosis (based on histopathologic quick section analysis, if requested by the responsible transplant surgeon after macroscopic examination) and have a graft weight between 1 and 2.5 kg. Moreover, grafts must be connectable in terms of vascular anatomy . The goal is to maintain a dropout rate of no more than 50% for grafts that either fail quality assessment via NMP or cannot be successfully transplanted despite undergoing NMP quality assessment. Additionally, the organ must not yet have been treated using a dynamic preservation procedure (HOPE or NMP). Allocation of Discarded Grafts The allocation of declined liver grafts to patients in the experimental arm of the study is carried out by `Eurotransplant´ and enables the rapid allocation of declined liver grafts to patients in ExTra study centres according to the “first-come-first-serve principle”: Liver accepted, procured, transported to a German centre, and considered non-transplantable: Competitive offer to centres in the DSO-region where the liver is located or Offer to procurement centre. Liver accepted, procured, and considered non-transplantable at donor hospital: Competitive offer to centres in the DSO-region where the liver is located (including the procurement centre). Liver accepted, procured, transported to a non-German centre, and considered non-transplantable: Competitive offer to centres in the closest* DSO-region where the liver is located or Offer to procurement centre* [*land-based transportation only] Liver not accepted until 3rd line rescue allocation and not procured: Competitive offer to centres in the DSO-region where the liver is located. Organ procurement and NMP The liver grafts are retrieved by the local donor teams of the according to established clinical protocols, stored in preservation solution on ice, and transported to the study centre until NMP begins. Declined grafts are subjected to an end-ischemic "Back-to-Base" NMP, with either the OrganOx Metra or the XVIVO LiverAssist device currently being used, as both systems are CE-marked medical devices by the respective manufacturers and have published data for quality assessment of initially non-acceptable liver grafts. The perfusion is carried out according to the manufacturer's instructions (under MDR) (OrganOx Metra: according to the recommendations from the manufacturer in Oxford; LiverAssist: according to the specifications from XVIVO B.V. (Netherlands) following the Groningen protocol) under the responsibility of the participating study centres. Grafts remain in NMP until the recipient's hepatectomy is completed or are removed from the device and preserved again by static cold storage if the perfusion time exceeds the validated perfusion duration (OrganOx: 24 hours of perfusion; LiverAssist: 6 hours of perfusion according to the manufacturer's specifications). Criteria for Quality Assessment Quality assessment using NMP in the experimental arm is performed according to previously published viability criteria for initially declined liver grafts, which are mandatory for all participating study centres, with minor device-specific modifications. These criteria are based on the Birmingham criteria used in the VITTAL trial for viability assessment of DBD and DCD grafts with the OrganOx Metra device and are comparable to the Groningen criteria previously established with the LiverAssist device, with the exception of biliary viability parameters, which were required for the assessment of DCD grafts (12, 15, 17). The decision to use or reject a graft after quality assessment by NMP (i.e. start of recipient hepatectomy) is made at least 4 hours after the start of perfusion by the transplant surgeon, based on: Lactate clearance 7.30 (without correction for at least one hour) Glucose metabolism (falling perfusate glucose value with consistent downward trend) Maintenance of stable arterial and portal venous flows (OrganOx Metra: 150 and 500 mL/min respectively) Homogeneous perfusion with soft consistency of the parenchyma Methods: Participants, interventions and outcomes Study setting {9} This multicentre RCT will be performed in participating German academic hospitals with an active liver transplantation program in addition to experience with NMP of liver grafts and a NMP device on-site. Initiating centre is the Department of Surgery Campus Charité Mitte | Campus Virchow-Klinikum, Charité – Universitätsmedizin Berlin. Participating study centres will be added to the clinicaltrials.gov registry entry. Eligibility criteria {10} Eligible are all adult patients (≥18 years) listed for liver transplantation who have a ReMELD-Na-Score ≤ 21 points and do not have the option of receiving Standard or Non-Standard Exception points. Inclusion Criteria Able to consent ≥ 18 years old Listed as status “transplantable” by the transplant conference of the study centre for liver transplantation, according to the guidelines of the German Medical Association valid at the time of inclusion ReMELD-Na ≤2, not eligible for Standard or Non-Standard Exceptions Standard and Non-Standard Exceptions are defined in the Eurotransplant liver allocation manual chapter 5.1.14. A list of applicable Standard Exceptions points for Germany can be found in chapter 5.10.4, Non-Standard Exceptions are evaluated by external auditors (chapter 5.9.1.4) Medically suitable and informed for transplantation with an organ that fulfils extended donor criteria (Eurotransplant ECD criteria) Patient information and written consent to participate in the Extra trial No participation in another interventional study during participation Exclusion Criteria Listed for retransplantation High-Urgency Listing Listed for combined organ transplantation Pregnancy Who will take informed consent? {26a} Before inclusion in the study (e.g. randomization), each patient is informed by the local study physician in charge about the nature, objectives, expected benefits and possible risks of the study, both orally and in writing. Each patient must declare his or her written consent to participate in the study. The patient must be given sufficient time and opportunity to decide on his or her participation and to clarify any open questions before the study measures are initiated. The informed consent is signed and personally dated by the patient and the treating physician. If the patient can give consent but is unable to sign personally, a witness must confirm the oral explanation by signing. Additional consent provisions for collection and use of participant data and biological specimens {26b} Patient will need to provide additional consent as an “opt-in” for collection of blood, perfusate, bile and liver tissue for future research. These samples are intended for translational studies, identifying potential biomarkers for outcome prediction. Interventions Explanation for the choice of comparators {6b} Patients waiting for a liver graft have a high mortality, and the waiting time for transplantation is significantly longer for patients with a low MELD score. Therefore, it is justified to offer a liver graft that has been initially declined in the regular organ allocation system but is deemed objectively suitable through quality assessment via NMP. The option to receive a liver graft through the regular allocation process remains available to all study participants. The intervention—although it is not yet the clinical standard and data from comparable donor and recipient populations in Germany are still lacking—is based on a series of international study results on the quality assessment of initially declined grafts through NMP for patients with a low MELD score. The study will either provide a foundation for the routine use of NMP for quality assessment of initially declined liver grafts, which would increase the number of available liver grafts in Germany or show that this option is not feasible for the German donor and recipient population. Additionally, the study, through standardized biomarker collection, will provide insights into the assessment of marginal grafts and may reveal future opportunities to save such organs, addressing the imbalance between the supply and demand of donor organs. Intervention description {11a} After randomization, patients are randomized to either the intervention or control arm for 12 months. In the control arm, patients receive a liver graft following the regular allocation procedure. In the ExTra trial arm, there is the option of: receive a liver graft with a graft that has been declined by all German transplant centres but meets established objective viability criteria at the NMP (ExTra-LT), or receive a liver graft via the regular liver allocation process (LT) when a graft becomes available - whichever comes first. If patients are not transplanted within 12 months, they continue to be regularly listed on the waiting list without the possibility of option 1 and are censored. As part of the ExTra LT quality assessment, the liver is removed from the cold preservation solution in the transplant centre in an end ischemic “back-to-base” approach, prepared, cannulated and connected to the liver perfusion machine according to the respective manufacturer's specifications. A prerequisite for the quality assessment is an evaluation time of at least four hours under normothermic conditions (37°C). The quality criteria listed under 8.1 apply. If the liver fulfils the above criteria after 4 hours of perfusion and is assessed as transplantable based on the assessment of the transplant surgeon in charge, the recipient is then initiated for surgery and the liver is transplanted. Both patients who receive an ExTra LT or a liver graft after standard allocation are followed up in hospital and after discharge at regular intervals. Criteria for discontinuing or modifying allocated interventions {11b} Participation in the ExTra trial is voluntary, and participants have the right to withdraw from the study at any time at their own request and without giving reasons. This will not have any negative impact on the patient's medical treatment. A discontinuation of participation occurs when a patient withdraws his or her consent or decides against further participation. If possible and the patient is willing to provide information, the reason for the discontinuation will be asked for and documented, but without putting pressure on the patient. The following events can be considered as discontinuation criteria: Personal wish of the patient: The patient can withdraw from the study at any time and without giving reasons. Pregnancy: Pregnancy is a criterion for exclusion to avoid potential risks to the foetus and the mother. Serious complications or side effects: SAE/SADE Significant protocol violations: Exclusion may occur in the event of significant deviations from the study protocol. Non-compliance with the requirements specified in this study protocol without sufficient justification. Examples of this may include the registration of a recipient who does not meet all the inclusion/exclusion criteria, or the omission of visits or inadequate documentation of these. Loss of contact, change of location or change of treating physician : If the patient can no longer be reached or changes the location or physician of treatment, so that further participation in the study is no longer possible, this may result in early withdrawal. In addition, there are specific criteria that can lead to exclusion: Withdrawal of consent to accept livers with expanded donor criteria : Should the patient withdraw consent to accept livers that meet the expanded donor criteria, study participation will be terminated. Organ failure requiring combined organ listing : Should there be an organ failure of another organ (e.g. heart or kidney) requiring combined listing for multiple organs, the patient will be excluded from the study. Disease progression while listed as non-transplantable: If a patient is deemed non-transplantable due to an infection or other event and the ReMELD-Na is >21, patients are not directly excluded. The period of non-transplantable status is documented, and the MELD score reevaluated once the patient reaches a transplantable state. Only if the patient is listed as status as transplantable and the ReMELD-Na remains >21 points, patients can no longer participate in the study. Survival data is censored up until this point. Strategies to improve adherence to interventions {11c} Patients are managed by the respective study centre as part of the waiting list management for liver transplantation. This includes, for example, regular blood samples for updating the MELD score to determine urgency. As part of the study, compliance is expected to be similar to the waiting list for liver transplantation. Ensuring compliance is the responsibility of the respective study centres or the transplant program. No further measures are necessary for the patients. After liver transplantation, regular check-ups/study visits (V3-V5) are organized via the respective liver transplant outpatient clinic. These measures are also part of the regular course of follow-up care for liver transplantation. As the patients are also examined psychosomatically as part of the evaluation for liver transplantation regarding their presumed compliance, a high level of adherence can be expected. Relevant concomitant care permitted or prohibited during the trial {11d} Parallel study participation is not planned. Patients who are currently in an interventional clinical trial cannot be included. Likewise, participants in the ExTra trial will not be able to participate in further interventional studies during the intervention phase (i.e. 12 months after study inclusion) and a further 12 months after transplantation during the intervention phase. It will be mentioned in the patient information that the participant may not participate in several studies at the same time. If a study participant is included in several interventional studies and this becomes known to the study management, he/she will be excluded from the study and the responsible study centre may be closed. Provisions for post-trial care {30} After participation has ended, there will be no further active follow-up as part of the study. All data collected will be evaluated in the context of the final analysis using pseudonyms to fulfil the study objectives. Outcomes {12} Primary Endpoint: „Time-to-Transplant“ defined as the time period between randomization and transplantation Safety Endpoint: 3-month graft and patient survival, defined as the need for retransplantation or death within the first 3 months after ExTra-LT. The DSMB will evaluate these data on a quarterly basis. Secondary endpoints: Competing Events Death Disease Progression ReMELD-Na >21 while listed as “transplantable” Contraindication for liver transplantation Recovery (no transplantation required) Number of patients listed for transplantation after 12 months Overall patient survival (from randomization to death) Quality of Life (EQ5DL) Graft utilization rate (Used organs / Offered organs on the waiting list)) Cost-effectiveness (Transplantation-associated costs) Other endpoints for patients who receive a liver transplantation during the 12-month intervention period: Early graft function (measured by the Early Allograft Failure Simplified Estimation (EASE) Score) & Balance of Risk (BAR) Score Duration of intensive care unit stay Length of hospital stay Comprehensive Complication Index (CCI) Biliary complications Ischemic-Type Biliary Lesions (clinically and as part of the planned MRCP 12 months after liver transplantation) 1-year patient survival (post-transplantation) 1-year graft survival Acceptance rate (1 / number of unrealized organ offers [accepted for the patient either primarily or within the extended/rescue allocation but not transplanted]) Graft-Rescue Rate (livers that meet quality criteria during NMP / all organs assessed through NMP in the study) Translational Outcomes: Biomarkers in tissue, perfusate, bile, and laboratory chemistry for outcome prediction (Early Allograft Dysfunction according to the criteria of Olthoff et al. (17) as well as 3-month graft survival) through NMP Including DNA and RNA analyses for the aforementioned purpose and future research (i.e., the purpose of the analyses will be determined in the future). Explanation of the clinical relevance of efficacy and harm outcomes The goal of the Extra trial is to demonstrate that the waiting time for liver transplantation in patients with a ReMELD-Na-Score ≤21 without access to Standard or Non-Standard Exceptions can be significantly reduced by utilizing liver grafts that were initially deemed non-transplantable based on clinical criteria but meet predefined quality criteria after 4 hours of NMP, compared to patients who are not offered this option. This is of particular clinical relevance given the increasing number of organs that are declined in Germany, despite new technologies enabling quality assessment of these potential liver grafts. The utilization rate of the grafts, safety, and cost-effectiveness will be evaluated as secondary endpoints. The results of this study could therefore change clinical practice and help address the medical-social dilemma of organ shortages in liver transplantation by integrating transplant quality assessment through NMP into clinical practice. This would enable the acceptance of livers that are currently declined and could therefore significantly increase organ utilization in Germany. To further clarify the impact of this clinical study, a translational evaluation will be conducted to identify novel biomarkers for assessing and predicting graft quality in NMP. The required platforms are available at Charité – Universitätsmedizin Berlin. Participant timeline {13} The proposed study duration is 66 months (01/06/2025 – 30/11/2030). The study will commence recruitment on June 1 st , 2025, with an anticipated recruitment period of 36 months, concluding on May 31 st , 2028. Each participant will be enrolled in the study for a maximum duration of 24 months, comprising an intervention phase of up to 12 months, followed by a 12-month follow-up period after transplantation. The final participant follow-up is expected to be completed by May 31 st , 2030, after which the study will proceed with data analysis and dissemination activities. The study is scheduled to conclude by November 30 th , 2030. The flow of participants throughout the study is summarized in Figure 2, while all trial procedures are detailed in Table 2. Deviations from Standard Medical Examination Practice In the context of the study, three points deviate from the standard care: Quality assessment using NMP (as a quality assessment tool in the Extra trial arm as part of the study), The storing of blood, tissue, bile and perfusate samples for the central biobank, and Routine MRCP (magnetic resonance cholangiopancreatography) 12 months after liver transplantation. It is important to distinguish between biological samples that are needed to assess the quality of the NMP or to assess the immediate postoperative course and are used as part of the ExTra trial, and samples that are collected and stored for future research (Biobank ZeBanC, optional). In detail, this means: ExTra-Study: Normothermic Machine Perfusion (NMP) Device-independent (currently usable: XVIVO LiverAssist or OrganOx Metra), provided that clinical data for quality assessment of declined liver grafts are available At least 4 hours of Quality Assessment V2.2.5 - V2.2.9 are therefore optional for perfusion times >4h Opt-In : Biobank (via ZeBanC) for future research ZeBanC provides all centres with sample collection and aliquoting sets ( including stretching tubes ) as well as a coordinated set of instructions for the processing and transport of the samples. Sample processing and documentation is carried out at the centres by the study personnel there Transfer of samples on dry ice. Transportation costs are covered by the project. Blood will be collected from the patient before liver transplantation, 1 hour after reperfusion and on postoperative days 1 and 3. Blood samples will be taken regularly as part of preoperative care and postoperative follow-up. Thus, only additional material will be collected as part of the study. A wedge biopsy of the liver is performed before machine perfusion or after completion of organ preparation, after completion of NMP (ExTra arm only) and 1 h after reperfusion. The perfusate is taken before, 15 minutes after the start of perfusion, every hour after the start of perfusion and at the end of the NMP (ExTra LT study arm only). Bile is collected every 2 hours during the perfusion and at the end of the NMP (ExTra LT study arm only). ExTra-Study: MRI Abdomen with MRCP – Evaluation of biliary complications A routine MRCP will be performed 12 months after liver transplantation to assess biliary complications. The examination should be performed at 1.5 T or 3T. Essential sequences are axial and coronal T2-weighted, 3D and 2D MRCP, diffusion-weighted imaging (DWI) and T1-weighted in-phase/out-of phase sequences. Contrast-enhanced imaging with Gadolinium is optional but recommended for vascular and perfusion assessment. Hepatobiliary contrast agents can also be used if clinically indicated. An exemplary protocol is provided in table 1. The costs are covered by the project. Medical History Comprehensive medical history will be documented for each participant, including Age Height Weight Gender Blood group Indication for LT labMELD/ReMELD-Na Pre-existing conditions Waiting List Participants' organ offers on the waiting list will be recorded. Type of offer Number of offers Reason for turn-down Period of non-transplantable status Laboratory Values Regular laboratory tests will be conducted to monitor the patient's clinical condition. These include: Blood count AST ALT GGT AP Bilirubin INR Creatinine Urea Donor Information Donor-related data will be collected to evaluate organ quality and compatibility. Relevant parameters include: Donation Date Blood Group Rh Factor Age Height Weight HCV Ag HBc Ab HIV Ag Split Donation Centre Cause of Death Noradrenaline Leukocytes Thrombocytes Sodium Potassium Creatinine Urea AST ALT GGT AP Bilirubin INR PT CRP Cold ischemia time Frozen section results Preoperative Transplant Candidate Status The participant's condition prior to transplantation will be assessed through various preoperative indicators. labMELD/ReMELD-Na Dialysis Ventilation Noradrenalin Other catecholamines Time on waiting list Quality Assessment with NMP Normothermic machine perfusion (NMP) will be employed for organ quality assessment. Data collected include Lactate Bile Perfusate-pH Glucose in perfusate Arterial Flow Portal Flow Parenchyma appearance Postoperative Transplant Recipient Status Postoperative monitoring will focus on: Dialysis Ventilation Noradrenaline Other catecholamine Packed red blood cells (intraoperative) Fresh Frozen Plasma (intraoperative) Platelet concentrates (intraoperative) Prothrombin complex concentrate Tranexamic acid Fibrinogen Progress Information Long-term follow-up will include Postoperative complications Complication Management Other special features during treatment Rejection Re-admission to hospital Length of stay in hospital (upon discharge) Length of stay in intensive care (upon discharge) Dialysis Retransplantation Relisting Death Biliary Complications Costs Revenue Profit Biobank Biological samples will be collected for future research. These include : Patient blood Tissue (prior to machine perfusion, 15 minutes on pump, at the end of perfusion, after reperfusion in situ) Perfusate Bile Sample size {14} The primary statistical objective is to show that the cause-specific hazard ratio for the transplant risk between the two randomized groups is not equal to 1. The assumptions for the data-generating process are based on current data from the European Liver Transplant Registry in 2022: Within 12 months, 43.6% of patients with a ReMELD-Na ≤ 21 who were not eligible for Standard or Non-Standard Exception were transplanted, 19.1% had a competing event (death, progression or recovery), and 37.2% remained on the waiting list and were censored in this study. As a treatment effect, an increase in the transplantation rate of 20 percentage points to 63.6% was assumed, while the risk of the competing event remains unchanged. A 20% increase in the transplantation rate through the ExTra option is realistic, as 385 liver transplantations were performed in Germany in 2022 in patients with ReMELD-Na ≤ 21 without extraordinary MELD criteria, while 133 of 217 declined grafts would have been potentially acceptable after a quality assessment using NMP, representing approximately 20% additional grafts in the study population based on an estimated 50% acceptance rate following NMP. Assuming exponential distributions for time to transplant and time to competing event, the data were simulated to fit this pattern. The parameter of the exponential distribution for time to transplant (in months) was 0.057 for the control group and 0.104 for the intervention group. The parameter for the competing risk was 0.0251 for both groups. A Cox proportional hazards model was used to estimate the transplant hazard ratio between the ExTra LT group and the control group. Based on 1,000,000 simulations, a sample size of N=83 per group was calculated for a two-sided type I error of 0.05 and a power of 0.8. Considering a dropout rate of 10%, a total of 93 patients will be recruited per group. A median of 36 transplantations is expected in the control arm. It is expected that 4-29 additional transplantations (median: 17) will be performed in the experimental arm. This number of cases can probably be reached with a recruitment period of 36 months. A 12-month intervention phase is planned, followed by a 12-month follow-up phase. The study will thus end when all 83 patients in each treatment group have completed the 12-month follow-up after randomization/transplantation. Recruitment {15} All patients with a ReMELD-Na ≤21 without eligibility for Standard or Non-Standard Exceptions, who are listed in the status transplantable for liver transplantation, and medically suitable and informed for transplantation with so-called marginal organs from donors who meet extended donor criteria, will be recruited for the ExTra trial at the respective study centres. It is up to the respective study centres to decide whether the patients are suitable to receive livers from donors who meet the extended donor criteria. For this purpose, regular information must be provided as part of the listing for liver transplantation. The primary recruitment measure should be a personal discussion as part of the information on liver transplantation during consultation hours, which must take place before listing. For this purpose, the respective doctors providing information and the transplant office in the recruiting centres will be informed and sensitized. In addition, information flyers will be made available in the respective transplant outpatient clinics so that potential study participants can inform themselves independently. All patients who present themselves personally on the waiting list as part of routine management (e.g. laboratory check for the MELD score) and fulfil the inclusion criteria should also be contacted personally. Based on the current number of patients on the waiting list and the multicentre study design, as well as the long recruitment period, the achievability of the specified number of patients is given. The calculation of the number of cases was based on a drop-out rate of 10%; no further replacement of patients in the study arms is planned. We assume that there will be no screening failures due to the high degree of regulation of organ transplantation. Assignment of interventions: allocation Sequence generation {16a} Patients are randomised as block randomisation in a 1:1 ratio and is centrally managed through the eCRF. This means that patients will be evenly distributed between the two study arms (control group with standard allocation and experimental group with the ExTra option). To ensure an even distribution of key clinical characteristics across both treatment arms, the randomization will be stratified according to the following prognostic variables: ReMELD-Na-Score at the time of transplantation (6 months) Concealment mechanism {16b} This trial is conducted as an open-label study without blinding; therefore, no concealment of the allocation sequence is required. Participants will be assigned to study groups based on the predetermined randomization process, which will be centrally managed to ensure transparency and adherence to the study protocol. Since both participants and investigators will be aware of the assigned interventions, no additional measures such as sealed envelopes or central telephone randomization will be implemented. Implementation {16c} The allocation sequence will be generated by an independent statistician using a computer-based randomization system via the eCRF to ensure an unbiased assignment of participants. Participant enrolment will be carried out by designated study investigators at each participating centre. They will assess eligibility based on predefined inclusion and exclusion criteria before obtaining informed consent. Assignment to interventions will be conducted centrally by the study coordination team, following the generated allocation sequence. Since this is an open-label trial, both participants and investigators will be informed of the assigned intervention upon enrolment. Assignment of interventions: Blinding Who will be blinded {17a} This trial is conducted as an open-label study without blinding. All involved parties are aware of the treatment group. Procedure for unblinding if needed {17b} No Procedure for unblinding is necessary, as this is an open-label study. Data collection and management Plans for assessment and collection of outcomes {18a} A comprehensive data management plan will be created to define the processes for data handling, cleaning, and quality control in the trial. The key aspects are summarized below: Data collection Data collection is carried out using electronic case report forms (eCRFs). The secuTrial study software is used for this purpose. The study data is recorded online and transferred directly to the study server's database. The data transfer between the workstation (at the trial site) and the study server is carried out via a secure connection (SSL encryption) so that the transferred study data cannot be manipulated. Patient data is only stored in pseudonymized form. The study software automatically generates a pseudonym for each new patient to be added. The unambiguous assignment to the patient is done via a paper printout, which will be stored securely. All patient-related data are recorded in pseudonymized form. For this purpose, a non-descriptive pseudonym is used from which the patient's identity cannot be inferred on its own. To obtain unique patient identification numbers, a combination of a fixed trial centre number and a consecutive centre-specific patient number is chosen. The patient identification number is assigned centrally as part of the internet-based randomization. Each principal investigator (principal investigator at the trial site) maintains a patient identification list in which the patient identification numbers are linked to the full patient names of the participants, patient identification numbers and, if applicable, date of birth. This list serves to enable the later identification of participating individuals. It must be treated with absolute confidentiality and must not leave the trial centre. Only the local study team and the monitor have access to this list. The original files can be viewed by monitors, auditors and inspectors. The patient identification list must be archived for at least ten years after the end of the study. In addition, the participation of relevant individuals in the study is noted in the respective patient file . Monitoring Monitoring is carried out by means of regular on-site visits and an internal review of data quality. The frequency of on-site visits is based on an assessment of all study characteristics, including the type, objective and methodology of the study. A risk-based approach is applied as described in the monitoring plan. Clinical monitoring is conducted according to the monitoring plan. It includes, but is not limited to, the review of laboratory values and adverse events. The investigator allows for study-related monitoring at the site, audits, IEC reviews, and inspections by local or state health authorities, if regulated by local law. Direct access to the electronic Case Report Form (eCRF) and to all source documents, including medical records, laboratory reports and medical test results, is provided to ensure verification by the Clinical Research Associates (CRA), auditors and regulatory inspectors. All eCRFs and informed consent forms are available for inspection. The accuracy of the recorded data is ensured by direct comparison with the source documents. The sponsor also monitors compliance with the study protocol and other relevant legal requirements. Plans to promote participant retention and complete follow-up {18b} To minimize attrition and ensure comprehensive data collection, participants will receive detailed information about the study, its objectives, and the importance of follow-up assessments during the informed consent process. A dedicated study coordinator will serve as the primary contact for all study centres, maintaining regular communication. Given the complexity of liver transplantation and the extended follow-up period required, follow-up trial visits will be tried to co-align with regular post-transplantation examinations in the respective outpatient clinic of the study centre. All reasons for withdrawal or protocol deviations will be documented systematically, allowing for an analysis of potential impacts on study outcomes. Retention strategies will be continuously evaluated throughout the study, with regular assessments of adherence rates and the identification of potential barriers to follow-up. The study team will monitor participant engagement and proactively address challenges that may affect retention. Data management {19} Data recording and record keeping Data collection is done via a server-based electronic CRF (eCRF) with remote data entry (RDE). The trial site/sponsor stores all data electronically. All entries in the CRF are checked for plausibility and consistency immediately during data entry. These checks generate “soft” or “hard” warnings and prompt the user to recheck and possibly change the data before the information is/can be saved. The checks are planned with the principal investigator and incorporated after confirmation. Additional checks must be defined in the study-specific data validation plan (DVP). These checks are/can be very complex and are carried out in SAS/R at specific points in time (milestones, time frames, specific dates) after the database information has been exported. In addition, the responsible data manager checks the exported data sequentially for implausibility over the entire period of the study. Inconsistencies, implausible or missing data are flagged by a data management query in the eCRF. The potentially incorrect information can be corrected by directly changing the values in the eCRF or must be marked as accepted errors or false reports. Changes to the documented information are tracked via the audit trail, which is a basic function of the eCRF. Most incorrect data are corrected within the eCRF. A data correction performed by data management (SEC - self evidence correction, documented deletion of incorrect data) can be added as a second level of control. All missing data or inconsistencies must be resolved by the responsible investigator before the database is locked (soft lock/hard lock). Detailed information on deviations from the protocol can be documented in the study software, either as patient-independent/site-specific or patient- or drug-specific protocol violations. After completion of the study and after all data entry has been finalized, the database is closed for further data entry. This process is documented. Data Storage and Access to Data The originals of all central study documents, including the documentation forms, are stored at the study centre (with the study director) for at least 10 years after completion of the clinical study. The investigator/head of the trial centre stores the administrative documents that have been created (correspondence with the ethics committee, principal investigator, trial centre), the patient identification list, the signed declarations of consent, copies of the documentation sheets and the general trial documentation (protocol, amendments) for the above-mentioned period. The original data of the study patients (medical records) must be stored for the archiving period applicable to the study sites (the investigators), but for no less than 10 years. Confidentiality {27} The data protection requirements of the GDPR, the Federal Data Protection Act (BDSchG), and the State Data Protection Acts (LDSchG) all apply. As part of the study, it is necessary to collect and process personal data (e.g. full name, initials of first and last name, date of birth, address) and data on treatment and disease progression (e.g. medical findings, types of treatment, prescribed medications) from the study participants. These data are collected at the study centre and stored electronically in pseudonymized form (i.e., without direct reference to the patient's name) with the help of a patient identification number, transmitted to the responsible data processing centre and evaluated. In the event of a patient's revocation of consent to the study, including further data collection, no further data will be collected from the time of revocation. The data collected so far will continue to be used and evaluated within the study. If a patient only discontinues the study treatment, the data required for the study can continue to be collected and used. Patients are informed that their disease-related data will be stored in pseudonymized form and used for scientific evaluations (publications). Patients have the right to be informed about the stored data. Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} Biological specimens collected for future studies will be processed, stored, and managed through the central biobank at the Charité – Universitätsmedizin Berlin (ZeBanC), ensuring standardized and high-quality sample handling across all participating centres. ZeBanC provides all centres with specialized sample collection and aliquoting sets, including stretching tubes, along with detailed procedural instructions to ensure uniform sample processing, documentation, and transport. Blood samples will be collected at multiple time points, including before liver transplantation, one hour after reperfusion, and on postoperative days one and three. These samples will include 10 mL of serum, 10 mL of EDTA whole blood, and one PAXgene Blood DNA sample. Since blood sampling is a routine part of preoperative care and postoperative follow-up, only additional material necessary for the study will be obtained. In addition to blood, a wedge biopsy of the liver will be performed before machine perfusion or after organ preparation, after completion of normothermic machine perfusion (NMP) in the ExTra arm, and one hour after reperfusion. Perfusate samples will be collected at defined time points, including before the start of perfusion, 15 minutes after initiation, at hourly intervals during the procedure, and at the conclusion of NMP in the ExTra LT study arm, with 1.5 mL per sample. Additionally, bile samples will be collected every two hours during perfusion and at the end of NMP in the same study arm, with 1 mL per sample. Sample processing is conducted on-site by trained study personnel at each centre following standardized protocols to ensure consistency. Th For transportation to ZeBanC, all samples will be transferred to dry ice to maintain the integrity of the biological materials during transportation. The transportation costs will be fully covered by the project. Statistical methods Statistical methods for primary and secondary outcomes {20a} Hypotheses: The primary null hypothesis to be rejected is that the cause-specific hazard ratio for transplant risk between the two randomized groups is equal to 1. Consequently, the alternative hypothesis is that the cause-specific hazard ratio for transplant risk between the two randomized groups is not equal to 1. Intent-to-treat population The primary statistical analysis is based on the intention-to-treat population. This consists of all randomized patients and includes the group allocation as specified by the randomization. This means that the patients are analysed independently of protocol violations (which are not an exclusion criterion). Transplanted cohort Secondary analyses will be conducted in the cohort that received a liver graft during the 12-month intervention period. Population for the safety analysis The population for the safety analysis includes all patients who were randomized. Primary endpoint The primary endpoint of time-from-randomization-to-transplantation is evaluated on the intention-to-treat cohort, the hazards between the ExTra LT group and the control group are compared using cause-specific Cox proportional hazards models. The intervention effect is given in the form of the hazard ratio with 95% confidence interval, and it is tested whether this differs from 1. Death on the waiting list, disease progression (ReMELD-Na >21 at listing with transplantable status or contraindication of liver transplantation) and recovery (transplantation no longer necessary) are considered as competing events. Patients who have not yet received a graft after 12 months and are therefore still on the waiting list are administratively censored. In the Cox proportional hazards analysis, it is adjusted for the centre effect, ReMeld-Na-Score at the time of transplant (6 months). A two-sided significance level of 5% is used. In addition, the probability of transplantation for both groups are calculated using Aalen-Johansen estimators (Kaplan-Meier for competing risks) with 95% confidence intervals based on a complementary log-log transformation and displayed over time. Competing events The secondary endpoints include, among others, competing events (death, disease progression, recovery) and are also evaluated on the intention-to-treat cohort. Again, the time from randomization until the occurrence of the event is examined. For death (corresponds to waiting list mortality) and the composite of disease progression and recovery, cause-specific Cox proportional hazards models are calculated. The same variables as for the primary endpoint are used for adjustment (centre effect, ReMELD-Na-Score at the time of transplantation (6 months), perfusion device used (OrganOx Metra or LiverAssist), and age and sex). The effect of the intervention on the competing events is given in the form of the hazard ratio with 95% confidence interval and it is tested whether it differs from 1. These analyses are accompanied by the Aalen-Johansen estimates with 95% confidence intervals of the ExTra LT group and the control group. These reflect the estimated probability of the competing events since randomization. Differences between the curves are discussed regarding all cause-specific hazard ratios. Secondary endpoints The overall survival of patients between randomization to the end of follow-up (maximum 24 months) is examined in the intention-to-treat cohort using Kaplan-Meier analyses. The Kaplan-Meier curves of the ExTra LT group and the control group are compared using the log-rank test. A significance level of 5% is applied. A Cox proportional hazards regression is used to adjust for the influence of the variables centre effect, ReMELD-Na-Score at the time of transplantation (6 months), perfusion device used (OrganOx Metra or LiverAssist), as well as age and gender. The number of patients listed for transplantation in each group after 12 months will be descriptively described. Likewise, the utilization rate (used organs / offered organs) will be descriptively analysed. Furthermore, the “graft rescue rate” (livers that meet the quality criteria during NMP / all livers that were assessed by NMP as part of the study) will be descriptively presented. Quality of life will be assessed using EQ5DL and the differences in the course of time compared to the value for randomization between the two intervention groups are compared. The costs associated with transplantation or hospitalization for transplantation between the groups are modelled using linear regression. The dependent variable is costs, and the independent variables are ExTra LT or control group, centre, ReMELD-Na-Score at the time of transplantation (6 months), perfusion device used (OrganOx Metra or LiverAssist), and BAR score. 1-year graft and 1-year patient survival will be compared using Kaplan-Meier analyses in the cohort of transplanted patients. In addition to the comparison between the two study arms, the grafts that took place with livers that met the quality criteria during NMP will be compared with the standard grafts. The other secondary endpoints in the cohort of graft recipients, Ease score, Balance of Risk (BAR) score, duration of stay in the intensive care unit, length of hospital stay, Comprehensive Complication Index (CCI) and biliary complications (ischemic-type biliary lesions (clinical and as part of the planned MRCP 12 months after liver transplantation) are analysed according to their scale level and distribution function using adequate statistical methods. Interim analyses {21b} The DSMB will assess the safety endpoint of 3-month graft and patient survival defined as the need for retransplantation or death in the first 3 months after liver transplantation (ExTra LT) using Kaplan-Meier analysis. The pseudonymized reporting of the safety endpoints is planned at the beginning of each quarter via the principal investigator to the DSMB members. Depending on the results, the DSMB may recommend to the principal investigator that the study be terminated. Methods for additional analyses (e.g. subgroup analyses) {20b} Further secondary exploratory endpoints include translational investigations. These involve the use of biomarkers in tissue, perfusate, bile and laboratory chemistry, as well as other aspects of DNA and RNA analyses by NMP to predict outcome (early allograft dysfunction according to the criteria of Olthoff et al. (17) and 3-month graft survival). Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} The analysis population will follow an intention-to-treat (ITT) approach, meaning all randomized participants will be analysed according to their originally assigned study arm, regardless of protocol deviations or adherence to the intervention. This ensures that the estimated treatment effects reflect real-world applicability while preserving the benefits of randomization. For cases of protocol non-adherence, including recipients who withdraw after implantation, all available data will be included in the analysis. The primary outcome, time-to-transplant, will be assessed using a cause-specific Cox proportional hazards regression model, accounting for competing risks such as clinical improvement, deterioration, or death, which may preclude transplantation under the ExTra study conditions. Missing data will be addressed through multiple imputation methods when feasible. The feasibility of imputation will depend on the proportion of missing data, the availability of auxiliary variables, and the assumption that missingness is at random. Data integrity will be maintained through real-time monitoring in the electronic Case Report Form (eCRF), where inconsistencies, implausible values, or missing data points will trigger data management queries. Investigators will be required to address all flagged issues before the database lock (soft lock/hard lock). Corrections can be made directly in the eCRF, and if necessary, a self-evident correction (SEC) process will be applied, with all changes documented in an audit trail. Plans to give access to the full protocol, participant level-data and statistical code {31c} Authorized representatives from the sponsor and the host institution will be granted direct access for trial-related monitoring, audits, and inspections. To ensure thorough verification, direct access to the electronic Case Report Form (eCRF) and all source documents, including medical records, laboratory reports, and medical test results, will be provided to auditors, and regulatory inspectors. All eCRFs and informed consent forms will be available for inspection. Oversight and monitoring Composition of the coordinating centre and trial steering committee {5d} Trial Management Team The trial management team consists of the principal investigator, the coordinating investigator and the study coordinator. The trial management team will be responsible for running the day-to-day necessities of the trial, coordinating study sites, and communicating with the steering committee and the DSMB. Trial Steering Committee The Steering Committee is responsible for providing scientific advice regarding the study. This committee will meet regularly, virtually or in person, to monitor subject recruitment, study progress, and compliance with the protocol. This committee is responsible for reassessing the benefit-risk ratio based on the recommendations of the DSMB, for decisions on discontinuing the study, for reviewing the results, for determining the presentation and publication methods, and for selecting secondary projects and publications. Composition of the data monitoring committee, its role and reporting structure {21a} The Data Safety Monitoring Board (DSMB) consists of four independent physicians, two hepatologists and two transplant surgeons. Prof. Julia Wendon (UK) has earned an outstanding international reputation in the care of critically ill patients with liver disease. Prof. Christoph Roderburg (Germany) has extensive experience in conducting clinical trials in hepatology and gastroenterology but is not involved in the care of liver graft recipients. Prof. Markus Selzner (Canada) and Prof. Madhukar Patel (USA) have in-depth expertise in the quality assessment of declined liver grafts by NMP (e.g. NCT 02478151, Toronto). The DSMB will discuss the study protocol, the necessary safety mechanisms and the review of the safety endpoint with the principal investigator before the study begins. The rights and obligations are contractually regulated. The “Guideline on data monitoring committees” of the European Medicines Agency (EMEA/CHMP/EWP/5872/03 Corr) serves as a guideline. The DSMB will assess the safety endpoint of 3-month graft and patient survival defined as the need for retransplantation or death in the first 3 months after liver transplantation (ExTra LT) using Kaplan-Meier analysis. The pseudonymized reporting of the safety endpoints is planned at the beginning of each quarter via the principal investigator to the DSMB members. Depending on the results, the DSMB may recommend to the principal investigator that the study be terminated. Adverse event reporting and harms {22} Since two medical devices (according to §2 (1) MDR) can be used in the intervention arm in the ExTra trial, the vigilance definitions of AE, SAE and DD of the MDR apply. In addition, further legal definitions of the national legislator may have to be considered. In the present study, the medical devices (with CE marking) are used within the scope of the intended purpose as specified by the manufacturer, without the use of additional invasive or stressful procedures (in accordance with §47(3) MPDG). In this study, vigilance measures are conducted according to the study design and risk-benefit ratio. The study director assesses adverse events and takes any necessary measures. Since the ExTra trial does not evaluate the performance or safety of a medical device, but rather compares the use of two CE-marked medical devices in the intervention arm (according to the manufacturer's intended purpose) with the standard of care, the reporting of suspected serious incidents in accordance with MPAMIV (see 11.1) is carried out by the trial centres/users or operators in accordance with national rules and regulations. Vigilance Definitions (MDR and MPAMIV) Term Definition Adverse event (AE) (acc. to Art. 2(57) MDR) „Adverse event” means any untoward medical occurrence, unintended disease or injury, or unfavourable clinical symptom, including abnormal laboratory findings, in subjects, users or other persons, related to a clinical investigation, even if not related to the investigational device; Serious adverse event (SAE) (acc. to Art. 2 (58) MDR ) “Serious adverse event'” means an adverse event that resulted in any of the following: (a) death; (b) a significant deterioration in the health of a subject that resulted in any of the following: (i) life-threatening illness or injury, (ii) permanent disability or impairment of bodily function, (iii) hospitalization or prolongation of existing hospitalization, (iv) medical or surgical intervention to prevent life-threatening illness or injury or permanent disability or impairment of bodily function, (v) chronic disease, c) foetal jeopardy, foetal death, or congenital physical or mental defect or birth defect; Device deficiency (DD) (acc. to Art. 2 (59) MDR) “Device Deficiency” (DD) refers to any inadequacy in the identification, quality, durability, reliability, safety or performance of a test product, including malfunctions, application errors or inadequacies in the information provided by the manufacturer. In particular, any deficiency that led to the termination of liver machine perfusion, make transplantation impossible or endanger patient safety as a result. Incident (acc. to Art. 2 (64) MDR) „I ncident” means any malfunction or deterioration in the characteristics or performance of a device, including errors of use due to ergonomic features, made available on the market, as well as any inadequacy of the information supplied by the manufacturer and any undesirable side-effect; Serious incident (acc. to Art. 2 (65) MDR) „Serious i ncident” means an incident which, directly or indirectly: a) resulted in, could have resulted in, or could result in: death of a patient, user or other person; b) led to, or could lead to, temporary or permanent serious deterioration in the health of a patient, user or other person; c) created a serious risk of harm to public health; Suspected serious incident In Germany, there is an additional legal definition for an: „ presumed serious incident” (according to § 2 MPAMIV, Medical Devices User Reporting and Information Ordinance): „ suspected serious incident” (is) an incident that cannot be ruled out as being due to an undesirable side effect of a product, a malfunction, a deterioration in the properties or performance of a product, including application errors due to ergonomic features or an inadequacy in the information provided by the manufacturer, and that directly or indirectly resulted in, or could have resulted in, one of the following: 1. the death of a patient, user or other person, 2. the temporary or permanent serious deterioration of a patient's, user's or other person's state of health, or 3. a serious risk to public health. Adverse Events (AEs) A number of adverse events (AEs) occur with some frequency during the postoperative course in patients undergoing liver transplantation and are therefore not considered unexpected. For this study, the following pre-defined events that may occur in the postoperative course and are likely related to the surgery and/or standard intraoperative or postoperative medications are not considered AEs and therefore do not need to be recorded in the eCRF unless the responsible study physician classifies the event as a serious adverse event (SAE): Nausea. Alteration in bowel function – including constipation, diarrhoea, bloating, flatulence or ileus – that resolves without intervention. Pain at the surgical incision. Transient changes in vital signs (fever, hypo- or hypertension, brady- or tachycardia, hypoxia) that resolve and do not require intervention. Pruritus (itching). Fatigue or lethargy; insomnia. Confusion, altered mental status, or dizziness. Radiographic findings/changes that do not require intervention. Wound dehiscence (wound opening). Hyperglycaemia, worsening of existing hyperglycaemia, or development of diabetes mellitus. Other (expected) adverse events, including those listed below, are documented as AEs in the eCRF regardless of their severity. General: Infection (lungs, urinary tract, blood, bile, wound, abdomen) Rejection Kidney dysfunction incl. dialysis Liver dysfunction Heart failure Respiratory failure incl. respiratory therapy Events related to the disease/procedure/operation: Early graft dysfunction (according to the definition by Olthoff et al. 2010) Hospitalization for suspected rejection Occurrence and treatment of abdominal or wound infection Respiratory failure requiring mechanical ventilation Hospitalization for pre-existing illness that has not worsen Clinically significant abnormal laboratory findings or other abnormal assessments related to the condition being evaluated (unless the investigator judges them to be more serious than would be expected for the patient's condition) The study doctor will judge as to whether an abnormal laboratory finding, or other abnormal assessment is clinically significant. However, if in the opinion of the investigator the frequency or severity of the event is greater than expected, it must be reported as an AE/SAE. Causality Assessment Both the study physician and the study management determine whether the event is related to the medical device, procedure or other circumstances. The causal relationship of the event with the tested therapeutic strategy is categorized as follows: Yes: The event is closely related in time to the use of the medical device/therapeutic strategy and another aetiology is highly unlikely. Possible: The AE occurred in close temporal relation to the use of the medical device/therapeutic strategy and there is no conflicting evidence that could reasonably explain the subject's condition. No: The AE is not related to the medical device/therapeutic strategy. Documentation All adverse events must be documented in the patient's study documentation. In addition, all AEs and SAEs will be recorded in the eCRF from the date of randomization until the end of study participation. Pre-existing illnesses or symptoms documented prior to randomization will be recorded as the participant's medical history (not an AE). If these conditions or symptoms worsen during the course of the study, they must be evaluated by an investigator and also documented in the patient's medical record as an AE. If they meet the criteria for an AE and an SAE, they must be recorded in the eCRF and reported using the SAE report form. All SAEs must be documented in the eCRF, regardless of whether the study physician suspects a causal relationship with the medical device or the study procedure. The type of event, the onset, duration, severity, measures, outcome and causality assessment should be documented as a minimum. The following must also be assessed: Whether or not the event is a serious adverse event Whether the adverse event was caused by a device deficiency Whether the adverse event was caused by user error AEs must be followed up until they have resolved, the AE has stabilized, or the study has been completed. As soon as further/new relevant information on the event is available (e.g. discharge letter), the documentation in the eCRF must also be updated and electronically signed/sent. Copies of the discharge letter, any reports of examinations performed and/or diagnostic findings should only be provided upon request. All required data should be recorded on the SAE reporting form. Adverse events occurring during the study should be handled according to established standards to protect the life and health of the study participants. It is the responsibility of the local study doctor to record all directly observed adverse events, and all spontaneously reported adverse events by the participant. In addition, each participant should be asked specifically about adverse events at each visit/contact. Adverse events must be documented on the provided forms for recording (serious) adverse events. Reporting Every SAE must be reported to the pharmacovigilance team of Charité within 24 hours of the study doctor becoming aware of the event. SAEs are to be reported via eCRF. The study director is to be informed of any pregnancy as soon as it becomes known. There will not be any follow-up of the pregnancy. Events reported on paper must be recorded in the eCRF as soon as the database is available again. At the time of initial reporting, the following minimum information must be provided: Identifiable patient: subject ID and study arm Identifiable reporter: study site, study physician including contact details, date of notification Description of the SAE Medical device used in the intervention arm Assessment of a causal relationship with the MP, the procedure and others Measures taken If requested, the investigational site will provide the pharmacovigilance team with a copy of the pseudonymized accompanying documentation (e.g. hospital records, laboratory results, autopsy results) of all SAEs and safety events. The study management must be informed of this. The principal investigator will promptly inform the relevant ethics commissions about any events that could affect the safety of the participants, the conduct of the study or the benefit-risk ratio of the study. Frequency and plans for auditing trial conduct {23} Auditing of the trial conduct will be performed according to the monitoring plan to ensure compliance with the study protocol, Good Clinical Practice (GCP), and regulatory requirements. Clinical monitoring will be conducted at regular intervals and will include a review of laboratory values, adverse events, adherence to protocol-defined procedures, and data integrity checks. Investigators must allow for study-related audits, Institutional Ethics Committee (IEC) reviews, and inspections by local or state health authorities, as required by applicable regulations. Protocol deviations will be documented and categorized based on their impact on study outcomes. Significant protocol deviations, which could influence data completeness, accuracy, or patient safety, will be subject to further review. Any deviations from the protocol necessary to protect the rights, safety, or well-being of participants in an emergency may be implemented without prior consultation with the study management team but must be fully documented in the source records and recorded in the eCRF Serious breaches of GCP or the trial protocol that could significantly affect patient safety or the scientific validity of the study will be reported promptly. If a serious breach is suspected, the sponsor must be notified within one working day, after which the case will be reviewed. If necessary, the breach will be reported to the Ethics Committee. Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} Changes or amendments to the study protocol may only be initiated and authorized by the study management. The ethics committee(s) will be informed of any changes to the study protocol. If necessary, renewed approval will be obtained (as part of a substantial amendment). Changes requiring approval must not be implemented before being reviewed by the ethics committee. Substantial amendments are changes that: Affect the safety of the participants, Require additional data collection or analyses that necessitate changes to patient information and/or consent, Impact the interpretation of scientific documents on which the study is based or influence the scientific validity of study results, Significantly alter the management or conduct of the study Dissemination plans {31a} The primary outcomes of the study will be published in peer-reviewed journals relevant to the field of transplantation. All publications, abstracts, and other outputs will be reviewed by the Steering Committee prior to submission to ensure consistency, scientific integrity, and proper attribution of authorship. Data analysis will be conducted on a study-wide basis, and all results will be reported as such. Individual participating centres will not independently publish or present study data without prior approval from the Steering Committee. The principal investigator will oversee the final compilation of results, and each participating centre will be required to review and sign off on the final report before submission for publication. The trial will be registered, and the identifier will be included in all presentations and publications. Secondary analyses or additional publications based on ExTra trial data must be approved by the Steering Committee, and investigators proposing such analyses must submit a formal request. If approved, the proposing author will take the lead in developing the resulting publications, with authorship reflecting contributions from all participating centres in accordance with established guidelines. Beyond scientific publications, study findings will be communicated through conference presentations, professional meetings, and public engagement activities to ensure that the broader medical community and patient advocacy groups are informed of the study’s implications. Results may also be shared in relevant clinical trial registries and reporting databases as required by regulatory and funding bodies. To uphold confidentiality, all investigators and site personnel agree to maintain strict confidentiality regarding study-related data until official results are published. No study data will be shared or disclosed without prior authorization from the sponsor and coordinating centre. Discussion The ExTra trial addresses a critical challenge in liver transplantation: the need to improve organ utilization and reduce waitlist mortality. In Germany, high waitlist mortality rates emphasize the urgent need for strategies that optimize the allocation of available donor livers. The study’s primary endpoint, “time-to-transplant”, is of particular relevance, as reducing the time between listing and transplantation has direct implications for patient survival, quality of life, and healthcare resource utilization. By assessing whether NMP allows for more livers to be safely transplanted, the study aims to provide evidence for expanding organ acceptance criteria and improving the efficiency of liver allocation. The study design includes a comprehensive set of secondary outcomes that reflect key aspects of liver transplantation. These include competing events such as death, disease progression (e.g., ReMELD-Na >21), contraindications for transplantation, and recovery without transplantation, as well as long-term measures such as overall patient survival, quality of life (EQ5DL), and cost-effectiveness. Additionally, utilization rate—defined as the proportion of used organs relative to those offered on the waiting list—serves as a crucial metric for assessing the trial’s impact on organ allocation efficiency. A significant strength of the trial is the broad interest from German transplant centres, with nearly all centres having expressed their willingness to participate. However, a key operational challenge remains the limited access to NMP devices in Germany, as well as the financial burden associated with these devices, which are currently not reimbursed by health insurers. While perfusion kits and consumables are covered for patients enrolled in the trial, broader implementation of NMP beyond the study setting will require sustainable funding strategies. These economic barriers could influence the long-term feasibility of integrating NMP into routine clinical practice, even if the trial demonstrates its benefits. Beyond its immediate clinical objectives, the ExTra trial also has important translational implications. The establishment of a centralized biobank within the study framework will facilitate the collection and storage of biological specimens, including tissue, perfusate, bile, and blood samples. This resource has the potential to drive future research, particularly in the development of biomarkers for predicting organ viability and early graft dysfunction. By incorporating genetic and molecular analyses (including DNA and RNA profiling), the study could contribute to identifying novel markers that improve organ assessment, ultimately enhancing the selection process for liver transplantation. In addition to clinical and translational endpoints, the study’s safety evaluation is a key component. Three-month graft and patient survival will be closely monitored, with quarterly reviews by the Data and Safety Monitoring Board (DSMB). Additional outcomes for patients who undergo transplantation include early graft function (EASE Score, BAR Score), duration of intensive care unit and hospital stay, complications (including biliary complications assessed by MRCP at 12 months), and 1-year graft and patient survival. These measures will provide a comprehensive evaluation of the impact of NMP on both short- and long-term transplant success. Overall, the ExTra trial is designed not only to improve liver transplant accessibility but also to pave the way for future innovations in organ assessment and preservation. By addressing key limitations in organ utilization and incorporating translational research components, the study has the potential to fundamentally change the approach to liver transplantation in Germany and beyond. This study will provide the evidence basis to help address challenges related to device availability and reimbursement and potentially ensure that NMP can be implemented at scale. Trial status Funding was approved on the 19 th of September 2024. The initial application for ethics approval was submitted on the 28 th of January 2025 and final approval granted on the 2 nd of April 2025. This is study protocol version 1.1. Recruitment is scheduled to begin on June 1 st , 2025, and is expected to be finished 36 months later on May 31 st , 2028. Abbreviations AE Adverse Event BAR Balance of Risk Score CCI Comprehensive Complication Index EASE Early Allograft Failure Simplified Estimation eCRF Electronic Case Reporting Form DFG Deutsche Forschungsgemeinschaft (German Research Foundation) DD Device deficiency DNA Deoxyribonucleic acid DSMB Data Safety Monitoring Board DSO Deutsche Stiftung Organtransplantation (German Organ Transplantation Foundation) GCP Good Clinical Practice ITT Intention-to-Treat labMELD Calculated MELD score, without Standard or Non-Standard Exception points LT Liver Transplantation MP Machine Perfusion MELD Model for End-Stage Liver Disease MDR Medical Device Regulation MPAMIV Medizinprodukte-Anwendermelde- und Informationsverordnung (Medical Devices User Reporting and Information Ordinance) MRCP Magnetic Resonance Cholangiopancreatography NMP Normothermic Machine Perfusion ReMELD-Na Refitting Model of End-stage liver disease with Sodium (Na+) RNA Ribonucleic acid SAE Serious Adverse event Declarations Acknowledgements We extend our sincere gratitude to Dr. Hynek Mergental (Queen Elizabeth Hospital Birmingham) and Professor Vincent E. de Meijer (Rijksuniversiteit Groningen) for their expert contributions to the trial design and for advising on the funding proposal submitted to the German Research Foundation. We also wish to acknowledge Dr. Serge Vogelaar, Marieke de Rosner - van Rosmalen, and Axel Jens from Eurotransplant for their invaluable assistance in developing a robust allocation algorithm and supporting the ExTra trial. Finally, we are grateful to Dr. Axel Rahmel, head of the German Organ Transplantation Foundation, for his guidance on the grant proposal and his support in organizing transport logistics within the study framework. Simon Moosburner and Nathanael Raschzok are participants of the BIH Charité (Advanced) Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin. These results were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – [RA 3044/6-1]. For the main report of this study submitted for publication, along with related methodology and health economic papers, posters, or presentations, authorship will be determined in accordance with the International Committee of Medical Journal Editors guidelines (http://www.icmje.org/ethical_1author.html). Members of the Steering Committee and DSMB will be mentioned in the Acknowledgements of the main publication, along with their institutional affiliations, if not determined as authors. The contributions of the trial management group (principal investigator, coordinating investigator und study coordinator), coordinating centre, and funder will be +recognized in all study-related publications and presentations. To recognize the funder, the following disclaimer must be included: “These results were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – [RA 3044/6-1]” Authors’ contributions {31b} NR is the principal investigator of the trial. SM is the coordinating investigator. DPM, IMS, and JP are co-applicants of the trial. MM is the study coordinator. RS is the responsible statistician. DZ performed sample size and primary endpoint calculations. JW, CR, MS, and MSP are members of the DSMB. NR, DPM, IMS, MSP, AP and UF conceived the trial design. SM drafted and revised the study protocol. DPM, RS, IMS, MS, MP and NR designed this study and were essential in obtaining funding. IMS and JP provided guidance and institutional support. JW and CR submitted essential feedback on possible adverse events. MM translated the initial German study protocol to an English draft. All authors contributed to critically revising the study protocol. Funding {4} This trial is funded by the German Research Foundation (DFG) [RA 3044/6-1]. Availability of data and materials {29} No study data will be presented in oral or written form without approval from the Steering Committee. Submission of papers for peer-reviewed publication will require approval from all listed authors, and study results will be reviewed and approved by all participating centres before publication. Following the release of trial findings, reasonable requests for data access will be considered and reviewed by the Steering Committee. Ethics approval and consent to participate {24} The study protocol (version 1.0), patient informed consent form, supporting information on the medical devices used in the trial and previous publications from literature were submitted to the ethics committee of the Charité – Universitätsmedizin Berlin on the 28 th of January 2025. Approval was obtained on the 2 nd of April 2025. Consent for publication {32} The informed consent materials are provided as supplementary documents. This article does not include any identifiable clinical details of participants, nor will such information be disclosed in the subsequent publication of trial results. Competing interests {28} The authors declare that they have no financial or non-financial competing interests related to the ExTra trial. The principal investigator nor the coordinating study site has any conflicts of interest that could influence the design, conduct, analysis, or reporting of the study. Authors’ information 1 Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Charité– Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany 2 BIH Biomedical Innovation Academy, BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité– Universitätsmedizin Berlin, Berlin, Germany 3 Department of Hematology, Oncology and Cancer Immunology | CVK, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. 4 Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. 5 Department of Surgery, Division of Surgical Transplantation, University of Texas Southwestern Medical Center, Dallas, TX 6 Institute of Liver Studies, King's College Hospital, and School of Immunology and Microbial Sciences, King's College London, London, United Kingdom. 7 Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Düsseldorf, Germany. 8 Department of Surgery, Ajmera Transplant Centre, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada. 9 Department of General, Visceral and Transplant Surgery, University Hospital Münster, Münster, Germany 10 Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany References Neuberger J (2016) An update on liver transplantation: A critical review. J Autoimmun 66:51–59 Ritschl PV, Wiering L, Dziodzio T, Jara M, Kruppa J, Schoeneberg U et al (2020) The Effects of MELD-Based Liver Allocation on Patient Survival and Waiting List Mortality in a Country with a Low Donation Rate. J Clin Med. ;9(6) Moosburner S, Sauer IM, Weiss B, Pratschke J, Raschzok N (2023) How many liver grafts could be recovered after implementation of donation after cardiac death in Germany? J Hepatol 79(3):e118–e20 Husen P, Hornung J, Benko T, Klein C, Willuweit K, Buechter M et al (2019) Risk Factors for High Mortality on the Liver Transplant Waiting List in Times of Organ Shortage: A Single-Center Analysis. Ann Transpl 24:242–251 Umgelter A, Hapfelmeier A, Kopp W, van Rosmalen M, Rogiers X, Guba M et al (2017) Disparities in Eurotransplant liver transplantation wait-list outcome between patients with and without model for end-stage liver disease exceptions. Liver Transpl 23(10):1256–1265 Moosburner S, Raschzok N, Schleicher C, Bosebeck D, Gassner J, Ritschl PV et al (2020) [Declined Liver Grafts - Analysis of the German Donor Population from 2010 to 2018]. Z Gastroenterol MacConmara M, Hanish SI, Hwang CS, De Gregorio L, Desai DM, Feizpour CA et al (2020) Making Every Liver Count: Increased Transplant Yield of Donor Livers Through Normothermic Machine Perfusion. Ann Surg Michelotto J, Gassner J, Moosburner S, Muth V, Patel MS, Selzner M et al (2021) Ex vivo machine perfusion: current applications and future directions in liver transplantation. Langenbecks Arch Surg 406(1):39–54 Boerger L, Hillebrandt KH, Czigany Z, Lurje G, Gassner JMGV, Patel MS et al (2023) Ex Vivo Liver Machine Perfusion Reduces the Length of Hospital Stay in Recipients of Allografts from Elderly Donors: A Systematic Review. Adv Ther. ;6(6) Mergental H, Perera MT, Laing RW, Muiesan P, Isaac JR, Smith A et al (2016) Transplantation of Declined Liver Allografts Following Normothermic Ex-Situ Evaluation. Am J Transpl 16(11):3235–3245 Mergental H, Laing RW, Kirkham AJ, Perera M, Boteon YL, Attard J et al (2020) Transplantation of discarded livers following viability testing with normothermic machine perfusion. Nat Commun 11(1):2939 van Leeuwen OB, de Vries Y, Fujiyoshi M, Nijsten MWN, Ubbink R, Pelgrim GJ et al (2019) Transplantation of High-risk Donor Livers After Ex Situ Resuscitation and Assessment Using Combined Hypo- and Normothermic Machine Perfusion. Ann Surg 270(5):906–914 Reiling J, Butler N, Simpson A, Hodgkinson P, Campbell C, Lockwood D et al (2020) Assessment and Transplantation of Orphan Donor Livers: A Back-to-Base Approach to Normothermic Machine Perfusion. Liver Transpl 26(12):1618–1628 Quintini C, Del Prete L, Simioni A, Del Angel L, Diago Uso T, D'Amico G et al (2022) Transplantation of declined livers after normothermic perfusion. Surgery 171(3):747–756 van Leeuwen OB, Bodewes SB, Lantinga VA, Haring MPD, Thorne AM, Bruggenwirth IMA et al (2022) Sequential Hypothermic and Normothermic Machine Perfusion Enables Safe Transplantation of High-risk Donor Livers. Am J Transpl Olumba FC, Zhou F, Park Y, Chapman WC, Group RI (2023) Normothermic Machine Perfusion for Declined Livers: A Strategy to Rescue Marginal Livers for Transplantation. J Am Coll Surg 236(4):614–625 Laing RW, Mergental H, Yap C, Kirkham A, Whilku M, Barton D et al (2017) Viability testing and transplantation of marginal livers (VITTAL) using normothermic machine perfusion: Study protocol for an open-label, non-randomised, prospective, single-arm trial. BMJ Open 7(11):1–15 Additional Declarations The authors declare no competing interests. Tables 1-2 are available in the supplementary files section. Supplementary Files Tables.docx Tables 1-2 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6834797","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Method Article","associatedPublications":[],"authors":[{"id":467420656,"identity":"191a2a6a-44ae-46fe-8abc-5382d68edf68","order_by":0,"name":"Simon Moosburner","email":"","orcid":"https://orcid.org/0000-0003-1879-4788","institution":"Charité - Universitätsmedizin Berlin","correspondingAuthor":false,"prefix":"","firstName":"Simon","middleName":"","lastName":"Moosburner","suffix":""},{"id":467421945,"identity":"a7283543-5513-4a5b-b22d-f7dfa3df4fb8","order_by":1,"name":"Igor M. Sauer","email":"","orcid":"https://orcid.org/0000-0001-9355-937X","institution":"Charité - Universitätsmedizin Berlin","correspondingAuthor":false,"prefix":"","firstName":"Igor","middleName":"M.","lastName":"Sauer","suffix":""},{"id":467421946,"identity":"7353849d-6039-4eb6-8b86-06bb1d3958ad","order_by":2,"name":"Mateja Mandac","email":"","orcid":"","institution":"Charité - Universitätsmedizin Berlin","correspondingAuthor":false,"prefix":"","firstName":"Mateja","middleName":"","lastName":"Mandac","suffix":""},{"id":467421947,"identity":"636b4712-79e4-4ecd-bd46-e76eda5037ac","order_by":3,"name":"Dominik P. Modest","email":"","orcid":"https://orcid.org/0000-0002-6853-0599","institution":"Charité - Universitätsmedizin Berlin","correspondingAuthor":false,"prefix":"","firstName":"Dominik","middleName":"P.","lastName":"Modest","suffix":""},{"id":467421948,"identity":"655e729e-92b0-46ce-b812-d00fdd805c46","order_by":4,"name":"Dario Zocholl","email":"","orcid":"https://orcid.org/0000-0002-9218-6919","institution":"Charité - Universitätsmedizin Berlin","correspondingAuthor":false,"prefix":"","firstName":"Dario","middleName":"","lastName":"Zocholl","suffix":""},{"id":467421949,"identity":"9473dd6c-98b9-497e-8420-197c01f9b75c","order_by":5,"name":"Regina Stegherr","email":"","orcid":"https://orcid.org/0000-0002-0528-348X","institution":"Charité - Universitätsmedizin Berlin","correspondingAuthor":false,"prefix":"","firstName":"Regina","middleName":"","lastName":"Stegherr","suffix":""},{"id":467421950,"identity":"30732829-e7ef-4b5f-bafc-69b460ecac40","order_by":6,"name":"Madhukar S. Patel","email":"","orcid":"https://orcid.org/0000-0001-7508-899X","institution":"University of Texas Southwestern Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Madhukar","middleName":"S.","lastName":"Patel","suffix":""},{"id":467421951,"identity":"b6b01a79-6760-4cac-87c8-7a8c6de251d3","order_by":7,"name":"Julia Wendon","email":"","orcid":"","institution":"King's College Hospital London","correspondingAuthor":false,"prefix":"","firstName":"Julia","middleName":"","lastName":"Wendon","suffix":""},{"id":467421952,"identity":"c8d89153-00d4-42cf-af9c-f691f19d54d3","order_by":8,"name":"Christoph Roderburg","email":"","orcid":"","institution":"University Hospital Düsseldorf","correspondingAuthor":false,"prefix":"","firstName":"Christoph","middleName":"","lastName":"Roderburg","suffix":""},{"id":467421953,"identity":"2168e44b-6d06-4800-95b2-44cbfbedc7c1","order_by":9,"name":"Markus Selzner","email":"","orcid":"","institution":"Ajmera Transplant Centre, Toronto General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Markus","middleName":"","lastName":"Selzner","suffix":""},{"id":467421954,"identity":"f379c7ce-920d-431c-8f57-f68f97705668","order_by":10,"name":"Andreas Pascher","email":"","orcid":"","institution":"University Hospital Münster","correspondingAuthor":false,"prefix":"","firstName":"Andreas","middleName":"","lastName":"Pascher","suffix":""},{"id":467421955,"identity":"8f23235e-8d83-42dc-95c2-167772a704df","order_by":11,"name":"Uli Fehrenbach","email":"","orcid":"","institution":"Charité - Universitätsmedizin Berlin","correspondingAuthor":false,"prefix":"","firstName":"Uli","middleName":"","lastName":"Fehrenbach","suffix":""},{"id":467421956,"identity":"112c6bdd-df58-4665-a06d-88fe85355689","order_by":12,"name":"Johann Pratschke","email":"","orcid":"","institution":"Charité - Universitätsmedizin Berlin","correspondingAuthor":false,"prefix":"","firstName":"Johann","middleName":"","lastName":"Pratschke","suffix":""},{"id":467421957,"identity":"050355b0-d3dc-4d4c-8ff4-b7ef148217cc","order_by":13,"name":"Nathanael Raschzok","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-5074-7063","institution":"Charité - Universitätsmedizin Berlin","correspondingAuthor":true,"prefix":"","firstName":"Nathanael","middleName":"","lastName":"Raschzok","suffix":""}],"badges":[],"createdAt":"2025-06-06 07:50:22","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":true,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6834797/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6834797/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":84566969,"identity":"529a62fc-ee45-4025-ab3e-eac1e1700a62","added_by":"auto","created_at":"2025-06-13 14:26:07","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2335799,"visible":true,"origin":"","legend":"\u003cp\u003eTrial Design\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6834797/v1/32d0b94a29f3e44d091984d4.jpg"},{"id":84566970,"identity":"90e08798-02e8-430b-9592-dfc1ab9e0867","added_by":"auto","created_at":"2025-06-13 14:26:07","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1338620,"visible":true,"origin":"","legend":"\u003cp\u003eOverview of Trial Procedure\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6834797/v1/839f4c020e9d2e14c78ff009.jpg"},{"id":84568437,"identity":"b84822e1-ae39-41e3-9850-3a652aeb8b9e","added_by":"auto","created_at":"2025-06-13 14:50:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6348094,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6834797/v1/4973bca6-92a9-43a2-9a80-20cbdf4a9d06.pdf"},{"id":84566968,"identity":"c6c7bf7e-5bad-487c-8c8f-3080077efe1b","added_by":"auto","created_at":"2025-06-13 14:26:07","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":25017,"visible":true,"origin":"","legend":"\u003cp\u003eTables 1-2\u003c/p\u003e","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6834797/v1/ebf1c5e4e768b500356900a4.docx"}],"financialInterests":"\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003eTables 1-2 are available in the supplementary files section.\u003c/p\u003e","formattedTitle":"\u003cp\u003ePilot, open, prospective, randomized, multicentre trial on quality assessment of declined liver grafts by normothermic \u003cstrong\u003eex\u003c/strong\u003e vivo machine perfusion for decreasing time to \u003cstrong\u003etra\u003c/strong\u003ensplantation: study protocol for the ExTra-Trial\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003ch2\u003eBackground and rationale {6a}\u003c/h2\u003e\n\u003cp\u003eLiver transplantation (LT) is the preferred treatment for patients with advanced liver cirrhosis, hepatocellular carcinoma within Milan criteria, and severe metabolic or autoimmune liver disease (1). However, the number of patients on the liver transplant waiting list exceeds the number of available organs. In Germany, the success of LT has been undermined by a dramatic decline in organ donations over the past decade (2, 3). In 2022, only 748 out of 1,296 patients (58%) on the waiting list received a liver graft. The outcome for patients on the waiting list remains unsatisfactory: A study from Essen showed that the 12-month survival rate without transplantation was 46%, compared to 78% after a liver transplant (4). Comprehensive data from the Eurotransplant registry show that between 2006 and 2015, 32% of patients were removed from the waiting list because they became too ill to receive a graft or died while waiting (5). This problem particularly affects patients with a lab MELD \u0026le;25 who are not eligible for Standard or Non-Standard Exception criteria. These patients wait significantly longer for a graft (2022: 112 vs. 54 days, p\u0026lt;0.001) and have a significantly lower 12-month transplantation rate (44% vs. 70%, p\u0026lt;0.001, unpublished data) compared to the general population of listed patients. The imbalance between supply and demand is further exacerbated by the fact that about 24% of all liver grafts offered for transplantation in Germany are declined due to the donor\u0026apos;s age or overall morbidity (6). This issue exists worldwide, with discard rates in the USA being similarly high (13%) (7).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe liver allocation process in Germany is strictly regulated and managed by Eurotransplant, in cooperation with the German organ procurement organization `Deutsche Stiftung Organtransplantation\u0026acute; (DSO, German Organ Transplantation Foundation). Each organ is allocated according to a specific algorithm. The decision to accept or reject a liver graft for a recipient is based on appropriately matching the donor\u0026apos;s clinical data with that of a potential recipient, as well as logistical considerations. To address the current organ shortage, liver grafts from donors with extended criteria (ECD) are increasingly used for transplantation. However, up to 24% of all liver grafts offered for transplantation are declined, mainly due to the donor\u0026apos;s age, macrosteatosis, or long cold ischemia time, as these factors are associated with an increased risk of graft dysfunction, graft failure, and death, particularly in recipients with a high MELD score. The decision-making process is primarily based on the subjective expertise of the accepting transplant surgeon, supported by scores that consider both donor and recipient factors. Objective tools for assessing graft function are not routinely used in clinical practice for conventional static cold storage or hypothermic oxygenated liver machine perfusion. Pilot studies have shown that NMP enables the assessment of organs clinically deemed unsuitable for transplantation using viability criteria such as lactate clearance or bile production(8, 9).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTransplantation of initially declined liver grafts following quality assessment by NMP has been investigated in seven non-randomized, single-centre clinical studies in the UK, the Netherlands, Australia, and the USA (10-16). The commercially available OrganOx Metra (OrganOx Limited, Oxford, UK), the Liver Assist device (XVIVO B.V., Groningen, Netherlands), and a non-commercial device developed in Cleveland were used in these studies. The OrganOx Metra and the institutionally developed device were used for pure end-ischemic perfusion (10, 11, 13, 14, 16), while the protocol established in Groningen for the Liver Assist device consisted of one hour of hypothermic oxygenated machine perfusion (HOPE), followed by controlled oxygenated rewarming (COR) and 2.5 hours of NMP for quality assessment(12, 15).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe ExTra trial will randomize patients on the waiting list to demonstrate that declined liver grafts, which meet predefined quality criteria after at least four hours of NMP, can be used to reduce the waiting time for liver transplantation in patients with a low MELD score who are not eligible for Standard or Non-Standard Exceptions. This is of clinical relevance given the increasing number of livers declined for transplantation in Germany, despite new technologies enabling quality assessment of these potentially transplantable organs. The utilization rate of grafts, safety, cost-effectiveness, and the effect on the waiting list practice will be evaluated as secondary endpoints. The results of this study could therefore change clinical practice in Germany and help address the medical-social dilemma of organ shortages in liver transplantation by integrating graft quality assessment through NMP into clinical practice. This could enable the acceptance of livers that are currently declined, which would certainly increase organ utilization in Germany. To further leverage the impact of this clinical study, a translational companion study will be conducted to identify novel biomarkers for assessing and predicting graft quality in NMP.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eObjectives {7}\u003c/h2\u003e\n\u003cp\u003eThe objective of the ExTra trial is to demonstrate that the waiting time for liver transplantation in patients with a ReMELD-Na-Score \u0026le;21 (equivalent to MELD \u0026le;25), who are not eligible for Standard or Non-Standard Exception criteria, can be significantly reduced by utilizing liver grafts that were initially deemed non-transplantable based on clinical criteria but meet predefined quality criteria after at least four hours of end-ischemic NMP, compared to patients who are not offered this option.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe result will be verified by a randomized control group without the ExTra treatment option. Randomization against the standard treatment is necessary to evaluate the current waiting time in this population, as the number of actual grafts performed depends heavily on the availability of grafts as well as the performance and acceptance criteria of the individual transplant centres. Access to the regular allocation process is available to all candidates in the entire study population, regardless of randomization, at any time.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eTrial design {8}\u003c/h2\u003e\n\u003cp\u003eThis is a prospective, multicentre, randomized, open-label, two-arm clinical study. Since all interventions and all medical devices used in the study are CE-certified and are used in accordance with the intended purpose defined by the respective manufacturer, without any additional burdensome or invasive measures, the study qualifies as a clinical study under \u0026sect;47 (3) of the German Medical Devices Act (MPDG). The study is conducted in accordance with the Professional Code of Conduct for Physicians (\u003cem\u003eBerufsordnung der \u0026Auml;rzte\u003c/em\u003e).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study population will be randomized 1:1 to the experimental or control arm (Figure 1). Liver transplantation in the context of regular organ allocation can be performed in both arms according to the centre\u0026rsquo;s decision, i.e. using static cold storage, hypothermic or normothermic machine perfusion for organ preservation. Quality assessment of grafts judged clinically unacceptable by NMP is reserved for the experimental arm.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe experimental intervention, i.e. the ExTra option, will be offered for a period of 12 months from randomization, due to the expected medical deterioration of patients on the waiting list. It is important to note that in the experimental arm, treatment consists of either:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003ereceiving a liver transplant with a graft that has been declined by all German transplant centres but meets established objective quality criteria during NMP, or\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ereceiving a liver transplant via the regular liver allocation process when a graft becomes available, whichever occurs first.\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDeclined liver grafts considered for quality assessment must not have macrovesicular steatosis \u0026gt;60%, fibrosis grade \u0026gt;F3, or cirrhosis (based on histopathologic quick section analysis, if requested by the responsible transplant surgeon after macroscopic examination) and have a graft weight between 1 and 2.5 kg. Moreover, grafts must be connectable in terms of vascular anatomy\u003cstrong\u003e.\u0026nbsp;\u003c/strong\u003eThe goal is to maintain a\u003cstrong\u003e\u0026nbsp;\u003cstrong\u003edropout rate of no more than 50%\u003c/strong\u003e\u0026nbsp;\u003c/strong\u003efor grafts that either\u003cstrong\u003e\u0026nbsp;\u003cstrong\u003efail quality assessment via NMP\u003c/strong\u003e\u0026nbsp;\u003c/strong\u003eor\u003cstrong\u003e\u0026nbsp;cannot be successfully transplanted despite undergoing NMP quality assessment.\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAdditionally, the organ must not yet have been treated using a dynamic preservation procedure (HOPE or NMP).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eAllocation of Discarded Grafts\u003c/h3\u003e\n\u003cp\u003eThe allocation of declined\u0026nbsp;liver grafts to patients in the experimental arm of the study is carried out by `Eurotransplant\u0026acute; and enables the rapid allocation of declined liver grafts to patients in ExTra study centres according to the \u0026ldquo;first-come-first-serve principle\u0026rdquo;:\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eLiver accepted, procured, transported to a German centre, and considered non-transplantable:\u003col\u003e\n \u003cli\u003eCompetitive offer to centres in the DSO-region where the liver is located or\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eOffer to procurement centre.\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n \u003cli\u003eLiver accepted, procured, and considered non-transplantable at donor hospital:\u003col\u003e\n \u003cli\u003eCompetitive offer to centres in the DSO-region where the liver is located (including the procurement centre).\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n \u003cli\u003eLiver accepted, procured, transported to a non-German centre, and considered non-transplantable:\u0026nbsp;\u003col\u003e\n \u003cli\u003eCompetitive offer to centres in the closest* DSO-region where the liver is located or\u003c/li\u003e\n \u003cli\u003eOffer to procurement centre* [*land-based transportation only]\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n \u003cli\u003eLiver not accepted until 3rd line rescue allocation and not procured:\u0026nbsp;\u003col\u003e\n \u003cli\u003eCompetitive offer to centres in the DSO-region where the liver is located.\u0026nbsp;\u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eOrgan procurement and NMP\u003c/h3\u003e\n\u003cp\u003eThe liver grafts are retrieved by the local donor teams of the according to established clinical protocols, stored in preservation solution on ice, and transported to the study centre until NMP begins. Declined grafts are subjected to an end-ischemic \u0026quot;Back-to-Base\u0026quot; NMP, with either the OrganOx Metra or the XVIVO LiverAssist device currently being used, as both systems are CE-marked medical devices by the respective manufacturers and have published data for quality assessment of initially non-acceptable liver grafts. The perfusion is carried out according to the manufacturer\u0026apos;s instructions (under MDR) (OrganOx Metra: according to the recommendations from the manufacturer in Oxford; LiverAssist: according to the specifications from XVIVO B.V. (Netherlands) following the Groningen protocol) under the responsibility of the participating study centres. Grafts remain in NMP until the recipient\u0026apos;s hepatectomy is completed or are removed from the device and preserved again by static cold storage if the perfusion time exceeds the validated perfusion duration (OrganOx: 24 hours of perfusion; LiverAssist: 6 hours of perfusion according to the manufacturer\u0026apos;s specifications).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eCriteria for Quality Assessment\u003c/h3\u003e\n\u003cp\u003eQuality assessment using NMP in the experimental arm is performed according to previously published viability criteria for initially declined liver grafts, which are mandatory for all participating study centres, with minor device-specific modifications. These criteria are based on the Birmingham criteria used in the VITTAL trial for viability assessment of DBD and DCD grafts with the OrganOx Metra device and are comparable to the Groningen criteria previously established with the LiverAssist device, with the exception of biliary viability parameters, which were required for the assessment of DCD grafts (12, 15, 17).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe decision to use or reject a graft after quality assessment by NMP (i.e. start of recipient hepatectomy) is made at least 4 hours after the start of perfusion by the transplant surgeon, based on:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eLactate clearance \u0026lt; 2.5 mmol/L\u003c/li\u003e\n \u003cli\u003eAnd two or more of the following:\u003col class=\"decimal_type\"\u003e\n \u003cli\u003eEvidence of bile production\u003c/li\u003e\n \u003cli\u003eMaintenance of a perfusate pH \u0026gt;7.30 (without correction for at least one hour)\u003c/li\u003e\n \u003cli\u003eGlucose metabolism (falling perfusate glucose value with consistent downward trend)\u003c/li\u003e\n \u003cli\u003eMaintenance of stable arterial and portal venous flows (OrganOx Metra: 150 and 500 mL/min respectively)\u003c/li\u003e\n \u003cli\u003eHomogeneous perfusion with soft consistency of the parenchyma\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Methods: Participants, interventions and outcomes","content":"\u003ch2\u003eStudy setting {9}\u003c/h2\u003e\n\u003cp\u003eThis multicentre RCT will be performed in participating German academic hospitals with an active liver transplantation program in addition to experience with NMP of liver grafts and a NMP device on-site. Initiating centre is the Department of Surgery Campus Charit\u0026eacute; Mitte | Campus Virchow-Klinikum, Charit\u0026eacute; \u0026ndash; Universit\u0026auml;tsmedizin Berlin. Participating study centres will be added to the clinicaltrials.gov registry entry.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eEligibility criteria {10}\u003c/h2\u003e\n\u003cp\u003eEligible are all adult patients (\u0026ge;18 years) listed for liver transplantation who have a ReMELD-Na-Score \u0026le; 21 points and do not have the option of receiving Standard or Non-Standard Exception points.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eInclusion Criteria\u003c/h3\u003e\n\u003cul class=\"decimal_type\"\u003e\n \u003cli\u003eAble to consent\u003c/li\u003e\n \u003cli\u003e\u0026ge; 18 years old\u003c/li\u003e\n \u003cli\u003eListed as status \u0026ldquo;transplantable\u0026rdquo; by the transplant conference of the study centre for liver transplantation, according to the guidelines of the German Medical Association valid at the time of inclusion\u003c/li\u003e\n \u003cli\u003eReMELD-Na \u0026le;2, not eligible for Standard or Non-Standard Exceptions\u003col\u003e\n \u003cli\u003eStandard and Non-Standard Exceptions are defined in the Eurotransplant liver allocation manual chapter 5.1.14. A list of applicable Standard Exceptions points for Germany can be found in chapter 5.10.4, Non-Standard Exceptions are evaluated by external auditors (chapter 5.9.1.4)\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n \u003cli\u003eMedically suitable and informed for transplantation with an organ that fulfils extended donor criteria (Eurotransplant ECD criteria)\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePatient information and written consent to participate in the Extra trial\u003c/li\u003e\n \u003cli\u003eNo participation in another interventional study during participation\u003c/li\u003e\n\u003c/ul\u003e\n\u003ch3\u003eExclusion Criteria\u003c/h3\u003e\n\u003cul\u003e\n \u003cli\u003eListed for retransplantation\u003c/li\u003e\n \u003cli\u003eHigh-Urgency Listing\u003c/li\u003e\n \u003cli\u003eListed for combined organ transplantation\u003c/li\u003e\n \u003cli\u003ePregnancy\u003c/li\u003e\n\u003c/ul\u003e\n\u003ch2\u003eWho will take informed consent? {26a}\u003c/h2\u003e\n\u003cp\u003eBefore inclusion in the study (e.g. randomization), each patient is informed by the local study physician in charge about the nature, objectives, expected benefits and possible risks of the study, both orally and in writing.\u003c/p\u003e\n\u003cp\u003eEach patient must declare his or her written consent to participate in the study. The patient must be given sufficient time and opportunity to decide on his or her participation and to clarify any open questions before the study measures are initiated. The informed consent is signed and personally dated by the patient and the treating physician. If the patient can give consent but is unable to sign personally, a witness must confirm the oral explanation by signing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAdditional consent provisions for collection and use of participant data and biological specimens {26b}\u003c/h2\u003e\n\u003cp\u003ePatient will need to provide additional consent as an \u0026ldquo;opt-in\u0026rdquo; for collection of blood, perfusate, bile and liver tissue for future research. These samples are intended for translational studies, identifying potential biomarkers for outcome prediction.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eInterventions\u003c/h2\u003e\n\u003ch2\u003eExplanation for the choice of comparators {6b}\u003c/h2\u003e\n\u003cp\u003ePatients waiting for a liver graft have a high mortality, and the waiting time for transplantation is significantly longer for patients with a low MELD score. Therefore, it is justified to offer a liver graft that has been initially declined in the regular organ allocation system but is deemed objectively suitable through quality assessment via NMP. The option to receive a liver graft through the regular allocation process remains available to all study participants. The intervention\u0026mdash;although it is not yet the clinical standard and data from comparable donor and recipient populations in Germany are still lacking\u0026mdash;is based on a series of international study results on the quality assessment of initially declined grafts through NMP for patients with a low MELD score. The study will either provide a foundation for the routine use of NMP for quality assessment of initially declined liver grafts, which would increase the number of available liver grafts in Germany or show that this option is not feasible for the German donor and recipient population. Additionally, the study, through standardized biomarker collection, will provide insights into the assessment of marginal grafts and may reveal future opportunities to save such organs, addressing the imbalance between the supply and demand of donor organs.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eIntervention description {11a}\u003c/h2\u003e\n\u003cp\u003eAfter randomization, patients are randomized to either the intervention or control arm for 12 months. In the control arm, patients receive a liver graft following the regular allocation procedure. In the ExTra trial arm, there is the option of:\u0026nbsp;\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003ereceive a liver graft with a graft that has been declined by all German transplant centres but meets established objective viability criteria at the NMP (ExTra-LT), or\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ereceive a liver graft via the regular liver allocation process (LT) when a graft becomes available - whichever comes first.\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eIf patients are not transplanted within 12 months, they continue to be regularly listed on the waiting list without the possibility of option 1 and are censored.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs part of the ExTra LT quality assessment, the liver is removed from the cold preservation solution in the transplant centre in an end ischemic \u0026ldquo;back-to-base\u0026rdquo; approach, prepared, cannulated and connected to the liver perfusion machine according to the respective manufacturer\u0026apos;s specifications. A prerequisite for the quality assessment is an evaluation time of at least four hours under normothermic conditions (37\u0026deg;C). The quality criteria listed under 8.1 apply. If the liver fulfils the above criteria after 4 hours of perfusion and is assessed as transplantable based on the assessment of the transplant surgeon in charge, the recipient is then initiated for surgery and the liver is transplanted.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBoth patients who receive an ExTra LT or a liver graft after standard allocation are followed up in hospital and after discharge at regular intervals.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u003c/h2\u003e\n\u003cp\u003eParticipation in the ExTra trial is voluntary, and participants have the right to withdraw from the study at any time at their own request and without giving reasons. This will not have any negative impact on the patient\u0026apos;s medical treatment. A discontinuation of participation occurs when a patient withdraws his or her consent or decides against further participation. If possible and the patient is willing to provide information, the reason for the discontinuation will be asked for and documented, but without putting pressure on the patient.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe following events can be considered as discontinuation criteria:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003ePersonal wish of the patient: The patient can withdraw from the study at any time and without giving reasons.\u003c/li\u003e\n \u003cli\u003ePregnancy: Pregnancy is a criterion for exclusion to avoid potential risks to the foetus and the mother.\u003c/li\u003e\n \u003cli\u003eSerious complications or side effects: SAE/SADE\u003c/li\u003e\n \u003cli\u003eSignificant protocol violations: Exclusion may occur in the event of significant deviations from the study protocol. Non-compliance with the requirements specified in this study protocol without sufficient justification. Examples of this may include the registration of a recipient who does not meet all the inclusion/exclusion criteria, or the omission of visits or inadequate documentation of these.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eLoss of contact, change of location or change of treating physician\u003c/strong\u003e: If the patient can no longer be reached or changes the location or physician of treatment, so that further participation in the study is no longer possible, this may result in early withdrawal.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eIn addition, there are specific criteria that can lead to exclusion:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eWithdrawal of \u003cstrong\u003econsent to accept livers with expanded donor criteria\u003c/strong\u003e: Should the patient withdraw consent to accept livers that meet the expanded donor criteria, study participation will be terminated.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eOrgan failure requiring combined organ listing\u003c/strong\u003e: Should there be an organ failure of another organ (e.g. heart or kidney) requiring combined listing for multiple organs, the patient will be excluded from the study.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDisease progression while listed as non-transplantable:\u0026nbsp;\u003c/strong\u003eIf a patient is deemed non-transplantable due to an infection or other event and the ReMELD-Na is \u0026gt;21, patients are not directly excluded. The period of non-transplantable status is documented, and the MELD score reevaluated once the patient reaches a transplantable state. Only if the patient is listed as status as transplantable and the ReMELD-Na remains \u0026gt;21 points, patients can no longer participate in the study. Survival data is censored up until this point.\u003c/li\u003e\n\u003c/ul\u003e\n\u003ch2\u003eStrategies to improve adherence to interventions {11c}\u003c/h2\u003e\n\u003cp\u003ePatients are managed by the respective study centre as part of the waiting list management for liver transplantation. This includes, for example, regular blood samples for updating the MELD score to determine urgency. As part of the study, compliance is expected to be similar to the waiting list for liver transplantation. Ensuring compliance is the responsibility of the respective study centres or the transplant program. No further measures are necessary for the patients. After liver transplantation, regular check-ups/study visits (V3-V5) are organized via the respective liver transplant outpatient clinic. These measures are also part of the regular course of follow-up care for liver transplantation. As the patients are also examined psychosomatically as part of the evaluation for liver transplantation regarding their presumed compliance, a high level of adherence can be expected.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u003c/h2\u003e\n\u003cp\u003eParallel study participation is not planned. Patients who are currently in an interventional clinical trial cannot be included. Likewise, participants in the ExTra trial will not be able to participate in further interventional studies during the intervention phase (i.e. 12 months after study inclusion) and a further 12 months after transplantation during the intervention phase. It will be mentioned in the patient information that the participant may not participate in several studies at the same time. If a study participant is included in several interventional studies and this becomes known to the study management, he/she will be excluded from the study and the responsible study centre may be closed.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eProvisions for post-trial care {30}\u003c/h2\u003e\n\u003cp\u003eAfter participation has ended, there will be no further active follow-up as part of the study. All data collected will be evaluated in the context of the final analysis using pseudonyms to fulfil the study objectives.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eOutcomes {12}\u003c/h2\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary Endpoint:\u003c/strong\u003e \u0026bdquo;Time-to-Transplant\u0026ldquo; defined as the time period between randomization and transplantation\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety Endpoint:\u003c/strong\u003e 3-month graft and patient survival, defined as the need for retransplantation or death within the first 3 months after ExTra-LT. The DSMB will evaluate these data on a quarterly basis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary endpoints:\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eCompeting Events\u0026nbsp;\u003col\u003e\n \u003cli\u003eDeath\u003c/li\u003e\n \u003cli\u003eDisease Progression\u003cul\u003e\n \u003cli\u003eReMELD-Na \u0026gt;21 while listed as \u0026ldquo;transplantable\u0026rdquo;\u003c/li\u003e\n \u003cli\u003eContraindication for liver transplantation\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n \u003cli\u003eRecovery (no transplantation required)\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n \u003cli\u003eNumber of patients listed for transplantation after 12 months\u003c/li\u003e\n \u003cli\u003eOverall patient survival (from randomization to death)\u003c/li\u003e\n \u003cli\u003eQuality of Life (EQ5DL)\u003c/li\u003e\n \u003cli\u003eGraft utilization rate (Used organs / Offered organs on the waiting list))\u003c/li\u003e\n \u003cli\u003eCost-effectiveness (Transplantation-associated costs)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOther endpoints for patients who receive a liver transplantation during the 12-month intervention period:\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eEarly graft function\u003c/strong\u003e (measured by the Early Allograft Failure Simplified Estimation (EASE) Score) \u0026amp; Balance of Risk (BAR) Score\u003c/li\u003e\n \u003cli\u003eDuration of intensive care unit stay\u003c/li\u003e\n \u003cli\u003eLength of hospital stay\u003c/li\u003e\n \u003cli\u003eComprehensive Complication Index (CCI)\u003c/li\u003e\n \u003cli\u003eBiliary complications\u0026nbsp;\u003col\u003e\n \u003cli\u003eIschemic-Type Biliary Lesions (clinically and as part of the planned MRCP 12 months after liver transplantation)\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003e1-year patient survival\u003c/strong\u003e (post-transplantation)\u003c/li\u003e\n \u003cli\u003e1-year graft survival\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAcceptance rate\u003c/strong\u003e (1 / number of unrealized organ offers [accepted for the patient either primarily or within the extended/rescue allocation but not transplanted])\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eGraft-Rescue Rate\u003c/strong\u003e (livers that meet quality criteria during NMP / all organs assessed through NMP in the study)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eTranslational Outcomes:\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eBiomarkers in tissue, perfusate, bile, and laboratory chemistry for outcome prediction\u003c/strong\u003e(Early Allograft Dysfunction according to the criteria of Olthoff et al. (17) as well as 3-month graft survival) through NMP\u003col\u003e\n \u003cli\u003e\u003cstrong\u003eIncluding DNA and RNA analyses for the aforementioned purpose and future research\u003c/strong\u003e (i.e., the purpose of the analyses will be determined in the future).\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003ch3\u003eExplanation of the clinical relevance of efficacy and harm outcomes\u003c/h3\u003e\n\u003cp\u003eThe goal of the Extra trial is to demonstrate that the waiting time for liver transplantation in patients with a ReMELD-Na-Score \u0026le;21 without access to Standard or Non-Standard Exceptions can be significantly reduced by utilizing liver grafts that were initially deemed non-transplantable based on clinical criteria but meet predefined quality criteria after 4 hours of NMP, compared to patients who are not offered this option. This is of particular clinical relevance given the increasing number of organs that are declined in Germany, despite new technologies enabling quality assessment of these potential liver grafts. The utilization rate of the grafts, safety, and cost-effectiveness will be evaluated as secondary endpoints. The results of this study could therefore change clinical practice and help address the medical-social dilemma of organ shortages in liver transplantation by integrating transplant quality assessment through NMP into clinical practice. This would enable the acceptance of livers that are currently declined and could therefore significantly increase organ utilization in Germany. To further clarify the impact of this clinical study, a translational evaluation will be conducted to identify novel biomarkers for assessing and predicting graft quality in NMP. The required platforms are available at Charit\u0026eacute; \u0026ndash; Universit\u0026auml;tsmedizin Berlin.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eParticipant timeline {13}\u003c/h2\u003e\n\u003cp\u003eThe proposed study duration is 66 months (01/06/2025 \u0026ndash; 30/11/2030). The study will commence recruitment on June 1\u003csup\u003est\u003c/sup\u003e, 2025, with an anticipated recruitment period of 36 months, concluding on May 31\u003csup\u003est\u003c/sup\u003e, 2028. Each participant will be enrolled in the study for a maximum duration of 24 months, comprising an intervention phase of up to 12 months, followed by a 12-month follow-up period after transplantation. The final participant follow-up is expected to be completed by May 31\u003csup\u003est\u003c/sup\u003e, 2030, after which the study will proceed with data analysis and dissemination activities. The study is scheduled to conclude by November 30\u003csup\u003eth\u003c/sup\u003e, 2030. The flow of participants throughout the study is summarized in Figure 2, while all trial procedures are detailed in Table 2.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eDeviations from Standard Medical Examination Practice\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eIn the context of the study, three points deviate from the standard care:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eQuality assessment using NMP (as a quality assessment tool in the Extra trial arm as part of the study),\u003c/li\u003e\n \u003cli\u003eThe storing of blood, tissue, bile and perfusate samples for the central biobank, and\u003c/li\u003e\n \u003cli\u003eRoutine MRCP (magnetic resonance cholangiopancreatography) 12 months after liver transplantation.\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eIt is important to distinguish between biological samples that are needed to assess the quality of the NMP or to assess the immediate postoperative course and are used as part of the ExTra trial, and samples that are collected and stored for future research (Biobank ZeBanC, optional).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn detail, this means:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003e\u003cstrong\u003e\u003cu\u003eExTra-Study:\u003c/u\u003e\u003c/strong\u003eNormothermic Machine Perfusion (NMP)\u003col\u003e\n \u003cli\u003eDevice-independent (currently usable: XVIVO LiverAssist or OrganOx Metra), provided that clinical data for quality assessment of declined liver grafts are available\u003col class=\"decimal_type\"\u003e\n \u003cli\u003eAt least 4 hours of Quality Assessment\u003c/li\u003e\n \u003cli\u003eV2.2.5 - V2.2.9 are therefore optional for perfusion times \u0026gt;4h\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003e\u003cu\u003eOpt-In\u003c/u\u003e\u003c/strong\u003e: Biobank (via ZeBanC) for future research\u003col\u003e\n \u003cli\u003eZeBanC provides all centres with sample collection and aliquoting sets (\u003cstrong\u003e\u003cem\u003eincluding stretching tubes\u003c/em\u003e\u003c/strong\u003e) as well as a coordinated set of instructions for the processing and transport of the samples.\u0026nbsp;\u003cul\u003e\n \u003cli\u003eSample processing and documentation is carried out at the centres by the study personnel there\u003c/li\u003e\n \u003cli\u003eTransfer of samples on dry ice. Transportation costs are covered by the project.\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n \u003cli\u003eBlood will be collected from the patient before liver transplantation, 1 hour after reperfusion and on postoperative days 1 and 3. Blood samples will be taken regularly as part of preoperative care and postoperative follow-up. Thus, only additional material will be collected as part of the study.\u003c/li\u003e\n \u003cli\u003eA wedge biopsy of the liver is performed before machine perfusion or after completion of organ preparation, after completion of NMP (ExTra arm only) and 1 h after reperfusion.\u003c/li\u003e\n \u003cli\u003eThe perfusate is taken before, 15 minutes after the start of perfusion, every hour after the start of perfusion and at the end of the NMP (ExTra LT study arm only).\u003c/li\u003e\n \u003cli\u003eBile is collected every 2 hours during the perfusion and at the end of the NMP (ExTra LT study arm only).\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n \u003cli\u003eExTra-Study: MRI Abdomen with MRCP \u0026ndash; Evaluation of biliary complications\u003col\u003e\n \u003cli\u003eA routine MRCP will be performed 12 months after liver transplantation to assess biliary complications. The examination should be performed at 1.5 T or 3T. Essential sequences are axial and coronal T2-weighted, 3D and 2D MRCP, diffusion-weighted imaging (DWI) and T1-weighted in-phase/out-of phase sequences. Contrast-enhanced imaging with Gadolinium is optional but recommended for vascular and perfusion assessment. Hepatobiliary contrast agents can also be used if clinically indicated. An exemplary protocol is provided in table 1. The costs are covered by the project.\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ch3\u003eMedical History\u003c/h3\u003e\n\u003cp\u003eComprehensive medical history will be documented for each participant, including\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eAge\u003c/li\u003e\n \u003cli\u003eHeight\u003c/li\u003e\n \u003cli\u003eWeight\u003c/li\u003e\n \u003cli\u003eGender\u003c/li\u003e\n \u003cli\u003eBlood group\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eIndication for LT\u003c/li\u003e\n \u003cli\u003elabMELD/ReMELD-Na\u003c/li\u003e\n \u003cli\u003ePre-existing conditions\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eWaiting List\u003c/h3\u003e\n\u003cp\u003eParticipants\u0026apos; organ offers on the waiting list will be recorded.\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eType of offer\u003c/li\u003e\n \u003cli\u003eNumber of offers\u003c/li\u003e\n \u003cli\u003eReason for turn-down\u003c/li\u003e\n \u003cli\u003ePeriod of non-transplantable status\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ch3\u003eLaboratory Values\u003c/h3\u003e\n\u003cp\u003eRegular laboratory tests will be conducted to monitor the patient\u0026apos;s clinical condition. These include:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eBlood count\u003c/li\u003e\n \u003cli\u003eAST\u003c/li\u003e\n \u003cli\u003eALT\u003c/li\u003e\n \u003cli\u003eGGT\u003c/li\u003e\n \u003cli\u003eAP\u003c/li\u003e\n \u003cli\u003eBilirubin\u003c/li\u003e\n \u003cli\u003eINR\u003c/li\u003e\n \u003cli\u003eCreatinine\u003c/li\u003e\n \u003cli\u003eUrea\u003c/li\u003e\n\u003c/ul\u003e\n\u003ch3\u003e\u0026nbsp;\u003c/h3\u003e\n\u003ch3\u003eDonor Information\u003c/h3\u003e\n\u003cp\u003eDonor-related data will be collected to evaluate organ quality and compatibility. Relevant parameters include:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eDonation Date\u003c/li\u003e\n \u003cli\u003eBlood Group\u003c/li\u003e\n \u003cli\u003eRh Factor\u003c/li\u003e\n \u003cli\u003eAge\u003c/li\u003e\n \u003cli\u003eHeight\u003c/li\u003e\n \u003cli\u003eWeight\u003c/li\u003e\n \u003cli\u003eHCV Ag\u003c/li\u003e\n \u003cli\u003eHBc Ab\u003c/li\u003e\n \u003cli\u003eHIV Ag\u003c/li\u003e\n \u003cli\u003eSplit\u003c/li\u003e\n \u003cli\u003eDonation Centre\u003c/li\u003e\n \u003cli\u003eCause of Death\u003c/li\u003e\n \u003cli\u003eNoradrenaline\u003c/li\u003e\n \u003cli\u003eLeukocytes\u003c/li\u003e\n \u003cli\u003eThrombocytes\u003c/li\u003e\n \u003cli\u003eSodium\u003c/li\u003e\n \u003cli\u003ePotassium\u003c/li\u003e\n \u003cli\u003eCreatinine\u003c/li\u003e\n \u003cli\u003eUrea\u003c/li\u003e\n \u003cli\u003eAST\u003c/li\u003e\n \u003cli\u003eALT\u003c/li\u003e\n \u003cli\u003eGGT\u003c/li\u003e\n \u003cli\u003eAP\u003c/li\u003e\n \u003cli\u003eBilirubin\u003c/li\u003e\n \u003cli\u003eINR\u003c/li\u003e\n \u003cli\u003ePT\u003c/li\u003e\n \u003cli\u003eCRP\u003c/li\u003e\n \u003cli\u003eCold ischemia time\u003c/li\u003e\n \u003cli\u003eFrozen section results\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003ePreoperative Transplant Candidate Status\u003c/h3\u003e\n\u003cp\u003eThe participant\u0026apos;s condition prior to transplantation will be assessed through various preoperative indicators.\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003elabMELD/ReMELD-Na\u003c/li\u003e\n \u003cli\u003eDialysis\u003c/li\u003e\n \u003cli\u003eVentilation\u003c/li\u003e\n \u003cli\u003eNoradrenalin\u003c/li\u003e\n \u003cli\u003eOther catecholamines\u003c/li\u003e\n \u003cli\u003eTime on waiting list\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eQuality Assessment with NMP\u003c/h3\u003e\n\u003cp\u003eNormothermic machine perfusion (NMP) will be employed for organ quality assessment. Data collected include\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eLactate\u003c/li\u003e\n \u003cli\u003eBile\u003c/li\u003e\n \u003cli\u003ePerfusate-pH\u003c/li\u003e\n \u003cli\u003eGlucose in perfusate\u003c/li\u003e\n \u003cli\u003eArterial Flow\u003c/li\u003e\n \u003cli\u003ePortal Flow\u003c/li\u003e\n \u003cli\u003eParenchyma appearance\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003ePostoperative Transplant Recipient Status\u003c/h3\u003e\n\u003cp\u003ePostoperative monitoring will focus on:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eDialysis\u003c/li\u003e\n \u003cli\u003eVentilation\u003c/li\u003e\n \u003cli\u003eNoradrenaline\u003c/li\u003e\n \u003cli\u003eOther catecholamine\u003c/li\u003e\n \u003cli\u003ePacked red blood cells (intraoperative)\u003c/li\u003e\n \u003cli\u003eFresh Frozen Plasma (intraoperative)\u003c/li\u003e\n \u003cli\u003ePlatelet concentrates (intraoperative)\u003c/li\u003e\n \u003cli\u003eProthrombin complex concentrate\u003c/li\u003e\n \u003cli\u003eTranexamic acid\u003c/li\u003e\n \u003cli\u003eFibrinogen\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eProgress Information\u003c/h3\u003e\n\u003cp\u003eLong-term follow-up will include\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003ePostoperative complications\u003c/li\u003e\n \u003cli\u003eComplication Management\u003c/li\u003e\n \u003cli\u003eOther special features during treatment\u003c/li\u003e\n \u003cli\u003eRejection\u003c/li\u003e\n \u003cli\u003eRe-admission to hospital\u003c/li\u003e\n \u003cli\u003eLength of stay in hospital (upon discharge)\u003c/li\u003e\n \u003cli\u003eLength of stay in intensive care (upon discharge)\u003c/li\u003e\n \u003cli\u003eDialysis\u003c/li\u003e\n \u003cli\u003eRetransplantation\u003c/li\u003e\n \u003cli\u003eRelisting\u003c/li\u003e\n \u003cli\u003eDeath\u003c/li\u003e\n \u003cli\u003eBiliary Complications\u003c/li\u003e\n \u003cli\u003eCosts\u003c/li\u003e\n \u003cli\u003eRevenue\u003c/li\u003e\n \u003cli\u003eProfit\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eBiobank\u003c/h3\u003e\n\u003cp\u003eBiological samples will be collected for future research. These include\u003cstrong\u003e:\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003ePatient blood\u003c/li\u003e\n \u003cli\u003eTissue (prior to machine perfusion, 15 minutes on pump, at the end of perfusion, after reperfusion in situ)\u003c/li\u003e\n \u003cli\u003ePerfusate\u003c/li\u003e\n \u003cli\u003eBile\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eSample size {14}\u003c/h2\u003e\n\u003cp\u003eThe primary statistical objective is to show that the cause-specific hazard ratio for the transplant risk between the two randomized groups is not equal to 1. The assumptions for the data-generating process are based on current data from the European Liver Transplant Registry in 2022: Within 12 months, 43.6% of patients with a ReMELD-Na \u0026le; 21 who were not eligible for Standard or Non-Standard Exception were transplanted, 19.1% had a competing event (death, progression or recovery), and 37.2% remained on the waiting list and were censored in this study.\u003c/p\u003e\n\u003cp\u003eAs a treatment effect, an increase in the transplantation rate of 20 percentage points to 63.6% was assumed, while the risk of the competing event remains unchanged. A 20% increase in the transplantation rate through the ExTra option is realistic, as 385 liver transplantations were performed in Germany in 2022 in patients with ReMELD-Na \u0026le; 21 without extraordinary MELD criteria, while 133 of 217 declined grafts would have been potentially acceptable after a quality assessment using NMP, representing approximately 20% additional grafts in the study population based on an estimated 50% acceptance rate following NMP.\u003c/p\u003e\n\u003cp\u003eAssuming exponential distributions for time to transplant and time to competing event, the data were simulated to fit this pattern. The parameter of the exponential distribution for time to transplant (in months) was 0.057 for the control group and 0.104 for the intervention group. The parameter for the competing risk was 0.0251 for both groups. A Cox proportional hazards model was used to estimate the transplant hazard ratio between the ExTra LT group and the control group.\u003c/p\u003e\n\u003cp\u003eBased on 1,000,000 simulations, a sample size of N=83 per group was calculated for a two-sided type I error of 0.05 and a power of 0.8. Considering a dropout rate of 10%, a total of 93 patients will be recruited per group. A median of 36 transplantations is expected in the control arm. It is expected that 4-29 additional transplantations (median: 17) will be performed in the experimental arm.\u003c/p\u003e\n\u003cp\u003eThis number of cases can probably be reached with a recruitment period of 36 months. A 12-month intervention phase is planned, followed by a 12-month follow-up phase. The study will thus end when all 83 patients in each treatment group have completed the 12-month follow-up after randomization/transplantation.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eRecruitment {15}\u003c/h2\u003e\n\u003cp\u003eAll patients with a ReMELD-Na \u0026le;21 without eligibility for Standard or Non-Standard Exceptions, who are listed in the status transplantable for liver transplantation, and medically suitable and informed for transplantation with so-called marginal organs from donors who meet extended donor criteria, will be recruited for the ExTra trial at the respective study centres. It is up to the respective study centres to decide whether the patients are suitable to receive livers from donors who meet the extended donor criteria. For this purpose, regular information must be provided as part of the listing for liver transplantation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe primary recruitment measure should be a personal discussion as part of the information on liver transplantation during consultation hours, which must take place before listing. For this purpose, the respective doctors providing information and the transplant office in the recruiting centres will be informed and sensitized. In addition, information flyers will be made available in the respective transplant outpatient clinics so that potential study participants can inform themselves independently. All patients who present themselves personally on the waiting list as part of routine management (e.g. laboratory check for the MELD score) and fulfil the inclusion criteria should also be contacted personally.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBased on the current number of patients on the waiting list and the multicentre study design, as well as the long recruitment period, the achievability of the specified number of patients is given. The calculation of the number of cases was based on a drop-out rate of 10%; no further replacement of patients in the study arms is planned. We assume that there will be no screening failures due to the high degree of regulation of organ transplantation.\u003c/p\u003e\n\u003ch2\u003eAssignment of interventions: allocation\u003c/h2\u003e\n\u003ch2\u003eSequence generation {16a}\u003c/h2\u003e\n\u003cp\u003ePatients are randomised as block randomisation in a 1:1 ratio and is centrally managed through the eCRF. This means that patients will be evenly distributed between the two study arms (control group with standard allocation and experimental group with the ExTra option).\u003c/p\u003e\n\u003cp\u003eTo ensure an even distribution of key clinical characteristics across both treatment arms, the randomization will be \u003cstrong\u003estratified\u003c/strong\u003e according to the following prognostic variables:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eReMELD-Na-Score\u003c/strong\u003e at the time of transplantation (\u0026lt;13 or \u0026ge;13),\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eWaiting Time\u0026nbsp;\u003c/strong\u003e(0\u0026ndash;6 months or \u0026gt;6 months)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eConcealment mechanism {16b}\u003c/h2\u003e\n\u003cp\u003eThis trial is conducted as an open-label study without blinding; therefore, no concealment of the allocation sequence is required. Participants will be assigned to study groups based on the predetermined randomization process, which will be centrally managed to ensure transparency and adherence to the study protocol. Since both participants and investigators will be aware of the assigned interventions, no additional measures such as sealed envelopes or central telephone randomization will be implemented.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eImplementation {16c}\u003c/h2\u003e\n\u003cp\u003eThe allocation sequence will be generated by an independent statistician using a computer-based randomization system via the eCRF to ensure an unbiased assignment of participants. Participant enrolment will be carried out by designated study investigators at each participating centre. They will assess eligibility based on predefined inclusion and exclusion criteria before obtaining informed consent. Assignment to interventions will be conducted centrally by the study coordination team, following the generated allocation sequence. Since this is an open-label trial, both participants and investigators will be informed of the assigned intervention upon enrolment.\u003c/p\u003e\n\u003ch2\u003eAssignment of interventions: Blinding\u003c/h2\u003e\n\u003ch2\u003eWho will be blinded {17a}\u003c/h2\u003e\n\u003cp\u003eThis trial is conducted as an open-label study without blinding. All involved parties are aware of the treatment group.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eProcedure for unblinding if needed {17b}\u003c/h2\u003e\n\u003cp\u003eNo Procedure for unblinding is necessary, as this is an open-label study.\u003c/p\u003e\n\u003ch2\u003eData collection and management\u003c/h2\u003e\n\u003ch2\u003ePlans for assessment and collection of outcomes {18a}\u003c/h2\u003e\n\u003cp\u003eA comprehensive data management plan will be created to define the processes for data handling, cleaning, and quality control in the trial. The key aspects are summarized below:\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eData collection is carried out using electronic case report forms (eCRFs). The secuTrial study software is used for this purpose. The study data is recorded online and transferred directly to the study server\u0026apos;s database. The data transfer between the workstation (at the trial site) and the study server is carried out via a secure connection (SSL encryption) so that the transferred study data cannot be manipulated. Patient data is only stored in pseudonymized form. The study software automatically generates a pseudonym for each new patient to be added. The unambiguous assignment to the patient is done via a paper printout, which will be stored securely.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll patient-related data are recorded in pseudonymized form. For this purpose, a non-descriptive pseudonym is used from which the patient\u0026apos;s identity cannot be inferred on its own. To obtain unique patient identification numbers, a combination of a fixed trial centre number and a consecutive centre-specific patient number is chosen. The patient identification number is assigned centrally as part of the internet-based randomization.\u003c/p\u003e\n\u003cp\u003eEach principal investigator (principal investigator at the trial site) maintains a patient identification list in which the patient identification numbers are linked to the full patient names of the participants, patient identification numbers and, if applicable, date of birth. This list serves to enable the later identification of participating individuals. It must be treated with absolute confidentiality and must not leave the trial centre. Only the local study team and the monitor have access to this list. The original files can be viewed by monitors, auditors and inspectors. The patient identification list must be archived for at least ten years after the end of the study.\u003c/p\u003e\n\u003cp\u003eIn addition, the participation of relevant individuals in the study is noted in the respective patient file\u003cem\u003e.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ch3\u003eMonitoring\u003c/h3\u003e\n\u003cp\u003eMonitoring is carried out by means of regular on-site visits and an internal review of data quality. The frequency of on-site visits is based on an assessment of all study characteristics, including the type, objective and methodology of the study. A risk-based approach is applied as described in the monitoring plan.\u003c/p\u003e\n\u003cp\u003eClinical monitoring is conducted according to the monitoring plan. It includes, but is not limited to, the review of laboratory values and adverse events. The investigator allows for study-related monitoring at the site, audits, IEC reviews, and inspections by local or state health authorities, if regulated by local law.\u003c/p\u003e\n\u003cp\u003eDirect access to the electronic Case Report Form (eCRF) and to all source documents, including medical records, laboratory reports and medical test results, is provided to ensure verification by the Clinical Research Associates (CRA), auditors and regulatory inspectors. All eCRFs and informed consent forms are available for inspection.\u003c/p\u003e\n\u003cp\u003eThe accuracy of the recorded data is ensured by direct comparison with the source documents. The sponsor also monitors compliance with the study protocol and other relevant legal requirements.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003ePlans to promote participant retention and complete follow-up {18b}\u003c/h2\u003e\n\u003cp\u003eTo minimize attrition and ensure comprehensive data collection, participants will receive detailed information about the study, its objectives, and the importance of follow-up assessments during the informed consent process. A dedicated study coordinator will serve as the primary contact for all study centres, maintaining regular communication.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGiven the complexity of liver transplantation and the extended follow-up period required, follow-up trial visits will be tried to co-align with regular post-transplantation examinations in the respective outpatient clinic of the study centre. All reasons for withdrawal or protocol deviations will be documented systematically, allowing for an analysis of potential impacts on study outcomes. Retention strategies will be continuously evaluated throughout the study, with regular assessments of adherence rates and the identification of potential barriers to follow-up. The study team will monitor participant engagement and proactively address challenges that may affect retention.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eData management {19}\u003c/h2\u003e\n\u003ch3\u003eData recording and record keeping\u003c/h3\u003e\n\u003cp\u003eData collection is done via a server-based electronic CRF (eCRF) with remote data entry (RDE). The trial site/sponsor stores all data electronically. All entries in the CRF are checked for plausibility and consistency immediately during data entry. These checks generate \u0026ldquo;soft\u0026rdquo; or \u0026ldquo;hard\u0026rdquo; warnings and prompt the user to recheck and possibly change the data before the information is/can be saved. The checks are planned with the principal investigator and incorporated after confirmation.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAdditional checks must be defined in the study-specific data validation plan (DVP). These checks are/can be very complex and are carried out in SAS/R at specific points in time (milestones, time frames, specific dates) after the database information has been exported. In addition, the responsible data manager checks the exported data sequentially for implausibility over the entire period of the study.\u003c/p\u003e\n\u003cp\u003eInconsistencies, implausible or missing data are flagged by a data management query in the eCRF. The potentially incorrect information can be corrected by directly changing the values in the eCRF or must be marked as accepted errors or false reports. Changes to the documented information are tracked via the audit trail, which is a basic function of the eCRF.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMost incorrect data are corrected within the eCRF. A data correction performed by data management (SEC - self evidence correction, documented deletion of incorrect data) can be added as a second level of control. All missing data or inconsistencies must be resolved by the responsible investigator before the database is locked (soft lock/hard lock).\u003c/p\u003e\n\u003cp\u003eDetailed information on deviations from the protocol can be documented in the study software, either as patient-independent/site-specific or patient- or drug-specific protocol violations.\u003c/p\u003e\n\u003cp\u003eAfter completion of the study and after all data entry has been finalized, the database is closed for further data entry. This process is documented.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eData Storage and Access to Data\u003c/h3\u003e\n\u003cp\u003eThe originals of all central study documents, including the documentation forms, are stored at the study centre (with the study director) for at least 10 years after completion of the clinical study. The investigator/head of the trial centre stores the administrative documents that have been created (correspondence with the ethics committee, principal investigator, trial centre), the patient identification list, the signed declarations of consent, copies of the documentation sheets and the general trial documentation (protocol, amendments) for the above-mentioned period. The original data of the study patients (medical records) must be stored for the archiving period applicable to the study sites (the investigators), but for no less than 10 years.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eConfidentiality {27}\u003c/h2\u003e\n\u003cp\u003eThe data protection requirements of the GDPR, the Federal Data Protection Act (BDSchG), and the State Data Protection Acts (LDSchG) all apply. As part of the study, it is necessary to collect and process personal data (e.g. full name, initials of first and last name, date of birth, address) and data on treatment and disease progression (e.g. medical findings, types of treatment, prescribed medications) from the study participants. These data are collected at the study centre and stored electronically in pseudonymized form (i.e., without direct reference to the patient\u0026apos;s name) with the help of a patient identification number, transmitted to the responsible data processing centre and evaluated.\u003c/p\u003e\n\u003cp\u003eIn the event of a patient\u0026apos;s revocation of consent to the study, including further data collection, no further data will be collected from the time of revocation. The data collected so far will continue to be used and evaluated within the study. If a patient only discontinues the study treatment, the data required for the study can continue to be collected and used.\u003c/p\u003e\n\u003cp\u003ePatients are informed that their disease-related data will be stored in pseudonymized form and used for scientific evaluations (publications). Patients have the right to be informed about the stored data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003ePlans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}\u003c/h2\u003e\n\u003cp\u003eBiological specimens collected for future studies will be processed, stored, and managed through the central biobank at the Charit\u0026eacute; \u0026ndash; Universit\u0026auml;tsmedizin Berlin (ZeBanC), ensuring standardized and high-quality sample handling across all participating centres. ZeBanC provides all centres with specialized sample collection and aliquoting sets, including stretching tubes, along with detailed procedural instructions to ensure uniform sample processing, documentation, and transport.\u003c/p\u003e\n\u003cp\u003eBlood samples will be collected at multiple time points, including before liver transplantation, one hour after reperfusion, and on postoperative days one and three. These samples will include 10 mL of serum, 10 mL of EDTA whole blood, and one PAXgene Blood DNA sample. Since blood sampling is a routine part of preoperative care and postoperative follow-up, only additional material necessary for the study will be obtained.\u003c/p\u003e\n\u003cp\u003eIn addition to blood, a wedge biopsy of the liver will be performed before machine perfusion or after organ preparation, after completion of normothermic machine perfusion (NMP) in the ExTra arm, and one hour after reperfusion. Perfusate samples will be collected at defined time points, including before the start of perfusion, 15 minutes after initiation, at hourly intervals during the procedure, and at the conclusion of NMP in the ExTra LT study arm, with 1.5 mL per sample. Additionally, bile samples will be collected every two hours during perfusion and at the end of NMP in the same study arm, with 1 mL per sample. Sample processing is conducted on-site by trained study personnel at each centre following standardized protocols to ensure consistency. Th\u003c/p\u003e\n\u003cp\u003eFor transportation to ZeBanC, all samples will be transferred to dry ice to maintain the integrity of the biological materials during transportation. The transportation costs will be fully covered by the project.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eStatistical methods\u003c/h2\u003e\n\u003ch2\u003eStatistical methods for primary and secondary outcomes {20a}\u003c/h2\u003e\n\u003ch3\u003eHypotheses:\u003c/h3\u003e\n\u003cp\u003eThe primary null hypothesis to be rejected is that the cause-specific hazard ratio for transplant risk between the two randomized groups is equal to 1. Consequently, the alternative hypothesis is that the cause-specific hazard ratio for transplant risk between the two randomized groups is not equal to 1.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n\u003ch3\u003eIntent-to-treat population\u003c/h3\u003e\n\u003cp\u003eThe primary statistical analysis is based on the intention-to-treat population. This consists of all randomized patients and includes the group allocation as specified by the randomization. This means that the patients are analysed independently of protocol violations (which are not an exclusion criterion).\u003c/p\u003e\n\u003ch3\u003eTransplanted cohort\u003c/h3\u003e\n\u003cp\u003eSecondary analyses will be conducted in the cohort that received a liver graft during the 12-month intervention period.\u003c/p\u003e\n\u003ch3\u003ePopulation for the safety analysis\u003c/h3\u003e\n\u003cp\u003eThe population for the safety analysis includes all patients who were randomized.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003ePrimary endpoint\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint of time-from-randomization-to-transplantation is evaluated on the intention-to-treat cohort, the hazards between the ExTra LT group and the control group are compared using cause-specific Cox proportional hazards models. The intervention effect is given in the form of the hazard ratio with 95% confidence interval, and it is tested whether this differs from 1. Death on the waiting list, disease progression (ReMELD-Na \u0026gt;21 at listing with transplantable status or contraindication of liver transplantation) and recovery (transplantation no longer necessary) are considered as competing events. Patients who have not yet received a graft after 12 months and are therefore still on the waiting list are administratively censored. In the Cox proportional hazards analysis, it is adjusted for the centre effect, \u003cstrong\u003eReMeld-Na-Score\u003c/strong\u003e at the time of transplant (\u0026lt;13 or \u0026ge;13), \u003cstrong\u003ewaiting time before randomization\u0026nbsp;\u003c/strong\u003e(0\u0026ndash;6 months or \u0026gt;6 months). A two-sided significance level of 5% is used.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn addition, the probability of transplantation for both groups are calculated using Aalen-Johansen estimators (Kaplan-Meier for competing risks) with 95% confidence intervals based on a complementary log-log transformation and displayed over time.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eCompeting events\u003c/h3\u003e\n\u003cp\u003eThe secondary endpoints include, among others, competing events (death, disease progression, recovery) and are also evaluated on the intention-to-treat cohort. Again, the time from randomization until the occurrence of the event is examined. For death (corresponds to waiting list mortality) and the composite of disease progression and recovery, cause-specific Cox proportional hazards models are calculated. The same variables as for the primary endpoint are used for adjustment (centre effect, ReMELD-Na-Score at the time of transplantation (\u0026lt;13 or \u0026ge;13), waiting time before randomization (0\u0026ndash;6 months or \u0026gt;6 months), perfusion device used (OrganOx Metra or LiverAssist), and age and sex). The effect of the intervention on the competing events is given in the form of the hazard ratio with 95% confidence interval and it is tested whether it differs from 1.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThese analyses are accompanied by the Aalen-Johansen estimates with 95% confidence intervals of the ExTra LT group and the control group. These reflect the estimated probability of the competing events since randomization. Differences between the curves are discussed regarding all cause-specific hazard ratios.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eSecondary endpoints\u003c/h3\u003e\n\u003cp\u003eThe overall survival of patients between randomization to the end of follow-up (maximum 24 months) is examined in the intention-to-treat cohort using Kaplan-Meier analyses. The Kaplan-Meier curves of the ExTra LT group and the control group are compared using the log-rank test. A significance level of 5% is applied. A Cox proportional hazards regression is used to adjust for the influence of the variables centre effect, ReMELD-Na-Score at the time of transplantation (\u0026lt;13 or \u0026ge;13), waiting time before randomization (0\u0026ndash;6 months or \u0026gt;6 months), perfusion device used (OrganOx Metra or LiverAssist), as well as age and gender.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe number of patients listed for transplantation in each group after 12 months will be descriptively described. Likewise, the utilization rate (used organs / offered organs) will be descriptively analysed. Furthermore, the \u0026ldquo;graft rescue rate\u0026rdquo; (livers that meet the quality criteria during NMP / all livers that were assessed by NMP as part of the study) will be descriptively presented.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eQuality of life will be assessed using EQ5DL and the differences in the course of time compared to the value for randomization between the two intervention groups are compared.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe costs associated with transplantation or hospitalization for transplantation between the groups are modelled using linear regression. The dependent variable is costs, and the independent variables are ExTra LT or control group, centre, ReMELD-Na-Score at the time of transplantation (\u0026lt;13 or \u0026ge;13), waiting time before randomization (0\u0026ndash;6 months or \u0026gt;6 months), perfusion device used (OrganOx Metra or LiverAssist), and BAR score.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1-year graft and 1-year patient survival will be compared using Kaplan-Meier analyses in the cohort of transplanted patients. In addition to the comparison between the two study arms, the grafts that took place with livers that met the quality criteria during NMP will be compared with the standard grafts.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe other secondary endpoints in the cohort of graft recipients, Ease score, Balance of Risk (BAR) score, duration of stay in the intensive care unit, length of hospital stay, Comprehensive Complication Index (CCI) and biliary complications (ischemic-type biliary lesions (clinical and as part of the planned MRCP 12 months after liver transplantation) are analysed according to their scale level and distribution function using adequate statistical methods.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eInterim analyses {21b}\u003c/h2\u003e\n\u003cp\u003eThe DSMB will assess the safety endpoint of 3-month graft and patient survival defined as the need for retransplantation or death in the first 3 months after liver transplantation (ExTra LT) using Kaplan-Meier analysis. The pseudonymized reporting of the safety endpoints is planned at the beginning of each quarter via the principal investigator to the DSMB members. Depending on the results, the DSMB may recommend to the principal investigator that the study be terminated.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eMethods for additional analyses (e.g. subgroup analyses) {20b}\u003c/h2\u003e\n\u003cp\u003eFurther secondary exploratory endpoints include translational investigations. These involve\u003cu\u003e\u0026nbsp;\u003c/u\u003ethe use of biomarkers in tissue, perfusate, bile and laboratory chemistry, as well as other aspects of DNA and RNA analyses by NMP to predict outcome (early allograft dysfunction according to the criteria of Olthoff et al. (17) and 3-month graft survival).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eMethods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}\u003c/h2\u003e\n\u003cp\u003eThe analysis population will follow an intention-to-treat (ITT) approach, meaning all randomized participants will be analysed according to their originally assigned study arm, regardless of protocol deviations or adherence to the intervention. This ensures that the estimated treatment effects reflect real-world applicability while preserving the benefits of randomization.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor cases of protocol non-adherence, including recipients who withdraw after implantation, all available data will be included in the analysis. The primary outcome, time-to-transplant, will be assessed using a cause-specific Cox proportional hazards regression model, accounting for competing risks such as clinical improvement, deterioration, or death, which may preclude transplantation under the ExTra study conditions.\u003c/p\u003e\n\u003cp\u003eMissing data will be addressed through multiple imputation methods when feasible. The feasibility of imputation will depend on the proportion of missing data, the availability of auxiliary variables, and the assumption that missingness is at random.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData integrity will be maintained through real-time monitoring in the electronic Case Report Form (eCRF), where inconsistencies, implausible values, or missing data points will trigger data management queries. Investigators will be required to address all flagged issues before the database lock (soft lock/hard lock). Corrections can be made directly in the eCRF, and if necessary, a self-evident correction (SEC) process will be applied, with all changes documented in an audit trail.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003ePlans to give access to the full protocol, participant level-data and statistical code {31c}\u003c/h2\u003e\n\u003cp\u003eAuthorized representatives from the sponsor and the host institution will be granted direct access for trial-related monitoring, audits, and inspections. To ensure thorough verification, direct access to the electronic Case Report Form (eCRF) and all source documents, including medical records, laboratory reports, and medical test results, will be provided to auditors, and regulatory inspectors. All eCRFs and informed consent forms will be available for inspection.\u003c/p\u003e\n\u003ch2\u003eOversight and monitoring\u003c/h2\u003e\n\u003ch2\u003eComposition of the coordinating centre and trial steering committee {5d}\u003c/h2\u003e\n\u003ch3\u003eTrial Management Team\u003c/h3\u003e\n\u003cp\u003eThe trial management team consists of the principal investigator, the coordinating investigator and the study coordinator. The trial management team will be responsible for running the day-to-day necessities of the trial, coordinating study sites, and communicating with the steering committee and the DSMB.\u003c/p\u003e\n\u003ch3\u003eTrial Steering Committee\u003c/h3\u003e\n\u003cp\u003eThe Steering Committee is responsible for providing scientific advice regarding the study. This committee will meet regularly, virtually or in person, to monitor subject recruitment, study progress, and compliance with the protocol. This committee is responsible for reassessing the benefit-risk ratio based on the recommendations of the DSMB, for decisions on discontinuing the study, for reviewing the results, for determining the presentation and publication methods, and for selecting secondary projects and publications.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eComposition of the data monitoring committee, its role and reporting structure {21a}\u003c/h2\u003e\n\u003cp\u003eThe Data Safety Monitoring Board (DSMB) consists of four independent physicians, two hepatologists and two transplant surgeons. Prof. Julia Wendon (UK) has earned an outstanding international reputation in the care of critically ill patients with liver disease. Prof. Christoph Roderburg (Germany) has extensive experience in conducting clinical trials in hepatology and gastroenterology but is not involved in the care of liver graft recipients. Prof. Markus Selzner (Canada) and Prof. Madhukar Patel (USA) have in-depth expertise in the quality assessment of declined liver grafts by NMP (e.g. NCT 02478151, Toronto).\u003c/p\u003e\n\u003cp\u003eThe DSMB will discuss the study protocol, the necessary safety mechanisms and the review of the safety endpoint with the principal investigator before the study begins. The rights and obligations are contractually regulated. The \u0026ldquo;Guideline on data monitoring committees\u0026rdquo; of the European Medicines Agency (EMEA/CHMP/EWP/5872/03 Corr) serves as a guideline.\u003c/p\u003e\n\u003cp\u003eThe DSMB will assess the safety endpoint of 3-month graft and patient survival defined as the need for retransplantation or death in the first 3 months after liver transplantation (ExTra LT) using Kaplan-Meier analysis. The pseudonymized reporting of the safety endpoints is planned at the beginning of each quarter via the principal investigator to the DSMB members. Depending on the results, the DSMB may recommend to the principal investigator that the study be terminated.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAdverse event reporting and harms {22}\u003c/h2\u003e\n\u003cp\u003eSince two medical devices (according to \u0026sect;2 (1) MDR) can be used in the intervention arm in the ExTra trial, the vigilance definitions of AE, SAE and DD of the MDR apply. In addition, further legal definitions of the national legislator may have to be considered. In the present study, the medical devices (with CE marking) are used within the scope of the intended purpose as specified by the manufacturer, without the use of additional invasive or stressful procedures (in accordance with \u0026sect;47(3) MPDG). In this study, vigilance measures are conducted according to the study design and risk-benefit ratio. The study director assesses adverse events and takes any necessary measures.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSince the ExTra trial does not evaluate the performance or safety of a medical device, but rather compares the use of two CE-marked medical devices in the intervention arm (according to the manufacturer\u0026apos;s intended purpose) with the standard of care, the reporting of suspected serious incidents in accordance with MPAMIV (see 11.1) is carried out by the trial centres/users or operators in accordance with national rules and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ch3 style='margin:0in;text-align:justify;line-height:150%;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;border:none;font-weight:bold;'\u003eVigilance Definitions (MDR and MPAMIV)\u003c/h3\u003e\n\u003ctable style=\"width:470.1pt;margin-left:.1pt;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120.15pt;border: 1pt solid windowtext;padding: 0in 5.4pt;height: 6.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:11px;line-height: 150%;\"\u003eTerm\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 349.95pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;height: 6.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:11px;line-height: 150%;\"\u003eDefinition\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120.15pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cspan style=\"font-size:11px;line-height:150%;\"\u003eAdverse event (AE) (acc. to Art. 2(57) MDR)\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cspan style=\"font-size:11px;line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 349.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cspan style='font-size:11px;line-height:150%;font-family:\"Arial\",sans-serif;'\u003e\u0026bdquo;Adverse event\u0026rdquo; means any untoward medical occurrence, unintended disease or injury, or unfavourable clinical symptom, including abnormal laboratory findings, in subjects, users or other persons, related to a clinical investigation, even if not related to the investigational device;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120.15pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 62.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cspan style=\"font-size:11px;line-height:150%;\"\u003eSerious adverse event (SAE) (acc. to Art. 2 (58) MDR\u003c/span\u003e\u003cspan style=\"font-size:11px;line-height:150%;font-family:Calibri;\"\u003e)\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cspan style=\"font-size:11px;line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 349.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 62.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cspan style=\"font-size:11px;line-height:150%;\"\u003e\u0026ldquo;Serious adverse event\u0026apos;\u0026rdquo; means an adverse event that resulted in any of the following: (a) death; (b) a significant deterioration in the health of a subject that resulted in any of the following: (i) life-threatening illness or injury, (ii) permanent disability or impairment of bodily function, (iii) hospitalization or prolongation of existing hospitalization, (iv) medical or surgical intervention to prevent life-threatening illness or injury or permanent disability or impairment of bodily function, (v) chronic disease, c) foetal jeopardy, foetal death, or congenital physical or mental defect or birth defect;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120.15pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cspan style=\"font-size:11px;line-height:150%;\"\u003eDevice deficiency (DD) (acc. to Art. 2 (59) MDR)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cspan style=\"font-size:11px;line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 349.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cspan style=\"font-size:11px;line-height:150%;\"\u003e\u0026ldquo;Device Deficiency\u0026rdquo; (DD) refers to any inadequacy in the identification, quality, durability, reliability, safety or performance of a test product, including malfunctions, application errors or inadequacies in the information provided by the manufacturer. In particular, any deficiency that led to the termination of liver machine perfusion, make transplantation impossible or endanger patient safety as a result.\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120.15pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cspan style=\"font-size:11px;line-height:150%;\"\u003eIncident (acc. to Art. 2 (64) MDR)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cspan style=\"font-size:11px;line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 349.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cspan style=\"font-size:11px;line-height:150%;font-family:Calibri;\"\u003e\u0026bdquo;I\u003c/span\u003e\u003cspan style=\"font-size:11px;line-height:150%;\"\u003encident\u0026rdquo; means any malfunction or deterioration in the characteristics or performance of a device, including errors of use due to ergonomic features, made available on the market, as well as any inadequacy of the information supplied by the manufacturer and any undesirable side-effect;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120.15pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 62.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cspan style=\"font-size:11px;line-height:150%;\"\u003eSerious incident (acc. to Art. 2 (65) MDR)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 349.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 62.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cspan style=\"font-size:11px;line-height:150%;font-family:Calibri;\"\u003e\u0026bdquo;Serious i\u003c/span\u003e\u003cspan style=\"font-size:11px;line-height:150%;\"\u003encident\u0026rdquo; means an incident which, directly or indirectly: a) resulted in, could have resulted in, or could result in: death of a patient, user or other person; b) led to, or could lead to, temporary or permanent serious deterioration in the health of a patient, user or other person; c) created a serious risk of harm to public health;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120.15pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 62.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cspan style=\"font-size:11px;line-height:150%;\"\u003eSuspected serious incident\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cspan style=\"font-size:11px;line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 349.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 62.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cspan style=\"font-size:11px;line-height:150%;\"\u003eIn Germany, there is an additional legal definition for an:\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:11px;line-height:150%;font-family: Calibri;\"\u003e\u0026bdquo;\u003c/span\u003e\u003cspan style=\"font-size:11px;line-height:150%;\"\u003epresumed serious incident\u0026rdquo; (according to \u0026sect; 2 MPAMIV, Medical Devices User Reporting and Information Ordinance):\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:13px;font-family:\"Arial\",sans-serif;color:windowtext;margin:0in;text-align:justify;line-height:150%;border:none;'\u003e\u003cspan style=\"font-size:11px;line-height:150%;font-family:Calibri;\"\u003e\u0026bdquo;\u003c/span\u003e\u003cspan style=\"font-size:11px;line-height:150%;\"\u003esuspected serious incident\u0026rdquo; (is) an incident that cannot be ruled out as being due to an undesirable side effect of a product, a malfunction, a deterioration in the properties or performance of a product, including application errors due to ergonomic features or an inadequacy in the information provided by the manufacturer, and that directly or indirectly resulted in, or could have resulted in, one of the following: 1. the death of a patient, user or other person, 2. the temporary or permanent serious deterioration of a patient\u0026apos;s, user\u0026apos;s or other person\u0026apos;s state of health, or 3. a serious risk to public health.\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ch3\u003eAdverse Events (AEs)\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eA number of adverse events (AEs) occur with some frequency during the postoperative course in patients undergoing liver transplantation and are therefore not considered unexpected. For this study, the following pre-defined events that may occur in the postoperative course and are likely related to the surgery and/or standard intraoperative or postoperative medications are not considered AEs and therefore do not need to be recorded in the eCRF unless the responsible study physician classifies the event as a serious adverse event (SAE):\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eNausea.\u003c/li\u003e\n \u003cli\u003eAlteration in bowel function \u0026ndash; including constipation, diarrhoea, bloating, flatulence or ileus \u0026ndash; that resolves without intervention.\u003c/li\u003e\n \u003cli\u003ePain at the surgical incision.\u003c/li\u003e\n \u003cli\u003eTransient changes in vital signs (fever, hypo- or hypertension, brady- or tachycardia, hypoxia) that resolve and do not require intervention.\u003c/li\u003e\n \u003cli\u003ePruritus (itching).\u003c/li\u003e\n \u003cli\u003eFatigue or lethargy; insomnia.\u003c/li\u003e\n \u003cli\u003eConfusion, altered mental status, or dizziness.\u003c/li\u003e\n \u003cli\u003eRadiographic findings/changes that do not require intervention.\u003c/li\u003e\n \u003cli\u003eWound dehiscence (wound opening).\u003c/li\u003e\n \u003cli\u003eHyperglycaemia, worsening of existing hyperglycaemia, or development of diabetes mellitus.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eOther (expected) adverse events, including those listed below, are documented as AEs in the eCRF regardless of their severity.\u003c/p\u003e\n\u003cp\u003eGeneral:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eInfection (lungs, urinary tract, blood, bile, wound, abdomen)\u003c/li\u003e\n \u003cli\u003eRejection\u003c/li\u003e\n \u003cli\u003eKidney dysfunction incl. dialysis\u003c/li\u003e\n \u003cli\u003eLiver dysfunction\u003c/li\u003e\n \u003cli\u003eHeart failure\u003c/li\u003e\n \u003cli\u003eRespiratory failure incl. respiratory therapy\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eEvents related to the disease/procedure/operation:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eEarly graft dysfunction (according to the definition by Olthoff et al. 2010)\u003c/li\u003e\n \u003cli\u003eHospitalization for suspected rejection\u003c/li\u003e\n \u003cli\u003eOccurrence and treatment of abdominal or wound infection\u003c/li\u003e\n \u003cli\u003eRespiratory failure requiring mechanical ventilation\u003c/li\u003e\n \u003cli\u003eHospitalization for pre-existing illness that has not worsen\u003c/li\u003e\n \u003cli\u003eClinically significant abnormal laboratory findings or other abnormal assessments related to the condition being evaluated (unless the investigator judges them to be more serious than would be expected for the patient\u0026apos;s condition)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe study doctor will judge as to whether an abnormal laboratory finding, or other abnormal assessment is clinically significant. However, if in the opinion of the investigator the frequency or severity of the event is greater than expected, it must be reported as an AE/SAE.\u003c/p\u003e\n\u003cp id=\"_Toc190244518\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eCausality Assessment\u003c/h3\u003e\n\u003cp\u003eBoth the study physician and the study management determine whether the event is related to the medical device, procedure or other circumstances.\u003c/p\u003e\n\u003cp\u003eThe causal relationship of the event with the tested therapeutic strategy is categorized as follows:\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eYes:\u003col\u003e\n \u003cli\u003eThe event is closely related in time to the use of the medical device/therapeutic strategy and another aetiology is highly unlikely.\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n \u003cli\u003ePossible:\u003col\u003e\n \u003cli\u003eThe AE occurred in close temporal relation to the use of the medical device/therapeutic strategy and there is no conflicting evidence that could reasonably explain the subject\u0026apos;s condition.\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n \u003cli\u003eNo:\u003col\u003e\n \u003cli\u003eThe AE is not related to the medical device/therapeutic strategy.\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003ch3 id=\"_Toc190244519\"\u003eDocumentation\u003c/h3\u003e\n\u003cp\u003eAll adverse events must be documented in the patient\u0026apos;s study documentation. In addition, all AEs and SAEs will be recorded in the eCRF from the date of randomization until the end of study participation. Pre-existing illnesses or symptoms documented prior to randomization will be recorded as the participant\u0026apos;s medical history (not an AE). If these conditions or symptoms worsen during the course of the study, they must be evaluated by an investigator and also documented in the patient\u0026apos;s medical record as an AE. If they meet the criteria for an AE and an SAE, they must be recorded in the eCRF and reported using the SAE report form.\u003c/p\u003e\n\u003cp\u003eAll SAEs must be documented in the eCRF, regardless of whether the study physician suspects a causal relationship with the medical device or the study procedure. The type of event, the onset, duration, severity, measures, outcome and causality assessment should be documented as a minimum. The following must also be assessed:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eWhether or not the event is a serious adverse event\u003c/li\u003e\n \u003cli\u003eWhether the adverse event was caused by a device deficiency\u003c/li\u003e\n \u003cli\u003eWhether the adverse event was caused by user error\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eAEs must be followed up until they have resolved, the AE has stabilized, or the study has been completed. As soon as further/new relevant information on the event is available (e.g. discharge letter), the documentation in the eCRF must also be updated and electronically signed/sent. Copies of the discharge letter, any reports of examinations performed and/or diagnostic findings should only be provided upon request. All required data should be recorded on the SAE reporting form.\u003c/p\u003e\n\u003cp\u003eAdverse events occurring during the study should be handled according to established standards to protect the life and health of the study participants.\u003c/p\u003e\n\u003cp\u003eIt is the responsibility of the local study doctor to record all directly observed adverse events, and all spontaneously reported adverse events by the participant. In addition, each participant should be asked specifically about adverse events at each visit/contact.\u003c/p\u003e\n\u003cp\u003eAdverse events must be documented on the provided forms for recording (serious) adverse events.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3 id=\"_Toc190244520\"\u003eReporting\u003c/h3\u003e\n\u003cp\u003eEvery SAE must be reported to the pharmacovigilance team of Charit\u0026eacute; within 24 hours of the study doctor becoming aware of the event. SAEs are to be reported via eCRF. The study director is to be informed of any pregnancy as soon as it becomes known. There will \u003cu\u003enot be\u003c/u\u003e any follow-up of the pregnancy. Events reported on paper must be recorded in the eCRF as soon as the database is available again. At the time of initial reporting, the following minimum information must be provided:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eIdentifiable patient: subject ID and study arm\u003c/li\u003e\n \u003cli\u003eIdentifiable reporter: study site, study physician including contact details, date of notification\u003c/li\u003e\n \u003cli\u003eDescription of the SAE\u003c/li\u003e\n \u003cli\u003eMedical device used in the intervention arm\u003c/li\u003e\n \u003cli\u003eAssessment of a causal relationship with the MP, the procedure and others\u003c/li\u003e\n \u003cli\u003eMeasures taken\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIf requested, the investigational site will provide the pharmacovigilance team with a copy of the pseudonymized accompanying documentation (e.g. hospital records, laboratory results, autopsy results) of all SAEs and safety events. The study management must be informed of this.\u003c/p\u003e\n\u003cp\u003eThe principal investigator will promptly inform the relevant ethics commissions about any events that could affect the safety of the participants, the conduct of the study or the benefit-risk ratio of the study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eFrequency and plans for auditing trial conduct {23}\u003c/h2\u003e\n\u003cp\u003eAuditing of the trial conduct will be performed according to the monitoring plan to ensure compliance with the study protocol, Good Clinical Practice (GCP), and regulatory requirements. Clinical monitoring will be conducted at regular intervals and will include a review of laboratory values, adverse events, adherence to protocol-defined procedures, and data integrity checks. Investigators must allow for study-related audits, Institutional Ethics Committee (IEC) reviews, and inspections by local or state health authorities, as required by applicable regulations.\u003c/p\u003e\n\u003cp\u003eProtocol deviations will be documented and categorized based on their impact on study outcomes. Significant protocol deviations, which could influence data completeness, accuracy, or patient safety, will be subject to further review. Any deviations from the protocol necessary to protect the rights, safety, or well-being of participants in an emergency may be implemented without prior consultation with the study management team but must be fully documented in the source records and recorded in the eCRF\u003c/p\u003e\n\u003cp\u003eSerious breaches of GCP or the trial protocol that could significantly affect patient safety or the scientific validity of the study will be reported promptly. If a serious breach is suspected, the sponsor must be notified within one working day, after which the case will be reviewed. If necessary, the breach will be reported to the Ethics Committee.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003ePlans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}\u003c/h2\u003e\n\u003cp\u003eChanges or amendments to the study protocol may only be initiated and authorized by the study management. The ethics committee(s) will be informed of any changes to the study protocol. If necessary, renewed approval will be obtained (as part of a substantial amendment). Changes requiring approval must not be implemented before being reviewed by the ethics committee.\u003c/p\u003e\n\u003cp\u003eSubstantial amendments are changes that:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eAffect the safety of the participants,\u003c/li\u003e\n \u003cli\u003eRequire additional data collection or analyses that necessitate changes to patient information and/or consent,\u003c/li\u003e\n \u003cli\u003eImpact the interpretation of scientific documents on which the study is based or influence the scientific validity of study results,\u003c/li\u003e\n \u003cli\u003eSignificantly alter the management or conduct of the study\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eDissemination plans {31a}\u003c/h2\u003e\n\u003cp\u003eThe primary outcomes of the study will be published in peer-reviewed journals relevant to the field of transplantation. All publications, abstracts, and other outputs will be reviewed by the Steering Committee\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eprior to submission to ensure consistency, scientific integrity, and proper attribution of authorship.\u003c/p\u003e\n\u003cp\u003eData analysis will be conducted on a study-wide basis, and all results will be reported as such. Individual participating centres will not independently publish or present study data without prior approval from the Steering Committee. The principal investigator will oversee the final compilation of results, and each participating centre will be required to review and sign off on the final report before submission for publication. The trial will be registered, and the identifier will be included in all presentations and publications.\u003c/p\u003e\n\u003cp\u003eSecondary analyses or additional publications based on ExTra trial data must be approved by the Steering Committee, and investigators proposing such analyses must submit a formal request. If approved, the proposing author will take the lead in developing the resulting publications, with authorship reflecting contributions from all participating centres in accordance with established guidelines.\u003c/p\u003e\n\u003cp\u003eBeyond scientific publications, study findings will be communicated through conference presentations, professional meetings, and public engagement activities to ensure that the broader medical community and patient advocacy groups are informed of the study\u0026rsquo;s implications. Results may also be shared in relevant clinical trial registries and reporting databases as required by regulatory and funding bodies.\u003c/p\u003e\n\u003cp\u003eTo uphold confidentiality, all investigators and site personnel agree to maintain strict confidentiality regarding study-related data until official results are published. No study data will be shared or disclosed without prior authorization from the sponsor and coordinating centre.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe ExTra trial addresses a critical challenge in liver transplantation: the need to improve organ utilization and \u0026nbsp;reduce waitlist mortality. In Germany, high waitlist mortality rates emphasize the urgent need for strategies that optimize the allocation of available donor livers. The study\u0026rsquo;s primary endpoint, \u0026ldquo;time-to-transplant\u0026rdquo;, is of particular relevance, as reducing the time between listing and transplantation has direct implications for patient survival, quality of life, and healthcare resource utilization. By assessing whether NMP allows for more livers to be safely transplanted, the study aims to provide evidence for expanding organ acceptance criteria and improving the efficiency of liver allocation. The study design includes a comprehensive set of secondary outcomes that reflect key aspects of liver transplantation. These include competing events such as death, disease progression (e.g.,\u0026nbsp;ReMELD-Na \u0026gt;21), contraindications for transplantation, and recovery without transplantation, as well as long-term measures such as overall patient survival, quality of life (EQ5DL), and cost-effectiveness. Additionally, utilization rate\u0026mdash;defined as the proportion of used organs relative to those offered on the waiting list\u0026mdash;serves as a crucial metric for assessing the trial\u0026rsquo;s impact on organ allocation efficiency.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA significant strength of the trial is the broad interest from German transplant centres, with nearly all centres having expressed their willingness to participate. However, a key operational challenge remains the limited access to NMP devices in Germany, as well as the financial burden associated with these devices, which are currently not reimbursed by health insurers. While perfusion kits and consumables are covered for patients enrolled in the trial, broader implementation of NMP beyond the study setting will require sustainable funding strategies. These economic barriers could influence the long-term feasibility of integrating NMP into routine clinical practice, even if the trial demonstrates its benefits.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBeyond its immediate clinical objectives, the ExTra trial also has important translational implications. The establishment of a centralized biobank within the study framework will facilitate the collection and storage of biological specimens, including tissue, perfusate, bile, and blood samples. This resource has the potential to drive future research, particularly in the development of biomarkers for predicting organ viability and early graft dysfunction. By incorporating genetic and molecular analyses (including DNA and RNA profiling), the study could contribute to identifying novel markers that improve organ assessment, ultimately enhancing the selection process for liver transplantation.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn addition to clinical and translational endpoints, the study\u0026rsquo;s safety evaluation is a key component. Three-month graft and patient survival will be closely monitored, with quarterly reviews by the Data and Safety Monitoring Board (DSMB). Additional outcomes for patients who undergo transplantation include early graft function (EASE Score, BAR Score), duration of intensive care unit and hospital stay, complications (including biliary complications assessed by MRCP at 12 months), and 1-year graft and patient survival. These measures will provide a comprehensive evaluation of the impact of NMP on both short- and long-term transplant success.\u003c/p\u003e\n\u003cp\u003eOverall, the ExTra trial is designed not only to improve liver transplant accessibility but also to pave the way for future innovations in organ assessment and preservation. By addressing key limitations in organ utilization and incorporating translational research components, the study has the potential to fundamentally change the approach to liver transplantation in Germany and beyond. This study will provide the evidence basis to help address challenges related to device availability and reimbursement and potentially ensure that NMP can be implemented at scale.\u003c/p\u003e\n\u003ch2\u003eTrial status\u003c/h2\u003e\n\u003cp\u003eFunding was approved on the 19\u003csup\u003eth\u003c/sup\u003e of September 2024. The initial application for ethics approval was submitted on the 28\u003csup\u003eth\u003c/sup\u003e of January 2025 and final approval granted on the 2\u003csup\u003end\u003c/sup\u003e of April 2025. This is study protocol version 1.1. Recruitment is scheduled to begin on June 1\u003csup\u003est\u003c/sup\u003e, 2025, and is expected to be finished 36 months later on May 31\u003csup\u003est\u003c/sup\u003e, 2028.\u0026nbsp;\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAE Adverse Event\u003c/p\u003e\n\u003cp\u003eBAR Balance of Risk Score\u003c/p\u003e\n\u003cp\u003eCCI\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Comprehensive Complication Index\u003c/p\u003e\n\u003cp\u003eEASE\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Early Allograft Failure Simplified Estimation\u003c/p\u003e\n\u003cp\u003eeCRF\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Electronic Case Reporting Form\u003c/p\u003e\n\u003cp\u003eDFG\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Deutsche Forschungsgemeinschaft (German Research Foundation)\u003c/p\u003e\n\u003cp\u003eDD Device deficiency\u003c/p\u003e\n\u003cp\u003eDNA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Deoxyribonucleic acid\u003c/p\u003e\n\u003cp\u003eDSMB\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Data Safety Monitoring Board\u003c/p\u003e\n\u003cp\u003eDSO Deutsche Stiftung Organtransplantation (German Organ Transplantation Foundation)\u003c/p\u003e\n\u003cp\u003eGCP Good Clinical Practice\u003c/p\u003e\n\u003cp\u003eITT Intention-to-Treat\u003c/p\u003e\n\u003cp\u003elabMELD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Calculated MELD score, without\u0026nbsp;Standard or Non-Standard Exception\u0026nbsp;points\u003c/p\u003e\n\u003cp\u003eLT\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Liver Transplantation\u003c/p\u003e\n\u003cp\u003eMP Machine Perfusion\u003c/p\u003e\n\u003cp\u003eMELD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Model for End-Stage Liver Disease\u003c/p\u003e\n\u003cp\u003eMDR\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Medical Device Regulation\u003c/p\u003e\n\u003cp\u003eMPAMIV\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Medizinprodukte-Anwendermelde- und Informationsverordnung (Medical Devices User Reporting and Information Ordinance)\u003c/p\u003e\n\u003cp\u003eMRCP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Magnetic Resonance Cholangiopancreatography\u003c/p\u003e\n\u003cp\u003eNMP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Normothermic Machine Perfusion\u003c/p\u003e\n\u003cp\u003eReMELD-Na\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Refitting Model of End-stage liver disease with Sodium (Na+)\u003c/p\u003e\n\u003cp\u003eRNA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Ribonucleic acid\u003c/p\u003e\n\u003cp\u003eSAE \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Serious Adverse event\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eWe extend our sincere gratitude to Dr. Hynek Mergental (Queen Elizabeth Hospital Birmingham) and Professor Vincent E. de Meijer (Rijksuniversiteit Groningen) for their expert contributions to the trial design and for advising on the funding proposal submitted to the German Research Foundation. We also wish to acknowledge Dr. Serge Vogelaar, Marieke de Rosner - van Rosmalen, and Axel Jens from Eurotransplant for their invaluable assistance in developing a robust allocation algorithm and supporting the ExTra trial. Finally, we are grateful to Dr. Axel Rahmel, head of the German Organ Transplantation Foundation, for his guidance on the grant proposal and his support in organizing transport logistics within the study framework.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSimon Moosburner and Nathanael Raschzok are participants of the BIH Charit\u0026eacute; (Advanced) Clinician Scientist Program funded by the Charit\u0026eacute; \u0026ndash; Universit\u0026auml;tsmedizin Berlin. These results were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) \u0026ndash; [RA 3044/6-1].\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor the main report of this study submitted for publication, along with related methodology and health economic papers, posters, or presentations, authorship will be determined in accordance with the International Committee of Medical Journal Editors guidelines (http://www.icmje.org/ethical_1author.html). Members of the Steering Committee and DSMB will be mentioned in the Acknowledgements of the main publication, along with their institutional affiliations, if not determined as authors. The contributions of the trial management group (principal investigator, coordinating investigator und study coordinator), coordinating centre, and funder will be\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e+recognized in all study-related publications and presentations. To recognize the funder, the following disclaimer must be included: \u0026ldquo;These results were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) \u0026ndash; [RA 3044/6-1]\u0026rdquo;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAuthors\u0026rsquo; contributions {31b}\u003c/h2\u003e\n\u003cp\u003eNR is the principal investigator of the trial. SM is the coordinating investigator. DPM, IMS, and JP are co-applicants of the trial. MM is the study coordinator. RS is the responsible statistician. DZ performed sample size and primary endpoint calculations. JW, CR, MS, and MSP are members of the DSMB. NR, DPM, IMS, MSP, AP and UF conceived the trial design. SM drafted and revised the study protocol. DPM, RS, IMS, MS, MP and NR designed this study and were essential in obtaining funding. IMS and JP provided guidance and institutional support. JW and CR submitted essential feedback on possible adverse events. MM translated the initial German study protocol to an English draft. All authors contributed to critically revising the study protocol.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eFunding {4}\u003c/h2\u003e\n\u003cp\u003eThis trial is funded by the German Research Foundation (DFG) [RA 3044/6-1].\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials {29}\u003c/h2\u003e\n\u003cp\u003eNo study data will be presented in oral or written form without approval from the Steering Committee. Submission of papers for peer-reviewed publication will require approval from all listed authors, and study results will be reviewed and approved by all participating centres before publication. Following the release of trial findings, reasonable requests for data access will be considered and reviewed by the Steering Committee.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eEthics approval and consent to participate {24}\u003c/h2\u003e\n\u003cp\u003eThe study protocol (version 1.0), patient informed consent form, supporting information on the medical devices used in the trial and previous publications from literature were submitted to the ethics committee of the Charit\u0026eacute; \u0026ndash; Universit\u0026auml;tsmedizin Berlin on the 28\u003csup\u003eth\u003c/sup\u003e of January 2025. Approval was obtained on the 2\u003csup\u003end\u003c/sup\u003e of April 2025.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eConsent for publication {32}\u003c/h2\u003e\n\u003cp\u003eThe informed consent materials are provided as supplementary documents. This article does not include any identifiable clinical details of participants, nor will such information be disclosed in the subsequent publication of trial results.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eCompeting interests {28}\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no financial or non-financial competing interests related to the ExTra trial. The principal investigator nor the coordinating study site has any conflicts of interest that could influence the design, conduct, analysis, or reporting of the study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAuthors\u0026rsquo; information\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDepartment of Surgery, Campus Charit\u0026eacute; Mitte | Campus Virchow-Klinikum, Charit\u0026eacute;\u0026ndash; Universit\u0026auml;tsmedizin\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBerlin, corporate member of Freie Universit\u0026auml;t Berlin and Humboldt-Universit\u0026auml;t zu Berlin, Berlin, Germany\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u003c/sup\u003eBIH Biomedical Innovation Academy, BIH Charit\u0026eacute; Clinician Scientist Program, Berlin Institute of Health at Charit\u0026eacute;\u0026ndash; Universit\u0026auml;tsmedizin Berlin, Berlin, Germany\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e3\u003c/sup\u003eDepartment of Hematology, Oncology and Cancer Immunology | CVK, Charit\u0026eacute; - Universit\u0026auml;tsmedizin Berlin, Corporate Member of Freie Universit\u0026auml;t Berlin and Humboldt-Universit\u0026auml;t zu Berlin, Berlin, Germany.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e4\u003c/sup\u003eInstitute of Biometry and Clinical Epidemiology, Charit\u0026eacute; - Universit\u0026auml;tsmedizin Berlin, Corporate Member of Freie Universit\u0026auml;t Berlin and Humboldt-Universit\u0026auml;t zu Berlin, Berlin, Germany.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e5\u003c/sup\u003eDepartment of Surgery, Division of Surgical Transplantation, University of Texas Southwestern Medical Center, Dallas, TX\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e6\u003c/sup\u003eInstitute of Liver Studies, King\u0026apos;s College Hospital, and School of Immunology and Microbial Sciences, King\u0026apos;s College London, London, United Kingdom.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e7\u003c/sup\u003eDepartment of Gastroenterology, Hepatology and Infectious Diseases, University Hospital D\u0026uuml;sseldorf, D\u0026uuml;sseldorf, Germany.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e8\u003c/sup\u003eDepartment of Surgery, Ajmera Transplant Centre, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e9\u003c/sup\u003eDepartment of General, Visceral and Transplant Surgery, University Hospital M\u0026uuml;nster, M\u0026uuml;nster, Germany\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e10\u003c/sup\u003eDepartment of Radiology, Charit\u0026eacute; - Universit\u0026auml;tsmedizin Berlin, Corporate Member of Freie Universit\u0026auml;t Berlin and Humboldt-Universit\u0026auml;t zu Berlin, Berlin, Germany\u003cbr\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNeuberger J (2016) An update on liver transplantation: A critical review. J Autoimmun 66:51\u0026ndash;59\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRitschl PV, Wiering L, Dziodzio T, Jara M, Kruppa J, Schoeneberg U et al (2020) The Effects of MELD-Based Liver Allocation on Patient Survival and Waiting List Mortality in a Country with a Low Donation Rate. J Clin Med. ;9(6)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoosburner S, Sauer IM, Weiss B, Pratschke J, Raschzok N (2023) How many liver grafts could be recovered after implementation of donation after cardiac death in Germany? J Hepatol 79(3):e118\u0026ndash;e20\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHusen P, Hornung J, Benko T, Klein C, Willuweit K, Buechter M et al (2019) Risk Factors for High Mortality on the Liver Transplant Waiting List in Times of Organ Shortage: A Single-Center Analysis. Ann Transpl 24:242\u0026ndash;251\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUmgelter A, Hapfelmeier A, Kopp W, van Rosmalen M, Rogiers X, Guba M et al (2017) Disparities in Eurotransplant liver transplantation wait-list outcome between patients with and without model for end-stage liver disease exceptions. Liver Transpl 23(10):1256\u0026ndash;1265\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoosburner S, Raschzok N, Schleicher C, Bosebeck D, Gassner J, Ritschl PV et al (2020) [Declined Liver Grafts - Analysis of the German Donor Population from 2010 to 2018]. Z Gastroenterol\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMacConmara M, Hanish SI, Hwang CS, De Gregorio L, Desai DM, Feizpour CA et al (2020) Making Every Liver Count: Increased Transplant Yield of Donor Livers Through Normothermic Machine Perfusion. Ann Surg\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMichelotto J, Gassner J, Moosburner S, Muth V, Patel MS, Selzner M et al (2021) Ex vivo machine perfusion: current applications and future directions in liver transplantation. Langenbecks Arch Surg 406(1):39\u0026ndash;54\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoerger L, Hillebrandt KH, Czigany Z, Lurje G, Gassner JMGV, Patel MS et al (2023) Ex Vivo Liver Machine Perfusion Reduces the Length of Hospital Stay in Recipients of Allografts from Elderly Donors: A Systematic Review. Adv Ther. ;6(6)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMergental H, Perera MT, Laing RW, Muiesan P, Isaac JR, Smith A et al (2016) Transplantation of Declined Liver Allografts Following Normothermic Ex-Situ Evaluation. Am J Transpl 16(11):3235\u0026ndash;3245\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMergental H, Laing RW, Kirkham AJ, Perera M, Boteon YL, Attard J et al (2020) Transplantation of discarded livers following viability testing with normothermic machine perfusion. Nat Commun 11(1):2939\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Leeuwen OB, de Vries Y, Fujiyoshi M, Nijsten MWN, Ubbink R, Pelgrim GJ et al (2019) Transplantation of High-risk Donor Livers After Ex Situ Resuscitation and Assessment Using Combined Hypo- and Normothermic Machine Perfusion. Ann Surg 270(5):906\u0026ndash;914\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReiling J, Butler N, Simpson A, Hodgkinson P, Campbell C, Lockwood D et al (2020) Assessment and Transplantation of Orphan Donor Livers: A Back-to-Base Approach to Normothermic Machine Perfusion. Liver Transpl 26(12):1618\u0026ndash;1628\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQuintini C, Del Prete L, Simioni A, Del Angel L, Diago Uso T, D'Amico G et al (2022) Transplantation of declined livers after normothermic perfusion. Surgery 171(3):747\u0026ndash;756\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Leeuwen OB, Bodewes SB, Lantinga VA, Haring MPD, Thorne AM, Bruggenwirth IMA et al (2022) Sequential Hypothermic and Normothermic Machine Perfusion Enables Safe Transplantation of High-risk Donor Livers. Am J Transpl\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOlumba FC, Zhou F, Park Y, Chapman WC, Group RI (2023) Normothermic Machine Perfusion for Declined Livers: A Strategy to Rescue Marginal Livers for Transplantation. J Am Coll Surg 236(4):614\u0026ndash;625\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLaing RW, Mergental H, Yap C, Kirkham A, Whilku M, Barton D et al (2017) Viability testing and transplantation of marginal livers (VITTAL) using normothermic machine perfusion: Study protocol for an open-label, non-randomised, prospective, single-arm trial. BMJ Open 7(11):1\u0026ndash;15\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"f07eefb1-cbac-4cd2-b198-e4a46d7ee1ed","identifier":"10.13039/501100001659","name":"Deutsche Forschungsgemeinschaft","awardNumber":"RA 3044/6-1","order_by":0}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Charité - University Medicine Berlin","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Liver Transplantation, RCT, Extended Criteria Donors, Waitlist Time","lastPublishedDoi":"10.21203/rs.3.rs-6834797/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6834797/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLiver transplantation remains the only curative option for end-stage liver disease, yet high waitlist mortality and organ scarcity continue to challenge the field. The randomized multicentric ExTra trial aims to improve donor utilization by evaluating whether normothermic machine perfusion (NMP) allows for safe transplantation of liver grafts that would otherwise be discarded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ExTra trial is a prospective, randomized, multicentre study conducted across German transplant centres. Participants listed for liver transplantation with a ReMELD-Na-Score ≤ 21 who are not eligible for Standard or Non-Standard Exceptions will be randomized for a one-year intervention period into two groups: the experimental arm, in which they have - in addition to regular organ allocation - the extra option to receive a graft that was initially deemed non-transplantable based on clinical criteria, but meets specified quality criteria after at least four hours of NMP, and the control arm, which consists of conventional allocation procedures alone. The primary endpoint is time-to-transplant, defined as the period between randomization and transplantation. Secondary outcomes include competing events (death, disease progression, or recovery without transplantation), graft and patient survival, quality of life, and cost-effectiveness. Additional analyses will assess early graft function, ICU and hospital stay, biliary complications, and 1-year post-transplant outcomes. A centralized biobank will collect perfusate, tissue, and blood samples for biomarker research. Safety will be monitored through quarterly reviews by the Data and Safety Monitoring Board (DSMB).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ExTra trial seeks to establish NMP as a tool for improving organ utilization and reducing waitlist mortality by quality assessment of severely marginal liver grafts. Nearly all German transplant centres have expressed their interest in participating, though limited access to NMP devices and lack of reimbursement remain key barriers to broader implementation of this technology in Germany. By generating high-quality clinical and translational data, the trial has the potential to reshape the liver graft allocation process, provide key insights in liver physiology, and contribute to the development of biomarkers for organ assessment by NMP. The findings will be essential for future integration of NMP into clinical routine.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e: ClinicalTrials.gov NCT06874296. Registered March 2025\u003c/p\u003e","manuscriptTitle":"Pilot, open, prospective, randomized, multicentre trial on quality assessment of declined liver grafts by normothermic ex vivo machine perfusion for decreasing time to transplantation: study protocol for the ExTra-Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-13 14:26:02","doi":"10.21203/rs.3.rs-6834797/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"99a07457-e062-4a41-8c87-e5f485777e4e","owner":[],"postedDate":"June 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":49625994,"name":"Hepatobiliary \u0026 Transplant Surgery"}],"tags":[],"updatedAt":"2025-06-13T14:26:03+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-13 14:26:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6834797","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6834797","identity":"rs-6834797","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}